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CardioVascular Journal of Africa (official journal for PASCAR)

• Pre-anesthetic ECG findings in children in Nigeria • Relationship between fatty liver disease and atherosclerosis • Congenital heart disease and Down syndrome • Elevated magnesium levels and coronary artery ectasia • Strain and strain rate echocardiography in Wilson’s disease • Cardiovascular risk factors in schoolchildren in Angola

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Cardiovascular Journal of Africa . Vol 27, No 5, September/October 2016

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• Cardiovascular risk factors in south-western Nigeria

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ISSN 1995-1892 (print) ISSN 1680-0745 (online)

Vol 27, No 5, SEPTEMBER/OCTOBER 2016

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

From the Editor’s Desk 275 Out-of-hospital cardiac arrest P Commerford

Cardiovascular Topics 276 Pre-anesthetic echocardiographic findings in children undergoing non-cardiac surgery at the University of Benin Teaching Hospital, Nigeria WE Sadoh • P Ikhurionan • C Imarengiaye 281

Gender-based differences in the relationship between fatty liver disease and atherosclerosis H-J Kim • C-W Lim • JH Lee • H-B Park • Y Suh • Y-H Cho • T-Y Choi • E-S Hwang • D-K Cho

287

Congenital heart disease and Down syndrome: various aspects of a confirmed association S Benhaourech • A Drighil • A El hammiri

291

Could the novel ‘double-hole’ technique be an alternative for the inflow occlusion method? S Bozok • G Ilhan • H Kazdal • B Ozpak • I Yurekli • S Bayrak • M Kestelli

294 The relationship between elevated magnesium levels and coronary artery ectasia M Yolcu • E Ipek • S Turkmen • Y Ozen • E Yıldırım • A Sercelik • FR Ulusoy 299 Relationship between site of myocardial infarction, left ventricular function and cytokine levels in patients undergoing coronary artery surgery I Kiris • S Kapan • C Narin • M Ozaydın • MC Cure • R Sutcu • H Okutan 307 Strain and strain rate echocardiography in children with Wilson’s disease C Karakurt • S Çelik • A Selimoğlu • İ Varol • H Karabiber • S Yoloğlu 315

Cardiovascular risk factors in pre-pubertal schoolchildren in Angola ABT Silva • DP Capingana • P Magalhães • MAA Gonçalves • M del CB Molina • SL Rodrigues • MP Baldo • MSB Mateus • JG Mill

INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET

Editors

SUBJECT Editors

Editorial Board

Editor-in-Chief (South Africa) Prof Pat Commerford

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Heart Failure Dr g visagie Paediatric dr s brown Paediatric Surgery Dr Darshan Reddy Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology)

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

PROF MM SATHEKGE Nuclear Medicine/Society PROF J KER (SEN) Hypertension, Cardiomyopathy, PROF YK SEEDAT Cardiovascular Physiology Diabetes & Hypertension

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

CONTENTS Vol 27, No 5, SEPTEMBER/OCTOBER 2016

322

Clustering of cardiovascular risk factors in semi-urban communities in south-western Nigeria R Oluyombo • PO Akinwusi • MA Olamoyegun • OE Ayodele • MB Fawale • OO Okunola • TO Olarewaju • A Akinsola

328

Patient outcomes following after-hours and weekend admissions for cardiovascular disease in a tertiary hospital in Calabar, Nigeria V Ansa • A Otu • A Oku • U Njideoffor • C Nworah • C Odigwe

PUBLISHED ONLINE (Available on www.cvja.co.za and in Pubmed) Case Reports

e1 Takotsubo cardiomyopathy post liver transplantation A Vachiat • P Manga • K McCutcheon • A Mahomed • G Schleicher • L Brand • J Botha • M Sussman e4 Active schistosomiasis, severe hypereosinophilia and rapid progression of chronic endomyocardial fibrosis AO Mocumbi • C Goncalves • A Damasceno • C Carrilho

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

275

From the Editor’s Desk Out-of-hospital cardiac arrest Terminology may drive our perceptions of activities and our actions in response to the events we see occurring around us. Is it time to take the P (pulmonary) out of CPR (cardiopulmonary resuscitation) when referring to witnessed out-of-hospital cardiac arrests (OHCA)? I was prompted to consider this when I was personally involved in resuscitation of an individual who suffered an out-of-hospital cardiac arrest when walking his dog, as I was walking mine, in a park near our home. He collapsed a few metres in front of me, immediately after tossing a ball for his dog to chase, and when I examined him he was wheezing, cyanosed and pulseless. I immediately started compression-only CPR (CO-CPR) as I understood this was the accepted standard. It was gratifying to see the cyanosis resolve. Fortunately paramedics with a defibrillator arrived within 15 minutes and the patient was transferred to hospital in a stable condition and discharged, neurologically intact, after implantation of an implantable cardiac defibrillator. I was interested in the responses of fellow citizen bystanders, some of whom felt that compression only, neglecting ventilation, was incorrect, and tried to correct my approach. First-responder ambulance personnel similarly seemed anxious to interrupt chest compression to place an oral airway despite the fact that the patient was pink (as opposed to earlier cyanosis) and there was audible air exchange. By happy coincidence, shortly after that incident, I reviewed, for our departmental journal club, an article that reinforced my opinions and one that I believe should be more widely disseminated. In a perspective article in Circulation, Gordon Ewy1 clearly describes the benefits of CO-CPR for witnessed out-of-hospital arrest, the experimental animal work supporting it, and its successful implementation in the state of Arizona. The results were impressive. In all patients with OHCA, the survival rate was 7.8% in those receiving guidelines CPR and 13.3% in those receiving CO-CPR. In the subset of patients with witnessed cardiac arrest and a shockable rhythm, survival rate was 17.7% in those receiving guidelines CPR and 34% in those receiving CO-CPR. It is emphasised that this applies to OHCA were oxygenation immediately prior to the arrest is normal, and does not apply in other circumstances, such as in hospital, where hypoxia may in

Professor PJ Commerford

fact contribute to the arrest. This report documents succinctly and clearly one of the few real advances and successes in the management of witnessed out-of-hospital cardiac arrest in several decades and should be read and widely disseminated. 1.

Ewy

GA.

Circulation

2016;

CIRCULATIONAHA.116.023017.

PJ Commerford Editor-in-Chief

134:

695–697.

doi:

10.1161/

276

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 27, No 5, September/October 2016

AFRICA

Cardiovascular Topics Pre-anesthetic echocardiographic findings in children undergoing non-cardiac surgery at the University of Benin Teaching Hospital, Nigeria Wilson E Sadoh, Paul Ikhurionan, Charles Imarengiaye

Abstract Background: A pre-anaesthestic echocardiogram (echo) is requested for most non-cardiac surgeries to identify possible cardiac structural anomalies. Objective: To describe the prevalence and spectrum of structural cardiac abnormalities seen in various non-cardiac conditions. Methods: We carried out a retrospective review of pre-anaesthetic echos performed over five years on children scheduled for non-cardiac surgery. The requests were categorised according to referring specialities, and the biodata and echo findings were noted. Results: A total of 181 children and 181 echocardiograms were studied, and 100 (55.2%) of the patients were male. Most of the children (87, 48.1%) with oro-facial clefts were referred from dentistry. Of the 181 children, 39 (21.5%) had cardiac abnormalities, most (34, 87.2%) of whom had congenital heart disease (CHD). Ophthalmic requests with suspected congenital rubella syndrome (CRS) had the highest prevalence of 8/12 (66.7%) while the lowest was oro-facial clefts at 15/87 (17.2%). Atrial septal defect was the commonest abnormality, found in 14 patients (35.9%). Conclusion: Pre-anaesthetic echo should be performed, especially for children with suspected CRS and other congenital anomalies, requiring non-cardiac surgery. Keywords: pre-anaesthetic, echocardiography, children, noncardiac surgery, congenital rubella syndrome, cleft lip and palate, Nigeria Submitted 17/7/15, accepted 26/1/16 Published online 9/9/16 Cardiovasc J Afr 2016; 27: 276â&#x20AC;&#x201C;280

www.cvja.co.za

DOI: 10.5830/CVJA-2016-006

Department of Child Health, University of Benin Teaching Hospital, Benin, Nigeria Wilson E Sadoh, MB BS, FWACP, MPH, sadohehi@yahoo.com Paul Ikhurionan, MB BS

Department of Anesthesiology, University of Benin Teaching Hospital, Benin, Nigeria Charles Imarengiaye, MB BS, FWACS

Patients requiring non-cardiac surgery, with suspected or symptomatic structural cardiac anomalies, may have increased peri-operative risk.1 This often necessitates a request for further cardiovascular evaluation, including echocardiography (echo) as part of the pre-anaesthetic evaluation to reduce anaesthetic risk.1 Other patients undergoing non-cardiac surgery may have conditions commonly associated with congenital heart diseases (CHD), such as children with cleft lip and palate,2 those with suspected congenital rubella syndrome (CRS) and other congenital malformations.3 The presence of congenital anomalies in one system may be associated with increased incidence of congenital anomalies in other systems.4 In particular, the presence of associated CHD increases the anaesthetic risk. It therefore becomes imperative that children with such suspected cardiac anomalies or those with conditions commonly associated with CHD and undergoing non-cardiac surgery are evaluated for the presence of cardiovascular anomaly. From studies in Nigeria, the prevalence of CHD in children with cleft lip and palate ranges from 9.5 to 20%.5-7 The prevalence is higher in those with cleft palate than in those with cleft lip only. This relatively high prevalence of CHD in children with oro-facial cleft has prompted the policy in most centres of pre-anaesthetic echo for all such patients. Congenital rubella syndrome is characterised by a triad of deafness, cataract and cardiac malformation.8 Affected children with cataract, which is the commonest ocular manifestation, would prompt presentation to the ophthalmologist. The children are referred for cardiovascular evaluation, including echocardiography, to confirm or exclude possible cardiac anomalies. Although a variety of CHDs have been found in children with CRS, patent ductus arteriosus (PDA) tends to be the predominant CHD reported.9 Adenotonsilar hypertrophy (AH) is a common cause of obstructive sleep apnoea syndrome and other sleep disorders in childhood.10 This is a common childhood presentation to ear, nose and throat (ENT) surgeons. Commonly associated with AH are ventricular hypertrophy and other rhythm abnormalities that may increase anaesthetic risk during adenotonsilectomy.11 Following the increasing availability of echocardiographic services in the country, some patients being prepared for non-cardiac surgeries are referred for pre-anaesthetic cardiovascular evaluation, including echo. The cost of echo is often high and this increases the cost of surgery. This study was conducted to describe the prevalence and spectrum of structural cardiac abnormalities seen in the children with various non-cardiac conditions, referred to our echo laboratory.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

Methods The study was carried out in the echocardiography laboratory of a tertiary institution. It was a retrospective review of children aged from birth to 17 years who were referred either by the anaesthetist or surgeon for pre-anaesthetic echocardiographic evaluation. Some children were referred because they had congenital malformations for which they required surgery and therefore needed to exclude concomitant congenital heart defects. Others were referred for routine pre-anaesthetic cardiovascular examination, including echo, for conditions such as oro-facial clefts, congenital rubella syndrome and adenoidal hypertrophy. Occasionally, some were referred by the anaesthetist or clinician because of abnormal cardiovascular findings on clinical evaluation. The routine cases were often referred by surgeons while the ones with incidental findings were often referred by anaesthetists. The children were grouped according to the referring departments/specialities, including restorative dentistry, ophthalmology, ENT and other units. The other units included paediatric surgery, and cardiothoracic and plastic surgical units. The haematology department referred one child with sickle cell anaemia for echo in preparation for stem cell transplantation. This case was added to the other units. The echocardiography register/report sheet included information on age, gender and indication for the procedure, in addition to the echo findings. The study period was five years, between July 2009 and June 2014. Permission was obtained from the institutional ethics committee to use the patients’ data. A transthoracic echo was performed by the paediatric cardiologist in the centre. Each child had two-dimensional, M-mode and Doppler examinations in multiple views. Left ventricular function was evaluated by measuring the fractional shortening (FS) and ejection fraction (EF) with the Teichholz Table 1. Conditions requiring surgery referred from the various departments Conditions

Number

Percentage

Cleft lip

21.0

Cleft lip/palate

16.0

Cleft palate

11.1

Facial cleft

1.1

Paroditis

0.6

Dentistry

Ophthalmology 17

9.4

Strabismus

Cataract extraction

0.6

Ptosis

0.6

Eye agenesis

0.6

ENT Adenoidectomy

method, using the Aloka Prosound SSD-4000SV (Aloka, Meerbusch, Germany). Analysis of the reports was done according to the recommendations of the American Society of Echocardiography.12 Any cardiac abnormality detected on echo was noted. This included CHD and acquired abnormalities such as ventricular hypertrophy and pericardial disease. Right ventricular hypertrophy (RVH) was diagnosed when the free wall was > 5 mm, measured at end-diastole.13 Left ventricular hypertrophy (LVH) was diagnosed when the left ventricular posterior wall was > 13 mm, measured in systole.14 Other diagnoses were based on standard echo findings. The diagnosis of CRS was made using the World Health Organisation case definition.15 No confirmatory laboratory tests were done because the facilities were not available.

Statistical analysis The data were coded and entered into IBM-SPSS version 20.1 (Chicago, IL) and analysed using the same statistical tool. The frequencies of cardiac abnormalities are presented in simple percentages. Continuous variables such as age are presented as means and standard deviation (SD), or median and range if the range of values was wide. The median values of the ages, FS and EF between variables were compared using the Kruskal– Wallis test. The association between variables, such as cardiac abnormality and referring specialities, was compared using the χ2 test. Significance was set at p < 0.05 at 95% confidence level.

Results There were 181 children recruited over the study period, of whom 100 (55.2%) were males. The mean age was 3.0 ± 3.5 years with a range of two days to 16 years. The median age was 1.7 years. The 181 children were referrals from dentistry (90, 49.7%), ENT (25, 13.8%), ophthalmology (19, 10.5%) and other units (46, 26.0%). The distribution of conditions requiring surgery for the referred children from the various departments is shown in Table 1. The median ages of the cases according to the referring department/speciality are as follows: children referred from other units were 2.0 years (range: 2 weeks – 16 years), ENT 3.0 years (range: 1–13 years), ophthalmology 2.0 years (range: 3 months – 11 years) and dentistry 10 months (range: 2 days – 14 years). The difference between the median ages of patients referred by the various specialities was statistically significant (p = 0.01). Of the 181 cases referred, 39 (21.5%) had cardiac abnormalities on echo. The abnormalities were CHD in 34 children (87.2%), and ventricular hypertrophy in five (12.8%). The 39 children with cardiac abnormalities consisted of 22 males (56.4%) and

12.7

Meamatomy

0.6

Mastoidectomy

0.6

5.5

Tracheo-oesophageal fistula

2.2

Anorectal abnormalities

1.7

Referring speciality

6.1

Tumours

Stem cell transplantation

Other units Congenital limb abnormalities

Other congenital anomalies

Other surgeries ENT = ear nose and throat.

277

Table 2. Distribution of cases with cardiac abnormalities by referring department Number of cases referred

Number with cardiac anomaly

Percentage

Dentistry

16.7

1.1

ENT

20.0

0.6

Ophthalmology

45.0

8.3

Other units

21.7

ENT = ear nose and throat.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

Table 3. Distribution of the type of cardiac abnormalities by referring specialities VentricuASD/ ASD/ lar hyperASD PDA VSD AVSD VSD PDA trophy CCHD Total

Referring speciality Dentistry

–

ENT

–

Ophthalmology

–

Other units

–

Stem cell transplant Total

ASD = atrial septal defect, PDA = patent ductus arteriosus, VSD = ventricular septal defect, AVSD = atrioventricular septal defect, CCHD = cyanotic congenital heart disease, ENT = ear nose and throat.

17 females (43.6%). The median age of the 39 children was 1.1 years (range: 2 days to 16 years). The distribution of the 39 children with cardiac abnormalities according to the referring departments is shown in Table 2. The highest percentage of cases with cardiac abnormalities was in patients referred from ophthalmology (9/20, 45.0%). Of the 34 children with CHD, 31 (91.2%) had acyanotic CHD while three (8.8%) had cyanotic CHD. The commonest cardiac abnormality was isolated atrial septal defect (ASD) in 14 cases (35.9%), followed by isolated patent ductus arteriosus (PDA) in seven (17.9%). The cardiac abnormalities in the group with cyanotic CHD were tetralogy of Fallot, two cases (one was repaired), and one case of single ventricle. The distribution of cardiac abnormalities by referring department/speciality is given in Table 3. Twelve children had suspected congenital rubella syndrome with cataract, and eight (66.7%) of these had cardiac abnormalities. They were all CHD cases and consisted of three with ASD (37.5%), three with PDA (37.5%), one with ventricular septal defect (VSD) (12.5%) and one with atrioventricular septal defect (AVSD) (12.5%). Most (87, 96.7%) of the 90 children referred from dentistry had cleft lip or palate. Of the 87 cases, 38 (43.7%) had cleft lip only, cleft palate only was present in 20 (23.0%), and cleft lip and palate was present in 29 children (33.3%). Of the 90 cases, 15 children (16.7%) had cardiac anomalies, and all were CHD. Of the three categories of oro-facial cleft, the highest proportion of CHD was found in children with cleft lip and palate (7/29, 24.1%), compared to children with cleft palate only (4/20, 20.0%), and those with cleft lip only (2/38, 5.3%). There was a significantly higher proportion of CHD in children with any form of cleft palate (12/49, 24.5%), compared to those with cleft lip only (2/38, 5.4%) (p = 0.019, OR = 5.8, 95% CI = 1.2–27.9). The distribution of type of CHD among children with different Table 4. Distribution of the type of cardiac abnormalities in children with cleft lip/palate Type of CHD

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types of cleft lip and palate abnormalities is shown in Table 4. No cardiac abnormality was seen in the case referred for echocardiography prior to stem cell transplantation. Among the children with ventricular hypertrophy, three with RVH were referred for evaluation for adenoidectomy. Two others with LVH were cases of Wilm’s tumour and Burkitt’s lymphoma, referred for evaluation for biopsy under general anaesthesia. The rest of the children from other units who had CHD consisted of two cases of omphalocoele, two with anorectal anomalies (Hirshsprung and imperforate anus), and a case of repaired tetralogy of Fallot requiring hernia repair. Of the 46 children referred from other units, 28 (60.9%) had a form of congenital anomaly. Of the 28, five (17.9%) had CHD and none of the 18 without congenital anomaly had CHD. The difference was however not statistically significant (p = 0.14, OR = 7.1, CI = 0.37–137.20). The median (range) FS and EF values of the study population were 38.0% (28.5–57.0) and 70.0% (56.8–81.1), respectively. Table 5 shows the FS and EF values of the study population by referring specialities. There was no statistically significant difference between FS and EF values by specialities (p = 0.48 and 0.70, respectively for FS and EF). The median (range) FS values of children with and without cardiac abnormalities were 35.0% (31.7–44.3) and 37.8% (28.0– 49.0), respectively (p = 0.64). The median (range) EF values of children with and without cardiac abnormalities were 67.3% (61.2–79.3) and 70.2% (56.8–81.1), respectively (p = 0.73).

Discussion In this study, 21.5% of children presenting for pre-anaesthetic echo for non-cardiac surgery had cardiac anomalies. The percentage in our study is lower than the 35% obtained in a study by Oyati et al. in Zaria,15 Nigeria, on children with non-cardiac congenital anomalies. The lower value in our study may have been due to the lower proportion of children with congenital anomalies in our study. There is a higher risk of concurrent congenital anomalies, including CHD, in children with congenital anomalies.4 The high value of echocardiographically confirmed cardiac anomalies in our study supports the continued practice of echocardiography for such children, considering the increased anaesthetic risk that the presence of cardiac malformation may present. The 16.7% prevalence of CHD in children with cleft lip and palate in our study is consistent with the 15% recorded by Otaigbe et al.6 in Port Harcourt, Nigeria, but lower than the 20% obtained in a similar study in Kano.7 The latter two studies consisted of small sample sizes and may have precluded drawing strong inferences from the studies, compared to our study with a sample size of 87 children.

Cleft lip

Cleft palate

Cleft lip/palate

Total

ASD

PDA

–

VSD

–

Referring specialities

Fractional shortening median (range)

p-value

Ejection fraction median (range)

p-value

PDA, ASD

–

Dentistry

38.0 (43.0–49.0)

0.48

70.0 (64.2–81.1)

0.70

ENT

36.5 (29.0–40.0)

67.6 (59.0–72.9)

Ophthalmology

37.3 (34.0–40.0)

68.7 (65.4–72.0)

Other units

37.5 (28.0– 47.2)

71.7 (56.8–79.8)

TOF Total (%)

–

2 (15.4)

4 (30.8)

7 (53.8)

13 (100.0)

CHD = congenital heart disease, ASD = atrial septal defect, PDA = patent ductus arteriosus, VSD = ventricular septal defect, AVSD = atrioventricular septal defect, TOF = tetralogy of Fallot.

Table 5. Median values of fractional shortening and ejection fraction by referring specialities

*p-values for the difference in median fractional shortening and ejection fraction values between specialities. ENT = ear nose and throat.

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CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 27, No 5, September/October 2016

The 16.7% prevalence of CHD we found is higher than the 9.5% seen in the study by Aimede et al.5 in Abeokuta, but much lower than the prevalence in the study by Sun et al.16 from eastern China. These various values may reflect the different influences of environmental factors on cleft lip/palate. Congenital cardiac anomaly was more prevalent in cases of cleft palate, and in a combination of cleft lip and palate, the prevalence was even higher. This is in keeping with previous works.5-7,17 Suspected CRS was the commonest ophthalmological referral for echo in this study and speaks to the endemicity of CRS in our environment. The high value of CRS in our study may be due to the lack of routine rubella vaccination in the nation. The highest prevalence (45.0%) of cardiac anomalies was found among children referred from ophthalmology. This may have been due to the high proportion of CRS among the referred children. Cardiac malformations are particularly common among children with CRS, especially when the infection occurs early in pregnancy.18 In our study, 66.7% of children with suspected CRS had cardiac anomalies. This high value is consistent with the findings of 85.7 and 72% by Otaigbe et al.6 in Port Harcourt, Nigeria and Kyaw-Zin-Thant et al. in Myanmar, respectively.19 This finding also suggests that cardiac anomaly is more likely in children referred for cataract extraction than for any other non-cardiac surgical condition. This is because CRS is a common cause of childhood cataract. The number of suspected cases of CRS over a five-year period in this study (12) is higher than the seven cases seen by Otaigbe et al.9 in Port Harcourt, Nigeria. This may reflect the different levels of activity of the virus in different localities. The cardiovascular anomalies in children with cleft lip/ palate were all CHD. The spectrum of CHD consisted mostly of acyanotic CHD, as documented in the studies from Port Harcourt and Kano.6,7 The commonest CHD was atrial septal defect (ASD) followed by VSD. These CHDs were similarly reported in earlier studies from Nigeria and outside Nigeria.6,7,17 The preponderance of ASD may suggest that most of the children with cleft lip/palate would be asymptomatic and appear apparently normal on clinical evaluation. This further buttresses the need for echo evaluation prior to anaesthesia. PDA and ASD were the commonest CHD in children referred from ophthalmological surgery, of whom most had suspected CRS. Most previous studies on children with CRS also demonstrated PDA and ASD as common CHDs.8,9 Most children referred from ENT were for adenoidectomy, which suggests that the condition is quite prevalent in children. Only three of the 20 cases with adenoidal hypertrophy had ventricular hypertrophy. The low prevalence of ventricular hypertrophy in children with obstructive sleep airway syndrome has similarly been reported in an earlier study from Ibadan.20 It was recommended from the Ibadan study that cardiovascular evaluation be reserved for children with severe disorder. However considering the two cases (10%) of ASD among children referred from ENT in our study, it might be worthwhile continuing to request echocardiograms for all children with adenoidal hypertrophy, not only to identify ventricular hypertrophy but also to detect possible CHD in these children. Most previous works studied the echo changes in children with cancers on chemotherapy.21,22 Ventricular echo indices appeared normal in cancer patients who were not on chemotherapy.21 In our study however, we noted the presence of left ventricular

279

hypertrophy in the two oncology cases referred for echo. It is not clear whether the advanced stages of the disease were responsible for the findings in this study. It is important therefore to study this group of patients further to evaluate cardiac function, since the number of these subjects in our study was small. It is particularly important, as most patients present with advanced stages of cancer in our environment, and a number of them undergo anaesthesia for surgery to debulk masses or for open biopsy. The children referred from dentistry were significantly younger than those from other specialities. This finding may speak to the need to repair oro-facial clefts early for cosmetic reasons, to preserve phonation and prevent other complications such as aspiration pneumonitis. The children referred from ENT were the oldest, probably since most were for adenotonsillectomy. It takes a while for adenoidal hypertrophy to reach levels that can cause obstructive sleep apnoea syndrome and therefore the need for surgical intervention. The left ventricular function of the study population was adequate, irrespective of whether they had cardiac anomalies or not. This was demonstrated by the normal median values of the EF and FS in the study population and the lack of a significant difference between the median FS and EF of the children with cardiac anomalies and those without anomalies. There are limitations to the interpretation of our results. It was a retrospective review with the attendant problems of missing records, poor documentation or insufficient clinical information. However the problems of missing records or poor documentation were obviated by the single source of echocardiography and uniform documentation of findings. Secondly, the observed prevalence of cardiac anomalies does not represent the prevalence in the community. Most of the children were delivered in the hospital or sought further care in our centre. Echo detection of cardiac anomalies in the children referred for pre-anaesthetic evaluation remains the strength of this study.

Conclusion Of the children referred for pre-anaesthetic echo evaluation, 21.5% had cardiac anomalies. The 16.7% prevalence of CHD among children with oro-facial clefts was high. Children with cleft palate had a higher prevalence of CHD compared with those with cleft lip only. Suspected CRS was the commonest reason for ophthalmological referral and accounted for 66.7% of cases with CHD. There was a low prevalence of ventricular hypertrophy in children with AH, some of whom had CHD, prompting the need for continued pre-anaesthetic echo evaluations. The cardiac anomalies were mostly acyanotic CHD. The children with congenital anomalies from other surgical units were more likely to have a positive echocardiographic screening. It is therefore recommended that pre-anaesthetic echocardiographic evaluation should be continued for children, especially those with suspected CRS and oro-facial clefts, and those with congenital anomalies.

References 1.

Canty DJ, Royse CF, Kilpatrick D, Bowman L, Royce AG. The impact of focused transthoracic echocardiography in pre-operative clinic. Anaesthesia 2012; 67: 618â&#x20AC;&#x201C;625.

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Ademiluyi SA, Oyeneyin JO, Sowenumo GO. Associated congenital abnormalities in Nigerian children with cleft lip and palate. West Afr J Med 1989; 8: 135–138.

George IO, Frank-Briggs AI, Omamabo RS. Congenital rubella hospital. World J Pediatr 2009; 5: 287–291.

congenital malformations in children in Lagos. West Afr J Med 2009;

Ogunrinde GO, et al. Echocardiographic findings in children with surgi-

28: 323–237.

cally correctable non-cardiac congenital anomalies. Ann Trop Paediatr

Aimede OS, Alalere GO, Adedayo O, Adeshola S. Orofacial clefts: our

2009; 29: 41–44. 16. Sun T, Tian H, Wang C, Yin P, Zhu Y, Chen X, et al. A survey of

Otaigbe B, Akadiri O, Eigbobo J. Clinical and echocardiographic find-

congenital heart disease and other organic malformations associated

ings in an African pediatric population of cleft lip/palated patients: a

with different types of orofacial clefts in Eastern China. PloS One 201; 8: e54726.

Asani MO, Aliyu I. Pattern of congenital heart defects among children

17. Ademiluyi SA, Oyeneyin JO, Sowemimo GO. Associated congenital

with orofacial clefts in Northern Nigeria. J Cleft Lip Palate Craniofacial

abnormalities in Nigeria children with cleft lip and palate. West Afr J Med 1989; 8: 135–138.

Morice A, Ulloa-Gutierrez R, Avilla-Augero ML. Congenital rubella

18. Mason WH. Rubella. In: Kliegman RM, Stanton BF, St Geme III JW,

syndrome: progress and future challenges. Expert Rev Vaccines 2009;

Schor NF, Behman RM (eds). Nelson Textbook of Pediatrics. 20th edn.

8: 323–332. 9.

Kluwer/Lippincott Williams & Wilkins, 2010: 123–157. 15. Oyati AI, Danbauchi SS, Ameh EA, Mshelbwala PM, Anumah MA,

Anom 2014; 1: 85–87. 8.

tion of right ventricular hypertrophy. Am Heart J 1983; 105: 611–614. 14. Armstrong WF, Thomas R. Evaluation of systolic functions of the left

diseases associated with identified syndromes and other extra-cardial

preliminary report. Niger J Cardiol 2013; 10: 6–8. 7.

1995; 8: S1–S8.

ventricle. Feigenbaum’s Echocardiography. 7th edn. New Delhi: Wolters

Ekure EN, Animashaun A, Bastos M, Ezeaka VG. Congenital heart

experience in two suburban health facilities. Dentistry 2013; 3: 155. 6.

ous quality improvement in echocardiography. J Am Soc Echocardiogr 13. Baker BJ, Scovil JA, Kane JJ, Murphy ML. Echocardiographic detec-

syndrome: pattern and presentation in a southern Nigerian tertiary 4.

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Philadelphia: Elsevier 2015: 1548–1552.

Otaigbe BE, Tabansi PN, Agbedeyi GO. Echocardiographic findings

19. Kyaw-Zin-Thant, Win-Mar-OO, Thein-Thein-Myint, Than-Nu-Shwe,

in clinically confirmed congenital rubella syndrome cases seen at the

Aye-Maung-Han, et al. Active surveillance for congenital rubella

University of Port Harcourt Teaching Hospital, Nigeria. West Afr J Med 2012; 31: 135–138.

syndrome in Yangon, Myanmar. Bull World Health Org 2006; 84: 12–20. 20. Fasunla AJ, Onakoya PA, Ogunkunle OO, Mbam TT, Nwaorgu OGB.

10. Richardson MA, Seid AB, Cotton RT, Benton G, Kramer M. Evaluation of tonsils and adenoids in sleep apnoea syndrome. Laryngoscope 1980; 90: 1106–1110.

Routine electrocardiography request in adenoidectomy: is it necessary? Indian J Otolaryngol Head Neck Surg 2011; 63: 330–335. 21. Navarrete-Rodriguez EM, Zapata-Tarres MM, Vizcaino-Alarcon A,

11. Wilkinson AR, McCormick MS, Freeland AP, Pickering D. Electrocardiographic signs of pulmonary hypertension in children who snore. Br Med J 1981; 181: 1579–1581.

Garduno-Espinosa J, Dorantes-Acosta E, et al. Role of echocardiogram in children with cancer. Bol Med Hosp Infant Mex 2013; 70: 129–132. 22. Kremer LC, Caron HN. Anthracycline cardiotoxicity in children. N Engl

2017

12. American Society of Echocardiography. Recommendations for continu-

J Med 2004; 351: 120–121.

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Gender-based differences in the relationship between fatty liver disease and atherosclerosis Hyun-Jin Kim, Chae-Wan Lim, Jae Hyuk Lee, Hyung-Bok Park, Yongsung Suh, Yoon-Hyeong Cho, Tae-Young Choi, Eui-Seok Hwang, Deok-Kyu Cho

Abstract Background: Carotid intima–media thickness (CIMT) is a surrogate of subclinical atherosclerosis. Fatty liver disease is also linked to increased risk of cardiovascular events. The aim of this study was to evaluate the association between fatty liver disease and CIMT according to gender. Methods: Patients who had undergone carotid and abdominal ultrasound between June 2011 and December 2013 were retrospectively evaluated. The differences between the CIMT values measured in the common carotid artery and the prevalence of carotid plaque in patients with fatty liver disease and those with normal livers were investigated. Results: Out of a total of 1 121 patients, the men had more fatty liver disease than the women. The mean CIMT of the men was significantly higher than that of the women, and the men had more plaque than the women. The women with fatty liver disease had a significantly higher mean CIMT value and more plaque than the women with normal livers. The differences between the men with fatty liver and those with normal livers in mean CIMT values and in the prevalence of plaque were not significant. In the women, multivariate analysis showed that fatty liver disease was independently associated with subclinical atherosclerosis [adjusted hazards ratio (HR) 1.65, 95% confidence interval (CI) 1.007–2.697, p = 0.047]. Conclusions: The men had more fatty liver disease, carotid plaque and higher CIMT values than the women. Fatty liver disease was a useful predictor of atherosclerosis, especially for the female study patients. Keywords: carotid intima–media thickness, fatty liver, atherosclerosis

Submitted 13/1/16, accepted 17/2/16 Published online 14/3/16 Cardiovasc J Afr 2016; 27: 281–286

www.cvja.co.za

DOI: 10.5830/CVJA-2016-014

Carotid intima–media thickness (CIMT) is a surrogate of subclinical atherosclerosis and a predictor of cardiovascular events.1-3 Because CIMT can easily be estimated by ultrasonography, the assessment of CIMT is an effective means of predicting cardiovascular events in asymptomatic patients.4 In addition, for predicting cardiovascular risk, measuring the thickness of the intima–media of the common carotid artery plus evaluating whether or not plaque is present on the ultrasound images have been suggested to be a good alternative to ultrasound evaluation of all carotid artery segments.5 Fatty liver disease is widely accepted as the hepatic expression of the metabolic syndrome.6 Patients with fatty liver disease have an increased risk of cardiovascular events, and it was found to be an independent risk factor of cardiovascular disease.7-9 The prevalence of fatty liver disease is different between men and women and between younger and older individuals.10 A previous study found that the male gender was a risk factor for fatty liver disease.11 In addition, there are also gender and age differences in the presence of carotid atherosclerosis.4,5 Although fatty liver disease is linked to increased risk of cardiovascular events, patients with fatty liver disease confirmed by abdominal ultrasound are not always evaluated with regard to atherosclerosis. To date, there are no specific guidelines stipulating that patients with ultrasound-confirmed fatty liver disease should undergo evaluation for subclinical atherosclerosis. The aim of this study was to evaluate the association between fatty liver disease and CIMT in patients stratified by gender.

Methods Division of Cardiology, Department of Internal Medicine, Myongji Hospital, Gyenggi-Do, South Korea Hyun-Jin Kim, MD Chae-wan Lim, MD Jae hyuk Lee, MD Hyung-Bok Park, MD Yongsung Suh, MD Yoon-Hyeong Cho, MD Tae-Young Choi, MD Eui-Seok Hwang, MD Deok-Kyu Cho, MD, chodk1234@daum.net

Department of Translational Medicine, College of Medicine, Seoul National University, Seoul, South Korea Hyun-Jin Kim, MD

Patients who visited the Healthcare Centre of the Myongji Hospital in South Korea for routine check ups between June 2011 and December 2013 were screened retrospectively. Among a total of 23 474 patients considered for inclusion in the study, 1 366 underwent both carotid and abdominal ultrasound. Of these, the following patients with conditions that could lead to chronic liver disease were excluded from the study: 60 patients positive for hepatitis B surface antigen, six positive for hepatitis C antibody, and 179 with excessive alcohol consumption (≥ 20 g/day)12 (Fig. 1). A total of 1 121 patients were assessed in this study. The study was approved by the local institutional review board and was conducted according to the Declaration of Helsinki. Written informed patient consent was exempted by the institutional review board.

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Abdominal ultrasound Patients who visited the healthcare centre for routine check up from June 2011 to December 2013 (n = 23 474)

Patients who had carotid and abdominal ultrasound performed (n = 1 366)

60 with hepatitis B virus 6 with hepatitis C virus 179 with excessive alcohol consumption (≥ 20 g/day)

Final analysis (n = 1 121) Fig. 1. The study population.

Clinical and laboratory assessments The patients’ demographic and clinical characteristics were reviewed using electronic records. The following were extracted: age, gender, waist and hip circumference, height, weight, history of diabetes, hypertension and dyslipidaemia. Each patient’s body mass index (BMI) was calculated, and obesity was defined as BMI > 30 kg/m2.13 The waist-to-hip ratio was calculated. The following laboratory data were extracted: fasting glucose, haemoglobin (Hb) A1c, homocysteine, apolipoprotein A-1, apolipoprotein B, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase levels.

Carotid ultrasound CIMT measurements of both common carotid arteries were performed using a high-resolution ultrasonography Vivid E9 ultrasound system (GE Healthcare, Little Chalfont, UK) equipped with an 11-l linear transducer. Far-wall mean CIMT measurements of longitudinal images were performed at end diastole in a 10-mm segment located 10 mm proximal to the carotid bulb. Only plaque-free segments of the common carotid arteries were used for CIMT analysis. An experienced ultrasonographer used semi-automated edge-detection software to calculate the mean CIMT value from a single CIMT measurement from the left and a single one from the right common carotid artery, and then averaged the values of the left and right sides. Carotid plaque was identified as a focal increase in the CIMT of greater than 15 mm or greater than 50% of the surrounding wall.14 Both common carotid arteries, the carotid bifurcations, and internal and external carotid arteries were evaluated for plaque. We defined subclinical atherosclerosis as a CIMT value higher than the 75th percentile or the presence of carotid plaque.

Abdominal ultrasound was performed by a different experienced ultrasonographer using an Acuson Sequoia 512 ultrasound system (Siemens Medical Solutions, USA) equipped with a 4-C1 curved transducer. Fatty liver disease (fatty infiltration of the liver) was diagnosed on ultrasound if the liver showed diffuse hyperechogenicity relative to the cortex of the right kidney.15 Normal hepatic parenchymal echogenicity was considered to be equivalent to the echogenicity of the cortex of the right kidney.16 The study patients were divided into those with fatty liver disease and those with normal livers, based on the ultrasonographic findings.

Statistical analysis All categorical data were summarised as frequencies and percentages, and continuous variables are presented as means and standard deviations. The Pearson chi-squared test was used for comparison of categorical variables, and the Fisher exact test was used for comparison of categorical variables with 20% or more of the expected cell frequencies lower than 5. The Student’s t-test was used for comparison of continuous variables, and the Mann–Whitney U-test was used for sample sizes lower than 30 in at least one group. Linear-by-linear association was also used to determine trends for CIMT and the presence of plaque according to age groups. Univariate followed by multivariate logistic regression analyses were performed to evaluate the association between fatty liver disease and atherosclerosis, with adjustment for individual risk factors, such as age, BMI, hypertension, waist circumference, and triglyceride, HDL-C and fasting glucose levels, which included the components of the metabolic syndrome. A p-value less than 0.05 was considered statistically significant. All data management and analyses were performed using SPSS v 18.0 (SPSS Inc, Chicago, IL).

Results A total of 630 men and 491 women (aged 51.7 ± 11.5 and 54.5 ± 11.2 years, respectively) were included in the analysis. Table 1 shows the baseline characteristics of these patients. The men had significantly higher values for waist-to-hip ratio (0.9 ± 0.1 vs 0.8 ± 0.1, p < 0.001) and BMI (25.5 ± 3.2 vs 24.5 ± 3.6 kg/m2, p < 0.001) than the women. Systolic and diastolic blood pressures were also significantly higher in the men, and the men had a higher prevalence of diabetes and dyslipidaemia than the women. In addition, the mean fasting glucose levels and liver function test values (AST, ALT, AST/ALT, GGT) were significantly higher in the men than women. There were no significant differences in total cholesterol and LDL-C levels between the men and women, but the triglyceride level was significantly higher in the men. A total of 472 of 1 121 (42.1%) patients had fatty liver disease. A significantly higher proportion of men than women had fatty liver disease (51.4 vs 30.1%, p < 0.001) (Table 2). Fig. 2A shows the prevalence of fatty liver disease in men and women, stratified by age. A significantly higher proportion of men than women aged 60 years and under had fatty liver disease. There was no difference in the prevalence of fatty liver disease between the male and female patients aged older than 60 years. The mean CIMT measurement of men was significantly higher than that of the women (0.79 ± 0.17 vs 0.76 ± 0.17 mm,

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Table 1. Baseline characteristics of the study patients All (n = 1121)

Men (n = 630)

Women (n = 491)

p-value for difference

Table 2. Gender differences for carotid atherosclerosis and prevalence of ultrasonographic fatty liver disease All (n = 1121)

Men (n = 630)

Women (n = 491)

p-value for difference

Age (years)

52.9 ± 11.5

51.7 ± 11.5

54.5 ± 11.2

< 0.001

CIMT (mm)

0.78 ± 0.17

0.79 ± 0.17

0.76 ± 0.17

Waist circumference (cm)

81.8 ± 9.4

85.5 ± 7.9

77.2 ± 9.1

< 0.001

Presence of plaque (n, %)

291 (26.0)

192 (30.5)

99 (20.2)

Hip circumference (cm)

94.5 ± 6.2

95.4 ± 6.0

93.3 ± 6.3

< 0.001

75th percentile CIMT (mm)

0.90

0.92

0.88

0.9 ± 0.1

0.8 ± 0.1

< 0.001

163.7 ± 9.1

169.7 ± 6.2

156.1 ± 5.9

< 0.001

CIMT ≥ 75th percentile or presence of plaque (n, %)

448 (40.0)

269 (42.8)

179 (36.5)

0.032

Ultrasonographic fatty liver disease (n, %)

472 (42.1)

324 (51.4)

148 (30.1)

< 0.001

Waist-to-hip ratio Height (cm) Weight (kg)

67.5 ± 12.5

73.6 ± 11.4

59.6 ± 8.9

< 0.001

BMI (kg/m2)

25.1 ± 3.4

25.5 ± 3.2

24.5 ± 3.6

< 0.001

SBP (mmHg)

121.8 ± 12.8

122.7 ± 11.7

120.7 ± 14.1

0.011

DBP (mmHg)

74.7 ± 9.8

76.3 ± 9.3

72.7 ±10.0

< 0.001

365 (32.6%)

210 (33.3%)

155 (31.6%)

Previous history Hypertension

0.532

Diabetes

155 (13.8%)

104 (16.5%)

51 (10.4%)

0.003

Dyslipidaemia

499 (44.5%)

314 (49.8%)

185 (37.7%)

< 0.001

100.3 ± 21.2 103.7 ± 23.8 96.0 ± 16.3 (5.57 ± 1.18) (5.76 ± 1.32) (5.33 ± 0.9)

< 0.001

Fasting glucose (mg/dl) (mmol/l)

5.8 ± 0.8

5.8 ± 0.9

5.7 ± 0.6

0.058

11.2 ± 4.1

12.5 ± 4.5

9.9 ± 3.1

< 0.001

Apolipoprotein A-1 (mg/dl) 142.9 ± 23.9

137.4 ± 22.3

149.2 ± 24.2

< 0.001

91.0 ± 21.3

93.3 ± 21.4

88.5 ± 21.0

0.001

Total cholesterol (mg/dl) (mmol/l)

191.8 ± 34.4 191.3 ± 34.2 192.4 ± 34.8 (4.97 ± 0.89) (4.95 ± 0.89) (4.98 ± 0.9)

0.588

Triglycerides (mg/dl) (mmol/l)

138.5 ± 89.3 158.6 ± 99.6 112.8 ± 65.6 < 0.001 (1.57 ± 1.01) (1.79 ± 1.13) (1.27 ± 0.74)

LDL-C (mg/dl) (mmol/l)

112.7 ± 29.9 113.4 ± 29.8 111.7 ± 30.1 (2.92 ± 0.77) (2.94 ± 0.77) (2.89 ± 0.78)

HDL-C (mg/dl) (mmol/l)

49.3 ± 11.6 (1.28 ± 0.3)

HbA1c (%) Homocysteine (µmol/l) Apolipotrotein B (mg/dl)

0.356

43.0 ± 9.7 53.5 ± 12.5 < 0.001 (1.11 ± 0.25) (1.39 ± 0.32)

AST (IU/l)

25.5 ± 12.2

26.6 ± 11.2

24.2 ± 13.3

0.001

ALT (IU/l)

25.5 ± 18.4

28.6 ± 17.7

21.6 ± 18.5

< 0.001

1.2 ± 0.4

1.1 ± 0.4

1.3 ± 0.5

< 0.001

GGT (IU/l)

42.8 ± 63.0

57.1 ± 78.5

24.3 ± 23.7

< 0.001

ALP (IU/l)

130.4 ± 86.0

132.9 ± 87.6

127.3 ± 83.8

0.283

AST/ALT ratio

BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HbA1c: haemoglobin A1c; LDL-C: low-density lipoprotein cholesterol; HDL-C: highdensity lipoprotein cholesterol; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gamma-glutamyl transpeptidase; ALP: alkaline phosphatase.

respectively; p = 0.001) and a significantly higher proportion of men had plaque (30.5 vs 20.2%, p < 0.001). The 75th percentiles for the mean CIMT value of the men and women were 0.92

60 40 20

C 1.5 p = 0.049 p = 0.038 p = 0.001 p = 0.005 p = 0.037 p = 0.006

Carotid IMT (mm)

Fatty liver disease (%)

and 0.88 mm, respectively. In addition, a significantly higher proportion of men than women had a CIMT value higher than the 75th percentile or had plaque (42.8 vs 36.5%, p = 0.032) (Table 2). Fig. 2B and C show the mean CIMT values and prevalence of plaque stratified by gender and age. In all age groups, a higher proportion of men than women had plaque, and men had significantly higher CIMT values. Moreover, the mean CIMT values and rates of plaque deposition showed an increasing trend with age in both men and women (p for trend < 0.001 in both genders for both CIMT and plaque). The mean CIMT values and the prevalence of carotid plaque were significantly higher in both men and women with a history of hypertension and diabetes, compared to those without hypertension and diabetes (Table 3). In addition, the mean CIMT values and plaque rates were significantly higher in women with a higher waist circumference (≥ 80 cm) than women with lower waist circumferences (< 80 cm), in women with dyslipidaemia than women without dyslipidaemia, and in women with fatty liver disease than women without fatty livers. Similar differences were not seen for the men with and without these conditions. Table 4 shows the results of univariate and multivariate analysis of factors in relation to subclinical atherosclerosis, stratified by gender. Univariate analysis found that older age, history of hypertension, and high fasting glucose levels were significantly associated with subclinical atherosclerosis in men. Multivariate analysis found that older age [hazard ratio (HR) 1.11, 95% confidence interval (CI): 1.084–1.130, p < 0.001] and high fasting glucose levels (HR 1.01, 95% CI: 1.001–1.018, p =

B 80 p = 0.017 p < 0.001 p < 0.001 p = 0.019 p = 0.940 p = 0.303

–

CIMT: carotid intima–media thickness.

80 Presence of plaque (%)

0.001 < 0.001

1.0

0.5

p=.

p = 0.445 p = 0.003 p = 0.001 p = 0.010 p = 0.032

60 40 20

0 Age 20–30 31–40 41–50 51–60 61–70 > 70

0.0 Age 20–30 31–40 41–50 51–60 61–70 > 70

0 Age 20–30 31–40 41–50 51–60 61–70 > 70

Patient 14 15 104 37 168 109 195 190 113 98 36 42 (n)

Men

Women

Men

Women

Men

Women

Fig. 2. M ean carotid intima–media thickness (CIMT), presence of carotid plaque and fatty liver disease, stratified by gender and age. (A) The prevalence of fatty liver disease was significantly different between men and women under the age of 60 years. (B, C) The mean CIMT values and prevalence of carotid plaque tended to increase with age in both men and women. Among all age groups, the men had significantly higher CIMT values and a higher prevalence of plaque than the women.

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Table 3. CIMT and percentage of subjects with carotid plaques according to binary risk factors Men (n = 630) Variable

CIMT (mm)

Waist circumference

p-value

Presence of plaque (%)

0.101

≥ 90 cm (M), ≥ 80 cm (W)

0.81 ± 0.16

< 90 cm (M), < 80 cm (W)

0.79 ± 0.17

History of hypertension 0.82 ± 0.16

0.78 ± 0.17

History of diabetes 0.85 ± 0.15

0.78 ± 0.17

History of dyslipidaemia 0.79 ± 0.16

0.79 ± 0.17

Fatty liver disease

< 0.001

Yes

0.79 ± 0.17

0.80 ± 0.16

BMI (kg/m2)

13.1 < 0.001

0.821

17.5 0.016 17.0 < 0.001

0.635 0.81 ± 0.17

29.6 0.017

0.001 29.7

0.73 ± 0.17

31.4

0.024 25.4

0.74 ± 0.18

30.1

< 0.001 43.1

0.78 ± 0.16

30.9

< 0.001 35.5

0.75 ± 0.17

27.4

0.549

15.4

0.83 ± 0.16

46.2

0.001

< 0.001 0.73 ± 0.17

24.3

p-value

27.7

0.81 ± 0.15

42.9

Presence of plaque (%)

< 0.001

0.513

p-value

0.73 ± 0.17

32.2

0.851

Yes

CIMT (mm) 0.80 ± 0.17

26.7

0.001

Yes

p-value 0.185

0.007

Yes

Women (n = 491)

16.0 0.465

0.771

> 30

0.78 ± 0.18

16.4

0.78 ± 0.14

22.0

≤ 30

0.79 ± 0.16

31.8

0.76 ± 0.17

20.0

CIMT: carotid intima–media thickness; BMI: body mass index.

0.034) were independent predictors of subclinical atherosclerosis in men. Univariate analysis showed that fatty liver disease, larger waist circumference, older age and history of hypertension were associated with subclinical atherosclerosis in women. Multivariate analysis found that fatty liver disease was an independent predictor of subclinical atherosclerosis in women (HR 1.65, 95% CI: 1.007–2.697, p = 0.047). Older age (HR 1.08, 95% CI: 1.056–1.107, p > 0.001) and hypertension (HR 1.82, 95% CI: 1.135–2.902, p = 0.013) were also independent predictors of subclinical atherosclerosis in women. Although a significantly higher proportion of men aged 60 years and under had fatty liver disease than the women (Fig. 2A), fatty liver disease was significantly associated with increased CIMT or plaque formation in women aged 60 and under (HR 2.13, 95% CI: 1.268–3.562, p = 0.004). The association between fatty liver disease and subclinical atherosclerosis in men aged 60 and under was not significant (HR 1.10, 95% CI: 0.753–1.608, p = 0.620). Moreover, although there was no difference in the prevalence of fatty liver disease between the male and female patients older than 60 years, women with fatty liver disease tended to have subclinical atherosclerosis (HR 1.85, 95% CI: 0.929–3.683, p = 0.080). Fatty liver disease in older men was not

associated with subclinical atherosclerosis (HR 1.35, 95% CI: 0.647–2.803, p = 0.456).

Discussion The prevalence of fatty liver disease was higher in the men than the women in our study, especially in patients aged 60 years and under. The mean CIMT value was higher and the presence of plaque was more in men than women, regardless of age. Interestingly, a significantly higher mean CIMT value was found in the women with fatty liver disease than in the women with normal livers, and women with fatty liver had more carotid plaque than women with normal livers. Fatty liver disease was independently associated with subclinical atherosclerosis in the women only, which was defined as a higher CIMT value (≥ 75th percentile ≥ 0.88 mm) or presence of carotid plaque. CIMT values and the prevalence of carotid plaque increased with age for both genders in our study cohort. The differences in CIMT values between genders persisted for all age groups, and the differences in the prevalence of plaque between genders persisted for groups of study patients. These results are consistent with the findings of the Gutenberg Heart study, in which early

Table 4. Univariate and multivariate analysis for risk of subclinical atherosclerosis Men (n = 630)

Women (n = 491)

Univariate analysis

Multivariate analysis

Univariate analysis

Variables

CI (95%)

Multivariate analysis HR

CI (95%)

Age

1.10

1.082–1.123

1.11

1.084–1.130

1.09

1.068–1.115

1.08

1.056–1.107

BMI (kg/m2)

0.99

0.945–1.043

1.04

0.989–1.096

Waist circumference (cm)

1.01

0.993–1.034

1.04

1.016–1.060

Hypertension

1.88

1.342–2.628

2.88

1.942–4.276

1.82

1.135–2.902

Fatty liver disease

1.05

0.765–1.440

2.09

1.408–3.102

1.65

1.007–2.697

Triglycerides (mg/dl)

1.00

0.997–1.001

1.00

1.000–1.005

HDL-C (mg/dl)

1.00

0.982–1.015

0.99

0.972–1.002

Fasting glucose (mg/dl)

1.02

1.008–1.024

1.01

1.000–1.023

1.01

1.001–1.018

BMI: body mass index; HDL-C: high-density lipoprotein cholesterol; HR: hazard ratio; CI: confidence interval. Subclinical atherosclerosis is defined as an increased CIMT value (≥ 75th percentile CIMT) or the presence of plaque.

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atherosclerosis was more frequent in men than women and was significantly associated with age.17 An Asian study performed in Taiwan also found that CIMT was significantly greater in men than women.18 A Korean multicentre epidemiological study found carotid plaques in 17% of a healthy population with a mean age of 49 years and in 35% of hyperlipidaemic, hypertensive patients with a mean age of 51 years.19 Our study found a similar prevalence of carotid plaques (26.0% of the total study population and 30.5% of men and 20.2% of women). In addition, our results revealed the characteristics of arterial aging and growth of intimal smooth muscle cells that increased with age, along with the presence of vascular plaque. Along with an earlier study,20 our study found that the prevalence of fatty liver disease was significantly higher in men than women. Many factors may contribute to gender differences in the prevalence of fatty liver disease. First, the men had a significantly larger waist-to-hip ratio than the women. The prevalence of fatty liver disease is significantly higher in people with a large waist-to-hip ratio. An increased waist-to-hip ratio is directly correlated with increased visceral adipose tissue, which is associated with hepatic insulin resistance in men; and insulin resistance is also associated with fatty liver disease.21,22 Other factors, including sex hormones and gender lifestyle differences may also be associated with gender differences in the prevalence of fatty liver disease.20 We suspect that the baseline characteristics of men, including factors indicating the presence of the metabolic syndrome, may also have contributed to the higher prevalence of fatty liver disease and carotid plaque, as well as higher CIMT values in the male than in the female participants in our study. Vascular remodelling, which presents with signs of endothelial dysfunction, increasing thickness of the carotid intima–media, and vascular plaque, is associated with aging.23 BMI, metabolic risk factors, including increased waist circumference, blood pressure, glycated haemoglobin level, HDL-C and triglyceride levels, and lifestyle risk factors, including smoking and alcohol consumption, are also associated with increased CIMT and risk of atherosclerosis.24,25 Because the male participants in our study had many factors at baseline that indicated a significantly worse clinical profile than the female participants, we analysed the association of some of the components of the metabolic syndrome with CIMT values or presence of carotid plaque, stratified by gender. Our study found different gender-based risk factors for increased CIMT or prevalence of carotid plaque. Among the metabolic risk factors of the women, waist circumference, dyslipidaemic status, and fatty liver disease had significantly more effect on the presence of CIMT and carotid plaque than those factors in men. To determine the hazard ratio of fatty liver disease for developing subclinical atherosclerosis, we adjusted these components of the metabolic syndrome for multivariate analysis. As we have shown, the prevalence of fatty liver disease is lower in women of reproductive age compared to men of the same age. There was no difference in the prevalence of fatty liver disease between women after menopause (older than 60 years) and men of the same age. These findings may be associated with the protective effect of oestrogen, which is an important regulator of lipid metabolism and has a protective effect against the progression of liver steatohepatitis.26,27

285

Previous studies found that oestrogen receptor-gene knockout, aromatase knockout, and double oestrogen receptorgene knockout mice displayed elevated triglyceride levels; and mice with congenital oestrogen deficiency developed fatty liver disease.27-30 We believe that women who have fatty liver disease may have an abnormal oestrogen receptor-signalling pathway associated with the regulation of lipid metabolism. In addition, oestrogen has been known to prevent age-related adverse vascular remodelling via the inhibition of smooth muscle cell proliferation and endothelial dysfunction, and by improving vascular tone.23,31 Hence, we believe that women with fatty liver disease who have a defective oestrogen receptor-signalling pathway may have endothelial dysfunction and subclinical atherosclerosis. Our findings demonstrate that carotid artery evaluation for patients with fatty liver disease, especially for women, has an important role. We believe there should be gender-based screening for subclinical atherosclerosis and modification of risk factors for cardiovascular events. Assessment of CIMT, as a surrogate of subclinical atherosclerosis, may help to further predict cardiovascular events in female patients. Our study has several limitations. The main limitation was that it was a retrospective observational study. Also, our crosssectional study could not infer causality. Third, our data were derived from an Asian cohort at a single institution; therefore, the study findings on the association of fatty liver disease with CIMT may not necessarily be transferable to other ethnicities.

Conclusion The men had more fatty liver disease, more carotid plaque and higher CIMT values than the women in our study. Fatty liver disease was a useful predictor of atherosclerosis, especially for the female study patients. Women with fatty liver disease should undergo monitoring by carotid ultrasound for early detection of atherosclerosis and timely protection against cardiovascular events.

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Congenital heart disease and Down syndrome: various aspects of a confirmed association Sanaa Benhaourech, Abdenasser Drighil, Ayoub El Hammiri

Abstract Background: Congenital heart disease (CHD) is frequently described in patients with Down syndrome (DS) and is the main cause of death in this population during the first two years of life. The spectrum of CHD patterns in DS varies widely worldwide; this variation could be due to sociodemographic, genetic and geographic factors. Methods: A six-year retrospective, descriptive study was carried out from December 2008 to October 2014, based on the Paediatric Unit CHD registry of Ibn Rochd University Hospital. Clinical, echocardiographic and outcomes data were collected and sorted according to confirmation of the syndrome. Results: Among 2 156 patients with CHD, 128 were identified with Down syndrome. The genders were equally represented (gender ratio 1) and the median age at diagnosis was 9.5 months (2 days to 16 years). The median age of mothers at delivery was 39 years (16–47). Of the 186 CHD lesions reported, the most common was atrioventricular septal defect (AVSD, 29%), followed by ventricular septal defect (VSD, 21.5%) and atrial septal defect (ASD, 19.9%). The most common associations of CHD were AVSD + ASD (10%) and VSD + ASD (7.8%). Surgery was the most common modality of treatment (54.3%). The overall mortality rate was 14.1%. Conclusion: Our study confirmed that the profile and type of CHD in DS in the Moroccan setting exhibited slight differences in the distribution of these CHDs compared with European neighbours and other Western countries. Further studies are needed to determine which variables have an impact on these differences. Keywords: Down syndrome, congenital heart disease, epidemiology, therapeutic

Methods

Submitted 6/9/15, accepted 2/3/16 Cardiovasc J Afr 2016; 27: 287–290

www.cvja.co.za

DOI: 10.5830/CVJA-2016-019

Down syndrome (DS), which is caused by trisomy on chromosome 21, is by far the most common and best known chromosomal disorder in humans and the most common cause of intellectual disability.1-3 This trisomy gives rise to multiple complications as part of the syndrome. Congenital heart disease (CHD) is the leading cause of mortality and morbidity during Cardiology Department, University Hospital Ibn Rochd, Casablanca, Morocco Sanaa Benhaourech, MD, Sanaa_b19@hotmail.fr Abdenasser Drighil, MD Ayoub El Hammiri, MD

the first two years of life in the DS population,1,4 and 40 to 63.5% of DS patients have CHD.4-6 It has been suggested that the profile and type of these CHDs are variable according to the different geographical areas around the world.7,8 Recent studies in Norway also suggest a seasonal variation in the occurrence of DS and birth defects, and provide indirect evidence of the causal role of environmental factors, since genetic factors do not exhibit seasonality.9 Because Morocco is bordered by European countries, it has been suggested that a combination of local factors and regional proximity could play a significant role in the CHD profile in the DS population. However, in a given context, it is important to be familiar with the incidence and anatomical characteristics of CHD in DS, as well as the associated complications and causes of morbidity and mortality, in order to apply preventative measures and to improve the patient’s quality of life. In addition, because the type of CHD and the timing of repair affect the prognosis, timely treatment of cardiac abnormalities is crucial for optimal survival.10 The lack of reliable data from African countries is a limiting factor in addressing the issue of geographical variations around the world. The reported rates of different features of CHDs in DS patients between countries in close proximity are quite similar, such as the USA and Mexico or other Latin-Americans countries.3,4,8,11 This could be explained by regional proximity, which may have a greater effect in instances of geographical areas with longstanding populations, as is the case in the Mediterranean area. Morocco is a North African country that has historical links with European populations in the Mediterranean area, but also with those of Africa in the south. This study sought to determine the prevalence and profile of CHD in DS in the Moroccan context and to compare this with the international literature.

This retrospective, descriptive, monocentric study was based on the Paediatric Unit CHD registry of Ibn Rochd University Hospital. All CHD-affected patients diagnosed with DS (with or without chromosomal studies) during the period from December 2008 to November 2014 were included in the study. Phenotypic clinical features matching with DS recorded in the medical charts were as follows: mongoloid facies, protruding tongue, transverse single palmar crease, brachycephaly, depressed nasal bridge, small, low-set ears, and upward-slanted eyes with epicanthic fold, short neck and hypotonia. General characteristics such as gender, age of diagnosis and mother’s age at delivery were also recorded. The examination protocol during echocardiographic assessment was as follows: subxiphoid imaging followed by a segmental approach for description of the major cardiovascular structures in sequence, with the image apex at the bottom of the video. We recorded all videos of the examinations and all cases underwent

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detailed review by the paediatric cardiologist (AD) to classify CHD according to standard nomenclature used by the Society of Thoracic Surgery congenital heart surgery database (Table 1).12

25 20

Statistical analysis Data are reported as mean ± SD or median with intervals. We used the t-test for paired data. The SPSS 20 (IBM SPSS Statistics version 20 x86 Multiple languages) and Origin statistical packages were used.

Results We recorded 2 156 patients with CHD and of these, 128 (6%) had DS. The median age of patients at diagnosis was 9.5 months (2 days to 16 years), with 40.4% of patients diagnosed before six months of age. The male-to-female ratio was 1:1. The median age of mothers at delivery was 39 years (16–47) (Fig. 1) and the consanguinity rate was 22%. The distribution of different types of CHD is shown in Table 1. Overall, 186 CHDs were diagnosed in our study population; 75 patients (58.6%) had a single cardiac lesion versus 56 (41.4%) with multiple cardiac lesions. When considering individual CHDs, atrioventricular septal defect (AVSD, 29.9%) was the most common cardiac abnormality. Among these AVSDs, the complete form was the most frequent type, found in cases 46 cases (85.2%) and, of those complete forms of AVSD, Rastelli class C AVSD was found to be the most frequent and was reported in 34 cases (74%). Table 1. Types of congenital heart defects in patients with Down syndrome CHD feature, n (%) (n = 186)

Atrioventricular septal defect (AVSD)

54 (29)

Complete AVSD

46/54 (85)

• Rastelli type A

12/54 (26)

• Rastelli type B

• Rastelli type C

34/54 (74)

• Balanced

45/54 (98)

• Unbalanced

1 (1.9)

Intermediate AVSD

7 (12.9)

Perimembranous

4/40 (10) 4/40 (10)

Inlet

4/40 (10)

Sinus venosus

37 (19.9) 35/37 (95) 2/37 (5)

Patent ductus arteriosus (PDA)

31 (16.7)

Tetralogy of Fallot (FT)

10 (5.4)

Valvular disease

6 (3.2)

Mitral valvular insufficiency

5/6 (83)

Aorticvalvular insufficiency

1/6 (17)

Other

8 (4.3)

Left superior vena cava

3/8 (37)

Pulmonary stenosis

2/8 (25)

Coartaction of the aorta

1/8 (12)

PAPVC

1/8 (12)

Double outlet right ventricle

1/8 (12)

PAPVC: partial anomalous pulmonary venous connection.

<20

20–25

25–30

30–35

35–40

>45

40–45

Fig. 1. Mothers’ ages of patients with Down syndrome at delivery.

Ventricular septal defect (VSD) was the second most common cardiac abnormality (21.5%). Perimembranous VSDs were reported in 28 cases (70%) and other VSD forms were reported in 16 cases (30%). Atrial septal defect (ASD, 19.9%) was the third most common single lesion. Most of these ASDs were of ostium secundum form (95%), while the other forms (sinus venosus) were noted in 5%. Patent ductus arteriosus (PDA) was diagnosed in 16.57% and tetralogy of Fallot (TOF) in 5%. The most frequent associations of CHD were AVSD + ASD (9.3%), VSD + ASD (6.2%) and VSD + PDA (5.5%). Pulmonary arterial hypertension (PAH) was seen in 68 patients (53%) and Eisenmeiger syndrome in four patients (3.1%). Surgery was indicated in 54% (69 patients) but for many reasons (no agreement from the parents, lack of financial resources, etc), a surgical procedure was done in only 42 patients. In those surgically treated patients, 87% presented with ASD, and 68, 64 and 60% with VSD, PDA and AVSD, respectively (Fig. 2). In addition, 23 and 15% of patients remained either under medical treatment or observation, respectively. The mortality rate observed in our population was 14.1%, and another 29.7% were lost to follow up (Table 2). For those 100

87%

28/40 (70)

Muscular

Ostium secundum

40 (21.5)

Subpulmonary

Atrial septal defect (ASD)

1/54 (2)

Partial AVSD Ventricular septal defect (VSD)

61%

60%

68%

64%

Type of CHD

40 20 0

19%21%

All patients

22%19%

AVSD

18% 14%

VSD

7% 7%

ASD

21% 14%

PDA

surgery group non-surgery group lost to follow-up subgroup

Fig. 2. Rates of surgical procedures for the whole group of patients with Down syndrome and congenital heart disease and for the most frequent congenital heart defects in these patients. AVSD: atrioventricular septal defect; VSD: ventricular septal defect. ASD: atrial septal defect; PDA: patent ductus arteriosus.

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patients with an indication for surgery who were operated on, 79% survived. On the other hand, for the patients having a surgical indication but were not operated on, only 31% survived.

Discussion CHD in DS is reported to be as high as 40 to 63% and is a major cause of morbidity and early mortality in these patients.4,6,8,13 It has been suggested that when characterising the profiles and types of CHD in DS, the dominant lesions observed are variable according to the different geographical areas around the world.7,8 Hence, for a given country, to know the profile and characteristics of CHD in DS is of great importance, first to improve survival by timely treatment of cardiac anomalies,10 and second to apply appropriate preventative measures. In this study, we sought to determine the distribution of CHD in DS in the Moroccan setting. As our institution is a referral centre for approximately one-quarter of the population of our country, the results observed in this study may reflect the national trends of CHD in DS. AVSD was the most common cardiac abnormality and VSD the second most common abnormality. Together, AVSD and VSD cases represented 50% of CHDs in our setting. ASD, isolated PDA and tetralogy of Fallot were recorded at rates of 19.9, 16 and 5%, respectively. DS is the most common autosomal abnormality. The frequency is about one case in 600 live births.1-3 This syndrome, which is by far the most common and best known chromosomal disorder in humans, is characterised by intellectual disability, dysmorphic facial features and other distinctive phenotypic traits.1-4,6 DS is primarily caused by trisomy of chromosome 21, which is the most common trisomy among live births. In 94% of patients with DS, full trisomy 21 is the cause; mosaicism (2.4%) and translocations (3.3%) account for the remaining cases.14,15 Approximately 75% of the unbalanced translocations are de novo, and approximately 25% result from familial translocation.14 Two different hypotheses have been proposed to explain the mechanism of gene action in DS: developmental instability (i.e. loss of chromosomal balance) and the so-called gene-dosage Table 2. Fate of patients with Down syndrome and congenital heart disease Patients with DS and CHD

Number of patients (%) (n = 128)

• Dead

18 (14.1)

• Alive

72 (56.3)

• Lost to follow up Patients with an indication for surgery Patients operated on

38 (29.7) 69/128 (54) 42/69 (61)

• Dead

8/42 (19)

• Alive

33/42 (79)

• Lost to follow up Patients not operated on

1/42 (2) 13/69 (19)

• Dead

9/13 (69)

• Alive

4/13 (31)

• Lost to follow up Patients with no indication for surgery

14/69 (20) 59/128 (46)

• Dead

1/59 (2)

• Alive

35/59 (59)

• Lost to follow up

23/59 (39)

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effect.15 According to the gene-dosage effect hypothesis, the genes located on chromosome 21 have been overexpressed in cells and tissues of DS patients, and this contributes to the phenotypic abnormalities.16 There has been much interest in trying to identify the exact location of CHD susceptibility genes. Although trisomy 21 is a risk factor for CHD, it is not a sufficient requirement (about 40–60% of people with trisomy 21 do not have CHD). Molecular mapping studies suggested the presence of a ‘critical region’ that is responsible for the various CHD phenotypes, and narrowed the region to D21S3 (defined by VSDs) through to PFKL (defined by tetralogy of Fallot), containing 39 human genes and 25 predicted genes. One of these genes, DSCAM, is known to mediate cell–cell adhesion, thought to be essential to the process of cellular adhesion and fusion of endocardial cushions. It is speculated that the overexpression of DSCAM can lead to a disturbance of normal epithelial– mesenchymal transformation and/or mesenchyme cell migration or proliferation, thus resulting in an increase in the adhesive property of the cushion fibroblasts, leading to the various heart defects.17 As observed during this study, median age of the mothers at delivery was 39 years (16–47). The occurrence of DS is strongly dependent on maternal age, and advanced maternal age remains the only well-documented risk factor for maternal meiotic non-disjunction. With a maternal age of 45 years, the risk is one in 30 to 50 live births.18 However, understanding of the basic mechanism behind the maternal age effect is lacking. Some studies also suggest a role for consanguinity19 (Fig. 1). In our study, the most common lesion was AVSD (29%), followed by VSD (21.5%) and ASD (19.9%). The most common associations of CHD were AVSD + ASD (10%) and VSD + ASD (7.8%) (Table 1). In the international literature, the most common CHDs in DS from reports from western European countries and the USA are the following: endocardial cushion defect (43%), which results in AVSD/AV canal defect; VSD (32%); secundum atrial septal defect (10%); tetralogy of Fallot (6%); and isolated PDA (4%). About 30% of patients have several cardiac defects.3,4,6,13 However, in Asia, isolated VSDs have been reported to be the most common defect, observed in about 40% of patients,20 whereas in most reports from Latin America, the secundum type of ASD is suggested to be the most common lesion.8,11 This study on CHD in DS in the Moroccan setting exhibited similar results to those of Western countries in terms of major CHDs in DS, but the prevalence rates of ASVD and VSD were lower. This has also been reported by others1,7,8,20 and reinforces the findings of a variation in profile and type of CHD in DS in the different geographical areas around the world. Since our study exhibited similar CHD dominant lesions in DS to those of Morocco’s neighbouring European countries, it suggests that, despite the level of development of the different countries, a combination of factors and regional proximity most likely plays a significant role in such similarities. However, regional proximity alone cannot explain all the differences, as studies in African countries that also have regional proximity with Europe, such as Libya, have exhibited results that globally encompassed the spectrum of CHD in DS seen in Europe but with quite different rates in the different CHDs.21 As illustrated by the differences in reported rates of the different CHDs in

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DS between countries in close proximity, such as the USA and Mexico or other Latin American countries,3,4,8,11 it appears that regional proximity may have a greater effect in cases of geographical areas with long-standing populations, as in the Mediterranean area. About 40.4% of the patients were evaluated during the first six months of life and all had echocardiograms (100%). As reported by others,22 age at evaluation of CHD is an important factor for the reduction in mortality and morbidity rates. It has been suggested that when the associated heart abnormalities are leftto-right shunts, the prognosis is more favourable than when there is associated AVSD, which is linked to pulmonary hypertension, a condition in itself related to high mortality rates.23 The high mortality rate observed in our study was associated with many factors, including non-consent of the parents for surgery and the fact that a substantial number of cases did not undergo surgery because of insufficient financial resources (Fig. 2). For various reasons, a substantial number of patients were lost to follow up. This high rate probably reflects the difficulties for families and the health system to cope with such diseases in the context of a developing country (Table 2).

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De Rubens Figueroa J, del Pozzo Magana B, Pablos Hach JL, Calderon Jimenez C, Castrejon Urbina R. [Heart malformations in children with Down syndrome]. Rev Espanola Cardiol 2003; 56(9): 894–899. PubMed PMID: 14519277.

Hwang BF MP, Jaakkola JJK. Seasonal variation of birth defects in Norway. Biomedicine 2013; 3(2): 95–101. doi: 10.1016/j. biomed.2013.04.002.

10. Formigari R, Di Donato RM, Gargiulo G, Di Carlo D, Feltri C, Picchio FM, et al. Better surgical prognosis for patients with complete atrioventricular septal defect and Down’s syndrome. Ann Thorac Surg 2004; 78(2): 666–672; discussion 72. doi: 10.1016/j.athoracsur.2003.12.021. PubMed PMID: 15276542. 11. Vida VL, Barnoya J, Larrazabal LA, Gaitan G, de Maria Garcia F, Castaneda AR. Congenital cardiac disease in children with Down’s syndrome in Guatemala. Cardiol Young 2005; 15(3): 286–290. doi: 10.1017/S1047951105000582. PubMed PMID: 15865831. 12. Surgeons SoT. Congenital Heart Surgery Database v2.30 2008. Available from: http://www.sts.org/sections/stsnationaldatabase/datamanagers/ congenitalheartsurgerydb/datacollection/index.html. 13. Vis JC, Duffels MG, Winter MM, Weijerman ME, Cobben JM, Huisman SA, et al. Down syndrome: a cardiovascular perspective. J Intellect Disabil Res 2009; 53(5): 419–425. doi: 10.1111/j.1365-

Conclusion As suggested in the international literature, our study confirmed that the profile and type of CHDs in DS in the Moroccan context exhibited slight differences in the distribution of these CHDs compared with its European neighbours and/or other Western countries. Further studies are needed to determine which variables have an impact on these differences.

2788.2009.01158.x. PubMed PMID: 19228275. 14. Peterson MB. Nondisjunction in trisomy 21: origin and mechanisms. Cytogenet Cell Genet 2000; 91: 199–203. 15. Reeves RH, Baxter LL, Richtsmeier JT. Too much of a good thing: mechanisms of gene action in Down syndrome. Trends Genet 2001; 17(2): 83–88. PubMed PMID: 11173117. 16. Cheon MS, Shim KS, Kim SH, Hara A, Lubec G. Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part IV). Amino Acids 2003; 25(1):

References 1.

Levenson D. Talking about Down syndrome. Am J Med Genet (Part A) 2009; 149A(4): vii–viii. doi: 10.1002/ajmg.a.32867. PubMed PMID: 19322889.

Down JL. Observations on an ethnic classification of idiots. 1866. Mental Retard 1995; 33(1): 54–56. PubMed PMID: 7707939.

Chen H. Down syndrome: Medscape; 2015 [cited June 2015]. Available from: http://emedicine.medscape.com/article/943216-overview.

c0. PubMed PMID: 19212162. 19. Venugopalan P, Agarwal AK. Spectrum of congenital heart defects associated with Down Syndrome in high consanguineous Omani population. Indian Pediat 2003; 40(5): 398–403. PubMed PMID: 12768040.

TJ, et al. Population-based study of congenital heart defects in Down

congenital heart disease in Hong Kong. Pediatric Cardiol 2000; 21(2):

Paladini D, Tartaglione A, Agangi A, Teodoro A, Forleo F, Borghese

148–157. doi: 10.1007/s002469910025. PubMed PMID: 10754087. 21. Elmagrpy Z, Rayani A, Shah A, Habas E, Aburawi EH. Down syndrome and congenital heart disease: why the regional difference

A, et al. The association between congenital heart disease and Down

as observed in the Libyan experience? Cardiovasc J Afr 2011; 22(6):

syndrome in prenatal life. Ultrasound Obstet Gynecol 2000; 15(2):

306–309. doi: 10.5830/CVJA-2010-072. PubMed PMID: 22159317;

104–108. doi: 10.1046/j.1469-0705.2000.00027.x. PubMed PMID: 10775990.

PubMed Central PMCID: PMC3721875. 22. Vilas Boas LT, Albernaz EP, Costa RG. Prevalence of congenital heart

Laursen HB. Congenital heart disease in Down’s syndrome. Br Heart

defects in patients with Down syndrome in the municipality of Pelotas,

J 1976; 38(1): 32–38. PubMed PMID: 1252293; PubMed Central

Brazil. J Pediat 2009; 85(5): 403–407. doi: doi:10.2223/JPED.1934.

PMCID: PMC482966. 7.

Neonatal Care 2009; 9(1): 27–30. doi: 10.1097/01.ANC.0000346092.50981.

20. Jacobs EG, Leung MP, Karlberg J. Distribution of symptomatic

9843040.

Childhealth 2015; 25: 23–29. 18. Hartway S. A parent’s guide to the genetics of Down syndrome. Adv

Freeman SB, Taft LF, Dooley KJ, Allran K, Sherman SL, Hassold syndrome. Am J Med Genet 1998; 80(3): 213–217. PubMed PMID:

41–47. doi: 10.1007/s00726-003-0009-9. PubMed PMID: 12836057. 17. Marder LTR, Pascall E. Cardiac problems in Down syndrome. Pediat

PubMed PMID: 19662319.

Narayanan DL, Yesodharan D, Kappanayil M, Kuthiroly S, Thampi

23. Guia JM, Bosch V, Castro FJ, Tellez C, Mercader B, Gracian M.

MV, Hamza Z, et al. Cardiac spectrum, cytogenetic analysis and thyroid

[Influential factors in mortality rate from congenital heart disease. Study

profile of 418 children with down syndrome from South India: a cross-

of 1,216 children in the Autonomous Community of Murcia (1978-

sectional study. Indian J Pediat 2014; 81(6): 547–551. doi: 10.1007/

1990)]. Rev Espanola Cardiol 2001; 54(3): 299–306. PubMed PMID:

s12098-013-1088-6. PubMed PMID: 23934063.

11262371.

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Could the novel ‘double-hole’ technique be an alternative for the inflow occlusion method? Sahin Bozok, Gokhan Ilhan, Hızır Kazdal, Berkan Ozpak, Ismail Yurekli, Serdar Bayrak, Mert Kestelli

Abstract Background: Inflow occlusion on beating heart and cardiopulmonary bypass techniques have been proposed for the removal of foreign material, such as stents, catheters and mass lesions, from cardiac chambers. However, both techniques are not devoid of disadvantages and complications. In this article, we define an alternative, novel ‘double-hole’ technique, which is based on opening the right atrium without cardiopulmonary bypass. Methods: Bovine hearts were obtained from a local supermarket. Two purse-string sutures were placed in the right atrium using 2-0 braided, non-absorbable polyester suture material, one close to the auricle, and the other close to the interatrial septum. The guidewire of a haemodialysis catheter was inserted through the superior vena cava into the right atrium and passed all the way through the right ventricle. Results: We suggest that the double-hole technique may be useful, especially in revision cases with adhesions. Further research should be performed to document the efficacy and safety of this method. Conclusion: We are aware that further extensive research is necessary to investigate the utility of this novel technique in contemporary cardiovascular surgery. We believe the doublehole technique has the potential to become a safe, practical and effective measure in the future. Keywords: inflow occlusion, foreign body, extraction, doublehole technique, extracorporeal circulation.

Department of Cardiovascular Surgery, Faculty of Medicine, Recep Tayyip Erdogan University, Training and Research Hospital, Rize, Turkey Sahin Bozok, MD, sahinboz@yahoo.com Gokhan Ilhan, MD

Department of Anesthesiology and Reanimation, Faculty of Medicine, Recep Tayyip Erdogan University, Training and Research Hospital, Rize, Turkey Hızır Kazdal, MD

Department of Cardiovascular Surgery, Faculty of Medicine, Izmir Katip Celebi University, Atatürk Training and Research Hospital, İzmir, Turkey Berkan Ozpak, MD Ismail Yurekli, MD Mert Kestelli, MD

Institute of Oncology, Dokuz Eylul University, Izmir, Turkey Serdar Bayrak, MD

Submitted 5/10/15, accepted 2/3/16 Published online 12/4/16 Cardiovasc J Afr 2016; 27: 291–293

www.cvja.co.za

DOI: 10.5830/CVJA-2016-020

Inflow occlusion on a beating heart (IOBH) is a technique that was used more often in cardiovascular surgery before the cardiopulmonary bypass (CPB) era. Nowadays, this technique is reserved for cases such as pulmonary or aortic valvotomy, cardiac injury, atrial septectomy and extraction of intracardiac thrombus or foreign body.1-3 CPB can alternatively be used for these operations. Complications may arise due to technical issues, such as tissue injury during cannulation or embolic events. Peri-operative problems arising from the inflammatory process caused by extracorporeal circulation signify that CPB is not a technique devoid of complications, in comparison to IOBH.1 To eliminate the disadvantages of IOBH and CPB, we have developed a novel technique on a bovine heart. We hope that the ‘double-hole’ technique could provide a safe and effective alternative in the removal of foreign material such as catheters and pacemaker leads.

Methods All animal studies were carried out with the approval of the Institutional Animal Care and Use Committee. Bovine hearts were obtained from a local supermarket. Two purse-string sutures were placed in the right atrium using 2-0 braided, non-absorbable polyester suture material (Ticron®, Covidien, Norwalk, CT 06856, USA), one close to the auricle, and the other close to the interatrial septum. The guidewire of a haemodialysis catheter was inserted through the superior vena cava into the right atrium and passed all the way through the right ventricle. A stab wound was made within the purse-string sutures and the left index finger was introduced into the right atrium through the dilated hole, close to the auricle. In the right hand, a curved haemostatic clamp was introduced through the dilated hole, close to the interatrial septum (Fig. 1A). A guidewire or catheter inside the right atrium was pushed towards the other hole with the tip of the left index finger and caught with the clamp in the other hole, held by the right hand, and extracted (Fig. 1B). Following visualisation and extraction, the wire was cut into proximal and distal pieces. The proximal piece was extracted (Fig. 2A), and the distal piece was then removed (Fig. 2B). Repetition of this procedure revealed that we were able to retrieve the wire with the clamp every time, and the two pieces of wire were removed, where after the right atrium was closed with snares.

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Fig. 1. A. Two purse-string sutures are placed, one close to the auricle and the other close to the interatrial septum. The left index finger is inserted into the ventral hole and a closed clamp is inserted into the dorsal hole. B. The clamp is opened inside the right atrium. The clamp is closed after the left index finger pushes the wire between the jaws of the clamp. The wire held by the clamp is extracted.

Discussion IOBH is a well-known but uncommonly used technique to remove mass lesions and foreign material such as pacemaker leads and catheters from the right atrium.1 In this technique, blood flow from the superior and inferior vena cavae to the right atrium is prevented by occlusion with snares, and the right atrium is then opened. This method has significant disadvantages, such as bleeding, hypotension, air embolism, difficulty of surgical exposure, and the necessity to be performed in a short time. Cardiac and neurological complications may occur due to systemic and cerebral malperfusion, particularly in occlusions of more than three minutes.2 CPB may be required, particularly in cases with complicated right atrial material. This necessity arises owing to co-morbidities of the patient, extension of the material, and the potential for pulmonary embolism. Studies have demonstrated that the use of CPB is particularly common in cases with co-existence of A

extracardiac tumours and large, invasive right atrial thrombus.4-6 Both IOBH and CPB techniques may be used in the extraction of intracardiac pacemaker leads,6 and in tracheal stent implantation.7 CPB can alternatively be used for these interventions, but widespread inflammatory response, length of operation and intubation times, and duration of intensive care unit and hospital stays are limitations of the technique.3 These limitations become even more apparent in cases with co-morbidities.1 To overcome these disadvantages, we have developed a novel double-hole technique for the removal of foreign material (e.g. catheters, pacemaker leads) in a bovine heart model. In the IOBH technique, the superior and inferior vena cavae should be free from the surrounding tissue. A polyester tape is placed around each vena cava to provide occlusion of inflow. Complications such as bleeding and air embolisation may be minimised in the double-hole technique since it involves B

Fig. 2. A. The extracted wire is cut into two pieces. B. Removal of the distal part of the wire.

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less traumatic and more haemostatic steps such as a pursestring suture, a smaller hole for clamp insertion, and gentler manipulation with the finger. The technique we describe is easy and practical to perform. While the wire is manipulated with the left index finger, it can easily be grasped repeatedly with the clamp in the right hand. Results of our preliminary report indicate that the double-hole technique could be a safe and effective option for the extraction of pacemaker leads and catheters from the right atrium. We suggest that this technique may be especially useful in revision cases with adhesions. Further research should be performed to document the efficacy and safety of this method. The main limitation of this experimental study is that the right atria of the bovine heart are much smaller than those of a human heart. Larger atriae may cause more difficulty during surgery. Secondly, the usefulness of this procedure may in fact be limited to wires that are partly trapped in the right atrium, and hence this would include pacer wires and ‘errant’ guidewires. It may not be appropriate for guidewires having left the right atrium and travelled to the right ventricle or pulmonary artery.

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plan to assess this technique in an in vivo model to corroborate its potential as a less-invasive extraction procedure in future research.

References 1.

Gokalp O, Yurekli I, Yilik L, et al. Comparison of inflow occlusion on the beating heart with cardiopulmonary bypass in the extraction of a mass lesion or a foreign body from the right heart. Eur J Cardiothorac Surg 2011; 39: 689–692.

Singh J, Dhaliwal RS, Biswal S, et al. Inflow occlusion in the era of modern cardiac surgery. J Thorac Cardiovasc Surg 2006; 132: 1246.

Bobadilla JL, Wigfield CH, Chopra PS. Inflow occlusion pulmonary embolectomy in the modern era of cardiac surgery. J Thorac Cardiovasc Surg 2006; 131: 484–486.

Vilaca IB, Almeida Pinto J, Teixeira JF, et al. Renal cell carcinoma extending into the right atrium. Case report. Rev Port Cir Cardiotorac Vasc 2008; 15: 105–108.

Talay S, Ay D, Erkut B. A rare complication of patent ductus arteriosus coil occlusion involving a foreign body migrating rapidly from the femoral vein to the right ventricle. Turk Gogus Kalp Dama 2013; 21(2):

Conclusion We believe the double-hole technique has the potential to become a safe, practical and effective measure in the future. Further extensive research is necessary to investigate the utility of this novel technique in contemporary cardiovascular surgery. We

470–472. 6.

Leprince P, Nataf P, Cacoub P, et al. Septicemia and endocarditis related to transvenous pacing leads of pacemakers: surgical indications and results. Arch Mal Coeur Vaiss 1995; 88: 241–246.

Erden IA, Ayhan B, Saylan A, et al. Tracheal stent implantation with extracorporeal circulation. Turk Gogus Kalp Dama 2014; 22(1): 163–167.

Cardiovascular disease market set to grow very slowly to $146.4 billion by 2022, says GBI Research The cardiovascular disease market, which includes hypertension, dyslipidaemia and thrombotic events, is set to grow from $129.2 billion in 2015 to $146.4 billion by 2022, at a very modest compound annual growth rate of 1.8%, according to business intelligence provider GBI Research. The company’s latest report states that this relative stagnation can be attributed to major product approvals coinciding with key patent expirations. Within cardiovascular disease there are a number of blockbuster products that have recently gone off-patent, and others are expected to in the coming years, many of which belong to significant players. For example, the current market leader, AstraZeneca’s Crestor (rosuvastatin), generated around $7 billion in 2011, with revenues expected to drop sharply following the expiration of its patent on 8 July 2016. Total annual revenues are forecast to be around $1.3 billion in 2022. Thomas Jarratt, associate analyst for GBI Research, explains: ‘Unlike AstraZeneca, some key players will experience revenue growth resulting from the introduction of new products to market. In particular, Sanofi’s Praluent

(alirocumab) is expected to help mitigate losses associated with falling revenues of its key products Lovenox (enoxaparin) and Plavix (clopidogrel). ‘Novartis’ heart-failure drug Entresto was introduced to market in July 2015, and GBI Research expects its revenues to increase dramatically during the forecast period. Entresto is a combination drug, which has shown efficacy in clinical trials. Coupled with a high cost, which amounts to over $4 500 annually per patient, the drug contributes to a very high revenue forecast of $5.7 billion by 2022.’ The sheer number of expirations and approvals means the structure of the market will shift significantly. Current market leader AstraZeneca is set to mitigate the damage associated with the introduction of generic Crestor through the rising revenues attributed to its antiplatelet drug Brilinta. Jarratt continues: ‘the market shares of Sanofi and Novartis are expected to increase strongly over the forecast period, leading to Sanofi becoming market leader, and both brands achieving revenues in excess of $7 billion by 2022.’ Source: AfricaPCR 2016

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The relationship between elevated magnesium levels and coronary artery ectasia Mustafa Yolcu, Emrah Ipek, Serdar Turkmen, Yücel Ozen, Erkan Yıldırım, Alper Sertcelik, Fatih Rıfat Ulusoy

Abstract Background: Coronary artery ectasia (CAE) without specific symptoms is the localised or diffuse swelling of the epicardial coronary arteries. Magnessium (Mg) plays an important role in cardiac excitability, vascular tonus, contractibility, reactivity and vasodilatation. In our research, we aimed to study the vasodilatory effect of Mg in the aetiopathogenesis of ectasia. Methods: Patients identified during routine coronary angiograms in our clinic between January 2010 and 2013 were included in the study. Sixty-two patients with isolated CAE, 57 with normal coronary angiograms (NCA), 73 with severe coronary artery disease (CAD), and 95 with stenosis of at least one coronary artery and CAE (CAD + CAE) were included in the study. Serum Mg levels were measured in mg/ dl after 12 hours of fasting. Results: There were no statistically significant differences between the groups in terms of age, hypertension, smoking, hyperlipidaemia, diabetes mellitus, family history of coronary artery disease and medications used. Serum glucose, thyroid stimulating hormone (TSH), urea, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, sodium and potassium levels were similar in all groups. Serum Mg levels were 1.90 ± 0.19 mg/dl in patients with isolated CAE, 1.75 ± 0.19 mg/dl in those with CAD, 1.83 ± 0.20 mg/dl in those with CAD + CAE, and 1.80 ± 0.16 mg/dl in the NCA group. These results show that Mg levels were higher in ectasia patients with or without CAD.

Department of Cardiology, Arel Universty, Private Medicana Camlica Hospital, Istanbul, Turkey Mustafa Yolcu, MD, yolcudoctor@gmail.com

Department of Cardiology, Erzurum Region Training and Research Hospital, Erzurum, Turkey Emrah Ipek, MD Erkan Yıldırım, MD Fatih Rıfat Ulusoy, MD

Department of Cardiology, Sani Konukoğlu Medical Centre, Gaziantep, Turkey Serdar Turkmen, MD Alper Sertcelik, MD

Department of Cardiovascular Surgery, Kartal Kosuyolu High Specialty Education and Research Hospital, Erzurum, Turkey Yücel Ozen, MD

Conclusions: The histopathological characteristics of patients with CAE were similar to those with CAD. The specific mechanism of abnormal luminal dilatation seen in CAE however remains to be elucidated. Mg is a divalent cation with powerful vasodilatory effects. In our study, serum Mg levels were found to be statistically higher in ectasia patients with or without CAD.

Keywords: coronary artery ectasia, magnessium, pathophysiology Submitted 28/1/14, accepted 8/3/16 Published online 21/4/16 Cardiovasc J Afr 2016; 27: 294–298

www.cvja.co.za

DOI: 10.5830/CVJA-2016-023

Coronary artery ectasia (CAE) without specific symptoms is the localised or diffuse swelling of the epicardial coronary arteries to at least 1.5 times the adjacent normal coronary segment.1,2 It is congenital or acquired and several studies have reported its incidence at 0.3–5%.1,3 Atherosclerosis, congenital factors, and inflammatory or connective tissue disorders may play a role in the aetiology, however, the aetiopathogenesis remains unclear despite some molecular, cellular and vascular mechanisms being defined in previous studies.4,5 In several studies, other vascular structures were shown to be involved in CAE patients, which indicates CAE is a vascular disease and not localised to the coronary arteries. Therefore factors other than atheroscleosis may play a role in its aetiopathogenesis. Magnesium, the second most abundant intracellular cation, is an essential element that plays a crucial role in cardiac and vascular functions. Magnesium regulates contractile proteins, modulates transmembrane transport of calcium (Ca2+), sodium (Na+) and potassium (K+), acts as a co-factor in the activation of ATPase, controls regulation of energy-dependent cytoplasmic and mitochondrial metabolism, and influences DNA and protein synthesis at the subcellular level.6,7 Small changes in concentration of extracellular and/or intracellular free Mg have important effects in cardiac excitability, vascular tonus, contractibility, reactivity and growth.8,9 Low levels of intracellular Mg lead to abnormal vascular cell growth, inflammation, fibrosis and contraction, resulting in positive vascular remodelling. Dosing with Mg was found to cause vasodilatation and to have anti-inflammatory effects.8,9 In our study, we aimed to study the vasodilatory effect of Mg in the aetiopathogenesis of ectasia, and the long-term effects of elevated Mg levels on the vascular structure, leading to abnormal coronary dilatation.

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Methods A total of 4 800 patients identified during routine coronary angiograms in our clinic between January 2010 and 2013 were included in the study. The study was planned to be prospective and was approved by the local ethics committee. After coronary angiography, the patients were informed about the study and written consents were given. Sixty-two patients with isolated CAE, 57 with normal coronary angiograms (NCA), 73 with severe coronary artery disease (CAD), and 95 with stenosis of at least one coronary artery and CAE (CAD + CAE) were included in the study. All of the patients were questioned on their cardiovascular risk factors and medication used. Routine biochemical and haematological laboratory tests were done. Previous history of myocardial infarction, percutaneous coronary intervention, left ventricular hypertrophy, left ventricular dysfunction [ejection fraction (EF) < 50%], moderate to severe valvular disease, rhythms other than sinus, congenital heart disease, chronic obstructive lung disease and/or cor pulmonale, chronic systemic illness, active infection, renal failure, neoplastic disease, antioxidant drug usage and alcohol abuse were the exclusion criteria. Coronary angiography was performed on a Siemens Axiom Artis angiography device with standard Seldinger’s technique using isohexol. In order to evaluate each coronary artery, at least four views from the left and two views from the right side were taken. Patients were allocated into four groups: patients with CAD, those with isolated CAE, those with CAD + CAE, and subjects with normal coronary angiograms. Angiographic images were evaluated by two independent researchers. Isolated CAE was defined as dilatation of at least one epicardial coronary artery to 1.5 times the reference vessel diameter and absence of critical stenosis (> 50%) in any of the coronary arteries. NCA were defined as the absence of angiographic atherosclerosis during routine coronary angiography; 60% or greater stenosis in at least one epicardial coronary artery was defined as CAD. CAD + CAE was defined as 60% or greater stenosis in at least one epicardial coronary artery and the presence of ectasia in any of the coronary arteries. Serum Mg levels were measured in mg/dl after 12 hours of fasting. Haemograms, renal and liver function tests, lipid profiles, serum glucose and electrolytes and thyroid stimulating hormone (TSH) levels were also evaluated in all patients.

Statistical analysis Statistical analysis was performed using the SPSS 14 (SPSS Inc, Chicago, IL, USA) statistics program. Data are given as percentages and mean ± standard deviation. ANOVA and post hoc Tukey tests were used in the comparison of parametric variables between groups. A chi-squared test was performed in the comparison of non-parametric values and percentages. Statistical significance level was taken as p ≤ 0.05.

Results The mean age was 62 ± 10 years in the CAE patients, 61 ± 11 years in CAD patients, 64 ± 8 years in those with CEA + CAD, and 59 ± 8 years in the NCA patients. There was no statistically significant difference between the groups in terms of

age, hypertension, smoking, hyperlipidaemia, diabetes mellitus, family history of CAD, and medications used (Table 1). Serum glucose, calcium, TSH, urea, total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, sodium and potassium levels were similar in both groups (Table 2). Serum creatinine level was within normal limits in all patients, however creatinine values were statistically lower in the NCA group (p = 0.024). High-density lipoprotein (HDL) cholesterol levels were lowest in the CAD patients and highest in the isolated ectasia group, and this difference was statistically significant (p = 0.003). Serum Mg levels were 1.90 ± 0.19 mg/dl in isolated CAE patients, 1.75 ± 0.19 mg/dl in those with CAD, 1.83 ± 0.20 mg/ dl in those with CAD + CAE, and 1.80 ± 0.16 mg/dl in the NCA group. These results showed that Mg levels were higher in the ectasia patients with or without CAD.

Discussion Mg is a divalent cation with powerful vasodilatory effects. In our study, serum Mg levels were found to be statistically higher in the ectasia patients with or without CAD. CAE is dilatation of the coronary arteries to at least 1.5 times normal, and the basic pathogenic mechanism is destruction of the musculo-elastic layers of the arterial tunica media, and the accumulation of collagen in place of elastin, leading to thinning of the arterial wall.1,5,10 Injury of the media causes decreased stress tolerance of the vessel wall to intraluminar pressure, leading to progressive dilatation and ectasia formation.10,11 In a pathological examination, atherosclerosis is detected in more than 50% of patients, however connective tissue disorders and vasculitides can also be present.11 CAE can be divided into four different types according to the classification of Markis and colleagues. Type 1 indicates diffuse ectasia in two to three different vessels, type 2 shows diffuse disease in one vessel and local disease in another, type 3 is diffuse disease in one vessel, and type 4 indicates localised or segmental ectasia. In our study there were 24 (16%) patients with type 1

Table 1. Comparisons of cardiovascular risk factors and the medications used

Parameters Age (years) Gender (M/F) Hypertension (n) Diabetes mellitus (n) Hyperlipidaemia (n) Family history of CAD (n) Smoking (n) Calcium channel blockers (n) Beta-blockers (n) Angiotensin converting enzyme inhibitors (n) Angiotensin receptor blockers (n) Diuretics (n) Oral antidiabetic (n)

Isolated CAE (n = 62)

CAD (n = 73)

CAD + CAE (n = 95)

62 ± 10 45/17 43 13 11 18

61 ± 11 39/34 56 21 13 25

64 ± 8 76/19 74 25 29 36

33 12

32 20

24 21

NCA (n = 57) p-value 0.062 59 ± 8 17/40 35 12 9 16

0.000 0.119 0.648 0.080 0.543

49 23

24 12

0.482 0.744

20 16

38 33

12 11

0.051 0.084

0.471

15 11

22 13

40 16

16 10

0.084 0.998

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Table 2. Comparisons of clinical parameters and magnessium Clinical parameters Fasting blood glucose (mg/dl) (mmol/l) Urea (mg/dl) Serum creatinine (mg/dl) (mmol/l)

Isolated CAE (n = 62)

CAD (n = 73)

CAD + CAE (n = 95)

NCA (n = 57)

109 ± 28 (6.05 ± 1.55)

113 ± 25 (6.27 ± 1.39)

118 ± 39 (6.55 ± 2.16)

108 ± 25 (5.99 ± 1.39)

p-value 0.197

35 ± 10

36 ± 10

32 ± 10

0.114

0.91 ± 0.20 (80.44 ± 17.68)

0.88 ± 0.22 (77.79 ± 19.45)

0.92 ± 0.31 (81.33 ± 27.40)

0.80 ± 0.15 (70.72 ± 13.26)

0.024¥ 0.102

Sodium (mg/dl)

139 ± 2.09

139 ± 2.67

140 ± 2.24

139 ± 2.60

Potassium (mEq/l)

4.32 ± 0.43

4.17 ± 0.42

4.28 ± 0.43

4.12 ± 0.57

0.054

Total cholesterol (mg/dl) (mmol/l)

192 ± 43 (4.97 ± 1.11)

188 ± 35 (4.87 ± 0.91)

180 ± 39 (4.66 ± 1.01)

179 ± 36 (4.64 ± 0.93)

0.142

Triglycerides (mg/dl) (mmol/l)

146 ± 79 (1.65 ± 0.89)

171 ± 112 (1.93 ± 1.27)

151 ± 82 (1.71 ± 0.93)

136 ± 59 (1.54 ± 0.67)

0.133

HDL cholesterol (mg/dl) (mmol/l)

46 ± 12 (1.19 ± 0.31)

39 ± 8.8 (1.01 ± 0.23)

42 ± 9.5 (1.09 ± 0.25)

44 ± 10 (1.14 ± 0.26)

0.003µ√

LDL cholesterol (mg/dl) (mmol/l)

118 ± 36 (3.06 ± 0.93)

114 ± 27 (2.95 ± 0.70)

108 ± 34 (2.80 ± 0.88)

105 ± 29 (2.72 ± 0.75)

0.095

TSH (mIU/l)

0.99 ± 0.87

1.10 ± 1.45

1.12 ± 1.21

1.16 ± 1.35

0.895

Magnesium (mg/dl)

1.90 ± 0.19

1.75 ± 0.19

1.83 ± 0.20

1.80 ± 0.16

0.000√£&

Calcium (mg/dl)

9.69 ± 0.32

9.64 ± 0.28

9.67 ± 0.33

9.58 ± 0.41

0.103

NCA vs CAD + CAE (p < 0.05); µCAD vs NCA (p < 0.05); √CAD vs CAE (p < 0.05); £CAE vs NCA (p < 0.05); & CAD vs CAD + CAE (p < 0.05).

CAE, 43 (27%) with type 2, 54 (34%) with type 3, and 36 (23%) with type 4 CAE. The histopathological characteristics of CAE are similar to those of CAD, however the specific mechanism of abnormal luminal dilatation seen in CAE remains to be elucidated. Negative remodelling is found in stenotic CAD, however positive remodelling is seen in CAE.12 In a study by Yolcu and colleagues, it was shown that serum levels of plasminogen activator inhibitor-1, which causes an increase in activity of matrix metalloproteinase, increased in patients with isolated ectasia, suggesting different pathways other than atherosclerosis in ectasia formation.12 Yetkin and colleagues showed that carotid–intima media thickness was statistically lower in CAE patients with stenotic CAD than in individuals who had CAD alone, and reported that ectasia was not an atherosclerotic process limited to the coronary arteries.13 In previous studies, aortic aneursym, dilatations in lower-extremity varicose veins, basillary artery aneurysm and varicocele were reported to be more frequent in isolated ectasia patients.12 These findings propose that positive remodelling in the vessel wall, which is not common in the atherosclerotic process, plays a role in the aetiopathogenesis of CAE. Mg2+, which works as an allosteric modulator of several proteins, controls nucleotide and protein synthesis, regulates Na+, K+, and Ca2+ channels, and plays a crucial role in enzymatic reactions involving kinases, is an abundant intracellular divalent cation.14,15 Less than 1% of the total body Mg2+ concentration circulates in the blood, and it is stored primarily in bone and the intracellular compartments of muscle and soft tissue.15,16 Mg2+ regulates vascular tone, cardiac rhythm and platelet-activated thrombosis.17,18 Mg stimulates nitric oxide release, which has a potent vasodilatory effect, from the endothelium. It is a co-factor for the delta-6-desaturase enzyme, which plays an important role in the synthesis of prostoglandin E1 (it has vasodilatory and antiplatelet effects) from linoleic acid.19 An increase in extracellular Mg concentration causes vasodilatation, a reduction in vascular resistance, an increase in capacitance function in peripheral, coronary and cerebral

arteries, and a decrease in agonist-induced vasoconstriction. Mg deficiency causes oxidative stress, inflammation, decreased luminal diameter, medial hypertrophy, vascular remodelling, it potentiates agonist-evoked vasoconstriction, and increases vascular tonus.20 As a result of increased intracellular Mg2+ concentration [(Mg2+)i], vasodilation occurs and agonist-induced vasoconstriction decreases. Reduced (Mg2+)i leads to hypercontractility and it impairs vasorelaxation.21 Mg is a unique calcium antagonist, has an effect on most types of calcium channels in vascular smooth muscle, and can decrease intracellular calcium levels.22 Inactivation of calmodulin-dependent myosin light-chain kinase activity and decreased contraction are among the major effects of decreased intracellular calcium levels.22 Consequently, this causes arterial relaxation, lower peripheral and cerebral vascular resistance, it relieves vasospasm, and results in a decline in arterial blood pressure.22 As a calcium antagonist, Mg decreases the activity of voltagedependent calcium channels, diminishing calcium release from the sarcoplasmic reticulum.23 In some in vivo and in vitro studies, Mg was shown to have vasodilatory effects on the aorta, and mesenteric, skeletal muscular, uterine and cerebral arteries.23 In previous studies, Mg was reported to play a role in the aetiopathogenesis and management of eclampsia and hypertension. Eclampsia is characterised by myogenic vasoconstriction of the cerebral arterioles and arteries, increased permeability of the blood–brain barrier, and oedema formation due to acute blood pressure increase.23 In those patients, intravenous Mg, due to its calcium antagonist effect on smooth muscle, caused relaxation and vasodilatation.23 It also limits vasogenic oedema in cerebral endothelium by a calciumdependent secondary messenger system, leading to decreased paracellular permeability and stress fibre contraction.23 Mg is now being used in coronary stents because of its strong antiproliferative and vasodilatory effects. In a study by Yener and colleagues, it was shown that Mg supplementation after coronary artery bypass surgery may delay the onset of atrial fibrillation.24

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In studies related to the aetiopathogenesis of hypertension, a Mg deficiency was reported to have hypertensive effects, and dietary Mg intake was related to hypotension, showing the reverse positive relationship between blood pressusure and serum Mg levels.20 The basic mechanism at play is blood pressure regulation by Mg via modulating vascular tone and reactivity.20 The direct vascular effect of Mg was first suggested in early 1990 in a study in which Mg salt infusion was reported to have a blood pressure-lowering effect by decreasing peripheral vascular resistance, with a mild increase in myocardial contractility.25 Observational studies support these clinical findings and acute Mg infusion causes hypotension via its vasodilatory effect.26 Similar to previous studies, our research found CAE to be significantly more prevalent in males.1,2,4 Although serum creatinine levels were in the normal range in all our study groups, there was a statistically significant difference between the groups, due possibly to small differences in creatinine levels. However in the review by Cunningham and colleagues, it was reported that in the early stages of renal failure, there was no change in Mg metabolism but in the end stage, Mg levels were affected.27 Therefore normal creatinine levels in our study groups probably did not affect the Mg balance.27 In our study, there was a significant difference in HDL cholesterol levels between the groups. In a study by Randell and colleagues, HDL cholesterol levels were found to be positively correlated with Mg levels. Our results are consistent with this study, showing higher Mg and HDL cholesterol levels in isolated ectasia and lower levels in CAD patients, indicating that there was no impact of this correlation on our results.28 In our study, serum Mg levels were statistically higher in isolated ectasia patients than in the NCA and CAD groups. Mg levels were lowest in the CAD group. Mg levels in the CAD + CAE group were higher than in the NCA group but lower than in the isolated ectasia group. The higher levels of Mg in the CAD + CAE than in the CAD group reached statistical significance. White blood cell count, as an indicator of inflammation, was significantly lower in isolated ectasia patients than in the CAD group, relating to the anti-inflammatory effect of Mg. Another inflammatory marker, ESR, was also found to be higher in CAD patients than in isolated ectasia patients. Mg in the extracellular fluid constitutes only 1% of the total body Mg concentration. However our findings suggest that chronically higher levels of serum Mg, with its anti-inflammatory effects, play a crucial role in the pathogenesis of ectasia by leading to vasodilation and negative remodelling. We proposed that factors other than atherosclerosis may play an important role in ectasia formation.

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Cardiol 2007; 96(6): 331–339. 2.

Markis JE, Joffe CD, Cohn PF, Feen DJ, Herman MV, Gorlin R. Clinical significance of coronary arterial ectasia. Am J Cardiol 1976; 37(2): 217–222.

Aksu T, Uygur B, Durukan Koşar M, Güray U, Arat N, Korkmaz S, et al. Coronary artery ectasia: its frequency and relationship with atherosclerotic risk factors in patients undergoing cardiac catheterization. Anadolu Kardiyol Derg 2011; 11(4): 280–284.

Giannoglou GD, Antoniadis AP, Chatzizisis YS, Damvopoulou E, Parcharidis GE, Louridas GE. Prevalence of ectasia in human coronary arteries in patients in northern Greece referred for coronary angiography. Am J Cardiol 2006; 98(3): 314–318.

Isner JM, Donaldson RF, Fortin AH, Tischler A, Clarke RH. Attenuation of the media of coronary arteries in advanced atherosclerosis. Am J Cardiol 1986; 58(10): 937–939.

Hoenderop JG, Bindels RJ. Epithelial Ca2+ and Mg2+ channels in health and disease. J Am Soc Nephrol 2005; 16(1): 15–26.

Laurant P, Touyz RM. Physiological and pathophysiological role of magnesium in the cardiovascular system: implications in hypertension. J Hypertens 2000; 18(9): 1177–1191.

Tammaro P, Smith AL, Crowley BL, Smirnov SV. Modulation of the voltage-dependent K+ current by intracellular Mg2+ in rat aortic smooth muscle cells. Cardiovasc Res 2005; 65(2): 387–396.

Touyz RM, Yao G. Modulation of vascular smooth muscle cell growth by magnesium-role of mitogen-activated protein kinases. J Cell Physiol 2003; 197(3): 326–335.

10. Lin CT, Chen CW, Lin TW, Lin CL. Coronary artery ectasia. Tzu Chi Med 2008; 20(14): 270–274. 11. Yilmaz H, Sayar N, Yilmaz M, Tangürek B, Cakmak N, Gürkan U, et al. Coronary artery ectasia: clinical and angiographical evaluation. Turk Kardiyol Dern Ars 2008; 36(8): 530–535. 12. Yolcu M, Yetkin E, Heper G. Comparison of plasma levels of von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) ın patients with and without coronary artery. J Invas Cardiol 2011; 15: 146–150. 13. Yetkin E, Acikgoz N, Aksoy Y, Bariskaner E, Sivri N, Akturk E, et al. Decreased carotid intima–media thickness in patients with coronary artery ectasia compared with patients with coronary artery disease. Coron Artery Dis 2005; 16(8): 495–498. 14. Wolf FI, Cittadini A. Magnesium in cell proliferation and differentiation. Front Biosci 1999; 4: D607–D617. 15. Rubin H. The logic of the membrane, magnesium, mitosis (MMM) model for the regulation of animal cell proliferation. Arch Biochem Biophys 2007; 458: 16–23. 16. Fox C, Ramsoomair D, Carter C. Magnesium: Its proven and potential clinical significance. South Med J 2001; 94: 1195–1201. 17. Altura BM, Altura BT. New perspectives on the role of magnesium

Conclusion The histopathological characteristics of patients with CAE were similar to those with CAD. The specific mechanism of abnormal luminal dilatation seen in CAE however remains to be elucidated. Mg is a divalent cation with powerful vasodilatory effects. In our study, serum Mg levels were found to be statistically higher in ectasia patients with or without CAD.

in the pathophysiology of the cardiovascular system. II: Experimental aspects. Magnesium 1985; 4: 245–271. 18. Shechter M, Merz CN, Paul-Labrador M, Meisel SR, Rude RK, Molloy MD, et al. Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease. Am J Cardiol 1999; 84: 152–156. 19. Houston M. The role of magnesium in hypertension and cardiovascular disease. J Clin Hypertens (Greenwich) 2011; 13: 843–847. 20. Sontia B, Touyz RM. Role of magnesium in hypertension. Arch Biochem

References 1.

Biophys 2007; 458(1): 33–39. 21. Yogi A, Callera GE, Antunes TT, Tostes RC, Touyz RM. Transient

Yetkin E, Waltenberger J. Novel insights into an old controversy: is

receptor potential melastatin 7 (TRPM7) cation channels, magnesium

coronary artery ectasia a variant of coronary atherosclerosis?. Clin Res

and the vascular system in hypertension. Circ J 2011; 75(2): 237–245.

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22. Altura BM, Altura BT, Carella A, Gebrewold A, Murakawa T, Nishio

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human heart. Am J Cardiol 1991; 67(16): 1435–1437.

A. Mg2+–Ca2+ interaction in contractility of vascular smooth muscle:

26. Resnick LM, Gupta RK, DiFabio B, Barbagallo M, Mann S, Marion R,

Mg2+ versus organic calcium channel blockers on myogenic tone

et al. Intracellular ionic consequences of dietary salt loading in essential

and agonist-induced responsiveness of blood vessels. Can J Physiol

hypertension. Relation to blood pressure and effects of calcium channel blockade. J Clin Invest 1994; 94(3): 1269–1276.

Pharmacol 1987; 65: 729–745. 23. Euser AG, Cipolla MJ. Magnesium sulfate for the treatment of eclampsia: a brief review. Stroke 2009; 40(4): 1169–1175.

27. Cunningham J, Rodrıguez M, Messa P. Magnesium in chronic kidney disease Stages 3 and 4 and in dialysis patients. Clin Kidney J 2012;

24. Yener AU, Ozkan T, Cicek MC, Baysal E, Dogan E, Cicek OF, et al. Magnesium; the electrolyte that delays the formation of atrial fibrillation. Exp Clin Cardiol 2014; 20(1): 2624–2633.

5(Suppl 1): i39–i51. 28. Randell EW, Mathews M, Gadag V, Zhang H, Sun G. Relationship between serum magnesium values, lipids and anthropometric risk

25. Vigorito C, Giordano A, Ferraro P, Acanfora D, De Caprio L, Naddeo

factors. Atherosclerosis 2008; 196: 413–419.

C, et al. Hemodynamic effects of magnesium sulfate on the normal

Conﬁdence Through Clinical and Real World Experience1-3 #1 NOAC prescribed by Cardiologists* Millions of Patients Treated Across Multiple Indications4 References: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales December 2015. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). S4 XARELTO ® 10 (Film-coated tablets). Reg. No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg. PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATION: Prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. S4 XARELTO ® 15 and XARELTO ® 20 (Film-coated tablets). Reg. No.: XARELTO ® 15: 46/8.2/0111; XARELTO ® 20: 46/8.2/0112. Each film coated tablet contains rivaroxaban 15 mg (XARELTO ® 15) or 20 mg (XARELTO ® 20). PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). HCR: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.MKT.GM.01.2016.1265 *Impact RX Data Oct - Dec 2015 NOAC: Non Vitamin K Oral Anticoagulant

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299

Relationship between site of myocardial infarction, left ventricular function and cytokine levels in patients undergoing coronary artery surgery Ilker Kiris, Sahin Kapan, Cuneyt Narin, Mehmet Ozaydın, Medine Cumhur Cure, Recep Sutcu, Huseyin Okutan

Abstract Background: The purpose of this study was to examine the relationship between left ventricular (LV) function, cytokine levels and site of myocardial infarction (MI) in patients undergoing coronary artery bypass grafting (CABG). Methods: Sixty patients undergoing CABG were divided into three groups (n = 20) according to their history of site of myocardial infarction (MI): no previous MI, anterior MI and posterior/inferior MI. In the pre-operative period, detailed analysis of LV function was done by transthoracic echocardiography. The levels of adrenomedullin, interleukin-1-beta, interleukin-6, tumour necrosis factor-alpha (TNF-α) and angiotensin-II in both peripheral blood samples and pericardial fluid were also measured. Results: Echocardiographic analyses showed that the anterior MI group had significantly worse LV function than both the group with no previous MI and the posterior/inferior MI group (p < 0.05 for LV end-systolic diameter, fractional shortening, LV end-systolic volume, LV end-systolic volume index and ejection fraction). In the anterior MI group, both plasma and pericardial fluid levels of adrenomedullin and and pericardial fluid levels of interleukin-6 and interleukin1-beta were significantly higher than those in the group with no previous MI (p < 0.05), and pericardial fluid levels of adrenomedullin, interleukin-6 and interleukin-1-beta were significantly higher than those in the posterior/inferior MI group (p < 0.05).

Department of Cardiovascular Surgery, Medifema Private Hospital, Izmir, Turkey Ilker Kiris, MD, kirisilker@yahoo.com

Department of Cardiovascular Surgery, Medical Park Antalya Hospital, Antalya, Turkey Sahin Kapan, MD Huseyin Okutan, MD

Department of Cardiovascular Surgery, Egepol Private Hospital, Izmir, Turkey Cuneyt Narin, MD

Department of Cardiology, Suleyman Demirel University Medical School, Isparta, Turkey Mehmet Ozaydın, MD

Department of Biochemistry, Recep Tayyip Erdogan University Medical School, Rize, Turkey Medine Cumhur Cure, MD

Department of Biochemistry, Ataturk Education and Research Hospital, Katip Celebi University, Izmir, Turkey Recep Sutcu, MD

Conclusions: The results of this study indicate that (1) patients with an anterior MI had worse LV function than patients with no previous MI and those with a posterior/inferior MI, and (2) cytokine levels in the plasma and pericardial fluid in patients with anterior MI were increased compared to patients with no previous MI. Keywords: cytokine, left ventricle, myocardial infarction, coronary artery bypass grafting, pericardium, plasma Submitted 9/6/14, accepted 8/3/16 Cardiovasc J Afr 2016; 27: 299–306

www.cvja.co.za

DOI: 10.5830/CVJA-2016-027

Transmural myocardial infarction (MI) results in neurohormonal activation as a compensation for the impaired contractile force of the myocardium.1 This neurohormonal activation is known to result in the synthesis and release of several cytokines and growth factors by the injured myocardium into the circulation. Plasma levels of tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) have been found to increase in patients with left ventricular (LV) dysfunction as their functional heart failure classification deteriorates.2 Serum concentrations of pro-inflammatory cytokines such as interleukin-1-beta (IL-1β), IL-6 and high-sensitivity C reactive protein were reported to be significantly elevated in patients with non-ST elevation acute coronary syndrome in whom new coronary events developed.3 Serneri et al.4 reported that the clinical course of heart failure is associated with a progressive increase in formation of cardiac angiotensin-II. Yoshitomi et al. reported that plasma adrenomedullin increased in the early phases of acute MI and was further elevated in patients with congestive heart failure.5 All these findings reveal a possible relationship between circulating levels of pro-inflammatory cytokines and LV function after acute MI. In addition to increased cytokine levels in the circulation after acute MI and congestive heart failure, the injured myocardium may also produce cytokines locally and subsequently release them into the pericardial fluid. Since the layers of pericardium are lined with mesothelial cells, derived from the same stem cells as vascular endothelial cells, it is speculated that these cells may also synthesise and release vasoactive substances into the pericardial fluid.6 The cytokines in pericardial fluid may reflect the extent of coronary atherosclerosis and may also directly promote the atherosclerotic process. Consistent with this hypothesis, the level of IL-1β in pericardial fluid in patients with ischaemic heart disease was found to be

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higher than in patients with both valvular and congenital heart disease.7 Namiki et al.8 reported that endothelin-1 concentrations in the pericardial fluid were more elevated in patients with ischaemic heart disease than in those with non-ischaemic heart disease. In addition, Ege et al.9 reported that levels of IL-2R, IL-6, IL-8 and TNF-α in pericardial fluid were significantly higher than in the serum in patients with MI. The pericardial fluid is partially formed from cardiac interstitial fluid, which migrates through the epicardium,10 therefore vasoactive substances released into the myocardial interstitium may appear in the pericardial fluid.6 Although levels of pro-inflammatory cytokines are well documented in both MI and heart failure, the relationship between cytokine levels, LV function and location of MI has not been fully clarified. The purpose of this study was to examine the relationship between LV function, cytokine levels and site of MI in patients undergoing coronary artery bypass grafting (CABG). For this purpose, the patients undergoing CABG were divided into three groups according to the history of site of MI: anterior MI, posterior/inferior MI and no previous MI. LV function was analysed by transthoracic echocardiography and the levels of adrenomedullin, TNF-α, IL-1β, IL-6 and angiotensin-II in both the plasma and pericardial fluid were measured in these subgroups of patients.

Methods From September 2006 to September 2007, 60 patients who underwent primary CABG surgery were enrolled in this prospective study. There were 54 (90%) males and the mean age of the patients was 60.89 ± 9.39 years. Coronary angiography and 12-lead electrocardiograms (ECG) were performed on each patient. All patients had documented coronary artery disease, defined as more than 75% stenosis in one or more of the principal coronary arteries, determined by coronary angiography. Patients who had a recent MI in the last three weeks, emergent operation, coronary artery re-operation, cardiogenic shock, complications of acute MI (LV aneurysm, post-infarction ventricular septal defect or free wall rupture), haemodynamically significant valvular disease (severe regurgitation of more than two degrees or severe stenosis requiring surgical intervention), atrial fibrillation, active infectious disease, malignancies, chronic inflammatory disease or renal dysfunction were excluded from the study. The baseline characteristics of the patients are shown in Table 1. Ongoing drug treatment included beta-blockers, angiotensin converting enzyme inhibitors, nitrates, calcium channel blockers and diuretics. All drugs were withheld on the day of the study. According to the ECG and cardiac catheterisation findings, patients were divided into three groups.1 The group with no previous MI (n = 20) included patients with no documented history of transmural MI. The anterior MI group (n = 20) included patients who had a total occlusion in the left anterior descending (LAD) coronary artery or q-waves in at least two anterior ECG leads. The posterior/inferior MI group (n = 20) included patients who had a total occlusion in the right coronary artery (RCA) or left circumflex coronary artery (LCx), or q-waves in the posterior–inferior ECG leads. This study was conducted in accordance with guidelines

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approved by the ethics committee at our institution. Informed consent was obtained from each participant prior to inclusion in the study. Standard anaesthesia and anaesthetic techniques were used in all patients by the same anaesthesiology team. Following a median sternotomy, the ascending aorta was cannulated for arterial inflow and the right atrial appendage was cannulated with a two-stage cannula for venous uptake. A cardioplegic tack was introduced into the aortic root, proximal to the aortic cannulation site for antegrade cardioplegic delivery. Heparin was given at a dose of 3 mg/kg for systemic anticoagulation, and cardiopulmonary bypass was established. Myocardial protection was maintained initially using cold (0–4°C) crystalloid cardioplegia solution, followed by cold blood (10ºC) cardioplegia, and finally warm blood (37°C) cardioplegia. Mild systemic hypothermia (32°C) was applied. We used the left and right internal thoracic arteries and the radial artery as arterial grafts, and the saphenous vein as venous graft during CABG. If the left internal thoracic artery was in optimal condition and had pulsatile flow, it was preferentially anastomosed to the left anterior descending coronary artery. After a median sternotomy, the mediastinal adipose tissue and thymus were displaced from the pericardium, which was opened and pericardial fluid was collected. Contact between the pericardial fluid and blood was meticulously avoided. Arterial blood samples were simultaneously withdrawn from an intra-arterial cannula. The samples were immediately transferred into glass tubes and centrifuged at 3 500 rpm for four minutes. The samples were kept at –80°C for subsequent assays. Levels of adrenomedullin, IL-6, TNF-α, IL-1β and angiotensin-II in the plasma and pericardial fluid were measured. Adrenomedullin levels were measured with a commercial kit (Phoenix Pharmaceuticals Inc, CA, USA) using the enzyme immunoassay (EIA) method. IL-6, TNF-α and IL-1β levels were measured with commercial kits (Biosource Diagnostics, Nivelles, Belgium) using the EIA method. Angiotensin-II levels were measured with a commercial kit (Biosource Diagnostics, Nivelles, Belgium) and radioimmunoassay (RIA) method. LV function was analysed in detail in all patients pre-operatively by transthoracic echocardiography (Vingmed System 5 Performance™, General Electric, USA). Measured indices of LV function were LV end-diastolic diameter (LVEDD), LV end-diastolic volume (LVEDV), LV end-diastolic volume index (LVEDVI), LV end-systolic diameter (LVESD), LV end-systolic volume (LVESV), LV end-systolic volume index (LVESVI), fractional shortening (FS) and LV ejection fraction (LVEF). A two-dimensional echocardiogram from the apical view was used for determination of LVEF by single-plane planimetry of the left ventricle (modified Simpson method).

Statistical analysis For continuous variables, results are presented as mean ± standard deviation (SD). As the values obtained were not normally distributed, non-parametric methods were used for tests of significance. The Kruskall–Wallis test was used to compare the means between the three groups (no previous MI, anterior MI and posterior/inferior MI). If this test indicated a significant difference between the groups, the Mann–Whitney U-test was used to compare differences between the groups.

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Table 1. Baseline characteristics of the patients No previous MI (n = 20)

Male/female

301

Table 2. Details of surgery and the early postoperative period

Anterior MI (n = 20)

Posterior/ inferior MI (n = 20)

p-value

18/2

1.00

Age (years)

57.65 ± 8.15

63.26 ± 9.90

61.90 ± 9.60

0.097

Body mass index (kg/m2)

26.03 ± 8.31

27.10 ± 7.86

26.81 ± 9.02

0.842

CPB time (min)

99.25 ± 25.08 94.81 ± 25.47 111.44 ± 33.59

0.254

ACC time (min)

55.93 ± 16.57 51.81 ± 15.08

57.11 ± 16.57

0.740

6.88 ± 1.48

9.11 ± 8.29

8.02 ± 4.79

0.642

2.00 ± 0.00

2.11 ± 0.32

2.35 ± 0.87

0.190

Positive inotropic drugs

0.072

Parameters

Drugs

Number of distal anastomoses

No previous MI (n = 20)

Anterior MI (n = 20)

Posterior/ inferior MI (n = 20)

p-value

2.62 ± 0.80

2.54 ± 0.82

2.66 ± 0.48

0.136

Beta-blockers

0.054

Extubation time (h)

ACE inhibitors

0.061

1.00

Stay in intensive care unit (days)

0.062

Hypertension

0.089

Hyperlipidaemia

0.414

Intra-aortic balloon pump

0.765

Smoking

Nitrates Calcium channel blockers

0.189

Acute renal failure

–

0.437

Diabetes mellitus

0.298

Exitus

–

0.382

COPD

0.851

CPB = cardiopulmonary bypass, ACC = aortic cross-clamping time.

Peripheral artery disease

1.00

Cerebrovascular event

1.00

Coronary artery stenting

0.596

Left main coronary artery disease

0.574

COPD = chronic obstructive pulmonary disease.

Categorical variables are presented by frequency counts, and differences between the groups with regard to categorised data were compared with the chi-squared test. All calculations were performed using a standard statistical package (SPSS 15.0, SPSS Inc, Chicago, IL, USA). All p-values < 0.05 were interpreted as statistically significant.

Results The groups were homogenous for baseline characteristics in the pre-operative period (p > 0.05 for all comparisons) (Table 1). Details of the surgery performed and the early postoperative period is shown in Table 2. For the whole group of patients, mean number of distal anastomoses was 2.45 ± 0.81, cardiopulmonary bypass time was 101.77 ± 28.71 min, and aortic cross-clamping time was 54.93 ± 16.19 min. The mean extubation time and length of stay in the intensive care unit were 7.98 ± 5.52 hours and 2.15 ± 0.56 days, respectively. Off-pump CABG was performed in one patient in the group with no previous MI, in four patients in the anterior MI group and in two patients in the posterior/inferior MI group. Two patients in the anterior MI group and one patient in the posterior/inferior MI group underwent re-exploration due to excessive mediastinal bleeding in the early postoperative period. The left internal thoracic artery (ITA) was anastomosed to the LAD in 57 patients and a saphenous vein graft was used for the remaining patients. The right ITA was used as a graft in four patients in the group with no previous MI, and in two patients in the posterior/inferior MI group. The radial artery was used as a graft in two patients in the posterior/inferior group. Positive inotropic support was used in 21 patients, and intra-aortic balloon pump was required in four in the early postoperative period. There were two in-hospital deaths. The patient in the anterior MI group died due to acute renal failure. The patient in the posterior/inferior MI group died due to low cardiac output and multiple organ failure. There were no statistically significant differences between

the groups in terms of parameters of the intra-operative and early postoperative periods (p > 0.05 for mean number of distal anastomosis, cardiopulmonary bypass time, aortic crossclamping time, extubation time, length of stay in intensive care unit, use of positive inotropic support, insertion of intra-aortic balloon pump, incidence of acute renal failure and mortality). Levels of adrenomedullin, IL-6 and TNF-α in the plasma are shown in Fig. 1A. Levels of IL-1β and angiotensin-II in the plasma are shown in Fig. 1B. The plasma level of adrenomedullin in the anterior MI group (0.42 ± 0.15 ng/ml) was significantly higher than that in the group with no previous MI (0.30 ± 0.07 ng/ml) and the posterior/inferior MI group (0.33 ± 0.05 ng/ml) (p = 0.002 and p = 0.043, respectively) (Fig. 1A). There were no statistically significant difference between the plasma levels of IL-6 in the group with no previous MI, the anterior MI and posterior/inferior MI groups (3.14 ± 2.84, 3.62 ± 2.93 and 3.53 ± 2.91 pg/ml, p = 0.414) (Fig. 1A). There were no statistically significant difference between the plasma levels of TNF-α in the group with no previous MI, the anterior MI and the posterior/inferior MI groups (4.48 ± 2.93, 6.63 ± 4.41 and 4.38 ± 1.78 pg/ml, p = 0.322) (Fig. 1A). There were no statistically significant differences between the plasma levels of IL-1β in the group with no previous MI, the anterior MI and the posterior/inferior MI groups (4.15 ± 2.64, 4.62 ± 3.83 and 4.46 ± 2.86 pg/ml, p = 0.977) (Fig. 1B). The plasma level of angiotensin-II in the anterior MI group was significantly higher than that in the group with no previous MI (91.30 ± 26.40 vs 60.80 ± 27.94 pmol/l, p = 0.002) (Fig. 1B). Levels of adrenomedullin and IL-1β in the pericardial fluid are shown in Fig. 2A. Levels of IL-6, TNF-α and angiotensinII in the pericardial fluid are shown in Fig. 2B. The level of adrenomedullin in the pericardial fluid in the anterior MI group was significantly higher than that in the group with no previous MI (0.52 ± 0.14 vs 0.42 ± 0.08 ng/ml, p = 0.028) (Fig. 2A). The level of IL-1β in the pericardial fluid in the anterior MI group (10.54 ± 5.17 pg/ml) was significantly higher than that in both the group with no previous MI (5.96 ± 3.68 pg/ml) and the posterior/inferior MI group (6.08 ± 4.10 pg/ml) (p = 0.008 and p = 0.005, respectively) (Fig. 2A). The level of IL-6 in the pericardial fluid in the anterior MI group (193.51 ± 62.29 pg/ml) was significantly higher than that in both the group with no previous MI (105.25 ± 69.71 pg/ml) and the posterior/inferior MI group (139.91 ± 54.18 pg/ml) (p = 0.000

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B 12.00

100.00

8.00

Levels (pg/ml)

10.00

6.00 4.00 2.00 0.00

120.00

60.00 40.00 20.00

* No previous MI

80.00

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0.00

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Plasma adrenomedullin

No previous MI

Anterior MI

Posterior/inferior MI

Plasma IL-1-beta

Plasma IL-6

Plasma angiotensin

Plasma TNF-alpha

Fig. 1. A . The levels of adrenomedullin, IL-6 and TNF-alpha in plasma. *p < 0.05 for adrenomedullin in the anterior MI group vs in the other groups. B. The levels of IL-1-beta and angiotensin-II in plasma. *p < 0.05 for angiotensin in the anterior MI group vs in the group with no previous MI. IL-6 = interleukin-6, TNF-alpha = tumour necrosis factor-alpha, IL-1-beta = interleukin1-beta, Angiotensin = angiotensin-II.

and p = 0.033, respectively) (Fig. 2B). There were no statistically significant differences between the levels of TNF-α in the pericardial fluid in the group with no previous MI, the anterior MI and the posterior/inferior MI groups (13.08 ± 8.66, 19.01 ± 10.37 and 14.99 ± 6.85 pg/ml, p = 0.203) (Fig. 2B). The level of angiotensin-II in the pericardial fluid in the anterior MI group was significantly higher than that in the group with no previous MI (21.83 ± 14.48 vs 14.60 ± 5.25 pmol/l, p = 0.019) (Fig. 2B). The results of LVEDD, LVEDV and LVEDVI in the three groups are shown in Fig. 3A. The results of LVESD, LVESV and LVESVI in the groups are shown in Fig. 3B. The results of FS (%) and EF (%) in the groups are shown in Fig. 3C. The mean LVEDD in the anterior MI group was significantly higher than that in the group with no previous MI (53.39 ± 4.43 vs 49.05 ± 3.79 mm, p = 0.004) (Fig. 3A). There were no A

statistically significant differences between the mean LVEDV in the group with no previous MI, the anterior MI and the posterior/inferior MI groups (113.97 ± 31.13, 127.14 ± 39.19 and 118.20 ± 33.55 ml, respectively, p = 0.474) (Fig. 3A). There were no statistically significant differences between the mean LVEDVI in the group with no previous MI, the anterior MI and the posterior/inferior MI groups (63.22 ± 18.58, 73.03 ± 24.34 and 65.57 ± 18.54 ml/m2, p = 0.366) (Fig. 3A). The mean LVESD in the anterior MI group (39.23 ± 5.46 mm) was significantly higher than that in both the group with no previous MI (32.10 ± 5.25 mm) and the posterior/inferior MI group (33.75 ± 4.54 mm) (p = 0.000 and p = 0.003, respectively) (Fig. 3B). The mean LVESV in the anterior MI group (76.29 ± 25.95 ml) was significantly higher than that in both the group with no previous MI (55.24 ± 21.76 ml) and the posterior/ B 300.00

15.00

10.00 5.00 0.00

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Anterior MI

Pericardial adrenomedullin Pericardial IL-1-beta

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Levels (pg/ml)

20.00

200.00

100.00 * 0.00

No previous MI

Anterior MI

Posterior/inferior MI

Pericardial IL-6 Pericardial TNF-alpha Pericardial angiotensin

Fig. 2. A . The levels of adrenomedullin and IL-1-beta in pericardial fluid. *p < 0.05 for adrenomedullin in the anterior MI group vs in the group with no previous MI, †p < 0.05 for IL-1-beta in the anterior MI group vs in the other groups. B. The levels of IL-6, TNF-alpha and angiotensin-II in pericardial fluid. *p < 0.05 for IL-6 in the anterior MI group vs in the other groups, †p < 0.05 for angiotensin-II in the anterior MI group vs in the group with no previous MI. TNF-alpha = tumour necrosis factor-alpha, IL-1-beta = interleukin-1-beta, Angiotensin = angiotensin-II.

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inferior MI group (62.35 ± 19.86 ml) (p = 0.002 and p = 0.028, respectively) (Fig. 3B). The mean LVESVI in the anterior MI A 200.00 150.00 100.00 *

50.00 0.00

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LVEDD (mm) LVEDV (ml) LVEDVI (ml/m2)

B 120.00 *

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Anterior MI

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LVESD (mm) LVESV (ml) LVESVI (ml/m2)

C 60.00 * 40.00 * 20.00

0.00

No previous MI FS (%)

Anterior MI

Posterior/inferior MI LVEF (%)

Fig. 3. Results of echocardiographic analyses. A. *p < 0.05 for LVEDD in the anterior MI group vs in the group with no previous MI. B. *p < 0.05 for LVESD, LVESV and LVESVI in the anterior MI group vs in the other groups. C. *p < 0.05 for FS and LVEF in the anterior MI group vs in the other groups. LVEDD = left ventricular enddiastolic diameter, LVEDV = left ventricular end-diastolic volume, LVEDVI = left ventricular end-diastolic volume index, LVESD = left ventricular end-systolic diameter, LVESV = left ventricular end-systolic volume, LVESVI = left ventricular end-systolic volume index, FS = fractional shortening, LVEF = left ventricular ejection fraction.

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group (43.74 ± 16.11 ml/m2) was significantly higher than that in both the group with no previous MI (30.52 ± 12.02 ml/m2) and the posterior/inferior MI group (34.67 ± 11.76 ml/m2) (p = 0.002 and p = 0.026, respectively) (Fig. 3B). The mean LVEF in the anterior MI group (36.90 ± 12.21%) was significantly lower than that in both the group with no previous MI (51.62 ± 10.97%) and the posterior/inferior MI group (46.00 ± 7.54%) (p = 0.002 and p = 0.024, respectively) (Fig. 3C). The differences in FS values between the groups were similar to the differences in EF values (Fig. 3C).

Discussion The results of this study indicate that (1) the patients who had suffered an anterior MI had worse LV function than both those with no previous MI and those with posterior/inferior MI, and (2) the levels of pro-inflammatory cytokines in the plasma and pericardial fluid in patients with anterior MI were increased compared to patients with no previous MI. Adrenomedullin, a 52-amino acid peptide with structural homology to calcitonin gene-related peptide, was initially isolated from human phaeochromocytoma.11 Adrenomedullin is synthesised by many mammalian tissues, including the adrenal medulla, endothelial and vascular smooth muscle cells, myocardium and central nervous system.12 Clinical studies suggest that synthesis of adrenomedullin is up-regulated during myocardial ischaemia. Measurement of plasma levels of adrenomedullin in patients in the acute stages of MI showed elevated circulating levels of adrenomedullin within 24 to 48 hours of admission, which gradually decreased over a three-week period.13 On the other hand, Miyao et al.14 reported that in patients with acute MI, increased plasma levels of adrenomedullin in the very early phase of acute MI returned to normal limits approximately four weeks later. In our study, the timespan between MI and CABG was three weeks or longer. We found that plasma adrenomedullin levels in both the anterior MI and the posterior/inferior MI groups were higher than that in the group with no previous MI. In agreement with the results of Miyao et al.,14 our results suggest that the elevated adrenomedullin levels were most likely a consequence of the recent MI. It is generally considered that pericardial fluid is not merely an ultra-filtrate of plasma, but also a transudate from the cardiac interstitium.15 Adrenomedullin mRNA is expressed by several cardiovascular tissues, including the cardiomyocytes, vascular endothelial and smooth muscle cells.12 Therefore, it can be assumed that the level of adrenomedullin in pericardial fluid may increase concomitantly with plasma levels. Supporting this assumption, increased pericardial fluid concentrations of adrenomedullin have been reported in patients with cardiac remodelling.16 Additionally, adrenomedullin levels were reported to be slightly higher in the pericardial fluid than in the plasma in patients undergoing CABG.17 Consistent with this report, we also found that adrenomedullin levels in the pericardial fluid were slightly higher than those in the plasma in all three groups. In our study, the anterior MI group had the worst LV function, as shown by echocardiography. Miyao et al. suggested that adrenomedullin levels in patients with acute MI may indirectly reflect the extent of ventricular dysfunction.14 In addition,

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mechanical stretch, angiotensin-II and pro-inflammatory cytokines synthesised in the infarcted area may also stimulate adrenomedullin production.12 Activation of the renin–angiotensin–aldosterone system commonly accompanies MI.18 Angiotensin-II, a potent vasoconstrictor, is involved with vascular tone and endothelial function, cardiac contractility, impulse propagation, and it stimulates the formation and secretion of aldosterone from the adrenal gland.19 We found increased levels of angiotensin-II in both the plasma and pericardial fluid in the anterior MI group. Schunkert et al.20 reported that plasma angiotensin-II levels were increased six weeks after experimental MI in rats with congestive heart failure. Both our finding and the results reported by Schunkert et al.20 suggest activation of the renin–angiotensin system and a subsequent increase in circulating angiotensin-II. On the other hand, Huang et al.21 found that in rats three months after subjection to MI, the plasma renin level was increased but plasma angiotensin-II levels were not different from those in the control group. The authors concluded that decreased lung angiotensin converting enzyme activity could possibly have contributed to keeping plasma angiotensin-II levels in the normal range. Another explanation may be the clearance of angiotensin-II from the circulation in the three-month period after MI. Serneri et al.4 found that the clinical course of heart failure is associated with a progressive increase in cardiac angiotensinII formation, as expressed by the mean aorta–coronary sinus concentration gradient. In agreement with this study, we found the highest pericardial fluid angiotensin-II level was in the anterior MI group, the group which had the worst LV function. IL-6 is a classic multifunctional cytokine, with several activities that could explain its potential importance in acute coronary syndromes.22 In addition, IL-6 has been suggested as a marker of severity of coronary artery disease, since increased plasma concentrations and activated myocardial gene expression have been demonstrated after MI. IL-1 is a prototypic pro-inflammatory cytokine with a wide range of actions systemically and at the cardiovascular level.23 The IL-1 family encompasses IL-1α, IL-1β and IL-1Ra and is mainly produced by monocytes and macrophages, and to a lesser degree by endothelial cells.23 Birner et al.24 performed a human study in which plasma N-terminal proBNP (NT-proBNP) and IL-6 levels were measured in a large group of patients in the chronic phase after MI and found that both NT-proBNP and IL-6 levels were significantly elevated in subjects with MI compared to the control group. When they analysed NT-proBNP and IL-6 levels with regard to EF, they observed a significant increase in NT-proBNP levels in the presence of LV dysfunction. By contrast, IL-6 level did not increase further in MI subjects with LV dysfunction, compared to MI subjects with preserved LV function. These findings may suggest that plasma levels of IL-6 are not as sensitive as NT-proBNP as a biomarker of LV dysfunction in the presence of MI. We also found that the levels of IL-6 and IL-1β in plasma did not differ significantly between the groups. The lack of significant elevation of plasma levels of IL-6 in patients with MI in our study could have been due to insufficient numbers of patients. These findings could also be interpreted that levels of IL-6 and IL-1β in plasma were not influenced by the site of MI.

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On the other hand, the elapsed time from MI seems to be an important factor in the marker role of IL-6 and IL-1β on MI. In addition, IL-1α and IL-1β lack a signal peptide and they are not readily secreted into the systemic circulation and therefore determination of plasma level is unreliable.25 Plasma levels of IL-1Ra, a sensitive marker of biologically active IL-1β, and IL-6 were measured at the time of admission to the coronary care unit and 48 hours later in patients who were hospitalised due to unstable angina.25 The authors found that a fall in IL-1Ra and IL-6 48 hours after admission was associated with an uneventful course. In our study, complicated medical conditions such as development of new cardiac events, emergent operation, cardiogenic shock or complications of acute MI were all exclusion criteria. Therefore the lack of difference in plasma levels of IL-6 and IL-1β in our study could also be partly due to their relatively stable medical status and the absence of major new-onset cardiac events. We also found that pericardial fluid levels of IL-1β and IL-6 were markedly increased in the anterior MI group. This indicates that pericardial fluid levels of these two cytokines may be superior to plasma levels as a marker of LV dysfunction in the setting of MI. It has also been reported that pericardial concentrations of IL-1β may reflect the extent of ischaemic heart disease and that elevated IL-1β concentrations in pericardial fluid may also directly promote the process of coronary atherosclerosis.7 TNF-α is a multifunctional circulating cytokine derived from endothelial and smooth muscle cells as well as macrophages associated with coronary atheroma.26,27 TNF-α possesses cytotoxic and negative inotropic actions, aggravates the inflammatory process, and plays a role in neutrophil pre-activation and ischaemic injury.28,29 Brunetti et al.30 reported that levels of TNF-α in patients with acute coronary syndrome were associated with a worse prognosis at follow up. Prior data have demonstrated that those individuals with evidence of severely reduced ejection fraction and clinical heart failure had markedly elevated levels of TNF-α.31,32 Torre-Amione et al.33 also reported that concentrations of TNF-α were high in patients with heart failure, in association with noticeable activation of the renin– angiotensin system. There was, however, a wide variation in TNF-α levels between patients and in many it was not detected. Dutka et al.34 examined the concentrations of circulating TNF-α in patients with congestive heart failure and found that the mean concentration of TNF-α was greater than the upper 95% confidence interval for healthy controls, but there was considerable between- and within-patient variation. Therefore the authors concluded that the stimulus resulting in enhanced plasma concentrations of TNF-α in congestive heart failure remains unclear and concentrations at any particular time were not prognostic. In our study, although both plasma and pericardial fluid TNF-α levels in the anterior MI group were slightly higher than those in the other groups, the differences were not statistically significant. We believe that the lack of statistically significant elevation in the levels of TNF-α in the anterior MI group, the group which had the poorest LV function, may have been due to the absence of severe clinical heart failure. Another explanation could be that the wide variation in TNF-α levels between patients resulted in relatively high standard deviations and precluded finding significant differences with statistical analysis.

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In our study, although LV function in the anterior MI group was significantly worse than that in the posterior/inferior MI group, only adrenomedullin level in the plasma and levels of IL-6 and IL-1β in pericardial fluid in the anterior MI group were significantly higher than those in the posterior/inferior MI group. Reviewing these findings, one may consider that there was a weak correlation between enhanced cytokine levels and depressed LV function. We believe these findings suggest that cytokine levels in the pericardial fluid may be superior to plasma levels as a molecular marker of LV dysfunction in the setting of MI. In addition, the number of patients included in our study may have been insufficient to observe a statistically significant difference in the levels of cytokines between the MI groups.

Limitations Our study was subject to certain limitations. First, we did not measure the extent of infarcted myocardial tissue by means of myocardial perfusion imaging techniques. Since the magnitude of MI may affect cytokine levels, one may consider that changes in cytokine levels may be partly attributed to the area of non-contractile myocardial tissue. However, we believe that a detailed assessment of LV function by echocardiography is sufficient to clarify the effect of MI on contractile myocardial tissue of the left ventricle. In addition, the aim of this study was to examine the relationship between MI site, cytokine levels and LV function. Therefore the relationship between the magnitude of MI and cytokine levels was beyond the scope of this study. Second, in our study, the elapsed time between MI and CABG was three weeks or longer. This interval may be sufficient for an increase in certain cytokines, such as adrenomedullin and angiotensin-II, but too long for other cytokines, such as IL-6 or IL-1β, to remain high in the systemic circulation. The time points at which cytokines peak and the intervals in which cytokines remain high in the plasma differ. As Tashiro et al.35 stated, concentrations of monocyte-related cytokines dynamically change during the course of acute MI, suggesting that they may contribute to the inflammatory and subsequent proliferative responses in acute MI. Therefore levels in the pericardial fluid appear to be more reliable and superior to levels in the plasma as a molecular marker in the early stages of MI and LV dysfunction. Third, the absence of a control group in our study is another limitation but pericardial fluid samples are obtained by pericardiocentesis or during cardiac surgery. Therefore obtaining pericardial fluid samples from healthy individuals was not possible, for ethical reasons.

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LV dysfunction in the setting of MI. However, further clinical studies with larger patient numbers are required to clarify the prognostic or biomarker role of cytokines in pericardial fluid related to LV dysfunction or remodelling after acute MI. The abstract of this study was presented in 57th International Congress of the European Society for Cardiovascular Surgery, Barcelona, Spain, 24–27 April 2008. The study was financially supported by the Department of Scientific Research Projects, Suleyman Demirel University (project no: 1389-M-06). None of the authors has financial or other relationships that would influence assessment of the data or that would constitute a conflict of interest.

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Conclusions We found that (1) patients with anterior MI had worse LV function than both patients with no previous MI and those with posterior/inferior MI, and (2) the levels of pro-inflammatory cytokines in plasma and pericardial fluid in patients with anterior MI were increased compared to patients with no previous MI. The finding of elevated pro-inflammatory cytokine levels in patients with anterior MI could be interpreted as reflecting both the magnitude of MI and/or LV dysfunction and the site of MI. Our results also suggest that cytokine levels in pericardial fluid were superior to plasma levels as a molecular marker of

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cardium, epicardium, and myocardium to large molecules: stretchdependent effects. Circ Res 1992; 71: 159–173. 16. Tambara K, Fujita M, Nagaya N, et al. Increased pericardial fluid concentrations of the mature form of adrenomedullin in patients with cardiac remodeling. Heart 2002; 87: 242–246. 17. Nishikimi T, Shibasaki I, Iıda H, et al. Molecular forms of adrenomedullin in pericardial fluid and plasma in patients with ischaemic heart disease. Clin Sci 2002; 102: 669–677. 18. Anavekar NS, Solomon SD. Angiotensin II receptor blockade and ventricular remodelling. J Renin Angiotensin Aldosterone Syst 2005; 6(1): 43–48. 19. Timmermans P, Benfield P, Chiu AT. Angiotensin II receptors and functional correlates. Am J Hypertens 1992; 5: 221–235.

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Events CSI AFRICA 2016 CSI AFRICA 2016: catheter interventions in congenital, structural and valvar heart disease from 25–26 November 2016 in Kampala, Uganda. Topics: Paravalvar leak closure, left atrial appendage closure, pulmonary valve replacement, echo evaluation of ASDs and VSDs, coarctation stenting, ASD closure, VSD closure, trans-septal puncture, PDA closure, pulmonary valvoplasty, mitral valvoplasty, how to develop structural, congenital and valvar interventions in Africa, challenging cases, problems and complications. Who should attend: Adult and paediatric interventional cardiologists, cardiothoracic surgeons, anaesthesiologists, imaging specialists and colleagues of other disciplines who wish to know more about the field. All PASCAR members will receive a 20 % discount on registration fees. Please register online: www.csi-congress.org/africa

SOSECAR – PAFCIC 2016 joint congress 4th congress of Senegalese Society of Cardiology (SOSECAR) and the 17th Pan-African (PASCAR) course on interventional cardiology, from 8-10 December 2016 at the Palais Des Congres of King Fahd Palace Hotel, Dakar.

Main theme: Interventional cardiology in Africa: challenges and prospects Sub-themes: cardio-respiratory arrest: the heart and diabetes Please submit abstract documents to: sosecarpafcic2016@gmail.com before the submission deadline: 25 October 2016.

23rd Annual Conference of The Egyptian Society of Cardiothoracic Surgery 23rd annual conference of The Egyptian Society of Cardiothoracic Surgery in collaboration with National Heart Institute of Egypt, from 4–7 April 2017 at Mena House Hotel, Cairo, Egypt. Workshops: RV-PA conduit implantation, electrophysiology anatomy for ablation surgery, aortic repair, simulation for wire-based techniques, basic anatomy of the heart for junior staff, TEE for surgeons and anaesthetics, endoscopic vein harvesting, coronary anastomoses (hands on). Main topics: minimal invasive surgery, aortic root surgery, TEVAR, surgery for heart failure, cardiovascular perfusion, RV-PA connections, AV valve repair in infants, staging modalities in lung cancer, woman in cardiac surgery, personal skill development for surgeons. Kindly submit abstracts before the deadline 31 December 2016. Please check the link for abstract form: www.escts2017.com

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Strain and strain rate echocardiography in children with Wilson’s disease Cemşit Karakurt, Serkan Çelik, Ayşe Selimoğlu, İlknur Varol, Hamza Karabiber, Saim Yoloğlu

Abstract Objective: This study aimed to evaluate strain and strain rate echocardiography in children with Wilson’s disease to detect early cardiac dysfunction. Methods: In this study, 21 patients with Wilson’s disease and a control group of 20 age- and gender-matched healthy children were included. All the patients and the control group were evaluated with two-dimensional (2D) and colour-coded conventional transthoracic echocardiography by the same paediatric cardiologist using the same echocardiography machine (Vivid E9, GE Healthcare, Norway) in standard precordial positions, according to the American Society of Echocardiography recommendations. 2D strain and strain rate echocardiography were performed after the ECG probes of the echocardiography machine were adjusted for ECG monitoring. Longitudinal, transverse and radial strain, and strain rate were assessed from six basal and six mid-ventricular segments of the left ventricle, as recommended by the American Society of Echocardiography. Results: Left ventricular wall thickness, systolic and diastolic diameters, left ventricular diameters normalised to body surface area, end-systolic and end-diastolic volumes, cardiac output and cardiac index values were within normal limits and statistically similar in the patient and control groups (p > 0.05). Global strain and strain rate: the patient group had a statistically significant lower peak A longitudinal velocity of the left basal point and peak E longitudinal velocity of the left basal (VAbasR) point, and higher global peak A longitudinal/ circumferential strain rate (GSRa) compared to the corresponding values of the control group (p < 0.05). Radial strain and strain rate: end-systolic rotation [ROT (ES)] was statistically significantly lower in the patient group (p < 0.05). Longitudinal strain and strain rate: end-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05).

Segmental analysis showed that rotational strain measurement of the anterior and lateral segments of the patient group were statistically significantly lower than the corresponding values of the control group (p < 0.05). Segmental analysis showed statistically significantly lower values of end-systolic longitudinal strain [STSR (ES)] of the basal lateral (p < 0.05) and end-systolic longitudinal strain [SLSC (ES)] of the basal septal segment (p < 0.05) in the patient group. End-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05). Segmental analysis showed statistically significantly lower values of endsystolic longitudinal strain [SLSC (ES)] of the mid-anterior and basal anterior segments (p < 0.05), end-systolic longitudinal strain [STSR (ES)] measurements of the posterior and mid-posterior segments, end-systolic longitudinal displacement [DLDC (ES)] of the basal posterior, mid-posterior and mid-antero-septal segments in the patient group. Conclusion: Cardiac arrhythmias, cardiomyopathy and sudden cardiac death are rare complications but may be seen in children with Wilson’s disease due to copper accumulation in the heart tissue. Strain and strain rate echocardiography is a relatively new and useful echocardiographic technique to evaluate cardiac function and cardiac deformation abnormalities. Our study showed that despite normal systolic function, patients with Wilson’s disease showed diastolic dysfunction and regional deformation abnormalities, especially rotational strain and strain rate abnormalities.

Keywords: 2D strain, strain rate echocardiography, speckle tracking, Wilson’s disease Submitted 14/7/14, accepted 8/3/16 Published online 13/5/16 Cardiovasc J Afr 2016; 27: 307–314

www.cvja.co.za

DOI: 10.5830/CVJA-2016-028

Department of Pediatric Cardiology, Faculty of Medicine, Inonu University, Malatya, Turkey Cemşit Karakurt, MD, ckarakurt@yahoo.com Serkan Çelik, MD

Department of Pediatric Gastroenterology, Faculty of Medicine, Inonu University, Malatya, Turkey Ayşe Selimoğlu, MD İlknur Varol, MD Hamza Karabiber, MD

Department of Biostatistics, Faculty of Medicine, Inonu University, Malatya, Turkey Saim Yoloğlu, MD

Wilson’s disease is an autosomal recessive metabolic liver disease related to mutation of the copper-transporting ATPase, ATP7B, an intracellular copper transporter mainly expressed in the hepatocytes.1,2 Wilson’s disease is characterised by excessive copper deposition in the body, primarily in the liver and brain, resulting from inability of the liver to excrete copper in the bile. Cardiac arrhythmias, cardiomyopathy and sudden cardiac death are rare complications but may be seen in children with Wilson’s disease due to copper accumulation in the heart tissue.3-6 The aims of our study were to determine potential differences in strain and strain rate between patients with Wilson’s disease and age-matched controls, and to detect early cardiac dysfunction.

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Methods In this study, 21 patients with Wilson’s disease who applied to our hospital’s Paediatric Gastroenterology Department between May and October 2013 were included (α = 0.05, 1–β = 0.8, changing ratio = 0.0015). The control group consisted of 20 ageand gender-matched healthy children. Patients with any chronic disease, obesity and hypertension in addition to Wilson’s disease or history of drug use that may have affected cardiac function were excluded from the study. Diagnosis of Wilson’s disease was made by the Paediatric Gastroenterology Department, based on the presence of signs of liver or neurological disease and the detection of Kayser– Fleischer rings, low ceruloplasmin, and elevated levels of urinary and hepatic copper. Liver biopsies were done for all patients and associated histological changes in the liver were confirmed. Before the study, approval of the ethics committee of the Medical School of Inonu University in accordance with Declaration of Helsinki was received. Age, body weight, height and body surface area were recorded in the patient and control groups. The age at diagnosis of Wilson’s disease was also recorded in the patient group. All subjects were evaluated with ECG before echocardiographic evaluation. All patients and controls were evaluated with two-dimensional (2D) and color-coded conventional transthoracic echocardiography by the same paediatric cardiologist, using the same echocardiography machine (Vivid E9, GE Healthcare, Norway) in the standard precordial positions, according to the American Society of Echocardiography recommendations.7 Left ventricular dimensions, left ventricular wall thickness, end-diastolic and end-systolic volumes, stroke volume, cardiac index, ejection fraction and fractional shortening were measured using M-mode echocardiography in the parasternal long-axis view. 2D strain and strain rate echocardiography were performed

Fig. 1. E chocardiograph shows segmental analysis of left ventricle after 2D speckle tracking from the apical fourchamber view.

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by a paediatric cardiologist after the ECG probes of the echocardiography machine (Vivid E9, GE) were adjusted for ECG monitoring. Grey images were obtained from the apical four-, three- and two-chamber, and short-axis view at the papillary muscle position using tissue harmonic imaging with frame rates of 70 per second. All the images that were obtained in the left lateral decubitus position and under ECG monitoring were stored for offline analysis. 2D strain and strain rate measurements were performed using the ECHOPAC software package. As previously described, the endocardial border was traced manually on a single end-diastolic frame and the software automatically tracked the contour on subsequent frames. Tracking accuracy was verified in real time and corrected by adjusting the region of interest or by manually correcting the contour to ensure optimal tracking. If required, region-of-interest width or smoothing functions were changed for optimal tracking. Once the contours were approved by the paediatric cardiologist, the software calculated longitudinal, transverse, radial and global strains for the respective segments. For long-axis strain and strain rate evaluation, the atrioventricular valve closure time was selected manually. As described, longitudinal and transverse radial strain, and strain rate were assessed from six basal and six mid-ventricular segments of the left ventricle, as recommended by the American Society of Echocardiography (Figs 1–4). This included apical, mid- and basal segments from the four-, two- and three-chamber view of the left ventricle, and anterior, septal and inferior segments from the short-axis view of the left ventricle.

Statistical analysis SPSS 16.0 was used for statistical analysis. The normality was tested using the Kolmogorov–Smirnov test. The unpaired t-test was used to test for differences between categorical data of

Fig. 2. Echocardiograph shows segmental analysis of left ventricle after 2D speckle tracking from the apical two-chamber view.

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Fig. 3. E chocardiograph shows segmental analysis of the left ventricle after 2D speckle tracking from the apical long-axis view.

Fig. 4. Echocardiograph shows segmental analysis of the left ventricle after 2D speckle tracking from the parasternal short-axis view.

the patient and control groups. The ANOVA test was used to evaluate 2D strain and strain rate values of the two groups for each segment. The LD test was applied in the second test to determine the groups that differed significantly. All the results are expressed as mean ± standard deviation; p-values < 0.05 were considered statistically significant.

longitudinal velocity of the left basal point, peak E longitudinal velocity of the right basal point, and peak A longitudinal velocity of the left basal point (cm/s). While the control group had statistically significantly lower global peak A longitudinal/circumferential strain rates, the patient group had statistically significantly lower peak

Results The study included 21 patients with Wilson’s disease and 20 healthy age-matched children. The patient group consisted of 11 males and 10 females, and the control group, nine males and 11 females. Demographic data of the patient and control groups are shown in Table 1. There were no statistically significant differences between the patient and control groups (p > 0.05). The mean age at diagnosis was 9 ± 2.24 years (5–13) in the patient group. All the subjects had normal sinus rhythm. Wolf– Parkinson–White syndrome was detected in one patient’s ECG. No structural heart disease was detected with conventional 2D colour-coded transthoracic echocardiography. Left ventricular wall thickness (IVSd, IVSs, LPWd, LWPDs), systolic and diastolic diameters (LVIDd, LVIDs), left ventricular diameters normalised to body surface area (LVEDd/m², LVEDs/m²), end-systolic and end-diastolic volumes (ESV, EDV), cardiac output and cardiac index values were within normal limits and statistically similar in the patient and control groups (p > 0.05). Demographic data, left ventricular wall thickness, dimensions, volumes and systolic function of the patient and control groups are shown Table 1.

Global strain and strain rate No statistically significant differences were found between the two groups for global longitudinal/circumferential strain rate, global peak systolic longitudinal/circumferential strain rate, global peak E longitudinal/circumferential strain rate, peak E

Table 1. Demographic data of left ventricular wall thickness, dimension, volume and systolic function of Wilson’s disease patients and controls Parameters

Patients (n = 21) mean ± SD

Controls (n = 20) mean ± SD

p-value

Age (years)

11.04 ± 3 .58 (5–17)

10.53 ± 2.8 (6–16)

0.61

11/10

9/11

0.64

Weight (kg)

38.1 ± 16.04 (14.5–68)

39.04 ± 13.2 (21.4–67)

0.84

Height (cm)

141.5 ± 20.2 (100–187)

141.1 ± 14.2 (120–168)

0.93

Body surface area (m3)

1.21 ± 0.33 (0.63–1.91)

1.22 ± 0.25 (0.9–1.72)

0.92

9 ± 2.24 (5–13)

–

IVSd (mm)

7.14 ± 1.10

6.45 ± 1.39

0.85

IVSs (mm)

10.76 ± 1.78

9.7 ± 1.65

0.56

LPWDd (mm)

5.42 ± 1.16

5.2 ± 1.36

0.56

LPWDs (mm)

9.52 ± 2.11

8.8 ± 1.28

0.1

LVIDd (mm)

41.6 ± 6.81

42.1 ± 4.52

0.79

LVEDd/m² (mm/m²)

35.5 ± 8.45

35.2 ± 5.16

0.92

LVEDs (mm)

24.8 ± 4.65

26.5 ± 6.09

0.32

LVEDs/m² (mm/m²)

21.05 ± 5.08

22.19 ± 4.68

0.46

EDV (ml)

83.38 ± 28.76

79.8 ± 20.41

0.65

ESV (ml )

24.28 ± 11.89

29.5 ± 20.79

0.32

SV (ml)

60.85 ± 20.53

55.80 ± 13.65

0.36

CI (ml/min)

4.60 ± 1.32

3.98 ± 0.78

0.077

EF (%)

71.76 ± 6.51

69.90 ± 5.33

0.32

FS (%)

40.9 ± 5.62

39.1 ± 4.54

0.26

Gender (male/female)

Age of diagnosis

–

EDV: end-diastolic volume, ESV: end-systolic volume, SV: stroke volume, CI: cardiac index, EF: ejection fraction, FS: fractional shortening, CI: cardiac index.

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A longitudinal velocity of the left basal point and peak E longitudinal velocity of the left basal point (p < 0.05). Global strain and strain rate values of the patients and controls are shown in Table 2.

Radial strain and strain rate No statistically significant differences were found between the two groups for the most negative peak circumferential strain (SLSC peak G), negative systolic peak circumferential strain (SLSC peak S), positive systolic peak circumferential strain (SLSC peak P), end-systolic circumferential strain [SLSC (ES)] and end-systolic radial displacement [DTDR (ES)] (p > 0.05). End-systolic rotation [ROT (ES)] was statistically significantly lower in the patient group (p < 0.05). Segmental analysis showed that rotational strain measurement of the anterior segment was statistically significantly lower (–0.78 ± 3.16) in the patient group (p = 0.019). The lateral segment was also statistically significantly lower in the patient group (–1.17 ± 3.17) (p = 0.14). Radial strain and strain rate measurements of patients and controls are shown in Table 3. Radial strain and strain rate values according to the segments are shown in Table 4.

Longitudinal and transverse strain and strain rate Four chambers: longitudinal and transverse strain and strain rate measurements are shown in Table 5. No statistically significant differences were found between the two groups for the most negative peak longitudinal strain (SLSC peak G), negative Table 2. Global strain and strain rate values of Wilson’s disease patients and controls

Parameters

Patients (n = 21) (mean ± SD)

Controls (n = 20) (mean ± SD)

p-value

–17.11 ± 3.69

0.70

GSRs (1/s)

–1.07 ± 0.20

–1.02 ± 0.23

0.17

GSRe (1/s)

1.54 ± 0.40

1.59 ± 0.46

0.35

GSRa (1/s)

0.74 ± 0.44

0.53 ± 0.23

0.02

–11.25 ± 2.95

–11.20 ± 2.53

0.91

VEbasL (cm/s)

systolic peak longitudinal strain (SLSC peak S), positive systolic peak longitudinal strain (SLSC peak P), the most negative peak transverse strain (STSR peak G), end-systolic longitudinal strain [STSR (ES)] and end-systolic longitudinal displacement [DLDC (ES)]. End-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05). Segmental analysis showed statistically significantly lower levels of end-systolic longitudinal strain [STSR (ES)] of the basal lateral (p < 0.05), and statistically significantly lower levels of end-systolic longitudinal strain [SLSC (ES)] of the basal septal segment (p < 0.05) in the Table 4. Radial strain and strain rate values according to segment Strain according to segment

Patients (n = 21) (mean ± SD)

Controls (n = 20) (mean ± SD)

p-value

SLSC peak S (%) Anterior

–9.55 ± 7.79

–9.71 ± 8.90

0.94

Lateral

–3.68 ± 5.75

–4.34 ± 5.76

0.69

Posterior

–6.60 ± 8.31

–3.48 ± 8.57

0.21

Inferior

–19.95 ± 6.84

–20.01 ± 5.32

0.97

Septal

–27.83 ± 6.57

–27.03 ± 4.63

0.64

Anterior septal

–23.85 ± 7.69

–23.28 ± 6.11

0.78

2.33 ± 2.89

2.18 ± 2.34

0.84

Lateral

4.31 ± 4.33

5.56 ± 6.30

0.41

Posterior

4.44 ± 6.25

7.37 ± 9.59

0.20

Inferior

1.71 ± 4.20

0.69 ± 0.90

0.29

Septal

1.31 ± 6.10

0.25 ± 0.56

0.44

Anterior septal

1.48 ± 5.37

0.43 ± 0.984

0.39

SLSC peak P (%)

SLSC (ES) (%)

–17.30 ± 3.22

GS (%)

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VESbasR (cm/s)

–9.22 ± 3.03

–9.91 ± 3.00

0.16

VAbasL (cm/s)

–6.69 ± 2.991

–5.09 ± 1.930

0.001

VAbasR (cm/s)

–5.95 ± 2.807

–4.65 ± 2.129

0.002

GS: global peak longitudinal/circumferential strain, GSGRs: global peak systolic longitudinal/circumferential strain rate, GSRe/1s: global peak E longitudinal/ circumferential strain rate, GSRa1/s: global peak A longitudinal/circumferential strain rate, VEbasL: left basal peak E longitudinal velocity, VEbasR: right basal peak E longitudinal velocity point, VAbasL: left basal peak A longitudinal velocity, VAbasR: right basal peak A longitudinal velocity.

Table 3. Radial strain and strain rate measurements of Wilson’s disease patients and controls

–9.21 ± 7.78

–9.50 ± 8.93

0.90

Lateral

–1.93 ± 7.40

–2.07 ± 8.98

0.95

Posterior

–4.49 ± 10.16

–0.89 ± 12.05

0.26

Inferior

–19.28 ± 7.42

–19.77 ± 5.35

0.80

Septal

–27.05 ± 7.05

–26.87 ± 4.62

0.91

Anterior septal

–23.46 ± 7.80

–23.14 ± 6.03

0.88

STSR (ES) Anterior

42.87 ± 19.56

44.36 ± 16.27

0.78

Lateral

39.94 ± 17.33

41.01 ± 16.22

0.83

Posterior

36.04 ± 15.37

39.35 ± 19.90

0.52

Inferior

38.72 ± 17.77

48.70 ± 19.12

0.06

Septal

43.58 ± 19.31

48.87 ± 16.59

0.32

Anterior septal

45.29 ± 20.14

47.21 ± 16.18

0.72

6.70 ± 1.93

6.14 ± 2.10

0.34

Lateral

7.75 ± 1.74

6.98 ± 2.25

0.18

Posterior

6.16 ± 1.55

5.79 ± 2.04

0.48

Inferior

3.34 ± 2.02

3.88 ± 2.23

0.39

Septal

2.70 ± 1.64

3.146 ± 2.16

0.41

Anterior septal

4.22 ± 1.58

4.10 ± 1.78

0.81

DTDR (ES) (mm)

Strain

Patients (n = 21) (mean ± SD)

Controls (n = 20) (mean ± SD)

p-value

SLSC peak G (%)

–16.45 ± 10.74

–16.09 ± 9.85

0.77

ROT (ES ) (°)

SLSC peak S (%)

–15.22 ± 11.57

–14.64 ± 11.38

0.67

–0.78 ± 3.16

1.33 ± 2.72

0.01

0.82

Lateral

–3.60 ± 3.30

–1.17 ± 3.17

0.01

SLSC peak P (%)

2.60 ± 5.09

2.75 ± 5.46

SLSC (ES) (%)

–14.20 ± 12.41

–13.71 ± 12.89

0.74

Posterior

–7.04 ± 3.89

–5.48 ± 4.79

0.22

STSR (ES) (%)

41.04 ± 18.29

44.92 ± 17.47

0.72

Inferior

–8.76 ± 4.34

–7.75 ± 5.36

0.47

DTDR (ES) (mm)

5.145 ± 2.54

5.01 ± 2.48

0.65

Septal

–5.07 ± 3.49

–4.13 ± 4.01

0.38

ROT (ES) (°)

–4.49 ± 4.53

–2.84 ± 5.06

0.004

Anterior septal

–1.45 ± 3.06

SLSC peak G: the most negative peak circumferential strain, SLSC peak S: negative systolic peak circumferential strain, SLSC peak P: positive systolic peak circumferential strain, SLSC (ES): end-systolic circumferential strain, DTDR (ES): end-systolic radial displacement, ROT (ES): end-systolic rotation.

0.13 ± 3.181

0.09

SLSC peak S: negative systolic peak circumferential strain, STSR (ES): end-systolic longitudinal strain, SLSC peak P: positive systolic peak circumferential strain, SLSC (ES): end-systolic circumferential strain, DTDR (ES): end-systolic radial displacement, ROT (ES): end-systolic rotation (°).

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patient group. Longitudinal and transverse strain and strain rate measurements from four and two chambers and the apical longaxis views are shown in Table 6. Table 5. Longitudinal and transverse strain and strain rate values according to segment from the four-chamber view Strain according to Patients (n = 21) Controls (n = 20) segment (mean ± SD) (mean ± SD) p-value SLSC peak G (%) Basal septal 0.57 –21.07 ± 2.32 –21.46 ± 2.62 Mid-septal 0.80 –20.52 ± 2.20 –20.67 ± 2.17 Apical septal 0.54 –17.56 ± 3.72 –18.20 ± 3.70 Apical lateral 0.26 –15.56 ± 4.59 –16.91 ± 3.75 Mid-lateral 0.23 –14.42 ± 4.35 –15.89 ± 4.24 Basal lateral 0.98 –14.10 ± 5.66 –14.07 ± 5.44 SLSC peak S (%) Basal septal 0.47 –20.74 ± 2.50 –21.26 ± 2.67 Mid-septal 0.79 –20.40 ± 2.27 –20.56 ± 2.22 Apical septal 0.62 –17.04 ± 3.72 –17.57 ± 3.93 Apical lateral 0.26 –15.30 ± 4.60 –16.67 ± 3.93 Mid-lateral 0.20 –13.96 ± 4.70 –15.58 ± 4.26 Basal lateral 0.86 –12.79 ± 6.79 –12.42 ± 7.98 SLSC peak P (%) Basal septal 0.83 0.29 ± 0.47 0.26 ± 0.41 Mid-septal 0.48 0.07 ± 0.29 0.03 ± 0.09 Apical septal 0.53 0.25 ± 1.29 0.08 ± 0.31 Apical lateral 0.35 0.23 ± 1.20 0.001 ± 0.03 Mid-lateral 0.38 0.38 ± 0.72 0.22 ± 0.55 Basal lateral 0.78 2.76 ± 5.00 3.11 ± 4.03 STSR peak P (%) Basal septal 0.30 32.31 ± 18.40 37.90 ± 20.18 Mid-septal 0.22 26.00 ± 15.45 31.24 ± 14.79 Apical septal 0.19 21.90 ± 14.32 26.700 ± 11.13 Apical lateral 0.14 19.82 ± 14.28 25.82 ± 14.04 Mid-lateral 0.13 20.38 ± 14.76 27.33 ± 17.61 Basal lateral 0.012 22.64 ± 17.76 31.21 ± 21.17 STSR peak G (%) Basal septal 0.42 –20.53 ± 2.50 –21.12 ± 2.68 Mid-septal 0.76 –20.32 ± 2.26 –20.51 ± 2.17 Apical septal 0.61 –16.95 ± 3.81 –17.49 ± 3.86 Apical lateral 0.26 –15.14 ± 4.72 –16.53 ± 3.90 Mid-lateral 0.18 –13.66 ± 5.11 –15.44 ± 4.29 Basal lateral 0.17 –11.58 ± 9.45 –12.64 ± 6.89 SLSC (ES) (%) Basal septal 0.25 28.43 ± 20.12 35.12 ± 21.41 Mid-septal 0.16 23.91 ± 16.32 30.12 ± 15.08 Apical septal 0.15 20.64 ± 14.76 26.02 ± 11.08 Apical lateral 0.15 18.58 ± 14.74 24.56 ± 14.35 Mid-lateral 0.17 17.53 ± 16.27 24.30 ± 18.47 Basal lateral 0.69 16.90 ± 21.08 24.79 ± 22.54 STSR (ES) (%) Basal septal 0.95 12.14 ± 2.18 12.18 ± 2.69 Mid-septal 0.87 6.64 ± 1.52 6.73 ± 2.23 Apical septal 0.45 1.60 ± 0.74 1.81 ± 1.25 Apical lateral 0.77 2.88 ± 1.32 2.78 ± 0.96 Mid-lateral 0.69 7.23 ± 2.47 7.46 ± 1.34 Basal lateral 0.66 11.06 ± 3.50 11.33 ± 2.27 DLDC (ES) (mm) Basal septal 0.014 1.85 ± 1.74 3.16 ± 1.89 Mid-septal 0.06 1.97 ± 1.34 2.81 ± 1.85 Apical septal 0.14 1.55 ± 1.06 2.01 ± 1.15 Apical lateral 0.46 1.89 ± 0.91 2.05 ± 0.59 Mid-lateral 0.66 3.66 ± 1.26 3.52 ± 1.073 Basal lateral 0.35 5.97 ± 1.77 5.51 ± 1.64 SLSC peak G: the most negative peak longitudinal strain, SLSC peak S: negative systolic peak longitudinal strain, SLSC peak P: positive systolic peak longitudinal strain, SLSC (ES): end-systolic longitudinal strain, STSR peak P: positive peak transverse strain, STSR peak G: the most negative peak transverse strain, STSR (ES): end-systolic longitudinal strain, DLDC (ES): end-systolic longitudinal displacement.

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Two chambers: there were no statistically significant differences found between the two groups for the most negative peak longitudinal strain (SLSC peak G), negative systolic peak longitudinal strain (SLSC peak S), positive systolic peak longitudinal strain (SLSC peak P), the most negative peak transverse strain (STSR peak G), end-systolic longitudinal strain [STSR (ES)] and end-systolic longitudinal displacement [DLDC (ES)]. End-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05). Segmental analysis showed statistically significantly lower values of end-systolic longitudinal strain [SLSC (ES)] of the mid-anterior and basal anterior segments (p < 0.05) in the patient group. The most negative peak longitudinal strain (SLSC peak S) value was –18.00 ± 3.33 in the mid-anterior segment of the patient group and –14.9723 ± 6.23886 in the mid-anterior segment of the control group (p < 0.05) (Tables 7, 8). Apical long-axis (APLAX): there were no statistically significant differences found between the two groups for the most negative peak longitudinal strain (SLSC peak G), negative systolic peak longitudinal strain (SLSC peak S), positive systolic peak longitudinal strain (SLSC peak P), the most negative peak transverse strain (STSR peak G), end-systolic longitudinal strain [STSR (ES)], end-systolic longitudinal displacement [DLDC Table 6. Longitudinal and transverse strain and strain rate measurements from the four- and two-chamber, and apical long-axis views Patients (n = 21) (mean ± SD)

Controls (n = 20) (mean ± SD)

SLSC peak G (%)

–17.21 ± 4.82

–17.87 ± 4.55

0.22

SLSC peak S (%)

–16.70 ± 5.27

–17.34 ± 5.39

0.29

SLSC peak P (%)

0.66 ± 2.36

0.62 ± 1.99

0.84

STSR peak P (%)

23.84 ± 16.25

30.03 ± 17.05

Strain according to segment

p-value

Four-chamber view

STSR peak G (%)

–16.36 ± 6.11

–17.29 ± 5.08

0.001 0.15

SLSC (ES) (%)

21.00 ± 17.61

27.49 ± 17.75

STSR (ES) (%)

6.93 ± 4.41

7.05 ± 4.32

0.80

2.819 ± 2.08

3.180 ± 1.84

0.11

SLSC peak G (%)

–18.73 ± 5.44

–17.56 ± 7.24

0.13

SLSC peak S (%)

–18.46 ± 5.48

–17.34 ± 7.54

0.16 0.07

DLDC (ES) (mm)

0.002

Two-chamber view

SLSC peak P (%)

0.38 ± 0.87

0.72 ± 2.03

STSR peak P (%)

25.55 ± 18.21

31.68 ± 17.63

STSR peak G (%)

–18.32 ± 5.42

–17.23 ± 7.51

0.005 0.16

SLSC (ES) (%)

20.46 ± 19.14

29.17 ± 18.67

STSR (ES) (%)

7.25 ± 5.11

6.72 ± 5.25

0.40

DLDC (ES) (mm)

3.44 ± 2.25

3.35 ± 2.23

0.73

0.001

Apical long-axis view (APLAX) SLSC peak G (%)

–17.73 ± 5.92

–17.18 ± 5.36

0.36

SLSC peak S (%)

–17.38 ± 5.84

–16.97 ± 5.43

0.49

SLSC peak P (%)

0.62 ± 3.76

0.54 ± 1.18

0.80

STSR peak P (%)

24.15 ± 1.92

26.40 ± 20.12

0.32

STSR peak G (%)

–17.21 ± 6.08

–16.84 ± 5.45

0.55

SLSC (ES) (%)

20.02 ± 22.72

23.04 ± 21.12

0.20

STSR (ES) (%)

7.35 ± 5.11

6.85 ± 4.52

0.33

DLDC (ES) (mm)

2.71 ± 2.10

2.68 ± 1.69

0.89

SLSC peak G: the most negative peak longitudinal strain, SLSC peak S: negative systolic peak longitudinal strain, SLSC peak P: positive systolic peak longitudinal strain, SLSC (ES): end-systolic longitudinal strain, STSR peak P: positive peak transverse strain, STSR peak G: the most negative peak transvers strain, STSR (ES): end-systolic longitudinal strain, DLDC (ES): end-systolic longitudinal displacement (mm).

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(ES)] end-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P). Segmental analysis showed that end-systolic longitudinal strain [STSR (ES)] measurements of the basal posterior and mid-posterior segments were statistically significantly lower in the patient group (p < 0.05). End-systolic longitudinal displacement [DLDC (ES)] of the basal posterior, mid-posterior and mid-anterior septal segments were statistically significantly lower in the patient group (p < 0.05).

Discussion Wilson’s disease is an autosomal recessive inherited disease, characterised by excessive copper storage in the body, especially the liver and brain, and also in the heart tissue due to reduced biliary copper excretion secondary to loss of the mutation for copper-transporting ATPase (ATP7B). Wilson’s disease, characterised by excessive copper deposition in the body, primarily in the liver and brain, results from an inability of the liver to excrete copper in the bile.1,2 Cardiac involvement of Wilson’s disease has not been sufficiently investigated. Electrocardiographic abnormalities, cardiac arrhythmias, cardiomyopathy, autonomic dysfunction and sudden cardiac death are rare complications but may be seen in children with Wilson’s disease due to copper accumulation in the heart tissue.3-5 Arat et al. showed increased P-wave dispersion in adults with cardiologically asymptomatic Wilson’s disease.6 In another study on adults, electrocardiographic abnormalities, including left ventricular hypertrophy, early repolarisation, biventricular hypertrophy, premature atrial or ventricular contractions, atrial fibrillation, sino-atrial block and Mobitz type 1 atrioventricular block were detected in 34% of the patients.6 Electrocardiographic abnormalities are not uncommon in Wilson’s disease and are presumably related to an underlying cardiomyopathy due to deposition of copper in the heart.5 We previously evaluated 22 children with Wilson’s disease with 24-hour ECG monitoring and our study showed that one patient had first-degree atrioventricular block, one had frequent sinus exit block, and four had rare ventricular ectopic beat.8 In our study, all the patients were assessed with ECG before echocardiographic evaluation. Only one patient had Wolf–Parkinson–White pattern, but there were no arrhythmias or ECG abnormalities in any of the patients. We assumed that ECG abnormalities develop over a long period or in untreated patients. The major pathological findings of the myocardium in Wilson’s disease included the presence of interstitial and myocardial fibrosis, focal myocarditis and cardiac hypertrophy, conduction tissue degeneration, and early atherosclerosis due to the toxic effect of copper, leading to mitochondrial injury and lipid peroxidation, which is caused by reactive free oxygen radicals. Hlubocka et al. suggested that cardiac changes seen in Wilson’s disease are not only related to copper accumulation but also to free oxygen radicals.9 Therefore echocardiography is an important tool to assess asymptomatic Wilson’s patients. In this study, left ventricular wall thickness was increased and left ventricular end-diastolic diameter was decreased in patients with Wilson’s disease and the differences were statistically comparable to the results of the control group. Measurement of local and

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global myocardial function using non-invasive methods is a major aim in clinical cardiology.10 Cardiac systolic function may deteriorate in prolonged disease or in untreated patients. Table 7. Longitudinal and transverse strain and strain rate values according to segment from the two-chamber view Strain according to Patients (n = 21) Controls (n = 20) segment (mean ± SD) (mean ± SD) p-value SLSC peak G (%) Basal inferior 0.70 –21.80 ± 4.37 –21.14 ± 6.86 Mid-inferior 0.73 –21.24 ± 3.56 –20.69 ± 6.95 Apical inferior 0.87 –17.40 ± 3.73 –17.65 ± 6.61 Apical anterior 0.62 –11.41 ± 4.04 –12.17 ± 5.90 Mid-anterior 0.047 –18.00 ± 3.33 –14.97 ± 6.23 Basal anterior 0.06 –22.22 ± 5.04 –18.75 ± 7.16 SLSC peak S (%) Basal inferior 0.73 –21.75 ± 0.35 –21.20 ± 6.26 Mid-inferior 0.73 –21.18 ± 3.61 –20.62 ± 6.99 Apical inferior 0.83 –16.97 ± 3.72 –17.34 ± 7.44 Apical anterior 0.63 –10.99 ± 3.97 –11.75 ± 6.44 Mid-anterior 0.06 –17.72 ± 3.30 –14.78 ± 6.65 Basal anterior 0.07 –21.82 ± 4.94 –18.35 ± 7.63 SLSC peak P (%) Basal inferior 0.23 0.33 ± 0.49 0.62 ± 1.034 Mid-inferior 0.27 0.06 ± 0.18 0.52 ± 1.98 Apical inferior 0.39 0.46 ± 0.66 1.03 ± 3.14 Apical anterior 0.55 0.65 ±1.11 1.01 ± 2.53 Mid-anterior 0.35 0.20 ± 0.52 0.55 ± 1.67 Basal anterior 0.95 0.61 ± 1.50 0.63 ± 1.18 STSR peak P (%) Basal inferior 0.93 30.87 ± 12.70 30.60 ± 11.08 Mid-inferior 0.32 24.16 ± 8.65 26.84 ± 9.22 Apical inferior 0.06 20.89 ± 7.31 26.22 ± 11.44 Apical anterior 0.09 21.55 ± 13.51 29.40 ± 16.40 Mid-anterior 0.15 25.47 ± 23.34 35.20 ± 21.54 Basal anterior 0.180 30.20 ± 30.81 41.83 ± 26.16 STSR peak G (%) Basal inferior 0.66 –21.55 ± 4.19 –20.82 ± 6.76 Mid-inferior 0.68 –21.09 ± 3.52 –20.40 ± 7.23 Apical inferior 0.81 –16.92 ± 3.72 –17.32 ± 7.19 Apical anterior 0.61 –10.92 ± 3.95 –11.73 ± 6.37 Mid-anterior 0.07 –17.53 ± 3.26 –14.735 ± 6.58 Basal anterior 0.09 –21.61 ± 5.00 –18.36 ± 7.37 SLSC (ES) (%) Basal inferior 0.83 24.62 ± 16.37 25.58 ± 13.77 Mid-inferior 0.33 21.18 ± 10.41 24.35 ± 11.35 Apical inferior 0.07 19.02 ± 8.22 24.90 ± 12.82 Apical anterior 0.05 18.972 ± 13.33 28.12 ± 17.37 Mid-anterior 0.047 19.41 ± 23.34 33.33 ± 22.37 Basal anterior 0.038 19.51 ± 32.88 38.74 ± 26.77 STSR (ES) (%) Basal inferior 0.53 13.93 ± 3.22 13.21 ± 4.30 Mid-inferior 0.82 7.70 ± 1.99 7.55 ± 2.58 Apical inferior 0.811 2.06 ± 0.97 2.14 ± 1.27 Apical anterior 0.999 1.67 ± 1.15 1.67 ± 1.83 Mid-anterior 0.55 5.69 ± 1.81 5.24 ± 3.03 Basal anterior 0.14 12.19 ± 2.72 10.50 ± 4.68 DLDC (ES) (mm) Basal inferior 0.91 4.40 ± 1.88 4.46 ± 2.09 Mid-inferior 0.72 4.07 ± 1.71 3.89 ± 1.83 Apical inferior 0.90 2.49 ± 1.42 2.54 ± 1.30 Apical anterior 0.45 1.42 ± 0.94 1.64 ± 1.04 Mid-anterior 0.94 2.58 ± 1.57 2.5523 ± 1.75 Basal anterior 0.48 5.59 ± 2.74 5.00 ± 2.96 SLSC peak G: the most negative peak longitudinal strain, SLSC peak S: negative systolic peak longitudinal strain, SLSC peak P: positive systolic peak longitudinal strain, SLSC (ES): end-systolic longitudinal strain, STSR peak P: positive peak transverse strain, STSR peak G: the most negative peak transverse strain, STSR (ES): end-systolic longitudinal strain, DLDC (ES): end-systolic longitudinal displacement.

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In our study, systolic function of the left ventricle, wall thickness, left ventricular diameters, volumes, and cardiac index measurements were within normal limits. There were no Table 8. Longitudinal and transverse strain and strain rate values according to segment from the apical long-axis view Strain according to Patients (n = 21) Controls (n = 20) segment (mean ± SD) (mean ± SD) p-value SLSCC peak G (%) Basal anterior septal 0.24 –19.99 ± 2.75 –18.63 ± 5.80 Basal posterior 0.58 –16.60 ± 11.17 –15.34 ± 5.24 Mid-posterior 0.20 –18.27 ± 3.83 –17.08 ± 3.20 Apical posterior 0.86 –17.94 ± 4.47 –17.73 ± 4.48 Apical anterior septal 0.46 –15.33 ± 5.55 –16.56 ± 6.86 Mid-anterior septal 0.80 –18.01 ± 2.58 –17.72 ± 5.69 SLSC peak S (%) Basal anterior septal 0.31 –19.68 ± 3.06 –18.45 ± 5.81 Basal posterior 0.59 –16.29 ± 10.74 –15.06 ± 5.42 Mid-posterior 0.32 –17.98 ± 4.10 –17.018 ± 3.14 Apical posterior 0.96 –17.39 ± 4.56 –17.44 ± 4.80 Apical anterior septal 0.43 –14.91 ± 5.32 –16.21 ± 6.88 Mid-anterior septal 0.87 –17.82 ± 2.71 –17.64 ± 5.65 SLSC peak P (%) Basal anterior septal 0.42 0.25 ± 0.81 0.125 ± 0.28 Basal posterior 0.64 2.88 ± 8.90 2.07 ± 2.08 Mid-posterior 0.08 0.16 ± 0.49 0.43 ± 0.69 Apical posterior 0.84 0.15 ± 0.29 0.17 ± 0.42 Apical anterior septal 0.61 0.22 ± 0.36 0.30 ± 0.68 Mid-anterior septal 0.07 0.02 ± 0.06 0.14 ± 0.35 STSR peak P (%) Basal anterior septal 0.16 21.30 ± 22.17 29.87 ± 24.35 Basal posterior 0.88 35.91 ± 26.93 34.86 ± 25.61 Mid-posterior 0.88 27.98 ± 23.49 27.18 ± 18.86 Apical posterior 0.96 21.76 ± 18.45 21.56 ± 14.17 Apical anterior septal 0.67 19.14 ± 16.83 20.87 ± 13.64 Mid-anterior septal 0.26 18.56 ± 18.17 24.07 ± 19.07 STSR peak G (%) Basal anterior septal 0.39 –19.54 ± 3.04 –18.38 ± 5.85 Basal posterior 0.60 –16.04 ± 11.32 –14.81 ± 5.47 Mid-posterior 0.29 –17.89 ± 4.14 –16.87 ± 3.17 Apical posterior 0.92 –17.19 ± 4.63 –17.30 ± 4.75 Apical anterior septal 0.39 –14.66 ± 5.51 –16.09 ± 6.82 Mid-anterior septal 0.93 –17.68 ± 2.84 –17.59 ± 5.66 SLSC (ES) (%) Basal anterior septal 0.13 14.59 ± 24.85 24.53 ± 25.34 Basal posterior 0.94 28.05 ± 27.70 28.55 ± 28.82 Mid-posterior 0.87 24.35 ± 23.59 23.42 ± 21.06 Apical posterior 0.99 20.06 ± 19.09 20.12 ± 14.95 Apical anterior septal 0.61 17.58 ± 17.78 19.77 ± 14.08 Mid-anterior septal 0.22 15.53 ± 20.06 21.84 ± 19.12 STSR (ES) (%) Basal anterior septal 0.55 10.95 ± 3.58 11.50 ± 3.49 Basal posterior 0.004 13.75 ± 3.59 11.37 ± 2.26 Mid-posterior 0.0006 8.81 ± 2.56 7.20 ± 1.59 Apical posterior 0.005 3.23 ± 1.26 2.27 ± 1.216 Apical anterior septal 0.10 1.28 ± 1.61 2.21 ± 2.46 Mid-anterior septal 0.23 5.55 ± 2.96 6.56 ± 3.34 DLDC (ES) (mm) Basal anterior septal 0.11 1.77 ± 2.00 2.62 ± 2.11 Basal posterior 0.008 4.91 ± 2.08 3.57 ± 1.57 Mid-posterior 0.012 3.97 ± 1.59 2.95 ± 1.37 Apical posterior 0.53 2.46 ± 1.34 2.24 ± 1.31 Apical anterior septal 0.12 1.56 ± 1.37 2.17 ± 1.55 Mid-anterior septal 0.027 1.55 ± 1.50 2.54 ± 1.81 SLSC peak G: the most negative peak longitudinal strain, SLSC peak S: negative systolic peak longitudinal strain, SLSC peak P: positive systolic peak longitudinal strain, SLSC (ES): end-systolic longitudinal strain, STSR peak P: positive peak transverse strain, STSR peak G: the most negative peak transverse strain, STSR (ES): end-systolic longitudinal strain, DLDC (ES): end-systolic longitudinal displacement.

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statistically significant differences between the Wilson’s disease patients and the control group for left ventricular systolic function, wall thickness, diameter, volume and cardiac index (p > 0.05). Our patients were relatively young and the mean age at diagnosis was 9 ± 2.24 years, so their time from diagnosis was relatively short. Cardiac systolic function may deteriorate in the long term or due to serious disease. Tissue Doppler echocardiography, strain and strain rate echocardiography are relatively novel echocardiographic techniques and important tools to assess asymptomatic patients.11-14 Tissue Doppler imaging, which has recently allowed a detailed examination of cardiac function, is widely used to evaluate children with various conditions.14-17 Our previous study showed early diastolic dysfunction in patients with Wilson’s disease using tissue Doppler echocardiography. Despite its reliability, tissue Doppler echocardiography cannot show regional deformation and regional deformation abnormalities. Difficulties with angle dependency of tissue Doppler imaging, the effects of preload, and the translational motion of the heart were overcome by strain and strain rate echocardiography, which were then adopted as new models in the assessment of myocardial performance and local deformation properties.13-15 Strain imaging, based on speckle tracking, in particular, enabled assessment of myocardial motion and deformation irrespective of angle and geometry, allowing an improved examination of the myocardial mechanics. Our hospital is a liver transplantation centre, therefore, we aimed to assess a new group of children with Wilson’s disease using 2D strain and strain rate echocardiography. Strain and strain rate echocardiography are superior to tissue Doppler echocardiography in the evaluation of regional myocardial function because they are not affected by the translation and stretching of neighbouring myocardial segments.16 2D strain and strain rate echocardiography also can assess different clinical conditions, such as hypertension, obesity, post exercise, Marfan syndrome, healthy children and infants.15-18 To our knowledge, the literature presents no studies showing early detection of subclinical cardiac dysfunction in children with Wilson’s disease using 2D strain and strain rate echocardiography. Our study showed that among the global strain and strain rate parameters, Wilson’s disease patients had lower peak A longitudinal velocity of the left basal point (VAbasL) and peak E longitudinal velocity of the left basal (VEbasR) point than those of the control group (p < 0.05). The patients also had statistically significantly higher global peak A longitudinal/circumferential strain rate (GSRa) (p < 0.05). Longitudinal strain and strain rate from the four-chamber view showed that end-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05). Radial strain and strain rate analysis showed that end-systolic rotation [ROT (ES)] was statistically significantly lower in the patient group (p < 0.05). Longitudinal strain and strain rate from the two-chamber view showed that end-systolic longitudinal strain [SLSC (ES)] and positive peak transverse strain (STSR peak P) were statistically significantly lower in the patient group (p < 0.05). Segmental analysis also showed that rotational strain measurement of the anterior segment of the patient group, end-systolic longitudinal strain [STSR (ES)] of the basal lateral

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(p < 0.05), mid-anterior and basal anterior segments, and end-systolic longitudinal strain [SLSC (ES)] of the basal septal and lateral segments, and the most negative peak longitudinal strain (SLSC peak S) of the mid-anterior segment were statistically significant lower in the patient group (p < 0.05). Our study showed that in the early stages of Wilson’s disease, diastolic dysfunction due to copper accumulation may be heterogenous but in the long term, the heart could be affected globally. Early diastolic dysfunction can be detected using strain and strain rate echocardiography.

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titation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on standards, subcommittee on quantitation of two dimensional echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–367. 8.

Elkıran Ö, Karakurt C, Selimoglu A, Karabiber H, Koçak G, Çelik FS, et al. Subclinical diastolic dysfunction in children with Wilson’s disease assessed by tissue Doppler echocardiography: a possible early predictor of cardiac involvement. Acta Cardiol 2013; 68(2): 181–187.

Hlubocka Z, Marecek Z, Linhart A, Kejkova E, Pospisilova L, Martasek P, et al. Cardiac involvement in Wilson disease. J Inherit Metab Dis 2002; 25(4): 269–277.

Conclusion

10. Bharucha T, Mertens L. Recent advances in pediatric echocardiography.

Cardiac arrhythmias, cardiomyopathy and sudden cardiac death are rare complications but may be seen in children with Wilson’s disease due to copper accumulation in the heart tissue. Strain and strain rate echocardiography is a relatively new and useful echocardiographic technique to evaluate cardiac function and cardiac deformation abnormalities. In our study, despite normal systolic function, the patients with Wilson’s disease showed diastolic dysfunction and regional deformation abnormalities, especially rotational strain and strain rate abnormalities. We suggest that diastolic dysfunction, and rotational strain and strain rate abnormalities in Wilson’s disease may be progressive in untreated patients.

11. Angtuaco MJ, Vyas HV, Malik S, Holleman BN, Gosset JM, Sachadeva

Expert Rev Cardiovasc Ther 2013; 11(1): 31–47. R. Early detection cardiac dysfunction by strain rate imaging in children and young adult with Marfan syndrome. J Ultrasound Med 2012; 31: 1609–1616. 12. Black D, Bryant J, Peebles C, Davies L, Inskip H, Godfrey K, et al. Increased regional deformation of the left ventricle in normal children with increased body mass index: Implications for future cardiovascular health. Pediatr Cardiol 2013 Aug 29. Epub ahead of print. 13.

Bissiere J, Maufrais C, Baquet G, Schuster I, Dauzat M, Doucende G, et al. Specific left ventricular twist–untwist mechanics during exercise in children. J Am Soc Echocardiogr 2013; 26(11): 1298–1305.

14. Binnetoğlu FK, Baboğlu K, Altun G, Kayabey O. Effects that different types of sports have on the hearts of children and adolescents and the

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Cardiol 2013 Jul 25 Epub ahead of print.

Rosencrantz R, Schilsky M. Wilson’s disease: pathogenesis and clinical 245–259.

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Aggarwal A, Bhatt M. Update on Wilson disease. Int Rev Neurobiol 2013; 110: 313–348.

Echocardiography 2013; 30: 460–471. 16. Forsey J, Friedberg M, Mertens L. Speckle tracking echocardiography in pediatric and congenital heart disease. Echocardiography 2013; 30: 447–459. 17. Biswas M, Sudhakar S, Nanda N, Buckberg G, Pradhan M, Roomi AU,

Kuan P. Cardiac Wilson’s disease. Chest 1987; 91(4): 579–583.

et al. Two- and three-dimensional speckle tracking echocardiography:

Meenakshi-Sundaram S, Sinha S, Rao M, Prashanth LK, Arunodaya

clinical applications and future directions. Echocardiography 2013; 30:

GR, Rao S, et al. Cardiac involvement in Wilson’s disease – an electrocardiographic observation. J Assoc Physicians India 2004; 52: 294–296. 6.

88–105 18. Vaida M, Grybauskiene R, Vaskelyte J, Jonkaitiene R, Pavilioniene J,

Arat N, Kacar S, Golbasi Z, Akdogan M, Sokmen Y, Kuran S, et al. P

Jurkevicius R. Strain value in the assessment of left ventricular func-

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Cardiovascular risk factors in pre-pubertal schoolchildren in Angola Amílcar BT Silva, Daniel P Capingana, Pedro Magalhães, Mauer AA Gonçalves, Maria del Carmen B Molina, Sérgio L Rodrigues, Marcelo P Baldo, Miguel SB Mateus, José Geraldo Mill

Abstract Methods: The incidence of obesity is increasing worldwide, especially in countries with accelerated economic growth. We determined the prevalence of and associations between overweight/ obesity and cardiovascular risk factors in pre-pubertal (seven- to 11-year-old) schoolchildren (both genders, n = 198) in Luanda, Angola. Biochemical (fasting blood) and clinical examinations were obtained in a single visit. Data are reported as prevalence (95% confidence intervals) and association (r, Pearson). Results: Prevalence of overweight/obesity was 17.7% (12.4– 23.0%), high blood pressure (BP > 90% percentile) was 14.6% (9.7–19.5%), elevated glucose level was 16.7% (11.5–21.9%) and total cholesterol level > 170 mg/dl (4.4 mmol/l) was 69.2% (62.8–75.6%). Significant associations between body mass index (BMI) and systolic and diastolic BP (r = 0.46 and 0.40, respectively; p < 0.05) were found. No association between BMI and elevated glucose or cholesterol levels was found. Conclusion: The prevalence of cardiovascular risk factors was high in pre-pubertal schoolchildren in Angola and fat accumulation was directly associated with blood pressure increase but not with other cardiovascular risk factors. Keywords: obesity, overweight, children, blood pressure, cardiovascular risk Submitted 28/10/14, accepted 8/3/16 Cardiovasc J Afr 2016; 27: 315–321

www.cvja.co.za

DOI: 10.5830/CVJA-2016-029

Department of Physiological Sciences, Federal University of Espírito Santo, Espírito Santo, Brazil Amílcar BT Silva, MD Sérgio L Rodrigues, MD Marcelo P Baldo, MD José Geraldo Mill, MD, josegmill@gmail.com

Department of Physiological Sciences, School of Medicine, Agostinho Neto University, Luanda, Angola Amílcar BT Silva, MD Daniel P Capingana, MD Pedro Magalhães, MD Mauer AA Gonçalves, MD Miguel SB Mateus, MD

Department of Public Health, Federal University of Espírito Santo, Espírito Santo, Brazil Maria del Carmen B Molina, MD

Cardiovascular disease (CVD) is the leading cause of death worldwide. Although its most overt manifestations, such as hypertension, myocardial infarction and stroke, appear more frequently in adulthood, there is growing evidence that the risk factors for these events can appear precociously in the course of life, even in childhood.1-3 Some studies suggest that the pathophysiological processes leading to the onset of CVD in earlier phases of adult life could be detected as early as the foetal period.4-6 Hypertension and obesity are two cardiovascular risk factors with a high prevalence in the adult population in virtually all countries. Their incidence is occurring at increasingly younger ages; today, these conditions affect a significant proportion of children and adolescents.7-9 Therefore early evaluation of predisposing factors for these disorders, such as low birth weight10 and inadequate diet,11,12 may contribute to the adoption of early interventions for CVD prevention in adulthood.13 Obesity in adults has become a global pandemic, affecting both developed and developing countries.14 Given that the accumulation of body fat is due in large part to the adoption of inadequate dietary and lifestyle habits, it appears that the prevalence of obesity is increasing systematically in children and adolescents around the world. Following the overweight and obesity pandemic, an increased incidence of hypertension, type 2 diabetes and dyslipidaemia is to be expected.2,8 Dyslipidaemia, in parallel with insulin resistance, is one of the most important risk factors for the onset and progression of atherosclerosis, and probably has a direct relationship with obesity because both processes involve similar lifestyle predictors.14 The prevalence of dyslipidaemia in children and adolescents worldwide varies between 2.9 and 33%, depending on the cut-off points used and the age range of individuals included in the study.15 However, there is now strong evidence of an increased incidence of these conditions in the pre- and post-pubertal periods.16-18 Most studies, however, have been conducted in developed countries with few studies performed in Africa to date.19 Obesity and cardiovascular risk factors tend to increase in countries with rapid economic and social transformation. Angola is an African country that has experienced rapid economic growth over the last 15 years, following the end of the civil war. However, no existing studies have examined cardiovascular risk in Angolan children. Therefore the aim of this study was to determine the prevalence and severity of cardiovascular risk factors in pre-pubertal schoolchildren in Luanda, Angola, and to determine the contribution of excessive body weight to these findings.

Methods A cross-sectional, observational and descriptive study was conducted in a sample of children enrolled in the first cycle of

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primary education in a public school in Luanda, the Angolan capital. The project was carried out after obtaining authorisation from the Provincial Directorate of Education, the Education Chamber of Rangel municipality and the directors of the school 5008 (Our Lady of Light). Consent for the involvement of the community in the study was obtained in meetings with the school staff, parents and/ or guardians of the children and the children to clarify the study purposes and methods. The project was approved by the Independent Ethics Committee on Research of the Faculty of Medicine of Agostinho Neto University, following the standards procedures in human research in accordance with the Declaration of Helsinki. In the 2011 academic year, 1 015 students (aged five to 12 years) were enrolled in the Our Lady of Light school and 719 (70.8%) were eligible for the study (seven to 11 years). This school was chosen because it is near the Faculty of Medicine, where data were collected and because it is located in a neighborhood with most of the families belonging to the middle class. After meeting with parents or guardians, we sent an envelope containing an invitation letter and a questionnaire to a random subsample of 290 students. The questionnaire required completion for information on the conditions of birth and the child’s life, including pregnancy history, birth weight, period of exclusive breastfeeding, self-reported diseases, and sociodemographic information of the family. Information about birth weight and the duration of exclusive breastfeeding in addition to signing of the consent form were necessary for final inclusion in the project. Of the 290 questionnaires distributed, 248 (85.5%) were returned. Eleven children were excluded due to lack of essential information. Of the 237 selected, 23 did not appear at the venue for the examination. The set of examinations to investigate the presence of cardiovascular risk factors was performed on 214 children. All children were classified according to the Tanner scale,20 obtained by self-evaluation of genitalia and breast development. According to this procedure, 16 children were excluded from our analysis because they were in Tanner stage II, or because they had completed 12 years between enrolment and the examination. Therefore, the data in this study refer to 198 pre-pubertal (Tanner stage I) and apparently healthy schoolchildren. All study participants presented to the Laboratory of Functional Tests and Physiology of the Faculty of Medicine on a pre-scheduled morning in a fasting condition (10–14 hours). Examinations were performed from June 2012 to November 2013. A previous pilot study (March 2012) was performed on 30 children (not included in this study) to standardise the protocol and to train examiners. Sociodemographic data (age, gender, race, school grade), physical activity and dietary habits were obtained in an interview with the child and the mother or guardian. Blood was collected by venipuncture of the forearm and processed on the same day by the Department of Biochemistry (Faculty of Medicine) to determine glucose, urea, uric acid, creatinine, total cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels. Only reagents of BioSystems SA (Barcelona, Spain) were used. Low-density lipoprotein (LDL) cholesterol concentration was calculated by the Friedewald formula for triglycerides < 400 mg/dl (4.52 mmol/l).

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Biochemical variables in the blood were classified according to the criteria established by the American Academy of Pediatrics and the American Heart Association (American Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 2012).21 In brief, the lipid profile was classified as follows: • total cholesterol < 170 mg/d (< 4.4 mmol/l): acceptable; 170–199 mg/dl (5.15 mmol/l): borderline; ≥ 200 mg/dl (≥ 5.18 mmol/l): high • LDL cholesterol < 110 mg/dl (< 2.85 mmol/l): acceptable; 110–129 mg/dl (2.85–3.34 mmol/l): borderline; and ≥ 130 mg/ dl (≥ 3.37 mmol/l): high • triglycerides (0–9 years) < 75 mg/dl (< 0.85 mmol/l): acceptable; 75–99 mg/dl (0.85–1.12 mmol/l): borderline; ≥ 100 mg/dl (≥ 1.13 mmol/l): high • triglycerides (10–19 years) < 90 mg/dl (< 1.02 mmol/l): acceptable; 90–129 mg/dl (1.02–1.46 mmol/l): borderline; and ≥ 130 mg/dl (≥ 1.47 mmol/l): high • HDL cholesterol > 45 mg/dl (> 1.17 mmol/l): acceptable; 40–45 mg/dl (1.04–1.17 mmol/l): borderline; and < 40 mg/dl (< 1.04 mmol/l): low.21 According to fasting blood glucose criteria, the children were classified as normoglycaemic (60–99 mg/dl) (3.33–5.49 mmol/l), glucose intolerant (100–125 mg/dl) (5.55–6.94 mmol/l) or hyperglycaemic (> 125 mg/dl) (> 6.94 mmol/l). No child was on treatment with insulin or oral hypoglycaemic agents. Body weight was obtained using a digital electronic scale (SECA, Mod 763, Germany) with 0.1-kg precision while fasting and after voiding. Children were barefoot and clothed with undergarments only. Height was measured using a fixed stadiometer with 0.5-cm precision. The child was placed on the central part of the scale platform with heels together, head and buttocks resting against the stadiometer and eyes looking toward the Frankfurt horizontal plane. The body mass index (BMI) was calculated by dividing body weight by height squared (kg/m2). Percentiles (P) of height, weight and BMI of each child were calculated as presented in https:// www.bcm.edu/bodycomplab/.22 BMI classification was obtained according to the following World Health Organisation (WHO) parameters: underweight (BMI < P5), normal (BMI ≥ P5 and < P85), overweight (BMI ≥ P85 and < P95) and obese (BMI ≥ P95).23 The left arm circumference was obtained with an inelastic tape at the midpoint between the acromion (proximal) and olecranon process (distal). The waist (WC) and hip circumferences (HC) were measured with an inelastic tape with the child in a standing position and at the end-expiration phase. Measurements (0.1mm precision) were obtained in front of a mirror to facilitate the tape positioning in the horizontal plane. WC was measured at the midpoint between the lower edge of the rib cage and the anterior superior iliac crest. HC was measured at the level of the great trochanter, circling the hip on the most prominent point between the waist and the thigh. The waist-to-hip ratio (WHR) was obtained by dividing WC by HC. The thickness of four skinfolds (triceps, supra-iliac, subscapular and abdominal) was measured with a manual caliper (Sanny) with a precision of 1 mm. Body composition was obtained by tetrapolar bio-impedance with the Maltron BioScan Analyser (Model 916, Maltron Int Ltd, UK). Two electrodes were placed on the dorsal surface of the radiocarpal joint and metacarpal of the right hand and the other two on the dorsal surface of the right foot (tibiotarsal

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and metatarsal joint region) according to the manufacturer’s instructions. Body fat and percentage of body fat were used to indicate overall obesity. Blood pressure was measured with an automatic sphygmomanometer (OMRON®, Model HEM-742 IntelliSense INT, China) in the sitting position in a comfortable room and after bladder emptying. The cuff size was chosen according to the circumference of the child’s arm and the manufacturer’s recommendation. Three measurements were taken on the left arm at two-minute intervals after a five- to 10-minute resting period. The forearm was supported on a flat surface at nearly 120° with the arm. Resting systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were determined as the arithmetic mean of the last two measures. Pulse pressure (PP) was calculated as the difference between SBP and DBP. The mean arterial pressure (MAP) was calculated from the formula [SBP + (2 × DBP)]/3. The blood pressure percentile was determined using available software (https://www.bcm.edu/bodycomplab/), which accounts for the gender, height and age of each child. Blood pressure was classified according to the WHO criteria.23 Briefly, it was considered normal if the SBP and DBP were below the 90th percentile. If SBP or DBP were above the 95th percentile (P95), the child was included in the category of ‘high BP’. If the SBP or DBP was intermediary between the extremes (> P90 < P95), the child was classified as ‘borderline BP’.

Statistical analysis Continuous variables are expressed as mean ± standard deviation when normally distributed or as median and interquartile range when the normal distribution model was not accepted (Kolmogorov–Smirnov test). Comparison of two means was done with the Student’s t-test for normal variables, and comparison of two medians was performed with the Wilkinson test. The comparison of proportions of categorical variables in two or more groups was performed using the chi-squared test. Comparison of means in three or more groups was performed by one-way ANOVA followed by the post hoc Tukey’s test. The degree of association between continuous variables was obtained with Pearson’s correlation coefficient (r). A multivariate analysis (stepwise forward procedure) was used to indicate independent predictors of systolic and diastolic blood pressure. Gender, birth weight, age, height, body weight, body mass index, absolute and relative fat mass and lean mass (all with p < 0.05 in bivariate analysis) were included in the model as predictors. Co-linearity variables were automatically excluded from the model. Statistical analyses were performed using SPSS for Windows, version 20.0. The significance level for all tests was set at p < 5%.

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It can be observed (Table 1) that most of the anthropometric and biochemical variables were similar in pre-pubertal boys and girls, with the exception of HR, which was higher in girls, and WHR, which was higher in boys. According to BMI classification, excessive body weight was found in 17.7% of the sample (95% CI = 12.4–23.0%), with 7.1% being overweight and 10.6% obese. Eleven children were underweight and the remaining 152 (76.7%) children were of normal weight. Table 2 shows the anthropometric, haemodynamic and biochemical variables according to BMI classification. Age across the four groups was similar (p > 0.05). As expected, the current body weight of the overweight and obese groups was higher than that of the normal group. The current weight was 61% higher in the obese group than in the normal group. Interestingly, birth weight was also higher in the groups with excessive fat mass. As expected, other anthropometric variables related to fat accumulation were also different between the normal BMI group and the groups with excessive fat accumulation. The obese group showed 2.56 times more fat mass than the normal BMI group. While all biochemical variables were unaffected along BMI categories, except for triglycerides, which showed higher values in the obese group, a different pattern was observed in relation to blood pressure. An obvious gradient of increasing SBP and DBP values was observed from the underweight group to the obese group. SBP was statistically higher in the obese group compared with the underweight, normal and overweight groups, while the DBP was significantly different between the obese groups and the normal and underweight groups. Significant differences among other variables are shown in Table 2. Comparisons were performed between the normalTable 1. Physical and clinical characteristics of pre-pubertal schoolchildren in Luanda in 2012 All (n = 198)

p-value

Age (years)

9.43 ± 1.03

9.21 ± 1.12

9.29 ± 1.41

0.18

Birth weight (kg)

3.29 ± 0.56

3.12 ± 0.58

3.19 ± 0.58

0.05

Current weight (kg)

33.08 ± 9.06

33.07 ± 10.2

33.07 ± 9.72

0.99

Height (cm)

136.7 ± 8.05

137.8 ± 9.75

137.4 ± 9.12

0.44

BMI (kg/m2)

17.70 ± 4.0

17.19 ± 3.61

17.39 ± 3.76

0.36

WC (cm)

59.58 ± 8.94

58.38 ± 9.25

58.85 ± 9.13

0.37

HC (cm)

71.82 ± 9.71

71.95 ± 10.4

71.9 ± 10.12

0.93

WHR

0.82 ± 0.04

0.81 ± 0.04

0.81 ± 0.03

0.008

Fat mass (kg)

6.36 ± 3.97

6.85 ± 4.14

6.66 ± 4.07

0.41

Variables

Boys (n = 77) Girls (n = 121)

SBP (mmHg)

104.7 ± 8.9

103.8 ± 8.1

104.1 ± 4.2

0.46

DBP (mmHg)

62.6 ± 7.8

63.6 ± 6.3

63.2 ± 0.4

0.33

HR (bpm)

80.1 ± 9.5

84.7 ± 10.2

82.9 ± 13.4

0.002

Glycaemia (mg/dl)

87.4 ± 15.3

86.5 ± 14.4

86.8 ± 15.5

0.69

(mmol/l)

4.85 ± 0.85

4.80 ± 0.80

4.82 ± 0.86

TC (mg/dl)

170.9 ± 36.8

172.5 ± 34.4

171.8 ± 34.1

(mmol/l)

4.43 ± 0.95

4.47 ± 0.89

4.45 ± 0.88

Triglycerides (mg/dl)

66.3 ± 31.9

63.5 ± 29.4

64.6 ± 4.0

(mmol/l)

0.75 ± 0.36

0.72 ± 0.33

0.73 ± 0.05

Results

LDL-C (mg/dl)

102.1 ± 33.2

101.4 ± 33.2

101.7 ± 22.6

(mmol/l)

2.64 ± 0.86

2.63 ± 0.86

2.63 ± 0.59

Table 1 shows the main clinical characteristics of the sample, divided by gender. There was a predominance of girls (61.1%) and, as expected, children of black race (95.5%). Only nine children showed intermediate skin colour, suggesting a mixed ancestry of black and white. The boys had an overall birth weight higher than that of the girls, and a low birth weight (< 2 500 g) was reported in only 15 children.

HDL-C (mg/dl)

56.8 ± 13.1

59.5 ± 12.3

58.5 ± 9.1

(mmol/l)

1.47 ± 0.34

1.54 ± 0.32

1.52 ± 0.24

1.9 ± 0.8

1.8 ± 0.7

1.8 ± 0.3

LDL-C/HDL-C

0.75 0.54 0.89 0.13 0.28

Data presented as mean ± standard deviation, BMI; body mass index, WC, waist circumference; HC, hip circumference; WHR, waist/hip ratio, SBP; systolic blood pressure; DBP; diastolic blood pressure, HR; heart rate, TC, total cholesterol; LDL-C; low-density lipoprotein cholesterol, HDL-C; high-density lipoprotein cholesterol.

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Table 4. Prevalence of cardiovascular risk factors by gender

Table 2. Physical and clinical characteristics of pre-pubertal schoolchildren according to body mass index classification

Boys

BMI class

Underweight (n = 11)

Normal (n = 152)

Overweight (n = 14)

Obese (n = 21)

p-value

Age (years)

9.6 ± 1.1

9.2 ± 1.0

9.6 ± 1.3

9.4 ± 1.4

0.707

Birth weight (kg)

3.27 ± 0.6

3.12 ± 0.6

3.46 ± 0.4

3.47 ± 0.4#

0.046

Current weight (kg)

25.6 ± 6.6

30.1 ± 5.1

42.3 ± 8.8#

52.1 ± 11.1#§ < 0.001

Height (cm)

137.2 ± 15.4 136.4 ± 8.3 141.8 ± 10.8 141.7 ± 7.7

0.054

BMI (kg/m2)

13.3 ± 0.8#

16.2 ± 1.4

20.8 ± 1.4#

26.2 ± 3.6#§ < 0.001

WC (cm)

50.6 ± 4.7#

55.9 ± 4.7

68.1 ± 5.8#

78.5 ± 1.7#§ < 0.001

HC (cm)

62.4 ± 6.4

68.8 ± 6.1

83.7 ± 6.1

91.3 ± 7.8

WHR

0.81 ± 0.04

0.81 ± 0.04 0.81 ± 0.03

< 0.001

0.86 ± 0.03#§ < 0.001 15.3 ± 4.6#§ < 0.001

SBP (mmHg)

99.0 ± 8.9

DBP (mmHg)

60.7 ± 3.3

62.2 ± 6.4

65.3 ± 7.2

70.1 ± 7.5

< 0.001

HR (bpm)

85.5 ± 10.3

83.2 ± 10

81.4 ± 12.5

80.2 ± 9.7

0.585

Glycaemia (mg/dl) (mmol/l)

91.3 ± 13.4 5.07 ± 0.74

87.5 ± 14.5 83.7 ± 17.8 4.86 ± 0.80 4.65 ± 0.99

82.0 ± 14.8 4.55 ± 0.82

0.327

194.6 ± 40.9 170.6 ± 34.5 176.3 ± 35.3 166.3 ± 35.5 5.04 ± 1.06 4.42 ± 0.89 4.57 ± 0.91 4.31 ± 0.92

0.127

103.1 ± 7.6 106.1 ± 6.7

113.1 ± 8.9#§ < 0.001 #

63.4 ± 30.1 49.7 ± 17.9 0.72 ± 0.34 0.56 ± 0.20

77.5 ± 35.7§ 0.88 ± 0.40

0.039

115.6 ± 40.3 105.5 ± 32.4 109.4 ± 32.3 2.99 ± 1.04 2.73 ± 0.84 2.83 ± 0.84

97.5 ± 34.6 2.53 ± 0.90

0.458

Triglycerides (mg/dl) 75.8 ± 26.7 (mmol/l) 0.86 ± 0.30 LDL-C (mg/dl) (mmol/l)

10.5 ± 3.8#

#§

3.6 ± 0.7

TC (mg/dl) (mmol/l)

5.3 ± 1.8

Fat mass (kg)

HDL-C (mg/dl) (mmol/l)

63.5 ± 9.89 1.64 ± 0.26

58.7 ± 13.1 56.5 ± 8.67 1.52 ± 0.34 1.46 ± 0.22

54.9 ± 12.5 1.42 ± 0.32

0.256

LDL-C/HDL-C

1.83 ± 0.7

1.82 ± 0.7

1.89 ± 0.91

0.973

1.97 ± 0.6

weight group and the other three groups, and between the overweight and the obese groups only. Prevalence of cardiovascular risk factors according to BMI classification is shown in Table 3. No relationship between fat accumulation and the presence of risk factors was observed in this age group. Moreover, prevalence of risk factors was similar in both genders (Table 4). Normal blood pressure values were found in 166 (83.8%) children and elevated values were found in 29 (14.6%) children. Simultaneous elevation of both SBP and DBP was found in five children, while 16 showed an increase of only SBP and eight showed an increase of only of DBP. Hypertension was

p-value

Overweight

6.5

7.4

0.975

Obese

11.7

9.9

0.875

Prehypertension

10.4

9.9

0.893

Hypertension

5.2

4.1

0.996

Glucose intolerance

19.5

14.9

0.514

High TC (≥ 170 mg/dl) (≥ 4.4 mmol/l)

44.1

53.7

0.243

High LDL-C (≥ 110 mg/dl) (≥ 2.85 mmol/l)

41.5

40.5

0.998

Low HDL-C (< 45 mg/dl) (< 1.17 mmol/l)

18.2

4.1

0.002

High triglycerides

28.6

26.4

0.870

FHH

72.7

63.6

0.241

CV: cardiovascular, TC: total cholesterol, LDL-C; low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, FHH: family history of hypertension.

detected in nine children and pre-hypertension in 20, without significant difference between genders (prevalence of 3.5 and 11.1%, respectively). Positive familial history of hypertension was identified in 132 (66.7%) children. However, this trait was not associated with the presence of elevated blood pressure in the studied population (χ2 = 0.247, p = 0.618). Another cardiovascular risk factor investigated was dyslipidaemia. The frequency of this condition was quite high, with 69.2% of the sample having at least one lipid value out of the normal range for this age group. This finding was unrelated to gender (71.4% for boys vs 67.8% for girls, p = 0.70) and BMI. The most common change in lipid profile was the presence of high total cholesterol levels, followed by an increase in LDL cholesterol and triglyceride levels. Low HDL cholesterol level was found in 9.1% of children, without a significant difference between genders. Table 5 shows the correlations between the three indices of excessive fat accumulation and birth weight and cardiovascular risk factors. Either SBP or DBP were moderately associated with fat accumulation. This association was significant independent of global (BMI and % fat) or central (WC) obesity indices. However, no significant association was observed in our study between birth weight and blood pressure or other cardiovascular risk factors. An inverse correlation between fat accumulation and HDL cholesterol level and glycaemia was also observed. In a multivariate linear regression, we observed that body weight (kg) was the only independent predictor of SBP (SBP = 0.402 × body weight + 90.8) while the fat mass (kg) was the only independent predictor of DBP (DBP = 0.759 × fat mass + 58.1). Table 5. Correlation coefficient between age, anthropometric variable and birth weight in cardiovascular risk factors in pre-pubertal schoolchildren

Body weight Normal

High

Variable

Prehypertension

7.97

Hypertension

p-value 0.066

3.7

8.6

0.416

Glucose intolerance

17.2

14.3

0.868

High TC (≥ 170 mg/dl) (≥ 4.4 mmol/l)

50.3

48.6

0.998

High LDL-C (≥ 110 mg/dl) (≥ 2.85 mmol/l)

41.1

42.8

0.998

Low HDL-C (< 45 mg/dl) (< 1.17 mmol/l)

9.8

8.6

High triglycerides

Girls

CV risk factors

Table 3. Prevalence of cardiovascular risk factors in pre-pubertal schoolchildren according to presence of overweight or obesity (high weight group)

FHH

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BMI

% fat

Glycaemia

–0.146

0.02

–0.130

0.034 –0.095

0.092

0.000 0.50

–0.099

0.083 –0.006

0.136 –0.095

0.091

0.017 0.41

0.115

0.129

0.022

0.111 0.60

Triglycerides HDL-C

0.086 –0.16

0.081

0.014 –0.109

Age

Variable

0.143

0.064 –0.142

0.023 –0.02

0.40

SBP

0.370 < 0.05

0.462 < 0.05

0.20

0.929

0.460 < 0.05

DBP

0.401 < 0.05

0.432 < 0.05

0.416 < 0.05

0.128 0.03

Birth weight

0.169

0.208

0.193

26.9

28.6

0.985

111

68.1

0.469

TC: total cholesterol, LDL-C: low-density lipoprotein cholesterol, HDL-C: highdensity lipoprotein cholesterol, FHH: family history of hypertension.

0.009

0.002

0.02

0.003 –0.015 0.42

r: Pearson correlation coefficient; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC, total cholesterol; HDL-C: highdensity lipoprotein cholesterol; WC: waist circumference.

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Discussion The increased incidence of CVD risk factors is a growing reality in children and adolescents, according to studies in several countries.1,16,18,24-29 Few studies, however, have been carried out in African countries. Our study aimed to characterise the current prevalence and severity of CVD risk factors in pre-pubertal schoolchildren living in Luanda, Angola. Angola has experienced rapid economic growth in this century and as observed in other countries, this fact should translate into a rapid epidemiological transition affecting the whole population. Studies on this topic are inadequate in the Angolan population. Our study shows that the prevalence of overweight and obesity was approximately 14% in the studied age group and that fat accumulation correlated with high blood pressure values. More importantly, we also showed an unexpected elevated prevalence of dyslipidaemia (mainly high total cholesterol levels), which, according to our data, was not associated with fat accumulation. Similar to other studies in pre-pubertal children,16,25,26 no significant difference was found between boys and girls regarding physical and clinical characteristics, indicating that such differences will appear later on during puberty. Our study was performed in pre-pubertal children only, to avoid the confounding influence of sex hormones and fat accumulation on blood pressure and other cardiovascular risk factors. It was possible to confirm in this group of children that borderline or high blood pressure values were associated with fat accumulation, without significant differences if overall (BMI, % fat) or central obesity indices (WC) were considered. Some studies show a stronger association between DBP and central obesity. However, the small sample size and the relatively small number of obese and hypertensive children may have hampered such analysis. The prevalence of high blood pressure in our cohort was 14.6% (11.1% with pre-hypertension and 3.5% with hypertension), a figure similar to that found in other African countries such as Egypt,18 South Africa,24 the Seychelles26 and Sudan,28 as well as non-African countries, including Spain,17 United States,1 Canada,29 Argentina25 and Brazil.16,27 A study in young adults (18 to 29 years) in Angola,30 however, showed a prevalence of hypertension of 23%, suggesting a rapid increase in blood pressure during adolescence and early adulthood. According to our findings, it is likely that body fat accumulation during adolescence may contribute to increased blood pressure, thus contributing to early onset of hypertension in adults. Validating other findings,31 we observed that elevated blood pressure was higher in overweight and obese children. Constanzi et al. showed that schoolchildren with increased waist circumference were 2.8 times more likely to have high blood pressure levels than children with a normal waist circumference.27 Hypertension is a multifactorial disease and the pathogenesis of its relationship with fat accumulation is unknown. Sorof et al. showed that obesity-induced hypertension could be due in part to hyperactivity of the sympathetic nervous system, which is manifested as increased heart rate and blood pressure variability.32 This association, however, was not identified in our study since the overweight/obese children showed lower heart rates at rest. Another link between increasing blood pressure in children and fat accumulation is the increased thickness of the intima–

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media layer of arteries, leading to increased peripheral vascular resistance. Wunsch et al. showed an increased intima–media thickness in carotid ultrasonography of obese children. After a long period of physical activity and substantial weight loss, blood pressure reduction was followed by a proportional reduction of the carotid intima–media thickness, as well as in other blood biochemical parameters.33 Genetic and environmental factors have also been suggested to be linked to high blood pressure. Therefore we also investigated the association of high blood pressure in children with a familial history of hypertension. Despite the fact that 72.4% of children with high blood pressure reported a positive family history of hypertension, this association was not significant when compared with children with normal blood pressure and positive family history of the disease (χ2 = 0.247; p = 0.618). Our data are consistent with those of Shi et al.29 who also observed that the presence of family history of hypertension did not change the association of high blood pressure and BMI. Overweight and obesity is a huge health problem in developed countries, and its prevalence seems to increase rapidly in countries facing fast economic growth.23 Another study by our group in adults (20–72 years) indicated a prevalence of overweight and obesity of 29.3 and 19.6%, respectively.34 The increasing incidence of obesity is worrisome, not only because it represents a disease per se but also because it is an important risk factor for the development of diabetes and cardiovascular diseases in the future.35 The obesity pandemic therefore predicts the rise in incidence of other diseases in the near future. For this reason, obesity should be viewed as one of the most pressing health problems faced by public health authorities this century.23 The prevalence of obesity, however, has shown variable prevalence in different countries and in different populations within a single country, varying from one to 20%. In our study, we detected excessive weight in 17.7% of the studied sample, most reaching BMI values compatible with obesity, without significant gender differences. These figures are similar to studies in countries such as Egypt,18 the Seychelles,26 Sudan,28 Brazil16,27,36 and Switzerland,37 but differ from others studies, such as in South Africa, where children living in rural areas were studied.24 Urbanisation therefore seems to be an important factor facilitating the development of obesity in children. One feature that distinguishes our results from other studies was the higher prevalence of obesity than overweight. Similar results were found by Constanzi et al.27 in Brazilian schoolchildren with similar characteristics to those included in our study. The high prevalence of dyslipidaemia detected in our study is also noteworthy. Interestingly, dyslipidaemias were not associated with either fat accumulation or high blood pressure. However, the lack of a statistically significant association should be viewed with caution, given the small sample size of children showing obesity and/or hypertension. Our results suggest, however, that development of these cardiovascular risk factors may depend on different predictors. Dyslipidaemias, however, may be detected precociously because they may produce early changes in vascular structure, facilitating the development of atherosclerosis. Studies have alerted us to the increase in incidence of dyslipidaemia in children and adolescents.38,39 No epidemiological data on the prevalence of dyslipidaemia in this age group is

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available at the regional or national level in Angola, but a study conducted in adults observed that 50.1% showed low HDL cholesterol levels, while 11.1% showed hypercholesterolaemia, and 10.6% hypertriglyceridaemia.35 The cut-off point adopted in our study, however, was used to classify children from different genetic backgrounds and with different dietary patterns. The prevalence of dyslipidaemias found in our study [50% with total cholesterol levels > 170 mg/dl (4.4 mmol/l)] is higher than the values found in some studies38-41 that used the same cut-off points. Other studies (Muscatine study and Bogalusa Heart study) showed similar values to ours,42 however, the cut-off points were different from those used in our study, making comparisons impractical.42 Regardless of cut-off points, it is important to highlight the high prevalence of dyslipidaemia in children and adolescents. For some authors, the change is due to the development of insulin resistance, initially peripheral and later at the systemic level.43 In our study, 16.8% of the children with dyslipidaemia also showed impaired glucose tolerance. From the fasting glycaemia determinations, we did not find diabetic children in our sample. However, an inverse relationship was observed between BMI and fasting glycaemia. This finding may be due to the hyperinsulinaemic state of children with a higher body fat accumulation. Our study suggests that, similar to other countries in sub-Saharan Africa, the high prevalence of overweight and obesity and of other cardiovascular risk factor indicates a rapid epidemiological transition affecting not only adults but also children.44 Weight gain and dyslipidaemia may be associated with environmental factors related to lifestyle, including inappropriate eating habits and physical inactivity. The consequences of childhood dyslipidaemia on the cardiovascular health of adults was reported by Berenson et al.45 who described a positive association between the extent of arterial intima surface covered with atherosclerotic lesions and elevated cholesterol and triglyceride levels as well as low HDL cholesterol levels. According to Freedman et al.,46 dyslipidaemia and overweight/obesity in childhood causes accumulation of harmful effects over time, resulting in a thickened intima–media layer of large arteries, atherosclerosis, arterial stiffness and consequent increase in blood pressure, coronary artery disease and stroke.

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Blood pressure was measured on a single day, which is insufficient to establish a diagnosis of hypertension and rather requires confirmation by additional measures. Our analysis, however, was conducted by considering blood pressure as a continuous variable. Finally, cut-off points used in this study were based on international references not validated for the Angolan population. However, by using such international standards, comparison with other studies was possible.

Conclusions Our study shows a relatively high prevalence of obesity in pre-pubertal schoolchildren in Angola and suggests a possible association between fat accumulation and high blood pressure in this age group. However, a causal relationship cannot be established in this study given its transverse design. The high prevalence of dyslipidaemia in the studied population deserves attention in future studies, which should aim to investigate potential causal relationships, including eating habits and genetic factors. Early monitoring of blood pressure and lipid profile is necessary for adoption of adequate prevention policies in the area of cardiovascular health. We acknowledge the collaboration of directors, teachers, students, parents and guardians of the school Our Lady of Light (No 1170), the Graduate Program in Physiological Sciences UFES. Financial support was received from the Director of the Faculty of Medicine of the University of Agostinho Neto, Angola and CAPES (the Brazilian Federal Agency for the Support and Evaluation of Higher Education).

References 1.

Freedman DS, Patel DA, Srinivasan SR, Chen W, Tang R, Bond MG, Berenson GS. The contribution of childhood obesity to adult carotid intima–media thickness: the Bogalusa Heart Study. Int J Obes 2008; 32: 749–756.

Raitakari OT, Juonala M, Kahonen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. J Am Med Assoc 2003; 290(17): 2277–2283.

May AL, Kuklina EV, Yoon PW. Prevalence of cardiovascular disease risk factors among US adolescents, 1999–2008. Pediatrics 2012; 129(6):

Limitations Our study has some limitations. Children from a single school were included, therefore our data cannot be translated to the overall population of Luanda. Since the school is located in a neighbourhood with families belonging to the middle class, it represents only the population attending public school with such characteristics. Moreover, the final sample (n = 198) was sufficient to determine a prevalence around 10% only, with an estimated error of 3.5% and power of 90%, making our study inadequate for subgroup analysis. We only included pre-pubertal children in the analysis to avoid the influence of adolescence in fat accumulation. In this group, the association between body fat and blood pressure can be observed without the well-known influence of sex hormones. Therefore, most of the analysis was conducted in the overall sample, increasing the robustness of the conclusions.

1035–1041. 4.

Whitworth JA. World Health Organization – International Society of Hypertension Writing Group. 2003 World Health Organization (WHO). International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21(11): 1983–1992.

Law CM, Swiet M, Osmond C, Fayers PM, Barker DJP, et al. Initiation of hypertension in utero and its amplification throughout life. Br Med J 1993; 306: 24–27.

Ay L, van Houten VAA, Steegers EAP, Hofman A, Witteman JCM, Jaddoe VWV, et al. Fetal and postnatal growth and body composition at 6 months of age. J Clin Endocrinol Metab 2009; 94(6): 2023–2030.

Freira, S. Risco cardiovascular na infância e adolescência. Factores de Risco, No 23 Out – Nov, 2011.

Sorof J, Daniels S. Obesity hypertension in children: a problem of epidemic proportions. Hypertension 2002; 40: 441–447.

Lever AF, Harrap SB. Essential hypertension: a disorder of growth with origins in childhood? J Hypertension 1992; 10: 101–120.

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10. Barker DJP. Fetal origins of coronary heart disease. Br Med J 1995; 311: 171–174. 11. Kolacek S, Kapetanovic T, Luzar V. Early determinants of cardiovascular risk factors in adults. B. Blood pressure. Acta Paediatr 1993; 82: 377–382. 12. Wannamethee SG, Whincup PH, Shaper G, Walker M. Influence of fathers’ social class on cardiovascular disease in middle-aged men. Lancet 1996; 348: 1259–1263. 13. Naghettini AV, Belem JMF, Salgado CM, Junior HMV, Seronni EMX, et al. Evaluation of risk and protection factors associated with high blood pressure in children. Arq Bras Cardiol 2010; 94(4): 458–463. 14. Giuliano ICB, Caramelli B. Dyslipidemia in childhood and adolescence. Pediatria (São Paulo) 2008; 29(4): 275–285. 15. Al-Shehri SN, Saleh ZA, Salama MM, Hassan YM. Prevalence of hyperlipidemia among Saudi school children in Riyadh. Ann Saudi Med 2004; 24: 6–8.

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29. Shi Y, Groh M, Morrison H. Increasing blood pressure and its associated factors in Canadian children and adolescents from the Canadian Health Measures Survey. BMC Public Health 2012; 12: 388. 30. Simão M, Hayashida M, Santos CB, Cesarino EJ, Nogueira MS. Hipertensão Arterial entre Universitários da cidade de Lubango, Angola. Rev Latino-Am Enfermagem 2008; 16(4): 1–8. 31. Moser DC, Giuliano ICB, Titski ACK, Gaya AR, Silva MJC, Leite N. Anthropometric measures and blood pressure in school children. J Pediatr (Rio J) 2013; 89(3): 243–249. 32. Sorof JM, Poffenbarger T, Franco K, Bernard L. Portman RJ. Isolated systolic hypertension, obesity, and hyperkinetic hemodynamic states in children. J Pediatr 2002; 140: 660–666. 33. Wunsch R, Sousa G, Toschke AM, Reinehr T. Intima–media thickness in obese children before and after weight loss. Pediatrics 2006; 118: 2334–2339. 34. Capingana DP, Magalhães P, Silva ABT, Gonçalves MAA, Baldo MP,

16. Rodrigues AN, Moyses MR, Bissoli NS, Pires JGP, Abreu GR.

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Braz J Med Biol Res 2006; 39(12): 1637–1642. 17. Caro FA, Díaz Martínb JJ, Galán IR, Solís DP, Obaya RV y Guerrero SM. Factores de riesgo cardiovascular clásicos y emergentes en escolares Asturianos. An Pediatr (Barc) 2011; 74(6): 388–395. 18. Abolfotouh MA, Sallam SA, Mohammed SM, Loutfy AA, Hasab AA. Prevalence of elevated blood pressure and association with obesity in Egyptian school adolescents. Int J Hypertens 2011; 8 March: 952537. 19. Vorster HH. The emergence of cardiovascular disease during urbanisation of Africans. Public Health Nutr 2002; 5(1A): 239–243. 20. Tanner JM. Growth at Adolescence. Oxford: Blackwell, 1962. 21. National Cholesterol Education Program (NCEP) e da American Academy of Pediatrics (AAP), adaptado pelo National Heart, Lung, and Blood Institute. NIH Publication No. 12-7486; October 2012. 22. Baylor College of Medicine (BCM). Measuring body composition for health and nutrition. localizado no Site https://www.bcm.edu/bodycomplab/.

Health 2013; 13: 732. 35. Panico S, Mattiello A. Epidemiology of cardiovascular diseases in women in Europa. Nutr Metab Cardiovasc Dis 2010; 20(6): 379–385. 36. Mendonça MRT, Silva MAM, Rivera IR, Moura AA. Prevalência de Sobrepeso e Obesidade em Crianças Adolescentes da cidade de Maceió. Rev Assoc Med Bras 2010; 56(2): 192–196. 37. Larsson C, Hemell O, Lind T. Moderately elevated body mass index is associated with metabolic variables and cardiovascular risk factors in Swedish children. Acta Pӕdiatrica 2011; 100: 102–108. 38. Neto ODA, Silva RCR, Assis AMO, Pinto EJ. Factors associated with dyslipidemia in children and adolescents enrolled in public schools of Salvador, Bahia. Rev Bras Epidemiol 2012; 15(2): 335–345. 39. Franca ED, Alves JGB. Dislipidemia entre crianças e adolescentes de Pernambuco. Arq Bras Cardiol 2006; 87: 722–727. 40. Moura EC, Castro CM, Mellin AS, Figueiredo DB. Perfil lipídico em escolares de Campinas, SP, Brasil. Rev Saúde Pública 2000; 34: 499–505.

23. World Health Organization. Obesity: Preventing and managing the

41. Romero FG, Morán MR. Prevalence of dyslipidemia in non-obese

global epidemic, Vol 894. Geneva: Report of a WHO consultation.

prepuberal children and its association with family history of diabetes,

WHO technical report, 2000. 24. Monyeki KD, Kemper HCG, Makgae PJ. The association of patterning with blood pressure in rural South African children: The Ellisras longitudinal growth and health study. Int J Epidemiol 2006; 35: 114–120. 25. Montañés EC, Geraud AA, Sardiña NG, Bustos CL. Circunferncia de cintura, dislipidemia e hiprtensión arterial en prepúberes de ambos sexos. An Pediatr (Barc) 2007; 67(1): 44–50. 26. Chiolero A, Madeleine G, Gabriel A, Burnier M, Paccaud F, Bovet P. Prevalence of elevated blood pressure and association with overweight in children of a rapidly developing country. J Hum Hypertens 2007; 21: 120–127. 27. Constanzi CB, Halpern R, Rech RR, Bergmann ML, Alli LR, Mattos AP. Associated factors in high blood pressure among schoolchildren in a middle size city, southern Brazil. J Pediatria (Rio J) 2009; 85(4): 335–340. 28. Salman Z, Kirk GD, DeBoer MD. High rate of obesity – associated hypertension among primary schoolchildren in Sudan. Int J Hypertens 2011; 22 Dec: 629492.

high blood pressure, and obesity. Arch Med Res 2006; 37: 1015–1021. 42. Daniels SR, Greer FR. Lipid Screening and cardiovascular health in childhood. Pediatrics 2008; 122: 198. 43. Grundy SM. Multifactorial causation of obesity: implications for prevention. Am J Clin Nutr 1998; 67(S3): 563–572. 44. Belue R, Okoror TA, Iwelunmor J, Taylor KD, Degboe AN, Agyemang C, Ogedegbe G. An overview of cardiovascular risk factor burden in sub-Saharan African countries: a socio-cultural perspective. Global Health 2009; 5: 10. 45. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. Bogalusa Heart Study. New Engl J Med 1998; 338(23): 1650–1656. 46. Freedman DS, Patel DA, Srinivasan SR, Chen W, Tang R, Bond MG, Berenson. The contribution of childhood obesity to adult carotid intima-media thickness: The Bogalusa Heart Study. Int J Obes 2008; 32: 749–756.

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Clustering of cardiovascular risk factors in semi-urban communities in south-western Nigeria R Oluyombo, PO Akinwusi, MA Olamoyegun, OE Ayodele, MB Fawale, OO Okunola, TO Olanrewaju, A Akinsola

Abstract Background: In addition to poor socio-economic indices and a high prevalence of infectious diseases, there have been various reports of a rising prevalence of cardiovascular diseases, with associated morbidity and mortality in developing countries. These factors co-exist, resulting in a synergy, with serious complications, difficult-to-treat conditions and fatal outcomes. Hence this study was conducted to determine the clustering of cardiovascular disease risk factors and its pattern in semi-urban communities in south-western Nigeria. Methods: This was a cross sectional study over seven months in 11 semi-urban communities in south-western Nigeria. Results: The total number of participants was 1 285 but only 1 083, with 785 (65%) females, completed the data. Participants were 18 years and older, and 51.2% were over 60 years. The mean age was 55.12 ± 19.85 years. There were 2.6% current cigarette smokers, 22% drank alcohol and 12.2% added salt at the table, while 2% had been told by their doctors they had diabetes, and 23.6% had hypertension. The atherogenic index of plasma was at a high-risk level of 11.1%. Elevated total cholesterol and low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol levels were seen in 5.7, 3.7 and 65.1%, respectively. Prevalence of hypertension was 44.9%, diabetes was 5.2%, obesity with body mass index (BMI) > 30 kg/m2 was 5.7%, and abdominal circumference was 25.7%. Prevalence of clusters of two, three, and four or more risk factors was 23.1, 15.5 and 8.4%, respectively. Increasing age 2.94 (95% CI: 1.30–6.67), BMI 1.18 (95% CI:

Renal Unit, Department of Internal Medicine, Federal Teaching Hospital, Ido-Ekiti, Ekiti State, Nigeria R Oluyombo, MD, abuky2005@yahoo.co.uk

Cardiology Unit, College of Health Sciences, Osun State University, Osogbo, Nigeria PO Akinwusi, MD

Department of Internal Medicine, Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso, Oyo State, Nigeria MA Olamoyegun, MD OE Ayodele, MD

Department of Internal Medicine, Obafemi Awolowo University Teaching Hospitals, Ile-Ife, Osun State, Nigeria MB Fawale, MD OO Okunola, MD A Akinsola, MD

Renal Division, Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria TO Olanrewaju, MD

1.02–1.37), fasting plasma glucose level 1.03 (95% CI: 1.00– 1.05), albuminuria 1.03 (95% CI: 1.00–1.05), systolic blood pressure 1.07 (95% CI: 1.04–1.10), diastolic blood pressure 1.06 (95% CI: 1.00–1.11) and female gender 2.94 (95% CI: 1.30–6.67) showed increased odds of clustering of two or more cardiovascular risk factors. Conclusion: Clustering of cardiovascular risk factors is prevalent in these communities. Patterns of clustering vary. This calls for aggressive and targeted public health interventions to prevent or reduce the burden of cardiovascular disease, as the consequences could be detrimental to the country. Keywords: clustering, cardiovascular, risk factors Submitted 20/12/14, accepted 8/3/16 Published online 10/6/16 Cardiovasc J Afr 2016; 27: 322–327

www.cvja.co.za

DOI: 10.5830/CVJA-2016-024

Cardiovascular disease (CVD) is the leading cause of death globally, accounting for 17.3 million deaths per year. This is projected to increase to more than 23.6 million by 2030.1,2 It would be a crisis for developing countries to have to undergo this additional burden, as they are already faced with a multiple burden of other challenges, such as poor socio-economic indices, high prevalence of infectious diseases,3 and a trend towards highcaloric nutrition and sedentary lifestyles.4 An epidemic of CVD would have a detrimental effect on their already weakened health system. In developing nations, unlike in developed countries, greater proportions of younger people are affected. Eighty per cent of deaths resulting from CVD occur between the ages of 30 and 70 years in developing countries.5 This is in contrast to 14 and 12% reported for the USA and UK, respectively.6 This would lead to depletion of the already insufficient workforce and a worsening of the poor economic status in developing nations. Nearly half of the annual output loss of US$ 500 billion is attributable to CVD.7 There have been reports of increased prevalence of CVD risk factors in Nigeria, with hypertension, diabetes, hyperlipidaemia and obesity as the leading modifiable causes.8,9 Studies have shown co-existence and interaction of these risk factors, causing them to become difficult-to-treat conditions, and resulting in serious complications and fatal outcomes.10,11. Findings from south-western and southern Nigerian people show a trend towards a high risk of developing major cardiovascular events over a 10-year period, with a cardiovascular mortality of 33.5% among individuals in the productive age group.12,13 Nigeria is the most populous country in Africa and has a population of 169 million, with over 50% living in rural communities.3

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Surprisingly, in 2014, the World Health Organisation reported an absence of operational policies or action plans to reduce the risk factors for CVD. This is in spite of the goodwill adopted by world leaders at the United Nations General Assembly to reduce premature mortality from non-communicable diseases by 25% in 2025.4 Curtailing the challenge of CVD requires knowledge of its burden and risk factors, committed and effective socio-political interventions, and inexpensive strategies. This has contributed to the gradual and sustained decline in mortality in high-income countries. This study therefore set out to determine the prevalence and pattern of clustering of risk factors, as this will effectively influence formulation of policies to curb detrimental health consequences in developing countries such as Nigeria. It was also of importance to determine whether clustering of cardiovascular risk factors occurs in patients from the semi-urban areas that access medical treatment from the hospitals where we practice, so we can subvert the imminent cardiovascular disease epidemic.

Methods This was a cross-sectional study spanning seven months, conducted in 11 semi-urban communities in Ekiti and Osun States, south-western Nigeria. Each of the towns was randomly picked from six local government areas (two communities per local government area). Using multi-staged sampling, participants aged 18 years and older were enrolled into the study. In Osun state, Ilie in Olorunda local government was chosen. The local governments and towns chosen in Ekiti state were Ilejemeje (Iludun, Ilupeju), Ijero (Ayegunle, Oke-Iro), Ido-Osi (Ayetoro, Orin), Oye (Ilupeju, Itapa) and Moba (Osun, Ikun). In Ilie for instance, there were 32 compounds, out of which 16 were randomly selected. Out of these 16 compounds, eight were finally selected for the study. For some of the communities, convenient sampling was adopted for the peculiarities of these communities. The towns were predominantly agrarian with traders and few civil servants. Four hundred and sixty-eight and 835 participants were recruited from Osun and Ekiti states, respectively. Of the 1 285 enrolled in the study, 1 083 had complete data for analysis. The community leaders had given prior consent after formal briefing in the presence of other chiefs who were the compound leaders. Informed consent was taken in the language best understood. The study was approved by the ethics committees of Ladoke Akintola University of Technology Teaching Hospital and Federal Medical centre, Ido-Ekiti. Designated centres that were convenient for the subjects were used for the screening exercise. We used the World Health Organisation (WHO) STEPS questionnaires to obtain information from the participants.

Sampling Fasting blood samples (3 ml) were collected into lithium heparin bottles. Aseptic precautions were ensured. Fasting blood sugar was assayed with an Accu-check glucometer immediately after blood collection. The measuring range of the device for glucose is 50–600 mg/dl. Samples were thereafter taken to the chemical pathology laboratory of the Federal Medical Centre, Ido-Ekiti and Ladoke Akintola Teaching Hospital, Osogbo for analysis.

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Samples were analysed for concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and uric acid. For participants with TG values < 4.5 mmol/l, low-density lipoprotein cholesterol (LDL-C) was calculated from the Friedwald equation: LDL-C = (TC – HDL-C – TG)/5. Administration of questionnaires, biophysical measurements and collection of blood specimen was done by trained assistants who were also medical doctors. Three measurements were taken after the participants had rested for five minutes. Participants were encouraged not to smoke, take alcohol or undertake exercise for at least 30 minutes before blood pressure measurement. Validated blood pressure apparatus (Omron M X2 Basic, Omron health care Co Ltd, Kyoto, Japan) was used. The average of two measurements was used if the difference between them was not more than 5 mmHg. Height was measured to the nearest 0.1 cm using a standardised, marked measuring tape. Participants were asked to stand barefoot against a tape-marked vertical wall. Weight was measured to the nearest 0.1 kg using a standardised bathroom scale. Waist circumference was taken midway between the sub-costal margin and the iliac crest, to the nearest 0.1 cm.

Definitions Cardiovascular disease refers to a group of diseases involving the heart and blood vessels or the sequelae of poor blood supply due to a diseased vascular system. Hypertension was defined as blood pressure ≥ 140/90 mmHg or the use of antihypertensive medication(s). Diabetes was defined as a fasting plasma glucose level ≥ 7 mmol/l or a reported history of diabetes, or the use of glucose-lowering drugs. Dyslipidaemia was defined according to the Adult Treatment Panel (ATP) III guidelines14 as having one or more of the following factors present: TC ≥ 5.2 mmol/l, TG ≥ 1.7 mmol/l, HDL-C < 1.03 mmol/l in men and < 1.30 mmol/l in women, LDL-C ≥ 3.4 mmol/l, or a history of medication with lipidlowering drugs. High atherogenic index was defined as TC/ HDL-C ≥ 5. Indices of abnormal fat distribution were also defined according to the ATP III guidelines as waist circumference (WC) ≥ 94 cm in men and ≥ 80 cm in women; and body mass index (BMI) ≥ 25 kg/m2 as overweight and ≥ 30 kg/m2 as obese. Participants with high blood pressure or symptomatic diabetes were referred to hospital for treatment and encouraged to go for follow up.

Statistical analysis Data analysis was done using SPSS version 20.0 (SPSS Inc, Chicago, Illinois, USA). The prevalence of each of the cardiovascular risk factors was determined and they are presented as frequencies and percentages. Continuous variables are presented as mean ± SD while categorical variables are presented as frequencies and percentages. The prevalence of risk factors in clusters of two, three or more was determined. Multivariate analysis of risk factors associated with two or more risk factors was carried out and the results are expressed as odds ratios with 95% confidence interval (CI). A significance level of p < 0.05 was used.

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Results There were 785 (65%) females, mainly petty traders (41.4%) and farmers (28.1%). The mean age of participants was 55.12 ± 19.85 years (Table 1), with participants aged ≥ 60 years constituting 51.4%. Six hundred and twenty-three (51.6%) subjects had no formal education and only 8.3% had tertiary education. Eightyfour per cent earned less than N20 000 ($120 US) per month. We analysed the data of 1 083 participants. Two hundred and sixty-six (22%) subjects consumed alcohol, mainly beer (43.3%) and fresh palm wine (35.1%). Ninety-eight per cent added salt to their meals while cooking but only 12.2% added salt on the table while eating, and 43.5% were involved in vigorous activity that increased heart rate and breathing. Twenty-four (2%) participants had been told they had diabetes and 18 (75%) were receiving treatment from medical doctors, while seven (29%) used herbal remedies. There were 286 (23.6%) participants with a prior history of hypertension before the screening exercise. Thirty-two (2.6%) participants were current cigarette smokers, 69 (5.7%) had elevated total cholesterol levels, 244 (20.2%) elevated triglyceride levels, and 69 (5.7%) were obese; 65.1% had low HDL-C values, while 3.7% (45) had high LDL-C levels and 11.1% high-risk atherogenic plasma index. Diabetes and elevated uric acid levels were present in 63 (5.2%) and 422 (34.9%) participants, respectively. Systolic blood pressure (SBP) ≥ 140 mmHg and diastolic blood pressure (DBP) ≥ 90 mmHg were seen in 499 (41.3%) and 294 (22.4%), respectively. Two hundred and fifty (20.7%) participants had high systolic and diastolic blood pressures. Overall prevalence of hypertension was 542 (44.9%) subjects, of whom 383 (70.6%) were over 60 years of age. Participants with two or more risk factors were older than those with none (p = 0.001) (Table 2), and similarly, the higher the mean values of waist circumference, the more the clustering of risk factors. There was a mean difference in SBP (14.6 ± 2.8 mmHg, p < 0.01) and DBP (6.3 ± 1.4 mmHg, p < 0.01), waist circumference (5.9 ± 1.2 cm, p < 0.01) and BMI (4.4 ± 2.2 kg/m2, p = 0.36) between participants with two risk factors and those with no risk factors (p < 0.01). However, a mean difference in BMI of 3.4 ± 0.5 kg/m2 was significant between subjects with

Table 2. Stratification of clustering of cardiovascular risk factors and mean values of selected risk factors among the participants ≥ 4 risk factors

Variables*

No risk factor

1 risk factor

2 risk factors

3 risk factors

Age (years)

1083

47.4 ± 21.3

49.9 ± 21.1

57.1 ± 19.4

64.8 ± 15.7

p-value

63.5 ± 14.0 < 0.01

WC (cm)

1067

77.5 ± 7.3

78.5 ± 8.4

83.5 ± 11.4

87.2 ± 12.6

94.2 ± 12.1 < 0.01

BMI (kg/m2)

1078

20.8 ± 2.1

21.3 ± 3.0

22.1 ± 3.9

24.2 ± 6.9

26.8 ± 5.8

SBP (mmHg)

1070 124.0 ± 20.4 128.2 ± 23.8 138.7 ± 26.3 151.1 ± 27.2 155.8 ± 26.4 < 0.01

DBP (mmHg)

1070

73.7 ± 10.5

75.4 ± 11.7

TC (mmol/l)

1083

3.6 ± 0.9

3.3 ± 1.0

3.3 ± 1

3.4 ± 1.1

3.4 ± 1.5

0.04

LDL-C (mmol/l) 1083

1.5 ± 0.7

1.6 ± 0.8

1.6 ± 0.7

1.8 ± 0.9

1.9 ± 1.2

< 0.01

HDL-C (mmol/l) 1083

1.5 ± 0.6

1.0 ± 0.5

1 ± 0.4

0.9 ± 0.4

0.8 ± 0.4

< 0.01

TG (mmol/l)

1083

1.2 ± 0.9

1.2 ± 0.8

1.1 ± 0.8

0.58

TC/HDL-C

1083

2.8 ± 1.4

3.2 ± 2.5

3.3 ± 2.1

3.7 ± 2.5

4.1 ± 2.8

0.01

608

5.0 ± 0.8

5.3 ± 0.9

5.4 ± 1.2

5.7 ± 2.1

6.4 ± 2.9

< 0.01

FBG (mmol/l)

80.0 ± 13.2

85.4 ± 15.1

< 0.01

87.1 ± 11.6 < 0.01

*Mean of the variables ± SD. BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, TC: total cholesterol, LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, TC: total cholesterol, FPG: fasting plasma glucose.

three or more risk factors and those without any risk factors. At a mean difference of 0.34 ± 0.01 mmol/l, those with two or more risk factors had higher total cholesterol than those without risk factors (p = 0.006). Classification by body adiposity showed that participants with overweight (BMI > 25 kg/m2) and obesity (BMI > 30 kg/m2) had higher clusters (two or more) of cardiovascular risk factors than those with normal weight (34.5 vs 49.3 vs 42%, p = 0.01). The prevalence of one, two and three or more cardiovascular risk factors were 35.7, 32 and 7.7%, respectively. Fig. 1 shows the stratified age distribution of prevalence of the clusters of risk factors. Prevalence of clusters of two, three, and four or more risk factors was 23.1, 15.5 and 8.4%, respectively. The number and burden of risk factors (cluster) increased with age (Table 2, Fig. 2), and women had higher clustering of cardiovascular risk factors (p = 0.001) (Fig. 2). Selecting some risk factors, as shown in Fig. 4, participants with microalbuminuria had greater clusters of cardiovascular risk factors than those with normal values (21.2 vs 3.3%, p = 0.01). Similarly, as shown in Fig. 3, those with obesity (BMI > 30 kg/m2) (p = 0.001) and diabetes (p = 0.001) had more clusters (three or more) of cardiovascular risk factors. Multivariate analysis (Table 3) between the selected risk factors and clustering of two or more risk factors showed

Table 1. Demographic, clinical and laboratory parameters of the participants by gender Variables

Male Female (mean ± SD) (mean ± SD)

70 Total

p-value

1083

51.8 ± 21.4

57.0 ± 18.7

55.1 ± 19.9 < 0.01

1083

22.7 ± 19.5

24.0 ± 22.3

23.6 ± 21.4

WC (cm)

1083

80.7 ± 9.9

84.5 ± 12.5

83.2 ± 11.8 < 0.01

TC (mmol/l)

1083

3.4 ± 1.1

0.8

LDL-C (mmol/l)

1083

1.5

1.6

< 0.01

HDL-C (mmol/l)

1083

1.0

0.5

TG (mmol/l)

1083

1.0

0.9

< 0.01

Serum uric acid (mg/dl) 1083

8.4

6.7

< 0.01

0.3

SBP (mmHg)

1083 136.0 ± 25.4

137.5 ± 27.4 137.0 ± 26.8

DBP (mmHg)

1083

78.1 ± 13.6

80.1 ± 13.3

Urine ACR (mg/g)

754

15.0

20.0

0.05

FPG (mmol/l)

689 102.2 ± 30.5

98.2 ± 28.4

99.7 ± 29.3

0.08

79.4 ± 13.4 < 0.01

BMI: body mass index, WC: waist circumference, TC: total cholesterol, LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipoprotein cholesterol, TG: triglycerides, SBP: systolic blood pressure, DBP: diastolic blood pressure, ACR: albumin–creatinine ratio, FPG: fasting plasma glucose.

Clustered risk factors

Mean age (years) BMI (kg/m2)

0.28

p = 0.001

60 50 40 30 20

18–39

40–59

60–79

>80

Age groups of participants 1 risk factor

2 risk factors

3 risk factors

Fig. 1. Age groups of participants and clustering of cardiovascular risk factors.

50 45

3 risk factors

Clustered risk factors Female

Male

Fig. 2. D istribution of cardiovascular risk factors cluster between men and women.

increasing odds of clustering with increased age 1.07 (95% CI: 1.30–6.67), SBP 1.07 (95% CI: 1.04–1.10), DBP 1.06 (95% CI: 1.00–1.11) and BMI 1.18 (95% CI: 1.02–1.37).

Discussion This study has shown a high prevalence of cardiovascular risk factors and clustering of these risk factors among the study population. We found a prevalence of 32.9 and 8% of two and at least three cardiovascular risk clusters, respectively. Unlike in developed countries, but as seen in this study, the economically productive age groups were more affected. The co-existence and synergistic effects of clusters of risk factors may explain the high burden and poor outcome of cardiovascular events such as stroke and death among blacks.15-19 The rapidity of lifestyle changes, increased market globalisation and the genetic make-up of the population could also explain this high prevalence. This is disturbing because the majority of people in the country have a low socio-economic status, with 84% earning N20 000 ($120) or less per month. The economic and social impact of cardiovascular disease would therefore be Table 3. Multivariate adjusted analysis of cardiovascular risk factors and clustering of risk factors p-value

Exp

95% CI

Gender

1.080

0.01

2.94

1.30–6.67

Age

0.097

< 0.01

1.10

1.07–1.13

SBP

0.070

< 0.01

1.07

1.04–1.10

DBP

0.054

0.01

1.06

1.00–1.11

0.034

0.183

1.04

0.98–1.08

BMI

0.166

0.029

1.18

1.02–1.37

0.160

0.40

1.17

0.81–1.71

HDL-C

–1.829

< 0.01

0.16

0.06–0.41

LDL-C

0.262

0.180

1.30

0.89–1.90

FPG

0.029

0.005

1.03

1.00–1.05

ACR

0.033

0.007

1.03

1.00–1.05

Variables

SBP: systolic blood pressure, DBP: diastolic blood pressure, WC: waist circumference, BMI: body mass index, TC: total cholesterol, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, FPG: fasting plasma glucose, ACR: albumin–creatinine ratio.

0 Obesity by BMI

2 risk factors

Overweight

1 risk factor

5 Systolic hypertension

15 10

Diastolic hypertension

Elevated cholesterol

Low HDL-C

Impaired fasting glucose

Diabetes

Microalbuminuria

p = 0.001

Age

Prevalence of clustered cardiovascular risk factors

Prevalence of clustered risk factors for selected cardiovascular factors

50 45

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Abdominal obesity

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Fig. 3. Selected cardiovascular risk factors and weight of clustering of other risk factors.

heavy on a developing country such as Nigeria if this trend is sustained. With clustering of risk factors and increased clustering among the participants, the mean values of the risk factors were observed to be significantly related. There is a high rate of undiagnosed cardiovascular risk factors in Nigeria and the sub-region.8,9 The earlier the diagnosis is made the better the outcome, as this prevents progression to atherosclerosis, and worsening of non-conventional cardiovascular risk factors and associated end-organ damage, which is usually irreversible. This calls for regular screening and comprehensive examination of patients at every opportunity. Studies have shown the impressive results of early intervention programmes.20 Lifestyle changes and/or the use of medications to treat hypertension, for instance, would reduce morbidity and mortality rates.21,22 Nowadays, diets that are rich in saturated fats and refined carbohydrates and low in vegetables, and increasing sedentary lifestyles are replacing traditional diets. Males had a higher prevalence of a single risk factor, however, females had more clustering than males. This became more marked at middle age when clustering was more than doubled (Fig. 1). Our study showed significantly higher prevalence of low HDL-C, high LDL-C and triglyceride levels, obesity, and diastolic and systolic hypertension among women than men. These physiological mechanisms, in association with changes in their hormone levels with age, may be contributory. In a similar community study conducted by Oladapo et al.,9 more women than men had a high prevalence of clustering of risk factors. More men than women had high blood pressure until 45 years of age but thereafter women caught up and later surpassed men in prevalence and occurrence of hypertension, coronary heart disease and stroke.20-23 Studies have also shown that females reported less physical activity than males.24,25 In this study, the higher the number of clustered risk factors, the higher the mean values of the risk factors. This suggests the

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need for appropriate preventative and therapeutic intervention to retard progression and prevent poor outcomes, with our limited health resources. Access to healthcare will increase utilisation of health facilities, provide early intervention through medication and lifestyle changes, and ensure regular monitoring. Policies on good dietary audits and healthy lifestyles should be developed and effectively implemented. Regular screening of populations at risk should also be encouraged. There is evidence that therapeutic interventions are effective in treating overt medical conditions such as diabetes and hypertension, both of which in this study contributed significantly to clustering of risk factors.26,27 Similarly, obesity was associated with clustering of risk factors. This is in agreement with reports by Bayauli et al.28 in Congo and Dahiru29 in northern Nigeria. The odds of clustering of cardiovascular risk factors increase with degree of obesity. In 2010, about 3.6 million deaths were estimated to result from overweight and obesity, with 3.9% years lost and 3.8% lost in disability-adjusted life-years.30 Prevalence of obesity has increased, not only in adults but also among children and adolescents in both developed and developing countries. Increased adiposity is a significant risk factor for atherogenesis and increased coagulability. Obesity is described as a chronic and systemic inflammatory disease as a result of the release of enormous pro-inflammatory cytokines and increasing insulin insensitivity. The rising prevalence of obesity is a threat to global health. Microalbuminuria also increased the odds for cardiovascular risk clustering. Its presence suggests endothelial damage and it is an independent atherosclerotic risk factor.31 Its detection underscores high risk of cardiovascular disease and all-cause mortality, not just among people with diabetes but also in the general population.32,33 Prompt treatment of microalbumiuria among patients with diabetes, for instance, significantly ameliorates associated morbidity, such as diabetic nephropathy, which is usually a serious consequence. However, in view of the clustering of risk factors, multiple therapeutic approaches are suggested. This ensures coverage of most of the risk factors, as recommended in the guidelines.34,35 Varying reports have stressed the driving effect of hypertension and insulin resistance on other cardiovascular diseases. In this study, increasing blood pressure and plasma glucose levels were independently associated with increasing odds of clustering of risk factors. Few other studies have refuted the possible association, especially insulin resistance and other risk factors. Our study demonstrated that each of the cardiovascular risk factors has varying degrees of clustering. The interplay among these various factors leads to similar physiological and structural dysfunction. For instance, microalbuminuria, insulin insensitivity and diabetes are associated with endothelial dysfunction.36 Sloten et al. therefore suggested therapeutic interventions that would target the common pathology and control risk factors that interact rather than those that do not interact.37 Our study has some limitations. It was a cross-sectional study. We were unable to discuss the sequence of events, and causality could not be established for cardiovascular events. The diagnoses of diabetes and hypertension were made during one visit, although protocols as recommended in the guidelines were strictly adhered to. Also, microalbuminuria was checked only once, as efforts to collect the samples after three months were frustrated by poor participation. On average, about one out of four initial participants re-presented for the second screening.

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This was terminated after the third community was visited, with the same experience.

Conclusion This study has shown not only the presence of cardiovascular risk factors, as in other studies, but also a high prevalence of clusters of such risk factors. The pattern of clustering showed significant association with conventional cardiovascular risk factors. These clusters will increase the health burden, promote rapid progression to end-organ damage and increased mortality rates if there is no planned and appropriate intervention. This is of great concern as it also portends a dwindling socioeconomic status in developing nations. It is important to stress a comprehensive approach of primary, secondary and tertiary preventative measures and control of these factors in order to reduce the overall burden of cardiovascular diseases. We acknowledge the royal fathers and community leaders for their support. We also thank members of staff of the Comprehensive Health Centre, Ilie, and the supporting staff of the Department of Community Medicine, Federal Teaching Hospital, Ido-Ekiti.

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11. Guize L, Thomas F, Pannier B, Bean K, Jego B, Benetos A. All-cause mortality associated with specific combinations of the metabolic syndrome according to recent definitions. Diabetes Care 2007; 30(9): 2381–2387. 12. Oluyombo R, Olamoyegun MA, Olaifa O, Iwuala SO, Babatunde OA.

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3(5): 519–524. 32. Naidoo DP. The link between microalbuminuria, endothelial dysfunction and cardiovascular disease in diabetes. Cardiovasc J Sth Afr 2002; 13(4): 194–199. 33. Weir MR. Microalbuminuria and cardiovascular disease. Can J Am Soc Nephrol 2007; 2(3): 581–590.

19. Steyn K, Damasceno A. Lifestyle and related risk factors for chronic

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Indian industrial population. Indian J Med Res 2012; 135: 485–493. 21. Cappucio F P, Plange-Rhule J, Philips RO, Eastwood JB. Prevention of hypertension and stroke in Africa. Lancet 2000; 356: 677–678.

507–520. 36. Stehouwer CD, Henry RM, Dekker JM, Nijpels G, Heine RJ, Bouter LM. Microalbuminuria is associated with impaired brachial artery,

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flow-mediated vasodilation in elderly individuals without and with

for cardiovascular risk reduction in diverse and underserved racial/

diabetes: further evidence for a link between microalbuminuria and

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endothelial dysfunction- the Hoorn Study. Kidney Int 2004; 92(Suppl):

23. Pilote L, Dasgupta K, Guru V, Humphries KH, McGrath J, Norris C, et al. A comprehensive view of sex-specific issues related to cardiovascular disease. Can Med Assoc J 2007; 176: S1–S444. 24. Kruger J. Prevalence of regular physical activity among adults – United States, 2001 and 2005. Morb Mortal Wkly Rep 2007; 56: 1209–1212. 25. Naci H. Comparative effectiveness of exercise and drug intervention

S42–44. 37. Van Sloten TT, Henry RM, Dekker JM, Nijpels G, Unger T, Schram MT, Stehouwer CD. Endothelial dysfunction plays a key role in increasing cardiovascular risk in type 2 diabetes: the Hoorn study. Hypertension 2014; 64: 1299–1305.

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Patient outcomes following after-hours and weekend admissions for cardiovascular disease in a tertiary hospital in Calabar, Nigeria Victor Ansa, Akaninyene Otu, Affiong Oku, Uchenna Njideoffor, Charles Nworah, Clement Odigwe

Abstract Background: There are various reports of higher mortality rates occurring after admissions over the weekend and during after-hours. This study aimed to determine if there was a difference in mortality rates occurring during the weekend and after-hours among cardiovascular admissions in a tertiary hospital in Nigeria. Methods: A review of cardiovascular admissions (including stroke) was carried out at the University of Calabar Teaching Hospital in Nigeria from January 2010 to December 2013. All admissions to the medical wards from the emergency department and medical out-patient department clinics during the study period were included. Results: A total of 339 patients were studied and stroke was the commonest type of cardiovascular disease (CVD) admitted (187; 55.2%). Hypertension was the commonest cause of heart failure (70; 48.6%). Presentation to hospital during after-hours and length of stay of more than 14 days were significant predictors of death (OR: 3.37; 0.22). Conclusion: An increase in CVD mortality rates occurred during after-hours, most likely a consequence of uneven staffing patterns and poor access to equipment. Healthcare providers in Nigeria need to consider remedies to this with a view to reducing excess mortality rates. Keywords: cardiovascular disease, after hours, weekend, Calabar, poor outcome, staffing Submitted 27/5/15, accepted 8/3/16 Published online 12/4/16 Cardiovasc J Afr 2016; 27: 328–332

www.cvja.co.za

DOI: 10.5830/CVJA-2016-025

Cardiology Unit, Department of Internal Medicine, University of Calabar, Calabar, Cross River State, Nigeria Victor Ansa, MB BS, FWACP, FACP, FRCP, vic_ansa@yahoo.com Uchenna Njideoffor, MB BS Charles Nworah, MB BS Clement Odigwe, MB BS, FMCP, FWACP

Department of Internal Medicine, University of Calabar, Calabar, Cross River State, Nigeria Akaninyene Otu, MB BCh, MPH, FWACP

Department of Community Medicine, University of Calabar, Calabar, Cross River State, Nigeria Affiong Oku, MB BCh, MPH, FWACP

Staffing of hospitals generally tends to be lower during weekends and after-hours.1 After-hours services entail engaging in or operating after the legal or conventional closing time during weekdays. Considerable strain is put on health workers who cover these shifts due to lower staffing in hospitals during these periods. These health personnel also tend to be juniors who work with less supervision. This potentially poorer quality of medical care2 tends to occur irrespective of the fact that the incidence of many medical diseases is similar from day to day.3 Also, very ill patients may present during after-hours, as disease appears to be no respecter of time. Various researchers have demonstrated strong associations between these staffing variations and higher mortality rates during weekends and after-hours.4-6 A ‘weekend effect’ has been demonstrated in various studies to occur for a variety of diagnoses, including stroke, myocardial infarction, pulmonary embolism and ruptured aortic aneurysm.1,7-9 Delays in the review of patients and in obtaining senior opinions have been suggested as contributing factors to avoidable mortalities at these times.10 These findings pose a strong challenge to the concept of equity, which posits that patients receive equal care regardless of when they present to hospital. The majority of studies on hospital mortality rates during weekends and after-hours have been carried out in developed countries with considerably stronger healthcare systems, compared to developing nations. Very little research has been done in Nigeria to see if the reported increase in mortality rates in hospitals during the weekend and after-hours applies in our context. This assessment is crucial as identiﬁcation and quantiﬁcation of increased weekend mortality rates may promote the redesign of healthcare services in order to improve outcomes. Nwosu and colleagues, in their study of in-patient data in all wards of a tertiary hospital in Nigeria, found a significant difference in hospital mortality rates between weekdays and weekends only in patients admitted to the labour ward.11 In this study, we aimed to investigate cardiovascular admissions, including stroke, in the University of Calabar Teaching Hospital (UCTH), to determine if there was a significant difference in mortality rates occurring during the weekend or after-hours compared with regular working hours.

Methods This retrospective medical record review was carried out in UCTH from January 2010 to December 2013. The UCTH is the only tertiary health facility in the Cross River state, which is in south-eastern Nigeria. It receives referrals from across the state and its environs. All admissions to the medical wards from the emergency department and medical out-patients’ department clinics during

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the study period were included. This comprised adults over 18 years of age. Cardiovascular admissions, including strokes, were then extracted. After-hours was considered to be between 16:00 on one day and 08:00 the next day. Weekends were defined as the period from 16:00 on Friday to 08:00 on Monday. All other times were defined as weekdays. Socio-demographic data such as age, gender, ethnicity, marital status and occupation were captured. Other data such as day and time of admission, clinical diagnosis, and length of stay in hospital, as well as outcome of the admission were also ascertained. The case definition for cardiovascular disease was any disorder of the heart and/or blood vessels and included the following: coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, arrhythmias, deep-vein thrombosis and pulmonary embolism, and their complications. Ethical clearance was obtained from the Health Research and Ethics Committee (HREC) of the UCTH.

Statistical analysis Data were analysed using STATA V 13.0 (Stata Corp Lp, College of Station Texas, USA). Continuous variables were presented as means or median and interquartile ranges (for skewed data), while categorical variables were presented as percentages. The chi-squared test was used to test the significance of association Table 1. Socio-demographic characteristics of the subjects Variable

Frequency

Percentage

Age (years) < 29

4.4

30–39

10.6

between categorical variables. Continuous variables were also converted into categorical variables and compared using the chi-squared test (or Fischer’s exact test where indicated). A logistic regression model was built to identify covariates of poor outcome among the patients studied. A p-value of < 0.05 was regarded as the level of statistical significance.

Results A total of 339 patients were admitted during the study period and this accounted for 34.5% of the total medical admissions. Most (286; 84.4%) of these admissions occurred via the emergency department while 53 (15.6%) came via the medical out-patients’ clinic. Females were in the majority (207; 61.1%) with a male:female ratio of 1:1.05 (p = 0.92). The median age of all participants was 55 years with an interquartile range of 47–65 years. The commonest occupational category among the patients was skilled non-manual (120; 35.4%), while professional workers were fewest (7; 2.1%), as shown in Table 1. With regard to the type of cardiovascular disease (CVD) diagnosed on presentation to hospital, stroke was most common (187; 55.2%) and this was closely followed by congestive heart failure (CHF) in 144 (42.5%) patients. The causes of heart failure included hypertension (70; 48.6%), dilated cardiomyopathy (51; 35.4%), rheumatic heart disease (2; 1.4%) and anaemia (21; 14.6%) (Fig. 1). More patients (257; 75.8%) presented during weekdays compared with over the weekends, as shown in Table 2. Of the 339 patients studied, slightly more than half (198; 58.4%) presented during working hours, while 141 (41.6%) presented during after-hours. The consultant’s review of the studied patients tended to occur mostly within two to seven days of admission (54%) and few patients (23; 6.8%) were reviewed by Table 2. Profile of cardiovascular disease/presentation

40–49

13.9

50–59

104

30.7

Variable

≥ 60

137

40.4

Type of cardiovascular disease

Male

132

38.9

Female

207

61.1

Arrhythmias

Gender

Occupation

Frequency

Percentage

Stroke

187

55.2

Heart failure (CHF)

144

42.5

2.4

Causes of heart failure

Professional

2.1

Hypertension

48.6

Managerial

15.6

Dilated cardiomyopathy

35.4

Skilled manual

14.5

Anaemia

14.6

120

35.4

Rheumatic heart disease

1.4

Retired

28.0

Student

4.4

Weekdays

257

75.8

Weekends

24.2

Working hours

198

58.4

After hours

141

41.6

4.0

Skilled non-manual

50 45 40 35 30 25 20 15 10 5 0

48.6

Time of presentation

First contact doctor

35.4

Consultant Senior resident Registrar/house officer

1.4

Fig. 1. Causes of heart failure.

Anaemia

1.8

319

98.2

Days to consultant review

14.6

Hypertension Dilated cardiomyopathy

Rheumatic heart disease

≤1

133

39.2

2–7

183

54.0

6.8

< 14

197

54.4

> 14

152

45.6

Days admitted

CHF: congestive heart failure.

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consultants more than seven days after admission, as shown in Table 2. In 4% of all patients studied, a consultant was the first contact doctor. More patients (54.4%) were admitted for less than 14 days, compared with those admitted for a longer time. Bivariate analysis revealed that being over 55 years of age, type of CVD, rheumatic heart disease and anaemia as causes of heart failure, as well as duration of hospitalisation were significantly associated with poor outcome (p < 0.05), as shown in Table 3. Further subgroup analysis revealed that patients with CHF had a higher risk of a poor outcome compared with those who had CVD due to stroke or arrhythmias. Variables that were not significantly associated with poor outcome were gender, status of first contact doctor, mode of admission, time of day seen, day of presentation and promptness of consultant’s review. A logistic regression model was built using seven variables, as show in Table 4. Presentation to hospital during after-hours and hospital stay of more than 14 days were significant predictors of poor outcome. Those who presented to hospital after hours were three times more likely to have a poor outcome, compared to those who presented within regular working hours. Also, patients who were admitted for more than 14 days had a greater likelihood of having a poor outcome, compared with those who spent less than 14 days in hospital.

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Discussion This study has shown that most patients with CVD presenting at our centre in a developing country were in the sixth decade of life, which is two decades earlier than the typical presentation in developed countries. This corroborates the findings of the INTERHEART Africa study.12 Most of the patients were in the lower middle class (skilled non-manual), the so called ‘urban poor’, who have absorbed the Western lifestyle as a status symbol, an indication of the epidemiological transition currently taking place in this region. There were fewer professionals, in the higher socio-economic class, and this could have been attributed to their better awareness of cardiovascular risk factors and the adoption of healthy lifestyles, or better compliance with their medication. Another reason may have been that professionals do not commonly use public hospitals such as the one in which this study was carried out. The majority of the patients presented with stroke and this corroborates the findings in other studies, which have shown that stroke is more common in black hypertensives than in non-blacks,13,14 and that the risk of a first stroke is about twice as high in blacks as in whites.15 Stroke has been identified as a major health problem in Nigeria,16-18 which could be linked to a

Table 3. Bivariate analysis of variables with regard to poor outcome Variable

Died (%)

Discharged/ referred

≤ 55

29 (16.1)

> 55

43 (27.0)

p-value

LAMA (%)

Chi-squared test

129 (71.7)

22 (12.2)

6.17

0.04*

101 (63.5)

15 (9.4) 13 (9.8)

0.26

0.88

Age (years)

Gender Male

28 (21.2)

91 (68.9)

Female

44 (21.3)

139 (67.1)

24 (11.6)

Heart failure (CHF)

18 (12.5)

110 (76.4)

16 (11.5)

Stroke

54 (28.9)

113 (60.4)

20 (10.7)

7 (87.5)

1 (12.5)

Type of CVD

Arrhythmias

0 (0)

15.6

0.004*

First contact doctor Consultant

2 (14.3)

Senior resident

0 (0)

Registrar/HO

11 (78.6) 6 (100)

1 (1.7)

3.75

0.23

2.75

0.25

2.53

0.28

0.19

0.91

4.91

0.09

0 (0)

70 (21.9)

213 (66.8)

36 (11.3)

64 (22.4)

189 (66.1)

33 (11.5)

8 (15.1)

41 (77.4)

4 (7.5)

Admission route ED MOPD Time seen After hours

35 (24.8)

89 (63.1)

17 (12.1)

Working hours

37 (18.7)

141 (71.2)

20 (10.1)

Weekday

55 (21.4)

173 (67.3)

29 (11.3)

Weekend

17 (20.7)

57 (69.5)

Presented 8 (9.8)

Consultant’s review ≤ 1 day

35 (26.3)

81 (60.9)

> 1 day

37 (18.0)

149 (72.3)

20 (9.7)

≤ 14

56 (28.4)

113 (57.4)

28 (14.2)

> 14

16 (11.3)

117 (82.4)

9 (6.3) 6 (8.6)

17 (12.8)

Days admitted 23.8

< 0.001*

18.7

0.004*

Heart failure causes (n = 144) Hypertension

9 (12.8)

55 (78.6)

Dilated cardiomyopathy

1 (2.0)

44 (86.2)

Rheumatic heart disease

1 (50.0)

Anaemia

7 (33.4)

10 (47.6)

6 (11.8) 0 (0) 4 (19.0)

LAMA: left against medical advice, ED: emergency department, MOPD: medical out-patients’ department.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

Table 4. Predictors of poor outcome among all patients Odds ratio

95% confidence interval

p-value

≤ 55

1.89

0.73–4.86

0.19

> 55

1 0.44–2.47

0.92

0.31–3.34

0.99

0.31–0.56

0.04*

0.38–3.21

0.86

0.33–2.05

0.68

0.08–0.59

0.003*

Variable Age (years)

Gender Female Male

1.05 1

Route of admission ED MOPD

1.01 1

Presentation time After hours Working hours

3.37 1

Day presented Weekday

1.10

Weekend

Causes of heart failure Other Hypertension

0.83 1

Duration of admission (days) ≤ 14

0.22

> 14

ED: emergency department, MOPD: medical out-patients’ department.

high incidence of severe hypertension owing to poor compliance with medication and lifestyle-modification strategies. Often in our setting, however, the patient may even be unaware of the presence of hypertersion.19 The exact mechanism for the higher frequency of stroke in blacks remains unclear. In our series, most patients presented during weekdays and the majority during working hours. This pattern of presentation may be attributed to the preference of patients or caregivers to present at these times with the hope that they will receive better care. Weekends and after hours are often characterised by the constraints of understaffing and poor access to specialised services.10 This study revealed that the odds of dying were significantly higher among those who presented during after-hours, compared with those who presented during working hours. Therefore for every 10 deaths among patients admitted during after-hours, we would expect three among patients admitted during normal working hours. Being hospitalised for more than 14 days was also a predictor of mortality. However, being admitted over the weekend was not found to be a predictor of mortality. The significantly higher mortality rate registered during afterhours may have been multifactorial. There are usually fewer workers during after-hours and these tend to be juniors with less clinical experience. Some of these may be filling in for regular staff and may not have a good knowledge of the patients and the internal workings of the particular unit. Handing-over sessions may not be effectively implemented, resulting in serious gaps in clinical knowledge that may adversely affect crucial management decisions. Also, there tends to be fewer supervisors during after-hours to provide oversight in various clinical scenarios.20,21 Ancillary services such as laboratories and radiology, which provide crucial support in the management of critically ill patients, are usually less accessible during after-hours. These factors may all have contributed to higher mortality rates being recorded during after-hours.

331

Interestingly, the higher mortality rate was not recorded when weekend admissions were compared with weekday admissions. It has been noticed in our hospital that admission rates tend to decline over the weekends. This may be due to the perception within the populace that only skeletal services can be obtained over the weekends. It is possible that the more critically ill patients are taken to private hospitals during the weekend instead of being brought to our centre. This might account for the lack of difference between in-hospital mortality rates during weekends compared with weekdays. The higher mortality rates among those who were in hospital for more than 14 days may have been linked to disease severity. It is likely that those who remained in hospital for longer periods suffered from more severe forms of disease that led inexorably to poorer outcomes. This finding is in agreement with a report that highlighted a strong correlation between the high Acute Physiology and Chronic Health Evaluation (APACHE) III and multiple-organ dysfunction syndrome scores and prolonged length of stay for critically ill patients in the intensive care unit.22,23 Our findings suggest that healthcare providers in Nigeria should consider the potential increase in mortality rate that may arise as a consequence of uneven staffing patterns, especially during after-hours. The economic implications of striving to achieve and maintain a consistent level of staffing naturally come to the fore. Although it has been suggested that maintaining high levels of staffing may sometimes be economical, it is often not feasible. However, innovation is required to ensure that such re-organisation represents an efﬁcient use of scarce resources. A limitation of this study is that owing to the high cost and sometimes unavailability of facilities for neuro-imaging, the majority of patients with stroke did not have imaging records, so the different types of stroke could not be clearly determined.

Conclusion Our findings confirm that outcome is poor for cardiovascular admissions during after-hours but not during weekends. It is suggested that patients may deliberately be avoiding seeking medical care in public institutions during weekends. The increase in CVD mortality may be as a consequence of uneven staffing patterns, especially during after-hours. Healthcare providers in Nigeria should strive to achieve and maintain a consistent level of staffing, especially during after-hours and weekends, despite the economic implications. This is often not feasible, therefore innovation is required to ensure that such re-organisation represents an efﬁcient use of scarce resources.

References 1.

Bell CM, Redelmeier DA. Mortality among patients admitted to hospitals on weekends as compared to weekdays. N Engl J Med 2001; 345: 663–668.

Freemantle N, Richardson M, Wood J, et al. Weekend hospitalization and additional risk of death: an analysis of in-patient data J R Soc Med 2012; 105: 74–84.

DeCoster C, Roos NP, Carriere KC, Peterson S. Inappropriate hospital use by patients receiving care for medical conditions: targeting utilization review. Can Med Assoc J 1997; 157: 889–896.

Marco J, Barba R, Plaza S, et al. Analysis of mortality of patient admit-

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tion in the United Kingdom: a practical approach to management. J

ted to internal medicine wards on the weekend. Am J Med Qual 2010;

Human Hypertens 2007; 21: 183–211.

25: 312–318. 5.

Barba R, Losa JE, Velasco M, et al. Mortality among adult patients

15. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke

admitted to the hospital on weekends. Eur J Intern Med 2006; 17:

statistics 2015. Update: a report of the American Heart Association. Circulation 2015; e29–322.

322–324. 6.

Aylin P, Yunus A, Bottle A, et al. Weekend mortality for emergency

16. Ogah SO, OkpechiI, Chukwunoye II, Falase AO, Stewart S, Silwa K.

admissions: A large multi-centre study. Qual Saf Health Care 2010: 19:

Blood pressure, prevalence of hypertension and hypertension related

213–217.

complications in Nigerian Africans: a review. World J Cardiol 2012;

Saposnik G, Baibergenora A, Bayer N. Hachinski V. Weekends: a

4(12): 327–340.

dangerous time for having a stroke? Stroke 2007; 38: 1211–1215. 8.

17. Ansa VO, Ekott JU, Bassey EO. Profile of cardiovascular admissions at the University of Uyo Teaching Hospital,Uyo: a five year review. Nig J

Kostis WJ, Demissie K, Marcella SW, Shao YH Wilson AC, Moreyra

ClinPract 2008; 11(1): 22–24.

AE. Weekend versus weekday admission and mortality from myocardial infarction. N Engl J Med 2007; 356: 1099–1109. 9.

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18. Ogun SA, Ojini FI, Ogunbo B, Kolapo KO, Danesi MA. Stroke in

Hasegawa Y, Yoneda Y, Okuda S, Hamada R, Toyota A, Gotoh J, et al.

South west Nigeria; a 10 year review. Stroke 2005; 36: 1120–1122.

The effect of weekends and holidays on stroke outcome in acute stroke

19. Wahab KW. The burden of stroke in Nigeria. Int J Stroke 2008; 3:

units. Cerebrovasc Dis 2005; 20: 325–331.

290–292

10. McQuillan P, Pikinston S, Allan A, Taylor B. Short A, et al. Confidential

20. Thorpe KE. House staff supervision and working hours: implications

inquiry into quality of care before admission to intensive care. Br Med

of regulatory change in New York State. J Am Med Assoc 1990; 263:

J 1998; 3165: 1853–1858.

3177–3181.

11. Nwosu BO, Eke NO, Obi-Nwosu A, Osakwe OJ, Eke CO, Obi NP.

21. McKee M, Black N. Does the current use of junior doctors in the

Weekend versus weekday hospital deaths: analysis of in-patient data in a

United Kingdom affect the quality of medical care? Soc Sci Med 1992; 34: 549–558.

Nigeria tertiary healthcare centre. Nig J of Clin Pract 2013; 16: 501–504. 12. Steyn S, Silwa K, Hawken S, Commerford P, Onen C, Damasceno A,

22. Barie PS, Hydo LJ, Fischer EP, Rue LW, Cryer HG, Hébert PC, et al.

et al. Risk factors associated with myocardial infarction in Africa – the

Utility of illness severity scoring for prediction of prolonged surgical critical care. J Trauma 1996; 40(4): 513–518.

INTERHEART Africa study. Circulation 2005; 112: 3554–3561. 13. Balarajan R. Ethnicity and variation in mortality from CHD. Health

23. Bhonagiri D, Pilcher DV, Bailey MJ. Increased mortality associated with

Trends 1996; 28; 45–51.

after-hours and weekend admission to intensive care unit: retrospective analysis. Med J Afr 2011; 194(6): 287–292.

14. Lip GYH, Barnett AH, Bradbury A, Cappuccio FP, Gill PS, Hughes E, Imray C, Jolly K, Patel K. Ethnicity and cardiovascular disease preven-

CSI Africa CATHETER INTERVENTIONS IN CONGENITAL, STRUCTURAL AND VALVAR HEART DISEASE November 25-26, 2016 | Kampala | Uganda EDUCATION GRANT FOR YOUNG FELLOWS Dear Colleagues, We are delighted to announce that the CSI Foundation is able to give out a limited number of educational grants to young fellows from Africa. Recipients of the grant will get free access to CSI Africa 2016 in Kampala, Uganda on November 25-26. This will be an opportunity for young physicians to get an overview of the most important catheter therapies of congenital, structural and valvar heart interventions. The educational grant will enable young professionals to network with experienced colleagues from the continent as well as the international faculty

of CSI. After the conference all attendees will be invited to join the CSI Africa mailing list - a great tool to stay in touch and exchange ideas and experiences. If you would like to apply for the grant, please send your CV to s.kolkova@cme4u.org by Monday, October 24, 2016. We look forward to seeing you in Kampala! Shakeel A. Qureshi, Horst Sievert, Sulaiman Lubega On behalf of the course directors

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CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 27, No 5, September/October 2016

Case Report Takotsubo cardiomyopathy post liver transplantation Ahmed Vachiat, Keir McCutcheon, Adam Mahomed, Gunter Schleicher, Liezl Brand, Jean Botha, Martin Sussman, Pravin Manga

Abstract A patient with end-stage liver disease developed stressinduced Takotsubo cardiomyopathy post liver transplantation, with haemodynamic instability requiring a left ventricular assist device. We discuss the diagnosis and management of this condition. Keywords: Takotsubo cardiomyopathy, liver transplantation, left ventricular assist device Submitted 25/9/15, accepted 11/3/16 Cardiovasc J Afr 2016; 27: e1â&#x20AC;&#x201C;e3

www.cvja.co.za

DOI: 10.5830/CVJA-2016-032

Case report

function. Pre-transplant echocardiography revealed a left ventricular ejection fraction (LVEF) of 75% and moderate pulmonary hypertension with a systolic pulmonary artery pressure (PAP) of 41 mmHg. Cardiac catheterisation and coronary angiography prior to transplantation revealed normal coronary arteries and a mean PAP of 28 mmHg, falling to 23 mmHg after nitric oxide inhalation. His pulmonary vascular resistance was found to be 2.05 Wood units. The patient underwent an orthotopic liver transplantation. Standard procedure during the transplantation required cross clamping of the abdominal aorta while the hepatic artery anastomosis was being performed. Post transplantation he developed acute left ventricular dysfunction (LVEF 23%) with apical ballooning and basal hypercontractility, which is typical of Takotsubo cardiomyopathy, requiring inotropic support (Fig. 1). His ECG showed sinus

A 56-year old male was admitted to hospital for liver transplantation. He had end-stage liver disease (MELD score 22) due to cirrhosis caused by hepatitis C virus infection and alcohol abuse. In addition, he had diabetes and was moderately overweight (body mass index of 32 kg/m2). He had no other risk factors for ischaemic heart disease and had normal renal Division of Cardiology, Department of Internal Medicine, University of Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa Ahmed Vachiat, MB BCh (Wits), FCP (SA), MMed, Cert Cardiology (SA), Ahmed.Vachiat@wits.ac.za Pravin Manga, MB BCh (Wits), FCP (SA), PhD Keir McCutcheon, BSc (Hons), MSc, MB BCh (Wits), FCP (SA), Cert Cardiology (SA) Adam Mahomed, MB BCh (Wits), FCP (SA), Cert Gastroenterol (SA)

Wits Donald Gordon Medical Centre, University of Witwatersrand, Parktown, Johannesburg, South Africa Ahmed Vachiat, MB BCh (Wits), FCP (SA), MMed, Cert Cardiology (SA), Ahmed.Vachiat@wits.ac.za Pravin Manga, MB BCh (Wits), FCP (SA), PhD Keir McCutcheon, BSc (Hons), MSc, MB BCh (Wits), FCP (SA), Cert Cardiology (SA) Adam Mahomed, MB BCh (Wits), FCP (SA), Cert Gastroenterol (SA) Gunter Schleicher, MB BCh (Wits), DTM&H, MMed, FCP (SA), Cert Pulmonology (SA) Liezl Brand, MB ChB (Stell), FCP(SA), Cert Pulmonology (SA) Jean Botha, MB BCh (Wits), FCS (SA)

Milpark Hospital, Parktown, Johannesburg, South Africa Martin Sussman, MB BCh (Wits), FCS (Cardiothoracic Surgery)

Fig. 1. Parasternal long-axis view showing apical and midcavity ballooning (green arrow) and basal hypercontractility (yellow arrows).

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

tachycardia with no ischaemic changes. The hs-troponin T level was 0.154 ng/ml and pro-BNP concentration was also elevated to 22 842 ng/l. However, 72 hours later he showed no improvement in his left ventricular function and despite increasing doses of inotropic support, he remained hypotensive. A decision was therefore made to insert the Tandem Heart left ventricular assist device (LVAD). The patient’s haemodynamics were stabilised with the LVAD and the inotropes were gently weaned. Therapy was commenced with carvedilol, enalapril and spironolactone. His left ventricular function gradually improved (Fig. 2) and he was weaned from the LVAD after nine days. He recovered well and at discharge 25 days post transplantation, his LVEF was 69%. At the four-month posttransplantation review he remained asymptomatic and his LVEF had improved to 75%.

Discussion Takotsubo cardiomyopathy or acute non-ischaemic stress cardiomyopathy is a well described cause of transient acute left ventricular dysfunction, leading to haemodynamic instability and ventricular arrhythmias. At our transplantation centre with an experience of over 240 liver transplants, this is the first case of acute stress cardiomyopathy that we have encountered post liver transplantation. Patients with cirrhosis requiring liver transplantation demonstrate an impaired systolic and diastolic response to stress, as well as electrophysiological abnormalities, a condition termed cirrhotic cardiomyopathy.1 These cardiac disturbances are most likely mediated by decreased beta-adrenergic receptor density and dysfunction, increased circulating inflammatory mediators with cardiodepressant properties and repolarisation changes.1 Liver transplant patients are therefore more vulnerable to perioperative cardiac stress. The prevalence of Takotsubo cardiomyopathy post liver transplantation has been reported to range between one and

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7%. In a large retrospective review of 1 460 liver transplant records in a single centre, the overall prevalence of Takotsubo cardiomyopathy was found to be 1.2%.2 Furthermore they found an association of Takotsubo cardiomyopathy with higher MELD scores, renal insufficiency and malnutrition prior to transplantation. Also 52% of these patients had a significant history of alcohol abuse.2 The cause of the acute left ventricular decompensation post transplantation in our patient is not clear. The patient’s coronary angiogram was normal prior to transplantation. It is possible that the underlying propensity to an impaired ventricular response to stress, history of alcohol abuse as well as the acute increase in left ventricular afterload secondary to aortic cross clamping during surgery may have contributed to the acute global left ventricular dysfunction. Strategies for managing acute left ventricular dysfunction post liver transplantation are not well defined. Standard approaches with diuretics, and inotropic and vasopressor support are the mainstays of initial management. However, if these fail, percutaneous devices for circulatory support need to be considered. Intra-aortic balloon pumps are used acutely in the setting of hypotensive crises secondary to acute coronary syndromes. However, they are rarely considered as a bridge to myocardial recovery. LVAD implantation is a well-described therapy in highly selected patients with refractory end-stage heart failure.3 They are also used as a bridge to myocardial recovery following acute myocardial injury where recovery of myocardial function is expected. We postulated that our patient may have suffered a non-ischaemic stress cardiomyopathy. Takotsubo cardiomyopathy occurs predominantly in females and the interesting aspects of this case are that it occurred in a male patient, as well as occurring post liver transplantation. The patient showed a poor response to inotropic and vasopressor support and therefore the decision for LVAD implantation was made early, which possibly contributed to his rapid recovery.

Conclusion Thus far there is only one reported case of the successful use of ventricular assist device for acute left ventricular decompensation post liver transplantation.4 Our case study demonstrates the importance of thorough pre-operative assessment of transplantation patients and the multi-disciplinary support necessary for those patients who deteriorate in the immediate post-transplant period. We acknowledge the following colleagues, who were also involved in the management of the patient: N Patel, M Chohan, P Williams, Z Adham and R Britz.

References 1.

Raval Z, Harinstein ME, Skaro AI, Erdogan A, DeWolf AM, Shah SJ, et al. Cardiovascular risk assessment of the liver transplant candidate. J Am Coll Cardiol 2011; 58(3): 223–231.

Fig. 2. Left ventricular recovery post LVAD implantation.

Yataco ML, Difato T, Bargehr J, Rosser BG, Patel T, Trejo-Gutierrez JF, et al. Reversible non-ischaemic cardiomyopathy and left ventricular

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

dysfunction after liver transplantation: a single-centre experience. Liver

American Heart Association Task Force on Practice Guidelines

Int 2014; 34(6): e105–110.

Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009; 53(15): e1–e90.

Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. 2009 Focused update incorporated into the ACC/AHA 2005

Moguilevitch M, Rufino M, Leff J, Delphin E. Novel approach for

Guidelines for the Diagnosis and Management of Heart Failure in

heart failure treatment after liver transplantation. Liver Transpl 2015:

Adults A Report of the American College of Cardiology Foundation/

21(8): 1103–1104.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

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Case Report Active schistosomiasis, severe hypereosinophilia and rapid progression of chronic endomyocardial fibrosis AO Mocumbi, C Goncalves, A Damasceno, C Carrilho

Abstract Endomyocardial fibrosis (EMF) is a neglected restrictive cardiomyopathy of unknown aetiology and unclear natural history, which causes premature deaths in endemic areas. We present the case of a 13-year-old boy from a highly endemic area, presenting with concurrent signs of chronic EMF and severe hypereosinophilia associated with active schistosomal cystitis. We discuss the possible role of this parasitic infection in determining the progression of EMF in endemic areas for both conditions. Keywords: endomyocardial fibrosis, schistosomiasis, pathogenesis, management Submitted 20/10/15, accepted 11/3/16 Cardiovasc J Afr 2016; 27: e4–e6

www.cvja.co.za

DOI: 10.5830/CVJA-2016-030

Endomyocardial fibrosis (EMF) is a poorly understood restrictive cardiomyopathy that affects mainly children and adolescents in endemic areas of Africa, Asia and Latin America.1 The suggested pathogenesis is that of succession of necrosis, thrombosis and fibrosis, but this has been difficult to prove because most patients are seen in late stages of the disease. We describe a case of EMF with severe fibrosis associated with active schistosomiasis, hypereosinophilia and a fatal outcome.

Case report A 13-year-old boy of black ethnicity from an endemic zone of EMF was referred to hospital in congestive heart failure.

Instituto Nacional de Saúde, Maputo, Mozambique AO Mocumbi, MD, amocumbi@gmail.com

Eduardo Mondlane University, Maputo, Mozambique AO Mocumbi, MD A Damasceno, MD C Carrilho, MD

Maputo Central Hospital, Mozambique C Goncalves, MD A Damasceno, MD C Carrilho, MD

He reported a three-month history of progressive exertional dyspnoea without orthopnoea or paroxysmal nocturnal dyspnoea, as well as central, crushing and constant chest pain, which was exacerbated by exercise and alleviated on rest. He also complained of progressive painless abdominal distension, but denied having palpitations, wheeze, cough, night sweats, fever, or any gastrointestinal or urinary symptoms. His past medical history was uneventful, and he was not on medication prior to his first admission, two weeks before he was transferred. On examination he was alert, apyretic, had no neurological signs of disease or disorientation and presented a good general status. His heart rate was 108 beats/minute with a regular rhythm, blood pressure was 90/60 mmHg, and respiratory rate was 16 breaths/minute. Cardiac examination revealed raised jugular venous pressure, a visibly pulsating, palpable, non-displaced apex beat, and a mild holosystolic murmur on auscultation. Besides a bilateral inspiratory wheeze, the respiratory examination was unremarkable. The abdomen was soft, non-tender and mildly distended, with a 3-cm hepatomegaly and no other organomegaly. He was not jaundiced and there was no shifting dullness on abdominal examination. Blood examinations for malaria, human immunodeficiency virus, recent streptococcal infection, rheumatoid factor and syphilis were all negative. Erythrosedimentation rate was raised at 55 mm/h. White blood cell count was normal with marked eosinophilia. Stool examination for helminths was negative. The chest X-ray showed prominence of the pulmonary artery. The ECG revealed sinus rhythm, signs of right ventricular overload and non-specific repolarisation abnormalities. On transthoracic echocardiography, the right ventricular cavity was reduced and areas of endocardial thickening suggested fibrosis; the overall right ventricular function was preserved. The right atrium was dilated and moderate tricuspid regurgitation was present, allowing estimation of systolic pulmonary pressure at 85 mmHg. No images suggesting thrombi were detected on the right side of the heart. The left ventricle had marked thickening of the mural endocardium and a homogeneous mass occupying its apical third, suggesting a thrombus that did not interfere with the mitral valve function. Left ventricular systolic and mitral valve function were preserved; mild circumferential pericardial effusion was present. The results of rectal biopsy were inconclusive for schistosomal infection. A diagnosis of bilateral EMF with hypereosinophilia was made and the patient was managed with daily oral furosemide 40

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

mg, spironolactone 25 mg, warfarin 1.25 mg, and a single dose of 400 mg albendazole. Despite improvement with resolution of dyspnoea and chest pain after 24 hours, the patient died unexpectedly on day 6 while sleeping. Autopsy confirmed right ventricular diffuse endocardial fibrous thickening with amputation of the apex (Fig. 1A), aneurysmal dilatation of the right atrium, and extensive endocardial fibrosis of the left ventricle. The bifurcation of the aorta was filled with a large embolus (Fig 1B) that could have been seated at the left ventricular apex (Fig 1C). The bladder revealed active polypoid bilharzial cystitis (Fig 1D). On microscopy, typical endocardial fibrous thickening (Fig. 2A) and eosinophilic granulomas centred by viable Schistossoma eggs were found (Fig 2B). Additional features were chronic passive congestion of the liver, spleen and lung, as well as hepatic periportal fibrosis with the presence of eosinophilic granulomas.

Discussion This patient, coming originally from a known endemic region for EMF, had bilateral disease. He had concurrent signs of severe endocardial fibrosis, marked tissue hyper-eosinophilia and active Schistosoma haematobium granuloma in the bladder. He therefore presented with signs of both chronic EMF and active

schistosomal infestation, as defined by the presence of viable eggs and active granuloma. The patient had been relatively asymptomatic until three months prior to admission, in marked contrast with the severity of the echocardiographic and pathological features. Discrepancy between echocardiographic and clinical findings is not uncommon,2 and recent schistosomiasis may have contributed to aggravation of a stable chronic EMF. Although emergency surgery had been considered when the child was admitted, it was not performed due to the presence of extensive endocardial fibrosis with severe ventricular cavity amputation, pulmonary hypertension and electrocardiographic signs of myocardial ischaemia, all predictors of a bad prognosis. Since antithrombotic therapy was unavailable, the child was treated with warfarin only. Sudden death occurred probably due to ventricular arrhythmia that may have been determined by dislodgment of the large apical left ventricular thrombus and embolisation to the aortic bifurcation. Lofﬂer’s syndrome is used as a model to explain some clinical– pathological features of EMF,3 but eosinophilic myocarditis is rarely proven in these patients. Endomyocardial biopsy is rarely performed due to lack of expertise and non-existence of adequate facilities for catheterisation in endemic areas, as well as the presence of advanced disease and intracavitary thrombi, as

Fig. 1. T ypical features of right ventricular EMF include fibrosis and retraction (A). A large embolus that could have been seated at the left ventricular apex (B) is seen at the bifurcation of the abdominal aorta. Macroscopic evaluation also revealed extensive left ventricular endocardial fibrosis (C) and bilharzia polypoid cystitis (D).

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016

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Fig. 2. H istological features of EMF include endocardial thickening by fibrosis, with strands of fibrous tissue penetrating the inner myocardium (A). Eosinophilic granulomas centred by viable Schistosoma eggs were found in the bladder (B).

was the case in our patient. EMF can be associated with parasitic infestations and their attendant eosinophilia. An association with Schistosoma mansoni, haematobium and intercalatum has been reported.4-6 In the our case, Schistosoma infection may have been the trigger for clinical aggravation due to the superimposition of Loeffler’s syndrome on chronic fibrotic EMF. Although we found no calcification or other signs of chronic schistosomiasis, we cannot exclude previous episodes.

be improved to include inflammation, cardiac and coagulation biomarkers, thereby allowing its use for risk stratification and tailored management of this neglected cardiomyopathy.

References 1.

pathies: II. Endomyocardial fibrosis: myocardial disease. Heart 2008; 94(3): 384–390. 2.

Mocumbi AO, Ferreira MB, Sidi D, Yacoub MH. A population study of endomyocardial fibrosis in a rural area of Mozambique. N Engl J Med

Conclusion Our findings support the hypothesis of EMF being a progressive disease that may be linked to repetitive inflammatory insults, which may correspond with successive episodes of blood and endomyocardial hypereosinophilia triggered by parasitic infestation or other factors. They also suggest the need to explore new management approaches, including prevention of recurrences in patients with chronic, established disease. This should probably involve strict control of endemic parasitic infections, as well as the use of anti-inflammatory drugs and anticoagulants, mimicking the current standard of care in Loeffler’s syndrome. The EMF diagnosis and scoring system previously used in community screening, considering only the severity and distribution of structural lesions,2 could probably

Mocumbi AO, Yacoub S, Yacoub MH. Neglected tropical cardiomyo-

2008; 359(1): 43–49. 3.

Andy JJ, Ogunowo PO, Akpan NA, et al. Helminth associated hypereosinophilia and tropical endomyocardial fibrosis (EMF) in Nigeria. Acta Trop 1998; 69(2): 127–140.

Carneiro RC, Santos AL, Brant LC, et al. Endomyocardial fibrosis associated with mansoni schistosomiasis. Rev Soc Bras Med Trop 2011; 44: 644–645.

Assimeng J, Segbefia CI, Neequaye J. Endomyocardial fibrosis associated with Schistosoma haematobium infection. Ghana Med J 2014; 48(4): 225–227.

Bustinduy AL, Luzinda K, Mpoya S, et al. Endomyocardial fibrosis (EMF) in a Ugandan child with advanced hepatosplenic schistosomiasis: coincidence or connection? Am J Trop Med Hyg 2014; 91(4): 798–800.

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• Cardiovascular risk factors in south-western Nigeria

PUBLISHED ONLINE: • Takotsubo cardiomyopathy post liver transplant • Schistosomiasis and chronic endomyocardial fibrosis