CVJA Volume 25, Issue 2 by Clinics Cardive Publishing

MARCH/APRIL 2014 VOL 25 NO 2

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CardioVascular Journal of Africa (official journal for PASCAR)

• Comparison of left ventricular ejection fractions • Infective endocarditis and HIV • Neonatal arrhythmias • Behcet’s disease and cardiovascular involvement • Topical hypothermia in CABG surgery

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• Intra-uterine growth restriction and hypertension

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• Impact of prehypertension in adult black Nigerians • Optimal utilisation of sulphonylureas

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Cardiovascular Journal of Africa . Vol 25, No 2, March/April 2014

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PUBLISHED ONLINE: • Perforation during radiofrequency catheter ablation

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References 1. Sever PS, Dahlof B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

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Vol 25, No 2, MARCH/APRIL 2014

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

FROM THE editor’s desk

Comparison of estimates of left ventricular ejection fraction obtained from gated blood pool imaging, different software packages and cameras R Steyn • J Boniaszczuk • T Geldenhuys

An echocardiographic study of infective endocarditis, with special reference to patients with HIV DP Naidoo • SH Nel

Diagnosis, treatment and follow up of neonatal arrhythmias FK Binnetoğlu • K Babaoğlu • G Türker • G Altun

Behcet’s disease and cardiovascular involvement: our experience of asymptomatic Behcet’s patients Z Ulusan • AS Karadag • M Tasar • M Kalender • OT Darcin

Effects of topical hypothermia on postoperative inflammatory markers in patients undergoing coronary artery bypass surgery M Kadan • G Erol • BS Oz • M Arslan

PA Brink

Cardiovascular Topics

73 Intra-uterine growth restriction as a risk factor for hypertension in children six to 10 years old A Zamecznik • K Niewiadomska-Jarosik • A Wosiak • J Zamojska • J Moll • J Stańczyk 78

Impact of prehypertension on left ventricular mass and QT dispersion in adult black Nigerians OK Ale • JN Ajuluchukwu • DA Ok • AC Mbakwem

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

Editors

SUBJECT Editors

Acting Editor in Chief (South Africa) Prof PA Brink

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

Heart Failure Dr g visagie

PROF R DELPORT Chemical Pathology

Paediatric dr s brown

PROF BM MAYOSI Chronic Rheumatic Heart Disease

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular 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

Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne

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)

Review Article

Optimal utilisation of sulphonylureas in resource-constrained settings P Naidoo • V Rambiritch • N Butkow • S Saman

Vol 25, No 2, MARCH/APRIL 2014

CONTENTS

Letter to the Editor 86 Adverse effects of ethyl esters or oxidation products in omega-3 preparations? H Rupp • KG Rupp

Drug Trends

Cryoballoon ablation for atrial fibrillation is now possible in South Africa Anne Hahn

Bayer’s Xarelto ® is approved in South Africa across five additional indications

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

e1 Unusual perforation of the left ventricle during radiofrequency catheter ablation for ventricular tachycardia J-T Wu • J-Z Dong

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PETER WAGENAAR Cell 082 413 9954 e-mail: skylark65@myconnection.co.za The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published 10 times a year, the publication date being the third week of the designated month. Copyright: Clinics Cardive Publishing (Pty) Ltd.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014

From the Editor’s Desk As I expertly skirt some potholes in a town centre through which we are travelling, I ponder the upcoming edition of the journal. An editorial needs to be written and time is running short. I cannot afford to lose a tyre or worse, a wheel or axle today. In my head I peruse the articles while being mindful of the road. An interesting take on the Baker hypothesis hails from Poland (Zamecznik et al., page 73). I wonder what roads in Poland are like. The group assessed six- to 10-year-old children and stratified them into groups of appropriate for gestational age (AGA) and small for gestational age (SGA). They further sub-stratified into symmetric (everything small, but proportionately so) and asymmetric (low birth weight, but appropriate length and head circumference). I imagine a malnourished, thin baby with a visibly large head and eyes. This is a rather interesting study. At school-going age there was no difference in anthropometric measurements, yet the average blood pressure differed between the groups, being higher in the SGA group, with some intragroup differences caused by the type of growth stunting. They refer to articles supporting their findings (Woelk et al.1 and Thame et al.2). I must make time to have a look at these. I skirt another pothole. What are roads like, I wonder, in Lagos, Nigeria, the source of our next article? The economy I believe has been exploding, and gross domestic product, a measure of wealth creation, has surpassed that of South Africa. Nigeria has been a source of sophisticated work on cardiac function, which has recently been published in the journal. In this issue, Ale and co-workers studied left ventricular mass and QT dispersion (QTd) in prehypertensive individuals. The QT interval is of special interest to me, and QTd has its traps, called slaggate in my home language, literally translated as potholes. This is encapsulated in one of the articles referred to (Sahu et al.3). Ale and co-workers concluded that echocardiography, albeit expensive, may be a good tool for risk stratification in prehypertension, but that the usefulness of the ECG is limited. A thud, as I encounter a pothole, breaks my train of thought. Yes, I am still in South Africa. This makes me think of the review by Naidoo et al. (page 83) on diabetes mellitus and the use of sulphonylureas; the good and bad aspects. Looking at the authorship, it is not quite free of industrial interest, yet it is timely. The authors used the opportunity to introduce some

new kids on the block, albeit expensive and not time-tested, the di-peptidyl peptidase IV inhibitors, glucagon-like peptide analogues and sodium glucose co-transporter inhibitors. Use of the last is limited in a resource-constrained environment, but they suggest that, where hypoglycaemia is not a problem, there may be a place for their use where public safety is concerned, such as bus drivers with diabetes mellitus. And so the journey continues. I hope I can recover the train of thought when home. Yes, once again there are a few articles from Turkey, one from Ankara and one from Çanakkale (I must go and look on my map where these cities are). These studies documented arrhythmias in neonates (Binnetoglu et al., page 58), cardiovascular involvement in Bechet’s disease (Ulusan et al., page 63) and the effect of topical hypothermia on postoperative inflammatory markers (Kadan et al., page 67). From South Africa, not surprisingly, as this country has more HIV-positive individuals than any other (http://www.who.int/ en/), Nel and Naidoo (page 50) present an article on endocarditis, HIV and echocardiographic findings. A technical article (Steyn et al., page 44) draws attention to the fact that in radionucleotide imaging, different software does not measure ejection fractions equally. Once again, the print issue is complemented by onlineonly publication of a case report. Ah, I am home at last. PAUL A BRINK, MB ChB, PhD, paul@clinicscardive.com Department of Internal Medicine, Faculty of Health Sciences, University of Stellenbosch and Tygerberg Hospital, Tygerberg

References 1.

Woelk GB, Emanuel I, Weiss NS, Psaty BM. Birth weight and blood pressure among children in Harare, Zimbabwe. Arch Dis Child Fetal Neonatal Ed 1998; 79: 119–122. Thame M, Osmond C, Wilks RJ, Bennett FI, McFarlane-Anderson N, Forrester TE. Blood pressure is related to placental volume and birth weight. Hypertension 2000; 35: 662–667. Sahu P, Lim PO, Rana BS, Struthers AD. QT dispersion in medicine; electrophysiological Holy Grail or fool’s gold. Q J Med 2000; 93: 425–431.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014

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Cardiovascular Topics Comparison of estimates of left ventricular ejection fraction obtained from gated blood pool imaging, different software packages and cameras Rachelle Steyn, John Boniaszczuk, Theodore Geldenhuys Abstract Objective: To determine how two software packages, supplied by Siemens and Hermes, for processing gated blood pool (GBP) studies should be used in our department and whether the use of different cameras for the acquisition of raw data influences the results. Methods: The study had two components. For the first component, 200 studies were acquired on a General Electric (GE) camera and processed three times by three operators using the Siemens and Hermes software packages. For the second part, 200 studies were acquired on two different cameras (GE and Siemens). The matched pairs of raw data were processed by one operator using the Siemens and Hermes software packages. Results: The Siemens method consistently gave estimates that were 4.3% higher than the Hermes method (p < 0.001). The differences were not associated with any particular level of left ventricular ejection fraction (LVEF). There was no difference in the estimates of LVEF obtained by the three operators (p = 0.1794). The reproducibility of estimates was good. In 95% of patients, using the Siemens method, the SD of the three estimates of LVEF by operator 1 was ≤ 1.7, operator 2 was ≤ 2.1 and operator 3 was ≤ 1.3. The corresponding values for the Hermes method were ≤ 2.5, ≤ 2.0 and ≤ 2.1. There was no difference in the results of matched pairs of data acquired on different cameras (p = 0.4933) Conclusion: Software packages for processing GBP studies are not interchangeable. The report should include the name and version of the software package used. Wherever possible, the same package should be used for serial studies. If this is not possible, the report should include the limits of agreement of the different packages. Data acquisition on different cameras did not influence the results.

Department of Nuclear Medicine, Groote Schuur Hospital, University of Cape Town, South Africa Rachelle Steyn, MBChB, FCNP, MMed (Nuc Med), rachelle.steyn@gmail.com John Boniaszczuk, NAT DIP RAD (NM) Theodore Geldenhuys, NAT DIP RAD (NM)

Keywords: gated blood pool studies, cameras, software packages, results Submitted 3/7/13, accepted 18/11/13 Cardiovasc J Afr 2014; 25: 44–49

www.cvja.co.za

DOI: 10.5830/CVJA-2013-082

Serial measurement of LVEF using gated blood pool (GBP) imaging is an established technique for monitoring LVEF in patients undergoing chemotherapy with cardiotoxic medication and in patients after heart transplants.1,2 The nuclear medicine department at Groote Schuur Hospital performs up to a thousand GBP studies annually. The majority of these studies are for patients receiving cardiotoxic chemotherapy and have a significant impact on patient management. In our hospital, the radiation oncologists consider not starting cardiotoxic chemotherapy if the LVEF is below 50% and terminating chemotherapy if there is a 10% decrease. In patients who have had heart transplants, the cardiologists start patients on glucocorticosteroids if a patient’s LVEF decreases by10%. It is therefore imperative that serial studies on an individual patient are comparable. Two software systems are used in our nuclear medicine department. The Siemens system (Siemens Medical Solutions, Chicago, USA) was introduced in February 2006 and the Hermes system (Hermes Medical Solutions, Stockholm Sweden) in September 2007. After the introduction of the Hermes system, we found large differences between the LVEFs calculated by the two systems. This was confirmed by a pilot study and is consistent with the literature that different software programs for processing equilibrium gated radionuclide studies cannot be used interchangeably.3-7 The department also uses two different cameras, a General Electric (GE) Starcam 400 AC single-head and a Siemens Signature Series e.cam dual-head camera to acquire the raw data. These are then transferred to the Siemens and Hermes processing systems. This study was done to determine how the software packages used for processing GBP studies should be integrated into our department and if the use of different cameras for acquisition influences results. The study had two components. The first examined the values and reproducibility of estimates of LVEF from two software packages using data acquired on the GE

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014

gamma camera and processed independently by three operators. The second component examined the values and reproducibility of estimates of LVEF calculated with the same software packages using matched pairs of raw data acquired on both gamma cameras (GE and Siemens) processed by one operator.

Methods Since October 2007 the raw data of all GBP studies done in the department have been stored in a Hermes electronic archive in the original format. These studies, acquired on the GE camera, were therefore available for reprocessing. All the patients were referred to our department as part of their diagnostic work-up. The majority of studies were done for patients receiving cardiotoxic chemotherapy. A minority (< 5%) of the studies were done for patients who had heart transplants. For the first component of the investigation, 200 studies acquired on the GE camera were selected using random-number tables to identify folder numbers of patient studies archived between 1 October 2007 and 15 July 2009. There were 1 952 studies performed on 1 473 patients during this period. For the second component, 200 patients were studied. Two sets of data were acquired for each patient, the second immediately after the first. One of the sets was acquired on the GE and the other on the Siemens camera, the order depended on the availability of the cameras. This produced 200 matched pairs of data (Fig. 1). Ethics approval for the study was obtained from the Research Ethics Committee, Health Sciences Faculty, University of Cape Town.

Imaging protocol An in-vivo method for labelling the red blood cells was used. One red blood cell labelling vial (Nuclear Technology Products, Pelindaba, SA) containing 20 mg sodium pyrophosphate and

FIRST COMPONENT

SECOND COMPONENT

200 studies

Two studies were from the same patient, the second study was excluded

One study was not captured, one study was a duplicate and seven patients had two studies (baseline and follow up). The duplicate study and the seven follow-up studies were excluded

199 studies

191 studies

Fig. 1. Flow diagram of studies excluded.

4 mg tin dichloride was reconstituted with 5 ml NaCl and 3.5 ml was injected intravenously, followed 20 minutes later by an injection of 800–900 MBq of Tc-99m sodium pertechnetate eluted from a NovaTec P generator manufactured by NTP Radioisotopes (Pty) Ltd of Pelindaba. The dose administered was in accordance with the Society of Nuclear Medicine guidelines.8 For all patients, anterior, left lateral and left anterior oblique images were recorded in a 64 × 64 matrix with the patient supine. For the left anterior oblique image, the angle of the detector head relative to the patient was adjusted to give the best septal delineation. The ECG–RR interval was divided into 24 frames, the beat acceptance window set at 30% and the energy window at 15%. A low-energy general purpose (LEGP) collimator manufactured by GE and zoom of 1.5 were used with the GE Starcam 400 AC single-head camera and acquisition was stopped when 8 000 kilocounts had been acquired. The GE camera was interfaced to an Alfanuclear acquisition system (IM512P Data and Image Processor version 2.0). A LEHR collimator manufactured by Siemens and a zoom of 2 were used on the Siemens Signature Series e.cam dual-head camera and acquisition was stopped when 8 000 kilocounts had been acquired. The Siemens camera was interfaced to a Siemens acquisition system (Version A4OA, Siemens Medical Solutions, Chicago USA).

Processing The studies were processed using the two methods available; one provided by Siemens (Gated Blood Pool Activity version 7.0.7.2, Siemens Medical Solutions, Chicago, USA) and one by Hermes (Functional Gated Analysis, FUGA version V4.7, Hermes Medical Solutions, Stockholm, Sweden ). Semi-automated programs were used because the automated programs of both vendors placed the background region of interest (ROI) in the bottom left-hand corner of the field of view. This results in a background ROI that is not periventricular. It overlies the spleen, aorta or other soft tissue structures. The default settings of the Siemens method was: a zoom of 2 was used; a Butterworth filter with a cut-off of 0.40 of the Nyquist frequency and order 5 was applied; the background ROI was placed on the end-systolic frame; X and Y shifts were 2 and the offset 4 pixels; height and width were 50%. The default settings of the Hermes method was: no zoom was used; a Butterworth filter with a cut-off of 5 as defined by Hermes and order 70 was applied; the background ROI was placed on the end-diastolic frame. In the first component of the study, the data acquired on the GE camera were processed three times by three independent operators. These were the senior author (operator 1), and two experienced radiographers (operators 2 and 3). The operators adjusted the position, shape and size of the background ROI. While processing, the operators recorded the number of beats rejected, whether the labelling of the red blood cells was good, satisfactory or poor (this was done using visual analysis), whether the quality of the tracking of the left ventricle was good, satisfactory or poor (this was done using visual analysis), where the program placed the background ROI, where the operator placed the background ROI, the size of the background ROI, as well as the mean counts within it.

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In the second component of the study, the data acquired on both the GE and Siemens cameras were processed three times by a single operator (operator 1) using the same software methods, default settings and intervention as for the first component.

Statistical analysis The results were entered into an EpiData version 3.1 database. Data were then exported for analysis into Microsoft Office 2007 Excel and STATA version 11.10 The Shapiro-Wilk test showed that the data were not normally distributed. Attempts at transformation were unsuccessful. (Tukeys ladder of transformations was used.) Parametric statistics were still applied however as it is deemed acceptable to apply parametric statistics if the number of subjects exceeds 30. Means, standard deviations (SDs) and ranges (maximum and minimum) of estimates of LVEF were calculated. The BlandAltman method of comparison analysis was used to assess the estimates of LVEFs as well as the impact of acquisition on different cameras. Analysis of variance was used to establish the statistical significance. The reproducibility of LVEFs was assessed using the SD of the three estimates of LVEF calculated by each operator for each method. 9

Results Values and reproducibility of estimates of LVEFs The left ventricle was not tracked in four studies when using the Siemens method. In all four studies the entire heart or the vascular structures above it were tracked. All three operators were in agreement in three of these studies. In one study only operator 3 was unable to track the left ventricle. The corresponding mean estimates of LVEF for these studies using the Hermes method were 36, 67, 66 and 74%. With the Hermes method, the left ventricle was not tracked in one study. In this study the entire heart was tracked. Operators 1 and 2 were in agreement in this study; operator 3 however, was able to track the left ventricle. The corresponding mean estimate of LVEF for this study using the Siemens method was 63%. These five studies were from different patients. The exclusion of the five studies left 194 studies for analysis. Table 1 summarises the values for the estimates of the LVEFs. There were no differences between the results obtained by the three operators but the Siemens method gave estimates that were 4.3% higher than those given by the Hermes method. The differences between the two methods were not related to the values obtained for the LVEFs, and the limits of agreement Table 1. Values of estimates of lvefs; all operators Siemens

Hermes

Mean Range Mean Range (%) SD (%) (%) SD (%) Operator 1 59.1 10.1 19.3–82.0 54.8 11.0 11.0–88 Operator 2 59.5 10.1 18–82.3 54.7 11.0 10.0–82.3 Operator 3 58.8 10.3 16.7–82 54.6 11.4 10.0–85 All operators 59 10.2 16.7–82.3 54.7 11.1 10.0–88 There was a difference between methods (F 650, 54; df 1, 97; p < 0.0001) but no difference between operators (F 1, 72; df 2, 97; p = 0.18) and no interaction between operator and method (F 0, 90; df 2, 97; p = 0.41).

Difference (Siemens–Hermes)

40.0 30.0 20.0

Upper LOA

10.0

Mean difference

0.0

Lower LOA

–10.0 –20.0

0.0

20.0

40.0 60.0 Mean LVEF (%)

80.0

100.0

Operator 1

Operator 2

Operator 3

All Operators

Limits of agreement (LOA)

–5.021 to 13.737

–3.995 to 13.441

–6.445 to 14.770

–5.180 to 14.010

Mean difference

4.358 (CI: 3.694– 5.022)

4.723 (CI: 4.106– 5.340)

4.162 (CI: 3.411– 4.913)

4.415 (CI: 4.024– 4.805)

Fig. 2. B land–Altman plot: difference between methods, all operators

between the two methods were almost identical for all three operators (Fig. 2). Of the five highest and five lowest estimates of LVEF obtained with each method by each operator, four of the highest five LVEFs and four of the lowest five LVEFs were from the same studies for each method by all three operators. Out of the five highest, three of the four were the same for both methods. Of the five lowest however, only one was the same for both methods. Table 2 summarises the reproducibility of the estimates of the LVEFs. There were 53 patients in whom the SD of the three estimates of the LVEFs was above the 95th percentile for both methods for one or more operators. In most of these patients, two of the three estimates obtained by any one of the operators for a method were similar. The difference between these two similar estimates (minimum difference) was 0% in 14 patients, 1% in 26 patients, 2% in eight patients and 3% in five patients. The difference between the highest and lowest estimates (maximum difference) for all three operators for both methods was 3% in eight patients, 4% in 17 patients, 5% in 19 patients, 6% in six patients, 8% in two patients and 9% in one patient. The maximum difference for all three operators was 6% or less for the Siemens method and 9% or less for the Hermes method. The difference between the minimum and maximum estimates was not associated with any particular level of LVEF. Table 2. Percentiles of the sds of the three estimates of lvef for the Siemens and Hermes methods

5th percentile 25th percentile 50th percentile 75th percentile 95th percentile

Siemens method Opera- Opera- Operator 1 tor 2 tor 3 0.0 0.0 0.0 0.6 0.6 0.0 0.6 0.6 0.6 1.2 1.2 0.6 1.7 2.1 1.3

Hermes method Opera- Opera- Operator 1 tor 2 tor 3 0.0 0.0 0.0 0.6 0.0 0.0 0.6 0.6 0.6 1.5 1.0 1.1 2.5 2.0 2.1

GE camera Siemens camera Mean (%) SD Range (%) Mean (%) SD Range (%) 58.7 10.4 4.0–84.3 57.9% 10.3 13.3–84.7 There was no difference between acquisitions on different cameras (GE and Siemens) processed by the Siemens method (F 0, 47; df 1, 37; p = 0.49). Table 4. Estimates of lvefs acquired on different cameras processed by the Hermes method GE camera Siemens camera Mean (%) SD Range (%) Mean (%) SD Range (%) 54.3 10.2 9.3–79 53.9 10.1 7–86.3 There was no difference between acquisitions on different cameras (GE and Siemens) processed by the Hermes method (F 0, 0.8; df 1, 368; p = 0.77).

Values and reproducibility of estimates of LVEFs acquired on two cameras Both studies of one patient could not be processed because the left ventricle could not be tracked by either method. There were a further seven studies from five patients in which the data acquired on one of the cameras could not be processed by one of the methods. Of these studies, four were acquired on the GE camera and three on the Siemens camera. For the studies acquired on the GE camera, the Siemens method tracked the heart and the left atrium in two studies (corresponding mean estimates of LVEF obtained by the Hermes method were 60 and 58%). The Hermes method tracked the heart and aorta in two studies (corresponding mean estimates of LVEF obtained by the Siemens method were 60 and 59%). For the studies on the Siemens camera, the Siemens method tracked the left atrium and the aorta in two studies (corresponding mean estimates of LVEF obtained by the Hermes method were 63 and 61%, respectively), and the Hermes method tracked the entire heart in one study (corresponding mean estimates of LVEF obtained by the Siemens method was 60%). This left 185 patients for analysis. Tables 3 and 4 summarise the values of the estimates of LVEF acquired on both cameras. There was no difference in the estimates. Bland–Altman plots (Figs 3 and 4) showed no bias in their distribution. Table 5 summarises the reproducibility of the estimates of LVEF from data acquired on the two cameras. There were 40 patients in which the SDs of the three estimates of the LVEFs were above the 95th percentile for both methods on both cameras. Table 5. Percentiles of the sds of the three estimates of lvefs for the GE and Siemens cameras GE camera Siemens Hermes method method 0.0 0.0 0.6 0.6 0.6 1.0 1.2 1.7 2.3 3.0

Siemens camera Siemens Hermes method method 0.0 0.0 0.6 0.6 0.6 1.0 1.2 1.5 3.1 2.9

Difference (camera 1 – camera 2)

Table 3. Estimates of lvefs acquired on different cameras processed by the Siemens method

5th percentile 25th percentile 50th percentile 75th percentile 95th percentile

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014

40.0 30.0 20.0

Upper LOA

10.0

Mean difference

0.0 –10.0 –20.0

Lower LOA 0.0

20.0

Limits of agreement (LOA) Mean difference

40.0 60.0 Mean LVEF (%)

80.0

100.0

–15.367 to 16.661 0.647 (CI: –0.508 to 1.802)

Fig. 3. B land–Altman plot: difference between cameras, Siemans method

In most of these patients, two of the three estimates obtained on one camera for a method were similar. The difference between the two similar estimates (minimum difference) was 0% in 14 patients, 1% in 10 patients, 2% in 10 patients, 3% in one patient, 4% in two patients, 5% in two patients, and 6% in one patient. The difference between the highest and lowest estimates (maximum difference) for both cameras for both methods was 1% in one patient, 4% in three patients, 5% in three patients, 6% in 14 patients, 7% in eight patients, 8% in four patients, 9% in three patients, 10% in one patient, 13% in one patient, 22% in one patient, and 33% in one patient. The differences of 22 and 33% were found in patients who were imaged on the Siemens camera and processed by the Siemens method. In both of these patients, it was documented by the operator that the tracking of the left ventricle was poor.

Discussion There is consensus in the literature that different software programs for processing GBP studies cannot be used interchangeably.3-7 Difference (camera 1 – camera 2)

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40.0 30.0 20.0 Upper LOA

10.0

Mean difference

0.0 –10.0 –20.0

Lower LOA 0.0

20.0

Limits of agreement (LOA) Mean difference

40.0 60.0 Mean LVEF (%)

80.0

100.0

–10.666 to 11.415 0.374 (CI: –0.422 to 1.171)

Fig. 4. B land–Altman plot: difference between cameras, Hermes method

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This was also found in our study, which showed the Siemens software gave higher estimates of LVEF than the Hermes software. Hiscock et al,3 who compared 18 workstation algorithm combinations including Siemens and Hermes, also found that the Siemens software gave estimates of LVEFs that were higher than estimates obtained from the Hermes software. The mean of 64 estimates of LVEF calculated with the Siemens software was 64.6% and with the Hermes software 61.3 and 61.7%. Differences in estimates of LVEF obtained from different software methods on the same patient could be attributed to variations in the algorithms used for edge detection in determining the ROI around the left ventricle and background subtraction. There was no documentation on the Siemens package available to us in the online user manual. There was limited documentation on the mathematical algorithms used in the Hermes software for determination of the left ventricular ROI and background subtraction. The Hermes software package used a variation on a second differential method for edge detection in determination of the left ventricular ROI. Background subtraction was performed in the background ROI outside the left ventricular ROI at the end of diastole, as well as on the non-ventricular counts within the end-diastolic region at end-systole. This could have resulted in an over-subtraction of background and account for a slightly lower LVEF. In the studies performed by Skrypniuk4 and Fair et al.,5 it is suggested that there is a need for software suppliers to supply more information on their software packages and to give guidance on data quality requirements as well as on any limits of operation. Fair et al.5 suggested that adequate testing of software packages against phantoms (if possible), and clinical testing on a reasonable number of patients should be done by software manufacturers. Because different software packages use different algorithms and give different values for LVEF, all reports of LVEF calculated from GBP studies should contain the name and version of the software package used to calculate the result. Wherever possible the same software should be used to process serial studies. When the same software is not used to process serial studies, ideally, all the raw data should be retrieved from an archive and reprocessed using the current software and a summary of all previous results included in the current report. If this is not possible, the mean difference and limits of agreement of the two software methods should be given. The pattern of our results for reproducibility is consistent with previous reports in the literature by van Royen et al.,11 Pfistererer et al.,12 , Hains et al.,13 Hiscock et al.,3 and Skrypniuk et al.4 Van Royen et al.11 found that repeat quantitative radionuclide assessments of LVEF can be expected to be within a 2–4% range if a study is processed twice by the same operator. Pfisterer et al.12 do not state how many times each study was processed, but found studies reprocessed by the same operator to be within a 1–3% range of each other and within a 1.4–5% range of each other if processed by different operators. We found that studies processed three times by the same operator were within a 3–6% range of each other for the Siemens method, and within a 3–9% range for the Hermes method. The reason for the wider range in our study is most probably due to the fact that our studies were processed three times. Two of our three estimates were always more closely related. The difference between the two closest estimates was ≤ 3% in all patients with

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both methods. Our study is in agreement with that done by Hains et al.13 were the SD of the difference between estimates of LVEFs calculated by one operator ranged from 0.5–0.8. Hiscock et al.,3 who also compared the Hermes and Siemens systems, reported the SDs of the difference between LVEFs calculated by one operator to be 1.80 and 2.56 for Hermes software systems. Their reported value for inter-operator variability for the Siemens software system, 4.79, was however much higher than the values of 0.6, 0.7 and 0.5 reported in our study for the three operators, respectively. The reason for the higher value is not known. Skrypnuik et al.4 reported the SD of the difference between LVEFs calculated by one operator to be 0.002. To date no articles on the influence of the acquisition of GBP studies on different cameras could be found in the English literature. In a study on the intra- and inter-observer reproducibility of LVEF estimates obtained from gated myocardial perfusion SPECT imaging and those obtained from GBP imaging, Castell-Conesa et al.14 collected data from two institutions, which acquired their data on different cameras. The issue of whether the acquisition of studies on different cameras had an effect on results was however not specifically addressed. Our study showed no difference in the results of the GBP studies acquired on different cameras. We suggest that each GBP study should be processed three times before reporting a result. In our study, two of the three LVEF estimates were closely related regardless of the software method used. The difference between the two closest estimates was always ≤ 3%. The mean of these two estimates would probably be the best representation of the patient’s LVEF. Anthracyclines have been used for the past 30 years in chemotherapy regimes. No consensus however exists on the optimal monitoring for cardiotoxic effects. Guidelines have been proposed, but none incorporate all of the necessary components of monitoring for chemotherapy-induced cardiotoxicity.15 Until such research is available, following one of the existing guidelines is the most practical solution. At our institution the oncologists use the guidelines as set out in the Oxford Textbook of Oncology.16 This guideline suggests that in patients with baseline LVEF estimates greater than 50%, doxorubicin treatment should be discontinued if the LVEF decreases by 10%, or if a value of 50% is reached. In patients with baseline LVEFs of less than 50% but greater than 30%, it is suggested that doxorubicin therapy should be discontinued if the LVEF decreases by 10% or if a value of less than 30% is reached. Skrypniuk et al.4 found the change in a LVEF value required to be 95% confident of a real change when carrying out repeat measurements on an individual patient to be 4.5%. It is therefore recommended that each department obtain their own percentage values for clinical decision-making for each software package used independently. In our study, the patients who had SDs for the three estimated LVEFs above the 95th percentile had differences between the highest and lowest (maximum difference) of the three estimates of 6% using the Siemens software method, and 9% using the Hermes software method. This implies that within our department, a reduction in the ejection fraction for a follow-up study of more than 6% is of clinical significance if processed using the Siemens software method, and 9% when using the Hermes software method. If the closest two of the three estimates

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of LVEF obtained by one operator is used, changes of more than 3% are of concern. A limitation of this study was that most of the LVEFs fell within the normal range.

Conclusion The results of this study are consistent with reports that software programs for processing GBP studies cannot be used interchangeably and each department must establish its own values for clinical decision-making. The software used to calculate the result should be identified in the report. Studies should be processed at least three times. The mean of the two closest estimates would probably be the best representation of the patient’s LVEF. Acquisition of GBP studies on different cameras did not influence results.

References 1.

Hesse B, Lindhardt TB, Acampa W, Anagnostopoulos C, Ballinger J, Bax JJ, et al. EANM/ESC guidelines for radionuclide imaging of cardiac function. Eur J Nucl Med Mol Imaging 2008; 35(4): 851–885. Hendel RC, Berman DS, Di Carli MF, Heidenreich PA, Henkin RE, Pellikka PA, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll Cardiol 2009; 53(23): 2201–2229. Hiscock SC, Evans MJ, Morton RJ, Hall DO. Investigation of normal ranges for left ventricular ejection fraction in cardiac gated blood pool imaging studies using different processing workstations. Nucl Med Commun 2008; 29(2): 103–109. Skrypniuk JV, Bailey D, Cosgriff PS, Fleming JS, Houston AS, Jarritt PH, et al. UK audit of left ventricular ejection fraction estimation from equilibrium ECG gated blood pool images. Nucl Med Commun 2005;

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26(3): 205–215. Fair JR, Heintz PH, TelepakRJ. Evaluation of new data processing algorithms for planar gated ventriculography (MUGA). J Appl Clin Med Phys 2009; 10(3): 173–179. PuchalAñé R, GuiraoMarín S, DomènechVilardell A, Rodríguez Gassén A, BajénLázaro MT, RicartBrulles Y, et al. Calculation of the left ventricular ejection fraction. Comparison between 4 different instruments. Rev Esp Med Nucl 2008; 27(6): 418–423. Bailey EA, Bailey DL. Results from an Australian and New Zealand audit of left ventricular ejection fraction from gated heart pool scan analysis. Nucl Med Commun 2012; 33(1): 102–111. Scheiner J, Sinusas A, Wittry MD, Royal HD, Machac J, Balon HR, et al. Society of Nuclear Medicine procedure guideline for gated equilibrium radionuclide ventriculography 2002. http://interactive.snm.org/ docs/pg ch01 0403.pdf. (accessed 10 September 2009). Lauritsen JM, Bruus M. EpiData (version 3). A comprehensive tool for validated entry and documentation of data. The EpiData Association, Odense Denmark, 2003–2004. Stata 11.1: StataCorp LP, 4905 Lakeway Station, TX 77845, USA. Van Royen N, Jaffe CC, Krumholz HM, Johnson KM, Lynch PJ, Natale D, et al. Comparison and reproducibility of visual echocardiographic and quantitative radionuclide left ventricular ejection fractions. Am J Cardiol 1996; 77(10): 843–850. Pfisterer ME, Battler A, Zaret BL. Range of normal values for left and right ventricular ejection fraction at rest and during exercise assessed by radionuclide angiocardiography. Eur Heart J 1985; 6(8): 647–655. Hains AD, Al-Khawaja I, Hinge DA, Lahiri A, Raftery EB. Radionuclide left ventricular ejection fraction: a comparison of three methods. Br Heart J 1987; 53(3): 242–246. Castell-Conesa J, Aguadé-Bruix S, García-Burillo A, González JM, Canela T, Oller G, et al. Reproducibility of measurements of left ventricular function with gated myocardial perfusion SPECT and comparison with blood pool radionuclide ventriculography. Rev Esp Cardiol 2004; 57(10): 931–938. Jannazzo A, Hoffman J, Lutz M. Monitoring of anthracycline-induced cardiotoxicity. Ann Pharmacother 2008; 42(1): 99–104. Valkoma R, Pauwels EKJ, Arnt JW. Nuclear medicine procedures. In: Peckham M, Pinedo HM, Veronesi U. Oxford Textbook of Oncology. Oxford: Oxford Medical, 1995; 1: 434. ISBN 0 19 262663 9.

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An echocardiographic study of infective endocarditis, with special reference to patients with HIV SH Nel, DP Naidoo Abstract Objective: The aim was to describe the echocardiographic features of patients with infective endocarditis (IE), and to compare the manifestations of IE in HIV-positive versus HIV-negative patients. Methods: The study was prospective in nature and screened patients referred to Inkosi Albert Luthuli Hospital (IALCH) with suspected IE between 2004 and 2007. Only patients with a definite diagnosis of IE according to the modified Duke criteria were enrolled for the purpose of the study. Inkosi Albert Luthuli hospital is an 842-bed tertiary referral centre, serving a KwaZulu-Natal population of 10 million people, who are of various races. Results: During this period, 91 patients were screened for IE. Seventy-seven (HIV infected, n = 17) satisfied the criteria for a definite diagnosis of IE. Blood cultures were positive in 46% of cases. The commonest organism was S aureus. Most patients had advanced valve disruption with heart failure and high peri-operative mortality. The clinical profile in the HIV-infected patients was similar to the that of the non-infected patients. The prevalence of echocardiographic complications (abscesses, aneurysms, perforations, fistulae and chordal ruptures) was 50.6% in the whole group. Except for the presence of leaflet aneurysms and root abscesses in four advanced (CD4 counts < 250 /mm3) HIV-infected cases, complications were not more frequent in the HIV-infected group. Conclusion: There was a high rate of culture-negative cases in this study, probably related to prior antibiotic usage; in this setting the modified Duke criteria have diagnostic limitations. No significant differences in the clinical presentation of infective endocarditis were noted between HIV-infected and HIV-negative patients. Keywords: infective endocarditis, HIV, rheumatic heart disease Submitted 8/3/12, accepted 29/11/13 Cardiovasc J Afr 2014; 25: 50â&#x20AC;&#x201C;57

www.cvja.co.za

DOI: 10.5830/CVJA-2013-084

Important developments during the last 20 years have facilitated rapid and accurate diagnosis of infective endocarditis (IE), and recent guidelines emphasise the role of early surgical Department of Cardiology, University of KwaZulu-Natal, Durban, South Africa SH Nel, MMed Sc, nel.samantha@yahoo.com DP Naidoo, FRCP, naidood@ukzn.ac.za

treatment when complications supervene.1,2 The emergence of prosthetic valve endocarditis, catheter-related endocarditis, and an increased incidence of antibiotic resistance has led to new challenges for the physician.3 From a microbiological standpoint, the rise in staphylococcal infections, and the immune paresis associated with HIV infection pose further diagnostic challenges that also have important implications for management.3 Bacteraemia is said to be common in HIV-positive patients, due to the numerous immunological defects present in this disease.4 Furthermore, in the setting of HIV exposure and altered immunity, infection is not uncommonly caused by unusual organisms, such as barbonella, salmonella, and listeria.1 This raises the question as to whether IE presents a somewhat different clinical and echocardiographic picture in the HIV-positive patient. It is known that the degree of immunosuppression, manifested by a reduced CD4 lymphocyte count, strongly correlates with the presence of echocardiographic abnormalities.5 Whether the immunosuppression associated with HIV may alter the clinical picture of valvular heart disease, particularly IE, is not clear. Since a decrease in CD4 count is thought to predispose to HIV-associated cardiac disease, this study was designed to determine the pattern of cardiac involvement in the HIV-infected subjects who develop IE.5,6

Methods The study prospectively screened a total of 91 patients with features of suspected IE between 2004 and 2007. The diagnosis of IE was made on clinical grounds. The modified Duke criteria were then used to classify IE as definite or probable.7 Only patients with a definite diagnosis of IE according to the modified Duke criteria were enrolled for the purpose of the study. Inkosi Albert Luthuli Hospital (IALCH) is an 842-bed tertiary referral centre, serving a population of 10 million people in whom rheumatic heart disease is endemic. The study protocol was approved by the Nelson R Mandela Research Ethics Committee (H095/04). The study has been structured in accordance with the Declaration of Helsinski (2000), which deals with research involving human subjects. All patients with suspected IE referred from peripheral hospitals to the Department of Cardiology at IALCH were assessed by clinicians who documented the clinical features of IE. Blood sampling was performed for estimation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum complement and blood cultures. Urine tested for microscopic haematuria and 12-lead electrocardiograms were performed on all patients. All study participants were tested for HIV (diagnosis of HIV was determined by an ELISA test), after adequate pre-test counselling by a qualified counsellor. If the results were positive, a CD4 count was done. The stage of HIV infection was assessed

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using both clinical features and the level of CD4 count. A broad description of the echocardiographic features of IE was documented for the study population as a whole. The clinical features, laboratory results and echocardiographic findings were compared in the HIV-infected and uninfected patients. Patients with a clinical diagnosis of suspected IE had an initial examination by transthoracic echocardiography (TTE) to look for echocardiographic evidence of infection, document haemodynamic status (valvular dysfunction, ventricular dimensions and ventricular function) and to determine the presence of predisposing conditions such as congenital, valvular or degenerative heart disease. Echocardiographic evidence of valve infection was accepted when any one of the following findings was identified: vegetation, paravalvular extension with abscess formation, or rupture and fistula formation, and prosthetic valve dehiscence. Leaflet or cuspal thickening, with/without areas of calcification found at TTE was taken as evidence of underlying rheumatic heart disease. Transoesophageal echocardiography (TEE) was performed within 24 to 48 hours of admission if paravalvular extension was suspected, or where TTE images were suboptimal, and in the case of mechanical prosthetic valves. It was performed in most patients except where patients were rushed to emergency surgery on the basis of the transthoracic echo findings. Echocardiography was performed on a Sequoia C256 (Acuson, Germany) cardiac ultrasound machine, using a 5-MHz transthoracic transducer for TTE, and a 7-MHz multiplane transoesophageal probe for TEE.

Statistical analysis Baseline characteristics of all patients were evaluated to describe the demographics and to identify any underlying risk factors. Comparisons between HIV-infected and HIV-negative patients for categorical outcomes (e.g. valvular assessment) were evaluated by means of chi-square tests or Fischer’s exact tests. Where the outcome was numerical (e.g. CD4 count), Mann–Whitney tests were used to compare mean ranks in the HIV-positive and HIV-negative groups. The Student’s t-test was used to determine differences between samples. The significance level was taken at p < 0.05.

Results Of the 91 patients screened for suspected endocarditis, 63 satisfied the diagnosis of definite IE by the Duke and 78 by the modified Duke criteria. According to the modified Duke criteria, 77 patients were classified as definite IE (HIV infected, n = 17, uninfected, n = 60), nine as possible IE, and five as rejected IE. The analysis that follows was performed on the 77 patients with definite IE (Table 1). Table 1. Duke criteria versus modified Duke criteria in the classifications of infective endocarditis

Definite Possible Rejected

Duke criteria Modified Duke criteria HIV+ HIV– Total HIV+ HIV– Total n = 18 (%) n = 73 (%) 91 n = 18 (%) n = 73 (%) 91 16 (88.9) 47 (64.4) 63 17 (94.4) 60 (82.2) 77 2 (11.1) 21 (28.8) 23 1 (5.6) 8 (10.9) 9 0 (0) 5 (6.8) 5 0 (0) 5 (6.8) 5

The mean participant age in the whole group was approximately 30 years, with a slight male preponderance (55%). Overall, there was a slight male predominance for the occurrence of IE in both groups of patients: 55% (n = 43) were male and 45.5% (n = 35) were female (Table 2). There were no significant differences in age, admission weight (61 vs 59 kg), and temperature (36.5 vs 37°C) between the HIV-infected and uninfected groups. Fever above 38°C was noted in four HIV-infected patients. The source of infection was not apparent in most patients, nor was there any information from the history about a childhood history of rheumatic fever or valvular heart disease. Other clinical features of infective endocarditis did not appear to be different in the two groups. Among the 17 HIVinfected patients, 11 had clubbing and five had heart failure. Hepatomegaly mirrored the findings of congestive heart failure and was found in five (29.4%) HIV-infected patients, and in 28 (46.7%) HIV-negative patients (p = 0.024) (Table 2). Thirty-six of the 78 patients with definite IE (46%) had positive blood cultures; 29 (37%) of these were from the HIV-negative patients, and seven (9%) were from the HIV-infected patients. S aureus was the commonest infecting bacterium in both groups of patients, and was found overall in 17 (47%) of those with positive cultures. Of these, four were HIV-infected and 13 were HIV negative (p = ns). The second most common infecting bacterium was S viridans (n = 7) (20%); of these one was in the HIV-infected group. One HIV-infected patient had an unusual organism; this was Propionibacterium. Significantly, higher elevation in the sedimentation rate and the C-reactive protein levels was noted in the HIV-infected group compared to the HIV-negative group. In addition, serum albumin level was markedly lower in the HIV-infected group (Table 3).

Echocardiographic findings All but one patient had findings suggestive of IE on TTE. These included the presence of vegetations, root abscesses or leaflet aneurysms (Table 4). Apart from these changes, 60 patients (78%) had leaflet thickening with/without reduced mobility or calcium on the valve apparatus that was suggestive of rheumatic heart disease; of these 51 were HIV negative, and nine were HIV Table 2. Demographic data and clinical features in HIV-positive and HIV-negative patients with infective endocarditis HIV+ HIV– Total Parameter n = 17 (%) n = 60 (%) n = 78 (%) p-value Age (years) 32 (22–50)* 31(12–64)* 63(80.8) 0.867 Gender: male 9 (53) 33 (55) 43(55.1) 1.000 female 8 (47) 27 (45) 35( 44.9) Body weight (kg) 61 (41–82)* 59 (43–79)* 120 (153.8) 0.585 Fever 4 (23.5) 3 (5) 7 (9.1) 0.024 Clubbing 11 (64.7) 32 (53.3) 43 (55.8) 0.102 Splinter haemorrhages 2 (11.8) 3 (5) 5 (6.5) 0.304 Emboli/stroke 3 (17.6) 6 (10) 9 (11.7) 1.000 Splenomegaly 2 (11.8) 3 (5) 5 (6.5) Heart failure/ 5 (29.4) 28 (47) 33 (43) 0.204 hepatomegaly Haematuria 3 (17.6) 19 (31.7) 22 (28) *Mean values with the ranges bracketed.

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Table 3. Comparison of laboratory features of HIV-positive and HIV-negative patients with infective endocarditis HIV+ HIV– Laboratory findings n = 17 (%) n = 60 (%) p-value White blood count (/l) 7.7 (2.46–23.14) 9 (4–29.4) 0.387 Lymphocyte (/l) 2.76 (0.44–18.2) 2.93 (0.26–6) 0.548 Platelets (/l) 273 (123–449) 229 (40–432) 0.675 Haemoglobin (mg/dl) 8.92 (5–11.2) 10.76 (6–14.2) 0.119 Sedimentation rate 110.8 (65–142) 62.5 (6–160) 0.024 (mm/h) C-reactive protein (mg/dl) 95.19 (0.17–265.3) 68 (0.02–336.4) 0.018 Urea (mmol/l) 7.6 (3–192) 13.87 (1.4–28.3) 0.091 Creatinine (mmol/l) 131.6 (57–770) 201.42 (43–851) 0.301 Serum albumin (g/dl) 26.94 (18–36) 33.6 (0.57–49) 0.031 Complement C3 (g/l) 1.48 (1.1–1.77) 1.09 (0.15–1.8) 0.001 Complement C4 (g/l) 0.308 (0.13–0.46) 0.25 ( 0.01–0.52) 0.120 Rheumatoid factor (+) 4 (23.6) 33 (55) 0.052 Haematuria 3 (17.6) 19 (31.7) Mean values with the ranges bracketed, except rheumatoid factor and haematuria.

infected. The remaining 17 patients had normal valves (nine HIV negative and eight HIV infected). Congenital defects were found in five patients [patent ductus arteriosus (one), bicuspid aortic valve (one), and ventricular septal defect (three) (one HIV infected and two HIV negative). Fifty-four (70.1%) patients underwent TEE. Of these, 51 had features suggesting IE. The remaining three patients with negative findings on TEE had thickened calcified valves (one), thickened leaflets with chordal rupture (one), and the last one had a normal valve. Vegetations were the predominant finding in 68 (88%) patients at echocardiography (Table 5). They were present in 11/17 (64.7%) of the HIV-infected patients, and in 57/61 (95%) of the HIV-uninfected patients. The remaining nine patients (six HIV-infected and three HIV-uninfected patients) did not have vegetations, but did show other echocardiographic features suggestive of IE. These were leaflet aneurysms in four and aortic root abscesses in four cases; one patient had a disrupted aortic valve without the presence of vegetations (Figs 1–3). In comparison with adjacent valvular tissue, vegetations appeared echogenic or homogenous in appearance, with an irregular shape. Single and multiple vegetations were seen with the same frequency in each group. Vegetation size was similar (11 mm) in each group (p = ns). There was no relationship between the size of the vegetation and the presence of complications such as abscess formation, aneurysm, stroke or fistula development. Complications occurred in four of the 13 HIV-negative Table 4. Echocardiographic findings in HIV-positive and HIV-negative patients with infective endocarditis HIV+ HIV– Total n = 17 (%) n = 60 (%) n = 77 (%) p-value Vegetations 11 (64.7) 57 (95) 68 (88.3) 0.447 Leaflet aneurysm 4 (23.5) 1 (1.7) 5 (6.5) 0.008 Abscess 3 (17.6) 3 (5) 6 (7.8) 0.118 Regurgitation 16 (94.1) 59 (98.3) 75 (97.4) Pericardial effusion 6 (35.3) 26 (43.3) 28 (36.4) 1.000 Chordal rupture/leaflet prolapse 6 (35.3) 20 (33.3) 26 (33.8)

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patients with vegetations larger than 10 mm. These were aortic root abscess (one), fistula (one) (Fig. 4), and two had strokes. None of the four HIV-infected patients with vegetations > 10 mm (11, 11, 11 and 11.6 mm) had complications associated with large vegetations (p = ns) . Extensive valve disruption was present in both groups, since patients presented at an advanced stage of infection. Except for the leaflet aneurysms and root abscesses, which were present in four and three HIV-infected patients, respectively, (two had both aneurysm and abscess, one had an abscess, one had an aneurysm), there did not appear to be any difference in the prevalence of valve-related complications between the two groups. Of the five aneurysms in the study, two were cuspal aneurysms of the aortic valve, (both HIV infected) and the remaining three aneurysms were located on the mitral valve (two HIV infected). Therefore, among the HIV-infected patients, leaflet aneurysms were found in the mitral (two) and aortic (two) position, and one HIV-negative patient had a leaflet aneurysm associated with a vegetation < 10 mm, affecting the mitral valve. One leaflet aneurysm was found along the annulus of a mitral prosthesis in an HIV-negative patient, confirmed at TEE (Fig. 2b) Aortic root abscesses were present in three patients in each group, and were of a larger size in the HIV-infected (0.73 × 1.2 cm) than the HIV-uninfected patients (0.3 × 0.45 cm), but this difference was not significant (p = 0.118) and was not related to a very low CD4 count in two patients (15, 150, 249 /mm3). There was no evidence of myocardial abscess formation. Like the aortic root abscesses, the leaflet aneurysms were larger in the HIV-infected patients (0.86 × 0.85 cm vs 0.21 × 0.3 cm) (p = 0.008). The mean ejection fraction (EF) in the HIV-uninfected patients was 59%, and in the HIV-infected patients, 62.9% (p = ns). Pericardial effusion was common and associated with heart failure and fluid overload in both groups (p = ns). Twenty-two of the 26 HIV-uninfected patients with pericardial effusions had severe valvular regurgitation; 12 (46.2%) showed signs of heart failure with fluid overload, and two of the remaining 10 patients had impaired systolic function (EF = 35% in both). All Table 5. Vegetation characteristics in HIV-positive and HIV-negative subjects HIV+ n = 17

HIV– n = 60

Total p-value Site Aortic 2 (11.8) 21 (35) 23 (29.9) 0.189 Mitral 4 (23.6) 21 (35) 25 (32.5) 0.001 Tricuspid 2 (11.8) 1 (1.7) 3 (3.9) Other site*** 0 (0) 4 (6.7) 4 (5.2) Mixed (aortic + mitral) 3 (17.6) 10 (16.7)** 13 (16.9) Mean size (mm) 11 (4–24)* 10 (3–30)* 10 (3–30)* 0.447 Vegetation number Single 6 (35.3) 32 (51.7) 38 (49.4) Multiple 5 (29.4) 25 (41.7) 30 (38.9) Total, n (%) 11 (64.7) 57 (95) 68 (88.3) Values expressed in brackets indicate percentages. *Mean values with the ranges bracketed **Includes one patient with a VSD who had mitral and tricuspid valve vegetations ***Other site refers to central line, pulmonary and prosthesis valves. The left atrial mural endocarditis is included with the mitral valve.

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Fig. 1. V egetations on the aortic valve (parasternal long-axis view) (A), and on the mitral valve chord (apical four-chamber view) (B), in an HIV-positive patient. Vegetations on the aortic valve (parasternal long-axis view) (C), and mitral valve (apical fourchamber view) (D), in a HIV-negative patient.

six HIV-infected patients with pericardial effusion had severe valvular regurgitation, two with heart failure and fluid overload, and none had impaired systolic function.

HIV stage and echocardiographic features The mean CD4 count in the HIV-infected patients was 189 /mm³. To determine any association with the stage of immunodeficiency, the echocardiographic findings were examined in the HIV-infected patients and stratified into two groups: CD4 counts < 200 /mm³ and > 200 /mm³. No striking differences emerged between the groups in vegetation size and number of valves affected, complication rate, organism, ejection fraction or outcome. Three of the four patients with leaflet aneurysms, and all of those with aortic root abscess had CD4 counts < 250 /mm³. The

four patients with S aureus infection all had CD4 counts < 250 / mm³ (248, 231, 149 and 139 /mm³). Three of the four patients with very low CD4 counts (< 100 /mm³) had vegetations, and the fourth had an aortic root abscess without vegetations.

Surgical findings In all patients, medical therapy with appropriate antibiotics had been instituted and continued for a total period of six weeks. Forty patients (34 HIV uninfected and six HIV infected) underwent valve-replacement surgery. At surgery, the underlying valve pathology was considered to be rheumatic in origin in 38 cases (95%). In the two remaining cases, the underlying valve was considered normal by the operating surgeon. Among the six HIV-infected cases, surgery revealed underlying rheumatic valve pathology in five patients; in the remaining patient the

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B B

Fig. 2. L eaflet aneurysm on the aortic and mitral valves in an HIV-infected patient (parasternal long-axis view) (A), and on the mitral annulus (arrows) (B), in the HIV-negative patient with a mitral prosthesis (fourchamber view on TEE).

morphology of the underlying valve tissue was normal. Eighteen (23.4%) patients (14 HIV uninfected and four HIV infected) died during the course of the study (p = ns). Three HIV-uninfected patients died after surgery. One had an aortic root abscess with fistula formation with coronary ostial occlusion and died in theatre. The second died on day seven in cardiogenic shock, and the third on day eight from an intracerebral haemorrhage. The CD4 counts in the HIV-infected patients who died were 139, 135, 149 and 249/mm³. One of these patients underwent emergency surgery for a disrupted right coronary cusp and died 35 days after surgery from a methicillin-resistant staphylococcal (MRSA) septicaemia acquired postoperatively. The remaining five HIV-infected patients who had surgery have not shown any features of re-infection, and remained stable after one year. Six patients (7.8%), all HIV negative, had advanced renal involvement. Four were receiving haemodialysis at the time of diagnosis.

Fig. 3. A ortic root abscess involving the non-coronary cusp (arrows) of the aortic valve in an HIV-infected (A), and an HIV-negative subject (B).

Discussion Few data exist on the clinical profile and echocardiographic findings of IE in HIV-infected patients in the developing world.8,9 Most reports of IE in HIV-infected individuals have focused almost exclusively on IE in intravenous drug users, and it has reportedly been rare in non-drug users.10 In this study we have shown that the clinical profile of IE in the HIV-positive patient is similar to that in the HIV-negative patient, and is characterised by fever, clubbing, murmurs and severe valve regurgitation. In contrast to Western series,10 the most common underlying predisposing abnormality observed in our study was rheumatic heart disease. Vegetations occurred on the mitral and aortic valves and there were three cases of right-sided endocarditis in patients with congenital heart disease (two of whom were HIV infected. The mean size of the vegetations was similar in both groups (11 mm) (Table 6); three out of the four patients with CD4 counts < 200/mm³ had slightly larger-sized vegetations (13 mm). These findings are in keeping with the report by Smith et al. who documented an 11.5% prevalence of infective endocarditis in HIV-positive subjects with bacteraemia.11 These authors showed that there was no difference in the clinical characteristics of

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Table 6. Echocardiographic features predictive of surgery Echo finding Vegetations Persistence after stroke > 10 mm Increase in size Valve dysfunction Perforated leaflets Valve regurgitation Impaired LV function Not responding to antibiotics Paravalvular extension Rupture/fistulae Abscess/aneurysm

HIV+ n = 17(%)

HIV– n = 60 (%)

Total

1 (5.9) 4 (23.5) –

– 13 (21.7) 1 (1.7)

1 17 1

1 (5.9) 16 (94.1) – –

1 (1.7) 55 (91.7) 3 (5) 1 (1.7)

2 71 3 1

– 7 (41.2)

1 (1.7) 4 (6.7)

1 11

Fig. 4. F istulous connection between a root abscess and the right atrium (arrow) in the parasternal short-axis view of an HIV-negative patient (A). The colour Doppler picture (B) shows flow across the fistulous connection into the right atrium. Fistulous connection between root abscess and right atrium (arrow) in the parasternal five-chamber view (C).

HIV-positive patients with and without IE.11 We noted that leaflet aneurysms and aortic root abscesses occurred in both HIV-positive and HIV-negative subjects, but the numbers were too small for a formal statistical comparison. In these cases, echocardiography revealed severe valve damage,

with peri-valvular extension of the infection leading to abscess formation and/or the development of fistula, features associated with a poor prognosis.12 Three patients died in the immediate postoperative phase (the first, coronary ostial occlusion, the second had cardiogenic shock, and the third patient was HIV positive and died from MRSA infection). A relationship between aneurysms and the HIV infection has been documented in vascular series,13 in which aneurysms have been found to be multiple and occur in unusual anatomical locations. In our cases, the root abscesses and leaflet aneurysms were larger in size in the HIV-positive patients. None of our patients had evidence of mycotic aneurysms elsewhere, which has been reported more frequently when presentation is delayed, especially in developing countries.14 In this study, pericardial effusion was a common finding in both groups, and was attributed largely to severe valve regurgitation and resulting heart failure. More than half (62%) the patients with pericardial effusion had failure of leaflet or cuspal coaption with a marked degree of haemodynamic compromise. However, markedly impaired systolic function with heart failure was not more frequent in HIV-negative patients. Pericardial effusions are considered to be a common form of cardiovascular involvement in HIV-infected individuals, the cause of which includes tuberculosis and pyogenic infection, particularly S aureus, as a result of endocarditis.15 The six patients with staphylococcal infection had small effusions that were not aspirated. Four patients in each group had evidence of extracardiac tuberculosis, but the cause of the pericardial effusion in these patients was thought to be valve destruction with heart failure. In this study, S aureus was the most common infecting bacterium, followed by S viridans. In the Western Cape, Koegelenberg et al.16 found that S viridans is still the most common bacterium in their group of HIV-positive patients. In Western series, S aureus is the commonest causative organism in HIV-infected patients; it is reported largely in intravenous drug users and has a predilection for the tricuspid valve. None of the patients recruited in our study were intravenous (‘mainline’) drug users. We did not find any multi-resistant organisms in the HIV-infected group. In the one HIV-infected patient with MRSA, S aureus was acquired postoperatively. In our study, 42 patients had negative blood cultures, an occurrence that was likely due to the setting of our study, a

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tertiary referral centre receiving patients who have already been started on antibiotics. In febrile patients with elevated ESR, clinicians at base hospitals (often far removed from laboratory facilities) feel obliged to administer antibiotic therapy prior to obtaining the results of initial investigations.16 A deficiency in the modified Duke criteria becomes apparent when diagnosing IE when blood cultures are negative; we have shown that these patients often have elevated sedimentation rates and C-reactive protein levels from repeated non-cardiac infection and anaemia. Using the surgical findings on operated cases as a gold standard, the positive predictive value of the modified Duke criteria was only 72%. The higher culture negativity in HIV-infected patients in our study also raises the possibility of non-bacterial thrombotic endocarditis (NBTE) in at least some of these cases.17 Serial negative blood cultures should alert the clinician to the possibility of NBTE, which has been reported in HIV-infected patients.16 These findings have significant implications for the prevalence and diagnosis of IE in HIV-positive patients. We found a similar rate of morbidity and mortality between HIV-infected and HIV-negative patients, in keeping with the data from Fowler et al., who found that overall morbidity and mortality related to cardiac disease in AIDS was low.18 There were four deaths among our HIV-infected patients (23.6%), and 14 among the HIV-negative patients (23.3%). Three of the four HIV-infected patients who died had CD4 counts < 100 /mm³. This is in keeping with data from our centre showing that surgery in HIV-infected patients with CD4 counts of > 400 /mm³ are likely to have early surgical outcomes similar to that in HIV-uninfected patients.19

Study limitations The small sample size of the study was a limiting factor. This could have been due to the poor referral system from the base hospital to our hospital, or in fact, that IE is not as common in HIV-positive patients as we had presumed. Also not all patients diagnosed with IE at TTE received a TEE. This was due to various reasons, such as a patient’s inability to tolerate the TEE probe and markedly elevated international normalised ratio (INR) levels at the time of examination. A further limitation in the study was the high rate of negative blood cultures. This was most likely the result of administration of antibiotics to the patient prior to referral to our institution, or in the case of the HIV-positive patients, the possibility of NBTE. Of the 91 patients initially screened, 77 were accepted as having had a definite diagnosis of IE, according to the modified Duke criteria. The remaining 14 were deemed not to have IE and excluded from the analysis. Whether any patients in this group had IE or not (true negative and false negative) could not be determined with certainty since they were not subjected to surgery. We believe the modified Duke criteria were responsible for the higher false-positive rates since it permits diagnosis of IE based on the echocardiographic criteria in the absence of positive blood cultures. While this reflected a potential flaw in the study, since the diagnosis of IE was based on the finding of vegetations in the absence of positive blood cultures, this study highlights the difficulty in diagnosis when the blood cultures are negative, placing more reliance on echocardiographic detection

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of vegetations. Unless supported by clinical features and bacteriological evidence, vegetations alone are not diagnostic of IE because they may represent healed infection. Furthermore, the diagnosis of IE postoperatively is rendered more difficult by the now common practice of leaving the chordal mechanisms intact. Five of the 33 patients clinically diagnosed as definite IE, and one possible IE, had no evidence of infection at operation, supporting the need for bacteriological confirmation of infection. Not all patients however were referred for surgery. The low CD4 counts in the HIV-positive patients meant an even smaller group of these patients were accepted for operation, as the acceptable CD4 level for surgery at our institution is CD4 count > 200 /mm³ In this study, attempts were made to more accurately define valve pathology on echocardiography. According to Taams et al., there are five distinct pathological features of IE that may be seen clearly on TEE and these are (1) mitral stenosis with vegetations; (2) myxomatous degeneration of leaflets with vegetations; (3) chordal rupture with vegetations; (4) chordal rupture without vegetations; and (5) mycotic aneurysms with fistulous connections.20 It is often difficult to decide on the underlying pathology with this degree of accuracy with TTE. In our study, harmonic imaging was employed to improve the diagnostic value of TTE by improving the image quality, as documented by Chirillo et al.21 Harmonic imaging works on the principle of limiting near-field artefacts, and because the harmonic energy increases with the distance the ultrasound wave propagates, most harmonics will result from the central ultrasound beam rather than the weaker side lobe artefacts.20 This modality is used primarily to enhance left ventricular endocardial borders. Its use did not really increase the resolution in visualising vegetations. Therefore, we used TEE to differentiate and define chordal rupture in association with vegetations, leaflet prolapse and flail leaflets. Our surgical findings revealed that even with TEE there were limitations, which were resolved at surgery when the subtlety of the findings could not be dissected.

Conclusion This study has shown no significant differences in the vegetation characteristics between HIV-infected and uninfected patients. Complications such as leaflet aneurysms and root abscesses occurred in patients with CD4 counts < 250 /mm3 in HIV-positive subjects, and appeared to be of a larger size when compared to the HIV-uninfected patients. The clinical outcome of medical and surgical therapy was also similar in both groups.

References 1. 2.

3. 4.

Moreillon P, Que YA. Infective endocarditis. Lancet 2004; 363: 139–149. The task force on the prevention, diagnosis and treatment of infective endocarditis of the European Society of Cardiology (ESC) Guidelines on the prevention, diagnosis and treatment of infective endocarditis (new version 2009). Eur Heart J 2009; 30: 2369–2413. Durack DT. Evaluating and optimizing outcomes of surgery for endocarditis (editorial). J Am Med Assoc 2003; 290(24): 3250–3251. Abraham J, Veledar E, Lerakis S. Comparison of frequency of active infective endocarditis by echocardiography in patients with bacteremia

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with and without human immunodeficiency virus. Am J Cardiol 2003; 91: 1500–1503. 5. Levy WS, Simon G, Rios J, Ross A. Prevalence of cardiac abnormalities in human immunodeficiency virus infection. Am J Cardiol 1989; 63: 86–89. 6. Barbaro G, Lorenzo G, Grisorio B, Barbarini G. Cardiac involvement in the acquired immunodeficiency syndrome: A multicentre clinical–pathological study. Aids Res Human Retroviruses 1998; 14(12): 1071–1077. 7. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994; 96: 200–208. 8. Todd AJ, Leslie SJ, McDougall M, Denvir MA. Clinical features remain important for the diagnosis of infective endocarditis in the modern era. Q J Med 2006; 99: 23–31. 9. Cicalini S. Forcina G. De Rosa F. Infective endocarditis in patients human with immunodeficiency virus infection. J Infect 2001; 42: 267–271. 10. Kaul S, Fishbein M, Siegel R. Cardiac manifestations of acquired immune deficiency syndrome: A 1991 update. Am Heart J 1990; 122(2): 535–544. 11. Smith D, Sherwood M, Crise, R, et al. A comparison of HIV positive patients with and without infective endocarditis: an echocardiographic study – the Emory endocarditis group experience. Am J Med Sci 2004; 328(3): 145–14.9 12. Evangelista A, González-Alujas MT. Echocardiography in infective endocarditis. Heart 2004; 90: 614–617.

13. Botes K, van Marie J. Surgical intervention for HIV related vascular disease. Eur J Vasc Endovasc Surg 2007; 34: 390–396. 14. Beynon RP, Bahl VK, Prendergast BD. Infective endocarditis. Br Med J 2006; 333: 334–339. 15. Katz A, Sadaniantz. Echocardiography in HIV cardiac disease. Cardiovasc Dis 2003; 45(14): 285–292. 16. Koegelenberg C, Doubell A, Orth H, Rueter H. Infective endocarditis: improving the diagnostic yield. Cardiovasc J Sth Afr 2004; 15(1): 14–19. 17. Lopez JA, Ross RS, Fishbein MC, Siegel RJ. Nonbacterial thrombotic endocarditis: A review. Am Heart J 1987; 113(3); 773–782. 18. Fowler VG, Sanders LL, Kuo Kong L, Scott McClelland R, Gottlieb GS, Li J, et al. Infective endocarditis due to Staphylococcus aureas: 59 prospectively identified cases with follow-up. Clin Infect Dis 1999; 28: 106–114. 19. Blyth DF, Buckels NJ, Sewsunker RR, Khan S, Mathiva TM. An experience with cardiopulmonary bypass in HIV-infected patients. Cardiovasc J Sth Afr 2006; 17(4): 178–185. 20. Taams M, Gussenhoven E, Egbert B, de Jaegere P, Roelandt J, Sutherland G, Bom N. Enhanced morphological diagnosis in infective endocarditis by transesophageal echocardiography. Br Heart J 1990; 63: 109–13. 21. Chirillo F, Pedrocco A, De Leo A, Bruni A, Totis O, Meneghetti P, Stritoni P. Impact of harmonic imaging on transthoracic echocardiographic identification of infective endocarditis. Heart 2005; 91: 329–333.

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61st annual conference of the Israeli Heart Society in association with the Israeli Society of Cardiothoracic Surgery

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014

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Diagnosis, treatment and follow up of neonatal arrhythmias Fatih Köksal Binnetoğlu, Kadir Babaoğlu, Gülcan Türker, Gürkan Altun Abstract Objective: This study aimed to evaluate the aetiology, spectrum, course and outcomes of neonates with arrhythmias observed in a tertiary neonatal intensive care unit from 2007 to 2012. Methods: Neonates with rhythm problems were included. The results of electrocardiography (ECG), Holter ECG, echocardiography and biochemical analysis were evaluated. The long-term results of follow up were reviewed. Results: Forty-five patients were male (68%) and 21 (32%) were female. Fifty-five patients (83.3%) were term, 11 (16.6%) were preterm, and 34% were diagnosed in the prenatal period. Twenty cases (30.3%) had congenital heart disease. Twenty-three patients (34.8%) were diagnosed during the foetal period. The most common arrhythmias were supraventricular ectopic beats and supraventricular tachycardia (SVT) at 39.3 and 22.7%, respectively. SVT recurred in five patients after the neonatal period. Conclusion: Supraventricular ectopic beats and SVT were the most common arrhythmias during the neonatal period. Although the prognosis of arrhythmias in the neonatal period is relatively good, regular monitoring is required. Keywords: arrhythmia, neonatal, supraventricular tachycardia Submitted 31/5/13, accepted 4/2/14 Cardiovasc J Afr 2014; 25: 58–62

www.cvja.co.za

DOI: 10.5830/CVJA-2014-002

Arrhythmias are seldom observed in the newborn period and rarely lead to serious consequences. The incidence is about 1% during the neonatal period and 1–3% in late pregnancy.1 Long-term tachycardia and bradycardia attacks induced by neonatal arrhythmias may lead to heart failure and hydrops foetalis.2 Because they may be a continuation of foetal arrhythmias, newborn arrhythmias are different from those occurring at later ages.3 For this reason, the early diagnosis of

Medical Faculty, Çanakkale Onsekiz Mart University, Çanakkale, Turkey Fatih Köksal Binnetoğlu, MD, koksaldr@yahoo.com

Department of Paediatric Cardiology, Kocaeli University, Kocaeli, Turkey Kadir Babaoğlu, MD Gürkan Altun, MD

Department of Neonatology, Kocaeli University, Kocaeli, Turkey Gülcan Türker, MD

arrhythmias in the prenatal period is essential for appropriate and optimal treatment in the postnatal period. In this study, we evaluated the type, clinical characteristics, treatment and follow up of newborns with arrhythmias.

Methods This study included 66 newborns (45 male, 21 female) diagnosed with arrhythmia in a tertiary hospital between 2007 and 2012. In all cases, sex, birth method, birth weight, week of pregnancy, maternal and gestational diseases, Apgar scores, and haematological and biochemical parameters were recorded. The results of electrocardiography (ECG) with 12 derivations, 24-hour Holter ECG and echocardiography were evaluated. Type, course of arrhythmia, detection time and treatments were analysed retrospectively. The patients were divided into three groups: irregular heart rhythm (ectopic beats, supraventricular premature beats and ventricular premature beats), bradyarrhythmia [sinus bradycardia, 2:1 atrioventricular (AV) block, complete AV block, long QT syndrome, etc], and tachyarrhythmias (sinus tachycardia, supraventricular tachycardia, ventricular tachycardia). Benign arrhythmias, such as sinus arrhythmia, nodal or junctional rhythms, wandering atrial rhythm, first-degree AV block and Wenckebach block were not included in the study. The statistical analysis of the results was carried out using the SPSS v13.0 (SPSS Inc., Chicago, IL, USA). Descriptive analyses of the normal variables are given as mean and standard deviation; data with non-normal distribution are given as minimum, maximum and median values.

Results Forty-five babies were male (68.2%) and 21 were female (31.8%). The average duration of pregnancy was 38.1 ± 2 weeks (34–41), and the average birth weight was 3 258 ± 508.6 g (2 200–4 500). Approximately 65% of the babies were delivered by Caesarean section; 83.3% were term and 16.6% were preterm (Table 1). The initial clinical presentations were apnoea, poor feeding, irritability, respiratory difficulties and cyanosis. Twenty-one babies were asymptomatic and arrhythmia was diagnosed during routine examination. Thirty patients had benign supraventricular premature beats or ventricular premature beats. Eleven patients had bradyarrhythmia and 25 had tachyarrhythmia (Table 2). Twenty-three patients (34.8%) were diagnosed in the foetal period. Six were premature and 17 were mature. Supraventricular premature beat was the most frequently diagnosed arrhythmia in the foetal period (Table 3). The mother of a baby with complete heart block diagnosed in the foetal period had Sjogren’s disease. Hydrops feotalis and foetal cardiomyopathy occurred in two babies with foetal supraventricular tachycardia (SVT).

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Table 1. Demographic features of the study group. Demographic features Sex, M/F Gestational age (week) Preterm delivery Term delivery Delivery mode Normal Caesarian Apgar score (5 minutes) Birth weight (g)

Number (mean ± standard deviation) 45/21 38.1 ± 2 (34–41) 11 55 28 38 8.5 ± 2 3 258 ± 508.6 (2 200–4 500)

Permanent junctional reciprocating tachycardia (PJRT) was the final diagnosis in patients with foetal cardiomyopathy after delivery. In addition, two babies had atrial flutter. All four of these patients were delivered at 37 weeks. The remaining baby was diagnosed in the 34th week with SVT. Digoxin was given to the mother. However, when rhythm control could not be maintained, sotalol was added and a partial response was achieved. The baby was delivered at 38 weeks. Babies who had complete AV block and 2:1 AV block were not treated in the intrauterine period. Twenty cases (30.3%) had accompanying congenital heart diseases. Atrial septal defect (ASD) was the most common cardiac pathology. Fifteen babies had ASD, ventricular septal defect or patent ductus arteriosus. Two babies, both of whom were term, had patent ductus arteriosus. Term babies with spontaneously closed ductus arteriosus after the first week were not included in this data. No premature baby subsequently showed patent ductus arteriosus after discharge. In babies with ASD, all defects were small or medium sized. Five babies had complex congenital heart diseases, such as AV septal defect,

Table 3. The types and frequency of arrhythmias diagnosed in the foetal period Arrhythmia type Irregular heart rhythm (ectopic beats) Supraventricular premature beats Ventricular premature beats Bradyarrhythmias Sinus bradycardia 2:1 AV block Complete AV block Tachyarrhythmia Supraventricular tachycardia Atrial flutter AV: atrioventricular.

Number of cases (n = 23) 15 13 2 3 1 1 1 5 3 2

Percent (%) 65.2 56.5 8.7 13 4.3 4.3 4.3 21.7 13 8.7

tetralogy of Fallot, or double-inlet left ventricle. Twenty-six patients had supraventricular premature beats and four had ventricular premature beats. Anti-arrhythmia treatment was given for two weeks to three months to only six patients who had frequent or couplet–triplet supraventricular premature beats or short-duration SVT attacks determined by 24-hour Holter monitoring. Supraventricular premature beats continued for one year in seven patients. After discharge, SVT did not occur in any patient with supraventricular premature beats. Patients with ventricular premature beats did not have any anti-arrhythmia treatment, and no additional arrhythmia occurred after the newborn period. Eleven babies had bradyarrhythmia, four of whom had sinus bradycardia. One had hypocalcaemia (DiGeorge syndrome), one had hypoglycaemia, and one had long QT syndrome. One baby did not have any pathology. One baby had bradyarrhythmia with

Table 2. Distribution and clinical characteristics of patients diagnosed with arrhythmia in the neonatal period n (%) Accompanying congenital heart disease (n) Accompanying other extracardiac problems 30 (45.4) 26 (39.3) VSDm (1), ASD (1), VSD + ASD (2), ASD A-V malformation + BAV (1), AVSD + HRV (2) Ventricular premature beats 4 (6) ASD (1), VSDm (1) Bradyarrhythmias 11 (16.6) Sinus bradycardia 3 (4.5) VSDp (1) Hypocalcaemia + DiGeorge (1), hypoglycaemia (1) 2:1 AV block 3 (4.5) TOF (1), atrial isomerism (1) Sepsis Complete AV block 3 (4.5) PDA (1), DILV (1) Hypothyroidism Intraventricular block 1 (1.5) – Hyperkalaemia (CAH) Long QT 1 (1.5) – – Tachyarrhythmia 25 (37.8) Sinus tachycardia 2 (3) – – Supraventricular tachycardia 23 (34.8) AVRT* 16 (24.2) Partial AVSD (1), ASD (3) Diaphragmatic hernia (1), co-anal atresia (1) Atrial flutter 5 (7.5) PDA (1), ASD (1) Metabolic asidosis, diaphragmatic hernia, hypoglycaemia MAT 1 (1.5) – – PJRT 1 (1.5) Dilated cardiyomyopathy (1) Foetal hydrops Total 66 (100) ASD: atrial septal defect, AV: atrioventricular, A-V: arteriovenous, AVSD: atrioventricular septal defect, AVRT: atrioventricular re-entrant tachycardia, BAV: bicuspid aortic valve, DILV: double-inlet left ventricule, HRV: hypoplastic right ventricule, CAH: congenital adrenal hyperplasia, MAT: multifocal atrial tachycardia, PDA: patent ductus arteriosus, PJRT: permanent junctional reciprocating tachycardia, TOF: tetralogy of Fallot, VSDm: muscular ventricular septal defect, VSDp: perimembranous septal defect. *Three babies had WPW. Arrhythmia type Irregular heart rhythm (ectopic beats) Supraventricular premature beats

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intraventricular block. This baby had severe hyperkalaemia (K+: 9.4 mEq/l) caused by congenital adrenal hyperplasia. Three patients had complete AV block and 2:1 AV block. Six patients had AV block – three with complete AV block and one in whom 2:1 AV block later progressed to complete AV block. Four patients with AV block underwent permanent pacemaker implantation. Two patients with tachyarrhythmia had sinus tachycardia. One of these patients had a persistent heart rate of 180–190 beats/min and was given short-term treatment with a beta-blocker, which was discontinued after the newborn period. The other baby did not have any treatment. Twenty-three babies had SVT: five had atrial flutter (AF), one had PJRT, one had multifocal atrial tachycardia (MAT), and the rest had atrioventricular re-entrant tachycardia (AVRT). No baby had atrioventricular nodal re-entrant tachycardia (AVNRT). Sinus rhythm was achieved with cardioversion in four patients with AF and in one patient with amiodarone infusion. In babies with SVT without AF, six were treated with adenosine, four were treated with amiodarone and application of ice to the face, two were treated with ice initially and then with adenosine, and two were treated with digoxin. Three babies with SVT had Wolf– Parkinson–White (WPW) syndrome. Digoxin or propranolol prophylaxis was given to all patients with SVT and AF. The average duration of follow up after the newborn period for all patients was 15 months (minimum three months, maximum six years). Twenty-three patients with SVT and three with frequent supraventricular premature beats continued anti-arrhythmia treatment after discharge (beta-blockers or digoxin). AF did not recur in any patients. Five patients with SVT had recurrence after the newborn period. In these patients, rhythm and speed control was achieved by treatment with sotalol. Patients with PJRT and multifocal atrial tachycardia required anti-arrhythmia treatment after the age of one year. Three patients with WPW syndrome continued to take propranolol prophylaxis. Four patients died in the newborn period. One baby with diaphragmatic hernia and one with co-anal atresia died because of respiratory problems after SVT treatment. The other baby had supraventricular premature beats diagnosed in the foetal period. In spite of spontaneously resolved supraventricular premature beats on the second postnatal day, this patient died because of metabolic disease. The remaining baby had tetralogy of Fallot 2:1 AV block, which progressed to complete AV block. This baby died because of sepsis after a pacemaker implantation. Apart from these four babies, no other patients died during the follow-up period.

Discussion The incidence of arrhythmia in the newborn period has been reported to be about 1%.4 Most of these arrhythmias are asymptomatic and rarely life-threatening. Various studies have identified that 15.3% of arrhythmic newborns have congenital heart disease. Atrial arrhythmias in particular are reported more frequently in newborns with congenital heart disease.5,6 In a study of 21 arrhythmic newborns, Satar et al.7 found a congenital heart disease rate of 38%, while Canpolat et al.8 reported a rate of 23.1%. Of our cases, 30.3% had congenital heart disease. Although in our study group the most frequent accompanying pathology was ASD, Satar et

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al.7 found that patent ductus arteriosus was the most frequent pathology. Ventricular and supraventricular premature beats are generally self-limiting, benign arrhythmias. Examination of healthy newborns before discharge determined a 1% frequency of premature beats. Premature beats may be secondary to metabolic and biochemical abnormalities and hypoxia; however, the majority have no clear underlying pathology.9 The prognosis for premature beats is generally very good, and most of them disappear after the first months of life. Of our patients, 39.3% had supraventricular premature beats and 6% had ventricular premature beats. Patients with ventricular premature beats did not have arrhythmia after the newborn period. Seven patients with supraventricular premature beats had persistent arrhythmia beyond one year, but none of them progressed to SVT. In a study by Poddar et al.,10 premature beats lasted up to early childhood and spontaneously resolved without complications in three of nine arrhythmic newborns. Our results were compatible with the literature. Congenital complete AV block had an observed rate of 1/15 000–20 000 for live births.11 Generally, it is secondary to structural cardiac defects or maternal systemic lupus erythematosus.12 Complete AV block with severe bradycardia leading to low cardiac output may result in heart failure. Symptomatic complete AV block and asymptomatic block with heart rate below 55 beats/min, accompanied by wide QRS escape rhythm or accompanying cardiomegaly, are indications for emergency pacemaker implantation.11 Canpolat et al.8 identified four patients (15.4%) with AV block, all of whom were diagnosed in the prenatal period. Only two had mothers with lupus or Sjogren’s disease. In our study, four of six patients with AV block underwent pacemaker implantation, and two were diagnosed in the prenatal period. While SVT is the most frequently observed type of tachycardia in the newborn period, it can cause postnatal irritability, feeding difficulties, tachypnoea, tachycardia and heart failure in the antenatal period. Many newborns can tolerate the first hours of SVT well, but if SVT continues longer than 6–12 hours, heart failure caused by stroke volume reduction may develop.13 Fifteen per cent of patients have a history of sepsis and medication.14 Additionally, babies with cardiac anomalies, such as Ebstein anomaly, transposition of the great arteries, and single ventricle are known to be at risk for SVT.11 In our study, SVT was the second most frequent arrhythmia (22.7%). This result was compatible with the literature. However, this rate is lower than the SVT rate found in the study by Satar et al.7 In a similar study,15 eight patients had major cardiac pathologies, such as Ebstein anomaly, AV septal defect, ventricular septal defect and tricuspid atresia. However, none of our patients had complex cardiac pathologies. AV nodal re-entrant tachycardia is rarely seen in the newborn and toddler periods. In this period, AV re-entrant tachycardia is more frequent. Naheed et al.16 studied 30 foetuses with SVT and did not detect AV nodal re-entrant tachycardia in the postnatal period. In a study by Ko et al.,17 only three of 137 (2.1%) had AV nodal re-entrant tachycardia. No patient in our study had AV nodal re-entrant tachycardia. In our cases with SVT, AV re-entrant tachycardia was the most frequent mechanism of tachycardia. In WPW syndrome, apart from the normal communicating

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paths, accessory pathways link the atrium and ventricles. According to Lupoglazoff and Denjoy, 70% of babies less than three months old with SVT have WPW pattern.18 In a study by Gillijam et al.,15 the rate of WPW syndrome was 34%. Kundak et al.19 studied 55 newborns with malignant rhythms; 22 had SVT and six had WPW syndrome. In our study, three patients had WPW syndrome. In another study,20 90 babies had WPW syndrome, one-third of whom had repeating SVT episodes after the age of one year. In this study, the majority of babies were given prophylactic anti-arrhythmia treatment. In our study, all three babies with WPW syndrome were given propranolol prophylaxis. These babies did not have an SVT episode during the long-term follow-up period, even after the newborn period. Gillijam et al.15 reported that most babies with a history of SVT had taken anti-arrhythmia treatment for 6–12 months after the last SVT episode. In our study, only five patients with SVT had repeating episodes beyond the newborn period, and it persisted beyond the age of one year in only two patients, which is compatible with the literature. Ventricular tachyarrhythmia, while rare in the newborn period, generally develops secondary to metabolic anomalies, such as hyperkalaemia, hypoglycaemia, metabolic acidosis and hypoxia. It resolves quickly with treatment of the underlying cause.21,22 In a study by Kundak et al.19 six patients had ventricular tachycardia, and three had SVT accompanied by ventricular tachycardia. In our study, none of the patients with metabolic acidosis, sepsis and hypoglycaemia had ventricular tachycardia. A proportion of newborn arrhythmias are a continuation of arrhythmias that began in the foetal period and extend into the postnatal period. Fifty per cent of patients who had isolated supraventricular premature beats were referred in the foetal period because of irregular heart rhythm. Less than 10% of foetal arrhythmias are in the form of continuous tachyarrhythmia and bradyarrhythmia.23 The most common foetal tachyarrhythmias are tachycardia with frequent supraventricular premature beats, SVT, AF and, rarely, ventricular tachycardia. Foetal supraventricular premature beats have a very good prognosis but 0.4% of cases may advance to life-threatening tachyarrhythmia.24 Foetal AF is mostly associated with structural cardiac anomalies; 7–43% of them progress to hydrops.25 The most important cause of foetal bradycardia is congenital AV block. Fifty per cent of foetal bradycardia foetuses have mothers with connective tissue diseases, such as lupus and Sjogren’s disease. The remaining 50% have underlying complex cardiac anomalies.26 In our study, 23 (34%) newborns had arrhythmias diagnosed in the foetal period. Three of these had SVT, and two had AF. One had complete AV block, and one had 2:1 AV block. Hydrops developed in one patient with foetal SVT.

References 1.

3. 4.

5. 6.

9. 10. 11.

12.

13. 14. 15.

16.

17.

18. 19.

Conclusion Although the frequency of arrhythmias in the newborn period is not high, supraventricular premature beats and SVT are the most frequently observed arrhythmias in this period. Diagnosis of arrhythmias in the prenatal period is essential for appropriate and optimal treatment in the postnatal period. Although the longterm prognosis for newborn arrhythmias is very good, patients should be monitored at appropriate intervals.

20.

21.

22.

Badrawi N, Hegazy RA, Tokovic E, Lotfy W, Mahmoud F, Aly H. Arrhythmia in the neonatal intensive care unit. Pediatr Cardiol 2009; 30: 325–330. Southall DP, Johnson AM, Shinebourne EA, Johnston PG, Vulliamy DG. Frequency and outcome of disordersof cardiac rhythm and conduction in a population ofnewborn infants. Pediatrics 1981; 68: 58–66. Strasburger JF, Cheulkar B, Wichman HJ. Perinatal arrhythmias: diagnosis and management. Clin Perinatol 2007; 34: 627–652. Long WA, Frantz EG, Henry GW, Freed MD and Brook M. Evaluation of newborns with possible cardiac problems. In Taeusch HW, Ballard RA, eds. Avery’s Diseases of the Newborn. 7th edn. Noida; Harcourt Asia, 2000, 711–763. Moura C, Vieira A, Guimaraes H, Areias JC. Perinatal arrhythmias – diagnosis and treatment. Rev Port Cardiol 2002; 21: 45–55. Zielinsky P, Dillenburg RF, de Lima GG, Zimmer LP. Fetal supraventricular tachyarrhythmias: experience of a fetal cardiology referral center. Arq Bras Cardiol 1998; 70: 337–340. Satar M, Narlı N, Özbarlas N ve ark. Yenidoğan döneminde aritmi gelişen 21 vakanın değerlendirilmesi. Çocuk Sağlığı ve Hastalıkları Dergisi 2006; 49: 107–111. Canpolat E, Korkmaz A, Yurdakök M ve ark. Neonatal aritmiler: yenidoğan yoğun bakım ünitesinde on yıllık deneyim. Çocuk Sağlığı ve Hastalıkları Dergisi 2002; 46: 187–194. Tanel RE, Rhodes LA. Fetal and neonatal arrhythmias. Clin Perinatology 2001; 28: 187–207. Poddar B, Basu S, Parmar VR. Neonatal arrhythmias. Indian J Pediatr 2006; 73: 131–134. Pinsky WW, Gillette PC, Garson AT, Mc Namara DG. Diagnosis, management and long-term results of patients with complete atrioventricular block. Pediatrics 1982; 69: 728–733. Litsey SE, Noonan JA, O’Connor WN, Cottrill CM, Mitchell B. Maternal connective tissue disease and congenital heart block: demonstration of immunoglobulin in cardiac tissue. N Engl J Med 1985; 312: 98–100. Park MK. Cardiac arrhytmias. In: Park MK. Pediatric Cardiology for Practitioners. 5th edn. Philedelphia: Mosby Elsevier, 2008: 417–444. Kantoch MJ. Supraventricular tachycardia in children. Indian J Pediatr 2005; 72: 609–619. Gilljam T, Jaeggi E, Gow RM. Neonatal supraventricular tachycardia: outcomes over a 27-year period at a single institution. Acta Paediatr 2008; 97: 1035–1039. Naheed ZJ, Strasburger JF, Deal BJ, Benson DW Jr, Gidding SS. Fetal tachycardia: mechanisms and predictors of hydrops fetalis. J Am Coll Cardiol 1996; 27: 1736–1740. Ko JK, Deal BJ, Strasburger JF, Benson DW Jr. Supraventricular tachycardia mechanisms and their age distribution in pediatric patients. Am J Cardiol 1992; 68-9: 1028–1032. Lupoglazoff JM, Denjoy I. Attitude toward arrhythmia in the neonate and infant. Arch Pediatr 2004; 11: 1268–1273. Kundak AA, Dilli D, Karagöl B ve ark. Non-benign neonatal arrhythmias observed in a tertiary neonatal ıntensive care unit. Indian J Pediatr 2012 Oct 4. (Epub ahead of print). Deal BJ, Keane JF, Gillette PC, Garson A Jr. Wolff-Parkinson-White syndrome and supraventricular tachycardia during infancy: management and follow-up. J Am Coll Cardiol 1985; 5: 130–135. Virdi VS, Bharti B, Poddar B, Basu S, Parmar VR. Ventricular tachycardia in congenital adrenal hyperplasia. Anaesth Intensive Care 2002; 30: 380–381. Singh D, Dutta S, Narang A. Hyperkalemia and ventricular tachycardia

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in ELBW infant. Indian Pediatr 2003; 40: 64–66. 23. Kleinman CS, Neghme RA. Cardiac arrhythmias in the human fetus. Pediatr Cardiol 2004; 25: 234–251. 24. Strasburger JF. Fetal arrhythmias. Prog Pediatr Cardiol 2000; 11: 1–17. 25. Kleinman CS, Copel JA,Weinstein EM, Santulli TV Jr, Hobbins JC.

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Treatment of fetal supraventricular tachyarrhythmias. J Clin Ultrasound 1985; 13: 265–273. 26. Copel JA, Friedman AH, Kleinman CS. Management of fetal cardiac arrhythmias. Obstet Gynecol Clin North Am 1997; 24: 201–211.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014

Behcet’s disease and cardiovascular involvement: our experience of asymptomatic Behcet’s patients Zeynep Ulusan, Ayse Serap Karadag, Mehmet Tasar, Mehmet Kalender, Osman Tansel Darcin Abstract Behcet’s syndrome is a systemic inflammatory disease associated with vasculitis, and arterial, venous and cardiac disorders. Thirty-eight Behcet’s disease patients were examined prospectively with echocardiography, ultrasonography and computed tomography, and coagulation parameters were determined. Deep venous insufficiency was found in 16 patients, venous thrombosis in seven, one patient had iliac artery stenosis, three had carotid arterial intimal proliferation, two patients had aortic annulus dilatation, six had aortic valve insufficiency, and three had mitral valve insufficiency. None had coagulation defects. To decrease morbidity and mortality rates, a multidisciplinary approach is important for early diagnosis of cardiovascular involvement in Behcet’s disease. Keywords: Behcet’s disease, venous thrombosis, valvular heart disease Submitted 23/7/13, accepted 4/2/14 Cardiovasc J Afr 2014; 25: 63–66

www.cvja.co.za

DOI: 10.5830/CVJA-2014-003

Behcet’s disease is generally defined by oral and genital ulcers and uveitis. It is also known as a recurrent multisystemic and inflammatory disease. It is mostly seen in Mediterranean countries and the Far East. The aetiology of Behcet’s disease is associated with viral, toxic, bacterial and immunological factors. It was defined in 1963 as an auto-immune disease caused by auto-antibodies against the oral mucosa. Vascular involvement is 2–7% and it is usually seen in patients between the ages of 20 and 40 years. Behcet’s disease is a non-specific arterial and venous vasculitis.1-8 Proximal and distal anastomotic aneurysm formation after surgery is not rare one to 12 months postoperatively. Recurrent surgical interventions increase the risk of mortality and morbidity.9,10 Cardiovascular involvement in Behcet’s disease

Kecioren Research and Training Hospital, Ankara, Turkey Zeynep Ulusan, MD, ulusanzeynep@hotmail.com

Department of Dermatology, 100.yil University Medical School, Van, Turkey Ayse Serap Karadag, MD

Department of Surgery, Konya Education and Research Hospital, Konya, Turkey Mehmet Tasar, MD Mehmet Kalender, MD Osman Tansel Darcin, MD

includes pericarditis, coronary arterial disease, cardiomyopathy and valvular dysfunction.11 The aim of this study was to report our experience of cardiovascular involvement with asymptomatic Behcet’s disease.

Methods From March 2008 to May 2009, 38 Behcet’s disease patients (20 women and 18 men) were prospectively analysed at the Kecioren Education and Research Hospital. International Behcet’s disease study group criteria were used for the diagnosis of Behcet’s disease in all patients.12 Follow up of the patients was one to 20 years (mean 10.5 years). Mean age was 37.8 years (range 33.8–41.7). After questioning the patients on their medical history and detailed physical examination, radiological and laboratory studies were undertaken. Patients who had formerly been diagnosed with Behcet’s disease and followed up were included in the study, whereas those who were newly diagnosed were not included. There was no history of smoking, hypertension, diabetes mellitus, rheumatic carditis or valve disease in the patients’ backgrounds. In some patients, no cardiac risk factors were detected except high levels of low-density lipoprotein cholesterol (LDL-C). No ventricular contractility disorder was detected on transthoracic electrocardiographic examinations. Echocardiographic diameters were measured as transthoracic and two-dimensional by Prob, which can screen between 2 and 4 or 1.5 and 4.5 MHz. Volumes were measured with two and four blank images by the modified Simpson’s method. Each valve structure and its function was evaluated by Vivid 3 pro series Ge Vivid 3 echocardiography (GE Medical Systems, Milwaukee, USA). Doppler ultrasonography was performed in B-mode and colour-mode spectral examinations with 13.5- and 9.4-MHz linear probes (Antares, Siemens AG, Medical Solutions Henkestr, Erlangen, Germany). Upper and lower extremity arterial and venous (for venous insufficiency, thrombosis, arterial stenosis and aneurysm) and carotid examinations were carried out. Thorax and abdominal computarised tomography was performed in 5-mm sections, initially unenhanced, three to five minutes after venecontrast substance was injected into the peripheral veins, to determine abdominal and thoracic vascular structures (Simens Somatom Sensation 16 software version A50 Germany). Blood samples were taken between 9:00 and 10:00 after an overnight fast and no viral, infectious or immunological diseases were detected. Laboratory studies were carried out on venous blood (9 units), which was centrifuged for 15 minutes at 20ºC and 4 500 rpm. It was decanted into silicone tubes (Vacutainer, Becton Dickinson, New Jersey, ABD) containing 0.105 M trisodium citrate (1 unit). Total cholesterol and triglyceride levels were detected by enzymatic methods (Roche Diagnostics, Mannheim,

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Germany). High-density lipoprotein cholesterol (HDL-C) levels were detected following sodium phosphotungustate–magnesium chloride precipitation. LDL-C levels were calculated according to the Friedwald formula. Leukocyte, platelet, erythrocyte, white blood cell, haematocrit and haemoglobin counts were performed by Sysmex 9000 (Roche Diagnostics) device. Coagulation screening tests, coagulation factors, inhibitors and fibrinolysis tests were performed using the Dade Behring System (BCS, Dade Behring, Marburg, Germany) as follows: • Prothrombin time (PT) and active partial thromboplastin time (aPTT) were measured using conventional methods and the results were saved on a coagulometer (BCS, Dade Behring). • D-dimer levels were measured with the Plus D-dimer test (Dade Behring) method. This is a turbidometric test enriched with latex, which was developed for quantitative analysis of cross-linked fibrin degradation products in human plasma. It is done by a Dade Behring coagulation analyser device. • Coagulation factors (F VII, F VIII, F IX, F X, F XI and F XII) were measured by coagulometric methods and in vitro diagnostic devices. • The activated protein:C resistance ratio (APCR) was measured using a modified APC kit and automatic coagulometer (BCS, Dade Behring). • In order to identify the von Willebrand factor ristocetin co-factor activity in human plasma, the thrombocyte agglutination method and in vitro diagnostic devices were used. • Antithrombin activity was measured using a Berichom ATIII using the synthetic chromogenic substrate method. • Protein C and S activities were measured with a coagulometric method. • Plasminogen and antiplasmin activities were measured using a chromogenic substrate method. • Lupus anticoagulants were identified using modified dilute Russell viper venom (LA scanning separator/LA2 conformation separator). • Fibrinogen levels were identified using Claus methods. • Plasminogen activator inhibitor levels were identified with activity-based functional tests.

Results The demographic variables and Behcet’s disease criteria are shown in Table 1. In the venous system, three patients had lower extremity deep-vein thrombosis (in one patient it was bilaterally). These three patients had ocular involvement. One patient had superior caval venous and bilaterally internal jugular venous Table 1. Demographic variables and criteria for Behcet’s disease. Parameters Age (years) Gender (male/female) Time since the diagnosis (years) Recurrent oral ulcer (%) Genital ulcer (%) Arthralgia (%) Leather findings (%) Eye involvement (%) Positive Paterji test (%)

n (%) 37.8 (33.8–41.7) 24/14 7.6 (6.1–9.1) 38 (100) 24 (63) 31 (84) 23 (62) 4 (10.5) 12 (3.2)

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thrombosis. Three patients had thrombosis in the vena saphena magna. Deep venous insufficiency was seen in 16 patients. In the arterial system, iliac artery occlusion was seen in one patient (this patient had in-stent stenosis and a history of balloon angioplasty). Three patients had carotid artery–intimal hyperplasia. Echocardiography: left ventricular systolic/diastolic diameter was 4.2–6/4.3–6 cm, the aortic annulus was 4 cm in two patients, six patients had 2+ aortic valve insufficiency, and three patients had 1+ mitral valve insufficiency. Aortic valve involvement was 16%; 24 patients (63%) had venous insufficiency, three had deep-vein thrombosis (they all also had ocular involvement). One patient had superior vena caval and bilaterally internal jugular venous thrombosis and ocular involvement. One patient had iliac arterial thrombosis and stent history. Three patients had carotid artery intimal hyperplasia. Table 2 shows laboratory results for coagulation and lipid parameters.

Discussion Behcet’s disease is a multi-systemic inflammatory disorder. Autoimmune factors are involved in its aetiology. Immune fluorescence studies revealed IgM, IgG and β1 globulin on the vascular endothelial walls and the serum contained increased amounts of IgD, IgG, IgM, C1, C2, C3, C4 and immune complexes. The increased prevalence of the HLA-B5 tissue gene group suggests a genetic role as aetiological factor.13-15 Vascular Behcet’s disease occurs more frequently in patients with ocular involvement. Behcet’s disease is a non-specific vasculitis involving both veins and arteries. Infiltration of lymphocytes, mononuclear cells and mast cells can be observed around the blood vessels, causing endothelial swelling and fibrinoid degeneration. Venous system involvement is mostly seen as thrombosis and/or varicosis. Table 2. Laboratory findings for coagulation and lipid parameters.

Parameters Total cholesterol (mg/dl) Low-density lipoprotein cholesterol (mg/dl) High-density lipoprotein cholesterol (mg/dl) Very low-density lipoprotein cholesterol (mg/dl) Triglycerides (mg/dl) Fibrinogen (mg/dl) D-dimer (µg/dl) Protein-S (%) Protein-C (%) Antithrombin 3 (%) PTT (sn) APTT (sn) Vitamin B12 (pg/dl) Folate (ng/dl) Homocysteine (mmol/l) Factor 5 (%)

Mini- MaxiMean mum mum value value value 167 149 227 148 69 185

Normal values 0–200 0–130

0–60

5–40

104 433 215 108 103 45 12.2 32 533 7.8 12.4 89.6

87 383 142 81 90 36 11.5 29 414 4.8 9.5 78.5

121 0–150 483 200–400 289 125–375 134 70–150 116 60–125 56 75–125 12.9 10–14 35 31–40 653 200–950 10.7 3–17 15.2 5–15 100.7 79–121

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Arterial system involvement is rare and may be seen as arterial thrombosis and aneurysm. Two-thirds of arterial involvement cases consist of aneurysm and the remaining one-third are occlusive arteritis. Vascular invasive interventions mostly end up with relapsing aneurysms at either the proximal or distal ends of grafts. Postoperative aneurysm progress ranges from one to 12 months. Even catheterisation for vascular imaging may cause aneurysms, and recurrent surgery increases the mortality rate and morbidity in patients with this disease. In patients with Behcet’s disease, cardiac involvement can be seen as pericarditis, acute myocardial infarction and cardiomyopathy. The involvement of heart valves is rare and is reported as case reports in the literature.16 Behcet’s disease vascular involvement increases the risk for mortality. Serious vascular complications including ischaemic cerebrovascular events, ischaemic bowel perforation, BuddChiari syndrome and perforation of aneurysms occur in 8% of patients and cause death in most patients. The most common vascular event is lower-extremity venous thrombosis. Thrombosis impairing venous return to the great vessels causes superior vena cava syndrome and Budd-Chiari syndrome.16,17 Dural venous thrombosis leads to intracranial hypertension.18,19 Patients with Behcet’s disease have a tendency to thrombosis because of an imbalance between procoagulant and anticoagulant factors. Lee et al. reported 90% of the 171 patients in one study and 3% in another had thrombosis.20 Antithrombin 3, protein C and protein S deficiencies increase susceptibility to hypercoagulation. Prothrombin G20210A polymorphism and factor V Leiden mutation (506Arg/gln) have been observed in idiopathic deep-vein thrombosis.16,17,21 Superior and inferior vena cava thrombosis have been reported at 9 and 2.5%, respectively.11 In our study we observed lowerextremity deep-vein thrombosis in three cases. One patient had a thrombosis in the superior vena cava and internal jugular vein and three had vena saphena magna thrombosis. Most commonly, arterial aneurysms are seen in the abdominal aorta, and in decreasing frequency, in the femoral artery, popliteal artery and pulmonary artery, respectively. In our study we did not detect any cases of aneurysm. We did find arterial occlusion in three (1%) patients, one of which was occlusion at the iliac level. In one study, prevalence was reported as 2.2% in a series including 450 cases.22 Arterial involvement is most common in the form of aneurysm and pseudo-aneurysm formation, and occasionally arterial stenosis. Arterial occlusion can result in organ failure and sometimes causes infarct. The involvement of major arteries usually occurs after an average of 5.8 years and mainly involves lower-extremity arteries, and rarely upper-extremity arteries. Ranked in ascending order of prevalence, the right pulmonary artery, femoral, popliteal, subclavian and carotid arteries are involved. Histopathological studies reveal non-specific vasculitis. Mononuclear and neutrophilic infiltration, endothelial proliferation, destruction of the elastic lamina, fibrinoid necrosis and thrombus are pathological evidence of the disorder seen at the tissue level. Combined treatment with corticosteroids, anticoagulants and immunosuppressive therapy is necessary.22-24 In a study by Hong et al., it was reported that carotid arterial intimal thickness increased compared to the control group, which included normal healthy subjects (carotid artery intima– media thickness in Behçet’s disease patients without significant

cardiovascular involvement).25 Uveitis or retinal vasculitis was found to correlate with increased carotid intimal thickness. While Balile et al. found increasing age and serum cholesterol levels in patients was directly proportional, with steroid use, a correlation was not found.27 In our study, in patients with carotid artery intimal thickening, there was no correlation between serum cholesterol levels, age and the use of steroid eye ointment, and none of the patients had retinal vasculitis. In a study conducted in Korea, an increase in regional arterial segmental stiffness was reported and it reached statistical significance.28 The exact pathophysiology of heart valve involvement causing insufficiency is unclear in patients with Behcet’s disease. Inflammation causes destruction of the valve tissue and dilatation of the ascending aorta and sinus Valsalva aneurysm. Histological findings varied from normal tissue to fibrosis independent of inflammation. Accumulation of inflammatory cells in the adventitia and media is seen in inflammatory cases. Neutrophils, lymphocytes, plasma cells, less frequently histiocytes and eosinophilic cells, and sometimes giant cells are observed. Fibrous thickening of the intima and adventitia can be traced. However, fibrous changes to the elastic membrane has also been reported.29 Valves with aortic regurgitation were found in six patients in our study but fibrous thickening was not observed in the structure of the valve, and the aortic annulus was normal except in two patients. Dilated cardiomyopathy has been reported in patients with Behcet’s disease. In our study, two patients presented with increased left ventricular diameter. Heart valve involvement is rare but if present, increases the mortality rate. We believe patients should be followed up with echocardiography annually. In our study, we detected increased incidence of venous insufficiency. To lower thrombosis risk in patients with Behcet’s disease, accompanying venous insufficiency should be diagnosed and treated early.

Conclusion Rates of heart and vascular involvement in Behcet’s disease range widely in the literature but this involvement increases the risk of mortality and morbidity, requiring a multidisciplinary approach.

References 1.

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Lehner T, Welsh KI, Batchelor JR. The relationship of HLA-B and DR phenotypes to Behçet’s syndrome. Recurrent oral ulceration and the class of immune complexes. Immunology 1982; 47: 581–587. Behçet’s Disease Research Committee of Japan. Skin hypersensitivity to streptococcal antigens and the introduction of systemic symptoms by the antigens in Behçet’s disease – a multicenter study. J Rheumatol 1989; 16: 506–511. Sezer TN. The isolation of a virus as the cause of Behçet’s disease. Am J Ophthalmol 1953; 36: 301–315. Hamzoi K, Ayed K, Slim A. Natural killer cell activity, interferon gamma and antibodies to herpes viruses in patients with Behçet’s disease. Clin Exp Immunol 1990; 79: 28–30. Münke H, Stöckmann F, Ramadori G. Possible association between Behçet’s syndrome and chronic hepatitis C virüs infection. N Engl J Med 1995; 332: 400–401. Özaran K, Aydıntug O, Tokgöz G, et al. Serum levels of IL-8 in patients

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with Behçet’s disease. Ann Rheum Dis 1995; 54: 610. Önder M, Gürer MA. Behçet’s disease: an enigmatic vasculitis. Clin Dermatol 1999; 17: 571–576. Direskeneli H, Hasan A, Shinnick T, et al. Recognition of B cell epitopes of the 65 kd HSP in Behçet’s disease. Scand J Immunol 1996; 43: 464–471. Park JH, Han MC, Bettmann MA. Arterial manifestations of Behçet disease. Am J Roentgenol 1984; 143: 821–825. Shimizu T, Ehrlich GE, Inaba G, Hayashi K. Behçet disease (Behçet syndrome). Semin Arthritis Rheum 1979; 8: 223–260. Marzban M, Mandegar MH, Karimi A, et al. Cardiac and great vessel involvement in ‘Behcet’s disease. J Cardiac Surg 2008; 23(6): 765–768. International study group for Behçet’s disease. Lancet 1990; 335: 1078–1080. Gülbay B, Acican T, Erçen Diken Ö, Pinar Önen Z. Familial Behçet’s disease of adult age: a report of 4 cases from a Behçet family. Intern Med 2012; 51(12): 1609–1611. Yilmaz S, Cimen KA. Familial Behçet’s disease. Rheumatol Int 2010; 30: 1107–1109. Baharav E, Weinberger A. The HLA-B*5101 molecule-binding capacity to antigens used in animal models of Behçet’s disease: a bioinformatics study. Med Assoc J 2012; 14(7): 424–428. Chang J-E, Lee Y-H, Lee J. Multiple cardiovascular complications in a patient with Behcet’s disease. Korean J Intern Med 2008; 23(2): 100–102. Sengül N, Demirer S, Yerdel MA, Terzioğlu G, Akin B, Gürler A, et al. Comparison of coagulation parameters for healthy subjects and Behçet disease patients with and without vascular involvement. World J Surg 2000; 24(12): 1584–1588. Ludwig J, Hashimoto E, McGill DB, van Heerden JA. Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd-Chiari syndrome. Mayo Clin Proc 1990; 65(1): 51–55. Okuda K, Kage M, Shrestha SM. Proposal of a new nomenclature for Budd-Chiari syndrome: hepatic vein thrombosis versus thrombosis of the inferior vena cava at its hepatic portion. Hepatology 1998; 28(5):

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1191–1198. 20. Lee YJ, Kang SW, Yang JI, Choi YM, Sheen D, Lee EB, et al. Coagulation parameters and plasma total homocysteine levels in Behcet’s disease. Thromb Res 2002; 106(1): 19–24. 21. Ozatli D, Sayinalp N, Büyükaşik Y, Karakuş S, Haznedaroglu IC, Kirazli S, et al. Unchanged global fibrinolytic capacity despite increased factor VIIa activity in Behçet’s disease: evidence of a prethrombotic state. Rheumatol Int 2002; 21(4): 137–140. 22. Hamza M. Large artery involvement in Behçet’s disease. J Rheumatol 1987; 14(3): 554–559. 23. Raza K, Thambyrajah J, Townend JN, Exley AR, Hortas C, Filer A, et al. Suppression of inflammation in primary systemic vasculitis restores vascular endothelial function: lessons for atherosclerotic disease? Circulation 2000; 102: 1470–1472. 24. Yoon NS, Lee SR, Kim KH, Hong YJ, Park HW, Kim JH, et al. Carotid artery intima–media thickness in Behcet’s disease patients without significant cardiovascular involvement. Korean J Intern Med 2008; 23(2): 87–93. 25. Juonala M, Viikari JS, Laitinen T, Marniemi J, Helenius H, Rönnemaa T, et al. Interrelations between brachial endothelial function and carotid intima-media thickness in young adults: the cardiovascular risk in young Finns study. Circulation 2004; 110(18): 2918–2923. 26. Hong SN, Park JC, Yoon NS, et al. Carotid artery intima-media thickness in Behcet’s disease patients without significant cardiovascular involvement. Korean J Int Med 2008; 23(2); 87–93. 27. Balik OL, Gur G, Lenk N, Artuz F, Alli N. Serum lipoprotein (a) levels and Behçet’s disease: is there an association? Int J Dermatol 2007; 46(8): 827–829. 28. Rhee MY1, Chang HK, Kim SK. Intima–media thickness and arterial stiffness of carotid artery in Korean patients with Behçet’s disease. J Korean Med Sci 2007; 22(3): 387–392. 29. Lee CW, Lee JS, Lee WK, et al. Aortic valve involvement in Behcet’s disease. A clinical study of 9 patients. Korean J Intern Med 2002; 17(1): 51–56.

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Effects of topical hypothermia on postoperative inflammatory markers in patients undergoing coronary artery bypass surgery Murat Kadan, Gokhan Erol, Bilgehan Savas Oz, Mehmet Arslan Abstract Background: We aimed to examine the effects of topical hypothermia on inflammatory markers in patients undergoing coronary artery bypass surgery. Methods: Fifty patients undergoing isolated coronary artery bypass surgery were included the study. They were randomised to two groups. Mild hypothermic cardiopulmonary bypass (28–32°C) was performed on both groups using standardised anaesthesiology and surgical techniques. Furthermore, topical cooling with 4°C saline was performed on patients in group I. We recorded peri-operative and intra-operative results of blood samples, pre-operative and postoperative outcomes of electrocardiography and echocardiography, diaphragm levels on X-ray, and the necessity of positive inotropic medication and intra-aortic balloon pump (IABP). Results: Time-dependent changes in blood samples were compared between the two groups. The changes on complement 3 (C3) and TNF-α levels were more significant in group I than group II (p < 0.05 and p < 0.001, respectively). Spontaneous restoration rate of sinus rhythm was higher in group II than group I (80 vs 32%, p < 0.01). Atrial fibrillation was seen in six patients in group I and one patient in group II (p < 0.05). IABP was performed on four patients (16%) in group I (p < 0.05). Diaphragmatic paralysis was seen in seven patients in group I but not in group II (p < 0.01). Partial pericardiotomy rates were compared within the groups but there was no statistically significant difference (p > 0.05). One patient in group I died on the 18th postoperative day, but operative mortality rate was not statistically significant between the two groups (p > 0.05). Conclusions: Topical hypothermia had a negative impact on inflammatory markers and postoperative morbidities. Keywords: cardiopulmonary bypass, hypothermia, topical cooling, diaphragmatic paralysis, postoperative atrial fibrillation Submitted 13/11/13, accepted 11/2/14 Cardiovasc J Afr 2014; 25: 67–72

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DOI: 10.5830/CVJA-2014-005

Department of Cardiovascular Surgery, Gulhane Military Academy of Medicine, Etlik, Ankara, Turkey Murat Kadan, MD, muratkadan@yahoo.com Gokhan Erol, MD Bilgehan Savas Oz, MD Mehmet Arslan, MD

Since Frey and Gruber’s theory in 1885 of circulating blood through a machine in order to pump and oxygenate it, cardiopulmonary bypass (CPB) has improved dramatically and has become almost indispensable in cardiac surgery today.1 However, there are many consequences such as inflammation and thrombosis.2 The notion that by changing the body temperature we could decrease inflammatory activity and thus mortality and morbidity rates has intrigued cardiac surgeons over time. Topical and systemic hypothermia is applied in many centres today but there is little data on the advantages and disadvantages of topical cooling. We aimed to investigate the effects of topical hypothermia on postoperative cardiac function in patients undergoing coronary artery bypass surgery.

Methods This study was approved by the ethics committee of Gulhane Military Academy of Medicine. Informed consent was obtained from all patients involved. Fifty-four patients diagnosed with coronary artery disease using coronary angiography (CAG) and who were not suitable for percutaneous or minimally invasive treatment techniques were included. The exclusion criteria included previous heart or pulmonary surgery, emergency revascularisation (within the first 24 hours after CAG), concomitant cardiac surgical procedures (valve repair or replacement, atrial or ventricular septal repair, aneurysmectomy, coronary endarterectomy etc.), left ventricular aneurysm diagnosed by echocardiography or angiography, myocardial infarction within the last two weeks, low ejection fraction (EF) (< 35%), and the necessity for pre-operative intra-aortic balloon pump (IABP), temporary or permanent pacemaker, and positive inotropic pharmacological drugs. Four patients who had ungraftable coronary arteries intraoperatively were also excluded from the study in order to obtain optimum standardisation. The remaining 50 patients were randomised into two groups. Group I patients included those undergoing surgery using 4°C saline for topical hypothermia and mild hypothermic CPB (28–32°C) (n = 25). Group II patients were to undergo surgery without topical hypothermia but mild hypothermic CPB (28–32°C) (n = 25). A median sternotomy was performed on all patients after general anaesthesia. Standard right atrial cannulation with two-staged venous cannula and aortic cannulation was performed after left internal mammarian artery (LIMA) harvesting (if it was to be used). A roller pump (Ann Arbor, Michigan, USA) and membrane oxygenator (Dideco Evo adult fiber oxygenator, Dideco, Mirandola, Italy) were used with mild hypothermia (28–32°C). The patient’s body temperature was measured with a rectal probe. Anticoagulation was provided at a dosage of 300 U/

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kg unfractionated heparin sulphate. Blood samples were collected for baseline evaluation in both groups from the coronary sinus via a retrograde cardioplegia cannula just before aortic cross clamping (ACC). Blood cardioplegia solutions at 20°C were delivered for initial cardioplegia in both antegrade and retrograde manner. Topical hypothermia was maintained with 1 000 ml of 4°C saline with induction of cardioplegia in patients in group I only. Maintenance cardioplegia (22°C blood cardioplegia solution) was delivered from the antegrade cannula at 20-minute intervals without topical cooling in both groups. Blood samples were collected again from the coronary sinus for evaluation of ischaemia just before maintenance cardioplegia was delivered in both groups. Blood cardioplegia solutions at 32°C were delivered after completion of the distal anastomosis, and then the ACC was removed. Topical myocardial rewarming was provided with 36°C saline in group I patients. Spontaneous defibrillation, dysrhythmias, and the necessity for defibrillation and pacemaker implantation were recorded at this time. The last blood samples for evaluation of reperfusion were collected inside the retrograde cannula in both groups, and then CPB was stopped after the body temperature reached 36°C. After neutralisation of anticoagulation, standard procedures such as control of bleeding, placing of pacemaker wires, and insertion of drainage tubes were performed. The operation was terminated with standard surgical techniques and the patients were transported to the intensive care unit (ICU). Maximum care was taken to avoid phrenic nerve injury during LIMA harvesting. The first intercostal artery was devascularised with haemostatic clips without cauterisation. Partial pericardiotomy was avoided as far as possible to prevent phrenic nerve injury. Patients who underwent cauterisation or partial pericardiotomy despite these protective methods were also recorded. Standard surgical procedures prevailed throughout the study. Routine pre-operative examinations were done. Echocardiographic evaluation was performed on all patients pre-operatively and just before discharge by the same cardiologist who was blinded to the patient population. Electrocardiograms were taken with the same device pre-operatively, at the 24th hour postoperatively and just before discharge. Troponin I (TnI), troponin T (TnT), myoglobin, CK-MB and lactate dehydrogenase (LDH) levels were assayed from blood samples, which were collected from the peripheral venous system pre-operatively and at the eighth and 24th hours of ACC. CK-MB and LDH levels were measured with spectrophotometric methods using an Olympus AU640 (Shizuoka-ken, Japan) device, myoglobin and TnI levels were measured using chemiluminescence on a Backman Coulter Access II (Fullerton CA, USA) device, and TnT levels were measured with electrochemiluminescence methods on a Roche Elecys 2010 (Tokyo, Japan) device. Thoracic X-rays were taken from the same machine (AMX-4 plus, General Electric Company, NWL Bordentown NJ, USA), at the same distance, with the same dosage for individual patients and with the same technician pre-operatively, 48 hours postoperatively and before discharge. Diaphragm levels, pleural effusions and other possible complications were recorded. TnI, TnT, myoglobin, complement 3 (C3), C4 and TNF-α levels were examined from blood samples, which were taken

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from the coronary sinus via the retrograde cardioplegia cannula for basal, ischaemia and reperfusion analysis as mentioned above. We aimed to determine the cardiac myocyte reserves directly by analysing myocardial enzymes and complement factors at different periods of ischaemia. C3 and C4 levels were measured with nephelometric methods, using Dade Behring BN II kits (Siemens, Germany), and TNF-α levels were measured with Elisa methods, using the Human TNF-alpha instant ELISA kits (e Bioscience, USA). Other parameters such as ACC time, total CPB time, cardioplegia amounts, number of proximal and distal anastomoses, necessity for defibrillation and pacemaker placement, and necessity for IABP and/or positive inotropic agents were recorded. Endotracheal intubation time, ICU length of stay, total drainage and transfusion amounts, dysrhythmias, necessity for re-operation, length of hospital stay, and existence of pleural effusion or diaphragmatic paralysis were also recorded. The patients were followed up on the first week and first month of discharge. ECGs were evaluated by the same cardiologist who was unaware of the patient population. New development of ischaemia-specific changes, such as ST-segment elevations, Q waves, Pardee waves and bundle branch blocks on ECG were seen as abnormal changes in myocardial function, while negative T waves were seen as pericardial reactions. The X-rays of patients were evaluated by a radiologist who was blinded to the patient population. Necessity for drainage and amounts of pleural effusions, diaphragm paralysis and elevations were recorded. Diaphragm changes above two or more ribs were determined as a positive result, according to the current literature data.3 Positive echocardiographic changes were determined as follows: new development of valve disorders, structural or transactional changes of the ventricular wall, aneurysm formation and a decrease in EF of more than 10%. In addition, haemodynamic parameters, respiratory parameters, blood gas levels, drainage amounts, muscle strength and body temperature were recorded for decisions on extubation time. Intubation time was recorded from the first intubation point in the operating room to the extubation point in ICU. All patients were discharged from ICU to clinical service after removal of their drainage tubes. Operative mortality was evaluated as mortality within the first 30 days.

Statistical analysis This was performed with the package program SPSS for Windows 15.0. Chi-square and Fisher’s exact tests were used for comparisons of qualitative data for both groups, and the t-test was used for comparisons of quantitative data of free samples. The paired t-test was used for quantitative data analysis of timedependent changes. Assessment of time-dependent changes of inter-group differences was done with two-way ANOVA for repeated measurements. Frequency and percentage data were used as a descriptive value for qualitative data, and arithmetic mean ± standard deviation as quantitative data. A p-value < 0.05 was considered statistically significant.

Results Fifty patients (42 male and eight female) were included in this

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study. The mean age of the patients was 62.8 ± 9.9 years (40–80) in group I, and 57.7 ± 9.4 years (39–84) in group II. With regard to demographic data of the patients, there was no significant difference between the groups other than hypertension. The pre-operative demographic data are given in Table 1. There was no statistically significant difference between the groups with regard to surgical data (p > 0.05). Mean aortic cross-clamp time was 55.76 ± 23.2 min in group I, and 53.44 ± 16.7 min in group II. The LIMA was used in 19 patients in group I and in 20 patients in group II. The right coronary artery was revascularised in 14 patients in both groups. Surgical data are given in Table 2. Excluding C3 and TNF-α levels in the time-dependent analysis, there were no statistically significant differences between any blood parameters. When we analysed the changes in C3 and TNF-α levels at every time point and the time-dependent changes, there was a statistically significant difference in favour of group II (C3: p < 0.05, TNF-α: p < 0.001). The blood sample results and time-dependent changes are given in Table 3 and Figs 1 and 2. There was a statistically significant difference between the groups with regard to spontaneous defibrillation of the heart. Sinus rhythm was spontaneously restored in 20 patients in group II, and in only eight in group I (p < 0.01). Atrial fibrillation postoperatively was seen in six patients in group I, and in only one patient in group II (p < 0.05). There was no significant difference between the groups with regard to other rhythm disorders (p > 0.05). There were four patients who needed IABP support in group I, whereas no patient needed this in group II (p < 0.05). Table 1. Pre-operative demographic data of the patients. Demographics Age (year) Gender (male/female) Height (cm) Weight (kg) BSA DM (n) HT (n) Dyslipidaemia (n) PAD (n) COPD (n) Renal failure (n) Pre-operative EF (%)

Group I (n = 25) 62.8 ± 9.9 22/3 169.8 ± 6.52 76.4 ± 9.03 1.868 ± 0.11 6 9 8 1 2 0 55.4 ± 7.79

Group II (n = 25) p-value 57.7 ± 9.4 > 0.05 20/5 > 0.05 166.24 ± 6.11 > 0.05 78.4 ± 9.93 > 0.05 1.852 ± 0.11 > 0.05 8 > 0.05 16 < 0.05 10 > 0.05 1 > 0.05 4 > 0.05 1 > 0.05 54.6 ± 7.02 > 0.05

Table 2. Intra-operative data of the patients. X clamp time (min) Total perfusion time (min) Hypothermia (°C) Cold cardioplegia (ml) Hot cardioplegia (ml) Distal anastomosis (n) Proximal anastomosis (n) LIMA use (n) RCA revascularisation (n)

Group I (n = 25) Group II (n = 25) 55.76 ± 23.2 53.44 ± 16.7 106.44 ± 40.5 104.28 ± 28.06 28.7 ± 0.93 28.8 ± 0.92 1035.6 ± 360.17 1014 ± 242.2 398 ± 82.25 414 ± 70 3 (2–6) 3 (2–5) 2 (1–4) 2 (1–5) 19 20 14 14

p-value > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05

In group I, seven patients had diaphragm elevation as a consequence of diaphragm paralysis, while none of the patients had diaphragm complications in group II (p < 0.01). There was no significant difference between the groups with regard to rates of partial pericardiotomy and LIMA use, which could have caused these diaphragm complications. Comparison of the patients’ data is given in Table 4. The necessity of using positive inotropes, ICU statistics, drainage and transfusion amounts, ECG and echocardiography changes, hospital length of stay and the other postoperative data are given in Table 5. Overall there was no statistically significant difference between the groups with regard to these categories (p > 0.05).

Discussion Initially, most cardiac surgeons believed that topical cooling was effective in cardiac performance as it increased myocyte Table 3. Blood sample results of the patients. Sample type Time Group I (n = 25) Group II (n = 25) TnI Pre-op 0.314 ± 0.97 0.204 ± 0.35 (ng/ml) Basal 0.326 ± 0.755 0.296 ± 0.251 Ischaemia 0.602 ± 0.886 0.415 ± 0.337 Reperfusion 0.938 ± 0.85 0.782 ± 0.372 8th hour 1.475 ± 0.479 1.09 ± 0.604 24th hour 1.51 ± 1.343 1.113 ± 0.854 TnT Pre-op 0.155 ± 0.497 0.042 ± 0.057 (ng/ml) Basal 0.149 ± 0.420 0.162 ± 0.208 Ischaemia 0.294 ± 0.603 0.201 ± 0.176 Reperfusion 0.330 ± 0.65 0.339 ± 0.204 8th hour 0.495 ± 0.725 0.367 ± 0.235 24th hour 0.417 ± 0.59 0.331 ± 0.217 Myoglobin Pre-op 43.24 ± 48.789 30.368 ± 8.470 (ng/ml) Basal 71.911 ± 40.82 91.028 ± 36.53 Ischaemia 105.06 ± 53.35 137.02 ± 50.49 Reperfusion 199.068 ± 88.52 253.22 ± 69.395 8th hour 156.17 ± 67.164 170.93 ± 81.62 24th hour 256.63 ± 196.79 233.48 ± 113.867 CK Pre-op 98.28 ± 98.99 91.56 ± 55.49 (U/l) 8th hour 411.04 ± 130.087 448.6 ± 181.39 24th hour 624.6 ± 245.75 599.21 ± 256.73 CK-MB Pre-op 13.32 ± 5.49 14.68 ± 4.63 (U/l) 8th hour 23.84 ± 6.414 24.8 ± 4.76 24th hour 20.88 ± 8.31 25.2 ± 8.225 LDH Pre-op 381.12 ± 61.42 378.32 ± 91.13 (U/l) 8th hour 518.12 ± 103.39 538.04 ± 129.84 24th hour 610.12 ± 110.98 581.84 ± 132.92 C3 Basal 0.6436 ± 0.119 0.601 ± 0.979 (g/l) Ischaemia 0.623 ± 0.104 0.592 ± 0.116 Reperfusion 0.593 ± 0.817 0.601 ± 0.876 C4 Basal 0.115 ± 0.219 0.107 ± 0.06 (g/l) Ischaemia 0.114 ± 0.20 0.109 ± 0.52 Reperfusion 0.109 ± 0.203 0.1068 ± 0.50 TNF-a Basal 8.566 ± 0.642 8.516 ± 0.722 (pg/ml) Ischaemia 9.556 ± 0.879 8.577 ± 0.676 Reperfusion 8.846 ± 0.602 8.544 ± 0.48

p-value > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 < 0.05 < 0.05 < 0.05 > 0.05 > 0.05 > 0.05 < 0.001 < 0.001 < 0.001

0.6500

9.800

0.643 ± 0.119

0.6400

0.6100

0.601 ± 0.876 0.601 ± 0.979 0.592 ± 0.116

0.593 ± 0.817

0.5800

9.200 9.000 8.800 8.600

8.846 ± 0.602

8.566 ± 0.642 8.561 ± 0.722

8.577 ± 0.676

8.544 ± 0.48

8.400

0.5700 0.5600

TNF-α (pg/ml)

C3 (g/l)

9.400

0.623 ± 0.104

0.6200

0.5900

9.556 ± 0.879

9.600

0.6300

0.6000

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p < 0.05 Basal

Ischaemia Group I

Reperfusion

8.200

p < 0.001

8.000

Basal

Ischaemia

Reperfusion

Group I

Group II

Fig. 1. B lood samples results and time-dependent changes in C3 levels.

Fig. 2. B lood samples results and time-dependent changes in TNF-a levels.

viability and decreased myocardial injury, therefore having a beneficial effect on contractile performance postoperatively. Nikas et al.4 reported that topical cooling had no effect on myocardial temperature; however, it increased postoperative complications such as diaphragmatic injury, arrhythmias and their consequences by hypothermic myocyte injury. They believed topical hypothermia to be detrimental in cardiac surgical modalities.4 After their study, topical cooling become controversial in many cardiac surgery centres.

Minatoya et al.5 compared cardiac normothermia under normothermic CPB with cardiac hypothermia (with topical cooling) under hypothermic CPB. They reported that hypothermia had more deleterious effects on cardiac myocytes and cardiac contractility. They assessed cardiac enzymes, echocardiography and ECG as an indirect indicator of myocardial damage.5 In our study we used pre-operative, intra-operative and postoperative levels of cardiac enzymes and complement factors as an indirect marker of the condition of cardiac myocytes and local myocardial inflammation.

Table 4. Comparison of the patients’ data. Group I (n = 25)

Group II (n = 25)

Positive inotropes Adrenaline (n) 14 11 Dopamine (n) 1 0 Dobutamine (n) 2 0 ICU Intubation time (h) 13.06 ± 3.66 13.28 ± 2.37 ICU stay (h) 29.4 ± 12.28 30.24 ± 20.99 Drainage and transfusions Total drainage (ml) 1022 ± 507.12 1004 ± 473.33 Total transfusion (ml) 764 ± 462.7 848 ± 476.20 ECG and echocardiography Significant ECG changes (n) 0 0 Significant EF changes (n) 1 1 Wall motion disorder (n) 2 0 Aneurysm formation (n) 0 0 Valve dysfunction (n) 0 0 Other complications Peri-operative MI (n) 0 0 Pacemaker need (n) 1 0 Low cardiac output (n) 1 0 Death (n) 1 0 Total hospital stay (day) 8.72 ± 2.42 8.20 ± 1.35

Blood samples p-value > 0.05 > 0.05 > 0.05 > 0.05 > 0.05

There were no significant differences between the groups with regard to blood samples, whereas we found a significant difference in time-dependent changes in C3 and TNF-α levels. C3 levels rapidly decreased during the ischaemic and reperfusion periods in group I. In group II, C3 levels decreased minimally in the ischaemic period, and returned to almost baseline values during the reperfusion period (Fig. 1). Normally, after placing the ACC, ischaemia and the inflammatory period begins, and therefore complement activation

> 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05

Table 5. Other postoperative data. Group I (n = 25)

Group II (n = 25) p-value

< 0.01

Atrial fibrillation (n)

< 0.05

Ventricular faibrillation (n) Other (n)

1 1

0 1

> 0.05 > 0.05

< 0.05

< 0.01

11 3

13 2

> 0.05 > 0.05

Spontaneous sinus rhythm restoration (n) Dysrhythmias

IABP require (n) Diaphragmatic complications Diaphragmatic elevation (n) Partial pericardiotomy (n) Pleural effusion (n)

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starts. With activation of the complement system, C3 is diverted to its subunits, C3a and C3b, and therefore the amount of C3 is rapidly decreased. The decrease is expected to be more severe if inflammation is severe.6 In this regard, time-dependent changes in C3 levels showed more inflammatory activity in group I. This may indicate that topical cooling caused more inflammation and therefore more injury to cardiac myocytes. Similarly, time-dependent changes in TNF-α levels were significant (p < 0.001). TNF-α, which is an early reactive cytokine of the inflammatory response, is released during the activation of the inflammatory period. During cardiac surgery, this would occur with ACC.7 In our study, TNF-α was rapidly increased with ACC and decreased to almost baseline levels in group I, whereas it showed quite a stable trend in group II (Fig. 2). This result supports the hypothesis of Nikas et al., who showed that local hypothermia caused more inflammation and local injury.4

Defibrillation requirement Most authors accept that spontaneous restoration of sinus rhythm after aortic declamping is an important indicator of myocardial function.8,9 Lichenstein et al. reported that the rate of spontaneous restoration of sinus rhythm was higher in patients without topical cooling.9 In our study, this rate was significantly higher in patients in group II than in those in group I (80 vs 32%, p < 0.01). The need for defibrillation was as follows: in group I, eight patients (32%) needed it once, seven patients (28%) needed it twice, and two (8%) needed it three or more times, whereas in group II, four patients (16%) needed it once and only one patient needed it twice. Therefore, if the requirement for defibrillation were an indicator for myocardial function, group I had poor myocardial function at an early phase of aortic declamping. We believe these results are related to topical cooling because this was the only variable that differed between the groups.

Incidence of dysrhythmias Atrial fibrillation (AF) is the most common type of arrhythmia seen after cardiac surgery (32.3%).10 The systemic inflammatory response plays an important role in the pathogenesis of these arrhythmias, and several risk factors such as older age, pre-operative history of AF, chronic obstructive pulmonary disease (COPD), long intubation time, long ACC time, renal insufficiency, and high amounts of drainage and transfusion were found to be responsible for postoperative AF.10-14 In our study, there was a statistically significant difference between the two groups for AF rates (six patients in group I vs one patient in group II, p < 0.05). The patients were randomised homogenously into the groups according to these risk factors. Therefore, based on these results, we consider that there was a direct relationship between topical cooling and postoperative AF.

IABP requirement In the literature, there are not many studies on the association between IABP and topical myocardial cooling. In one study, which compared the effects of cardiac hypothermic and

normothermic techniques, Calafiore et al. reported that there was no statistically significant difference between the type of technique used and the necessity for IABP.15 In our study, IABP was required in four patients (16%) in group I, while none of the patients required it in group II (p < 0.05). Although these results were statistically significant, we are not certain of the relationship between these two factors because indications for IABP are standardised worldwide in daily practice. However, it is usually dependent on the surgeon’s decision. We believe there was no definite association between necessity for IABP treatment and topical myocardial cooling.

Diaphragm pathology There was a statistically significant difference in diaphragm paralysis between the groups in our study (n = 7, 28% vs n = 0, 0%, p < 0.01). We believe the main pathogenesis was phrenic nerve injury. The phrenic nerve originates from the anterior horn of C3–C6, runs down the posteromedial part of the internal mammarian artery at the entrance of the thoracic cavity, spreads to the lateral surface of the pericardium and then reaches the diaphragm muscles. The main artery of this nerve, which may be damaged during LIMA harvesting due to its proximity to the internal mammarian artery, is the pericardiophrenic artery.16 This nerve can be damaged during LIMA harvesting and/or partial pericardiotomy, which is performed for tunnelling to the LIMA pedicle. Furthermore the damage may occur because of cold application. This type of injury primarily depends on nerve demyelisation and is usually reversible in one year.4 Phrenic nerve injury after cardiac surgery is reported at 2–17%.17 In another study, Nikas et al. compared diaphragm paralysis in 505 patients undergoing cardiac surgery with and without topical hypothermia, and they found similar result to those in our study. In this study, 25% of patients with topical hypothermia and 2% of those without topical hypothermia had diaphragm paralysis (p < 0.0001).4 In our study, the first intercostal artery was devascularised with a haemostatic clip and without cauterisation for maximal care of the phrenic nerve during LIMA harvesting. Partial pericardiotomy was performed carefully on 11 patients in group I and 13 patients in group II (p > 0.05). These patients were compared in each group for an association between possible phrenic nerve injury and partial pericardiotomy. There were no correlations between pericardiotomy, LIMA harvesting and phrenic nerve injury. Therefore cold injury seemed to be responsible for phrenic nerve injury and thus diaphragm paralysis.

Other parameters There was no statistically significant difference for necessity of positive inotrope, and drainage and transfusion amounts between the groups. Abacilar et al. reported a positive correlation between TNF-α level and postoperative mediastinal drainage amount.2 We found a similar relationship between these two parameters in our study, although not statistically significant. Robicsek et al. reported that cardiac myocyte dehydration due to relative hyperosmolarity secondary to hypothermal iced saline caused myocardial functional disorder, and with the progression

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of this process, cell death may occur in time.18 In another study, Conno et al. reported that topical cooling with iced saline may cause epicardial oedema via a hypothermic–hypo-osmolar effect and may create temporary ST-segment anomalies on ECG without myocardial functional disorders.19 We did not see any significant abnormalities in ECG or echocardiography in our study. Hamulu et al. reported that pre-operative cardiac dysfunction was an important risk factor for heart surgery and reported that mortality and morbidity rates were almost higher in patients with pre-operative EF < 35%.20 We excluded the patients with < 35% EF from our study for realistic results. None of our patients had major complications such as cerebrovascular events, renal insufficiency or infection. A 58-year-old male patient in group I, treated for diabetes mellitus and hypertension, was dead on postoperative day 18 due to cardiac and respiratory arrest at home. When we compared the risk factors of peri-operative mortality such as age, gender, concomitant diseases, myocardial function, EF and surgical parameters,21 we did not find any correlation between this patient and the remaining patients in either group.

Conclusion Although this was a randomised, controlled, prospective study, due to the small number of patients, it was not possible to make generalised comments regarding the results. Therefore, there is a need to perform more randomised studies with larger patient numbers. Since topical hypothermia was the only variable in the present study, it was shown to increase inflammatory activity. Therefore topical hypothermia had deleterious effects on the postoperative course, which affects postoperative morbidity and patient outcome.

7. 8.

9. 10.

11.

12.

13.

14.

15.

16.

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Intra-uterine growth restriction as a risk factor for hypertension in children six to 10 years old Agata Zamecznik, Katarzyna Niewiadomska-Jarosik, Agnieszka Wosiak, Justyna Zamojska, Jadwiga Moll, Jerzy Stańczyk Abstract Introduction: Intra-uterine growth restriction (IUGR) is present in about 3–10% of live-born newborns and it is as high as 20–30% in developing countries. Since the 1990s, it has been known that abnormalities during foetal growth may result in cardiovascular disease, including hypertension in adulthood. Methods: This study evaluated blood pressure parameters (using ambulatory blood pressure monitoring) in children aged six to 10 years old, born as small for gestational age (SGA), and compared them to their healthy peers born as appropriate for gestational age (AGA). Results: In the SGA group, an abnormal blood pressure level (prehypertension or hypertension) was present significantly more often than in the AGA group (50 vs 16%, p < 0.01). This relationship also occurred in association with the type of IUGR (asymmetric p < 0.01, symmetric p < 0.05). Conclusion: In SGA children, abnormal blood pressure values occurred more frequently than in AGA children. Keywords: birth weight, children, hypertension, intra-uterine growth restriction, small for gestational age Submitted 28/6/13, accepted 20/2/14 Cardiovasc J Afr 2014; 25: 73–77

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DOI: 10.5830/CVJA-2014-009

Intra-uterine growth restriction (IUGR) is an important issue for both neonatologists and paediatricians. It occurs in about 3–10% of live-born newborns. The most serious problem of IUGR exists in developing countries where it concerns up to 20–30% of liveborns.1

Department of Children’s Cardiology and Rheumatology of the 2nd Chair of Paediatrics, Medical University of Lodz, Poland Agata Zamecznik, MD, agazamek@gmail.com Katarzyna Niewiadomska-Jarosik, MD, PhD Justyna Zamojska, MD, PhD Jerzy Stańczyk, MD

Institute of Information Technology, Lodz University of Technology, Poland Agnieszka Wosiak, PhD, MSc

Department of Cardiology, Polish Mother’s Memorial Hospital Institute, Lodz, Poland Jadwiga Moll, MD, PhD

In 1967, the American Academy of Paediatrics introduced nomenclature according to neonatal birth weight as follows: appropriate for gestational age (AGA), located between the 10th and 90th percentile; large for gestational age (LGA), above the 90th percentile; and small for gestational age (SGA), below the 10th percentile.2 IUGR affects many newborns with birth weights below the 10th percentile. There are two types of IUGR. The first, which accounts for approximately 20–25% of all cases, is called symmetrical IUGR. The disturbances occur in the first or second trimester of pregnancy, during organogenesis. There is a decrease in all dimensions of the foetus’s body and internal organs, usually accompanied by a permanent reduction in growth potential. The second type is asymmetrical IUGR, constituting 75–80% of all cases of IUGR. This develops in the late second and third trimester of pregnancy and is the result of abnormal cell growth, rather than their quantity. In this type, infants have a low birth weight while other parameters remain normal (body length, head circumference). Due to this, Rohrer’s ponderal index [PI = birth weight × 100/length3 (g/cm3)] in this type is lower than in symmetrical IUGR.3 Published in the 1990s, ‘Barker’s hypothesis’ states that growth disorders appearing in intra-uterine life result in the later occurrence of cardiovascular disease, including high blood pressure.4,5 This is due to the fact that the developing foetus adapts to the undernutrition and insufficient amounts of oxygen through ‘metabolic programming’ and adaptation of the structure and function of certain organs (e.g. compensatory hypertrophy of the nephrons).6,7 In Europe, hypertension affects about 2–5% of children, and among teenagers and young adults it reaches 10%.8 The most common type among children under the age of seven years is secondary hypertension. The frequency of primary hypertension increases with age.9 Based on previous reports, it is known that children born with IUGR are likely to develop primary hypertension much earlier and more frequently than their peers with normal birth weight.10 The aim of this study was to compare blood pressure parameters in children born as SGA and compare them with their healthy peers born as AGA, and to determine the prevalence of prehypertension and hypertension in both groups, taking into consideration the type of hypotrophy (symmetrical/asymmetrical) and birth weight percentile (≤ 5th percentile/5–10th percentile).

Methods This was a prospective study carried out between 2010 and 2012 in the Department of Children’s Cardiology and Rheumatology of the 2nd Chair of Paediatrics at the Medical University of Lodz in Poland. The study group consisted of 50 children aged six to 10 years (mean 7 years 11 months ± 1 year 4 months) born at

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term as SGA (birth weight < 10th percentile for gestational age), which included 23 boys and 27 girls. In the SGA group there were two subgroups: symmetrical (n = 20) and asymmetrical IUGR (n = 30). SGA children were also divided into subgroups according to birth weight percentiles: ≤ 5th percentile (n = 23) and between the 5th and 10th percentile (n = 27). The control group consisted of 25 healthy volunteers born as AGA, and matched for gender (13 boys and 12 girls) and age with the study group (Table 1). Informed written consent was obtained from all the parents, and the study was approved by the research ethics committee. A perinatal history was taken of all the children including delivery, gestational age, weight, birth length, head circumference and ponderal index.3 Somatic parameters applied to the centiles were developed for the Polish population.11 Risk factors for IUGR were determined in both groups, including environmental factors: smoking, alcohol intake during pregnancy; maternal factors: hypertension, diabetes, infection during pregnancy; and placental factors: structural and functional anomalies of the placenta. A family history of cardiovascular disease was taken, including the occurrence of hypertension. The nutritional status of all the children was assessed from their height, weight and body mass index [BMI = weight/height2 (kg/m2)] by centiles developed for the Polish population.12 Echocardiography (Aloka Prosound Alpha 10) was done to evaluate cardiac structure and function. Left ventricular mass (LV mass) was measured in the parasternal short- and longaxis view, in M-mode projection. Two formulae were used to calculate LV mass: the Deveroux index (LV mass/body surface area), which is automatically calculated by the device, and de Simone index (LV mass/height2.7). Measurements was taken according to the American Society of Echocardiography.13 Triple oscillometric measurements of blood pressure, using a sphygmomanometer with an appropriate cuff adapted to the length and circumference of the patient’s arm, were taken in a controlled environment after at least five minutes of rest in a seated position. Children over seven years of age were assessed according to the centiles developed in the OLAF study,14 and younger children were assessed according to the Fourth Report Table 1. Characteristics of the groups.

Parameters Current weight (kg) Current height (cm) Current BMI (kg/m2) Birth weight (g) Birth length (cm) Head circumference (cm) Apgar score

AGA group (n = 25) x SD 26.96 8.59 128.36 10.46 16.15

2.7

SGA group (n = 50) p-value x SD 25.41 9.32 NS 125.01 9.79 NS 15.88

3.21

3409.2 489.75 2564.3 184.97 < 0.001 54.76 3.37 51.84 2.52 < 0.001 34.28 1.43 32.97 1.35 < 0.001 9.48 0.77 8.66 0.89 < 0.001

2.08 0.27 1.86 0.24 < 0.001 Ponderal index (g/cm3) Maternal age (years) 28.6 4.5 26.9 5.4 NS Gestational age (weeks) 39.1 0.78 39.1 0.94 NS SGA: small for gestational age; AGA: appropriate for gestational age; ponderal index [PI = birth weight (g) × 100/ birth length3 (cm3)]; BMI (body mass index) = weight (kg)/height2 (m2); p-value: statistical significance; NS: not significant.

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of the the Working Group on High Blood Pressure in Children and Adolescents.15 Ambulatory blood pressure monitoring (ABPM) was done during the normal activity of the child, using a recorder (Tracker Reynolds NIBP 2) combined with an appropriate-sized cuff placed on the non-dominant hand. Based on the analysis of measurements made every 20 minutes during the day and every 30 minutes during the night, the following were obtained: (1) mean systolic blood pressure (mean SBP): average values for the entire 24-hour period, (2) mean diastolic blood pressure (mean DBP): average values for the entire 24-hour period, (3) mean arterial pressure [MAP = (2 × DBP + SBP)/3] during the 24-hour period, (4) SBP load for the 24-hour period (defined as the percentage of valid ambulatory SBP measures above the 95th percentile of SBP for age, gender and height), (5) DBP load for the 24-hour period (defined as the percentage of valid ambulatory DBP measures above the 95th percentile of DBP for age, gender and height). According to recommendations developed by Urbina et al.,16 the following were determined: normal blood pressure (SBP of 24-hour period < 95th percentile and SBP load < 25%), prehypertension (SBP of 24-hour period < 95th percentile and SBP load 25–50%), or hypertension (SBP of 24-hour period > 95th percentile and SBP load ≥ 25%).

Statistical analysis Descriptive statistics were executed by computing the mean and standard deviation (SD) for scale variables, or frequencies for nominal variables. The significance level was computed for the differences between variables in the AGA and SGA groups. To evaluate the differences between the two groups, a parametric t-test and a non-parametric Mann-Whitney test were performed. The normality of scale variables was assessed using the Kolmogorov-Smirnov test. All tests were two sided and performed at the p < 0.05 level. Pearson and Spearman correlation coefficients were computed to evaluate the degree of association between variables either for the control or study group. Statistical analysis was performed using Statistica 10 software (StatSoft Inc., Tulsa, USA) and a dedicated author’s software based on Microsoft SQL Server 2008 database management system.

Results There were no statistically significant differences between the groups in the distributions of gender, age and anthropometric parameters (weight, height, BMI) at the time of the study. Likewise, except for body measurements (birth weight, length and head circumference), Apgar score, and other perinatal parameters (gestational and maternal age) did not differ statistically significantly (Table 1). There was a significant difference in PI between the symmetrical (mean 2.02 ± 0.26 g/cm3) and asymmetrical (mean 1.75 ± 0.16 g/cm3) subgroups (p < 0.01). Among the children in the SGA group, the occurrence of one or more risk factors for IUGR was observed significantly more often, regardless of the type of IUGR (r = 0.42, p < 0.01). An analysis was performed on the prevalence of risk factors of IUGR in children in the AGA and SGA groups, with an additional division into symmetrical and asymmetrical type.

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Table 2 shows a comparison of the number of children affected by a particular risk factor. Some of the children had more than one risk factor. Among the maternal factors, the most common risk factors that predisposed to the development of foetal growth restrictions were maternal infections during pregnancy (p < 0.01), and in the symmetrical subgroup, environmental factors such as smoking (p < 0.05) and alcohol consumption by the pregnant woman (p < 0.05). In oscillometric measurements of blood pressure, there was a statistically significant difference between the SGA and AGA groups in DBP (62.92 ± 7.32 vs 58.28 ± 9.59 mmHg, p < 0.05) but not in SBP (104.73 ± 9.66 vs 101.00 ± 10.59 mmHg, p > 0.05). Based on ABPM, hypertension was diagnosed in 18% of the children in the SGA group, while it was not found in any child in the AGA group (p < 0.05). However, abnormal blood pressure (ABPM meeting the criteria for hypertension or prehypertension) was diagnosed significantly more often in the SGA group compared with the AGA group (50 vs 16%, p < 0.01). This relationship also occurred in the asymmetrical (53 vs 16%, p < 0.01) and symmetrical subgroups (45 vs 16%, p < 0.05). A significantly higher blood pressure load (both systolic and diastolic) was found in the SGA patients. When comparing symmetrical and asymmetrical subgroups with the AGA group, the values of blood pressure load were also statistically significantly higher (Table 3). When analysing ABPM measurements more specifically, we found more significant results. Among children born with features of asymmetrical IUGR, there were higher mean SBPs during the daytime (116.03 ± 6.71 vs 112.44 ± 5.24 mmHg, p < 0.05), and MAPs during the daytime (85.17 ± 4.95 vs 82.23 ± 4.71 mmHg, p < 0.05), compared with those of the AGA group. Patients from the SGA group with a birth weight less than the 5th percentile were subjected to a separate analysis. In this group of children, IUGR risk factors also appeared significantly more often than in the AGA group (environmental factors such as smoking and alcohol consumption during pregnancy, and maternal factors) (p < 0.05). With oscillometric measurement, DBP was significantly higher in the subgroup below the 5th percentile than in the AGA group (63.78 ± 7.64 vs 58.28 ± 9.59 mmHg, p < 0.05) while SBP did not differ significantly. A significantly higher blood pressure load was also found in this group compared with children from the AGA group (SBP Table 2. The prevalence of risk factors for IUGR SGA group (p) (n = 50) Symmetrical Asymmetrical AGA group subgroup (p) subgroup (p) Risk factors (n = 25) (n = 20) (n = 30) Placental factors 0 5 ( NS) 3 (< 0.05) 2 ( NS) Maternal factors 4 23 (0.01) 10 (0.01) 13 (< 0.05) Environmental factors 5 23 (< 0.05) 12 (< 0.01) 11 (NS) SGA: small for gestational age; AGA: appropriate for gestational age; p: statistical significance of the differences in each case was assessed in relation to the AGA group; NS: not significant.

load: 25.83 ± 21.18 vs 13.72 ± 10.86 mmHg, p = 0.01; DBP load: 11.22 ± 8.20 vs 5.76 ± 5.20 mmHg, p < 0.01), as well as a higher mean SBP during the daytime (115.91 ± 6.91 vs 112.44 ± 5.24 mmHg, p < 0.05), higher mean DBP during the 24-hour period (65.17 ± 4.69 vs 62.60 ± 3.50 mmHg, p < 0.05), and a higher MAP during the daytime (85.22 ± 5.05 vs 82.23 ± 4.71 mmHg, p < 0.05) and during the 24-hour period (80.57 ± 4.81 vs 77.72 ± 3.65 mmHg, p < 0.05). The analysis showed a statistically significant negative correlation between the occurrence of abnormal blood pressure and birth weight (r = 0.29, p = 0.01). Nevertheless, the combined frequency of hypertension together with prehypertension among the SGA children was compared with the group of children born with a birth weight ≤ 5th percentile and those between the 5th and 10th percentiles. There was no statistically significant difference in instance of abnormal blood pressure values found between these two groups. Echocardiographic examination did not reveal any abnormalities in cardiac structure and function in either group of children. In five children from the SGA group and two patients from the AGA group, left ventricular hypertrophy was found (according to de Simone or Deveroux). The difference was not statistically significant. LV mass indices did not correlate significantly with abnormal blood pressure levels. The relationship between blood pressure and other birth parameters, i.e. body length, head circumference and ponderal index, was also examined. A study was conducted on the correlation of family history of hypertension and other cardiovascular diseases with blood pressure values. Factors such as gender, age of the child at the time of the study, and current weight, height and BMI were also analysed. None of these factors correlated significantly with frequency of abnormal blood pressure values.

Discussion The results of our study indicate that there were significant differences in the incidence of abnormal blood pressure values Table 3. Ambulatory blood pressure monitoring parameters. SGA group (p) (n = 50) Symmetrical Asymmetrical AGA group subgroup (p) subgroup (p) ABPM parameters (n = 25) (n = 20) (n = 30) SBP load (%) 13.72 ± 10.86 24.56 ± 20.78 (< 0.05) 23.45 ± 19.10 28.48 ± 25.74 (< 0.05) (< 0.05) DBP load (%) 5.76 ± 5.20 10.62 ± 9.90 (< 0.05) 10.05 ± 6.53 11.00 ± 11.72 (< 0.05) (< 0.05) Mean SBP (mmHg) 107.96 ± 5.12 110.86 ± 8.57 (NS) (24-hour period) 109.65 ± 7.03 111.67 ± 9.48 (NS) (< 0.001) Mean DBP (mmHg) 62.60 ± 3.50 64.72 ± 5.23 (NS) (24-hour period) 64.25 ± 4.13 65.03 ± 5.89 (NS) (NS) SGA: small for gestational age; AGA: appropriate for gestational age; SBP: systolic blood pressure; DBP: diastolic blood pressure; p: statistical significance of the differences in each case was assessed in relation to the AGA group; NS: not significant.

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between children born as SGA and AGA. Our research showed a higher frequency of high blood pressure values diagnosing prehypertension or hypertension in SGA patients, which is consistent with the reports of other investigators.17-19 Incidentally our results correspond with reports of a prospective multi-centre study of 950 American children, of whom 28% were children with IUGR. The authors of that study found that in a group of six-year-old children with IUGR, hypertension occurred in 25% of them, whereas in only 16% of the control group.18 In that study, as in ours, the children were of comparable ages (6–8 years), born at term, in whom IUGR was determined based on a birth weight of less than the 5th17 or 10th percentile,18 according to the centiles developed for the particular population. Since IUGR affects particularly developing countries, the article by Law et al. is relevant. It was based on children 3–6 years old from China and North and South America (Guatemala and Chile). The authors found a relationship between higher blood pressure values and lower birth weight.20 There are many other studies in African countries where similar results were observed.21,22 In all of these studies, analysis was made on the basis of average values from triple oscillometric measurements of blood pressure. In another large, retrospective study, the Collaborative Perinatal Project, analysis of blood pressure in seven-year-old children was based on a single measurement. In that population of more than 2 600 children born with IUGR, the presence of higher blood pressure values was not confirmed compared to children born as eutrophic.23 This method of blood pressure assessment did not show significant differences. In our study, the oscillometric method confirmed higher DBP but not SBP values. It appears therefore that, especially in young children, 24-hour ABPM during ordinary activity of the child is a much more accurate assessment, as was done in our study. The only research available to us that evaluated the association between birth weight and blood pressure assessment using ABPM measurements was in a group of 39 children with IUGR.6 However, the conclusions of Bilge et al. differed from ours despite similar methods and a similar age of the study group, although fewer children were included in the study. The authors did not observe a statistically significant higher incidence of abnormal blood pressure values among the IUGR children. It has been proven that higher blood pressure values are not only the result of low birth weight but also too rapid weight gain within the first two years of life, which can lead to overweight and obesity.24 On the other hand, from studies in low- and middle-income countries, it is known that in SGA children, undernutrition exists not only in the intra-uterine period but also during childhood.1 This can imply serious health consequences in later life, including higher risk of mortality.1,25 In our research, there were no significant differences in body weight, height and BMI at the time of the study between the SGA and AGA children. Therefore intra-uterine growth retardation was an independent risk factor for abnormal blood pressure in childhood, and their nutritional status did not matter. In this article, we also distinguished between children with symmetrical and asymmetrical IUGR among the SGA group on the basis of anthropometric measurements at birth, including ponderal index. In children with asymmetrical IUGR, higher daytime and 24-hour SBP as well as daytime MAP were found.

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This may suggest that this subgroup is more prone to higher blood pressure values in early childhood, due to normal growth potential. However, the size of this subgroup was rather small and this observation needs further investigation. When isolating the subgroup of SGA children according to birth weight (≤ 5th percentile and 5th–10th percentile), there was no significant difference in the incidence of abnormal blood pressure values. It appears that assessing intra-uterine growth restriction only on the basis of birth weight does not reflect the risk of developing hypertension. Some authors tried to find other perinatal parameters describing body proportions that better correlate with metabolic dysfunction and high blood pressure in later life.23 This encourages further investigation of the causes of more frequent and earlier occurrence of hypertension in IUGR children compared to healthy AGA children. The major limitation of this work was the relatively small group of patients. However, this was a single-centre study, which could constitute the beginning of a wider research. We intentionally used fewer subjects in the AGA group, so that they could be comparable to the subgroups of SGA children (asymmetrical and symmetrical).

Conclusion In children born as SGA, abnormal blood pressure values (prehypertension or hypertension) occurred more frequently than in healthy children. This correlation did not provide a significant relationship with the type of IUGR (symmetrical/asymmetrical) or birth weight percentile (< 5th percentile vs 5–10th percentile), which could have been the result of the small number of patients. It seems reasonable therefore that children born with IUGR should remain under paediatric care. In cases of elevated blood pressure values during standard medical examination or any other risk factors of cardiovascular disease, these patients should be directed to a more accurate assessment of blood pressure values using APBM.

References 1.

Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 2013; 382: 427–451. American Academy of Pediatrics Committee on the Fetus and Newborn: nomenclature for duration of gestation, birth weight and intrauterine growth. Pediatrics 1967; 39: 935–939. Lubchenco LO, Hansman C, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966; 37: 403–408. Barker DJ, Godfrey KM, Gluckman PD, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993; 341: 938–941. Ericsson JG, Forsen T, Tuomilehto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension 2000; 36: 790–794. Bilge I, Poyrazoglu S, Bas F, Emre S, Sirin A, Gokalp S, et al. Ambulatory blood pressure monitoring and renal functions in term small- for- gestational age children. Pediatr Nephrol 2011; 26: 119–126. Puddu M, Fanos V, Podda F, Zaffanello M. The kidney from prenatal to adult life: Perinatal programming and reduction of number of nephrons during development. Am J Nephrol 2009; 30: 162–170.

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Andrade H, Antonio N, Rodriques D, Da Silva M, Pêgo M, Providência LA. High blood pressure in the pediatric age group. Rev Port Cardiol 2010; 29: 413–432. Litwin M, Kułaga Z. Epidemiologia i etiologia nadciśnienia tętniczego u dzieci i młodzieży. In: Litwin M, Januszewicz A, Prejbisz A(ed). Nadciśnienie tętnicze u młodzieży i młodych dorosłych, 1st edn. Kraków: Medycyna Praktyczna, 2011: 27–34. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens 2000; 18: 815–831. Malinowski A, Chlebna-Sokół D. Dziecko łódzkie-metody badań i normy rozwoju biologicznego, 1st edn. Łódź: Ankal, 1998. Kułaga Z, Litwin M, Tkaczyk M, Różdżyńska A, Barwicka K, Grajda A, et al. The height, weight, and BMI for age of Polish school-aged children and adolescents relative to international and local growth references. BMC Public Health 2010; 10: 109. De Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, et al. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992; 20: 1251–1260. Kułaga Z, Litwin M, Grajda A, Kułaga K, Gurzkowska B, Góźdź M, et al. Oscillometric blood pressure percentiles for Polish normalweight school- aged children and adolescents. J Hypertens 2012; 30: 1942–1954. The Fourth Report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114: 555–576. Urbina E, Alpert B, Flynn J, Hayman L, Harshfield GA, Jacobson M, et al. Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young and the Council for High Blood Pressure Research.

Hypertension 2008; 52: 433–451. 17. Fattal-Valevski A, Bernheim J, Leitner Y, Redianu B, Bassan H, Harel S. Blood pressure values in children with intrauterine growth retardation. Israel Med Assoc J 2001; 3: 805–808. 18. Shankaran S, Das A, Bauer CR, Bada H, Lester B, Wright L, et al. Fetal origins of childhood disease. Arch Pediatr Adolesc Med 2006; 160: 977–981. 19. Strambi M, Messa G, Berni S, Capitani S, Pammolli A, Iacoponi F, et al. Basal and post-ischemic vascular compliance in children/ adolescents born small for gestational age. Pediatr Nephrol 2012; 27: 1541–1546. 20. Law CM, Egger P, Dada O, Delgado H, Kylberg E, Lavin P, et al. Body size at birth and blood pressure among children in developing countries. Int J Epidemiol 2001; 30: 52–57. 21. Woelk GB, Emanuel I, Weiss NS, Psaty BM. Birthweight and blood pressure among children in Harare, Zimbabwe. Arch Dis Child Fetal Neonatal Ed 1998; 79: 119–122. 22. Thame M, Osmond C, Wilks RJ, Bennett FI, McFarlane-Anderson N, Forrester TE. Blood pressure is related to placental volume and birth weight. Hypertension 2000; 35: 662–667. 23. Hemachandra A, Klebanoff M, Duggan A, Hardy JB, Furth SL. The association between intrauterine growth restriction in the fullterm infant and high blood pressure at age 7 years: result from the Collaborative Perinatal Project. Int J Epidemiol 2006; 35: 871–877. 24. Adair LS, Martorell R, Stein AD, Hallal PC, Sachdev HS, Prabhakaran D, et al. Size at birth, weight gain in infancy and childhood, and adult blood pressure in 5 low- and middle-income-country cohorts: when does weight gain matter? Am J Clin Nutr 2009; 89: 1383–1392. 25. Katz J, Lee AC, Kozuki N, Lawn JE, Cousens S, Blencowe H, et al. Mortality risk in preterm and small-for-gestational-age infants in lowincome and middle-income countries: a pooled country analysis. Lancet 2013; 382: 417–425.

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Cardiovascular Topics Impact of prehypertension on left ventricular mass and QT dispersion in adult black Nigerians OK Ale, JN Ajuluchukwu, DA Oke, AC Mbakwem Abstract Background: Prehypertension has been associated with target-organ damage. This study sought to determine the impact of prehypertension (PHT) on QT dispersion and left ventricular hypertrophy (LVH) in adult black Nigerians. Methods: One hundred and one subjects with office blood pressure (BP) < 140/90 mmHg were categorised according to their office BP into normotensive (BP < 120/80 mmHg, n = 57) and prehypertensive (BP 120–139/80–89 mmHg, n = 44) groups. Echocardiography and electrocardiography (ECG) were performed on the subjects. Results: Thirty-four males aged 53.65 ± 16.33 years and 67 females aged 52.42 ± 12.00 years were studied. The mean QT interval dispersion (QTd) of the normotensive (38.96 ± 11.06 ms) and prehypertensive (38.41 ± 11.81 ms) groups were similar (p = 0.81). Prehypertensive subjects had higher left ventricular mass (LVM) (165.75 ± 33.21 vs 144.54 ± 35.55 g, p = 0.024), left ventricular mass index 1 (LVMI-1) (91.65 ± 16.84 vs 80.45 ± 18.65 g/m2, p = 0.021) and left ventricular mass index 2 (LVMI-2) (54.96 ± 10.84 vs 47.51 ± 12.00 g/m2.7, p = 0.017). QTd was independent of echocardiographic and electrocardiographic LVH (p > 0.05). Conclusion: Compared with normotension, prehypertension is associated with higher LVM but similar QTd. This suggests that structural remodelling precedes electrical remodelling in prehypertension. Keywords: prehypertension, left ventricular hypertrophy, left ventricular mass, QT dispersion, adult black Nigerian Submitted 18/10/13, accepted 20/2/14 Cardiovasc J Afr 2014; 25: 78–82

www.cvja.co.za

DOI: 10.5830/CVJA-2014-010

Department of Medicine, College of Medicine, University of Lagos/Lagos University Teaching Hospital, Lagos, Nigeria OK Ale, MBBS, MPH, FMCP, gokeale@yahoo.com JN Ajuluchukwu, MBBS, MMed, FMCP DA Oke, MBBS, FMCP AC Mbakwem, MBBS, FWACP

The heterogeneity of individuals with blood pressure (BP) < 140/90 mmHg in terms of cardiovascular (CV) risk was reported as early as 1939 by Robinson and Brucer.1 BP in the range of 120–139/80–89 mmHg (labelled then as prehypertension) was observed to be associated with high risk of progression to hypertension (HT) and cardiovascular disease (CVD) later in life when compared with BP < 120/80 mm Hg.1 The term prehypertension was adopted in May 2003 by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High blood Pressure (JNC-7) to describe BP range of 120–139/80–89 mmHg.2 The resuscitation of this terminology/concept in JNC-7 was a sequel to the documentation of a higher morbidity in individuals with prehypertension in landmark publications.3-5 Prehypertension (PHT) was defined in JNC-7 not only to emphasise the excess risk associated with BP in this range, but also to focus increased clinical and public health attention on prevention.2,6,7 Prevalence rates of PHT among adults in the United States, Ghana and northern Nigeria have been reported to be 31, 40 and 58.7%, respectively.7-9 In most studies, including the ones above, PHT was more prevalent than hypertension.7-9 Though PHT is associated with increased risk of major CV events independently of other CV risk factors,10 most individuals (90%) with PHT have at least one cardiovascular risk factor such as dyslipidaemia, abdominal obesity, hyperinsulinaemia, impaired fasting glucose levels, insulin resistance, a prothrombotic state, tobacco use, endothelial dysfunction, and impaired vascular distensibility.6,7,9,10 QT interval dispersion (QTd) (the difference between the longest and the shortest QT intervals on a surface ECG), when excessive, is associated with increased risk of cardiovascular morbidity and mortality in population studies, and many clinical conditions, including hypertension.11,12 This has been related to ventricular electrical instability, providing the necessary substrate for lethal ventricular arrhythmias.12,13 Greater QTd and left ventricular mass have been demonstrated in hypertensive individuals compared with normal individuals.11,13,14 Considering the well-established, linear relationship between BP and the risk of cardiovascular events, the CV risk associated with PHT is intermediate between normotension and hypertension.2,3 Hence, electrocardiographic and echocardiographic indices of target-organ damage in PHT may also be intermediate between normotension and hypertension. The aims of this study were: (1) to compare the QTd and indices of left ventricular hypertrophy in adult black normal and prehypertensive subjects, and (2) to evaluate the relationship of QTd with electrocardiographic and echocardiographic indices in these subjects.

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Methods

One hundred and one consecutive, apparently healthy black Nigerian students, staff and retirees of the Lagos University Teaching Hospital and the College of Medicine, University of Lagos, aged between 26 and 86 years were recruited. They fulfilled the following criteria: age ≥ 18 years, no history of heart disease, including hypertension or other conditions known to affect QT interval and QTd (e.g. diabetes mellitus, dysautonomia), normal cardiac physical examination and fasting blood sugar level < 7 mmol/l. None of the subjects was on treatment with drugs known to affect QT interval (e.g. statins, macrolide antibiotics, halofantrine, amiodarone).15 Exclusion criteria were the presence of sustained non-sinus rhythm, intraventricular conduction defects and electrocardiograms in which the end of the T waves could not be reliably determined and/or QT interval from less than eight leads could be analysed.11 Subjects with suboptimal echo windows were also excluded from echocardiographic examination. Ethical clearance was obtained from the ethics and research committee of the Lagos University Teaching Hospital. The study was conducted to conform to the ethical tenets developed by the World Medical Association, as espoused in the Declaration of Helsinki. All subjects provided informed consent. All subjects were classified by office BP as either normotensive: normal BP (< 120/80 mmHg) (n = 57) or prehypertensive: prehypertensive BP (120–139/80–89 mmHg) (n = 44), according to the JNC-7 recommendations.2 A detailed medical history was obtained, physical examination was performed and anthropometric variables of height and weight were obtained. Trained personnel obtained measures of height and weight using a calibrated stadiometer and a weighing scale. Each subject’s height was measured without shoes, in the standing position, heels together, toes apart at a 45° angle and the head in the Frankfort horizontal plane. Weight was measured with the subject lightly clothed and without shoes. Body mass index (BMI) was calculated according to the formula:16 BMI = body mass (kg)/body height2 (m2). BMI < 25 kg/m2, 25 to < 30 kg/m2, and ≥ 30 kg/m2 were classified as normal, overweight and obese, respectively.16 Resting blood pressure was measured three times for each subject with a standard mercury sphygmomanometer on the right arm in a sitting position following a minimum of five minutes’ rest by a physician. Phases I and V Korotkoff sounds were used to determine systolic and diastolic BP measurements. The mean of the last two measurements was used in the analysis.

Electrocardiography All subjects had a resting simultaneous 12-lead electrocardiogram (ECG) using an Esaote P80 Power electrocardiograph machine. At a paper speed of 25 mm/s with the machine control set at standard response, a standard lead II rhythm strip of 13–16 complexes and a minimum of three cardiac cycles per lead were recorded. All electrocardiograms were analysed by a single observer blinded to the clinical data. QT and the preceding RR intervals were assessed manually with callipers and mean values were determined in three consecutive cycles. QT intervals were measured in all possible leads from the beginning of the QRS complex to the point of T wave offset, i.e. the point of the return of the T wave to the

isoelectric line.11 In the presence of the U wave interrupting the T wave, the nadir between the T and U waves was used to define the point of T wave offset. QT dispersion (QTd) in milliseconds was defined as the difference between the shortest (QTmin) and longest (QTmax) mean QT interval in each electrocardiogram.11 The QT interval was measured from the lead with the longest interval and was corrected for subjects’ heart rate using Bazett’s formula: 17     QT

___o QTc =  ______ √RR 

where QTc is the corrected QT interval, QTo is the observed QT interval in milliseconds, RR is the RR interval in milliseconds. QTc ≤ 440 ms and QTd = 30–60 ms were considered normal.18-20 ECG LVH was determined using the Araoye’s criteria21,22 for LVH in blacks [i.e. (1) SV2 + RV6 > 4.0 mV in males ≥ 30 years, SV2 + RV6 > 5.0 mV in males aged 15–29 years and SV2 + RV6 > 3.5 mV in females; (2) flat or inverted T waves in V5 or V6; (c) R1 amplitude > 1.2 mV. ECG LVH is diagnosed when any of the criteria is positive] and the Sokolow–Lyon voltage criteria.23 Araoye’s criteria has been shown to correlate well with echocardiographic LVH in Nigerians.24

Echocardiography Transthoracic echocardiography was performed on the first 60 consecutive subjects using a Hewlett Packard Sonos 2000 machine. Using the American Society of Echocardiography (ASE) recommendations,25 the following measurements were obtained: left ventricular internal diameter in diastole (LVIDd), left ventricular internal diameter in systole (LVIDs), interventricular septal thickness in diastole (IVSTd) and left ventricular posterior wall thickness in diastole (PWTd). Left ventricular mass (LVM) was derived using the ASE formula:25 Estimated LVM (g) = 0.80 [1.04 (LVIDd + PWTd + IVSTd)3 – LVIDd)3] + 0.6 g Left ventricular mass index was determined using two different methods. Left ventricular mass index 1 (LVMI-1) was calculated as the ratio of LVM to body surface area (g/m2).25 Subjects were was considered to have LVH if LVMI-1 was more than 134 g/m2 for men and more than 110 g/m2 for women.26 The second LVMI, i.e. LVMI-2 was derived by indexing LVM to height using the formula:27 LVMI-2 (g/m2.7) = LVM/height2.7. However only LVMI-1 was used for the determination of the presence or absence of LVH in the subjects.

Statistical analysis The SPSS 17.0 statistical software was used for data analysis. The data obtained were expressed as means and proportions. Statistical significance of variables was tested using the chi-square and Fisher’s exact test for categorical variables and the Student’s t-test for continuous variables. Analysis of variance was used to assess intra-observer variability of height and weight measures of the first 35 subjects.

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Table 1. Clinical characteristics of the study population

Characteristic Age Gender Male Female Weight (kg) Height (m)

Total Normotensive Prehypertenpopulation group sive group n = 101 n = 57 n = 44 Mean ± 2SD Mean ± 2SD Mean ± 2SD n (%) n (%) n (%) p-value 59.96 ± 13.54 50.74 ± 13.89 55.84 ± 12.65 0.06 0.94 34 (33.7) 19 (33.3) 15 (34.1) 67 (66.3) 38 (66.7) 29 (65.9) 69.10 ± 13.10 68.02 ± 12.32 70.50 ± 14.05 0.20 1.63 ± 0.08 1.63 ± 0.07 1.62 ± 0.10 0.44

26.17 ± 4.72 25.61 ± 4.63 26.89 ± 4.78 0.18 BMI (kg/m2) BMI class 0.35 Normal 45 (44.6) 29 (50.9) 16 (36.4) Overweight 35 (35.6) 18 (31.6) 18 (40.9) Obese 20 (19.8) 10 (17.5) 10 (22.7) SBP (mmHg) 118.27 ± 19.50 112.39 ± 6.24 125.89 ± 7.34 < 0.001 DBP (mmHg) 73.70 ± 7.43 71.05 ± 6.60 77.14 ± 7.10 < 0.001 MAP (mmHg) 88.56 ± 6.98 84.83 ± 5.61 93.39 ± 5.48 < 0.001 PP (mmHg) 44.56 ± 9.04 41.33 ± 6.86 48.75 ± 9.83 < 0.001 BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial blood pressure; PP, pulse pressure.

The strengths of the relationship between QTd and selected continuous variables were assessed with the Pearson’s correlation coefficient. Variables that demonstrated significant relationship to QT dispersion i.e. LVM, LVMI and LVMI-2 in the prehypertensive group were entered as independent variables into a standard (simultaneous) multiple regression model with QTd as the dependent variable. All tests were two-sided and values were considered statistically significant if p < 0.05.

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Nineteen (43%) of the prehypertensive subjects had both systolic (SBP) and diastolic blood pressure (DBP) within the prehypertensive range. This subpopulation of the prehypertensives with a mean age of 53.37 ± 10.96 years consisted of four male and 15 female subjects. Their mean QTd of 39.21 ± 13.46 ms was similar to QTd of the rest of the cohort (p > 0.05). The clinical characteristics of the study group are presented in Table 1. There were no differences in the age, gender and anthropometric measurements of the two groups. The prehypertensive group however had significantly higher BP indices. The electrocardiographic measures of the two groups are presented in Table 2. The heart rate, QTc, QTd and ECG LVH status of the two groups were similar. Table 3 shows the echocardiographic measurements of the groups. The prehypertensive group had significantly higher IVSTd, LVM, LVMI-1 and LVMI-2 values. The relationships of QTd to LVH determined by ECG and echocardiography are presented in Table 4. QTd was independent of LVH status, not only in the whole cohort, but also in the two groups. QTd correlated significantly with LVM (r = 0.58, p = 0.003), LVMI (r = 0.55, p = 0.006) and LVMI-2 (r = 0.49, p = 0.016) in the prehypertensive subjects. Several other variables were tested in both groups but did not correlate with QTd (p > 0.05): age, weight, height, BMI, SBP, DBP, pulse pressure (PP), heart rate, QTc, LVIDd, LVIDs, IVSTd, LVPWd, RWT and ejection fraction (EF). None of the independent variables (LVM, LVMI and LVMI-2 in the prehypertensive group) in the simultaneous regression model with QTd as the dependent variable made statistically significant contributions to the equation (computed R2 = 34%, adjusted R2 = 24%). The beta-values and the levels of significance were 0.50 and 0.31 for LVM, 0.04 and 0.96 for LVMI and 0.14 and 0.96 for LVMI-2.

Discussion

Results A total of 101 subjects aged between 26 and 86 years were enrolled into the study. The age of the normotensive (n = 57) and prehypertensive group (n = 44) of subjects ranged from 27–86 and 26–78 years, respectively. The ICC for the intra-observer assessment of the measures of height and weight are 0.97 and 0.96, respectively. Table 2. ECG measurements according to BP group. Total population n = 101 Mean ± 2SD n (%)

Normotensive group n = 57 Mean ± 2SD n (%)

Prehypertensive group n = 44 Mean ± 2SD n (%)

Characteristic p-value Heart rate 73.35 ± 10.94 72.11 ± 9.53 74.95 ± 12.47 0.38 (beats/min) QRS (ms) 79.96 ± 3.51 79.54 ± 3.46 80.50 ± 3.53 0.18 QTd (ms) 38.72 ± 11.34 38.96 ± 11.06 38.41 ± 11.81 0.81 QTc (ms) 417.92 ± 23.63 415.58 ± 23.25 420.95 ± 24.04 0.26 ECG LVH Sokolow–Lyon 8 (7.9) 4 (7.0) 4 (9.1) 0.73 Araoye’s code 10 (9.9) 4 (7.0) 6 (13.6) 0.33 QTc, corrected QT interval; QTd, QT dispersion, QRS, QRS duration, LVH, left ventricular hypertrophy.

PHT is an intermediate stage between normal BP and hypertension. The mechanisms of excess CV risk/end-organ Table 3. Echocardiographic measurements according to BP groups

Characteristic LVIDd (cm) LVIDs (cm) IVSTd (cm) LVPWd (cm) RWT (cm) LVM (g) LVMI-1(g/m2)

Total Normotensive Prehypertenpopulation group sive group n = 60 n = 36 n = 24 Mean ± 2SD Mean ± 2SD Mean ± 2SD n (%) n (%) n (%) p-value 4.52 ± 0.44 4.50 ± 0.41 4.55 ± 0.49 0.64 2.90 ± 0.43 2.93 ± 0.41 2.84 ± 0.46 0.43 1.05 ± 0.21 1.00 ± 0.20 1.15 ± 0.21 0.01 0.88 ± 0.14 0.88 ± 0.15 0.91 ± 0.13 0.29 0.40 ± 0.09 0.39 ± 0.09 0.41 ± 0.09 0.57 153.03 ± 35.91 144.54 ± 35.55 165.75 ± 33.21 0.024 84.93 ± 18.64

80.45 ± 18.65

91.65 ± 16.84

0.021

LVMI-2 (g/m2.7) 50.49 ± 12.02 47.51 ± 12.00 54.96 ± 10.84 0.017 EF (%) 72.72 ± 8.73 71.44 ± 8.57 74.65 ± 8.80 0.17 Echo LVH 2(3.33) 1(1.67) 1(1.67) 1.00 LVM, left ventricular mass; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy; LVIDd, left ventricular internal diameter in diastole; LVIDs, left ventricular internal diameter in systole; IVSTd, interventricular septal thickness in diastole; PWTd, left ventricular posterior wall thickness in diastole.

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Table 4. Relationship of QTd to LVH status. Total population Normotensive group LVH status QTd (ms) p-value QTd (ms) No LVH 38.77 ± 11.31 0.88 39.11 ± 11.10 LVH 38.13 ± 12.39 37.00 ± 11.94 Araoye No LVH 38.78 ± 10.78 0.88 39.36 ± 10.89 LVH 38.20 ± 16.44 33.75 ± 13.77 LVMI No LVH 39.72 ± 10.24 0.97 40.60 ± 10.70 LVH 40.00 ± 0.00 40.00 ± 0.00 QTd, QT dispersion; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index. LVH classification Sokolow–Lyon

damage associated with PHT are presumed to be the same as that of hypertension. This suggests that CV risk and end-organ damage in PHT, together with their surrogates such as QTd and LVH, are also intermediate. Increased QTd is a marker of increased myocardial electrical instability, which has been associated with hypertension.11,13,14 This study showed similar QTd values in normal and PHT subjects. This is at variance with the report by Dogru et al.28 of higher QT dispersion in prehypertensives when compared with normotensive individuals. Racial differences may contribute to this discrepancy. Studies have suggested significant differences in the cardiac structure and function of subjects of African descent compared with non-negroid subjects.29,30 This was further demonstrated in a study by Zhu et al. of white and black PHT subjects,31 which suggested that cardiovascular characteristics of prehypertension appear to be race dependent. The subjects in our study may have had lower BP values, i.e. closer to normotension than those in the above study, with a consequent blunting of the expected difference in the QTd values of the subjects with normal BP and PHT. Data have suggested a wide variation in the QTd of normal individuals (BP < 140/90 mmHg), hence it has been difficult to define what constitutes a normal QTd.11 This variation may reduce the ability of QTd to discriminate between prehypertension and normotension, with a consequent similarity observed in the QTd values of prehypertensive and normotensive subjects in this study. LVH, a compensatory mechanism for ventricular overload, is an independent risk factor for CV morbidity and mortality in normotensive and hypertensive individuals.32,33 The present study showed higher indices of LVH, i.e. IVSTd, LVM and LVMI in the PHT subjects. Manios et al.34 and Drukteinis et al.35 documented similar findings of higher LVM in prehypertensives than in normotensives, even after adjusting for co-variates. Conversely, Zhu et al.31 reported similar LVM values in normotensive and hypertensive subjects. Differences in study population and the methodology of BP measurement (use of ambulatory or office BP and different protocols) may have accounted for this variation. The normotensive and prehypertensive groups in the present study were however similar in terms of ECG LVH status. This may be attributed to the low sensitivity of ECG criteria in detecting LVH, therefore limiting their ability to measure milder changes in LVM expected in prehypertension.36,37 The report of Ang and Lang,38 that the sensitivities of ECG LVH criteria are substantially lower when tested in the general population than in a high-risk population, such as hypertensive patients, gives further credence to this view. Both ECG LVH

p-value 0.72 0.33 0.96

Prehypertensive group QTd (ms) 38.33 ± 11.72 39.25 ± 14.57 39.97 ± 10.67 41.17 ± 18.61 38.39 ± 9.58 40.00 ± 0.00

p-value 0.88 0.54 0.87

and echocardiographic LVH as prognostic factors for CVD may reflect different pathological processes and thereby influence prognosis in different ways.38 The demonstration of similar QTd in normotensive and prehypertensive subjects, together with a concomitantly higher LVM in PHT seen in our data suggests that left ventricular structural remodelling precedes electrical remodelling in a continuum of cardiovascular changes induced by increasing BP in prehypertension. This probably confers a higher sensitivity to LVM measurement over ECG parameters, such as QTd and LVH measurement in the detection of prehypertensive changes in the myocardium. The relatively small study population and the recording of the ECG at a speed of 25 mm/s, which is the usual speed of ECG recordings in clinical practice, were limitations in this study. QT interval measurements are more reproducible at faster paper speed recordings.11 Moreover, the cross-sectional design of this study precludes the establishment of a cause–effect relationship between prehypertension and increased LVM. This relationship, including the likelihood of reverse causality between LVM and prehypertension, will be better addressed by a prospective study. However, the findings of this study can serve as a basis for further studies on the effects of prehypertension in adult black Nigerians.

Conclusions The findings of similar ECG parameters (QTd and ECG LVH) in prehypertensive and normotensive subjects suggest a limitation in the usefulness of ECG for CV risk stratification in prehypertension. Conversely, echocardiography may be a good screening tool for the detection of prehypertensive changes in the heart. However, this may not be feasible in resource-poor countries such as Nigeria.

References 1.

Robinson SC, Brucer M. Range of normal blood pressure: a statistical and clinical study of 11,383 persons. Arch Intern Med 1939; 64: 409–444. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–1252. Lewinton S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific reference of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913.

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Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001; 358: 1682–1686. Vasan RS, Beiser A, Seshadri S, Larson MG, Kannel WB, D’Agostino RB, et al. Residual lifetime risk for developing hypertension in middleaged women and men: The Framingham Heart Study. J Am Med Assoc 2002; 287(8): 1003–1010. Gupta P, Nagarajau SP, Gupta A, Chikkalingaiah KBM. Prehypertension – time to act. Saudi J Kidney Dis Transpl 2012; 23(2): 223–233. Agyemang C, Owusu-Dubus E. Prehypertension in the Ashanti region of Ghana, West Africa: an opportunity for early prevention of clinical hypertension. Public Health 2008; 122: 19–24. Wang Y, Wang QJ. The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines: new challenges of the old problem. Arch Intern Med 2004; 164(19): 2126–2134. Isezuo SA, Sabir AA, Ohwovoriole AE, Fasanmade OA. Prevalence, associated factors and relationship between prehypertension and hypertension: a study of two ethnic African populations in Northern Nigeria. J Hum Hypertens 2011; 25: 224–230. Mainous AG, Everett CJ, Liszka H, King DE, Egan BM. Prehypertension and mortality in a nationally representative cohort. Am J Cardiol 2004; 94(12): 1496–1500. Sahu P, Lim PO, Rana BS, Struthers AD. QT dispersion in medicine; electrophysiological Holy grail or fool’s gold. Q J Med 2000; 93: 425–431. Mangoni AA, Kinirons MT, Swift CG, Jackson SH. Impact of age on QT interval and QT dispersion in healthy subjects: a regression analysis. Age Ageing 2003; 32: 326–331. Abdal-Barr MG, Safwat M, Nammas W. Would corrected QT dispersion predict left ventricular hypertrophy in hypertensive patients? Blood Press 2012; 21(4): 249–254. Ale OK, Ajuluchukwu JN, Oke DA, Mbakwem AC. QT Dispersion in Hypertensive Nigerians with and without Left Ventricular Hypertrophy. West Afr J Med 2013; 32(1): 57–61. Bednar MM, Harrigan EP, Anziano RJ Camm AJ, Ruskin JN. The QT interval. Prog Cardiovasc Dis 2001; 43(5 Suppl 1): 1–45. Micozzi MS, Albanes D, Jones DY, Chumlea WC. Correlations of body mass indices with weight stature, and body mass composition in men and women in NHANES I and II. Am J Clin Nutr 1986; 44: 725–731. Bazett HC. An analysis of the time relations of electrocardiograms. Heart 1920; 7: 353–370. Mirvis DM, Goldberger AL. Electrocardiography. In: Bonov RO, Mann DL, Zipes DB, Libby P (eds). Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th edn. Elsevier Sanders, 2012: 126–167. Djordjevic D, Deljanin Ilic M, Tasic I. Nearly two decades of QTc dispersion in cardiology. Med Biol 2007; 14(30): 107–111. Malik M, Batcharov VN. Measurement, interpretation, and clinical potential of QT dispersion. J Am Coll Cardiol 2000; 36: 1749–1766. Araoye MA. Left ventricular hypertrophy by electrocardiogram: A code system applicable to Negroes. Nig Postgrad Med J 1996; 3: 92–97. Araoye MA. Letter to the Editor: LVH by ECG. Nig Postgrad Med J 1999; 4: 189.

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23. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limbs leads. Am Heart J 1949; 37: 161–186. 24. Dada A, Adebiyi AA, Aje A, Oladapo OO, Falase AO. Comparison of Araoye’s criteria with standard electrocardiographic criteria for diagnosis of left ventricular hypertrophy in Nigerian hypertensives. West Afr J Med 2006; 25(3): 179–185. 25. Sahn DJ, De Maria A, Kisslo J and Weyman A. The Committee on M-mode Standardization of the American Society of Echocardiography: Recommendations regarding quantitation in M-mode echocardiography. Results of a survey of echocardiographic measurements Circulation 1978; 58: 1072–1083. 26. Levy D, Anderson KM, Savage DD, Kannel WB, Christiansen JC, Castelli WB. Echocardiographically detected left ventricular hypertrophy: Prevalence and Risk Factors. The Framingham Heart Study. Ann Intern Med 1988; 108(1): 7–13. 27. De Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, deDivitiis O, et al. MH. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992; 20: 1251–1260. 28. Dogru MT, Guneri M, Tireli E, Sahin O, Celik T, Iyisoy A. QT interval and dispersion differences between normal and prehypertensive patients: effects of autonomic and left ventricular functional changes. Anadolu Kardiyol Derg 2009: 9(1): 15–22. 29. Mayet J, Shahi M, Foale RA, Poulter NR, Server PS, McG Thom SA. Racial differences in cardiac structure and function in essential hypertension. Br Med J 1994; 1011–1014. 30. Chapman JN, Mayet J, Chang CL, Foale RA, Thom SA, Poulter NR. Ethnic differences in the identification of left ventricular hypertrophy in the hypertensive patient. Am J Hypertens 1999; 12: 437–442. 31. Zhu H, Yan W, Ge D, Treiber FA, Harshfield GA, Kapuku G, et al. Cardiovascular characteristics in American youth with prehypertension. Am J Hypertens 2007; 20(10): 1051–1057. 32. Schmieder RE. End organ damage in hypertension. Dtsch Arztebl Int 2010; 107(49): 866–873. 33. Brown DW, Giles WH, Croft JB. Left ventricular hypertrophy as a predictor of coronary heart disease mortality and the effect of hypertension. Am Heart J 2000; 140: 848–856. 34. Manios E, Tsivgoulis G, Koroboki E, Stamatelopoulos K, Papamichael C, Toumanidis S, et al. Impact of Prehypertension on Common Carotid Artery Intima-Media Thickness and Left Ventricular Mass. Stroke 2009; 40: 1515–1518. 35. Drukteinis JS, Roman MJ, Fabsitz RR, Lee ET, Best LG, Russell M, et al. Cardiac and systematic hemodynamic characteristics of hypertension and prehypertension in adolescents and young adults – The Strong Heart Study. Circulation 2007; 115: 221–227. 36. Bacharova L. Electrocardiography – Left ventricular mass discrepancies in left ventricular hypertrophy: electrocardiography imperfection or beyond perfection. J Electrocardiol 2009; 42: 593–596. 37. Reicheck N, Devereax RB. Left ventricular hypertrophy: relationship of anatomic, echocardiographic and electrocardiographic findings. Circulation 1981; 63: 1391–1398. 38. Ang DSC, Lang CC. The prognostic value of the ECG in hypertension: Where are we now? J Human Hypertens 2008; 22(7): 460–467.

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Review Article Optimal utilisation of sulphonylureas in resourceconstrained settings Poobalan Naidoo, Virendra Rambiritch, Neil Butkow, Selvarajah Saman Abstract Sulphonylureas (SUs) are oral anti-diabetic drugs (OADs) that were introduced more than 60 years ago. Clinicians are familiar with their use and they remain extensively used. However, the SU class is associated with adverse effects of weight gain and hypoglycaemia. In addition, their effects on cardiovascular events remain contentious. Newer classes of anti-diabetic agents have been developed and these agents are weight neutral (di-peptidyl peptidase IV inhibitors), while others reduce weight (glucagon-like peptide analogues and sodium glucose co-transporter inhibitors). Furthermore, the newer agents are less likely to cause hypoglycaemia and have a potentially better cardiovascular safety profile. However, the newer agents are more costly than SUs and their long-term safety is unknown. It is therefore likely that SUs will continue to be used, and more so in resource-limited settings. One may mitigate the adverse effects of weight gain and hypoglycaemia associated with the SU class by using members within this class that are less probable to cause these adverse effects. Furthermore, the specific SU must be used at the lowest effective therapeutic dose. In patients at high risk of SU-induced hypoglycaemic episodes (frail, clinically significant renal impairment), or patients in whom hypoglycaemic episodes may have devastating effects (bus drivers), newer anti-diabetic agents may be a justifiable alternative option. Keywords: type 2 diabetes mellitus, sulphonylureas, resourceconstrained settings

Boehringer Ingelheim, Johannesburg, South Africa

Poobalan Naidoo, BPharm, MB BCh, MMedSc (Pharmacol), FCP, poobalan.naidoo@boehringer-ingelheim.com

University of Kwa-Zulu Natal, Durban, South Africa Virendra Rambiritch, PhD

Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa Neil Butkow, PhD

Port Shepstone Regional Hospital and University of Kwa-Zulu Natal, Durban, South Africa Selvarajah Saman, MB BCh, MD, MRCP (UK), FRCP (UK)

Submitted 27/11/13, accepted 4/2/14 Cardiovasc J Afr 2014; 25: 83–85

www.cvja.co.za

DOI: 10.5830/CVJA-2014-007

Sulphonylureas (SUs) were developed in the 1950s.1 They reduce blood glucose levels by increasing insulin secretion from the pancreatic beta-cells. At the cellular level SUs block potasssium (KATP) channels and increase calcium influx, which results in the release of insulin from the vesicles.1 Currently there is an expansion in the therapeutic armamentarium of agents for type 2 diabetes. The therapeutic landscape is complex and comprises pharmacologically distinct molecules, including biguanides, sulphonylureas, incretin-based therapies and renal sodium glucose co-transporter (SGLT) inhibitors.2 As novel therapies are inevitably associated with increased costs, this article focuses on ways to utilise SUs in a manner that maximises efficacy and concurrently minimises adverse effects.

Efficacy and durability of glycaemic effect Type 2 diabetes patients benefit from intensive multifactorial riskfactor modification.3 In addition to control of blood glucose and glycosylated haemoglobin (HbA1c) levels, lifestyle modification (diet and exercise), and control of blood pressure and cholesterol levels are crucial to reduce the risk of cardiovascular disease in type 2 diabetes patients.3 For blood glucose control, HbA1c level is the most robust endpoint used in clinical trials to evaluate the efficacy of antidiabetic drugs. HbA1c is an indicator of three-month average blood glucose levels. Reduction in HbA1c levels reduces microvascular complications.4-6 SUs reduce HbA1c levels by approximately 1.5%,2 but their effect on cardiovascular outcomes is contentious. Their HbA1c level-reducing ability is adequate but durability is limited.7 Limited durability is probably secondary to type 2 diabetes mellitus being a progressive disease characterised by gradual reduction in beta-cell mass and function. If there are limited numbers of beta-cells, then the action of this class is limited because the mode of action necessitates the presence of betacells; they cannot increase insulin secretion if there are no betacells present to synthesise and release insulin. Furthermore, secondary failure has also been attributed to the detrimental effects of SUs on residual pancreatic beta-cells.8 Secondary failure rates were found to be lowest with gliclazide

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(7%), compared with glibenclamide (17.9%) and glipizide (25.6%).9

cost by using the newer SUs that have fewer propensities to cause hypoglycaemia compared to older agents.

Safety data

Newer classes of anti-diabetic agents

SUs cause weight gain and significantly increase the risk of hypoglycaemia.11,12 Hypoglycaemia appears to be associated with adverse vascular events and death.13 There are also issues with regard to cardiovascular safety. There is inconsistency in the results of clinical studies in respect of SUs and cardiovascular safety. The University Group Diabetes Program14 demonstrated increased cardiovascular mortality in patients treated with tolbutamide. However, the United Kingdom Prospective Diabetes Study (UKPDS)4 and the ADVANCE Collaborative Group5 did not show an association between treatment with an SU and adverse cardiovascular outcomes. In a meta-analysis of 33 studies, with more than a million study subjects, SU use was associated with a significantly increased risk of cardiovascular death (relative risk 1.27, 95% confidence interval 1.18–1.34, n = 27 comparisons).15 Monami et al.16 conducted a meta-analysis of randomised clinical trials to evaluate the cardiovascular safety of SUs. They concluded that ‘in type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of major adverse cardiovascular events (MACE) appears to be unaffected’. Given the inconsistency of the literature with regard to SUs and cardiovascular outcomes, a SU cardiovascular outcome trial is required to clarify the effect of SUs on cardiovascular outcomes.16,17 2,10

Dose–response relationships The literature supports the use of SUs at doses lower than the maximum manufacturer’s recommended dose.18 Studies have shown that as the dose of SU is increased, there is initially a direct relationship between dose and blood glucose-lowering effect.18 However, further dose increase results in no further reduction in blood glucose levels, and, when the dose is further increased, the glycaemic profile actually worsens.18 Modified-release formulations have further reduced the SU dose that is required, compared to the immediate-release pharmaceutical preparation.19 For example gliclazide is available in a modified-release formulation that uses less than half of the dose of the immediate-release formulation.19

Cost considerations SUs remain affordable. This is relevant in countries that have limited resources and competing healthcare problems. In sub-Saharan Africa, there are epidemics of not just metabolic and cardiovascular disease, but also infectious diseases.20 Tuberculosis and parasitic diseases such as malaria remain major healthcare challenges, while diabetes, hypertension and traumatic injuries are increasing.21 Therefore scarce medical resources must be distributed to various disease-management programmes. However, one may argue that managing SU-induced hypoglycaemic events (the cost of treating and in some cases the cost of admission), raises their cost. One may mitigate this added

The ideal anti-diabetic drug should be safe, efficacious and cost effective. It should not only reduce HbA1c levels but also reduce macro- and microvascular complications. Furthermore, it must not cause weight gain and hypoglycaemia, and must have durable efficacy and long-term safety. There is continuing research to develop newer agents to emulate the characteristics of an ideal anti-diabetic agent, and therefore better manage type 2 diabetes patients. Sodium glucose co-transporter (SGLT) inhibitors and incretinbased therapies are new classes of anti-diabetic agents. SGLT inhibitors reduce weight and have fewer propensities to cause hypoglycaemic events.22 This is in contrast to the SU class that increases weight and the number of hypoglycaemic episodes. Incretin-based therapies include glucagon-like peptide (GLP) analogues and di-peptidyl dipeptidase IV (DPPIV) inhibitors. GLP analogues reduce weight but are administered via the parenteral route. DPPIV inhibitors are weight neutral, have a low propensity for hypoglycaemia and are administered orally. The uncertainty surrounding adverse cardiovascular events associated with therapy with SUs remains,15 in contrast to the DPPIV class, which has both meta-analysis23 and a cardiovascular outcome trial24 that demonstrate cardiovascular safety of this new class. There are safety concerns with newer anti-diabetic agents. For example, issues related to pancreatitis and pancreatic cancer remain with incretin-based therapies.25 However, the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) and the International Diabetes Federation (IDF) have issued a joint statement saying that there is inadequate information presently to demonstrate a causal relationship between incretin-based therapy and pancreatitis and pancreatic cancer.26 There are also concerns with the SGLT inhibitor class and bladder and breast malignancies, and urinary and genital tract infections.22 The newer agents require further phase IV data to inform clinical use.

Maximising benefits and minimising adverse effects of SUs After considering the adverse effects, safety concerns, efficacy data and cost, one must use SUs in a manner that maximises efficacy while limiting the potential for adverse effects. The question is how does the clinician do this? One way is to choose the ‘right sulphonylurea, at the right dose, for the right patient’. The right sulphonyureas: the SUs share a common mode of action. However, there are differences in pharmacokinetics and pharmacodynamics between individual SUs. Some SUs have fewer propensities for hypoglycaemia and weight gain than others.27 South African treatment guidelines for type 2 diabetes specifically mention that glibenclamide must be phased out, and in the interim it must be dispensed only if renal function is known.28 Data derived from the UK General Practice Research Database (719 general practitioner practices, 34 052 patient-years of SU therapy) reported that in users of SUs, the annual risk of

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any hypoglycaemic event was 1.8%, rising to 2.0% in those aged > 65 years. The risk of SUs was greatest for glibenclamide; the study reported 25% fewer recorded episodes for gliclazide and 40% fewer for glipizide compared with glibenclamide.29 At the right dose: given the data on dose–response relationships of the class, it is prudent to use the lowest effective dose of SU, guided by efficacy parameters such as HbA1c levels. For the right patient: SUs are more likely to cause adverse effects in patients with risk factors for hypoglycaemia, including older, frail patients and patients with clinically significant renal impairment.30 In addition, any hypoglycaemic effect may be devastating for specific patients, such as bus drivers. Therefore SUs should perhaps be avoided in these groups and newer antidiabetic drugs considered.

Conclusion Cost issues remain a barrier between the newer anti-diabetic drugs and the majority of South African type 2 diabetes patients. SUs, if used at the right dose (the lowest possible effective dose), for the right patient (in younger patients without renal impairment), remain an option for the management of type 2 diabetes patients in resource-constrained settings.

References 1.

McGill JB. Pharmacotherapy in type 2 diabetes: a functional schema for drug classification. Curr Diabetes Rev 2012; 8(4): 257–267. 2. Mazzola N. Review of current and emerging therapies in type 2 diabetes mellitus. Am J Manag Care 2012; 18(1 Suppl): S17–26. 3. Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358(6): 580–591. 4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853. 5. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Eng J Med 2008; 358: 2560–2572. 6. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360(2): 129–139. 7. Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism 2006; 55(5 Suppl 1): S2–5. 8. Rendell M. The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 2004; 64(12): 1339–1358. 9. Harrower AD. Comparison of efficacy, secondary failure rate, and complications of sulfonylureas. J Diabetes Complication 1994; 8(4): 201–203. 10. Sehra D, Sehra S, Sehra ST. Sulfonylureas: do we need to introspect safety again? Expert Opin Drug Saf 2011; 10(6): 851–861. 11. Holstein A, Egberts E-H. Risk of hypoglycaemia with oral anti-diabetic agents in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes

2003; 111: 405–414. 12. Burge MR, Sood V, Sobhy TA, et al. Sulphonylurea-induced hypoglycaemia in type 2 diabetes mellitus: a review. Diabetes Obesity Metabolism 1999; 1: 199–206. 13. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010; 363(15): 1410–1418. 14. Klimt CR, Knatterud GL, Meinert CL, et al. A study of the effects of hypoglycemic agents on vascular complications in patients with adultonset diabetes. Diabetes 1970; 19: 747–830. 15. Phung OJ, Schwartzman E, Allen RW, et al. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med 2013; 30(10): 1160–1171. 16. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15(10): 938–953. 17. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 2013; 10(4): 289–301. 18. Rambiritch V, Naidoo P, Butkow N. Dose-response relationships of sulfonylureas: will doubling the dose double the response? South Med J 2007; 100(11): 1132–1136. 19. Rambiritch V, Naidoo P. Gliclazide modified release. Drugs 2005; 65(10): 1449–1450. 20. Ikem I, Sumpio BE. Cardiovascular disease: the new epidemic in subSaharan Africa. Vascular 2011; 19(6): 301–307. 21. Mollentze WF, Levitt NS, Delport R, et al. Round-table discussion: Management of the diabetic patient in a resource constrained environment. S Afr J Diabetes Vasc Dis 2009; 6(2): 66–73. 22. Riser Taylor S, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy 2013; 33(9): 984–999. 23. Johansen OE, Neubacher D, von Eynatten M, et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol 2012; 11: 3. 24. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369(14): 1317–1326. 25. Labuzek K, Kozłowski M, Szkudłapski D, et al. Incretin-based therapies in the treatment of type 2 diabetes--more than meets the eye? Eur J Intern Med 2013; 24(3): 207–212. 26. ADA/EASD/IDF Statement Concerning the Use of Incretin Therapy and Pancreatic Disease. http://www.diabetes.org/for-media/2013/ recommendations-for.html. Accessed August 08/2013. 27. Tessier D, Dawson K, Tetrault JP, et al. Glibenclamide vs. gliclazide in type 2 diabetes of the elderly. Diabet Med 1994; 11: 974–980. 28. Amod A, Ascott-Evans BH, Berg GI, et al. 2012 SEMDSA Guideline for the Management of Type 2 Diabetes. J Endocrinol Metabol Diabetes S Afr 2012; 17(2)(Suppl 1): S1–S95. 29. van Staa T, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulphonylureas. J Clin Epidemiol 1997; 50: 735–741. 30. Amiel SA, Dixon T, Mann R, et al. Hypoglycaemia in Type 2 diabetes. Diabet Med 2008; 25(3): 245–254.

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Letter to the Editor Adverse effects of ethyl esters or oxidation products in omega-3 preparations? Dear Sir We read with interest the article by Opperman and Benade, titled Analysis of the omega-3 fatty acid content of South African fish oil supplements: a follow-up study.1 We make the following comments. In humans, long-chain omega-3 fatty acids are required in numerous cellular mechanisms and are converted in small amounts from the plant-based precursor alpha-linolenic acid. It therefore seemed paradoxical when we found that in patients with dilative heart failure, the blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were reduced.2,3 We concluded that a deficiency in highly unsaturated fatty acids (HUFA) represents a key defect contributing to the rapid progression of heart failure requiring replacement therapy.4 It is therefore important to assess whether dietary supplement and pharmaceutical-grade omega-3 preparations vary not only in environmental pollutants,5 but also in adverse oxidation products. Opperman and Benade1 assessed differences in dietary supplement fish oils available on the South African market. Compared with their 2009 survey, almost a third of the supplements contained ethyl esters (EEs), which appeared to be associated with higher EPA and DHA levels. Although we share their contention that the presence of EEs should be declared on the supplement label, we do not see the evidence for their statement that the safety of a daily intake of EEs has not been confirmed in humans. In a major prospective, randomised clinical trial by the Gissi-Hf investigators,6 EPA/DHA was administered as EEs (omega-3-acid ethyl esters 90, Omacor®) manufactured as a drug according to FDA and EMA regulations. Adverse drug reactions did not differ from the placebo olive oil. Also the rate of discontinuation was not different from a vitamin E supplement.7 EEs are split in the gastrointestinal tract. When the intake of EEs and triglycerides was examined in humans, no differences in serum EPA and DHA levels were observed.8 EEs can therefore not accumulate in organs, as mentioned by Opperman and Benade.1 However, since EPA/DHA in the form of EEs appear to be more prone to autoxidation, the safety of dietary supplements containing EEs needs greater attention. Did the authors find differences in the levels of peroxides and conjugated dienes depending on the ester form? Did they calculate the intake of peroxides and conjugated dienes associated with a given EPA/DHA intake? According to our recent study on 63 dietary supplement fish oils from 13 countries,9 the peroxide intake for 1 g of EPA + DHA would be 8.6 ± 6.1 times higher compared with omega-3acid ethyl esters 90. The intake of secondary oxidation products measured as aldehydes would be 10.9 ± 4.4 times higher. In

this context it is important to note that the ingestion of less oxidised omega-3 supplements reduced circulating triglyceride and cholesterol levels, as opposed to highly oxidised omega-3 capsules, which had a negative effect on cholesterol levels.10 In view of the increasing evidence that the oxidation level of omega-3 fatty acid supplements can be a health risk, we consider it timely to change the perception that EPA/DHA is beneficial, irrespective of the source and the presence of oxidation products. Of particular concern is that the majority of fish oils exhibit a peroxide content above the recommended level of the Global Organisation for EPA and DHA Omega-3 (GOED), i.e. > 80% (South African market, photometric method),1 89% (market of 13 countries, photometric method),9 and 93% (Norwegian market, AOCS official method).11 Heinz Rupp, Rupp@uni-marburg.de Karin G Rupp, kg.rupp@gmx.de Experimental Cardiology Laboratory, Department of Internal Medicine – Cardiology, Philipps University, Marburg, Germany

References 1.

2. 3.

Opperman M, Benade S. Analysis of the omega-3 fatty acid content of South African fish oil supplements: a follow-up study. Cardiovasc J Afr 2013; 24: 297–302. Rupp H, Rupp TP, Alter P, Maisch B. N-3 polyunsaturated fatty acids and statins in heart failure. Lancet 2009; 373: 378–379. Rupp H, Rupp TP, Alter P, Maisch B. Inverse shift in serum polyunsaturated and monounsaturated fatty acids is associated with adverse dilatation of the heart. Heart 2010; 96: 595–598. Rupp H, Rupp TP, Alter P, Maisch B. Mechanisms involved in the differential reduction of omega-3 and omega-6 highly unsaturated fatty acids by structural heart disease resulting in “HUFA deficiency”. Can J Physiol Pharmacol 2012; 90: 55–73. Bourdon JA, Bazinet TM, Arnason TT, Kimpe LE, Blais JM, White PA. Polychlorinated biphenyls (PCBs) contamination and aryl hydrocarbon receptor (AhR) agonist activity of omega-3 polyunsaturated fatty acid supplements: implications for daily intake of dioxins and PCBs. Food Chem Toxicol 2010; 48: 3093–3097. Gissi-Hf investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223–1230. GISSI-Prevenzione investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999; 354: 447–455. Luley C, Wieland H, Grünwald J. Bioavailability of omega-3 fatty acids: ethylester preparations are as suitable as triglyceride prepara-

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tions. Akt Ernähr Med 1990; 15: 123–125. Rupp TP, Rupp KG, Alter P, Rupp H. Replacement of reduced highly unsaturated fatty acids (HUFA deficiency) in dilative heart failure: dosage of EPA/DHA and variability of adverse peroxides and aldehydes in dietary supplement fish oils. Cardiology 2013; 125: 223–231. 10. Garcia-Hernandez VM, Gallar M, Sanchez-Soriano J, Micol V, Roche 9.

E, Garcia-Garcia E. Effect of omega-3 dietary supplements with different oxidation levels in the lipidic profile of women: a randomized controlled trial. Int J Food Sci Nutr 2013; 64: 993–1000. 11. Ruyter B, Grimmer S, Thorkildsen T, Todorcevic M, Lalic M. Lite Oksiderte Omega-3 Oljer og Potensielle Helsefordeler. Trondheim: Rubin, 2010; 196: 1–60.

The 8th Annual Meeting of the National Scholarly Editors’ Forum of South Africa Wednesday 30 July 2014 Venue: Belmont Square Conference Centre, Rondebosch, Cape Town We are pleased to announce that the 8th annual meeting of the National Scholarly Editors’ Forum of South Africa will be held at the Belmont Square Conference Centre, Rondebosch, Cape Town on Wednesday 30 July 2014 from 10:00–16:30. The annual meeting is an opportunity for journal editors to exchange information and knowledge in our field. It is also an exceptional occasion to meet not only our disciplinary peers, but other experts who share the same interests. The ad hoc organising committee will draft the preliminary agenda and if you have any agenda items for discussion, please submit such items to me, Gugulethu (Gugulethu@assaf.org.za). In addition, if there are specific articles, research or reports that you would like to share with editors at this meeting, please send them to me as well. Please note that there are limited travel grants available. Please submit a motivation to me on Gugulethu@assaf.org.za. If you seek clarity on any NSEF-related matter, please contact Mrs Susan Veldsman at ASSAf on susan@assaf.org.za or 012 349-6611.

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Drug Trends in Cardiology Cryoballoon ablation for atrial fibrillation is now possible in South Africa Dr Razeen Gopal, head of the Mediclinic Panorama electrophysiology laboratory, recently discussed various successful procedures performed in their cardiac unit over the past three years that have radically changed the lifestyle of patients with serious cardiac conditions. ‘Over 1 000 people, including children, have benefitted from the advances in complex ablation procedures as the unit has become established as a centre of excellence, keeping pace with what is happening in the rest of the world’, he said. The first person to undergo cryoballoon ablation for atrial fibrillation was 35-yearold Hein Pieterse from Malmesbury, who suffered from paroxysmal atrial fibrillation. Dr Gopal mentioned that what touched him deeply was that although Hein is a young man, he had difficulty playing with his children because he was never sure when a chaotic heart rhythm might begin. He is now able to play golf, as well as romp with his children, with a regular heartbeat. The procedure was done 18 months ago and he has remained well. The cryoballoon ablation was the first operation of its kind performed in Africa. Extremely low-temperature ablation (effectively freezing) limits the activity of the heart tissue at the base of the pulmonary veins, which was triggering fibrillation by means of additional electrical signals.

Dr Razeen Gopal addressing the media.

The procedure involves insertion of two catheters (first a sheath and then the balloon inside it) from the groin through the femoral vein into the right atrium, then via small incisions, through the septum to the left atrium. The cryoballoon is placed at the base of one of the pulmonary veins. Dye provides a good contrast to show whether occlusion is complete, once the balloon has been inflated and before cooling. Freezing ablates the heart tissue in a circular band exactly where the malfunctioning cells are situated, thus blocking the faulty electrical signals. The procedure is repeated for the other pulmonary veins. As a surgeon who has experience with both radiofrequency (heat) ablation and cryotherapy, Dr Gopal explained that in his personal opinion, cryoballoon technology is safer because there is less perforation (so less healthy heart tissue is damaged), and the complication of induction of new rhythm disturbances is considerably reduced. Both methods are used in the unit as frozen balloon therapy is not suitable for all conditions. Although it is not possible to claim zero risk with any procedure, patients in the unit have had no serious complications and there have been no deaths. Dr Gopal attributes this success to the immense support of the dedicated cardiac team.

Children with life-threatening congenital cardiac conditions have also been treated. Dr Gopal stressed that drugs to regulate irregular heartbeat are always the first-line treatment but if this is unsuccessful, then ablation is considered. Sarah Sallie (15) of Woodstock had ventricular tachycardia and was unable to manage the five-minute walk to school without feeling exhausted. She now plays hockey and netball and recently completed a 10-km fun walk. Three children with Wolff–Parkinson–White syndrome, Geatwin Riddles (11) of Riversdale, Zanelle Francken (9) of Brackenfell and Braydon Kilroe (8) of East London, have undergone successful ablations to correct the accessory electrical pathway defect, and are now able to indulge in normal activities such as cricket, rugby and ballet. Another first for the unit was the implant of a quadripolar left ventricular pacemaker. Gerhardus van Zyl, who had advanced heart failure, was the first person in Africa to benefit from this most up-to-date procedure, and remains well almost a year later. Dr Gopal, who trained in Belgium and the UK, is actively involved in electrophysiology training in South Africa, as well as other African and Middle East countries. Anne Hahn

Dr Razeen Gopal with some of his patients. Back row: Hein Pieterse, Sarah Sallie and Gerhardus van Zyl. Front: Braydon Kilroe, Zanelle Francken and Geatwin Riddles.

REGISTRATION & ACCOMMODATION BOOKINGS OPEN

15th ANNUAL SA HEART CONGRESS SA Heart Congress 2014 will be held in Durban, from 16 – 19 October, with the central theme being ‘Bridging the Divide’. This is the divide that exists between current best practice – and the challenges encountered in implementing these ideals. All medical and allied professionals with an interest in cardiac health are warmly invited by the organising committee to attend.

For more information: EUROPA ORGANISATION AFRICA Tel +27 11 325 0020 Fax: +27 11 325 0028 or 0865 102 208 Email info@eoafrica.co.za

IN SOUTH AFRICA

at the SA Heart Association Congress

Bridging the Divide | 16 - 19 October 2014 International Convention Centre • Durban • South Africa

WEBSITE www.saheart.org/congress2014

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Advertorial Bayer’s Xarelto® is approved in South Africa across five additional indications Xarelto 15 and 20 for the prevention of stroke in patients with non-valvular atrial fibrillation, treatment of deep-vein thrombosis and pulmonary embolism, and the prevention of recurrent deep-vein thrombosis and pulmonary embolism. Johanesburg, South Africa, February 2014 Bayer HealthCare’s oral anticoagulant Xarelto® 15 and 20 (rivaroxaban) has been approved by the Medicines Control Council of South Africa for use in five new indications, making it the only new oral anticoagulant approved in six indications across the world. • New indications: 15 and 20 mg –– Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation –– Treatment of deep-vein thrombosis –– Prevention of recurrent deep-vein thrombosis –– Treatment of pulmonary embolism –– Prevention of recurrent pulmonary embolism. • Current indication: 10 mg –– The prevention of venous thromboembolism in patients undergoing major orthopaedic surgery of the lower limbs. ‘The approval in these new indications by the Medicines Control Council of South Africa marks the culmination of years of intensive research, and underscores Bayer’s innovative strength’, said Frans Labuschagne, CDH of Bayer HealthCare South Africa. ‘We are delighted to bring the benefits of rivaroxaban to patients and physicians in South Africa in need of a highly effective and convenient therapy against blood clots to prevent strokes and treat deep-vein thrombosis and pulmonary embolism.’ The approval of rivaroxaban for the prevention of atrial fibrillation-related stroke is based on the important clinical benefits demonstrated in ROCKET AF, a rigorous, double-blind global phase III study that compared once-daily rivaroxaban with warfarin in more than 14 000 patients. The results from the ROCKET AF trial were published in the New England Journal of Medicine (NEJM) in August 2011. The approval of rivaroxaban for the treatment of deep-vein thrombosis and pulmonary embolism, and the prevention of

recurrent deep-vein thrombosis and pulmonary embolism, following an acute deepvein thrombosis and pulmonary embolism, follows submission of data from the phase III EINSTEIN-DVT study, phase III EINSTEIN-PE study as well as data from the phase III EINSTEIN-Extension study. The EINSTEIN-DVT and EINSTEIN-Extension studies were published in the NEJM in December 2010 and the EINSTEIN-PE was published in NEJM in April 2012.

About venous and arterial thromboembolism Thrombosis is the formation of a blood clot inside a blood vessel, blocking a vein (venous thrombosis) or artery (arterial thrombosis). Venous and arterial thromboembolism (VAT) is caused when a clot becomes loose and is moved by the blood stream to obstruct another vessel, which can cause damage to vital organs. VAT encompasses two serious conditions: • Venous thromboembolism (VTE) occurs when part of a clot formed in a deep vein, for example in the leg (known as deep-vein thrombosis or DVT), is carried to another vessel which delivers blood to an organ. If this occurs in a vessel supplying blood to the lungs, it is known as a pulmonary embolism (PE), which can be rapidly fatal. • Arterial thromboembolism (ATE) occurs when oxygenated blood flow from the heart to another part of the body (via an artery) is interrupted by a blood clot. If this occurs in a vessel supplying the brain, this can lead to a stroke, which can be severely debilitating or fatal. If it occurs in a coronary artery, it can lead to acute coronary syndrome (ACS), a complication of coronary heart disease, which includes conditions such as myocardial infarction (heart attack) and unstable angina. VAT is an important cause of morbidity and mortality across a broad range of acute and chronic blood-clotting disorders and

requires active or preventative treatment to avoid potentially serious or fatal patient outcomes.

About atrial fibrillation Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with an increased risk of stroke, heart failure, dementia and death.1 AF confers a five-fold risk of stroke, and one in five of all strokes is attributed to this arrhythmia. Ischaemic strokes in association with AF are often fatal, and those patients who survive are left more disabled by their stroke and more likely to suffer a recurrence than patients with other causes of stroke. In consequence, the risk of death from AF-related stroke is doubled and the cost of care is increased 1.5-fold.2

About deep-vein thrombosis Venous thromboembolism is caused by the obstruction of a blood vessel by a blood clot. In the EU there are approximately 540 000 VTE-related deaths each year and it is estimated to be the third most common cardiovascular disease after myocardial infarction and stroke.3,4 Indeed, venous blood clots kill more people in Europe each year than breast cancer, prostate cancer, HIV/AIDS and transport accidents combined.3 DVT is the formation of a blood clot in a deep vein that partially or totally blocks the flow of blood. However, DVT can progress to become a potentially fatal PE if the blood clot breaks apart and travels to the lungs, ultimately blocking a blood vessel there. Even in the absence of a PE, DVT alone can have devastating and costly consequences such as postthrombotic syndrome and an increased risk of recurring blood clots, and therefore the achievement of treatment goals is critically important. The current treatment standard for DVT includes two

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drugs, low-molecular weight heparin administered by subcutaneous injection, followed by a vitamin K antagonist, a complex and often problematic regimen.5

About Xarelto® (rivaroxaban) Rivaroxaban is the most broadly indicated new oral anticoagulant and is marketed under the brand name Xarelto®. To date, Xarelto is now approved for six distinct uses in the venous–arterial thromboembolic space: • the prevention of stroke and systemic embolism in adult patients with nonvalvular AF • the treatment of DVT • the treatment of PE • the prevention of recurrent PE • the prevention of recurrent DVT • the prevention of VTE in patients undergoing major orthopaedic surgery of the lower limbs. Rivaroxaban is an oral anticoagulant that was discovered in Bayer HealthCare’s Wuppertal laboratories in Germany, and is being jointly developed by Bayer HealthCare and Janssen Research & Development, LLC (a Johnson & Johnson Company). It has a rapid onset of action with a predictable dose response and high bioavailability, no requirement for routine coagulation monitoring, as well as a limited potential for food and drug interactions. Anticoagulant medicines are potent therapies used to prevent or treat serious illnesses and potentially life-threatening conditions. Before initiating therapy with anticoagulant medicines, doctors should carefully assess the benefit and risk for the individual patient. Responsible use of Xarelto® is a very high priority for Bayer, and the company has developed a prescriber’s guide for doctors and a Xarelto® patient card for patients to support best practice. Prior to the new indications, Xarelto® was available for the prevention of VTE in patients undergoing major orthopaedic surgery of the lower limbs.6 Rivaroxaban is the only oral anticoagulant that has consistently demonstrated superior efficacy over enoxaparin for VTE prophylaxis in adult patients undergoing total hip or total knee replacement surgery.7

Rivaroxaban is approved in more than 120 countries worldwide and marketed by Bayer HealthCare in these indications, except in the US where it is marketed by Janssen Pharmaceuticals, Inc. In the US, rivaroxaban has been available since July 2011 for VTE prevention in adult patients following elective hip- or knee-replacement surgery. On 4 November 2013, rivaroxaban received further marketing approval to reduce the risk of stroke in patients with atrial fibrillation and for the treatment of DVT and PE in November 2012. In Europe, Xarelto has been available since 2008 for VTE prevention in adult patients following elective hip- or knee-replacement surgery. Rivaroxaban received further marketing approval in December 2009 for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and the treatment of DVT and prevention of recurrent DVT and pulmonary embolism following an acute DVT in adult patients. The treatment of PE followed in April 2012 and in May 2013 rivaroxaban 2.5 mg bid, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, for the prevention of atherothrombotic events after an acute coronary syndrome in adult patients with elevated cardiac biomarkers. In South Africa, Xarelto has been available since March 2010 for VTE prevention in adult patients undergoing major orthopaedic surgery of the lower limbs and today it is available for stroke prevention in non-valvular AF, treatment of PE and DVT and the prevention of recurrent PE and DVT. The extensive clinical trial programme supporting rivaroxaban makes it the most studied and widely published oral, direct factor Xa inhibitor. The studies, reported and ongoing, involve over 100 000 patients for the prevention and treatment of VAT disorders across a broad range of acute and chronic conditions, including stroke prevention in patients with atrial fibrillation, DVT/PE treatment and the prevention of recurrent DVT or PE, the secondary prevention of acute coronary syndrome, coronary or peripheral artery disease and chronic heart failure.

To learn more about thrombosis, please visit www.thrombosisadviser.com.

About Bayer HealthCare The Bayer group is a global enterprise with core competencies in the fields of healthcare, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR18.6 billion (2012), is one of the world’s leading innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 55 300 employees (31 December 2012) and is represented in more than 100 countries. More information is available at www.healthcare.bayer.com.

Contacts Anel Berning: Thrombosis Marketing Manager; anel.berning@bayer.com Lionel Dobell: Xarelto Product Manager; lionel.dobell@bayer.com Dr Naren Jairam: Xarelto Medical Advisor; naren.jairam@bayer.com 1.

2. 3. 4. 5.

6. 7.

Stefansdottir H, et al. Trends in the incidence and prevalence of atrial fibrillation in Iceland and future projections. Europace 2011; 13: 1110–1117 CammAJ-2010-Eur Heart J-v31p2369-MK. CohenAT-2007-ThrombHaemost-v98p756MK. Naess_JThrombHaemost_2007. Ansell J. 2004. Chest 2004 Sep;126(3 Suppl):204S-233S. ... American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy. Xarelto 10 South African Package Insert. Turpie AGG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty: Pooled analysis of four studies. Thromb Haemost 2011; 105: 444–453.

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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 deepvein 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.GM.10.2013.0821

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Forward-looking statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forwardlooking statements or to conform them to future events or developments.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 2, March/April 2014

Case Report Unusual perforation of the left ventricle during radiofrequency catheter ablation for ventricular tachycardia Jin-Tao Wu, Jian-Zeng Dong Case report

Abstract Cardiac perforation during catheter-based radiofrequency ablation procedures is relatively uncommon but potentially fatal if tamponade ensues. This complication should be promptly recognised. We present a case of incomplete perforation of the left ventricle with transient ST-segment elevation in leads V1 to V3 during catheter ablation of ventricular tachycardia. Complete perforation was avoided because of rapid diagnosis by the detection of subtle changes in electrode potentials and by performing angiography via an externally irrigated ablation catheter lumen. Keywords: cardiac perforation, tamponade, left ventricle, catheter ablation, ventricular tachycardia Submitted 27/3/13, accepted 9/12/13 Cardiovasc J Afr 2014; 25: e1–e4

www.cvja.co.za

DOI: 10.5830/CVJA-2013-087

Catheter-based radiofrequency ablation procedures are currently being performed in invasive laboratories with increasing frequency. An increased incidence of catheter-related complications may be encountered.1 One potentially fatal complication is acute haemorrhagic tamponade secondary to inadvertent cardiac perforation. Cardiac perforation should be promptly recognised to avoid subsequent tamponade. We present a case of incomplete perforation of the left ventricle with transient ST-segment elevation in leads V1 to V3 during catheter ablation of ventricular tachycardia (VT). Complete perforation was avoided because of rapid diagnosis by the detection of subtle changes in electrode potentials and by performing angiography via an externally irrigated ablation catheter lumen. This case study shows that physicians should be aware of the need to promptly recognise cardiac perforation.

Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, China Jin-Tao Wu, MD

Department of Cardiology, Centre for Atrial Fibrillation, Beijing Anzhen Hospital, Capital Medical University, Beijing, China Jian-Zeng Dong, MD, jz_d2007@aliyun.com

A 60-year-old woman with a history of drug-refractory paroxysmal VT underwent two unsuccessful catheter ablations at two different institutions nine years and one year previously. She was then referred to our centre for VT ablation. Her physical examination and chest X-ray were normal. Transthoracic echocardiography showed normal anatomical structure of the heart and left ventricular ejection fraction (60%). Arrhythmogenic right ventricular cardiomyopathy (ARVC) was excluded by myocardial magnetic resonance imaging. Percutaneous coronary artery angiography was performed before the ablation procedure and coronary artery disease was excluded. An electrophysiological study was then performed. Left subclavian vein access was obtained and a steerable 10-pole catheter (Inquiry™, IBI, St. Jude Medical, St Paul, MN, USA) was positioned in the coronary sinus. One quadripolar catheter (Cordis, Biosense Webster, Diamond Bar, CA, USA) was positioned in the right ventricle via left femoral vein access and another quadripolar catheter was positioned across the tricuspid valve to record the His bundle electrogram via right femoral vein access. Paroxysmal supraventricular tachycardia was excluded. The geometry of the right and left ventricle was reconstructed using the CARTO system with a 3.5-mm tip saline-irrigated ablation catheter (ThermoCool NaviStar, Biosense Webster). VT was induced by stimulation of the ablation catheter in the right ventricle (Fig. 1A, B). However, the tachycardia persisted for less than one minute before termination, and it was not induced again after termination. Pace mapping was then used first in the right ventricle, and then in the left. During mapping in the left ventricular apex, the heart at first failed to follow the impulse, and then the stimulation signal suddenly disappeared and the potential in the distal ablation catheter was significantly reduced (Fig. 2). Immediately after these findings were recognised, the catheter was slightly withdrawn. Subsequently, a stimulus signal occurred again. However, the ventricle still failed to respond to the stimulus signal (Fig. 2). Almost simultaneously, the patient complained of mild chest pain. A small amount of diluted contrast agent was then injected via the ablation catheter lumen to identify the location of the catheter tip. Angiography showed that the catheter had perforated the left ventricular apex, with the tip lying immediately under the epicardium (Fig. 3A, B). Subsequently, the ST segment in leads V1 to V3 was elevated (Fig. 4A), similar to what occurs in patients presenting with anteroseptal myocardial infarction. However, there was no significant change in blood pressure and heart rate in the patient and she did not complain of discomfort or mild chest pain.

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Echocardiography showed no pericardial effusion. Despite these findings, the operation was terminated. Elevated ST segment in leads V1 to V3 gradually decreased to normal after approximately 20 minutes (Fig. 4B). Echocardiography after one and 24 hours still showed no pericardial effusion.

Discussion The fatal complication of acute haemorrhagic tamponade did not occur in the patient because we promptly recognised cardiac perforation. One therefore should be cautious when performing an ablation or when a catheter is mapping the left ventricular apex, and too much tension should be avoided in the catheter. Subtle changes in electrode potentials should be promptly recognised to rapidly detect anomalies. If the heart suddenly fails to follow an impulse or a potential in the distal electrode of the catheter is significantly abruptly A

Fig. 1. E lectrocardiogram and intracardiac recordings during tachycardia. (A) Electrocardiogram showing tachycardia with a wide QRS. (B) Intracardiac recordings showing ventriculo-atrial dissociation. CS = coronary sinus; ABL = ablation, d, distal, p, proximal.

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reduced, it should be suspected that the catheter has probably penetrated the heart wall and the location of the catheter should be adjusted as soon as possible. Additionally, if an externally irrigated radiofrequency ablation catheter is used, a diluted contrast agent can be injected via the catheter lumen to ensure the location of the catheter tip. If the contrast agent rapidly spreads along the edge of the heart in angiography, the possibility that it has gone into the pericardial cavity should be considered, and the tip of the catheter might also have penetrated into the heart wall. The contrast agent did not rapidly spread in our patient, but slowly moved into a small region along the edge of the heart from the tip of the ablation electrode. These findings suggested that the catheter had caused incomplete perforation of the ventricle, with the tip lying immediately under the epicardium. Although there was incomplete perforation in the ventricular apex, the complication of acute tamponade did not occur in the patient under high-pressure conditions generated within that chamber during systole. This may be explained by the anatomical structure of the ventricular apex and the manner in which the muscle at the apex contracts. Most hearts have one small point at the apex of the left ventricle at which the thickness of the myocardium is 3 mm or less.2-4 Furthermore, the thickness of the left ventricular apical thin point does not significantly change at end-diastole and end-systole.5 In a previous study by Bradfield et al., left ventricular myocardial thickness increased rapidly on each side of the apical thin point, so that when measured 5 mm away on one side, the myocardial thickness was already 3.7 Âą 2.3 mm on the thinner side and 7.9 Âą 6.3 mm on the thicker side.2 The thickness of the epicardial fat at the apex was between 4.5 and 4.7 mm,2 and it was almost always thicker than the thickness of the myocardium

Fig. 2. R ecordings of potentials in the ablation catheter and an electrocardiogram during pacing mapping in the left ventricular apex. The recordings of potentials in the ablation catheter show that the stimulation signal (arrow) has disappeared and the potential (asterisk) in the proximal electrode of the catheter is significantly reduced. After the catheter was slightly withdrawn, the stimulus signal occurred again. However, the ventricle still failed to respond to the stimulus signal. ABL = ablation, d, distal, p, proximal.

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Fig. 3. F luoroscopic images of the site of the catheter that had perforated the left ventricle. (A, B) RAO and LAO projections showing the site of the catheter during injection of contrast agent via the ablation catheter lumen and just before injection. ABL = ablation.

at the apical thin point, but the fat provided no grip for a catheter. Therefore, it is not surprising that the catheter easily penetrated

the ventricular wall at the apex. The extremely thin strands of myocardial muscle at this site are unlikely to withstand the pressure generated within that chamber during systole. The whorled arrangement of the muscle fibres6 allows the narrow funnel to close off at the onset of systole, so that if the left ventricular apical thin part has an incomplete perforation, it is protected from the high pressure generated at the peak of contraction. In addition, our patient presented with transient ST-segment elevation in leads V1 to V3 following the catheter penetrating the left ventricular apex, which was probably associated with acute myocardial injury at the antero-apical region or vasospasm of the distal left anterior descending artery.7,8 This possibility is supported by the following aspects. First, according to fluoroscopy, the location of perforation of the ventricle was the antero-apical region near the anterior interventricular groove within which the left anterior descending artery runs. Second, previous studies8 have shown that ST-segment elevation or a Q wave in leads V1 to V3 is correlated with an antero-apical infarct instead of the traditionally termed anteroseptal acute myocardial infarction, and that the culprit narrowing is more frequently found in the mid to distal left anterior descending artery.

Conclusion Fig. 4. Electrocardiogram recording of transient ST-segment elevation in leads V1 to V3. (A) ST-segment elevation in leads V1 to V3 following the catheter penetrating the left ventricular apex. (B) The elevated ST segment in leads V1 to V3 was decreased to normal after approximately 20 minutes.

Our case highlights the importance of promptly recognising cardiac perforation. The detection of subtle changes in electrode potentials and performing angiography via an externally irrigated ablation catheter lumen may be useful for rapid diagnosis.

References 1.

Friedrich SP, Berman AD, Baim DS, Diver DJ. Myocardial perforation

2. 3.

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in the cardiac catheterization laboratory: incidence, presentation, diagnosis, and management. Cathet Cardiovasc Diagn 1994; 32: 99–107. (PMID: 8062380). Bradfield JW, Beck G, Vecht RJ. Left ventricular apical thin point. Br Heart J 1977; 39: 806–809. (PMID: 884031). Johnson KM, Johnson HE, Dowe DA. Left ventricular apical thinning as normal anatomy. J Comput Assist Tomogr 2009; 33: 334–337. (PMID: 19478623). Ferencik M, Abbara S, Hoffmann U, Cury RC, Brady TJ, Achenbach S. Left ventricular thin-point detection using multidetector spiral computed tomography. Am J Cardiol 2004; 93: 949–951. (PMID: 15050509). Baosheng G, Jun Y, Xiaona Y, Bing H, Ying Z, Shuxi G, et al. Left

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ventricular apical thin point viewed with two-dimensional echocardiography. Echocardiography 2009; 26: 988-990.(PMID: 19968688). Fox CC, Hutchins GM. The architecture of the human ventricular myocardium. Johns Hopkins Med J 1972; 130: 289–299. (PMID: 5018421). Shalev Y, Fogelman R, Oettinger M, Caspi A. Does the electrocardiographic pattern of “anteroseptal” myocardial infarction correlate with the anatomic location of myocardial injury? Am J Cardiol 1995; 75: 763–766. (PMID: 7717275). Bogaty P, Boyer L, Rousseau L, Arsenault M. Is anteroseptal myocardial infarction an appropriate term? Am J Med 2002; 113: 37–41. (PMID: 12106621).

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PUBLISHED ONLINE: • Perforation during radiofrequency catheter ablation