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• RV function and hepatosteatosis in non-alcoholic fatty liver disease • Left atrial function and conduction in Maras powder users and smokers • Postoperative atrial fibrillation with left atrial myxoma • Sickle cell trait and chronic kidney disease in Congolese patients • Clinical outcomes of IABP during coronary artery bypass surgery • Anaemia among heart failure patients at Brazzaville Hospital • Antibiotic recipe for arrhythmic disaster
Perindopril has proven outcomes in: • Coronary Artery Disease1 • Acute Myocardial Infarction2 • Stroke3 • End-stage Renal Failure4
PUBLISHED ONLINE • Unusual cause of large fibrinous pericardial effusion
Pearinda 4. Each tablet contains 4 mg perindopril tert-butylamine. Reg. No.: RSA S3 41/7.1.3/0649. NAM NS2 10/7.1.3/0476. Pearinda 8. Each tablet contains 8 mg perindopril tert-butylamine. Reg. No.: RSA S3 41/7.1.3/0650. NAM NS2 10/7.1.3/0477. For full prescribing information, refer to the package insert approved by the Medicines Control Council, April 2009. Pearinda Plus 4. Each tablet contains 4 mg perindopril tert-butylamine and 1,25 mg indapamide. Reg. No.: RSA S3 41/7.1.3/0633. NAM NS2 10/7.1.3/0611. For full prescribing information, refer to the package insert approved by the Medicines Control Council, April 2010. 1) The EUROPA study Investigators. “Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study)”. The Lancet 2003;362:782788. 2) The PREAMI study Investigators. “Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodelling and clinical outcome. Results of the randomized perindopril and remodelling in elderly with acute myocardial infarction (PREAMI) study”. Arch Intern Med 2006;166:659-666. 3) PROGRESS Collaborative Group. “Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack”. The Lancet 2001;358:1033-41. 4) Guerin AP, et al. “Impact of Aortic Stiffness Attenuation on Survival of Patients in End-Stage Renal Failure”. Circulation 2001;103;987-992. 5) Department of Health website http//www.doh.gov.za – Accessed on 26/03/2015. PAE178/06/2015.
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ISSN 1995-1892 (print) ISSN 1680-0745 (online)
Vol 26, No 3, MAY/JUNE 2015
CONTENTS
Cardiovascular Journal of Africa 103
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From the Editor’s Desk P Commerford
Cardiovascular Topics 104
Comparison of MMF with prednisone in terms of rejection and duration of activity of transplant in rabbits that underwent retroperitoneal heterotopic heart transplantation F Aygün • D Efe • K Durgut
109 Right ventricular function and its relationship with grade of hepatosteatosis in non-alcoholic fatty liver disease A Bekler • E Gazi • G Erbag • E Binnetoglu • A Barutcu • H Sen • A Temiz • B Altun 114 Evaluation of left atrial mechanical function and atrial conduction abnormalities in Maras powder (smokeless tobacco) users and smokers A Akcay • MN Aydin • G Acar • B Mese • M Çetin • M Akgungo • E Cabioglu • O Bozoglan • İ Ardic • M Çakıcı 120 Postoperative atrial fibrillation in patients with left atrial myxoma M Sahin • K Tigen • C Dundar • B Ozben • G Alici • S Demir • ME Kalkan • B Ozkan 125 Sickle cell trait is not associated with chronic kidney disease in adult Congolese patients: a clinic-based, cross-sectional study K Mukendi • FB Lepira • JR Makulo • KE Sumaili • PK Kayembe • MN Nseka 130 Analysis of clinical outcomes of intra-aortic balloon pump during coronary artery bypass surgery G Yumun • U Aydin • Y Ata • F Toktaş • AA Pala • AF Ozyazicioglu • T Turk • S Yavuz 134
Can empirical hypertonic saline or sodium bicarbonate treatment prevent the development of cardiotoxicity during serious amitriptyline poisoning? Experimental research MS Paksu • H Zengin • F Ilkaya • S Paksu • H Guzel • D Ucar • A Uzun • H Alacam • L Duran • N Murat • A Guzel
INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET
Editors
SUBJECT Editors
Editorial Board
Editor in Chief (South Africa) Prof Pat Commerford
Nuclear Medicine and Imaging DR MM SATHEKGE
prof PA Brink Experimental & Laboratory Cardiology
PROF A LOCHNER Biochemistry/Laboratory Science
PROF R DELPORT Chemical Pathology
PROF BM MAYOSI Chronic Rheumatic Heart Disease
Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT
Heart Failure Dr g visagie Paediatric dr s brown Paediatric Surgery Dr Darshan Reddy Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle
PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure
International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology)
PROF DP NAIDOO Echocardiography
DR GEORGE A MENSAH USA (General Cardiology)
PROF B RAYNER Hypertension/Society
PROF WILLIAM NELSON USA (Electrocardiology)
PROF MM SATHEKGE Nuclear Medicine/Society PROF J KER (SEN) Hypertension, Cardiomyopathy, PROF YK SEEDAT Cardiovascular Physiology Diabetes & Hypertension
DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)
DR J LAWRENSON Paediatric Heart Disease
PROF ERNST VON SCHWARZ USA (Interventional Cardiology)
PROF H DU T THERON Invasive Cardiology
PROF PETER SCHWARTZ Italy (Dysrhythmias)
140 Prevalence of anaemia among patients with heart failure at the Brazzaville University Hospital MS Ikama • BM Nsitou • I Kocko • NS Mongo • G Kimbally-Kaky • JL Nkoua
Vol 26, No 3, MAY/JUNE 2015
CONTENTS
Case Report 143 An antibiotic recipe for an arrhythmic disaster K McCutcheon • P Manga
drug trends in cardiology 146 AfricaPCR 2015, a brief report back 148 South African hospital the first in the Middle East, Africa, central Asia and Turkey to implant the world’s smallest, minimally invasive cardiac pacemaker
PUBLISHED ONLINE (Available on www.cvja.co.za, Pubmed and in Pubmed Central) Case Reports
e1 ST-elevation myocardial infarction following systemic inflammatory response syndrome Y Tan • Y Tu • D Tian • C Li • J-K Zhong • Z-G Guo e4 Treatment of right ventricular perforation during percutaneous coronary intervention G Gu • J Zhang • W Cui e7 An unusual cause of a large fibrinous pericardial effusion NC Tembani-Munyandu • R Makunike-Mutasa • L Katsidzira • A Chinogureyi e11 A fatal complication after repair of post-infarction ventricular septal rupture: heparininduced thrombocytopenia with thrombosis Y Nazli • N Colak • B Demircelik • MF Alpay • O Cakir • K Cagli
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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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103
From the Editor’s Desk A patient presenting with a large pericardial effusion of uncertain aetiology is a relatively common clinical problem facing practitioners in Africa. The optimal management of such patients, particularly in resource-constrained environments, remains unclear. Tuberculosis is generally considered to be the most important likely cause, particularly if numerous fibrin strands are seen to be present on echocardiography, and many practitioners would advocate the immediate institution of treatment for this disease under these circumstances. The issue is far from clear however. Treatment for tuberculosis, in addition to its obvious benefits, carries some risk of serious adverse events but it also has significant ‘minor’ side effects that are thoroughly unpleasant for patients. In addition, there is the risk of missing other treatable causes of such an effusion. While acknowledging that such a risk is real, many would argue it is relatively unimportant, given the fact that most alternative diagnoses are neither treatable nor curable. The counter-argument is that detailed and comprehensive investigation of all pericardial effusions may enhance diagnostic certainty and identify the few patients who may benefit from alternative treatment. The problem is that detailed investigations, including pericardiocentesis, advanced imaging studies or open biopsy carry their own risks, are often not available and if they are, the results of such investigations are largely untested in terms of diagnostic sensitivity and specificity. The case report of Tembani-Munyandu and colleagues (online, page e7) serves to highlight this problem. There is a great need for a properly structured, adequately powered study to evaluate the risks and benefits of instituting empirical therapy for tuberculosis, compared to aspiration and detailed investigation in patients with large pericardial effusions in Africa. Such a study would be complex, needing to recruit a range of patients, including persons both HIV positive and negative, but given the scope of the problem and the importance of the question being addressed, it is essential that it be conducted. The effects of liver disease on cardiac structure and function have been argued and discussed for decades with varied outcomes. Bekler and colleagues (page 110) demonstrated that patients with non-alcoholic fatty liver disease (NALFD) had right ventricular diastolic dysfunction. It is not clear whether the authors considered that these abnormalities of cardiac function were directly related to the NALFD or to accompanying components of the metabolic syndrome. Any therapeutic intervention that may be contemplated will require clarity in this regard. In hospital-based practice, it is alarming to see just how often QT prolongation on the ECG is ignored, missed and/or under-
Professor PJ Commerford
reported, and knowledge of the hazards of administering agents prolonging the QT interval and situations where such agents may be harmful is often limited. The case report of McCuthcheon and Manga (page 145) serves to draw attention to the use of commonly used drugs, in this case erythromycin, that can cause lethal arrhythmias in predisposed individuals when they are used inappropriately. Sahin and colleagues (page 121) report on the frequency of atrial fibrillation after surgery for left atrial myxoma. Not surprisingly, age proved to be one of the predictors of atrial fibrillation in this situation, as it does in all others. The mechanism/s of the powerful effects of age on the development of atrial fibrillation are complex and not fully explained but an age-associated relationship with the development of atrial fibrillation is not unexpected. Pat Commerford Editor-in-Chief
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Cardiovascular Topics Comparison of MMF with prednisone in terms of rejection and duration of activity of transplant in rabbits that underwent retroperitoneal heterotopic heart transplantation Fatih Aygün, Duran Efe, Kadir Durgut
Abstract Aim: In this study, mycophenolate mofetil (MMF) and methylprednisolone (MP) were compared in terms of rejection and duration of activity of the transplant in New Zealand rabbits that underwent retroperitoneal heart transplantation. Methods: Retroperitoneal heart transplantation was performed in New Zealand white rabbits. The animals were divided into two groups. MMF group (group 1) (10 donors, 10 recipients): 12.5 mg/kg MMF was administered orally for two days prior to the surgery; MP group (group 2) (nine donors, nine recipients): 2 mg/kg MP was administered intramuscularly for two days prior to the surgery. After the operation, we waited until all motor activity in the transplanted heart had stopped. The transplant was then removed and the recipient was sacrificed. A donor in the MP group was excluded since it died before the motor activity had stopped. Results: No statistically significant difference was found between the groups in terms of rejection score (p = 0.865). However, duration of motor activity was found to be statistically significantly longer in the MMF group, compared to the MP group (p = 0.013). Conclusion: In this experimental study, MMF was similar to MP in terms of rejection but had better efficacy in terms of duration of motor activity of the transplant. Keywords: heart transplantation, mycophenolate mofetil, methylprednisolone Submitted 21/3/14, accepted 28/5/14 Cardiovasc J Afr 2015; 26: 104–108
www.cvja.co.za
DOI: 10.5830/CVJA-2014-032
Department of Cardiovascular Surgery, Faculty of Medicine, Mevlana University, Konya, Turkey Fatih Aygün, MD, fatihaygun@ttmail.com
Department of Radiology, Faculty of Medicine, Mevlana University, Konya, Turkey Duran Efe, MD
Department of Cardiovascular Surgery, Faculty of Medicine, Erbakan University, Konya, Turkey Kadir Durgut, MD
Besides the bicaval anastomosis technique developed in recent years, orthotopic heart transplantation has been successfully performed in the treatment of thousands of patients with heart failure using the surgical technique defined in 1960 by Lower and Shumway.1 Heart transplantation has become more common along with advances in preserving organs, illumination of the immunological basis of transplantation, and the constitution of organ transplantation centres to obtain and share organs. The results of experienced centres are similar because heart transplantation has not developed substantially since the 1990s.2 Basic problems in the last decade include long waiting lists and extended waiting periods, increased numbers of emergent and pre-emptor patients, and prolonged duration of donor ischaemia. Today, although one-year life expectancy has been reported to be higher than 85%, and 10-year life expectancy 50–60% in the majority of heart surgery centres, it is estimated that the parametric curve will rise to 75% in the next decade along with advances made in recent years.3-5 Survival after heart transplantation has been extended and substantial progress has been made in heart transplantation practices along with the discovery of immunosuppressive agents. However, the side effects of these immunosuppressive agents and the presence of coronary lesions in the transplanted graft due to extended survival times have become a problem. Reduction in the number of side effects and prevention of the development of vascular lesions in transplanted hearts have been the target of new-generation immunosuppressive agents. Mycophenolate mofetil (MMF) is under investigation in terms of its effect on vascular lesions and survival in transplanted hearts, as well as non-cardiac transplantation and paediatric cardiac surgery.1,6 In the present study, the effect of MMF versus methylprednisolone (MP) on acute rejection and duration of motor activity in the transplant was investigated in a rabbit model of retroperitoneal heterotopic heart transplantation.
Methods In this study, 38 New Zealand rabbits weighing between 2 550 and 3 200 g were used. The study was conducted in accordance with the ethical committee directive for experimental animals of the Faculty of Medicine, Selçuk University, Meram and the Experimental Medicine Research and Practice Centre, which was prepared based on the Universal Declaration on Animal Welfare, European Convention for the Protection of Vertebrate Animals Used for Experimental or Other Scientific Purposes,
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and The Guide for the Care and Use of Laboratory Animals. In addition, the study was conducted with the approval of the ethics committee. Two groups were created; the MMF group: group 1 (donors = 10, recipients = 10) and the MP group: group 2 (donors = nine, recipients = nine). Weights of the rabbits in the MMF group varied between 2 550 and 3 200 g, whereas the weights in the MP group varied between 2 560 and 3 150 g. The two groups were divided into two subgroups, donor and recipient, for retroperitoneal heterotopic heart transplantation. The subjects of the MP recipient group received 10 mg/kg/day methylprednisolone intramuscularly for two days prior to the surgery (except for the day of surgery). Subjects of the MMF recipient group received 12.5 mg/kg/day orally via the gavage method for two days prior to the surgery (except for the day of surgery). Intramuscular ketamine hydrochloride (50 mg/kg) (Ketalar®, Phizer) and xylazine (10 mg/kg) (Xylazinbio® 2%, Bioveta) were administered to the animals. The dose was repeated as a cocktail containing ketamine (25 mg/kg) and xylazine (5 mg/kg) when necessary. After anaesthesia, the animals were left to breathe spontaneously and were provided with nasal oxygen (O2) support at a dose of 2 l/min. An intravenous catheter (24-gauge) was placed in each recipient through the marginal ear vein. Over the course of the procedure, 0.9% sodium chloride (NaCl) solution was infused at a speed of 4 ml/kg/hour. A catheter (22-gauge) was placed into the ear artery to monitor blood pressure. The anterior thoracic area and anterior abdominal wall of the recipient was shaved, electrocardiography was performed with electrodes placed on the anterior thoracic wall, and blood pressure was monitored by connecting the catheter placed into the ear artery to the pressure transducer (Mennen Medical Inc, Mercury, Revohot, Israel). The recipient was continuously monitored during abdominal exploration before the retroperitoneal heterotopic heart transplantation, during transplantation, and after transplantation. Systolic and diastolic blood pressures of the recipients in both groups were kept at the same level as pre-operative measurements. Positive inotropic support was provided as required. The recipient was placed on the operation table in a supine position. We planned to monitor the recipients for a maximum of four hours and then sacrifice. The abdomen was accessed through a median abdominal incision after monitoring and stabilising the recipients. The retroperitoneum was opened and the inferior vena cava and abdominal aorta were exposed. These two vascular configurations were explored and reversed with the use of tapes. Anticoagulation was provided with 100 U/kg of standard heparin (Nevparin®, Mustafa, Nevzat). Meanwhile, the donor subject was stabilised in a supine position and anticoagulation was provided with 100 U/kg of standard heparin. After sternotomy the donor heart was excised and crystalloid cardioplegia was administered through the aortic root. Four mini vascular clamps were placed in the recipient’s abdominal aorta and inferior vena cava to prevent blood flow to the anastomoses. Cold Hospira’s cardioplegia solution (Plegysol®, Meditera) was given through the ascending aorta of the donor’s heart according to the weight of the donor and at the appropriate pressure as soon as the vascular configurations were cut. The time between cutting the ascending aorta of the donor heart and administration of cardioplegia did not exceed 30 seconds in any of the groups. Cardioplegia pressure was kept at 15 mmHg.
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After the heart became plegic, the superior vena cava (SVC), inferior vena cava (IVC), and the left atrium were ligatured. The total duration of ischaemia was between 30 and 35 minutes in all subjects, and the second cold crystalloid cardioplegia was administered at the 20th minute. The target was perfusion of the whole heart and passive working of the left heart, whereas the working right heart was filled with blood. Anastomosis was performed between the ascending aorta of the transplant and the abdominal aorta of the recipient, and between the pulmonary artery of the transplant and the IVC of the recipient. Anastomosis was performed using 7/0 polypropylene suturing material. After transplantation, the vascular clamps in the abdominal aorta and the IVC of the recipient were removed (Fig. 1). The transplant worked spontaneously in sinus rhythm in all experimental groups. The heart, which was taken from the donor and retroperitoneally implanted in the recipient, functioned for between 2.5 and four hours in all subjects. Systolic and diastolic blood pressures of the recipients were kept the same as pre-operative values as far as possible. Dopamine hydrochloride (Dopamine®, Fresenius) and dobutamine (Dobutabag®, Baxter) were used as positive inotropic support and isotonic 0.9% NaCl solution was used for fluid replacement. After the abdominal aorta and IVC of the recipient were clamped, the heart implanted in the recipient was excised from the anastomosis lines when it stopped functioning. All recipient subjects were sacrificed at the end of a minimum of 2.5 hours and a maximum of four hours after the activity of the transplant had stopped, and the transplant was removed. Sacrificing was performed using 10% intracardiac formaldehyde after ketamine (50 mg/kg) and xylazine (10 mg/kg) administration via the intramuscular route.
Histopathological evaluation The excised transplant was put into 10% neutral formaldehyde solution and stored until examination. Sections were made of the endocardium and myocardium of the right ventricle. After staining with haematoxylin and eosin, the pathologist from the Department of Pathology, SUM Faculty of Medicine, who was blinded to the groups, examined four different areas under
Fig. 1. The heart was transplanted into the retroperitoneal area (arrow).
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Fig. 2. Focal or diffuse but sparse lymphocytic infiltration, grade 1.
Fig. 4. Multifocal aggressive lymphocytic infiltration, grade 3.
a light microscope. Sections were also taken from the rejected transplants of the recipients, stained with haematoxylin and eosin dye and examined under the light microscope. Histological findings on the endomyocardial sections were graded on the basis of the endomyocardial biopsy grading scheme, which is standardised by the International Society for Heart and Lung Transplantation (ISHLT). Grading was defined as follows: no lymphocytic infiltration: grade 0; focal or diffuse but rare lymphocytic infiltration: grade 1 (Fig. 2); unifocal aggressive lymphocyte infiltration: grade 2 (Fig. 3); multifocal aggressive lymphocyte infiltration: grade 3 (Fig. 4); diffuse aggressive polymorph infiltration: grade 4 (Fig. 5).
found to be a minimum grade 1 and maximum grade 4. Duration of motor activity of the transplants and biopsy scoring of the groups are shown in Table 1.
Statistical analysis Data were transferred into the computer. Statistical analyses were done using the SPSS program (SPSS Inc, Chicago, IL, USA). Since the number of subjects in the groups was not equal, they were compared by the Mann–Whitney U-test. Level of statistical significance was considered to be p < 0.05.
Results A total of 19 pairs of New Zealand rabbits were used in this study. The weight of the study subjects was a minimum of 2 550 g and a maximum of 3 200 g. Duration of motor activity after transplant was determined to be a minimum of 2.5 hours and a maximum of four hours in all subjects. Biopsy scoring was
Fig. 3. A focus of aggressive lymphocytic infiltration, grade 2.
Discussion In this study, a total of 19 transplantations were performed, of which 10 were in the MMF and nine in the MP group. We aimed to compare MMF, an immunosuppressive agent, with MP, a steroid. Either MMF or MP was administered to the recipients for two days prior to the surgery. The immunosuppressive agent was not given to the subjects on the day of surgery. The transplant, which was placed retroperitoneally, was excised after its motor activity had completely stopped. It was observed that duration of motor activity of the transplant was statistically significantly longer in the MMF group. No statistically significant difference was observed between the MMF and MP groups in terms of transplant rejection. Table 1. Duration of motor activity of the transplants, and biopsy scoring of the groups Group 1 (MMF) Group 2 (MP) (recipient) (recipient) (n = 10) (n = 9) Motor activating time (h) 3.20 ± 0.42 2.77 ± 0.26 Biopsy scoring 2.80 ± 1.23 2.78 ± 0.83 Biopsy scoring (grade) 2761 ± 196.1 2868.3 ± 202.2 *p-value was presented as a result of Mann–Whitney U-test.
p-value 0.013* 0.865*
Fig. 5. Diffuse aggressive polymorph infiltration, grade 4.
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Heart transplantation has improved over the last 30 years and has gradually become of increasing importance in the treatment of end-stage heart failure. Survival after transplantation has been extended with the use of immunosuppressive agents. Opportunistic infections, rejection and coronary vasculopathy in the cardiac allograft have led to the development of new immunosuppressive agents.7 Cyclosporine and tacrolimus have similar efficacy in protection against acute rejection in heart transplantation. However, they have similar nephrotoxicity and cardiovascular adverse events as well. Cardiac allograft coronary vasculopathy (CAV) is the best predictor of mortality five years after transplantation and accounts for 31% of deaths. Keogh found that neither cyclosporine nor tacralimus prevented the development of CAV, however, MMF did prevent CAV.8 With the use of immunosuppressive agents since the early 1980s, a dramatic improvement has been observed in the survival of patients who underwent solid organ transplantation. Understanding the immune mechanism causing rejection has led to the development of novel immunosuppressive agents, which are more immune specific and less toxic, and have better pharmacokinetic and higher rejection-preventing efficacy. MMF is an organosynthetic agent. Randomised, non-blind studies have demonstrated that MMF prevented acute rejection in patients who underwent kidney, heart and liver transplantation, and it could be used in the treatment of refractory rejection. Different from tacrolimus and cyclosporine, MMF does not cause neurotoxicity or nephrotoxicity. Compared with other agents, MMF inhibits B lymphocyte proliferation and reduces smooth muscle cell proliferation, and consequently may play a key role in the treatment of chronic rejection. Studies on the use of MMF in preventing acute rejection in patients who undergo heart transplantation are ongoing.9 A study presented by Roche Pharmaceutical Company at the subcommittee meeting of the Antiviral Drug Advisory Committee (ADAC) comprised 650 heart transplantations, in which the combination of MMF, cyclosporine and steroids was used in 289 cases. The study found that MMF was safe and effective for the prevention of rejection in patients who underwent heart transplantation.10 As a result, the US Food and Drug Administration (FDA) has approved the extension of indications for MMF use for the prevention of organ rejection in patients undergoing heart transplantation. Multiple drug therapy based on cyclosporine, steroids and azathioprine has improved the outcomes of solid organ transplantation. However, acute rejection episodes are not less common and influence short- and long-term prognosis after heart transplantation. The benefits of these agents are limited by their side effects, such as bone marrow suppression and renal dysfunction. Mathieu et al.11 retrospectively evaluated clinical and laboratory analyses obtained from 31 consecutive patients who underwent heart transplantation between 1996 and 1998 in the Montreal Heart Institute. It was found that the rejection-free period was significantly longer in the MMF group, the infectionfree period was similar, and there was no difference between the groups in terms of infectious agents. Initial studies recommended MMF because it reduces T and B lymphocyte proliferation and may decrease the frequency of acute rejection after renal transplantation. A randomised, double-blind, multi-centre, placebo-controlled study compared
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the reliability and efficacy of MMF. Result showed MMF was well-tolerated and significantly reduced the incidence of rejection in the six-month period after transplantation.12 Dipchand et al.13 retrospectively investigated patients who had undergone paediatric heart transplantation in the Hospital for Sick Children in Toronto, Canada. Of the 21 paediatric cases who received MMF, 12 were boys and nine were girls. Indication for transplantation was complex congenital heart disease in 14, cardiomyopathy in six and acute viral myocarditis in one case. The results of MMF were found to be encouraging for recipients of paediatric heart transplantation. Rose et al.14 conducted a double-blind study comprising 86 patients from three centres. The control group consisted of 650 patients from 28 centres. The patients randomly received cyclosporine (CYC) and steroids in addition to MMF or azathioprine (AZA). The levels of anti-HLA antibodies and anti-vimentin antibodies of the patients were measured using enzyme-linked immunoassay. The basis of the study was that vimentin is the major protein of anti-endothelial antibodies and the production of anti-vimentin antibodies long term is an independent risk factor for post-transplant coronary artery disease. Mean annual anti-vimentin antibody titres were found to be significantly higher in the AZA than the MMF group. Pharmacodynamics plays an important role in monitoring immunosuppression therapy. Previous studies have demonstrated significant correlation between pharmacodynamics, dose, and graft histology. A study investigated inhibition of lymphocyte proliferation and inhibition of expression of clusters of differentiation (CD) 134, CD71, CD11a and CD25 via flow cytometry. CYC was evaluated in vivo in rats, alone or in combination with MMF. Inhibition of lymphocyte function was assessed after 24 hours and found to be higher in all markers in the combination therapy compared to CYC therapy.15 Marcus et al.16 conducted a study to investigate the effects of CYC, FK 506 and MMF on leukocyte infiltration in grafts (over CD4, CD8, CD11a, CD18) after cardiac transplantation in rats. Transplantation was performed in 340 rats, which were divided into four groups: CYC, MMF, FK 506, and the control group not receiving immunosuppressive agent. It was observed that CYC and FK 506 decreased graft leukocyte infiltration (presence of CD4, CD8, CD11a and CD18 in the perivascular space and intra- and epicardial arteries) compared to the control group. It was determined that MMF reduced infiltration more significantly and acted earlier compared to the other two calcineurin inhibitors. Weigel et al.17 conducted a study including 36 patients who underwent orthotopic heart transplantation. The patients were divided into two groups, AZA and MMF. Within the groups, there was no difference between the recipients in terms of age, gender, indication for transplantation, donor age, and donor ischaemic period. The control group (n = 15) received CYC, AZA and prednisolone. The study group (n = 21) received MMF instead of AZA three months after transplantation. Activation markers CD25, CD38, CD69 and human leukocyte antigen (HLA-DR) (found in B lymphocytes), T cells and natural killer (NK) cells were measured by flow cytometry. A significant difference was observed in the reduction of B lymphocyte counts in the MMF group versus the AZA group. In addition, the percentage of CD38 B lymphocytes, activated T lymphocytes (CD4/CD25, CD8/CD38), HLA-DR and NK cells
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were decreased during MMF therapy. This study suggested that MMF therapy regulates the activation markers in B lymphocytes while decreasing B lymphocyte counts. A total of 22 orthotopic heart transplantations were performed between April 1995 and February 2002 in the Onasis Cardiac Surgery Centre.18 Within this period, 532 patients were selected and 223 were approved for pre-transplantation. AZA, CYC and steroids were used for initial immunosuppression, with MMF used instead of AZA in 16 patients. Gradually, AZA has been completely replaced by MMF in cases that have exceeded three years post transplant. A total of 19 patients were followed for more than one year after transplantation and it was found that one (5.3%) patient died, three (15.8%) developed rejection and three (15.8%) coronary artery disease. Klupp et al.19 divided rats that underwent allograft heart transplantation into four groups, each including six rats. Each of the groups receiving low- or high-dose MMF was divided into two subgroups. Pharmacokinetics (measured by high-performance liquid chromatography), pharmacodynamics and histological graft rejection scoring were performed in all animals on the sixth day. Rejection scoring was found to be more associated with MPA plasma concentration in terms of suppression of lymphocyte proliferation and transferrin receptor expression. Good lymphocyte suppression was provided in the low-dose group (5 mg/kg MMF BID) and ongoing pharmacodynamics were also good. No difference was found between low- and highdose groups in terms of rejection scores. In initial clinical studies, MMF has been used instead of AZA in triple therapies. In a randomised study comprising 50 patients from 28 centres, MMF was compared with AZA in triple therapy after cardiac transplantation. It was found that the need for rejection therapy was decreased and the one-year mortality rate was substantially reduced in the MMF group.5 Pethig et al.21 investigated systemic inflammatory response in patients who had undergone heart transplantation and had been receiving immunosuppressive agents containing AZA or MMF. Systemic inflammatory response was found to be lower in the MMF group. High-quality, randomised studies have demonstrated that MMF, when used together with CYC and steroids, reduced the frequency and intensity of rejection and improved the grafts, in patients who underwent heart and kidney transplantation.22 A limitation of our study was that the number of study subjects was low. Also the efficacy of MMF was investigated compared with only MP, but not with a control group. Since MP is an immunosuppressive agent approved by the scientific population, it was selected instead of placebo.
References
Conclusion
18. Magginas A, Adamopoulos S, Karavolias G, et al. Orthotopic heart
1. Bayezid Ö. Kalp Transplantasyonu. Akdeniz Üniversitesi Yayını, Antalya, 2003, No: 86. ISBN: 975-7669-69-6. 2. Özgen AG. Kalp Cerrahisi. Dicle Üniversitesi Yayını, Diyarbakır, 1999. ISBN: 975-7635-04-9. 3. Cohn LH, Edmunds LH. Cardiac Surgery in Adults, 2nd edn. New York, 2003. ISBN: 0-07-139129-0. 4. Paç M, Akçevin A, Aka A, Büket S, Sarıoğlu T. Kalp ve Damar Cerrahisi. MN Medikal & Nobel Tıp, Ankara, 2004. ISBN: 975-567-028-9. 5. Ross H, Hendry P, Dipchand A, et al. Canadian Cardiovascular Society Consensus Conference on Cardiac Transplantation 2001. Can J Cardiol 2003; 19(6): 620–654. 6. Wüthrich RP, Weinreich T, Ambühl PM, Candinas D, Binswanger U. Reduced kidney transplant rejection rate and pharmacoeconomic advantage of MMF. Nephrol Dial Transpl 1999; 14(2): 394–399. 7. Hunt SA. Current status of cardiac transplantation. J Am Med Assoc 1998; 280(19): 1692–1698. 8. Keogh A. Calcineurin ınhibitors in heart transplantation. Heart Lung Transpl 2004; 23(5): 202–206. 9. Holt CD, Sievers TM, Ghobrial RM, et al. Mycophenolate mofetil effects on clinical transplantation. BioDrugs 1998; 10(5): 373–384. 10. Clark C, Boyles S. Heart transplant patients to have option to prevent rejection. Blood Weekly 1998, 66(4): 507–515. 11. Mathieu P, Carrier M, White M, et al. Effect of mycophenolate mofetil in heart transplantation. Can J Surg 2000; 43(3): 202–206. 12. European Mycophenolate Mofetil Cooperative Study Group. Placebocontrolled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995; 345(8961): 1321–1325. 13. Dipchand AI, Benson L, McCrindle BW, et al. Mycophenolate mofetil in pediatric heart transplant recipients: A single center experience. Pediatr Transpl 2001; 5(2): 112–118. 14. Rose ML, Smith J, Dureau G, et al. Mycophenolate mofetil decreases antibody production after cardiac transplantation. J Heart Lung Traspl 2002; 21(2): 282–285. 15. Gummert JF, Barten MJ, Bartsch P, et al. Pharmacodynamic (PD) measurements of the immunsupressive effects of the combination of cyclosporine (CY) and mycophenolate mofetil (MMF): correlation between drug dose and lymphocyte function. J Heart Lung Transpl 2001; 20(2): 163. 16. Richter MC, Zahn S, Krause M, et al. Mycophenolate mofetil significantly reduces leukocyte graft infiltration after heterotopic cardiac transplantation in rat model comperative study with cyclosporine and FK 506. J Heart Lung Transpl 2003; 22(10): 1107–1116. 17. Weigel G, Griesmacher A, Karimi A, et al. Effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients. J Heart Lung Transpl 2002; 21(10): 107–109.
This study compared the effects of MMF and MP on duration of motor activity and rejection rate of transplants in rabbits that underwent retroperitoneal heterotopic heart transplantation. We found that MMF caused statistically significantly longer duration of motor activity in the transplanted hearts. No statistically significant difference was found between the MMF and MP groups in terms of transplant rejection rate. However, based on the absence of a significant difference with MP, which is a potent and important immunosuppressive agent in rescue therapy in terms of prevention of rejection, we concluded that MMF is also important for the prevention of rejection in transplantation.
transplantation: early clinical experience and results of a new transplantation centre. Hellenic J Cardiol 2003; 44(4): 102–107. 19. Klupp J, Gelder T, Dambrin C, et al. Sustained suppression of peripheral blood immune functions by trearment with mycophenolate mofetil correlates with reduced severity of cardiac allograft rejection. J Heart Lung Transpl 2004; 23(3): 334–351. 20. Pethig K, Heublein B, Wahlers T, et al. Mycophenolate mofetil for secondary prevention of cardiac allograft vasculopathy: ınfluence on ınflammation and progression of ıntımal hyperplasia. J Heart Lung Transpl 2004; 23(1): 61–66. 21. Mele TS, Halloran PF. The use of mycophenolate mofetil in transplant recipients. Immunopharmacology 2000; 47(2–3): 215–245.
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Right ventricular function and its relationship with grade of hepatosteatosis in non-alcoholic fatty liver disease Adem Bekler, Emine Gazi, Gokhan Erbag, Emine Binnetoglu, Ahmet Barutcu, Hacer Sen, Ahmet Temiz, Burak Altun
Abstract Objective: This study was designed to assess right ventricular systolic and diastolic function and its relationship with grade of hepatosteatosis (HS) in non-alcoholic fatty liver disease (NAFLD) patients using conventional and tissue Doppler echocardiography. Methods: NAFLD was diagnosed in 32 individuals (15 males, 17 females; 59% were grade I HS, 41% grade II–III HS) by means of ultrasonography. Twenty-two individuals, whose ultrasonography data did not show HS, comprised the control group (11 males, 11 females) and were included in the study. Right ventricular systolic and diastolic function and their relationship with grade of HS were assessed by conventional and tissue Doppler echocardiography. Additionally, right ventricular global function was assessed by myocardial performance index (MPI). Results: When compared by conventional echocardiographic parameters, there were no significant differences between the two groups. With tissue Doppler parameters, the tricuspid annulus peak early diastolic velocity and ratio of early-tolate diastolic velocity were lower in the patients than in the controls (p = 0.03, p = 0.02, respectively). The isovolumetric relaxation time and MPI were significantly higher (p < 0.001, p < 0.001, respectively) in the patient group. HS grade was positively correlated with right ventricular isovolumetric relaxation time and MPI index (r = 0.295, p = 0.03, r = 0.641, p < 0.001, respectively). Conclusion: These results show that right ventricular diastolic dysfunction (RVDD) in patients with NAFLD and degree of HS was associated with RVDD. Keywords: echocardiography, hepatosteatosis, right ventricular dysfunction Submitted 21/1/13, accepted 27/11/14 Cardiovasc J Afr 2015; 26: 109–113
www.cvja.co.za
DOI: 10.5830/CVJA-2014-068
Department of Internal Medicine, Canakkale Onsekiz Mart University, Çanakkale, Turkey Adem Bekler, MD, adembekler27@gmail.com Emıne Gazi, MD Gokhan Erbag, MD Emine Binnetoglu, MD Ahmet Barutcu, MD Hacer Sen, MD Ahmet Temiz, MD Burak Altun, MD
Non-alcoholic fatty liver disease (NAFLD) is increasingly recognised as the most common cause of chronic liver disease worldwide.1 NAFLD encompasses a spectrum of disorders, including variable degrees of simple hepatic steatosis (HS, fatty liver), non-alcoholic steatohepatitis (NASH) and cirrhosis. This disease is a common clinicopathological condition characterised by significant lipid deposition in the hepatocytes of the liver parenchyma in the absence of alcohol abuse, contributing medications and viral hepatitis. It is strongly associated with several cardiovascular risk factors such as obesity, insulin resistance, hypertension, hyperlipidaemia, coronary artery disease, obstructive sleep apnoea syndrome, oxidative stress, endothelial dysfunction and the metabolic syndrome.2-5 There are recent data suggesting that NAFLD is linked to increased cardiovascular risk independent from the broad spectrum of metabolic syndrome (MS) risk factors.6,7 Multiple mechanisms contribute to left ventricular dysfunction in obesity, including lipotoxicity associated with cardiac steatosis and lipo-apoptosis, alterations in fatty acid metabolism, overproduction of cardio-inhibitory cytokines, up-regulation of some neurohormones (especially angiotensin II), myocardial fibrosis and chronic overload with left ventricular dilatation and hypertrophy, and increased oxygen consumption.8 Evaluating the possible influence and correlation of metabolic, cardiovascular and liver biopsy parameters on cardiac left ventricular dysfunction, we found a positive correlation between left ventricular parameters and severity of liver damage (NAS score).9 Cardiac dysfunction determined by echocardiographic measurements in patients with NAFLD was also studied.10 Determination of myocardial velocity using tissue Doppler imaging (TDI) is a new technique that has recently been developed to analyse right ventricular function.11-14 This study aimed to investigate the association between right ventricular function and grade of hepatosteatosis (HS grade) in NAFLD patients using transthoracic and tissue Doppler echocardiography.
Methods Thirty-two patients, who were admitted to the Internal Medicine Clinic at our institution between 2011 and 2012 and were diagnosed with hepatosteatosis using abdominal ultrasonography (USG), performed for any reason, were included in the study, taking into account the exclusion criteria. Twenty-two persons were also included in the study as a control group. To eradicate the effects of other variables on the impact of NAFLD on right ventricular function, the control group was selected according to the demographic and laboratory characteristics of the patients with NAFLD. Each participant signed an informed consent form in accordance with the Declaration of Helsinki, and this study was approved by the local ethics committee of our hospital.
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The exclusion criteria were as follows: previous coronary artery disease (patients who had a history of myocardial infarction, unstable angina pectoris, angiographically proven significant coronary artery stenosis or had undergone revascularisation), congestive heart failure (left ventricular ejection fraction ≤ 40% or symptomatic heart failure), patients who had known or a history of valvular heart disease, pulmonary disease, pulmonary hypertension, left bundle branch block, a rhythm other than sinus, and pericarditis. Chronic alcohol consumption (more than 20 g/day), serum hepatitis B antigen or anti-hepatitis C viral antibody positivity, which are known to worsen NAFLD, were the other exclusion criteria. All medications were stopped 48 hours before the time of echocardiography. Fasting venous blood samples were taken to determine levels of blood glucose, electrolytes, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides.
Ultrasonography Although liver biopsy is currently the gold standard for distinguishing NAFLD forms, abdominal USG is the preferrred method for qualitative assessment of NAFLD.10 Abdominal USG was performed on all study participants by a single experienced physician who was blinded to the clinical and laboratory results of the study groups. The diagnosis of NAFLD was based on increased liver echotexture on ultrasonography [Siemens Antares (Erlangen, Germany)] compared with the kidneys, vascular blurring and deep attenuation.15 Fat infiltration in the liver was described in three ultrasonographic stages using published criteria.16,17 The liver was considered to be normal if there was normal hepatic echotexture and normal beam attenuation. Mild steatosis (grade I) was identified as a minimal increase in echogenicity of the liver parenchyma with a slight decrease in definition of the portal vein walls and minimal or no posterior beam attenuation. Severe steatosis (grade III) was identified as grossly increased hepatic parenchymal echotexture that permitted visualisation of the main portal vein walls alone. Smaller venules were not visualised, and there was increased posterior beam attenuation. Moderate steatosis (grade II) was identified by hepatic echogenicity, portal venous definition and beam attenuation between mild and severe parameters. According to USG results, 59% grade I HS and 41% grade II–III HS was found in the patients.
Echocardiography All patients underwent a complete transthoracic echocardiographic and tissue Doppler study using multiple views in the left lateral decubitus position. Echocardiographic measurements were calculated by two of three experienced cardiologists who were blinded to the current study. In case of disagreement, an opnion was obtained from the third cardiologist, and the final decision was made by consensus. This study was performed using a 3.5-Mhz transducer on a Vivid 7 GE ultrasonographic system. Echocardiographic measurements were made in accordance with the criteria recommended by the American Society of Echocardiography. All subjects were in sinus rhythm. The measurements were
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done on three consecutive heartbeats, and the average of these measurements was calculated. In the apical four-chamber view, the sample volume (size 2 mm) of the pulsed-wave Doppler was placed between the tips of the tricuspid leaflets. The tricuspid inflow velocity was traced and the following variables were measured: peak velocity of early (E) and late (A) filling and deceleration time (DT) of the E-wave velocity. In the parasternal long-axis view, the right ventricular (RV) diameter was measured using M mode from the RV anterior wall to the right side of the interventricular septum on the R wave of the electrocardiogram. RV longitudinal functions were assessed by pulsed tissue Doppler imaging (TDI). Pulsed Doppler sample volume (size 5 mm) was placed on the basal portion of the right ventricle at the level of the lateral tricuspid annulus from the apical four-chamber view. The Nyquist limit was set at 15 to 20 cm/s. For optimising the spectral display of myocardial velocities, the monitor sweep speed was adjusted at 50 to 100 mm/s. The pulsed TDI pattern has a positive myocardial systolic velocity (Sa) and two negative diastolic velocities: early (Ea) and late (Aa). The diastolic indices of myocardial early (Ea) and atrial contraction (Aa) peak velocities and myocardial systolic wave (Sa) velocity were measured and the ratio of Em/Am was calculated. TDI-derived myocardial performance index (MPI) of the right ventricle was measured by dividing the difference between the time interval from the end to the onset of the tricuspid annular velocity pattern during diastole (a) and the duration of the tricuspid Sa (b) by the tricuspid Sa duration (b). (a–b)
RV MPI = ____ b . Conventional and tissue Doppler echocardiographic parameters and their implications on right ventricular systolic and diastolic function are presented in Table 1.
Biochemical evaluation Blood samples were drawn from each patient after a 12-hour overnight fast for the determination of lipid profiles and glucose levels. Plasma glucose level was determined with the glucose oxidase/peroxidase method (Gordion Diagnostic, Ankara, Turkey). Levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were determined with enzymatic colorimetric assays by spectrophotometry. Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula.
Statistical analysis The SPPS version 20.0 software package was used for statistical analysis. All the data were expressed as mean ± standard deviation. The Kolmogorov–Smirnov test was used to determine normal disributions. Categorical variables were compared with the chi-square or Fisher’s exact test. Normally distributed variables were compared across groups by means of the Student’s t-test whereas variables that did not normally distribute were compared by means of the Mann–Whitney U-test. Spearman’s correlation analysis was used to evaluate the relationship between the variables. A p-value < 0.05 was considered significant.
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Table 1. Conventional and tissue Doppler echocardiographic parameters and their implications on right ventricular systolic and diastolic function Systolic function
Diastolic function
Parameters Conventional echocardiography Tricuspid E – + Tricuspid Aa – + Tricuspid E/A – + Tricuspid E DT – + Tissue Doppler imaging + – RV S′ – + RV Ea′ – + RV Aa′ – + RV Ea′/Aa′ RV deceleration time (ms) – + Isovolumetric relaxation time (ms) – + Isovolumetric contraction time (ms) + – Contraction time (ms) + – Myocardial performance index + + Tricuspid E: peak velocity of early diastolic filling, tricuspid A: peak velocity of atrial diastolic filling, tricuspid E DT: deceleration time of early diastolic filling, Ea: tricuspid lateral annulus early diastolic wave, Aa: tricuspid lateral annulus late diastolic wave, DT: tricuspid lateral annulus E-wave deceleration time, RV: right ventricular.
Results NAFLD was diagnosed in 32 individuals (15 males, 17 females; mean age 50 ± 9 years; 59% with grade I HS, 41% grade II–III HS) by means of ultrasonography data. Twenty-two individuals whose ultrasonography data did not show HS comprised the control group (11 males, 11 females; mean age 50 ± 10 years) and were included in the study. Table 2. Demographic and clinical characteristics of the groups Patient Control group group Parameters (n = 32) (n = 22) p-value Mean age (years) 0.979 50 ± 9 51 ± 10 Gender M/F 15/17 11/11 0.821 Body mass index (kg/m²) 0.094 29.8 ± 3.4 28.2 ± 3.2 Smoking, n (%) 5 (15) 7 (31) 0.160 Hypertension, n (%) 6 (18) 6 (27) 0.459 Diabetes mellitus n (%) 4 (12) 3 (13) 0.903 Dyslipidaemia, n (%) 11 (34) 5 (22) 0.357 Glucose (mg/dl) 105.4 ± 21.4 102.8 ± 28.9 (mmol/l) 5.85 ± 1.19 5.71 ± 1.60 0.174 AST (U/l) 0.711 25.7 ± 6.9 25.2 ± 7.4 ALT (U/l) 28.5 ± 12.1 26.1 ± 12.2 0.459 LDH (U/l) 159.5 ± 21.7 156.3 ± 17.8 0.672 Haemoglobin (g/dl) 0.622 14.1 ± 1.1 13.8 ± 1.3 Total cholesterol (mg/dl) 200.7 ± 40.3 184.3 ± 40.3 0.119 (mmol/l) 5.20 ± 1.04 4.77 ± 1.04 Triglyceride (mg/dl) 184 ± 85.5 158.4 ± 77.9 0.189 (mmol/l) 2.08 ± 0.97 1.79 ± 0.88 High-density lipoprotein (mg/dl) 40 ± 8.8 39.5 ± 11.2 0.433 (mmol/l) 1.04 ± 0.23 1.02 ± 0.29 Low-density lipoprotein (mg/dl) 124.7 ± 35 113.4 ± 35.8 0.144 (mmol/l) 3.23 ± 0.91 2.94 ± 0.93 AST: aspartate aminotransferase, ALT: alanine transaminase, LDH: lactate dehydrogenase.
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Table 3. Echocardiographic parameters between the patient group and the control group Parameters Patient group Control group p-value LVEDD (mm) 0.986 48.07 ± 3.82 48.47 ± 3.95 LVESD (mm) 0.140 29.8 ± 4.78 30.43 ± 4.22 IVS (mm) 0.720 10.08 ± 1.33 9.90 ± 1.19 LVEF (%) 0.762 68.01 ± 7.01 66.31 ± 6.59 RVEDD (mm) 0.523 28.78 ± 3.15 28.47 ± 3.67 LA diameter (mm) 0.710 36.35 ± 3.81 36.94 ± 3.08 RA diameter (mm) 0.535 32.99 ± 4.93 31.31 ± 4.72 Tricuspid E (cm/s) 0.888 55.8 ± 12.6 54.6 ± 8.3 Tricuspid A (cm/s) 0.156 47 ± 13 41.7 ± 9.6 Tricuspid E/A ratio 0.413 1.2 ± 0.4 1.3 ± 0.3 Tricuspid E DT (ms) 0.365 190.2 ± 30.4 193.6 ± 19.5 LVEDD: left ventricular end-diastolic diameter, LVESD: left ventricular end-systolic diameter, IVS: interventricular septum, LVEF: left ventricular ejection fraction, RVEDD: right ventricular end-diastolic diameter, LA: left atrium, RA: right atrium, tricuspid E: peak velocity of early diastolic filling, tricuspid A: peak velocity of atrial diastolic filling, tricuspid E DT: deceleration time of early diastolic filling.
Clinical characteristics of the 32 NAFLD patients and 22 control subjects are presented in Table 2. Age, gender, body mass index, diabetes mellitus, dyslipidaemia and smoking status were similar between the NAFLD patients and controls. Additionally, there were no significant differences with regard to laboratory results (Table 2). When compared in terms of echocardiographic features, the groups were similar in chamber diameter and standard Doppler parameters (Table 3). There were no significant differences for E, A, E/A and DT between the patients and controls. For tissue Doppler parameters, the Ea and Ea/Aa were lower in the patient group than in the control group (p < 0.001, p < 0.001, respectively). Isovolumetric relaxation time (IVRT) and MPI were significantly higher (p = 0.002, p < 0.001, respectively) in the patient group. There were no significant differences for Aa, DTa, Sa, isovolumetric contraction time (IVCT) and contraction time (CT) between the two groups. Tissue Doppler parameters are presented in Table 4. Grade of HS was positively correlated with right ventricular isovolumetric relaxation time and MPI (r = 0.295, p = 0.03, r = 0.641, p < 0.001, respectively). Correlations between grade of HS and echocardiographic parameters are shown in Table 5. Table 4. Right ventricular tissue Doppler echocardiographic parameters Patient Control Parameters group group p-value RV S-wave peak velocity (cm/s) 0.476 13.8 ± 2.1 14.3 ± 2.1 RV Ea-wave peak velocity (cm/s) 12.1 ± 3.1 0.03 14 ± 3.1 RV Aa-wave peak velocity (cm/s) 17.2 ± 3.6 0.061 15.5 ± 3.9 RV Ea/Aa ratio 0.02 0.7 ± 0.3 0.9 ± 0.4 Ea DT (ms) 0.679 166.2 ± 27.7 167.2 ± 22.7 IVRT (ms) 77.3 ± 8.5 61.5 ± 4.3 < 0.001 IVCT (ms) 0.072 66.4 ± 8.7 62.8 ± 9.9 CT (ms) 0.610 295.5 ± 27.6 302.1 ± 23 5 Tei index LV 0.50 ± 0.05 0.42 ± 0.03 < 0.001 RV: right ventricular, Ea: tricuspid lateral annulus early diastolic wave, Aa: tricuspid lateral annulus late diastolic wave, DT: tricuspid lateral annulus E-wave deceleration time, IVRT: isovolumetric relaxation time, IVCT: isovolumetric contraction time, CT: contraction time.
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Table 5. Correlations between grade of hepatosteatosis and echocardiographic parameters Parameters r p-value Ea 0.020 0.886 Ea/Aa –0.156 0.260 IVRT* 0.295 0.03 MPI* 0.641 < 0.001 *By hepatosteatosis, IVRT: isovolumetric relaxation time, MPI: right ventricular myocardial performance index, HS: hepatosteatosis.
Discussion The results of this study indicate that the presence of NAFLD was associated with impaired RV diastolic function (RVDF). In addition, the evidence showed that the existence of NAFLD was related to the extent of impairment in RVDF. NAFLD is more common in patients with impaired RVDF, obesity, insulin resistance, hypertension, hyperlipidaemia, coronary artery disease, obstructive sleep apnoea syndrome, oxidative stress, endothelial dysfunction and the metabolic syndrome. In this study, although RVDF was impaired, systolic function was preserved in NAFLD patients. Furthermore, HS grade was positively correlated with RV MPI. Several studies reported only diastolic left ventricular dysfunction, while others reported both diastolic and systolic left ventricular functional impairment in NAFLD patients with hypertension, insulin resistance, type 2 diabetes and/or the metabolic syndrome.18-20 Evaluating the possible influence and correlation of metabolic, cardiovascular and liver biopsy parameters on cardiac left ventricular dysfunction, we found a positive correlation between left ventricular parameters and severity of liver damage (NAS score).9 However, to the best of our knowledge, to date, no study has explored the involvement of right ventricular systolic and diastolic function and its relationship with HS grade in NAFLD patients. We speculated that the excessive lipid accumulation in hepatocytes that is a characteristic of NAFLD can lead to lipid deposition in cardiac myocytes, promoting RVDF. In addition, our study showed that significantly impaired RVDF was associated with HS grade in NAFLD according to TDI. However, we could not detect any significant difference in tricuspid lateral annulus systolic velocity between the NAFLD patients and controls. Therefore, right ventricular systolic function was not impaired in patients with NAFLD. MPI is a DTI-derived quantitative parameter used frequently in recent years to grade systolic and diastolic function. This index was first described by Tei et al.21 and is widely accepted because it correlates with more invasive measurements, is easy to reproduce and is easy to perform. In coronary artery disease, a prolonged MPI is an important disease precursor observed before the development of systolic dysfunction.22 A markedly prolonged MPI despite an unchanged tricuspid lateral annulus systolic velocity in NAFLD patients compared with the control group is compatible with the hypothesis that prolonged MPI stems from RVDD. In fact, RVDF deteriorates in NAFLD, and this deterioration is associated with grade of HS. There were some limitations to our study. The first was the small sample size. The second was that the diagnostic method depended on USG, and the exclusion of other secondary causes of chronic liver disease was not confirmed by liver biopsy. Although liver biopsy is currently the gold standard
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for distinguishing NAFLD forms, for assessing the severity of damage and prognosis, NAFLD can be detected as a bright liver on USG, which is possible to perform routinely. Moreover, liver USG has proven to be a sensitive, accurate and convenient diagnostic tool in detecting steatosis. Its sensitivity ranges from 60 to 94% and its specificity from 84 to 95%.15,23
Conclusion We found that there was significant impairment in diastolic function in non-diabetic and normotensive NAFLD patients compared to the controls. It should be kept in mind that diastolic function may be impaired while systolic function is preserved in NAFLD patients. We suggest that patients with NAFLD require aggressive cardiac risk-factor modification and closer follow up for the prevention of diastolic and systolic heart failure.
References 1.
Chitturi S, Farrell G, George J. Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock. J Gastroenterol Hepatol 2004; 19: 368–374.
2.
Marchesini G, Bugianesi E, Forlani G, et al. Non-alcoholic fatty liver, steatohepatitis and the metabolic syndrome. Hepatology 2003; 37: 917–923.
3.
Musso G, Gambino R, Bo S, et al. Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? A crosssectional comparison with ATP III criteria in non-obese non-diabetic subjects. Diabetes Care 2008; 31: 562–568.
4.
Lizardi-Cervera J, Chavez-Tapia NC, Pérez-Bautista O, et al. Association among C-reactive protein, fatty liver disease, and cardiovascular risk. Dig Dis Sci 2007; 52: 2375–2379.
5.
Wilfred de Alwis NM, Day CP. Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatology 2008; 48: 104–112.
6.
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363: 1341–1350.
7.
Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008; 168: 1609–1616.
8.
Peterson LR, Herrero P, Schechtman KB, et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 2004; 109: 2191–2196.
9.
Kleiner DE, Brunt EM, Van Natta M, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313–1321.
10. Futbolcu H, Yakar T, Duman D, et al. Impairment of the left ventricular systolic and diastolic function in patients with non-alcoholic fatty liver disease. Cardiol J 2010; 17: 457–463. 11. Dell’Italia LJ. Reperfusion for right ventricular infarction. N Engl J Med 1998; 338: 978–980. 12. Ulusoy RE, Yokusoglu M, Baysan O, et al. Ventricular functions, aortic elastic properties, and endothelial functions in patients with hypertensive response to treadmill exercise testing. Turk J Med Sci 2011; 41: 781–787. 13. Çiçekçioğlu H, Ergün İ, Uçar Ö, et al. Cardiac complications of secondary hyperparathyroidism in chronic hemodialysis patients. Turk J Med Sci 2011; 41: 789–794. 14. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996; 93:
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879–888. 15. Quinn SF, Gosink BB. Characteristic sonographic signs of hepatic fatty infiltration. Am J Roentgenol 1985; 145: 753–755. 16. Joseph AE, Saverymuttu SH, al-Sam S, et al. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol 1991; 43: 26–31. 17. Needleman L, Kurtz AB, Rifkin MD, et al. Sonography of diffuse benign liver disease: accuracy of pattern recognition and grading. Am J Roentgenol 1986; 146: 1011–1015. 18. Fallo F, Dalla Pozza A, Sonino N, et al. Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension. Nutr Metab Cardiovasc Dis 2009; 19: 646–653. 19. Goland S, Shimoni S, Zornitzki T, et al. Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease: echocardiographic
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and tissue Doppler imaging assessment. J Clin Gastroenterol 2006; 40: 949–955. 20. Bonapace S, Perseghin G, Molon G, et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 2012; 35: 389–395. 21. Tei C. New non-invasive index for combined systolic and diastolic venricular function. J Cardiol 1995; 26: 135–136. 22. Kang SM, Ha JW, Rim SJ, et al. Index of myocardial performance using Doppler-derived parameters in the evaluation of left ventricular function in patients with essential hypertension. Yonsei Med J 1998; 39: 446–452. 23. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745–750.
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Evaluation of left atrial mechanical function and atrial conduction abnormalities in Maras powder (smokeless tobacco) users and smokers Ahmet Akcay, M Naci Aydin, Gurkan Acar, Bulent Mese, Mustafa Çetin, Mehmet Akgungor, Eren Cabioglu, Orhan Bozoglan, İdris Ardic, Musa Çakıcı
Abstract Objective: In Turkey, a type of smokeless tobacco called Maras powder (MP) is widely used in the south-eastern region. Smokeless tobacco is found in preparations for chewing and for absorption by the nasal and oral mucosae. The purpose of this study was to investigate whether MP damages intra- and inter-atrial conduction delay and left atrial (LA) mechanical function as much as cigarette smoking. Method: A total of 150 chronic MP users (50 males, 32.5 ± 5.4 years), smokers (50 males, 32.1 ± 6.0 years) and controls (50 males, 30.1 ± 5.8 years) were included in the study. LA volumes were measured echocardiographically according to the biplane area–length method. Atrial electromechanical coupling was measured with tissue Doppler imaging and LA mechanical function parameters were calculated. Results: The LA passive emptying fraction was significantly decreased and LA active emptying volume (LAAEV) was significantly increased in the MP group (p = 0.012 and p = 0.024, respectively), and the LA active emptying fraction (LAAEF) was significantly increased in the smokers (p = 0.003). There was a positive correlation between the amount of MP used and smoking (pack years) with LAAEV and LAAEF (r = 0.26, p = 0.009 and r = 0.25, p = 0.013, respectively). Lateral atrial electromechanical intervals (PA) were significantly higher in MP users, and the septal mitral PA was statistically higher in the smokers (p = 0.05 and p = 0.04, respectively). Conclusion: We suggest that atrial electromechanical coupling intervals were prolonged and LA mechanical function was
Department of Cardiology, Faculty of Medicine, Kahramanmaras Sutcuimam University, Kahramanmaras, Turkey Ahmet Akcay, MD M Naci Aydin, MD Gurkan Acar, MD Mehmet Akgungor, MD Eren Cabioglu, MD İdris Ardic, MD
Department of Cardiovascular Surgery, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey Bulent Mese, MD Orhan Bozoglan, MD
Department of Cardiology, Faculty of Medicine, Adıyaman University, Adıyaman, Turkey Mustafa Çetin, MD, drmcetin@gmail.com Musa Çakıcı, MD
impaired in MP users and smokers, but there was no significant difference between the MP users and smokers. These findings may be markers of subclinical cardiac involvement and tendency for atrial fibrillation. Keywords: smokeless tobacco, atrial electromechanical intervals, left atrial function Submitted 23/1/14, accepted 27/11/14 Cardiovasc J Afr 2015; 26: 114–119
www.cvja.co.za
DOI: 10.5830/CVJA-2014-070
Tobacco use can be classified into smoking and smokeless tobacco. Smokeless tobacco is chewed or is absorbed by the nasal and oral mucosae. A type of smokeless tobacco called Maras powder (MP) is used mostly in the south-eastern region of Turkey, and in many cases users become addicted. It is obtained from a tobacco plant species known as Nicotiana rustica Linn. Nicotine concentrations in the tobacco used to produce MP are eight to 10 times higher than those in tobacco used to produce cigarettes.1 MP and its negative effects on the cardiovascular system have been well studied. MP is consumed in such a way that increase in oxidative stress is inevitable and as a result it accelerates the atherosclerotic process.2,3 Cigarette smoke includes nicotine and toxic substances such as carbon monoxide and polycyclic aromatic hydrocarbons.4 Inhalation of these substances predisposes to several different atherosclerotic syndromes,5,6 and is also associated with the occurrence of cardiac arrhythmia.7,8 The pathophysiological mechanism of cigarette smokinginduced cardiac arrhythmia is complicated, and the pro-fibrotic effect of nicotine on myocardial tissue with its consequent increased susceptibility to catecholamines, may play a role. Moreover, other components of cigarette smoking, such as carbon monoxide, as well as oxidative stress, are likely to cause the generation of arrhythmias. It is also known that cigarette smoking leads to cardiac autonomic dysfunction,9 and it has been implicated in prolonged QT intervals in healthy individuals.10 However, the nicotine concentration in the blood is more likely to cause the pro-arrhythmic effect of cigarette smoking.7,11 The risk of atrial and ventricular arrhythmia rises due to increased nicotine levels.9-12 The prolongation of intra- and inter-atrial electromechanical intervals and the inhomogeneous propagation of sinus impulses are well-known electrophysiological characteristics of atria that are prone to fibrillation.13 Left atrial (LA) volume and LA
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mechanical function have recently been identified as a potential indicator of cardiac disease and arrhythmias.14,15 Prolongation of atrial electromechanical interval and impaired LA mechanical function are associated with adverse clinical events, including atrial fibrillation, stroke, diastolic dysfunction and left ventricular failure.16,17 LA mechanical function and atrial conduction abnormalities have not been investigated in MP users and smokers. Therefore, our study was planned to evaluate whether MP damages intra- and inter-atrial conduction intervals and LA mechanical function as much as cigarette smoking.
Methods A total of 150 chronic MP users (50 males, mean age 32.5 ± 5.4 years), cigarette smokers (50 males, mean age 32.1 ± 6.0 years) and controls (50 males, mean age 30.1 ± 5.8 years) who referred to various out-patient departments (cardiology clinic, public health clinic, internal medicine clinic, cardiovascular surgery clinic) and were matched for age and gender, were included in the study. A medical history was taken and detailed physical examinations were performed on all subjects. The inclusion criterion was using MP for at least three years. A package of MP was considered sufficient to provide use of the powder for 20 occasions. Duration and frequency of MP use, duration of cigarette smoking and number of cigarettes smoked throughout the day were recorded. The entire study population’s demographic characteristics, biochemical parameters, lipid values and ECGs were obtained. Exclusion criteria were: history of coronary artery disease, arterial hypertension, hypercholesterolaemia, diabetes mellitus, primary cardiomyopathy, valvular heart disease, left ventricular ejection fraction (LVEF) less than 50%, bundle branch block, LV wall motion abnormality, renal failure, atrioventricular conduction abnormalities on electrocardiogram, thyroid dysfunction, anaemia, electrolyte imbalance, pulmonary disease, and poor-quality echocardiographic and electrocardiographic imaging. All patients were in sinus rhythm, and none was taking medication such as anti-arrhythmics, antihistamines, tricyclic antidepressants and antipsychotics. Written informed consent was obtained from each subject. The institutional ethics committee approved the study protocol.
Echocardiography In this study, a Vingmed Vivid Seven Pro, Doppler echocardiographic (GE Ultrasound, Horten, Norway) unit with a 2–4 MHz FPA probe was used. Tissue Doppler (TDI) echocardiography was performed with a transducer frequency of 3.5–4.0 MHz, adjusting the spectral pulsed Doppler signal filters to obtain the Nyquist limit of 15–20 cm/s, and using the minimal optimal gain setting. The monitor sweep speed was set at 50–100 mm/s to optimise the spectral display of myocardial velocities. A 12-lead electrocardiogram recording obtained from the same derivation (DII derivation) was recorded continuously during the echocardiographic examination in all study subjects. Two-dimensional, M-mode, pulsed and colour-flow Doppler echocardiographic examinations were performed by a cardiologist who was blinded to the clinical details and findings
of other examinations of each subject and control. During echocardiography, continuous one-lead electrocardiographic recordings were obtained. LA volumetric parameters were measured by transthoracic echocardiography in the left lateral position, in parasternal long axis, apical four chambers and two chambers. M-mode measurements and conventional Doppler echocardiographic examinations were performed according to the guidelines of the American Society of Echocardiography.18 All measurements were recorded as averages of three cardiac cycles. LA dimension, LV end-systolic and end-diastolic dimensions, diastolic ventricular septal thickness, and diastolic LV posterior wall thickness were measured in the parasternal long-axis view. LVEF was estimated using the Simpson’s rule. All echocardiographic examinations were performed by the same cardiologist. LA volumes were measured echocardiographically using the biplane area–length method in apical four-chamber and two-chamber views. LA maximal volume (Vmax) was recorded at the onset of mitral opening, LA minimal volume (Vmin) was recorded at the onset of mitral closure, and LA pre-systolic volume (Vp) was recorded at the beginning of the atrial systole (P wave on ECG). All volume measurements were corrected to body surface area, expressed as ml/m2 and the following LA emptying function parameters were calculated:19 LA passive emptying volume (LAPEV) = Vmax – Vp LAPEV
LA passive emptying fraction (LAPEF) = _______ V max
LA active emptying volume (LAAEV) = Vp – Vmin LAAEV
LA active emptying fraction (LAAEF) = _______ V p
LA total emptying volume (LATEV) = Vmax – Vmin LATEV
LA total emptying fraction (LATEF) = _______ V max
All measurements were repeated during three consecutive heart beats and the average of three consecutive measurements was obtained.
Atrial electromechanical coupling measurements For atrial electromechanical intervals in the apical four-chamber view, the pulsed Doppler sample volume was placed at the level of the LV lateral mitral annulus, septal mitral annulus and right ventricular (RV) tricuspid annulus. Atrial electromechanical intervals (PA) were measured as the time interval between the onset of the P wave on the electrocardiogram and the beginning of the late diastolic A wave at the lateral mitral annulus (lateral PA), septal mitral annulus (septal PA), and RV tricuspid annulus (RV PA). The difference between lateral PA and RV PA (lateral PA–RV PA) was defined as inter-atrial dyssynchrony, and the difference between septal PA and RV PA (septal PA–RV PA) as intra-atrial dyssynchrony.20
Reproducibility Intra-observer variability was assessed in 20 subjects selected randomly from the study groups by repeating the measurements
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under the same basal conditions. Reproducibility of atrial electromechanical intervals obtained by TDI was assessed by coefficient of variation (CV) between measurements. Intra- and inter-observer coefficients of variation for echocardiographic measurements were found to be < 5% and non-significant.
Statistical analysis All analyses were conducted using SPSS 15.0 (SPSS for Windows 15.0, Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation; categorical variables were defined as percentages. Categorical data were compared with the chi-square test. All numerical variables of the study groups presented a normal distribution. Mean values of continuous variables were therefore compared using analysis of variance (ANOVA), and the post hoc Tukey test was used for comparison of groups. Pearson’s correlation coefficients were used to assess the strength of the relationship between continuous variables. A p-value < 0.05 was considered significant. We performed the power analysis using G*Power software version 3.1.5. The power of our study was calculated to be 0.96.
Results Basic clinical and laboratory values, and M-Mode and two-dimensional echocardiographic measurements of the three Table 1. Clinical characteristics, laboratory and echocardiographic findings of the groups Group I controls (n = 50)
Group II smokers (n = 50)
Group III MP users (n = 50)
Age (years)
30.1 ± 5.8
32.1 ± 6
32.5 ± 5.4
0.086
BMI (kg/m2)
26.3 ± 3.7
25.9 ± 3.5
26.9 ± 3.9
0.462
BSA (m2)
1.96 ± 0.14
1.95 ± 0.15
1.92 ± 0.16
0.388
Systolic BP (mmHg)
125.3 ± 7.4
121.2 ± 6.4
120.7 ± 8.3
0.354
Diastolic BP (mmHg)
79.5 ± 6.3
78.5 ± 5.4
77.9 ± 5.8
0.789
Heart rate (beats/min)
72.2 ± 10.4
74.6 ± 9.6
74.5 ± 10.1
0.407
LVEDD (mm)
48.7 ± 3.1
47.7 ± 2.5
48.6 ± 3.4
0.224
IVS
9.5 ± 0.8
9.9 ± 0.8
9.8 ± 0.8
0.060
PW
8.7 ± 0.7
8.9 ± 0.6
9.1 ± 0.7
0.087
LVEF (%)
69.8 ± 2.6
68.4 ± 3.2
68 ± 3.4
0.314
LA dimension (mm)
33.2 ± 3.1
32.9 ± 2.7
34.3 ± 3.1
0.071
Mitral E velocity (cm/s)
78.9 ± 14.5
78.5 ± 14.8
81.0 ± 16.7
0.429
Mitral A velocity (cm/s)
57.3 ± 12.9
56.7 ± 10.9
56.4 ± 10.3
0.922
E/A
1.44 ± 0.38
1.41 ± 0.28
1.46 ± 0.32
0.398
sPAP (mmHg)
19.5 ± 3.8
19.4 ± 3.9
21.1 ± 3.5
0.057
Glucose (mg/dl)
92.7 ± 15.7
92.8 ±16.6
93.7 ± 19.8
0.951
(mmol/l)
5.14 ± 0.87
5.15 ± 0.92
5.20 ± 1.10
Total cholesterol (mg/dl)
184.5 ± 41.4
180.5 ± 46.8
174.0 ± 35
(mmol/l)
4.78 ± 1.07
4.67 ± 1.21
4.51 ± 0.91
Triglycerides (mg/dl)
151 ± 88.2
173.7 ± 112.4
186.6 ± 130
(mmol/l)
1.71 ± 1.00
1.96 ± 1.27
2.11 ± 1.47
HDL cholesterol (mg/dl)
42.8 ± 8.7
39.2 ± 9.1
39.8 ± 8.8
(mmol/l)
1.11 ± 0.23
1.02 ± 0.24
1.03 ± 0.23
LDL cholesterol (mg/dl)
110.2 ± 34.6
106.9 ± 36.5
100 ± 27.7
(mmol/l)
2.85 ± 0.90
2.77 ± 0.95
2.59 ± 0.72
–
13.6 ± 6.2
10.9 ± 6.6
Duration (pack years)
p-value
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groups are listed in Table 1. Age, body mass index (BMI), body surface area (BSA), systolic and diastolic blood pressure, heart rate, LV end-diastolic diameter, interventricular septal thickness, posterior wall thickness, LVEF, LA dimension, mitral E velocity, mitral A velocity, E/A ratio, systolic pulmonary artery pressure, and glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels were similar between the three groups (p > 0.05).
Left atrial mechanical function The three groups were similar with regard to Vmax, Vmin and Vp, LAPEV, LATEV and LATEF (p = 0.322, p = 0.052, p = 0.087, p = 0.161, p = 0.976, p = 0.170, respectively). However, LAPEF was significantly decreased and LAAEV was significantly increased in the MP groups but not in the control group (p = 0.012 and p = 0.024, respectively), and LAAEF was significantly increased in the cigarette smoking group and not in the control group (p = 0.003) (Table 2). The amount of MP used and cigarette smoking (pack years) were weakly but significantly correlated with LAAEV and LAAEF (r = 0.26, p = 0.009, r = 0.25, p = 0.013, respectively) (Figs 1, 2).
Atrial electromechanical intervals The atrial electromechanical coupling intervals measured from different sites by TDI are shown in Table 3. PA lateral was significantly higher in the MP users than in the controls. Also, PA septum was statistically higher in cigarette smokers than in the controls (p = 0.05 and p = 0.04, respectively). Intra- and inter-atrial dyssynchrony was prolonged in both MP users and cigarette smokers, but did not reach statistical significance. The measurements of atrial electromechanical coupling intervals were similar between MP users and cigarette smokers.
Discussion The main finding of this study was that atrial electromechanical coupling intervals were prolonged and left atrial mechanical function was impaired in MP users and cigarette smokers Table 2. Left atrial volume measurements in smokers, Maras powder users and control groups Group I controls (n = 50)
Group II smokers (n = 50)
Group III MP users (n = 50)
LA maximal volume (cm3/m2)
22.9 ± 5.3
21.7 ± 6.2
23.3 ± 5.5
0.322
LA minimal volume (cm3/m2)
8.9 ± 3.4
7.8 ± 2.8
9.2 ± 3.2
0.052
Volume at the onset of atrial systole (cm3/m2)
14.7 ± 4.7
14.5 ± 4.8
16.4 ± 4.3
0.087
LA passive emptying volume (cm3/m2)
8.2 ± 3.2
7.1 ± 3.4
6.9 ± 4.3
0.161
0.105
LA passive emptying fraction (%)
0.36 ± 0.11
0.297
LA active emptying volume (cm3/m2)
0.444 0.275
0.014*
BMI: body mass index, BSA: body surface area, BP: blood pressure, LV: left ventricular, LVEDD: LV end-diastolic dimension, EF: ejection fraction, HDL: high-density lipoprotein, LDL: low-density lipoprotein. All p-values > 0.05 (ANOVA test). *p-value for group II vs III.
5.8 ± 2.2
0.32 ± 0.12 0.28 ± 0.14* 6.8 ± 3.0
p-value
0.012
7.2 ± 2.5#
0.024
0.43 ± 0.11
0.003
LA total emptying volume (cm3/m2)
14.0 ± 3.3
13.9 ± 4.6
14.1 ± 4.2
0.976
LA total emptying fraction (%)
0.61 ± 0.9
0.63 ± 0.9
0.6 ± 1.0
0.170
LA active emptying fraction (%) 0.39 ± 0.10 0.46 ± 0.10§
LA = left atrial. *p = 0.012 versus group I, #p = 0.024 versus group I, §p = 0.003 versus group I.
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0.70 0.60 0.50 0.40 0.30 0.20 R linear = 0.061 2
0.10 5.00
10.00 15.00 20.00 25.00 30.00 35.00 Duration (pack years)
Left atrial active emptying volume (cm3/m2)
Left atrial active emptying fraction (%)
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25 20 15 10 5 R2 linear = 0.069 0 5.00
10.00
15.00 20.00 25.00 30.00 35.00 Duration (pack years)
Fig. 1. This shows positive correlations between LA active emptying fraction and the amount of MP use and cigarette smoking (pack years) (r = 0.25, p = 0.013).
Fig. 2. This shows positive correlations between LA active emptying volume and the amount of MP use and cigarette smoking (pack years) (r = 0.26, p = 0.009).
compared to healthy controls, but there was no significant difference between the MP users and cigarette smokers. Also, the amount of MP used and cigarette smoking (pack years) was correlated with LAAEV and LAAEF. This is the first study to determine the atrial electromechanical and mechanical functions of MP users and cigarette smokers. Cigarettes have widespread use and their smoke contains more than 4 000 toxic compounds, mainly nicotine. Various clinical and pathological investigations have shown that cigarette smoking caused atherosclerosis, myocardial infarction and heart failure,4 and nicotine abuse is associated with the occurrence of cardiac arrhythmias.9,12 The pro-arrhythmic effect of cigarette smoking seems to depend on the nicotine concentration in the blood.9 Increased nicotine levels increase atrial and ventricular vulnerability to fibrillation.9,12 These effects are more likely to depend on the inhibition of ion channels and conductionslowing properties. One factor known to cause a substantial slowing of electrical impulse propagation in cardiac tissue is an increase in the amount of interstitial collagen. It has been found that the prolonged administration of nicotine is also associated with the loss of intracellular K+ and the emergence of cardiac necrosis.21 Experimentally, Goette et al. established a linear correlation between nicotine dose and atrial collagen expression, leading
to symptomatic atrial fibrosis at a younger age.22 In previous reports, atrial conduction time was found to be prolonged independently of LA dilatation.20,23 In a study consisting of 50 smokers and 40 non-smokers, it was found that inter- and intra-atrial electromechanical delay was significantly higher in cigarette smokers compared with non-smokers, and the amount of smoking was strongly correlated with inter-atrial electromechanical delay.24 Distinct from that study, our study contained a third group, the MP users, and we also investigated left atrial mechanical function in our study population. Likewise, we found that although LA was not dilated, atrial conduction time was prolonged in both MP users and smokers. This may be explained as the negative effects of nicotine on cardiac structure and function. The development of interstitial fibrosis affects chamber geometry and mechanical performance of the heart and enhances the likelihood of cardiac arrhythmias, such as atrial fibrillation (AF). Moreover, in prospective, population-based and 16-year follow-up studies, it has been shown that smoking was associated with incidence of AF, with more than a two-fold increased risk of AF attributed to current smoking.25 The risk of AF increased with increasing cigarette years of smoking, and appeared to be somewhat greater among current smokers than former smokers with similar cigarette years of smoking.25 MP is a form of smokeless tobacco. The ash in this mixture transforms the alkaloids into a base form and provides easy absorption from the buccal mucosa.26 As MP contains six- to10fold more nicotine than cigarettes, it is preferred by addicts. It has been shown that urinary cotinine levels were three times higher in MP users than in cigarette smokers.27 Besides, MP is closely associated with traditional cardiovascular risk factors and endothelial dysfunction, as detected by low plasma NO levels.3 MP increases oxidative stress and lipid peroxidation levels, which are the best indicators of cytological damage.28 Because of the deleterious effects of cigarette smoking, especially the nicotine blood level, it stimulates the sympathetic nerve endings and increases adrenaline release, which in turn increases cardiovascular abnormalities.29 The probability of abnormalities of the cardiac conduction system and the
Table 3. Findings of atrial electromechanical coupling measured by tissue Doppler imaging Group I controls (n = 50)
Group II smokers (n = 50)
Group III MP users (n = 50)
p-value
Lateral PA (ms)
48.3 ± 9.8
53.9 ± 12.9
54.1 ± 14.1§
0.032
Septal PA (ms)
40.1 ± 8.7
46.3 ± 13.3#
45.8 ± 15.2
0.028
RV PA (ms)
34.1 ± 8.4
38.4 ± 9.9
37.5 ± 12.7
0.098
Lateral PA–septal PA (ms)
8.1 ± 3.5
7.9 ± 4.3
8.2 ± 3.9
0.687
Lateral PA–RV PA (ms)*
14.2 ± 8.9
15.5 ± 10.1
16.5 ± 8.4
0.443
Septal PA–RV PA (ms)**
6.0 ± 5.9
7.9 ± 8.8
8.2 ± 7.7
0.287
PA: the interval with tissue Doppler imaging, from the onset of P wave on the surface electrocardiogram to the beginning of the late diastolic wave (Am wave). *Inter-atrial dyssynchrony, **intra-atrial dyssynchrony. § p = 0.05 versus group I, #p = 0.04 versus group I.
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occurrence of cardiac arrhythmias in MP users with a high blood nicotine level may also be high. Furthermore, it is well known that myocardial ischaemia, systemic inflammation, oxidative stress and increased sympathetic activity play an important role in the pathogenesis of atrial fibrillation (AF). In addition, a case report was found that indicated that the use of MP may lead to the occurrence of paroxysmal AF.30 Atrial electromechanical delay can be measured by invasive or non-invasive methods. Recent studies have assessed atrial electromechanical delay with TDI echocardiography, which is an alternative, non-invasive method to invasive electrophysiological studies.31,32 In previous studies, it was found that atrial conduction time measured by TDI was an independent predictor of new-onset or recurrence of AF.13,31 LA mechanical function consists of reservoir, and passive and active emptying functions at different stages of the cardiac cycle. The reservoir function takes effect during ventricular systole, the passive emptying function in early diastole and the active emptying function during ventricular diastole in the presence of sinus rhythm. When LV dysfunction develops, the LA may possibly preserve adequate cardiac output by regulation of the reservoir and booster pump function. We demonstrated that LA mechanical function was impaired in MP users and smokers, but there was no significant difference between the MP users and cigarette smokers. LAPEF was significantly decreased and LAAEV was significantly increased in the MP group but not in the control group. LAAEF was significantly increased in the cigarette smoking group but not in the control group. LAPEF is related to elevated end-diastolic LV pressure, and the increase in LAAEV is associated with a compensatory mechanism in LA contraction. These findings may be an indirect indication that nicotine has greater effects on the atrial tissue over time. Additionally, Eroglu et al. demonstrated that chronic cigarette smoking caused changes in long-axis systolic and diastolic function of the right and left ventricles in healthy young subjects.33 Our study population consisted of relatively young subjects. LA electromechanical and mechanical functions were impaired in our smokers and MP users without overt cardiovascular disease, probably due to the negative effects of nicotine. This may be an early sign of atrial dysfunction preceding AF in these subjects.
Conclusion
Study limitations
11. Jolma CD, Samson RA, Klewer SE, Donnerstein RL, Goldberg SJ. Acute
On the basis of our findings, we suggest that atrial electromechanical coupling intervals were prolonged and left atrial mechanical function was impaired in MP users and cigarette smokers, but there was no significant difference between MP users and cigarette smokers. Furthermore, the amount of MP use and cigarette smoking (pack years) was correlated with LAAEV and LAAEF. These findings may be markers of subclinical cardiac involvement and a risk for AF.
References 1.
Saitoh F, Noma M, Kawashima. The alkaloid contents of sixty Nicotiana species. Phytochemistry 1985; 24: 477–480.
2.
Kilinc M, Okur E, Kurutas EB, Guler FI, Yildirim I. The effects of Maras powder (smokeless tobacco) on oxidative stres in users. Cell Biochem Funct 2004; 22: 233–236.
3.
Guven A, Tolun F. Effects of smokeless tobacco “Maras Powder” use on nitric oxide and cardiovascular risk parameters. Int J Med Sci 2012; 9: 786–792.
4.
Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol 1997; 29: 1422–1431.
5.
Ciftçi O, Günday M, Calişkan M, Güllü H, Güven A, Müderrisoğlu H. Light cigarette smoking and vascular function. Acta Cardiol 2013; 68: 255–261.
6.
Qiao Q, Tervahauta M, Nissinen A, Tuomilehto J. Mortality from all cause and from coronary heart disease related to smoking and changes in smoking during a 35-year follow-up of middle-aged Finnish men. Eur Heart J 2000; 21(19): 1621–1626.
7.
Mehta MC, Jain AC, Mehta A, Billie M. Cardiac arrhythmias following intravenous nicotine: experimental study in dogs. J Cardiovasc Pharmacol Ther 1997; 2: 291–298.
8.
Yashima M, Ohara T, Cao JM, Kim YH, Fishbein MC, Mandel WJ, et al. Nicotine increases ventricular vulnerability to fibrillation in hearts with healed myocardial infarction. Am J Physiol Heart Circ Physiol 2000; 278: 2124–2133.
9.
Niedermaier ON, Smith ML, Beightol LA, Zukowska-Grojec Z, Goldstein DS, Eckberg DL. Influence of cigarette smoking on human autonomic function. Circulation 1993, 88: 562–571.
10. Ileri M, Yetkin E, Tandoğan I, Hisar I, Atak R, Senen K, et al. Effect of habitual smoking on QT interval duration and dispersion. Am J Cardiol 2001; 88: 322–325.
The major limitation of our study was its cross-sectional design and lack of follow up of the patients. The subjects could not be followed up for episodes of arrhythmia, therefore, we do not know whether parameters of prolonged atrial electromechanical delay and impaired LA mechanical function can be used for the prediction of arrhythmias and heart failure in MP users and smokers. For these reasons, long-term follow up and large-scale prospective studies are needed to determine the predictive value of prolonged atrial electromechanical delay parameters and LA mechanical function in this population. The absence of detailed parameters of diastolic function and measurement of blood nicotine levels were also potential limitations of our study. Furthermore, factors such as the subjects’ diet and exercise habits, which may affect diastolic function, could not be evaluated in our study.
cardiac effects of nicotine in healthy young adults. Echocardiography 2002; 19: 443-448. 12. Hayashi H, Omichi C, Miyauchi Y, Mandel WJ, Lin SF, Chen PS, et al. Age-related sensitivity to nicotine for inducible atrial tachycardia and atrial fibrillation. Am J Physiol Heart Circ Physiol 2003; 285: 2091–2098. 13. Deniz A, Yavuz B, Aytemir K, Hayran M, Kose S, Okutucu S, et al. Intra-left atrialmechanical delay detected by tissue Doppler echocardiography can be a useful marker for paroxysmal atrial fibrillation. Echocardiography 2009; 26: 779–784. 14. Yilmaz M, Ozlem AO, Akgumus A, Peker T, Karaagac K, Vatansever F, et al. Left atrial mechanical functions in patients with the metabolic syndrome. Acta Cardiol 2013; 68: 133–137. 15. Acar G, Sayarlioğlu M, Akçay A, Sökmen A, Sökmen G, Yalçintaş S, et al. Evaluation of atrial electromechanical delay and left atrial mechanical functions in patients with rheumatoid arthritis. Turk Kardiyol Dern Ars 2009; 37: 447–453.
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raphy and P-wave dispersion in smokers. J Interv Card Electrophysiol
16. Modena MG, Muia N, Sgura FA, Molinari R, Castella A, Rossi R. Left
2012; 34: 247–253.
atrial size is the major predictor of cardiac death and overall clinical outcome in patients with dilated cardiomyopathy: a long-term follow up
25. Chamberlain AM, Agarwal SK, Folsom AR, Duval S, Soliman EZ,
study. Clin Cardiol 1997; 20: 553–560.
Ambrose M, et al. Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study. Heart
17. Simek CL, Feldman MD, Haber HL, Wu CC, Jayaweera AR, Kaul
Rhythm 2011; 8: 1160–1166.
S. Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function. J Am Soc
26. Erenmemisoglu A, Tekol Y, Kartal M. The use of a smokeless tobacco in our country “Maras Powder”. Turk J Med Sci 1992; 16: 567–576.
Echocardiogr 1995; 8: 37–47. 18. Quiñones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA.
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27. Cok I, Ozturk R. Urinary cotinine levels of smokeless tobacco (Maras powder) users. Human Exp Toxicol 2000; 19: 650–655.
Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the
28. Kilinc M, Okur E, Kurutas EB, Guler FI, Yildirim I. The effects of
Nomenclature and Standards Committee of the American Society of
Maras powder (smokeless tobacco) on oxidative stress in users. Cell Biochem Funct 2004; 22: 233–236.
Echocardiography. J Am Soc Echocardiogr 2002; 15: 167–184. 19. Toutouzas K, Trikas A, Pitsavos C, Barbetseas J, Androulakis A,
29. Edvinsson ML, Andersson SE, Xu CB, Edvinsson L. Cigarette smoking
Stefanadis C, et al. Echocardiographic features of left atrium in elite
leads to reduced relaxant responses of the cutaneous microcirculation. Vasc Health Risk Manag 2008; 4: 699–704.
male athletes. Am J Cardiol 1996; 78: 1314–1317. 20. Acar G, Akcay A, Sokmen A, Ozkaya M, Guler E, Sokmen G, et al. Assessment of atrial electromechanical delay, diastolic functions, and left atrial mechanical functions in patients with type 1 diabetes mellitus. J Am Soc Echocardiogr 2009; 22: 732–738. 21. Wenzel DG, Stark LG. Effect of nicotine on cardiac necrosis induced by isoproterenol. Am Heart J 1966; 71: 368–370.
30.
Sogut O, Sayhan MB, Ustundag M, Orak M. Paroxysmal atrial fibrillation after smokeless tobacco (Maras powder) use. J Chin Med Assoc 2009; 72: 265–267.
31. De Vos CB, Weijs B, Crijns HJ, Cheriex EC, Palmans A, Habets J, et al. Atrial tissue Doppler imaging for prediction of new-onset atrial fibrillation. Heart 2009; 95: 835–840.
22. Goette A, Lendeckel U, Kuchenbecker A, Bukowska A, Peters B, Klein
32. Antonini L, Ficili S, Pasceri V, Cianfrocca C, Galeazzi M, Pandozi
HU, et al. Cigarette smoking induces atrial fibrosis in humans via nico-
C, Aiello A, Santini M. A new echo-Doppler method to measure
tine. Heart 2007; 93: 1056–1063.
interatrial conduction time. Validation and clinical usefulness. Minerva
23. Sokmen A, Acar G, Sokmen G, Akcay A, Akkoyun M, Koroglu S, et al. Evaluation of atrial electromechanical delay and diastolic functions in patients with hyperthyroidism. Echocardiography 2013; 30: 1194–1201. 24. Akturk E, Yağmur J, Açıkgöz N, Ermiş N, Cansel M, Karakuş Y, et al. Assessment of atrial conduction time by tissue Doppler echocardiog-
Cardioangiol 2011; 59: 9–15. 33. Eroglu E, Aydin S, Yalniz F, Kalkan AK, Bayrak F, Degertekin M. Chronic cigarette smoking affects left and right ventricular long-axis function in healthy young subjects: a Doppler myocardial imaging study. Echocardiography 2009; 26: 1019–1025.
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Postoperative atrial fibrillation in patients with left atrial myxoma Muslum Sahin, Kursat Tigen, Cihan Dundar, Beste Ozben, Gokhan Alici, Serdar Demir, Mehmet Emin Kalkan, Birol Ozkan
Abstract Introduction: The aim of this study was to determine the factors associated with postoperative atrial fibrillation (AF) in patients with left atrial (LA) myxoma. Methods: Thirty-six consecutive patients with LA myxoma (10 men, mean age: 49.3 ± 15.7 years), who were operated on between March 2010 and July 2012, were included in this retrospective study. Pre-operative electrocardiograms and echocardiographic examinations of each patient were reviewed. Results: Postoperative AF developed in 10 patients, whereas there was no evidence of paroxysmal AF after resection of the LA myxoma in the remaining 26 patients. The patients who developed AF postoperatively were significantly older than those who did not develop AF (median: 61.5 vs 46 years; p = 0.009). Among the electrocardiographic parameters, only P-wave dispersion differed significantly between postoperative AF and non-AF patients (median: 57.6 vs 39.8 ms, p = 0.004). Logistic regression analysis revealed P-wave dispersion (OR: 1.11, 95% CI: 1.003–1.224, p = 0.043) and age (OR: 1.13, 95% CI: 1.001–1.278, p = 0.048) as independent predictors of postoperative AF in our cohort of patients. Conclusions: P-wave dispersion is a simple and useful parameter for the prediction of postoperative AF in patients with LA myxoma. Keywords: atrial fibrillation, left atrium, myxoma, postoperative, P-wave dispersion Submitted 5/5/13, accepted 27/11/14 Cardiovasc J Afr 2015; 26: 120–124
www.cvja.co.za
DOI: 10.5830/CVJA-2014-069
Paroxysmal atrial fibrillation (AF) is the most common arrhythmia following cardiac surgery such as coronary artery bypass grafting (CABG), and often occurs between the second and fourth postoperative days.1,2 The reported incidence of paroxysmal AF after CABG surgery varies widely, from five to Department of Cardiology, Kartal Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey Muslum Sahin, MD, sahinm78@yahoo.com Cihan Dundar, MD Gokhan Alici, MD Serdar Demir, MD Mehmet Emin Kalkan, MD Birol Ozkan, MD
Department of Cardiology, Marmara University School of Medicine, Istanbul, Turkey Kursat Tigen, MD Beste Ozben, MD
40%, which is lower than in cases of valvular cardiac surgery.3,4 Although this arrhythmia is usually benign and self-limiting, it may also be associated with increased risk of embolic events, haemodynamic instability, haemorrhagic complications, prolonged hospital stay and higher rates of re-admissions, increasing the healthcare costs.5-7 Several risk factors have been proposed for paroxysmal AF after CABG or valvular cardiac surgery, such as advanced age, genetic predisposition, chronic obstructive pulmonary disease, heart failure or increased peri-operative ischaemia.8-10 In addition, certain echocardiographic parameters such as left atrial (LA) diameter or left ventricular (LV) function, and electrocardiographic parameters including P-wave duration and P-wave dispersion (Pd) have been shown to be associated with postoperative AF.11-13 Although postoperative AF and its predictors after CABG and valvular surgery have been well researched, no study has been performed to explore the incidence or predictors of postoperative AF in patients with LA myxoma. The aim of this study was to identify the prevalence and predictors of postoperative AF in a pure cohort of patients with LA myxoma.
Methods This study complies with the principles outlined in the Declaration of Helsinki. The study was approved by the local ethics committee and all participants gave written informed consent to participate in the study. The electrocardiograms and echocardiographic recordings of the 44 consecutive patients with LA myxoma who underwent its excision in our centre between March 2000 and July 2012 were evaluated retrospectively. Previous history of AF or atrial flutter, use of anti-arrhythmic drugs other than beta-blockers, concomitant valvular disease other than mild mitral regurgitation, symptomatic heart failure, renal disease, thyroid disorders, chronic obstructive pulmonary disease, and presence of an implanted pacemaker were exclusion criteria. Patients who had undergone any surgery other than excision of a LA myxoma, including CABG, had sustained ventricular tachyarrhythmia or cardiogenic shock or died in the operating room were also excluded. All medical records including standard pre-operative 12-lead electrocardiograms (ECG), transthoracic echocardiography, laboratory tests and blood pressure measurements were carefully checked and documented. All patients were in sinus rhythm before surgical excision of the tumour and their cardiac rhythms were followed continuously during their stay in the intensive care unit for at least for 48 hours by direct rhythm monitoring. After discharge from the intensive care unit, the patients were followed up with daily ECGs and rhythm evaluation after complaints of palpitations, to diagnose any episodes of paroxysmal AF. All patients were re-evaluated three months
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after surgery and the ECG and echocardiographic examinations performed at that visit were also recorded. After the exclusion of patients with any missing information, the remaining 36 out of 44 patients with LA myxoma who were surgically treated in our institution were included in the study. Postoperative AF was defined as any episode of atrial tachyarrhythmia, including AF or atrial flutter that lasted more than 30 seconds, diagnosed with a rhythm monitor/telemetry and/or ECG, and/or initiation of treatment for atrial fibrillation such as amiodarone or cardioversion during hospitalisation.14,15 Surgery was performed via a median sternotomy under cardiopulmonary bypass with cardioplegic arrest. The LA myxoma was excised through a left atriotomy with trans-septal approach or via a biatrial approach in suitable cases. After removing the mass, the resulting atrial septal defect was repaired by direct suture or insertion of a Dacron patch.
Evaluation of pre- and postoperative ECGs All patients had standard pre-operative (one day before surgery) and postoperative (one week after surgery) 12-lead ECGs, which were recorded at a paper speed of 25 mm/s, a sensitivity of 1 mV/ cm and filter settings of 0.05–40 Hz. The ECGs were scanned and magnified five times.
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P-wave duration and dispersion were measured as previously described.16 Briefly, P-wave duration was measured in three consecutive complexes of each lead, from the junction between the iso-electric line and the beginning of the P-wave deflection to the junction between the end of the P wave and isoelectric line, by a single observer who was blinded to the patients. To improve accuracy, measurements were made using calipers and a magnifying lens. P-wave dispersion was defined as the time measured from the onset to the offset of the P wave. The Pmax and the Pmin were measured in all 12-lead surface ECGs. The Pd was defined as the difference between the Pmax and the Pmin. Intra-observer variability was found to be 4.5% for Pmax and 4.1% for Pd. A Pd > 40 ms was defined as increased Pd.17 The P–R interval, QRS duration, QT and rate-corrected QT interval were measured similar to previous studies.18,19
Evaluation of echocardiography All patients underwent transthoracic echocardiography, performed according to American Society of Echocardiography recommendations before surgery and three months after surgery.20 LA diameter and LV dimensions of the patients obtained by M-mode echocardiography in the parasternal long-axis view were recorded. Mitral regurgitation (MR) was graded by standard Doppler criteria.
Fig. 1. Measuring the tumour dimensions in different planes. LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle; arrow: myxoma.
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Table 1. The clinical characteristics of the patients Postoperative AF group (n = 10)
Table 3. The pre-operative echocardiographic parameters of the patients
Non-AF group (n = 26)
Median Min–max Median Min–max
Postoperative AF group (n = 10) p-value
Non-AF group (n = 26)
Median Min–max Median Min–max p-value
Age (years)
61.5
42–79
46
20–72
0.009
LA diameter (mm)
42
31–51
37
29–60
0.147
Body mass index (kg/m2)
28.5
20.7–35.1
25.9
17.9–41.1
0.168
LV end-diastolic diameter (mm)
48.5
45–64
48
38–64
0.241
31
23–55
29
23–40
0.107 0.019
Hypertension, n (%)
6 (60)
6 (23.1)
0.053
LV end-systolic diameter (mm)
Diabetes, n (%)
1 (10)
3 (11.5)
1.00
LV ejection fraction (%)
62.5
30–65
65
50–80
Hyperlipidaemia, n (%)
1 (10)
1 (3.8)
0.484
E/A
0.8
0.67–1.50
1.3
0.6–1.71
0.05
Tumour size (mm3)
21.2
9.4–63.7
17.2
4.2–51.3
0.331
AF: atrial fibrillation; Max: maximum; Min: minimum.
AF: atrial fibrillation; E/A: early/late diastolic peak flow velocity; LA: left atrium; LV: left ventricle; Max: maximum; Min: minimum.
Tumour dimensions were measured in three different planes. The maximum diameter in any of the planes was taken as a reference of the size of the tumour in that plane (Fig. 1). By calculating the average radius of the tumour in three different planes, the approximate echocardiographic volume of the tumour was calculated using the formula 4/3πr3.21
Statistical analysis Statistical analysis was performed using a statistical software program (SPSS for Windows, version 15.0; SPSS Inc, Chicago, Illinois, USA). Continuous variables were expressed as medians (min–max), controlled for normal distribution by the Kolmogorov–Smirnov test and compared using non-parametric tests (Mann–Whitney U-test) because of abnormal distribution. Categorical data between two or more groups were compared with the Pearson χ2 test. Pre- and postoperative ECG data were compared with the Wilcoxon test. A logistic regression analysis was used to determine significant predictors of postoperative AF in patients with LA myxoma. A p-value < 0.05 was considered statistically significant.
Results The study included 36 consecutive patients with LA myxoma (10 men, mean age: 49.3 ± 15.7 years). The most commonly reported symptom was dyspnoea, which was observed in 13 patients. Eight patients presented with palpitations, three with angina, five complained of syncope and seven had a transient ischaemic attack or cerebrovascular event. Seven patients were asymptomatic. The LA myxoma was excised through a left atriotomy in 19 patients, whereas the trans-septal and biatrial approach were used in the remaining nine and eight patients, respectively. After removing the mass, the resulting atrial septal defect was repaired Table 2. The pre-operative electrocardiographic parameters of the patients Postoperative AF group (n = 10)
by direct suture in 34 patients and by insertion of a Dacron patch in two. The tumour volume of the patients ranged from 4.2 to 63.7 cm3 (mean: 20.3 ± 12.7 cm3). The tumour volume of those with cerebral symptoms was significantly higher than in the other patients (median: 23.1 vs 14.3 cm³, p = 0.015). Ten patients had developed AF after surgery. The characteristics of the patients are shown in Table 1, while Tables 2 and 3 show their pre-operative electrocardiographic and echocardiographic parameters. The patients who developed AF postoperatively were significantly older than those who did not develop AF (median: 61.5 vs 46 years, p = 0.009). Among the electrocardiographic parameters, only Pd differed significantly between AF and non-AF patients (median: 57.6 vs 39.8 ms, p = 0.004). The LV ejection fraction (median: 62.5 vs 65%, p = 0.019) and mean E/A (median: 0.8 vs 1.3, p = 0.05) were lower in the AF group than in non-AF patients. The tumour volume was similar in AF and non-AF patients. The pre-operative and postoperative ECG findings are listed in Table 4. P-wave amplitude, duration and Pd differed significantly after the surgical procedure (p < 0.001, p = 0.001 and p < 0.001, respectively). We modelled a logistic regression analysis to determine the independent predictors of postoperative AF. Age, LA dimension, tumour volume, aortic cross-clamping time and Pd were included in the model. Logistic regression analysis revealed Pd (OR: 1.11, 95% CI: 1.003–1.224, p = 0.043) and age (OR: 1.13, 95% CI: 1.001–1.278, p = 0.048) as independent predictors of postoperative AF in our cohort of patients.
Discussion This study indicated that postoperative AF may also occur after the excision of the tumour in patients with LA myxoma. LA myxomas may cause severe mitral valve stenosis.22 Atrial arrhythmias such as AF or flutter may also be identified in Table 4. The electrocardiographic parameters of the patients one day before and one week after surgery
Non-AF group (n = 26)
Median
Min–max
Heart rate (beats/min)
76.5
64–127
85.5
53–109
0.349
P-wave amplitude (mV)
1.5
0.93–2.72
2.05
0.81–3.64
0.129
P-wave duration (ms)
124
99.6–129.2
112.4
57.6–134
0.069
P-wave dispersion (ms)
57.6
41.2–71.6
39.8
17.2–70
0.004
QTc dispersion (ms)
50
40–100
40
40–130
Increased P-wave dispersion (n)
10
Pre-operative
Median Min–max p-value
9
0.124 < 0.001
AF: atrial fibrillation; Max: maximum; Min: minimum; QTc: corrected QT interval.
Postoperative
Median
Min–max
Median
Min–max
p-value
82
53–127
86.5
64–144
0.606
P-wave amplitude (mV)
1.98
0.81–3.64
1.28
0.64–2.17 < 0.001
P-wave duration (ms)
117.2
57.6–134
98.4
70.8–126
P-wave dispersion (ms)
50.5
17.2–71.6
30
10–60
< 0.001
P–R interval (ms)
160
110–240
150
90–230
0.063
QRS interval (ms)
90
80–98
90
70–130
0.837
QTc dispersion (ms)
50
10–130
40
10–90
0.437
Heart rate (beats/min)
Max: maximum; Min: minimum; QTc: corrected QT interval.
0.001
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patients with atrial myxoma.23 Large myxomas may almost fully occupy the atrial outflow and lead to increased LA pressure.24 As a result, obstructing atrial outflow and atrial arrhythmias could contribute to elevated LA pressure and dilated LA cavity. Atrial overload or ventricular hypertrophy, which secondarily increased the chamber diameter and altered conduction, could lead to abnormal electrocardiography findings.25 Also tumour size may have been responsible for the changes on ECG.26 Harikrishnan et al.21 showed that larger tumour size correlated with LA enlargement on ECG in patients with LA myxoma. They also showed that evidence of LA enlargement on ECG disappeared in most patients after excision of the tumour. However, Aggarwal et al.27 found no correlation between tumour size and signs of LA enlargement on ECG. They found that only 35% of the patients with myxoma had signs of LA enlargement on ECG. In our study, we found that neither tumour volume nor LA dimensions correlated with postoperative AF. However, pre-operative Pd and age were independent predictors of postoperative AF in our cohort. We also found that P-wave duration, amplitude and Pd were significantly shortened after tumour resection. Abnormal P-wave morphology reflects abnormality of LA size and LA structural abnormalities.13 Previous reports8,28 showed that age and LA dimension are independent predictors for occurrence of AF after cardiac surgery. However, a prior study has demonstrated that age and LA dimension were not as powerful as abnormal P-wave morphology.13 Similar to previous studies,8,13,28 our results suggested that abnormal P-wave morphology was the main independent predictor for the development of postoperative AF but the aetiology of AF following cardiac surgery was multifactorial. Pre-operative factors such as age, previous rheumatic fever, hypertension, coronary syndromes, LV hypertrophy, LA enlargement, history of congestive heart failure, electrolytic imbalance, obesity, male gender, chronic obstructive pulmonary disease,29 and surgical factors such as traumatic laceration of the atrial tissue (suture line, haematoma and other traumatic causes)30 may increase the incidence of postoperative AF. LV diastolic dysfunction led to an increase in LV end-diastolic diameter and LA pressure. The elevated atrial pressure dilates the atrium and triggers non-homogeneous fibrosis, which changes the shape and geometry of the atrium. All these changes may induce atrial arrhythmias, especially atrial fibrillation.31,32 P-wave dispersion was also demonstrated to be influenced by elevated LA pressure.33 In our study, LV diastolic function was impaired in patients with postoperative AF. Although statistically non-significant, tumour volumes of postoperative AF patients were higher, suggesting a positive effect on atrial pressure. Higher atrial pressure may prolong the duration and dispersion of the P wave in this patient group. There was no difference between patient groups in terms of LA dimensions, which may have been a result of inaccurate measurement. LA volume or multiplane dimension measurements could clarify our results. Maximal P-wave duration and Pd have been shown to be a non-invasive predictor of AF in patients with mitral and aortic stenosis, dilated cardiomyopathy, acute myocardial infarction, and atherosclerotic heart disease.34,35 However, there has been no study evaluating the predictive value of Pd for postoperative AF in patients with LA myxoma. Our study
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suggests a significant association between postoperative AF and pre-operative Pd values in these patients. All patients who developed AF postoperatively had significantly increased Pd (more than 40 ms). We also found that patients who developed postoperative AF were significantly older than non-AF patients. Previous reports estimated a 24% increase in the incidence of new-onset postoperative AF with each additional five years of age.36 Age-related degenerative change and electrophysiological abnormality of atrial cells are the main causes of post-CABG AF in advanced age, mainly patients older than 70 years of age.37,38 Cardiac myxomas are the most common primary tumour of the heart, and roughly 90% of the tumours are located in the atria, with the LA accounting for 80% of those.25 The most common symptom is dyspnoea, followed by palpitation.39 Atrioventricular valve and outflow tract obstruction, and AF may contribute to dyspnoea and palpitation. Dyspnoea was the most common reported symptom in our study. Symptoms depend on the size, form, mobility and location of the tumour.40 The obstruction, mainly caused by large, pedunculated tumours, can decrease cerebral flow and lead to syncope. Also the risk of embolism is higher for polypoid or multilobular tumours.41 Twelve patients presented with cerebral symptoms in our study and their tumours were larger than those without cerebral symptoms.
Study limitations The retrospective design of our study and the small sample size were limitations. Third, there was no long-term Holter monitoring for the detection of AF episodes. Continuousrhythm Holter monitoring during the intensive care period, and telemetry monitoring up to discharge may be a more accurate method to detect transient episodes of AF during hospital stay. Fourth, tumour volume was calculated with the assumption that the tumour was spherical in shape.
Conclusion This study showed a high incidence of postoperative AF following surgery in patients with LA myxoma. To identify patients at risk for AF after surgery, Pd is an independent predictor and can be used for patient risk stratification.
References 1. Mahoney EM, Thompson TD, Veledar E, Williams J, Weintraub WS. Cost-effectiveness of targeting patients undergoing cardiac surgery for therapy with intravenous amiodarone to prevent atrial fibrillation. J Am Coll Cardiol 2002; 21; 40: 737–745. 2. Attaran S, Shaw M, Bond L, Pullan MD, Fabri BM. Atrial fibrillation postcardiac surgery: a common but a morbid complication. Interact Cardiovasc Thorac Surg 2011; 12: 772–777. 3. Hata M, Akiyama K, Wakui S, Takasaka A, Sezai A, Shiono M. Does warfarin help prevent ischemic stroke in patients presenting with post coronary bypass paroxysmal atrial fibrillation? Ann Thorac Cardiovasc Surg Aug 2012; 20. [Epub ahead of print]. 4. Treggiari-Venzi MM, Waeber JL, Perneger TV, Suter PM, Adamec R, Romand JA. Intravenous amiodarone or magnesium sulphate is not costbeneficial prophylaxis for atrial fibrillation after coronary artery bypass
124
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surgery. Br J Anaesth 2000; 85: 690–695.
graphic findings. Indian Heart J 2012; 64: 170–172.
5. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic
22. Mouine NN, Asfalou II, Raissouni MM, Benyass AA, Zbir el ME. Giant
features of chronic atrial fibrillation: the Framingham study. N Engl J
left atrial myxoma mimicking severe mitralvalve stenosis and severe
Med 1982; 306: 1018–1022. 6. Kowey PR. Atrial arrhythmias after cardiac surgery: Sisyphus revisited? J Am Coll Cardiol 1999; 34: 348–350. 7. Hakala T, Pitkänen O, Hippeläinen M. Feasibility of predicting the risk of atrial fibrillation after coronary artery bypass surgery with logistic regression model. Scand J Surg 2002; 91: 339–344. 8. Aranki SF, Shaw DP, Adams DH, Rizzo RJ, Couper GS, VanderVliet M, et al. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation 1996; 1(94): 390–397. 9. Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, et
pulmonary hypertension. Int Arch Med 2013; 19(6): 13. 23. Steger CM, Hager T, Ruttmann E. Primary cardiac tumours: a singlecenter 41-year experience. ISRN Cardiol 2012: 906109. 24. Fish RG, Takaro T, Crymes T. Left atrial pressure pulses in the presence of myxoma. Circulation 1959; 20: 413–418. 25. Wang JG, Li YJ, Liu H, Li NN, Zhao J, Xing XM. Clinicopathologic analysis of cardiac myxomas: Seven years’ experience with 61 patients. J Thorac Dis 2012; 4: 272–283. 26. Pinede L, Duhaut P, Loire R. Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases. Medicine (Baltimore) 2001; 80: 159–172.
al. Investigators of the Ischemia Research and Education Foundation;
27. Aggarwal SK, Barik R, Sarma TC, Iyer VR, Sai V, Mishra J, et al.
Multicenter Study of Perioperative Ischemia Research Group. A multi-
Clinical presentation and investigation findings in cardiac myxomas: new
center risk index for atrial fibrillation after cardiac surgery. J Am Med Assoc 2004; 14; 291: 1720–1729. 10. Ak K, Akgun S, Tecimer T, Isbir CS, Civelek A, Tekeli A, et al. Determination of histopathologic risk factors for postoperative atrial fibrillation in cardiac surgery. Ann Thorac Surg 2005; 79: 1970–1975. 11. Levy F, Debry N, Labescat AL, Meimoun P, Malaquin D, Marechaux S, et al. Echocardiographic prediction of postoperative atrial fibrillation
insights from the developing world. Am Heart J 2007; 154: 1102–1107. 28. Almassi GH, Schowalter T, Nicolosi AC, Aggarwal A, Moritz TE, Henderson WG, et al. Atrial fibrillation after cardiac surgery. A major morbid event? Ann Surg 1997; 226: 501–511. 29. Koniari I, Apostolakis E, Rogkakou C, Baikoussis NG, Dougenis D. Pharmacologic prophylaxis for atrial fibrillation following cardiac surgery: a systematic review. J Cardiothorac Surg 2010; 30(5): 121.
after aortic valve replacement for aortic stenosis: A two-dimensional
30. Sabzi F, Zokaei AH, Moloudi AR. Predictors of atrial fibrillation follow-
speckle tracking left ventricular longitudinal strain multicentre pilot
ing coronary artery bypass grafting. Clin Med Insights Cardiol 2011; 5:
study. Arch Cardiovasc Dis 2012; 105: 499–506.
67–75.
12. Hashemi Jazi M, Amirpour A, Zavvar R, Behjati M, Gharipour M.
31. Myeburg RJ, Kessler KM, Castellanos A. Recognition clinical assess-
Predictive value of P-wave duration and dispersion in post coronary
ment and management of arrhythmias and conduction disturbances. In:
artery bypass surgery atrial fibrillation. ARYA Atheroscler 2012; 8: 59–62.
Alexander RW, Schlant RC, Fuster V, eds. Hurst’s The Heart. New York:
13. Haghjoo M, Basiri H, Salek M, Sadr-Ameli MA, Kargar F, Raissi K, et al. Predictors of postoperative atrial fibrillation after coronary artery bypass graft surgery. Indian Pacing Electrophysiol J 2008; 1(8): 94–101.
MC Graw-Hill 1998; 873–941. 32. Murgatroyd FD, Camm AJ. Atrial arrhythmias. Lancet 1993; 341: 1317–1322.
14. Weimar T, Schena S, Bailey MS, Maniar HS, Schuessler RB, Cox JL,
33. Turhan H, Yetkin E, Senen K, Yilmaz MB, Ileri M, Atak R, et al. Effects
et al. The cox-maze procedure for lone atrial fibrillation: a single-center
of percutaneous mitral balloon valvuloplasty on P-wave dispersion in
experience over 2 decades. Circ Arrhythm Electrophysiol 2012; 5: 8–14.
patients with mitral stenosis. Am J Cardiol 2002; 89: 607–609.
15. Henri C, Giraldeau G, Dorais M, Cloutier AS, Girard F, Noiseux N, et
34. Uyarel H, Ozdöl C, Karabulut A, Okmen E, Cam N. Acute alcohol
al. Atrial fibrillation after pulmonary transplantation: incidence, impact
intake and P-wave dispersion in healthy men. Anadolu Kardiyol Derg
on mortality, treatment effectiveness, and risk factors. Circ Arrhythm Electrophysiol 2012; 5: 61–67.
2005; 5: 289–293. 35. Dilaveris PE, Andrikopoulos GK, Metaxas G, Richter DJ, Avgeropoulou
16. Ozuğuz U, Ergün G, Işık S, Gökay F, Tütüncü Y, Akbaba G, et al.
CK, Androulakis AM, et al. Effects of ischemia on P wave dispersion
Association between C-reactive protein, carotid intima-media thickness
and maximum P wave duration during spontaneous anginal episodes.
and P-wave dispersion in obese premenopausal women: an observational study. Anadolu Kardiyol Derg 2012; 12: 40–46. 17. Dilaveris PE, Gialafos EJ, Sideris SK, Theopistou AM, Andrikopoulos
Pacing Clin Electrophysiol 1999; 22: 1640–1647. 36. El-Chami MF, Kilgo P, Thourani V, Lattouf OM, Delurgio DB, Guyton RA, et al. New-onset atrial fibrillation predicts long-term mortality after
GK, Kyriakidis M, et al. Simple electrocardiographic markers for the
coronary artery bypass graft. J Am Coll Cardiol 2010; 55: 1370–1376.
prediction of paroxysmal idiopathic atrial fibrillation. Am Heart J 1998;
37. Dixon FE, Genton E, Vacek JL, Moore CB, Landry J. Factors predispos-
135: 733–738. 18. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353–370. 19. Zamirian M, Tavassoli M, Aghasadeghi K. Corrected QT interval and QT dispersion in cirrhotic patients before and after liver transplantation. Arch Iran Med 2012; 15: 375–377. 20. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R,
ing to supraventricular tachyarrhythmias after coronary artery bypass grafting. Am J Cardiol 1986; 58: 476–478. 38. Ommen SR, Odell JA, Stanton MS. Atrial arrhythmias after cardiothoracic surgery. N Engl J Med 1997; 336: 1429–1434. 39. Acebo
E,
Val-Bernal
JF,
Gómez-Román
JJ,
Revuelta
JM.
Clinicopathologic study and DNA analysis of 37 cardiac myxomas: a 28-year experience. Chest 2003; 123: 1379–1385.
Feigenbaum H, et al. Recommendations for quantitation of the left
40. Nogueira DC, Bontempo D, Menardi AC, Vicente WV, Ribeiro PJ,
ventricle by two-dimensional echocardiography. American Society
Evora PR. Left atrial myxoma as the cause of syncope in an adolescent.
of
Echocardiography Committee on Standards, Subcommittee
on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–367. 21. Harikrishnan S, Bohora S, Pillai VV, Sanjay G, Rajeev E, Tharakan JM, et al. Left atrial myxoma-influence of tumour size on electrocardio-
Arq Bras Cardiol 2003; 81: 206–9, 202–5. 41. Ha JW, Kang WC, Chung N, Chang BC, Rim SJ, Kwon JW, et al. Echocardiographic and morphologic characteristics of left atrial myxoma and their relation to systemic embolism. Am J Cardiol 1999: 83: 1579–1582.
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Sickle cell trait is not associated with chronic kidney disease in adult Congolese patients: a clinic-based, cross-sectional study K Mukendi, FB Lepira, JR Makulo, KE Sumaili, PK Kayembe, MN Nseka
Abstract Objective: The aim of this study was to evaluate the determinants of chronic kidney disease (CKD) with special emphasis on sickle cell trait (SCT). Methods: Three hundred and fifty-nine patients (171 men and 188 women), aged 18 years or older, with reduced kidney function (eGFR < 90 ml/min/1.73 m2) and seen at secondary and tertiary healthcare in Kinshasa were consecutively recruited in this cross-sectional study. Serum creatinine and haemoglobin electrophoresis were performed in each patient. CKD was defined as < 60 ml/min/1.73 m2. Logistic regression analysis was used to assess determinants of CKD with a special emphasis on SCT. A p-value < 0.05 defined the level of statistical significance. Results: SCT was present in 19% of the study population; its frequency was 21 and 18% (p > 0.05) in patients with and without CKD, respectively. In multivariate analysis, sickle cell trait was not significantly (OR: 0.38; 95% CI: 0.559–1.839; p = 0.235) associated with CKD; the main determinants were dipstick proteinuria (OR: 1.86; 95% CI: 1.094–3.168; p = 0.02), the metabolic syndrome (OR: 1.69; 95% CI: 1.033– 2.965; p = 0.03), haemoblobin ≥ 12 g/dl (OR: 0.36; 95% CI: 0.210–0.625; p = 0.001), and personal history of hypertension (OR: 2.16; 95% CI: 1.202–3.892; p = 0.01) and of diabetes mellitus (OR: 2.35; 95% CI: 1.150–4.454; p = 0.001). Conclusion: SCT was not an independent determinant of CKD in the present case series. Traditional risk factors emerged as the main determinants of CKD. Keywords: chronic kidney disease, determinants, sickle cell trait, black Africans Submitted 9/8/14, accepted 1/12/14 Cardiovasc J Afr 2015; 26: 125–129
www.cvja.co.za
DOI: 10.5830/CVJA-2014-076
Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kinshasa Hospital, Kinshasa, Democratic Republic of Congo K Mukendi, MD FB Lepira, MD, PhD, lepslepira@yahoo.fr KE Sumaili, MD MN Nseka, MD
School of Public Health/University of Kinshasa, Kinshasa, Democratic Republic of Congo PK Kayembe, MD
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with significant cardiovascular (CV) and renal morbidity and mortality rates, with substantial economic burden.1,2 Therefore, early identification of CKD patients at high risk of progression is urgently needed for early and targeted treatment to improve patient care.1-3 Diabetes and hypertension are the primary risk factors for CKD and ESRD but do not fully account for CKD and ESRD risk.1-3 Marked variability in the incidence of CKD suggests that factors other than diabetes and hypertension contribute to its aetiology.4 Family studies have suggested a genetic component to the aetiology of CKD and ESRD.5 In African Americans, high-risk common variants in the Apol1/MYH9 locus may explain up to 70% of the differences in ESRD rates between European and African Americans.5 While this finding has great implications for ESRD, the identification of additional risk factors for CKD, including genetic loci in association with estimated glomerular filtration rate (eGFR), may help to advance our understanding of the underpinnings of CKD in African Americans.5 In this era of identifying genetic risk factors for kidney disease, it may be appropriate to revisit one of the most common genetic disorders: sickle cell haemoglobinopathies.5 In this regard, sickle cell trait (SCT), present in approximately 7–9% of African Americans, has been reported to be a potential candidate gene.6 However, conflicting reports exist as to whether SCT is a risk factor for the progression of nephropathy.6,7 Haemoglobin S (HbS) was selected for in Africa because of the protection it affords from malarial infection, a scenario similar to the protection from trypanosomal infection provided by heterozygosity for APOL1 nephropathy risk variants.6 Whereas APOL1 contributes to risk for nephropathy in an autosomal recessive inheritance pattern, HbS reportedly had a dominant effect on risk, with SCT being associated with ESRD.6 In line with this finding, a few small studies on African Americans reported HbS as an independent risk factor for CKD and ESRD.8 However, other studies using a large sample of African Americans stated that SCT was not independently associated with susceptibility to ESRD in African Americans,6 highlighting the need for further studies in other populations such as those of sub-Saharan Africa where SCT is prevalent. Although SCT is very prevalent in black Africans,9 few studies have been conducted to assess the association between SCT and CKD.10 In Democratic Republic of Congo (DRC), the prevalence of CKD and SCT has been reported to be 12% and 17–24%, respectively.11-13 No study has evaluated the frequency of SCT among CKD patients to assess its association with reduced kidney function. Therefore, the aim of this clinic-based, crosssectional study was to assess the potential association between SCT and CKD among adult Congolese patients.
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Methods From 30 April to 24 August 2012, all consecutively appearing patients with known CKD seen in tertiary care (University of Kinshasa Hospital) and those with diabetes or hypertension regularly followed in secondary care (General Hospital of Kinshasa and Saint Joseph Hospital) were asked to participate in this cross-sectional study. Inclusion criteria were: age ≥ 18 years, antihypertensive treatment for at least three months, and written informed consent. The sample was a convenient one. Self-reported alcohol use, smoking habits, personal and family history of hypertension or diabetes, family history of sickle cell anaemia (SCA) and measure of adiposity [body mass index (BMI) and waist circumference (WC)] were obtained for all patients. Excessive alcohol intake was defined as regular intake of two or more glasses per day of beer or equivalent for at least one year, knowing that one glass of beer contains 10 g of alcohol.14 Smoking was defined as regular consumption of at least one cigarette per day for more than five years or having stopped smoking for less than five years.15 Overweight and obesity were defined as BMI ≥ 25 and ≥ 30 kg/ m², respectively.16 Central obesity was defined as WC > 94 cm in men > 80 cm in women.17 Seated blood pressure (BP) was measured using an electronic device Omron M3 on the left arm at the level of the heart after five minutes’ rest. Three consecutive BP measurements at two-minute intervals were made and the mean of the last two readings was used for analysis. Pulse pressure (PP) was calculated as systolic blood pressure (SBP) minus diastolic blood pressure (DBP) and was considered increased when > 60 mmHg.18 Hypertension was defined as BP ≥ 140/90 mmHg or current use of antihypertensive, whatever the level of BP.18 Heart rate was counted for a full minute. A 12-hour overnight fasting blood sample was collected from each patient for measurement of haemoglobin (Hb), total cholesterol (TC) and its sub-fractions [low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)], triglycerides (TG), glucose, uric acid and creatinine levels at the Laboratory of the National AIDS Control Program (NACP). LDL-C was calculated using the Friedewald formula.19 The metabolic syndrome (MetS) was defined according to 2009 consensus criteria.17 Diabetes was defined as plasma glucose > 7 mmol/l or current use of antidiabetic drugs, whatever the level of blood glucose.20 A uric acid level > 416 µmol/l was defined as hyperuricaemia.21 Serum creatinine concentrations were analysed based on a modified Jaffe reaction (picric acid) using an automated device (Dimension® XPand® Plus, Siemens). Estimated glomerular filtration rate (eGFR) was calculated using the modification of diet in renal disease (MDRD) equation,22 based on serum creatinine levels calibrated as described elsewhere.23 The Combur 9 test (Roche, France) was used on morning spot urine collections to determine semi-quantitative proteinuria; positive proteinuria was defined as Combur 9 test ≥ 1+.24 According to KDOQI,25 reduced kidney function and CKD were defined as GFR < 90 ml/min/1.73 m² and < 60 ml/min/1.73 m², respectively. Haemoglobin types were determined using isoelectrofocalisation electrophoresis (Capillaris, France) at the laboratory of Monkole Hospital in Kinshasa. This analytical method results in elution of haemoglobin variants and determines the proportion of these variants relative to the total haemoglobin
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concentration.26 It has been shown to be a reliable determinant of the HbS concentration and allows for the determination of HbS and HbC traits.26
Statistical analysis Data are expressed as mean ± standard deviation (SD) or relative frequency in percentages. Chi-square and Student’s t-tests were used for comparing categorical and normally distributed continuous variables, respectively. The Mann–Whitney test was used for non-normally distributed continuous variables. Multiple logistic regression analysis and the likelihood ratio method were performed with CKD as the dependent variable for the assessment of the strength and independence of association with CKD risk factors, among them, SCT alone or in interaction with hypertension or diabetes. Adjusted odds ratio (aOR) and their 95% confidence intervals (CI) were calculated for each variable. All statistical analyses were performed with SPSS for Windows, version 12.0 at the Division of Epidemiology and Biostatistics of Kinshasa Public Health School, University of Kinshasa.
Results A total of 359 patients with reduced kidney function (198 women and 161 men) were recruited in this study. Clinical characteristics of the study population as a whole and by renal functional status are given in Table 1. Their mean age was 56 ± 15 years; they had on average a BMI of 26 ± 5 kg/m², WC of 90 ± 14 cm, SBP of 143 ± 26 mmHg and DBP of 83 ± 13 mmHg. A family history of sickle cell disease (FH-SCD) was present in 6% of patients. Average levels of TC, HDL-C, TG, glucose, uric acid, Hb and eGFR were 5.32 ± 2.22 mmol/l, 1.49 ± 0.59 mmol/l, 1.31 ± 0.65 mmol/l, 8.16 ± 4.94 mmol/l, 360 ± 159 mmol/l, 11 ± 2.40 g/dl and 59 ± 46 ml/min/1.73 m2, respectively (Table 2). CKD was present in 188 patients (52%), of whom 40, 38 and 21% had CKD stage 3, 4 and 5, respectively (Tables 1, 2). The main causes of CKD were diabetes (44%), hypertension (39%), glomerulonephritis (14%) and other conditions (3%). Family history of sickle cell disease was present in 7 and 6% of patients with and without CKD, respectively; the difference was not statistically significant (p > 0.05). Compared to patients without CKD, those with CKD had on average higher levels of WC (92 ± 16 vs 88 ± 12 cm; p = 0.009), SBP (151 ± 26 vs 136 ± 24; p = 0.001), DBP (85 ± 15 vs 81 ± 13 mmHg; p = 0.001) and PP (66 ± 21 vs 54 ± 19 mmHg; p = 0.001). They also had higher levels of TG (1.42 ± 0.75 vs 1.22 ± 0.54 mmol/l; p = 0.017) and uric acid (442 ± 165 vs 277 ± 100 mmol/l; p = 0.001), and lower levels of HDL-C (1.39 ± 0.67 vs 1.58 ± 0.46 mmol/l; p = 0.014), glucose (7.5 ± 5.16 vs 8.94 ± 4.61) and Hb (10 ± 2.20 vs 12 ± 2.10 g/dl; p = 0.001). The proportion of subjects with proteinuria was also higher in CKD patients (37 vs 24%; p = 0.001). Table 3 summarises the distribution of CKD risk factors in the study population as a whole and by renal functional status. SCT was present in 19% of patients in the entire group, and 23 and 18% of those with and without CKD, respectively; the observed difference did not reach the level of statistical significance. Patients with CKD also had higher rates of the MetS (31 vs 24%; p = 0.001), anaemia (72 vs 42%; p = 0.001) and elevated PP (60 vs 39%, p = 0.001). Clinical and biological characteristics of CKD patients by Hb status are depicted in
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Table 1. Clinical characteristics of the study population as a whole and by renal functional status Whole group (n = 298) 56 ± 15
CKD– (n =171) 64 ± 10
CKD+ (n = 188) 64 ± 10
Variable n p-value Age (years) 359 Gender (%) 359 Males 45 41 48 0.548 Females 55 59 52 FH-SCD (%) 359 6 7 6 0.897 359 0.341 BMI (kg/m2) 25 ± 5 25 ± 5 26 ± 6 WC (cm) 359 0.009 90 ± 14 88 ± 12 92 ± 16 SBP (mmHg) 359 143 ± 26 0.001 136 ± 24 151 ± 26 DBP (mmHg) 359 0.001 83 ± 13 81 ± 14 85 ± 15 PP (mmHg) 359 0.001 60 ± 20 54 ± 19 66 ± 21 Causes of CKD 359 HT (%) 39 43 35 0.248 DM (%) 44 37 51 0.010 GN (%) 14 15 13 0.693 Other (%) 3 5 1 0.072 Stages of CKD 359 Stage 3 (%) 40 Stage 4 (%) 38 Stage 5 (%) 21 Data are expressed as mean ± standard deviation (SD) or relative frequency (%). FH-SCD, family history of sickle cell disease; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HT, hypertension; DM, diabetes mellitus; GN, glomerulonephritis; CKD, chronic kidney disease.
Table 4. Compared to CKD patients with normal Hb levels, those with SCT showed on average higher uric acid levels (560 ± 159 vs 413 ± 153 mmol/l; p = 0.001) and lower Hb levels (9 ± 1.80 vs 10 ± 2.20 g/dl; p = 0.001). Multivariate determinants of CKD with a special emphasis on SCT are presented on Table 5. SCT did not emerge as an independent determinant of CKD; the main determinants were hypertension, diabetes, the MetS and anaemia. The presence of diabetes, hypertension, the MetS and anaemia conferred 2.34fold (OR: 2.36 95% CI: 1.150–4.454; p = 0.001), 2.16-fold (OR: 2.16 95% CI: 1.202–3.892; p = 0.001), 1.69-fold (OR: 1.69 95% Table 2. Biological characteristics of the study population as a whole and by renal functional status Whole group (n = 359)
CKD– (n = 171)
CKD+ (n = 188)
11 ± 2.40
12 ± 2.10
10 ± 2.20
p-value 0.001
Variable Hb (g/dl)
n 330
Blood glucose (mg/dl)
350 8.16 ± 4.94 8.94 ± 4.61 7.50 ± 5.16 294 5.32 ± 2.22 5.14 ± 1.73 5.55 ± 2.22 294 3.04 ±1.65 2.99 ± 1.60 3.07 ± 1.70 294 1.49 ± 0.59 1.58 ± 0.46 1.39 ± 0.67
0.005
294 1.31 ± 0.65 1.22 ± 0.54 1.42 ± 0.75 Uric acid (mmol/l) 313 360 ± 159 277 ± 100 442 ± 165 Creatinine (µmol/l) 359 87 ± 44 80 ± 24 94 ± 54 eGFR (ml/min/1.73 m²) 359 59 ± 46 95 ± 39 26 ± 20
0.017
Dipstick proteinuria (%) 359
0.001
TC (mmol/l) LDL-C (mmol/l) HDL-C (mmol/l) TG (mmol/l)
24
24
37
0.312 0.662 0.014 0.001 0.001 0.001
Data are expressed as mean ± standard deviation (SD) or relative frequency (%). Hb, haemoglobin; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; eGFR, estimated glomerular filtration; CKD, chronic kidney disease.
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Table 3. CKD risk factors among the study population as a whole and by renal functional status Whole group CKD– CKD+ Variable n (n = 359) (n = 171) (n = 188) p-value HbAS (%) 330 19 18 21 0.715 Smoking (%) 359 4 5 3 0.499 Alcohol (%) 359 4 4 4 0.763 Overweigh/obesity (%) 359 29 29 30 0.715 MetS (%) 359 27 24 31 0.007 Anaemia (%) 330 57 42 72 0.001 Elevated PP (%) 359 49 39 60 0.001 Data are expressed as mean ± standard deviation (SD) or relative frequency (%). HbAS, sickle cell trait; MetS, the metabolic syndrome; PP, pulse pressure.
CI: 1.003–2.965; p = 0.038) and 3.12-fold (OR: 2.34 95% CI: 1.202–3.892; p = 0.001) greater risk for CKD, respectively, in comparison with patients without these risk factors.
Discussion The aim of this cross-sectional study was to assess determinants of CKD with a special emphasis on SCT. Traditional risk factors in isolation or combined as the MetS emerged as the main determinants of CKD; however, SCT was not associated with CKD. Our finding of increased risk for CKD in the presence of the MetS agrees with the results of previous reports on the determinants of CKD. Cheng et al.27 found a greater risk of
Table 4. Clinical and biological characteristics of CKD patients by haemoglobin genotype status HbAA HbAS Variable n (n =149) (n = 39) p-value Age, years 188 0.808 56 ± 15 55 ± 17 Gender (%) 188 Males 44 67 0.017 Females 56 33 188 0.189 BMI (kg/m2) 25 ± 5 26 ± 6 WC (cm) 188 0513 88 ± 12 89 ± 13 SBP (mmHg) 188 0.063 150 ± 21 158 ± 29 DBP (mmHg) 188 0.550 85 ± 13 86 ± 16 PP mm Hg 188 0.061 64 ± 20 71 ± 21 Hb (g/dl) 177 0.001 10 ± 2.20 09 ± 1.80 Glucose (mmol/l) 181 0.613 7.39 ± 4.00 7.83 ± 2.66 Uric acid (mmol/l) 157 0.001 413 ± 153 560 ± 159 TC (mmol/l) 133 0.570 5.55 ± 2.29 5.68 ± 2.32 LDL-C (mmol/l) 133 0.467 3.07 ± 1.70 3.12 ± 1.75 HDL-C (mmol/l) 133 0.398 1.36 ± 0.72 1.49 ± 0.43 TG (mmol/l) 133 0.397 1.38 ± 0.75 1.52 ± 0.79 Creatinine (µmol/l) 188 0.183 530 ± 183 707 ± 95 eGFR (ml/min/1.73 m²) 188 0.296 26 ± 20 23 ± 18 Data are expressed as mean ± standard deviation (SD) or relative frequency (%). BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; Hb, haemoglobin; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; eGFR, estimated glomerular filtration rate.
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Table 5. Multivariate independent determinants of chronic kidney disease Variable B SE OR (95% CI) p-value Constant 0.227 0.397 – – HbAS vs HbAA 0.953 0.810 0.38 (0.559–1.839) 0.235 DM+ vs DM– 1.343 0.282 2.36 (1.150–4.454) 0.001 HT vs NT 0.771 0.300 2.16 (1.202–3.892) 0.001 MetS+ vs MetS– 0.559 0.269 1.69 (1.033–2.965) 0.04 –1.015 0.278 0.36 (0.220–0.625) 0.001 Hb ≥ 12 vs 12 g/dl B, regression coefficient; SE, standard error; OR, odds ratio; Hb, haemoglobin; HbAS, haemoglobin with sickle cell trait; HbAA, normal haemoglobin; DM, diabetes mellitus; HT, hypertension; NT, normotension; MetS, the metabolic syndrome.
CKD (OR: 1.77 95% CI: 1.18–2.46) in patients with the MetS in comparison with those without this risk factor. A similar increased risk of CKD (OR: 1.55 95% CI: 1.34–1.80) was reported by Thomas et al.28 and Tanner et al.,29 respectively. Thomas et al.28 indicated that the risk of CKD increased with the number of individual MetS components. A higher increased risk of CKD (OR: 2.60 95% CI: 1.68–4.08) in the presence of the MetS was reported by Chen et al.30 This increased risk of CKD is thought to rely on MetS-associated insulin resistance and subsequent oxidative stress and endothelial dysfunction.27,31,32 SCT was not associated with CKD in the present study. Conflicting reports exist as to whether SCT is a risk factor for the development and progression of CKD.3,5,6-8 Earlier small-scale reports suggested SCT to be an independent risk factor for CKD and ESRD.7,8 Derebail et al.8 observed among 188 ESRD African Americans on dialysis a greater prevalence of SCT (15 vs 7%, p = 0.001) in comparison with that inferred from the newborn haemoglobinopathy screening programme; they suggested SCT to be an independent risk factor for CKD.5 Ajayi et al.10 found in black Africans a greater prevalence of microalbuminuria and proteinuria in type 2 diabetes patients with SCT in comparison with those with normal haemoglobin levels. All these authors speculated that the increased prevalence of SCT could be due to accelerated progression of kidney disease either as a direct consequence of SCT or by HbAS enhancing the deleterious effects of another co-morbid condition, such as diabetes, hypertension or autosomal polycystic kidney disease (APKD).3,5,7,8 With reference to methodological issues inherent in these cross-sectional studies and the geographical variations in the prevalence of HbAS, additional examination of SCT has been suggested in well-characterised, geographically diverse populations with advanced kidney disease.5 It may also be interesting to examine the interaction of SCT with other recently identified genetic risks for ESRD in black individuals, such as apolipoprotein 1 (APOL1) and non-muscle myosin heavy-chain 9 (MYH9).5 In line with the above suggestions, recent studies such as the present study reported no association between SCT and CKD.7 Bleyer et al.26 found in 376 African American diabetics that those with and without SCT had similar eGFR and prevalence of microalbuminuria. Using multivariate analysis, they noted no difference in the combined outcomes of peripheral vascular resistance, retinopathy and renal failure. In order to determine whether the HbAS genotype is associated with commonly reported aetiologies of ESRD, Hicks
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et al.6 evaluated cases (n = 3.258) with ESRD attributed to type 2 diabetes and non-diabetes causes, predominantly hypertension attributed and glomerular disease associated. In addition, relationships between APOL1 G1/G2 nephropathy risk variants and non-muscle MYH9 risk variants (E1 risk haplotype) and SCT were assessed to determine whether interactions between these genes were present. The SCT genotype frequencies were similar in the cases (8.7% in non-diabetic and 7.1% in type 2 diabetes ESRD) and the controls (7.2%). No evidence of association between HbAS and either diabetic or non-diabetic aetiologies of ESRD was detected in this large sample of African Americans. In addition, no evidence of APOL1 or MYH9 interaction with SCT was observed. The authors suggested both APOL1 and HbS to be associated with susceptibility to nephropathy in autosomal, recessive patterns, with no evidence of risk for nephropathy in individuals heterozygous for risk variants (e.g. those with SCT).6 They concluded that African Americans who have a single copy of the HbS gene are not at increased risk for developing non-diabetic or diabetic ESRD or subclinical nephropathy, relative to unaffected individuals.6 In addition, nephropathy risk variants in APOL1 function independently from HbS when contributing to non-diabetic ESRD.6 In contrast to earlier, smallscale reports using high-performance liquid chromatography (HPLC) to determine HbS, the strengths of this study include the large sample size and direct genotyping for HbS.6 The interpretation of the results of our study is confounded by some limitations. The cross-sectional design of the study precludes any causal relationship between CKD and associated risk factors. Moreover, the small sample size did not allow sufficient power to detect any additional associations. Definition of reduced kidney function and CKD was based on a unique determination of serum creatinine. As in earlier smaller studies, HbS determination was based on HPLC instead of direct genotyping of HbS. One wonders to what extent the conclusions of this clinic-based study could be extrapolated to the general population, given the bias in the referral of patients. The findings of our study, however, give some indications about the relationship between SCT and CKD, highlighting the need for a well-characterised study with a large sample of CKD patients.
Conclusion In the present case series of black Africans, SCT did not emerge as an independent determinant of CKD. Classic CKD risk factors in isolation or combined as the MetS emerged as the main determinants of CKD.
The authors gratefully thank Dr Jeremie Muwonga for the use of the facilities at the National Laboratory of the National AIDS Control Program for the analysis of biological samples. We thank Prof Dr Léon Tshilolo for his outstanding help in the determination of haemoglobin genotypes at the Laboratory of Monkole Hospital. We are indebted to the staff of the BDOM network for their commitment during the study. We thank Dr Kensese of the General Hospital of Kinshasa for his help during the study, and all the participants who by their consent made the study possible. We acknowledge the staff of the University of Kinshasa Hospital, Saint Joseph Hospital, especially Dr Josée Nkoyi, and the General Hospital of Kinshasa.
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References 1.
Levey AS, Andreoli SP, DuBose T, Provenzano R, Collins AJ. Chronic kidney disease: common, harmful, and treatable – World Kidney Day 2007. Clin J Am Soc Nephrol 2007; 2(2): 401–405.
2.
Meguid El Nahas A, Bello AK. Chronic kidney disease: the global challenge. Lancet 2005; 365(9456): 331–340.
3.
Shaw C, Sharpe CC. Could Sickle cell trait be a predisposing risk factor for CKD? Nephrol Dial Transplant 2010; 25: 2403–2405.
4.
Iyengar SK, Schelling JR, Sedor JR. Approaches to understanding susceptibility to nephropathy: from genetics to genomics. Kidney Int 2002; 61(1Suppl): S61–67.
5. 6.
8.
the Study of Obesity. Circulation 2009; 120(16): 1640–1645. 18. Guidelines Committee 2007 European Society of Hypertension– European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2007; 25: 1105–1187. 19. Friedewald WT, Levi RI, Fredrickson DS. Estimation of the concentration of LDL-cholesterol without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–508. 20. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26(Suppl1): S5–20. 21. Bayauli MP, Lepira FB, Kayembe PK, M’buyamba-Kabangu JR. Left ventricular hypertrophy and geometry in type 2 diabetes patients with
Am Soc Nephrol 2010; 21: 383–394.
chronic kidney disease. An echocardiographic study. Cardiovasc J Afr
Hicks PJ, Langefeld CD, Lu L, Bleyer AJ, Divers J, Nachman P, et al.
2012; 23(2): 73–77.
Sickle cell trait is not independently associated with susceptibility to
22. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendricksen S,
end-stage renal disease in African Amercians. Kidney Int 2011; 80(12):
et al. Using standardized serum creatinine values in the Modification of
Key NS, Derebail VK. Sickle cell trait: Novel clinical significance.
Diet in Renal Disease Study. Kidney Int 1997; 51: 1908–1919. 23. Sumaili EK, Krzesinski JM, Zinga CV, Cohen EP, Delanaye P,
Hematology Am Soc Hematol Educ Program 2010; 2010: 418–422.
Munyanga SM, Nseka NM. Prevalence of chronic kidney disease in
Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar
Kinshasa: results of a pilot study from the Democratic Republic of
AV. High prevalence of sickle cell trait in African Americans with ESRD. J Am Soc Nephrol 2010; 21: 413–417. 9.
International Atherosclerosis Society; and International Association for
Cavanaugh KL, Lanzkron S. Time to recognize an overlooked trait. J
1339–1343. 7.
129
Congo. Nephrol Dial Transplant 2009; 24(1): 117–122. 24. Longo AL, Lepira FB, Sumaili EK, Makulo JR, Mukumbi H, Bukabau
Weatherall DJ. The inherited diseases of hemoglobin are an emerging
JB, et al. Prevalence of low estimated glomerular filtration rate, protein-
global health burden. Blood 2010; 115(22): 4331–4336.
uria, and associated risk factors among HIV-infected black patients
10. Ajayi AA, Kolawole BA. Sickle cell trait and gender influence type 2 diabetic complications in African patients. Eur J Intern Med 2004; 15: 312–315.
using Cockroft-Gault and modification of diet in renal disease study equations. J Acquir Immune Defic Syndr 2012; 59(1): 59–64. 25. National Kidney Foundation K/DOQI clinical practical guidelines
11. Sumaili EK, Nseka MN, Lepira FB, Krzesinski JM, Makulo JR,
for chronic kidney disease: evaluation, classification and stratification.
Bukabau JB, et al. Screening for proteinuria and chronic kidney disease
Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002;
risk factors in Kinshasa: a World Kidney 2007 study. Nephron Clin Pract 2008; 110(4): c220–228. 12. Tshilolo L, Aissi LM, Lukusa D, Kinsiama C, Wembonyama S, Gulbis B, Vertongen F. Neonatal screening for sickle cell anaemia in the Democratic Republic of the Congo: experience from a pioneer project on 31 204 newborns. J Clin Pathol 2009; 62(1): 35–38. 13. Agasa B, Bosunga K, Opara A, Tshilumba K, Dupont E, Vertongen F, et al. Prevalence of sickle cell disease in a northeastern region of the Democratic Republic of Congo: what impact on transfusion policy? Transfus Med 2010; 20(1): 62–65. 14. Codreanu L, Perico N, Sharma SK, Schieppati A, Remuzzi G. Prevention programmes of progressive renal disease in developing nations. Nephrology 2006; 11(4): 321–328. 15. Orth SR, Stockmann A, Conradt C, Ritz E, Ferro M, Kreusser W, et al. Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney Int 1998; 8: 926–931. 16. World Health Organisation. Obesity: Preventing and managing the global epidemic. Report of a WHO Consultation. WHO Organ Techn Rep Ser 2000; 894: I–XII, 1–253. 17. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation;
39(2Suppl): S22–26. 26. Bleyer AJ, Reddy SV, Sujata L, Russell GB, AkinnifesI D, Bleyer AJ Jr, et al. Sickle cell trait and development of microvascular complications in diabetes mellitus. Clin J Am Soc Nephrol 2010; 5: 1015–1020. 27. Cheng HT, Huang JW, Chiang CK, Yen CJ, Hung JC. Metabolic syndrome and insulin resistance as risk factors for development of chronic kidney disease and rapid decline in renal function in elderly. J Clin Endocrinol Metab 2012; 97(4): 1268–1276. 28. Thomas G, Sehger AR, Kashyap SR, Srinivas TR, Kirwan JP, Navaneethan SD. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2011; 6(10): 2364–2373. 29. Tanner RM, Brown TM, Muntner P. Epidemiology of obesity, metabolic syndrome and chronic kidney disease. Curr Hypertens Rep 2012; 14(2): 152–159. 30. Chen J, Muntner P, Hamon LL, Jones DW, Batuman V, Fonseca V, et al. The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 2004; 140(3): 167–174. 31. Liao MT, Sung CC, Hung KC, Wu CC, Le L, Lu KC. Insulin resistance in patients with chronic kidney disease. J Biomed Biotechnol 2012; 2012: 691369. Doi: 10.1155/2012/691369. 32. Prieto D, Contreras C, Sanchez A. Endothelial dysfunction, obesity and insulin resistance. Curr Vasc Pharmacol 2014; 12(3): 412–426.
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Analysis of clinical outcomes of intra-aortic balloon pump during coronary artery bypass surgery Gunduz Yumun, Ufuk Aydin, Yusuf Ata, Faruk Toktaş, Arda Aybars Pala, Ahmet Fatih Ozyazicioglu, Tamer Turk, Senol Yavuz
Abstract Aim: The mortality rate in coronary artery bypass surgery increases with advancing patient age. This study was conducted to analyse and compare older (above 65 years of age) with younger patients (below 65 years of age) who had undergone coronary artery bypass surgery and had an intra-aortic balloon pump (IABP) inserted, comparing hospital stay, clinical features, intensive care unit stay, postoperative complications, and morbidity and mortality rates. Methods: One hundred and ninety patients who had undergone coronary artery bypass surgery and required IABP support were enrolled in this study. Patients younger than 65 years of age were considered young, and the others were considered old. Ninety-two patients were young and 98 were old. The mortality rates, pre-operative clinical characteristics, postoperative complications, and duration of intensive care unit and hospital stays of the groups were compared. The risk factors for mortality and complications were analysed. Results: One hundred and thirty-eight of the patients were male, and the mean patient age was 62.7 ± 9.9 years. The mortality rate was higher in the older patient group than the younger group [34 (37.7%) and 23 (23.4 %), respectively (p = 0.043)]. The cross-clamp time, mean ejection fraction, cardiopulmonary bypass time, and length of stay in the intensive care unit were similar among the groups (p > 0.05). Cardiopulmonary bypass time was the single independent risk factor for mortality in both groups. Conclusion: In this study, high mortality rates in the postoperative period were similar to prior studies regarding IABP support. The complication rates were higher in the older patient group. Prolonged cardiopulmonary bypass and advanced age were determined to be significant risk factors for mortality. Keywords: intra-aortic balloon pump, coronary artery bypass, mortality
Department of Cardiovascular Surgery, Namik Kemal University, Tekirdag, Turkey Gunduz Yumun, MD, gunduzyumun@gmail.com
Department of Cardiovascular Surgery, Bursa Yuksek Ihtisas Education and Research Hospital, Bursa, Turkey Ufuk Aydin MD Yusuf Ata MD Faruk Toktaş MD Arda Aybars Pala MD Ahmet Fatih Ozyazicioglu MD Tamer Turk MD Senol Yavuz MD
Submitted 22/11/14, accepted 22/1/15 Cardiovasc J Afr 2015; 26: 130–133
www.cvja.co.za
DOI: 10.5830/CVJA-2015-010
An intra-aortic balloon pump (IABP) increases coronary blood flow and reduces left ventricular afterload.1-3 It helps to increase the necessary amount of time for heart recovery in low cardiac output syndrome following a cardiopulmonary bypass (CPB) or ischaemic events. In earlier reports, researchers had suggested that postoperative heart failure was the single indication for IABP support.1,2 However, these indications have widened, and the use of IABP support has recently become more common. Frequently reported complications of IABP include bleeding, aorto-iliac injury and thrombocytopenia.4,5 In-hospital mortality and early mortality of patients requiring IABP support is high, ranging from 26 to 50%, due to the cardiac problems that initially led to the need for this support.6,7 The elderly population is continuously increasing across the globe. Parallel with this increase, the number of older patients being referred for coronary artery bypass grafting (CABG) has also increased.8 Although several studies have shown a significant increase in surgical mortality of elderly patients,9 there have been no studies regarding clinical outcomes of IABP in elderly patients. In the present study, we aimed to analyse and compare older with younger patients, regarding clinical features, postoperative complications, intensive care unit and hospital stays, and morbidity and mortality rates in patients who had undergone CABG surgery and required IABP support.
Methods Patients who had undergone CABG in our clinic between 2008 and 2013 were retrospectively evaluated. Patients who had undergone combined CABG and heart valve surgery were excluded. This study was granted the full approval of the institutional review board. Three hundred and eighty-eight (7.4%) of 4 940 consecutive patients required IABP support following CABG. Among these patients, IABP was used intra-operatively for 190 patients. One hundred and thirty-eight of the patients were male, and the mean patient age was 62.7 ± 9.9 years. The demographic characteristics of the patients are summarised in Table 1. All of the patients were operated on with standard CPB under general anaesthesia. Antegrade cardioplegia was used for cardiac protection. In all cases, an IABP catheter was inserted through the common femoral artery. In this study, IABP was used intra-operatively when weaning from CPB failed. Pre-operative IABP was used in cases of low cardiac output, unstable refractory angina, or persistent
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arrhythmia due to myocardial ischaemia.5,10 The patients were classified according to their ages: whether they were younger than 65 years or older. The mortality rate, complications of IABP, intra-operative properties, pre-operative clinical characteristics of patients, and length of stay in the intensive care unit (ICU) were recorded. The pre-operative parameters of the patients were age, gender, re-operation, hypertension, body mass index, diabetes mellitus, chronic renal failure, the value of the EuroSCORE, previous cerebrovascular accidents, left ventricular ejection fraction, left main coronary artery disease, chronic obstructive pulmonary disease (COPD), and the presence of a myocardial infarction more recently than one week previously. The pre-operative clinical characteristics, postoperative complications, duration of ICU and hospital stays, and mortality rates of the groups were compared.
Statistical analysis Demographic characteristics were compared using mean and median values. Parametric results were evaluated using the Student’s t-test and Tukey test. The chi-square method, Pearson’s test, and Fisher’s test were used to analyse the categorical parameters. Risk factors for mortality were assessed using a binary logistic regression analysis. The standard deviation value of p < 0.05 was considered significant. SPSS 18 was used for the statistical analysis.
Results In this study, 138 of the 190 patients were male. The mean patient age was 62.7 ± 9.9 years. Ninety-eight patients were younger than 65 years of age, and 90 patients were 65 years of age or older.
Table 1. Demographic characteristics of the patients Younger Older group group (n = 98) (n = 92) Total p-value 74/24 64/28 138/52 0.358 54.7 ± 6.1 71.4 ± 4.5 62.7 ± 9.9 < 0.001 0.121 37.1 ± 8.3 39.2 ± 9.5 38.1 ± 8.9 31 (31.9) 24 (26) 55 (27.7) 0.400 5 (5.1) 13 (14.1) 18 (9) 0.034 3 (3) 5 (5.4) 8 (4.2) 0.487 3 (3) 0 3 (1.5) 0.297 47 (48) 56 (60) 103 (54) 0.074 48 (49) 23 (25) 71 (37.3) 0.001 4 (4.1) 5 (5.4) 9 (4.7) 0.745 18 (18.3) 16 (17.4) 34 (17.9) 0.861 4 (0–10) 5 (2–10) 4 (0–10) < 0.001 0.112 27.2 ± 4 26.7 ± 4.4 27.2 ± 4.1 8 (8.1) 5 (5.4) 13 (6.8) 0.457 18 (18.3) 12 (13) 30 (15.8) 0.315
Gender (M:F) Mean age (years) Mean EF (%) MI, n (%) COPD, n (%) CRF, n (%) Redo, n (%) HT, n (%) DM, n (%) CVA, n (%) Recent MI, n (%) EuroSCORE BMI (kg/m2) LMCA, n (%) Prophylactic levosimendan, n (%) Emergency, n (%) 18 (18.3) 16 (17.4) 34 (17.8) 0.861 Pre-operative IABP, n (%) 8 (8.1) 9 (9.7) 17 0.405 COPD: chronic obstructive pulmonary disease, CRF: chronic renal failure, HT: hypertension, DM: diabetes mellitus, CVA: cerebrovascular accident, BMI: body mass index, LMCA: left main coronary artery disease, EF: ejection fraction.
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The number of patients with COPD and the mean EuroSCORE of the patients were higher in the older group. In contrast, the number of patients with diabetes mellitus was higher in the younger group. In terms of other demographic characteristics, there were no statistically significant differences between the groups (Table 1). The mean CPB times, mean crossclamp times, and number of grafts used were similar between the two groups (Table 2). Fifty-seven (30.1%) patients died in the first 30 days following the operation. Twenty-three of these patients were in the younger group. The mortality rate of the younger group was significantly lower compared to the older patients (p = 0.043). In the subgroup analysis, the mortality rate of emergent operations was similar in the both groups (p = 0.964). However, the mortality rate was higher in the older group for elective operations (p = 0.018). Among the surviving patients, the number of older patients, rate of emergency operations, mean EuroSCORE values, and number of patients with chronic renal failure were lower than that in the group of patients who died (Table 3). Binary logistic regression analysis showed that the only factor affecting mortality was prolonged CPB time. However, in the subgroup analysis of patients without emergency conditions, age was the second determinant of mortality (p = 0.018, OR = 5.5). In the subgroup analysis, CPB time and pre-operative chronic renal failure were independent risk factors for mortality in the older group. In the younger group, female gender, diabetes mellitus, high EuroSCOREs, emergency operations, prolonged CPB (p = 0.001, OR = 7.6), and prolonged stays in the ICU were independent risk factors for mortality (Table 4). In our study, a few serious complications were observed due to IABP support. Iliac artery injury occurred in two patients and peripheral ischaemia was observed in three patients. The other complications were thrombocytopenia and minor bleeding at the catheter site (Table 5). The rate of complications was similar between the groups.
Discussion Postoperative recovery in elderly patients requires a longer time period than for younger patients. Postoperative atrial fibrillation requiring medical treatment, and other complications occur more frequently in the elderly; the total intubation time was also longer for this group. Therefore, delayed recovery in the elderly may simply be due to the aging process affecting all organs.9 For this reason, elderly patients may need more mechanical support in cases of low cardiac output following CPB.
Table 2. Mortality rates and clinical outcomes of the patients Younger group Older group p-value Mortality, n (%) 23 (23.4) 34 (36.9) 0.043 Mortality, n (%)* 8 (44.4) 7 (41.1) 0.964 Mortality, n (%)** 15 (18.7) 27 (36) 0.018 CPB time (min) 0.786 143 ± 59 140 ± 58 Graft number 3.1 (2–5) 3.2 (2–5) 0.789 Cross-clamp time (min) 0.604 90 ± 34 88 ± 38 ICU time (day) 0.284 5.9 ± 4 6.6 ± 5 ICU: intensive care unit. CPB time: cardiopulmonary bypass time, *patients with emergency operation, **patients undergoing elective operation.
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Table 3. Parameters of patients who survived or died
Table 4. Factors for mortality in subgroup analysis
Patients who Patients who survived died (n = 133) (n = 57) p-value Pre-operative MI, n (%) 40 (30) 15 (26.3) 0.601 0.507 BMI (kg/m2) 27.5 ± 4.2 26.9 ± 4 EuroSCORE 4.2 (0–10) 5.1 (0-10) 0.030 DM, n (%) 47 (35.3) 24 (42.1) 0.377 CRF, n (%) 3 (2.2) 5 (8.7) 0.040 Mean EF (%) 0.562 38.4 ± 8 37.5 ± 9 Mean age (years) 0.051 61.8 ± 9.8 64.9 ± 10 Older patients, n (%) 58 (43.6) 34 (59.6) 0.043 Gender (M:F) 33/101 20/37 0.118 COPD, n (%) 12 (9) 6 (10.5) 0.746 Emergency operation, n (%) 19 (14.2) 15 (26.3) 0.047 LMCA, n (%) 8 (6) 5 (8.7) 0.490 CVA, n (%) 5 (3.7) 4 (7) 0.333 HT, n (%) 69 (51.8) 34 (59.6) 0.328 Re-operation, n (%) 3 (2.2) 0 0.555 Pre-operative IABP, n (%) 14 (10.5) 3(2.2) 0.405 CPB time (min) 130 ± 48 167 ± 72 < 0.001 Cross-clamp time (min) 0.180 87 ± 35 94 ± 36 CPB time: cardiopulmonary bypass time, COPD: chronic obstructive pulmonary disease, CRF: chronic renal failure, HT: hypertension, DM: diabetes mellitus, CVA: previous cerebrovascular accident, BMI: body mass index, LMCA: left main coronary artery disease.
Younger group Older group Odds ratio p-value Odds ratio p-value COBD 0.035 0.851 0.015 0.903 CRF 0.168 0.682 4.205 0.040 Re-operation 0.949 0.330 EF (%) 0.865 0.352 0.110 0.759 Age (years) 0.122 0.727 1.034 0.741 EuroSCORE 14.555 0.000 8.418 0.309 CPB time (min) 7.698 0.006 0.471 0.004 Cross-clamp time (min) 2.048 0.152 1.542 0.493 0.703 0.402 0.384 0.214 BMI (kg/m2) Emergency operation 5.401 0.020 0.400 0.536 Female gender 8.850 0.003 1.725 0.527 HT 2.007 0.157 0.095 0.189 MI 0.427 0.513 0.004 0.758 DM 7.477 0.006 0.560 0.949 ICU time 4.947 0.026 0.038 0.454 Levosimendan 0.228 0.633 0.131 0.845 CVA 1.634 0.201 0.021 0.717 LMCA 0.955 0.329 0.021 0.885 CPB time: cardiopulmonary bypass time, COPD: chronic obstructive pulmonary disease, CRF: chronic renal failure, HT: hypertension, DM: diabetes mellitus, ICU: intensive care unit, CVA: previous cerebrovascular accident, BMI: body mass index, LMCA: left main coronary artery disease.
In the present study, while the number of COPD patients was higher in the older group, the number of diabetes mellitus patients was lower than in the younger group. In addition, EuroSCORE values were higher in elderly patients. The mortality rate was higher in elderly patients; however, there were no statistically significant differences between the patients who had emergency surgery in both groups. It has been reported that IABP decreases the mortality rates of low cardiac output and severe myocardial ischaemia patients in the pre-operative period, provides support for patients who failed to wean from CPB during the intra-operative period, and prevents low cardiac output and medically refractory arrhythmias in ICU in the postoperative period.11,12 In this study, IABP was used in cases of low cardiac output, persistent angina pectoris, or arrhythmia due to myocardial ischaemia in the pre-operative period. In previous studies, the use of pre-operative IABP in high-risk patients was reportedly more advantageous than peri-operative IABP support. Böning et al. compared the use of pre-operative and peri-operative IABP in high-risk patients in their study. Their results indicate that the pre-operative use of IABP was advantageous for early and long-term mortality.13 Dyub et al. showed that in a meta-analysis involving 1 034 patients, the use of pre-operative IABP in high-risk patients reduced mortality.14 Holman et al. reported that when shock, urgent surgery, haemodynamic instability, and MI in the last three days were excluded, the use of pre-operative IABP did not have a positive effect on morbidity and mortality rates; however, the length of the hospital stay was less in these patients.15 Miceli et al. proposed a scoring system that predicts the need for IABP support in high-risk CABG patients.16 According to this study, heart failure, re-operations, emergency operations, left main coronary artery disease, patients over the age of 70
years, moderate and poor left ventricular function, and recent myocardial infarctions are independent risk factors for the need for IABP support. As a result of the study, the benefits of IABP support in patients with high-risk scores were emphasised. In our clinical practice, we did not use a risk-scoring system for prophylactic IABP support. In this study, we aimed to determine the pre-operative risk factors for mortality and other clinical outcomes. In previous studies, emergency surgery, a history of myocardial infarction, prolonged CPB, and concomitant peripheral artery occlusive disease were all found to be significant determinants of mortality in primary isolated CABG patients.17 Furthermore, risk-scoring systems were generated. We showed that the mortality rate of the older patient group was higher than that of the younger group. However, the logistic regression analysis indicated that the only independent risk factor for mortality was a prolonged CPB time. In addition, subgroup analysis revealed different results. For example, in the older patient group, chronic renal failure and prolonged CPB were identified as factors affecting mortality rate. In young patients, female gender, diabetes mellitus, emergency operations, higher EuroSCORE values, prolonged CPB, and prolonged stays in the ICU were independent risk factors for mortality. In elective operations advanced patient age and Table 5. IABP complications according to patient group Bleeding, n (%) Arterial injury, n (%) Mild thrombocytopenia, n (%) Extremity ischaemia, n (%) Total, n (%)
Younger group Older group p-value 1 (1) 4 (4.3) 0.200 0 2 (2.1) 0.233 10 (10.2) 15 (16.3) 0.309 1 (1) 2 (2.1) 0.611 12 (12.2) 23 (25) 0.023
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prolonged cardiopulmonary bypasses were identified as factors affecting mortality rates. Complications with the IABP were described in previous studies: limb ischaemia, thrombocytopenia, arterial rupture or dissection, and sepsis and local infections.4–6,10,18 Complication rates have been reported from 26 to 50% in different studies. The risk factors for IABP complications were stated as increased age, female gender, duration of IABP treatment, presence of diabetes mellitus, and having several risk factors (e.g. obesity, smoking, hypertension, cardiogenic shock, inotropic support, low cardiac output, increased systemic vascular resistance, and ankle–brachial pressure index < 0.8). In our study, the IABP complication rate was higher in older patients compared to younger ones (25 vs 12.2%). Mild thrombocytopenia was the most frequently detected complication. When thrombocytopenia is detected, IABP therapy is terminated immediately so that fewer bleeding complications occur. Limitations: our study was a single-institution, retrospective study, which had a relatively small sample size. This research may require repeating in multicentres with randomised trials. Unaccounted for confounders may have been inherent in such a retrospective analysis.
5.
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Cristenson JT, Cohen M, Ferguson JJ 3rd, Freedman RJ, Miller MF, Ohman EM, et al. Trends in intraaortic balloon counterpulsation complications and outcomes in cardiac surgery. Ann Thorac Surg 2002; 74(4): 1086–1090.
6.
MacGee E, MacCarthy P, Moazami N. Temporary mechanical circulatory support. Cardiac Surgery in the Adult. New York: MacGraw Hill, 2008: 507–533.
7.
Pi K, Block P, Warner M, et al. Major determinants of survival and nonsurvival of intra-aortic balloon pump. Am Heart J 1995; 130: 849–853.
8.
Dalrymple-Hay MJ, Alzetani A, Aboel-Nazar S, et al. Cardiac surgery in the elderly. Eur J Cardiothorac Surg 1999; 15: 61–66.
9.
Hirose H, Amano A, Yoshida S, MD, Takahashi A, Nagano N, Kohmoto T. Coronary artery bypass grafting in the elderly. Chest 2000; 117(5): 1220–1221.
10. Parissis H, Soo A, Al-Alao B. Intra-aortic balloon pump (ΙΑΒΡ): from the old trends and studies to the current ‘extended’ indications of its use. J Cardiothorac Surg 2012; 11(7): 128. 11. Ferguson JJ, Cohen M, Freedman RJ, Stone GW, Miller MF, Joseph DL, Ohman EM. The current practice of intra-aortic balloon counterpulsation: results from the Benchmark registry. Am Coll Cardiol 2001; 38(5): 1456–1462. 12. Theologou T, Bashir M, Rengarajan A, Khan O, Spyt T, Richens D,
Conclusion IABPs are important cardiac support instruments that are easily implemented and have beneficial effects for resolving transient ischaemic situations. Whether young or old, patients who require IABP support have a high risk of mortality. Moreover, elderly patients have increased incidences of co-morbid disease, which makes them even more at risk of death. We suggest that IABP might be used in the intra-operative period as a prophylactic device in elderly patients with multiple risk factors.
Field M. Preoperative intra aortic balloon pumps in patients undergoing coronary arteryn bypass grafting. Cochrane Database Syst Rev 2011; 19(1): 4472. 13. Böning A, Buschbeck S, Roth P, Scheibelhut C, Bödeker R, Brück M, Niemann B. IABP before cardiac surgery: clinical benefit compared to intraoperative implantation. Perfusion 2013; 28(2): 103–108. 14. Dyub AM, Whitlock RP, Abouzahr LL, Cinà CS. Preoperative intraaortic balloon pump in patients undergoing coronary bypass surgery: a systematic review and meta-analysis. J Card Surg 2008; 23(1): 79–86. 15. Holman WL, Li Q, Kiefe CI, McGiffin DC, Peterson ED, Allman RM, et al. Prophylactic value of preincision intra-aortic balloon pump:
References 1.
2.
16. Miceli A, Duggan SM, Capoun R, Romeo F, Caputo M, Angelini GD.
balloon pumping on coronary flow and metabolism in man. Circulation
A clinical score to predict the need for intraaortic balloon pump in
1971; 43–44(Suppl. I): 1–77.
patients undergoing coronary artery bypass grafting. Ann Thorac Surg
Swank M, Singh HM, Flemma RJ, et al. Effect of intra-aortic balloon dium. J Thorac Cardiovasc Surg 1978; 76: 538. Berne RM, Levy MN. Cardiovascular Physiology, 6th edn. St Louis. Mosby-Year Book, 1992, ch 8.
4.
120(6): 1112–1119.
Leinbach RC, Buckley MJ, Austen WG, et al. Effects of intra-aortic
pumping on nutrient coronary flow in normal and ischemic myocar3.
analysis of a statewide experience. J Thorac Cardiovasc Surg 2000;
2010; 90(2): 522–526. 17. Huang CH, Lai ST, Weng ZC. Risk factors for mortality in primary isolated coronary artery bypass grafting surgery. J Formos Med Assoc 2001; 100(5): 299–303. 18. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister
Harvey JC, Goldstein Jt, McCabe, et al. Complications of percutaneous
KE, Grover F, et al. Preoperative renal risk stratification. Circulation
intraaortic balloon pumping. Circulation 1981; 64(Suppl II): 11–114.
1997; 95: 878–884.
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Can empirical hypertonic saline or sodium bicarbonate treatment prevent the development of cardiotoxicity during serious amitriptyline poisoning? Experimental research Muhammet Sukru Paksu, Halit Zengin, Fatih Ilkaya, Sule Paksu, Hasan Guzel, Durmus Ucar, Adem Uzun, Hasan Alacam, Latif Duran, Naci Murat, Ahmet Guzel
Abstract Objective: The aim of this experimental study was to investigate whether hypertonic saline or sodium bicarbonate administration prevented the development of cardiotoxicity in rats that received toxic doses of amitriptyline. Method: Thirty-six Sprague Dawley rats were used in the study. The animals were divided into six groups. Group 1 received toxic doses of i.p. amitriptyline. Groups 2 and 3 toxic doses of i.p. amitriptyline, plus i.v. sodium bicarbonate and i.v. hypertonic saline, respectively. Group 4 received only i.v. sodium bicarbonate, group 5 received only i.v. hypertonic saline, and group 6 was the control. Electrocardiography was recorded in all rats for a maximum of 60 minutes. Blood
Paediatric Intensive Care Unit, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Muhammet Sukru Paksu, MD
Department of Cardiology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Halit Zengin, MD, drhzengin@yahoo.com.tr Adem Uzun, MD
Department of Pharmacology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Fatih Ilkaya, MD Hasan Guzel, MD
Department of Paediatrics, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Sule Paksu, MD
Department of Physiology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Durmus Ucar, MD
Department of Biochemistry, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Hasan Alacam, MD
Department of Emergency Medicine, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Latif Duran, MD
Department of Industrial Engineering, Faculty of Engineering, Ondokuz Mayis University, Samsun, Turkey Naci Murat, MD
Department of Paediatric Emergency, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey Ahmet Guzel, MD
samples were obtained to measure the serum levels of sodium and ionised calcium. Results: The survival time was shorter in group 1. In this group, the animals’ heart rates also decreased over time, and their QRS and QTc intervals were significantly prolonged. Groups 2 and 3 showed less severe changes in their ECGs and the rats survived for a longer period. The effects of sodium bicarbonate or hypertonic saline treatments on reducing the development of cardiotoxicity were similar. The serum sodium levels decreased in all the amitriptyline-applied groups. Reduction of serum sodium level was most pronounced in group 1. Conclusion: Empirical treatment with sodium bicarbonate or hypertonic saline can reduce the development of cardiotoxicity during amitriptyline intoxication. As hypertonic saline has no adverse effects on drug elimination, it should be considered as an alternative to sodium bicarbonate therapy. Keywords: amitriptyline, poisoning, cardiotoxicity, sodium bicarbonate, hypertonic saline Submitted 3/12/13, accepted 27/1/15 Published online 5/5/15 Cardiovasc J Afr 2015; 26: 134–139
www.cvja.co.za
DOI: 10.5830/CVJA-2015-014
Tricyclic antidepressant (TCA) drugs are commonly used to treat many neuropsychiatric diseases.1 Amitriptyline is the most commonly prescribed antidepressant, and it is a frequent cause of toxicity in drug overdoses. TCA overdose primarily affects the neurological, cardiovascular and respiratory systems.1,2 Blockage of the rapid sodium channels is responsible for drug-induced cardiotoxicity, which clinically manifests as PR, QT and QRS prolongation, ventricular or supraventricular arrhythmias, hypotension and heart failure.1,3 Sodium bicarbonate (NaHCO3) administration is the most widely accepted treatment to reduce amitriptyline-induced cardiotoxicity.2,4,5 However, at an alkaline pH, the volume distribution of amitriptyline expands, and the elimination time is longer. Therefore, NaHCO3 treatment is suggested only in the presence of cardiac findings.6 Hypertonic saline (HS) administration has been shown to be useful, particularly when cardiotoxicity is accompanied by hypotension.7-9 There is always a need for a medication to prevent cardiotoxicity that will save patients’ lives, especially when toxic
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doses have been ingested. Although studies have compared the efficacy of HS and NaHCO3 treatments in patients with cardiotoxicity, the role of these therapies to prevent or reduce cardiotoxicity in patients who may potentially develop severe toxicity has not been investigated. The aim of this experimental study was to compare the effect of early administration of HS or NaHCO3 on preventing cardiotoxicity in rats that had received toxic doses of amitriptyline.
Methods The experiments were performed on adult female Sprague Dawley rats weighing 250 to 300 g that were obtained from the Ondokuz Mayis University vivarium. The rats were kept in a vivarium maintained at 22 ± 1°C with a 12-hour alternating light–dark cycle. All the experiments were approved by the Institutional Animal Care and Use Committee of Ondokuz Mayis University, and adhered to the guidelines of the Committee on Human/ Animal Experimentation (institutional or regional), and the Helsinki Declaration of 1975, as amended in 1983. Amitriptyline was obtained from Sigma-Aldrich Chemical Co (St Louis, Missouri, USA). It was dissolved in distilled water at a concentration of 50 mg/4 ml. HS solution (3% sodium chloride, sodium 512 mEq/l) and NaHCO3 8.4% (sodium 1 mEq/ml) were used. The animals were randomly divided into six groups, with each group containing six rats. They were anesthetised (100 mg/kg ketamine and 0.75 mg/kg chlorpromazine i.p.) and then prepared for monitoring of electrocardiogram (ECG) parameters. Their survival time was recorded by a data-acquisition system (ML870/P, PowerLab 8/30, AD Instruments). Amitriptyline was administered at a dose 50 mg/kg i.p. to induce toxicity. The HS was administrated at a dose rate of 6 ml/kg, and the NaHCO3 was administrated at a dose rate of 3 mEq/kg. Both were administered via i.v. infusion and applied simultaneously with amitriptyline over a period of five minutes. To administer the dosage, i.v. cannulas were inserted into the tail of the rats. The toxic doses and treatments given to the different groups are shown in Table 1. ECGs were recorded on each rat for 60 minutes after the administration of the respective protocols. All records were evaluated by a cardiologist. On the ECG records, the R–R distance, height of the QRS and duration of the QT were measured. The R–R is the interval from the onset of one QRS complex to the onset of the next QRS complex, measured in seconds. The heart rate and the corrected QT (QTc) interval were calculated according to the R–R distance and the duration of the QT. Heart rate was calculated by dividing the R–R interval by 60 (heart rate = 60/R–R interval). Table 1. Design of study and groups and chemicals used Group
Drugs
1
Only amitriptyline (50 mg/kg i.p.)
2
Amitriptyline (50 mg/kg i.p.) + 3 mEq/kg NaHCO3 (diluted with normal saline of 1:1 ratio) during the five minutes (once)
3
Amitriptyline (50 mg/kg i.p.) + 6 ml/kg hypertonic saline during the five minutes (once)
4
Only 6 ml/kg hypertonic saline during the five minutes (once)
5
Only 3 mEq/kg NaHCO3 (diluted with normal saline of 1:1 ratio) during the five minutes (once)
6
Control group (none of the drugs or treatment)
The QRS duration was measured from the beginning of the Q wave to the end of the S wave. The QT interval was measured from the onset of the QRS complex to the end of the T wave, defined as the return to the TP isoelectric line. The QT interval was defined as the average of the QT intervals of three consecutive beats in each of the ECG leads. The QT intervals were also corrected for heart rate using Bazett’s formula. The QTc is equal to the QT interval in seconds divided by the square root of the preceding R–R interval in seconds. A decrease in the heart rate below 100 beats/minutes or the presence of asystole during recording was accepted as the exodus. To measure serum levels of sodium and ionised calcium, blood samples were obtained from the carotid arteries of the living rats 60 minutes after the administration of amitriptyline or other treatments, but immediately from the rats that had died.
Statistical analysis Statistical analyses were performed with IBM SPSS 21.0 (Chicago, IL, USA). The Kolmogorov–Smirnov test was used to evaluate the distribution of variables in relation to normal. Descriptive statistics were presented as the mean ± standard deviation. Statistical comparisons between all groups were performed with one-way ANOVA with a Tukey post-hoc test. Correlations between the quantitative data were analysed by the Pearson correlation test. The level of statistical significance was set at p < 0.05.
Results The characteristics of the rats in all groups were similar. In group 1, all the rats died in the first 25 minutes. Therefore, the statistical analyses with group 1 included data for only the first 25 minutes. The other inter-group statistical analyses included data obtained over 60 minutes. The initial heart rate was similar among the groups. The heart rates of the rats in groups 1, 2 and 3 decreased in direct proportion to time, with the decrease more marked in group 1. The heart rates of the rats in groups 4, 5 and 6 did not show significant change over time. Hypertonic saline or NaHCO3 administration, along with amitriptyline, ameliorated the reduction in the heart rates. There was no significant difference in the heart rates between the HS and NaHCO3 groups. Table 2 shows a comparison of the heart Table 2. Heart rate changes with time according to group Group
5th minute
Start
10th minute
15th minute
20th minute
25th minute
1
353 ± 21* 300 ± 37c 269 ± 31c,d,e 242 ± 31a,c,d,e 217 ± 28a,b,c,d,e 201 ± 28a,b,c,d,e
2
350 ± 17* 321 ± 34g
304 ± 34g 294 ± 34a,g,h,i 281 ± 33a,g,h,i 277 ± 32a,g,h,i
3
345 ± 19* 327 ± 25*
309 ± 30j
4
368 ± 26
5
346 ± 14* 343 ± 21*
6
352 ± 34* 346 ± 23c,g 344 ± 23e
Mean
352 ± 23
335 ± 35
p-value
0.542
0.003
*
373 ± 27
*
371 ± 23
290 ± 32j,k,l 285 ± 32b,j,k,l 285 ± 31b,j,k,l 379 ± 23c,g,j
377 ± 22c,g,j
344 ± 18d 345 ± 22d,h,k 346 ± 23d,h,k
347 ± 28d,h,k
c,g,j
375 ± 23c,j,g 352 ± 27e,i,l
348 ± 23e,i,l
347 ± 26e,i,l
324 ± 42
316 ± 53
309 ± 60
312 ± 61
0.000
0.000
0.000
0.000
The group with no difference from the others, p < 0.05 (acompared with groups 1 and 2, bcompared with groups 1 and 3, ccompared with groups 1 and 4, dcompared with groups 1 and 5, ecompared with groups 1 and 6, fcompared with groups 2 and 3, gcompared with groups 2 and 4, hcompared with groups 2 and 5, i compared with groups 2 and 6, jcompared with groups 3 and 4, kcompared with groups 3 and 5, lcompared with groups 3 and 6). *
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400
0.080
350
0.070 QRS interval (seconds)
Heart rate (beats/minute)
136
300 250 200 150 100 50 0
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0.060 0.050 0.040 0.030 0.020 0.010
0
5
10 15 20 25 30 35 40 45 50 55 60 Duration (minutes)
0.000
0
5
10 15 20 25 30 35 40 45 50 55 60 Duration (minutes)
Only amitriptyline
Amitriptyline + hypertonic saline
Only amitriptyline
Amitriptyline + hypertonic saline
Amitriptyline + sodium bicarbonate
Control
Amitriptyline + sodium bicarbonate
Control
Fig. 1. H eart rate changes of the amitriptyline-administered groups and control group with time.
Fig. 2. QRS changes of the amitriptyline-administered groups and control group with time.
rates of the rats in each group in each time period. The changes in the heart rates in the amitriptyline-treated groups (groups 1, 2 and 3) and the control group are shown in Fig. 1. The baseline QRS durations were similar among groups. The changes in the QRS durations in the groups that did not received amitriptyline (groups 4, 5 and 6) were non-significant, whereas the amitriptyline-administered groups (groups 1, 2 and 3) showed a statistically significant increase in the QRS duration. This increase was more marked in group 1. The increase in QRS duration was limited in the groups that received amitriptyline with HS or NaHCO3 (groups 2 and 3). There was no statistically significant difference between these groups in terms of increase in the duration of the QRS. A comparison of the QRS duration in each group in each time period is shown in Table 3, and a comparison of the change in QRS duration of the amitriptylinetreated groups (groups 1, 2 and 3) and control group is shown in Fig. 2. The baseline QTc durations were similar among the groups. There was no significant change in the QTc durations in the groups that did not receive amitriptyline (groups 4, 5 and 6). The QTc duration increased in the amitriptyline-treated groups (groups 1, 2 and 3), but the increase was more marked in group
1. The increase in the QTc duration was reduced in the groups administered HS or NaHCO3 with amitriptyline. There was no statistically significant difference between the two groups (groups 2 and 3) in terms of QTc prolongation. A comparison of the QTc duration of the groups in each time period is shown in Table 4, and a comparison of the change in duration of the QTc in the amitriptyline-treated groups and the control group is shown in Fig. 3. Serum samples for sodium and ionised calcium analyses were taken from the surviving rats at the 60th minute and from the non-survivors immediately after death. In the groups that received amitriptyline (groups 1, 2 and 3), the serum sodium levels had decreased. This decline was most evident in group 1, which did not receive any sodium-containing treatment. Hyponatraemia was more pronounced in group 2 than group 3. No subject developed hypernatraemia. The serum ionised calcium levels were higher in the groups that received amitriptyline and highest in the amitriptyline-only group (group 1). The distribution of the serum levels of ionised calcium and sodium in the groups is shown in Table 5. The serum sodium levels showed a strong positive correlation with heart rates, a strong negative correlation with QRS duration, and a
Table 3. QRS changes with time according to group Group
Start
5th minute
10th minute
15th minute
20th minute
25th minute
1
0.210 ± 0.001*
0.0303 ± 0.0015c,e
0.042 ± 0.01a,c,d,e
0.057 ± 0.014a,b,c,d,e
0.061 ± 0.130a,b,c,d,e
0.072± 0.02a,b,c,d,e
2
0.208 ± 0.001*
0.022 ± 0.010*
0.027 ± 0.006a
0.030 ± 0.005a
0.032 ± 0.006a,g,i
0.032 ± 0.006a,i
3
0.208 ± 0.003*
0.022± 0.002*
0.034 ± 0.008j,k,l
0.038 ± 0.008 b,k,l
0.037 ± 0.008b,j,k, l
0.038 ±0.009b,j,k,l
4
0.198 ± 0.001*
0.0190 ± 0.001c
0.020 ± 0.001c,j
0.020 ± 0.001c
0.019 ± 0.001c,g,j
0.020 ± 0.001c,j
5
0.202 ± 0.001*
0.020 ± 0.001*
0.020 ± 0.002d,k
0.020 ± 0.01d
0.021 ± 0.001d,k
0.020 ± 0.001d,k
6
0.195 ± 0.003*
0.0183 ± 0.02e
0.018 ± 0.001e,l
0.019 ± 0.002 e,k,l
0.019 ± 0.001e,i,l
0.019 ± 0.001e,i,l
Mean
0.204 ± 0.002
0.022 ± 0.007
0.027 ± 0.01
0.030 ± 0.015
0.031 ± 0.016
0.031 ± 0.018
p-value
0.782
0.032
0.000
0.000
0.000
0.001
The group with no difference from the others, p < 0.05 (acompared with groups 1 and 2, bcompared with groups 1 and 3, ccompared with groups 1 and 4, dcompared with groups 1 and 5, ecompared with groups 1 and 6, fcompared with groups 2 and 3, gcompared with groups 2 and 4, hcompared with groups 2 and 5, icompared with groups 2 and 6, jcompared with groups 3 and 4, kcompared with groups 3 and 5, lcompared with groups 3 and 6).
*
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Table 4. QTc changes with time according to group Group 1
Start
5th minute
10th minute
15th minute
20th minute
25th minute
0.119 ± 0.005*
0.115 ± 0.007*
0.154 ± 0.019a,c,d,e
0.187 ± 0.025a,b,c,d,e
0.255 ± 0.11a,b,c,d,e
0.277 ± 0.081a,b,c,d,e 0.129 ± 0.020a
2
0.118 ± 0.005*
0.115 ± 0.009*
0.119 ± 0.004a,f
0.124 ± 0.021a
0.124 ± 0.02a
3
0.119 ± 0.006*
0.124 ± 0.009*
0.143 ± 0.016f,j,k,l
0.150 ± 0.018 b,l
0.146 ± 0.02b
0.149 ± 0.021b
4
0.121 ± 0.006*
0.123 ± 0.007*
0.123 ± 0.007c,j
0.127 ± 0.07c
0.124 ± 0.005c
0.123 ± 0.008c
5
0.120 ± 0.002*
0.119 ± 0.005*
0.119 ± 0.004d,k
0.123 ± 0.005d
0.119 ± 0.004d
0.122 ± 0.005d
6
0.117 ± 0.006*
0.111 ± 0.009*
0.113 ± 0.007e,l
0.117 ± 0.007e,l
0.118 ± 0.001e
0.119 ± 0.008e
Mean
0.119 ± 0.006
0.118 ± 0.009
0.128 ± 0.180
0.138 ± 0.03
0.148 ± 0.065
0.146 ± 0.057
p-value
0.654
0.0055
0.000
0.000
0.000
0.000
The group with no difference from the others, p < 0.05 (acompared with groups 1 and 2, bcompared with groups 1 and 3, ccompared with groups 1 and 4, dcompared with groups 1 and 5, ecompared with groups 1 and 6, fcompared with groups 2 and 3, gcompared with groups 2 and 4, hcompared with groups 2 and 5, icompared with groups 2 and 6, jcompared with groups 3 and 4, kcompared with groups 3 and 5, lcompared with groups 3 and 6).
*
significant moderately negative correlation with QTc duration. Serum ionised calcium levels exhibited a significant moderately negative correlation with heart rate and a significant moderately positive correlation with QRS and QTc duration (Table 6).
Discussion The results of this experimental study suggest that administration of HS or NaHCO3 before toxicity occurs may reduce the development of cardiac toxicity in amitriptyline poisoning. Overdose of TCAs, including amitriptyline, are a major causes of drug-related deaths all over the world.10 Amitriptyline poisoning primarily affects the cardiovascular and neurological systems.1,11,12 It causes toxicity by blocking the voltage-gated sodium channels, which facilitate the fast flow of sodium into the cells.1,13 Anticholinergic and α-adrenergic blockage also contribute to this.1,3,13,14 Blockage of cardiac sodium and potassium channels may result in cardiac conduction delay, dysrhythmia and hypotension due to myocardial depression.1,2,4,14 This process may appear on the ECG as prolonged PR, QRS and QT times, sinus tachycardia, and supraventricular and
ventricular arrhythmias.1,11 The most important cause of death is persistent hypotension resulting from myocardial depression due to arrhythmias.3,5,10,12,13 The majority of patients who take toxic doses of amitriptyline enter a coma, but a minority develop life-threatening complications. Others often recover with supportive care, without subsequent problems.15,16 Despite defined scoring systems such as the Antidepressant Overdose Risk Assessment (ADORA),17 it is often difficult to distinguish these two groups of patients. In addition, the correlation between serum drug levels and clinical outcome is weak, and routine drug level analyses are not recommended.18,19 Various methods have been used to treat patients with severe cardiotoxicity due to amitriptyline overdose. These include serum alkalinisation with hypertonic NaHCO320 or hyperventilation,21 inotropic agents,4,22 magnesium sulphate,5 anti-arrhythmic drugs,2,14 glucagon12 haemoperfusion,23,24 or lipid emulsion.25 Although many studies have compared these treatment methods, no treatment has been shown to prevent or reduce the toxicity in patients who may potentially develop severe toxicity.
Table 5. Distribution of serum levels of ionised calcium and sodium according to group
0.300
QTc interval (seconds)
Group
0.250 0.200 0.150 0.100
Calcium 4.14 ± 0.4a
2
121.2 ± 6.2a
4.19 ± 0.4a
3
133.4 ± 10.9a
4.15 ± 1.0a
4
b
143.5 ± 3.4
2.85 ± 0.6b
5
145.7 ± 4.7b
2.52 ± 0.7b
6
147.8 ± 4.6b
1.83 ± 0.7b
Mean
133.8 ± 14.9
3.28 ± 1.1
p-value
0.000
0.000
No statically significant differences among groups 1, 2 and 3. b No statically significant differences among groups 4, 5 and 6. a
0.050 0.000
Sodium 111.2 ± 4.3a
1
0
5
10 15 20 25 30 35 40 45 50 55 60 Duration (minutes)
Only amitriptyline Amitriptyline + sodium bicarbonate
Amitriptyline + hypertonic saline
Table 6. Correlation between heart rate, QRS and QTc intervals and serum sodium and calcium levels Levels Sodium
Control
Fig. 3. Q Tc changes of the amitriptyline-administered groups and control group with time.
Calcium
Rate
QRS duration
p
0.000
0.000
0.000
r
0.794**
–0.776**
–0.612**
0.002
0.016
0.500**
0.399*
p
0.000
r
–0.0620*
*Correlation significant at the 0.05 level. **Correlation significant at the 0.01 level.
QTc duration
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Sodium bicarbonate is the first choice in the treatment of TCA-induced cardiotoxicity.4,5 There are several mechanism by which NaHCO3 treatment may confer beneficial effects. It may increase serum sodium levels and reduce cardiac arrhythmias resulting from the inhibition of sodium channels.4,11 It may reduce the alkaline pH of the serum concentration of the ionised fraction of the drug that is responsible for cardiotoxicity.20,26 In addition, it may give rise to volume expansion.4 Studies have shown that NaHCO3 treatment reduces the incidence of ventricular arrhythmias, prevents prolonged QRS and QT intervals, and improves hypotension.11,20 However, the disadvantages of this treatment include volume overload, hypokalaemia induced by alkalosis, and delay in the elimination of the drug in an alkaline pH.4 For this reason, it has been suggested that hypertonic NaHCO3 treatment should be used only in the presence of severe cardiac findings.6 Previous studies have frequently reported an association between TCA poisoning and hyponatraemia.24,27-29 Possible causes of this situation are sodium loss due to vomiting or gastric lavage, treatment with hypotonic fluids, or, most importantly, inappropriate secretion of antidiuretic hormone due to critical illness. Our clinical observations of patients with amitriptyline poisoning suggested that there might be a relationship between hyponatraemia and the degree of poisoning, particularly with regard to the presence of cardiac arrhythmias and seizures.30 Therefore, in this study, we aimed to investigate whether HS therapy initiated before the development of signs of systemic toxicity would reduce the development of cardiotoxicity. Hypertonic saline treatment is widely used for many indications, especially in hypovolaemic and septic shock, hyponatraemic encephalopathy and increased intracranial pressure syndrome, and clinicians have a very high degree of experience in this field.31-34 Earlier experimental studies have demonstrated the effects of the administration of HS in severe TCA poisoning.7-9 The main advantages of HS therapy are that it is cheap and accessible, and it has therapeutic properties in hyponatraemic, hypovolaemic or hypotensive patients. In this study, the rats administered toxic doses of amitriptyline developed severe cardiotoxicity that resulted in a prolonged QRS and QTc duration on ECG, slower heart rates and even death. The apparent relationship between the depth of hyponatraemia and the clinical outcome led us to believe that sodium may be a key player in the treatment. In our study, the administration of HS or NaHCO3 in the early stage of poisoning seemed to delay and reduce the development of toxicity. The effectiveness of both treatments was found to be similar. Similar amounts of sodium (~ 3 mEq/kg) were given to both groups. The group administered amitriptyline with NaHCO3 had borderline hyponatraemia. The cause of the more significant hyponatraemia in the group treated with HS is not clear. Further studies with different concentrations of sodiumcontaining fluids are needed to evaluate this issue. Interestingly, serum ionised calcium levels were higher in the groups that received amitriptyline than in the control group in our study. We did not study blood pH and other factors that affect calcium metabolism. Therefore, the pathophysiological basis of our findings is unclear. An additional limitation of this study is that we did not study factors affecting calcium metabolism and blood gases.
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Conclusion Amitriptyline poisoning is a common occurrence. Although the majority of cases improve with supportive therapy, cardiac complications may be life threatening in some cases. Although prospective, controlled human studies are needed, the results of this preliminary study suggest that amitriptyline poisoning leads to hyponatraemia, and early HS or NaHCO3 treatment may reduce the development of cardiac toxicity. As HS treatment does not affect serum levels of ionised calcium and potassium or change the drug elimination time, it may be preferred to NaHCO3 therapy.
References 1.
Mills K. Cylic Antidepressants. In: Brent J, Wallace KL, Burkhart KK, eds. Critical Care Toxicology: Diagnosis and Management of the Critically Poisoned Patient. Philadelphia: Elsevier Mosby 2005: 475–484.
2.
Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J 2001; 18(4): 236–241.
3.
Kalkan S, Aygoren O, Akgun A, Gidener S, Guven H, Tuncok Y. Do adenosine receptors play a role in amitriptyline-induced cardiovascular toxicity in rats? J Toxicol Clin Toxicol 2004; 42(7): 945–954.
4.
Knudsen K, Abrahamsson J. Epinephrine and sodium bicarbonate independently and additively increase survival in experimental amitriptyline poisoning. Crit Care Med 1997; 25(4): 669–674.
5.
Sarisoy O, Babaoglu K, Tugay S, Barn E, Gokalp AS. Efficacy of magnesium sulfate for treatment of ventricular tachycardia in amitriptyline intoxication. Pediatr Emerg Care 2007; 23(9): 646–68.
6.
Blackman K, Brown SG, Wilkes GJ. Plasma alkalinization for tricyclic antidepressant toxicity: a systematic review. Emerg Med (Fremantle) 2001; 13(2): 204–210.
7.
Hoegholm A, Clementsen P. Hypertonic sodium chloride in severe antidepressant overdosage. J Toxicol Clin Toxicol 1991; 29(2): 297–298.
8.
McCabe JL, Cobaugh DJ, Menegazzi JJ, Fata J. Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Ann Emerg Med 1998; 32(3 Pt 1): 329–233.
9.
McKinney PE, Rasmussen R. Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution. Ann Emerg Med 2003; 42(1): 20–24.
10. Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev 2005; 24(3): 205–214. 11. Geis GL, Bond GR. Antidepressant overdose: tricyclics, selective serotonin reuptake inhibitors, and atypical antidepressants. In: Erickson TB, Ahrens WR, Aks SE, et al. eds. Pediatric Toxicology: Diagnosis and Management of the Poisoned Child. 1st edn. New York: The McGrawHill Companies 2005: 296–302. 12. Kaplan YC, Hocaoglu N, Oransay K, Kalkan S, Tuncok Y. Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats. Hum Exp Toxicol 2008; 27(4): 321–325. 13. Tuncok Y, Kalkan S, Murat N, Arkan F, Guven H, Aygoren O, et al. The effect of the nitric oxide synthesis inhibitor L-NAME on amitriptylineinduced hypotension in rats. J Toxicol Clin Toxicol 2002; 40(2): 121–127. 14. Deegan C, O’Brien K. Amitriptyline poisoning in a 2-year old. Paediatr Anaesth 2006; 16(2): 174–177. 15. Caksen H, Akbayram S, Odabas D, Ozbek H, Erol M, Akgun C, et al. Acute amitriptyline intoxication: an analysis of 44 children. Hum Exp Toxicol 2006 Mar; 25(3): 107–110. 16. Foulke GE, Albertson TE, Walby WF. Tricyclic antidepressant overdose: emergency department findings as predictors of clinical course.
AFRICA
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 3, May/June 2015
Am J Emerg Med 1986; 4(6): 496–500. 17. Foulke GE. Identifying toxicity risk early after antidepressant overdose. Am J Emerg Med 1995; 13(2): 123–126.
139
Amitriptyline plasma protein binding: effect of plasma pH and relevance to clinical overdose. Am J Emerg Med 1986; 4(2): 121–125. 27. Degner D, Grohmann R, Kropp S, Ruther E, Bender S, Engel RR, et al.
18. Boehnert MT, Lovejoy FH, Jr. Value of the QRS duration versus the
Severe adverse drug reactions of antidepressants: results of the German
serum drug level in predicting seizures and ventricular arrhythmias
multicenter drug surveillance program AMSP. Pharmacopsychiatry
after an acute overdose of tricyclic antidepressants. N Engl J Med 1985; 313(8): 474–479. 19. Hulten BA, Heath A, Knudsen K, Nyberg G, Starmark JE, Martensson E. Severe amitriptyline overdose: relationship between toxicokinetics and toxicodynamics. J Toxicol Clin Toxicol 1992; 30(2): 171–179. 20. Sasyniuk BI, Jhamandas V, Valois M. Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate. Ann Emerg Med 1986; 15(9): 1052–1059. 21. Kingston ME. Hyperventilation in tricyclic antidepressant poisoning. Crit Care Med 1979; 7(12): 550–551. 22. Zuidema X, Dunser MW, Wenzel V, Rozendaal FW, de Jager CP. Terlipressin as an adjunct vasopressor in refractory hypotension after
2004; 37(Suppl 1): S39–45. 28. Henkin Y, Kaplan Z, Alkan M. Psychiatric presentation of hyponatremia associated with the use of amitriptyline – a report of two cases. Isr J Med Sci 1989; 25(10): 587–589. 29. Olgun H, Yildirim ZK, Karacan M, Ceviz N. Clinical, electrocardiographic, and laboratory findings in children with amitriptyline intoxication. Pediatr Emerg Care 2009; 25(3): 170–173. 30. Paksu S, Duran L, Altuntas M, Zengin H, Salis O, Ozsevik S, et al. Amitriptyline overdose in emergency department of university hospital: Evaluation of 250 patients. Hum Exp Toxicol 2014; 33(9): 980–990. 31. Bulger EM, Hoyt DB. Hypertonic resuscitation after severe injury: is it of benefit? Adv Surg 2012; 46: 73–85.
tricyclic antidepressant intoxication. Resuscitation 2007; 72(2): 319–323.
32. Lazaridis C, Neyens R, Bodle J, Desantis SM. High-osmolarity saline in
23. Bek K, Ozkaya O, Mutlu B, Dagdemir A, Sungur M, Acikgoz Y, et al.
neurocritical care: systematic review and meta-analysis. Crit Care Med
Charcoal haemoperfusion in amitriptyline poisoning: experience in 20 children. Nephrology (Carlton) 2008; 13(3): 193–197. 24. Islek I, Degim T, Akay C, Turkay A, Akpolat T. Charcoal haemoperfusion in a child with amitriptyline poisoning. Nephrol Dial Transplant 2004; 19(12): 3190–3191. 25. Kiberd MB, Minor SF. Lipid therapy for the treatment of a refractory amitriptyline overdose. Can J Emerg Med 2012; 14(3): 193–197. 26. Levitt MA, Sullivan JB, Jr., Owens SM, Burnham L, Finley PR.
2013; 41(5): 1353–1360. 33. Sood L, Sterns RH, Hix JK, Silver SM, Chen L. Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis 2013; 61(4): 571–458. 34. Van Haren FM, Sleigh J, Boerma EC, La Pine M, Bahr M, Pickkers P, et al. Hypertonic fluid administration in patients with septic shock: a prospective randomized controlled pilot study. Shock 2012; 37(3): 268–275.
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Prevalence of anaemia among patients with heart failure at the Brazzaville University Hospital Méo Stéphane Ikama, Bernice Mesmer Nsitou, Innocent Kocko, Ngamami Solange Mongo, Gisèle Kimbally-Kaky, Jean Louis Nkoua
Abstract Background: Heart failure (HF) is a frequent cause of hospitalisation in cardiology. Its prognosis depends on several risk factors, one of which is anaemia. Objectives: We aimed to determine the prevalence of anaemia in patients with heart failure, and evaluate its impact on their prognosis. Methods: This article describes a cross-sectional study with prospective collection of data, carried out from 1 January to 31 December 2010 in the Department of Cardiology at Brazzaville University Hospital, Congo. Patients admitted for heart failure were included. Anaemia was defined as a haemoglobin level < 12 g/dl for men and < 11 g/dl for women. Results: In total, 130 men (47.8%) and 142 women (52.2%) were recruited, mean age 56.9 ± 16.5 years. The prevalence of anaemia was 42%. Average levels of haemoglobin were 9.4 ± 1.8 and 13.8 ± 4.9 g/dl for the anaemic (A) and non-anaemic (NA) patients, respectively (p = 0.0001). Two hundred and forty-nine patients (91.5%) were in NYHA functional class III–IV. Forty-seven patients (17.3%) were on oral anticoagulation and 15 (5.5%) were on aspirin. The average duration of hospital stay was 19.1 ± 16.7 days, without a significant difference between the A and NA groups (19.4 ± 12 vs 18.8 ± 13.8 days; p = 0.79, respectively). Total mortality rate was 17%, with a significant difference between the A and NA groups (26 vs 10%; p = 0.001). Conclusion: This preliminary study showed a high prevalence of anaemia in patients with heart failure, and it had a negative effect on the prognosis. Keywords: heart failure, anaemia, prevalence, prognosis, Congo Submitted 27/7/14, accepted 3/2/15 Cardiovasc J Afr 2015; 26: 140–142
www.cvja.co.za
DOI: 10.5830/CVJA-2015-021
Heart failure (HF) is a frequent cause of hospitalisation in cardiology. Its prognosis depends on several factors, including
Cardiologie, CHU de Brazzaville, Brazzaville, Congo Méo Stéphane Ikama, MD, stephane.mikama@gmail.com Bernice Mesmer Nsitou, MD Ngamami Solange Mongo, MD Gisèle Kimbally-Kaky, PhD Jean Louis Nkoua, PhD
Hématologie clinique, CHU de Brazzaville, Brazzaville, Congo Innocent Kocko, MD
anaemia, which is common among patients with heart failure.1 Anaemia is an independent prognostic factor for mortality in chronic HF and is associated with higher rates of mortality, hospitalisation and re-admission.2,3 Anaemia is a powerful independent predictor of death and hospitalisation in systolic and diastolic dysfunction.2,4-7 In order to improve the management of patients suffering from systolic and diastolic HF, it is critical to understand the relationship between HF and anaemia, and the possible outcomes. The aim of this study was to determine the prevalence of anaemia in patients with heart failure and to evaluate its impact on the prognosis of patients in Brazzaville, Congo.
Methods This article describes a cross-sectional study with a prospective approach to data collection, carried out from 1 January to 31 December 2010 in the Department of Cardiology and Internal Medicine at Brazzaville University Hospital. The study included patients admitted for left or biventricular heart failure. Patients admitted for exclusively right heart failure, or a cause other than heart failure, as well as for sickle anaemia, were excluded. Anaemia was defined as a haemoglobin level < 12 g/dl for men and < 11 g/dl for women. Two hundred and seventy-two patients were selected and divided into two groups according to anaemic status: anaemic (n = 114) and non-anaemic patients (n = 158). Socio-demographics such as age, gender and socio-economic level were analysed, as well as clinical and echocardiographic parameters, including type of heart failure (left or biventricular), NYHA (New York Heart Association) functional class, the use of aspirin and/or oral anticoagulation, type of heart disease, and left ventricular ejection fraction (LVEF). In addition, we studied blood profiles, including haemoglobin level, renal function (estimated by glomerular filtration rate using the Cockroft– Gault equation; considered to be lowered if GFR < 60 ml/min). Finally, we analysed prognosis in terms of duration of hospital stay, and mortality rate (outcome for that same admission).
Statistical analysis The data were analysed with Epi-info 3.5.1 software. The chi-squared and ANOVA tests allowed the comparison of qualitative and quantitative variables, respectively. The significance level was p < 0.05.
Results A total of 272 patients were evaluated, including 130 men (47.8%) and 142 women (52.2%), with a mean age of 56.9 ± 16.5 years (range: 18–97). The prevalence of anaemia was 42%, with an average haemoglobin level of 11.9 ± 4.4 g/dl (range: 4.7–15.2).
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The average haemoglobin levels were 9.4 ± 1.8 and 13.8 ± 4.9 g/l in the anaemic (A) and non-anaemic (NA) patients, respectively (p = 0.0001). The main patient characteristics are shown in Table 1. Heart failure was biventricular in 233 cases (85.7%) and left HF in 39 cases (14.3%). Two hundred and forty-nine patients (91.5%) were in NYHA functional class III–IV, with no difference between the A and NA patients (p = 0.6). The heart diseases diagnosed were hypertensive heart disease in 106 cases (39.0%), dilated cardiomyopathy in 86 cases (31.6%), myocarditis in 27 cases (9.9%), valvular heart disease in 24 cases (8.8%), ischaemic heart disease in 15 cases (5.5%), and unspecified cause in 14 cases (5.1%). Average left ventricular ejection fraction was 48 ± 14.6% in A and 51.3 ± 15% in NA patients (p = 0.43). Average glomerular filtration rate was 54.6 ± 12.5 ml/min in A and 70.4 ± 10.2 ml/min in NA patients (p = 0.004). Forty-seven patients (17.3%) were on oral anticoagulation and 15 (5.5%) were on aspirin. The average duration of hospital stay was 19.1 ± 16.7 days, with no statistical difference between the A and NA patients (19.4 ± 12 vs 18.8 ± 13.8 days, respectively; p = 0.79). Total mortality rate was 17%, with a significant difference between the A and NA patients (26 vs 10%; p = 0.001). The comparison between A and NA patients is given in Table 2.
Discussion It has been shown that advanced age is a predictive factor of a strong prevalence of anaemia in heart failure.6,8 In our study, the patients were relatively young, with an average of 57 years, in comparison with large series in developed countries, where the median age of patients was 70 years.9,10 In Africa, very few studies have been conducted assessing anaemia in HF patients.11-13 In our study, the prevalence of anaemia in HF was 42%, near to the 49% that was found in France by Abassade et al.,10 and lower than the 64.3% found by Kuule et al. in Uganda.11 In the literature, the prevalence of anaemia is variable, from 4 to 61%, with the majority of studies finding it between 18 and 20%.14-16 This large variability may be explained by methodological differences, due mainly to the definition of anaemia.2,3,17-19
Table 1. Patient characteristics Patients Parameters (n = 272) Male gender, n (%) 130 (47.8) Age (years), SD (range) 56.9 ± 16.5 (18–97) Low socio-economic level, n (%) 211 (77.5) HIV +, n (%) 12 (4.4) Biventricular HF, n (%) 233 (85.7) NYHA III–IV, n (%) 249 (91.5) Haemoglobin (g/dl), SD (range) 11.9 ± 4.4 (4.7–15.2) Aspirin, n (%) 15 (5.5) Oral anticoagulation, n (%) 47 (17.3) LVEF (%), SD (range) 49.3 ± 14.7 (22–75) Hospitalisation stay (days), SD 19.1 ± 16.7 Mortality rate, n (%) 46 (17) HIV: human immunodeficiency virus; HF: heart failure; NYHA: New York Heart Association; LVEF: left ventricular ejection fraction.
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Most publications use the definition of anaemia by the World Health Organisation (anaemia is a haemoglobin concentration < 13 g/dl in men and < 12 g/dl in postmenopausal women), and by National Kidney Foundation (anaemia is a haemoglobin concentration < 12 g/dl in both men and postmenopausal women).20,21 The prevalence of anaemia in our study was therefore underestimated; it would have been higher if the WHO criteria for definition had been used. In chronic HF, factors associated with a high prevalence of anaemia include concomitant kidney disease, advanced age, female gender, African American ethnicity, diabetes, hypertension, and lower estimated glomerular filtration rates.5,8,22 In our study, the aetiological research on anaemia was not systematic. In general, the aetiology of anaemia in chronic HF is multifactorial, and multiple mechanisms contribute to anaemia in chronic HF:15,23 iron and other haematological deficiencies, renal insufficiency, the role of haemodilution, chronic diseases and ‘inflammation’, and the renin–angiotensin system. Iron deficiency appears to be the most common cause of anaemia in HF.24,25 In the African context,26 malnutrition, infectious pathology (intestinal parasites, HIV infection), and the congestive nature of HF (salt and water retention, advanced chronic HF) may partially explain the prevalence of anaemia in African subjects, the majority being hypertensive and potentially renal insufficient. A large number of studies have confirmed that anaemia is a strong, independent predictor of increased mortality rate and hospitalisation stay in patients with systolic and diastolic dysfunction, new-onset HF, and severe chronic HF.2,4-7,24 In our study, these reports were confirmed in terms of higher mortality rate, and longer hospital stay in the anaemic patients compared to non-anaemic sunjects.
Conclusion This preliminary study showed a high prevalence of anaemia in chronic HF patients and its negative impact on the prognosis (high mortality rate, longer hospitalisation) of patients. The prognosis of anaemic patients suffering from HF may be improved by treatment of the anaemia.
Table 2. Comparison between anaemic and non-anaemic patients NonAnaemic anaemic patients patients Parameters (n = 114) (n = 158) p-value Age (years) 54.9 ± 18.3 58.3 ± 15.1 0.105 Haemoglobin (g/dl) 9.4 ± 1.8 13.8 ± 4.9 0.0001 Biventricular HF, n (%) 101 (43.3) 132 (56.7) 0.159 NYHA III–IV, n (%) 106 (93) 143 (90.5) 0.6 Aspirin, n (%) 3 (2.5) 12 (7.6) 0.06 Oral anticoagulation, n (%) 19 (16.7) 28 (17.7) 0.47 LVEF (%) 48 ± 14.6 51.3 ± 14.9 0.43 Glomerular filtration rate (ml/min) 54.6 ± 12.5 70.4 ± 10.2 0.004 Hospitalisation stay (days) 19.4 ± 12 18.8 ± 13.8 0.79 Mortality rate, n (%) 30 (26) 16 (10) 0.001 HF: heart failure; NYHA: New York Heart Association; LVEF: left ventricular ejection fraction.
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References 1.
Sharma R, Francis DP, Pitt B, et al. Haemoglobin predicts survival in patients with chronic heart failure: a substudy of Elite II trial. Eur Heart J 2004; 25: 1021–1028.
2.
5.
people with chronic heart failure: the potential cost. Technol Health Care
prognosis in new cases of heart failure. Lancet 2003; 362: 211–212.
of anemia in patients with heart failure. Am J Med 2003; 114: 112–119.
18. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous eryth-
Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe
ropoietin and intravenous iron for the treatment of the anemia of severe,
heart failure. J Am Coll Cardiol 2003; 41: 1933–1939.
resistant congestive heart failure improves cardiac and renal function,
Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function
functional cardiac class, and markedly reduces hospitalizations. J Am
syndrome: correcting anemia in patients with resistant congestive heart
failure and preserved systolic function. Am Heart J 2006; 151: 457–462.
failure can improve both cardiac and renal function and reduces hospi-
O’Meara E, Clayton T, McEnlegart MB, et al. Clinical correlates and
talization. Clin Nephrol 2003; 60(Suppl 1): S93–S102.
consequences of anemia in a broad spectrum of patients with heart
20. World Health Organization/United Nations University/UNICEF. Iron
failure: results of the Candesartan in Heart Failure: Assessment of
deficiency anemia, assessment, prevention and control: a guide for
2006; 113: 986–994. Mitchell JE. Emerging role of anemia in heart failure. Am J Cardiol 2007; 99: 15D–20D. 9.
Coll Cardiol 2000; 35: 1737–1744. 19. Silverberg DS, Wexler D, Blum M, Iaina A. The cardio renal anemia
Felker GM, Shaw LK, Stough WG, et al. Anemia in patients with heart
Reduction in Mortality and Morbidity (CHARM) Program. Circulation 8.
2009; 17: 377–385. 17. Kalra PR, Collier T, Cowie MR, et al. Heamoglobin concentration and
Kosiborod M, Smith GL, Radford MJ, et al. The prognostic importance
dysfunction. J Am Coll Cardiol 2001; 38: 955–962.
7.
Chronic Heart Failure. Congest Heart Fail 2009; 15: 87–92.
with worse symptoms, greater impairment in functional capacity and a
and anemia as risk factors for mortality in patients with left ventricular 6.
2454–2461. 15. Drakos SG, Anastasiou-Nana MI, Malliaras KG, et al. Anemia in 16. Man-Fai Sim V, Chi Yuen Nam M, Riley S, et al. Anemia in older
J Am Coll Cardiol 2002; 39: 1780–1786.
4.
ogy, clinical correlates, and treatment options. Circulation 2006; 113:
Horwich TB, Fonarow GC, Hamilton MA, et al. Anemia is associated significant increase in mortality in patients with advanced heart failure.
3.
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programme managers, Geneva, WHO, 2001. 21. National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J kidney Dis 2002; 39(Suppl): S1–S266.
Cleland JGF, Swedberg K, Follath F, et al. The EuroHeart Failure
22. McCullough PA, Barnard D, Clare R, et al. Anemia and associ-
Survey Program. A survey on the quality of care among patients with
ated clinical outcomes in patients with heart failure due to reduced left
heart failure in Europe. Eur Heart J 2003; 24: 442–463. 10. Abassade P, Rabenirina F, Garcon P, et al. L’anémie dans l’insuffisance cardiaque. Ann Cardiol Angéiol 2009; 58: 289–292.
ventricular systolic function. Clin Cardiol 2013; 36: 611–620. 23. Katz SD. Mechanisms and treatment of anemia in chronic heart failure. Congest Heart Fail 2004; 10: 243–247.
11. Kuule JK, Seremba E, Freers J. Anemia among patients with congestive
24. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in
cardiac failure in Uganda – its impact on treatment and outcomes. S Afr
heart failure and is associated with poor outcomes. Circulation 2003;
Med J 2009; 99: 876–880.
107: 223–225.
12. Oyoo GO, Ogola EN. Clinical and sociodemographic aspects of conges-
25. Witte KK, Desilva R, Chattopadhyay S, et al. Are hematinic deficien-
tive heart failure patients at Kenyatta National Hospital, Nairobi. East
cies the cause of anemia in chronic heart failure? Am Heart J 2004; 147:
Afr Med J 1999; 76: 23–37.
924–930.
13. Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and
26. Mukaya JE, Ddungu H, Ssali F, et al. Prevalence and morphological
outcome of acute heart failure in 1006 Africans from 9 countries. Arch
types of anemia and hookworm infestation in the medical emergency
Intern Med 2012; 172: 1386–1394.
ward, Mulago Hospital, Uganda. S Afr Med J 2009; 99: 881–886.
14. Tang YD, Katz SD. Anemia in chronic heart failure: prevalence, etiol-
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Case Report An antibiotic recipe for an arrhythmic disaster Keir McCutcheon, Pravin Manga Case report
Abstract We describe the case of a patient who developed torsade de pointes during temporary pacemaker insertion after administration of intravenous erythromycin. The case highlights the dangers of administering drugs that prolong the QT interval in patients with complete atrioventricular block, and we discuss the underlying pathophysiological recipe that can lead to a potential arrhythmic disaster. Keywords: erythromycin, QT prolongation, complete heart block, pacing, torsade de pointes Submitted 10/7/13, accepted 11/1/15 Cardiovasc J Afr 2015; 26: 143–145
www.cvja.co.za
DOI: 10.5830/CVJA-2015-006
Torsade de pointes (TdP), a polymorphic ventricular tachycardia caused by dispersion of depolarisation within the ventricles, is an important complication of atrioventricular (AV) conduction disorders.1 Various classes of drugs including antimicrobials, antiarrhythmic and psychotropic drugs may lead to prolongation of the QT interval with an increased risk of TdP, especially in patients with other risk factors for QT prolongation. However, to date, there have been very few reports of TdP due to drugs in patients with AV block,2,3 and, to our knowledge, no case reports highlighting the hazard of using erythromycin in patients with complete AV block. The QT interval, which shortens during tachycardia and lengthens during bradycardia, is the most useful measure to predict a patient’s risk of developing TdP and several formulae are available to correct for heart rate, the commonest being Bazzet’s formula.4 Women normally have slightly longer QT intervals than men. We describe here a case of TdP during pacemaker implantation after erythromycin administration. The case highlights the potentially life-threatening effects of prescribing QT-prolonging drugs in patients with severe bradyarrhythmias.
Division of Cardiology, Department of Medicine, University of the Witwatersrand, and Charlotte Maxeke Academic Hospital, Johannesburg, South Africa Keir McCutcheon, BSc (Hons), MSc, MB BCh, FCP (SA), Cert Cardiol (SA), keir_mccutcheon@hotmail.com Pravin Manga, MB BCh, FCP (SA), PhD, FRCP (UK)
A 68-year-old woman, with a background of hypertension controlled on medical therapy, presented with vague symptoms of fatigue and poor exercise tolerance. She had no history of antibiotic, anti-arrhythmic or psychotropic drug use in the previous month. She had no history or family history of syncope or sudden cardiac death and had no other significant past medical history. However, she reported having an allergy to penicillin. The examination was unremarkable. Resting ECG showed a sinus rhythm at 100 beats per minute (bpm) with complete AV block and a ventricular escape at 33 bpm (Fig. 1, top strip). She was haemodynamically stable and was booked for permanent pacemaker implantation the following day. At the time of pacemaker implantation, it is usual protocol to give our patients prophylactic antibiotics during and after the procedure. Most patients receive a first-generation cephalosporin in three intravenous doses. However, because this patient had reported an allergy to penicillin, it was decided that an alternative antibiotic be used. While the patient was being draped for the procedure, a single dose of intravenous erythromycin 500 mg was infused. This was followed by insertion of a transvenous temporary pacing lead via the right femoral vein. The introduction of the transvenous lead into the right ventricle resulted in right ventricular ectopic beats during positioning in the right ventricle, and this resulted in the induction of polymorphic ventricular tachycardia (Fig. 1, middle strip), which required three rounds of DC cardioversion at 200 J over a period of approximately 15 minutes. This restored her to her baseline rhythm (Fig. 1, bottom strip). The patient was transferred back to the coronary care unit where she was given intravenous magnesium and, fortunately, the ventricular tachycardia did not recur. Cardiac catheterisation performed the following day revealed normal coronary arteries and blood results showed no electrolyte abnormality. Pacemaker implantation was subsequently performed without antibiotic cover and with no further episodes of TdP.
Discussion We present a case of TdP due to QT prolongation in a patient with complete AV block who received erythromycin. The patient was not on any other medication known to prolong the QT interval and her serum electrolyte levels were normal. The arrhythmia occurred during insertion of a temporary pacing lead and was treated emergently with electrical cardioversion. Permanent pacemaker implantation for complete AV block is a common cardiac procedure. Numerous drugs are administered
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Fig. 1. This shows the rhythm strip of the patient prior to administration of erythromycin (top strip), during direct-current cardioversion for torsade de pointes (middle strip), and after successful cardioversion (bottom strip). At baseline (top strip) the ECG demonstrates complete heart block with an uncorrected QT interval of 600 ms. The middle strip clearly demonstrates TdP, which is treated with electrical cardioversion in the centre of the middle strip, followed by return to the baseline dysrhythmia in the bottom strip.
at the time of pacemaker implantation, including antibiotics and anaesthetics. Ginwalla et al.,3 for example, described a case of haloperidol-induced TdP in a patient with complete AV block. The haloperidol was given to control agitation in an elderly gentleman, which resulted in TdP requiring defibrillation and intravenous magnesium. Their case and ours highlights the importance of doctors needing to be aware of what medications and electrolyte imbalances to avoid in patients with severe bradyarrhythmias. Our case highlights the care required in the peri-operative patient with complete AV block who may receive a number of potentially hazardous drugs. It has been known for many years that erythromycin prolongs the QT interval in susceptible individuals and can lead to potentially fatal dysrhythmias.5 The mechanism of QT prolongation due to erythromycin is related to blockade of potassium efflux in the plateau phase of the myocardial action potential.6.7 Daleau et al.8 were the first to demonstrate that the effect of erythromycin is to inhibit the rapid component of the
delayed rectifier current (IKr) in guinea pig myocytes. Prolongation of the action potential increases the risk of early after-depolarisations in M cells deep within the ventricular myocardium and creates marked dispersion of repolarisation across the ventricular wall.7 This sets the stage for maintaining the characteristic spiraling ventricular arrhythmia, TdP. The development of right ventricular ectopic beats during temporary pacemaker insertion can create the classic ‘short–long’ R–R intervals associated with polymorphic ventricular tachycardia initiation, which is then maintained by the erythromycin-induced dispersion of repolarisation. The mechanism of QT prolongation in patients with bradycardia-related TdP is poorly understood. Certainly, not all patients with AV block get prolongation of the QT or TdP. Kurita et al.9 demonstrated that patients with complete AV block with TdP have a bradycardia-sensitive repolarisation abnormality, which persists even after pacemaker implantation. However, there is little data on the actual mechanism responsible for QT prolongation and it may just be that those individuals
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who develop QT prolongation and TdP have an underlying genetic predisposition, resulting in prolongation of the action potential duration, which is exacerbated by the bradycardia.
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interval in a patient with schizoaffective disorder and complete AV block. Can J Psychiatry 2004; 49: 414. 3.
Ginwalla M, Biblo LA, Paydak H. Torsade de Pointes following intravenous haloperidol administration in a patient with complete heart block.
Conclusion Our case re-emphasises the risks involved in administering erythromycin to patients. In particular, patients with AV block should not receive this drug. The timing of the TdP is interesting because it coincided with the insertion of the temporary pacing lead. It is very likely that the ventricular ectopics induced by the temporary lead in the right ventricular apex precipitated the short–long cycle that led to the TdP. Instead of repeated DC cardioversion, we could have temporarily paced the patient at a more rapid rate to prevent the recurrence of the bradycardiainduced TdP. Based on data from Kurita et al.,9 a rate above 60 bpm would have been sufficient to prevent further episodes of TdP.
Wisconsin Med J 2009; 108: 48–50. 4.
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353–370.
5.
McComb JM, Campbell NPS, Cleland J. Recurrent ventricular tachycardia associated with QT prolongation after mitral valve replacement and its association with intravenous administration of erythromycin. Am J Cardiol 1984; 54: 922–923.
6.
Rubart M, Pressler ML, Pride HP, Zipes DP. Electrophysiological mechanisms in a canine model of erythromycin-associated log QT syndrome. Circulation 1993; 88: 1832–1844.
7.
Antzelevitch C, Sun Z-Q, Zhang Z-Q, Yan G-X. Cellular and ionic mechanism underlying erythromycin-induced long QT intervals and Torsade de Pointes. J Am Coll Cardiol 1996; 28: 1836–1848.
8.
Daleau P, Lessard E, Groleau M-F, Turgeon J. Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes. Circulation
References 1.
2.
Strasberg B, Kusniec J, Erdman S, Lewin RRF, Arditti A, Sclarovsky S,
1995; 91: 3010–3016. 9.
Kurita T, Ohe T, Marui N, Aihara N, Takaki H, Kamakura S, et
et al. Polymorphous ventricular tachycardia and atrioventricular block.
al. Bradycardia-induced abnormal QT prolongation in patients with
PACE 1986; 9: 522–526.
complete atrioventricular block with Torsade de Pointes. Am J Cardiol
Ziegenbein M, Kropp S. Lorazepam-induced prolongation of the QT
1992; 69: 628–633.
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Drug Trends in Cardiology AfricaPCR 2015, a brief report back It is difficult to be a dispassionate observer at a PCR course organised by the Europa Organisation. Sessions are designed to stimulate audience participation and dialogue, and AfricaPCR 2015 exemplified that approach. Held from the 26–28 March at the Forum, the Campus, in Bryanston, Johannesburg, the 2015 course had an audible buzz, with delegates being as interactive as the presenters, making for highly stimulating and informative sessions, with much take-home value. Case studies were particularly interesting because they were not presented as ‘show and tell’ exercises. Speakers presented the images pertaining to their respective cases, identified the challenges, but did not disclose how they had handled them. Instead, they invited the delegates to comment and debate how they would have treated the patient. Audience consensus or divergence regarding recommended strategies inevitably led to lively discussion, resulting in a ‘yes’ or ‘no’ vote for specific procedures. Case studies were rounded off by the speakers disclosing how they actually treated their respective patients, with the chairman of the session summarising the learning points. One of the course highlights was a
Sajidah Khan, course co-director.
special focus on radial PCI, with two workshops each day being dedicated to how to start a radial programme, and the tips and tricks needed to succeed with radial PCI. The workshops were sponsored by Terumo, who complemented them with a model of radial access and a radial simulator which proved to be an irresistible key attraction. Another highlight was a special focus on setting up a new catheterisation laboratory. Discussion centred on what the basic requirements were for paediatric and adult cardiology diagnostic and interventional procedures in the cath lab. When it came to tackling complications in the cath lab, Dr Otieno from Kenya aptly noted that if delegates hadn’t experienced complications yet, then they hadn’t used their cath labs sufficiently! • Fluoroscopic guidance was recommended in order to reduce the femoral access site complication rate. • Prof Jean Marco said that coronary perforation and pericardial tamponade were rare, with a frequency of less than 0.2% in PCI. He noted that 51% of perforations were guide wire related, making it vital to image the position of the guide wire. • The success rate in retrieving wandering stents and foreign bodies was
Medtronic and Biotronik stands.
approximately 70–90% when snares were used. • In the case of STEMI or cardiogenic shock, delegates were advised to call for assistance from cardiothoracic colleagues. • They were also encouraged to initiate a quality improvement programme by keeping records of complications that occurred in the cath lab and how they were resolved. A few major challenges were identified with regard to establishing more cath labs, or better functioning cath labs, in Africa. A shortage of equipment, or inadequate maintenance of equipment, appeared to be a common problem in some countries. There are currently 14 cath labs in Sudan, for example, but none with the equipment needed to do FFR. Angola has four cath labs, with only two being functional. The reason is that the equipment suppliers and technicians are based in another country. Therefore it is clearly imperative to secure the servicing and maintenance of equipment as a contractual obligation when signing a deal with an industry partner based elsewhere. Securing the funding to establish additional cath labs was clearly a challenge throughout the continent.
Prof Mpiko Ntsekhe.
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Based on personal experience, Prof Mpiko Ntsekhe from UCT Medical School recommended engaging with politicians in order to advocate for the establishment of new cath labs. He cited the opening of Namibia’s first cath lab a few years ago as an example, where politicians had been actively lobbied for support, with both presidents Thabo Mbeki and Sam Nujoma having attended the opening ceremony. Dr Bourlon drew on his experience in
Mauritania in order to identify what the basic requirements were for setting up a functional cath lab. These included having enough space and sufficient ventilation, adequate cooling for the equipment, no toilets near the lab, and adequate aftersales service. There was also consensus among delegates about access to echocardiograms being imperative. Dr Bourlon recommended having cardiothoracic surgery on site, but pointed out that many cath labs
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operated in Europe without them, with interventionists having accommodated themselves to a higher-risk environment. The 2016 AfricaPCR course will expand on the 2015 edition and course director Dr Farrel Hellig says, ‘It will aim to be even more inclusive with participation from as much of the African continent as possible. Education and resource development in the continent is clearly needed and AfricaPCR serves as a springboard.’
Delegates at AfricaPCR.
Radial access model.
Alecia van Wamelen, product manager, Terumo Corp.
Dr Farrel Hellig (far left), Dr William Wijns (far right), Jean Marco (end of table) with guests.
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South African hospital the first in the Middle East, Africa, central Asia and Turkey to implant the world’s smallest, minimally invasive cardiac pacemaker Groote Schuur Hospital in Cape Town is the first hospital in the Middle East, Africa, central Asia and Turkey to implant the world’s smallest pacemaker: the Medtronic Micra™ transcatheter pacing system (TPS). The device was implanted recently as part of the Medtronic global pivotal clinical trial. One-tenth the size of a conventional pacemaker and comparable in size to a large vitamin, the Micra TPS pacemaker is delivered directly into the heart through a catheter inserted into the femoral vein. Once positioned, the pacemaker is securely attached to the heart wall and can be repositioned if needed. The miniature device does not require the use
of wires, known as ‘leads’, to connect to the heart. Attached to the heart via small tines, the pacemaker delivers electrical impulses that pace the heart through an electrode at the end of the device. ‘This miniaturised technology is designed to provide patients with the advanced pacing technology of traditional pacemakers via a minimally invasive approach’, said Dr Ashley Chin, consultant cardiologist/ electrophysiologist at Groote Schuur Hospital and the University of Cape Town, who implanted this first Micra TPS. ‘We are proud that Groote Schuur Hospital was selected among an elite group of institutions to take part in this
global clinical trial. If positive, the results of the trial could potentially benefit the more than one million people globally who receive pacemakers each year.’ In contrast to current pacemaker implant procedures, the Micra TPS implant does not require a surgical incision in the chest and the creation of a ‘pocket’ under the skin. This eliminates a potential source of complications, and any visible sign of the device. The Medtronic Micra TPS is an investigational device worldwide. For more information, contact Michelle Burt on tel: 087 997 0120, cell: 083 295 1924 or e-mail: michelleb@ magna-carta.co.za.
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Case Report ST-elevation myocardial infarction following systemic inflammatory response syndrome Ying Tan, Yan Tu, Di Tian, Chen Li, Jian-Kai Zhong, Zhi-Gang Guo
Abstract Systemic inflammatory response syndrome (SIRS) complicated with ST-elevation myocardial infarction has rarely been reported, and the precise mechanisms of myocardial injury remain unclear. Here, we present a case involving a 45-year-old man who developed SIRS secondary to diabetesinduced infection, and who ultimately developed ST-elevation myocardial infarction with acute heart failure, fulminant diabetes, acute liver dysfunction, acute kidney dysfunction and rhabdomyolysis. The patient eventually recovered due to early detection, correct diagnosis and powerful treatment. Clinicians should be aware of this new type of myocardial infarction, which is induced by inflammatory injury, but is not due to a primary coronary event such as plaque erosion and/ or rupture, fissuring or dissection. Keywords: systemic inflammatory ST-elevation myocardial infarction
response
syndrome,
Submitted 28/1/14, accepted 27/11/14 Cardiovasc J Afr 2015; 26: e1–e3
www.cvja.co.za
DOI: 10.5830/CVJA-2014-071
Systemic inflammatory response syndrome (SIRS) results from a variety of severe clinical insults, such as infection, pancreatitis, trauma, surgery or other critical illness, and its diagnosis1 includes the presence of at least two of the following: (1) heart rate > 90 beats/min; (2) respiratory rate > 20 breaths/ min or carbon dioxide pressure (PaCO2) < 32 mmHg; (3) body temperature > 38°C or < 36°C; or (4) leukocyte count > 12 × 109 cells/l or < 4 × 109 cells/l.
Division of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China Ying Tan, MD Yan Tu, MD Di Tian, MD Chen Li, MD Jian-Kai Zhong, MD Zhi-Gang Guo, MD, guozhigang126@126.com
Division of Cardiology, The First People’s Hospital of Shunde, Guangdong, China Ying Tan, MD
Although the exact mechanisms of SIRS are unclear, in general, many scholars believe that SIRS is a clinical process that is characterised by generalised inflammatory hyper-reactivity caused by various severe clinical insults triggered by infectious factors and non-infectious host stimulatory agents. Extensive capillary leakage and mesenchymal oedema caused by various inflammatory mediators and cytokines lead to reduced blood perfusion of vital organs, microcirculatory disturbances, shock, and organ function decline or failure, ultimately resulting in multiple organ dysfunction syndrome (MODS) and multiple organ failure (MOF). When SIRS progresses to MODS and MOF, the mortality rate increases to a range of 30–80%, depending on the number of failed organs.2 Cardiovascular complications of SIRS include shock, pericardial effusion, and even non-specific ST–T changes in the electrocardiogram (ECG) that mimic acute myocardial infarction. However, ST-elevation myocardial infarction (STEMI) complicated by SIRS has rarely been reported, and most of the reported cases could not be classified as true myocardial infarction, according to cardiac enzyme levels and echocardiographic or angiographic findings. A literature review performed with PubMed, using the keywords ‘systemic inflammatory response syndrome (SIRS)’ and ‘ST-elevation acute myocardial infarction (STEMI)’, identified few reports in the English language literature between 1990 and 2013. In contrast to our case, two published reports by Samimi-Fard et al.3 and van Diepen et al.4 found that patients with STEMI may present with SIRS after primary percutaneous coronary intervention (PPCI). Conversely, our case showed that SIRS may cause STEMI, which is an extraordinary finding, given the absence of relevant coronary stenosis. Here, we report a case of SIRS-related myocardial infarction involving a 45-year-old man who developed SIRS secondary to diabetes-induced infection, followed by ST-elevation myocardial infarction with acute heart failure, fulminant diabetes, acute liver dysfunction, acute kidney dysfunction and rhabdomyolysis. Awareness of this type of myocardial infarction is critical to enable prompt diagnosis and treatment in similar cases.
Case report A 45-year-old man with a history of diabetes was admitted with cough, polyuria and polydipsia of one week’s duration. The patient had no medical history of hypertension and myocardial infarction. Upon physical examination, the patient was found to have a body temperature of 38.2°C, a respiratory rate of 23 breaths/min, a pulse rate of 106 beats/min and a systolic/diastolic
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blood pressure of 112/82 mmHg. A few moist crackles were apparent in the patient’s lungs. Laboratory studies revealed a white blood cell count of 23.02 × 109 cells/l with 88.6% neutrophils, and the following blood levels: alanine aminotransferase (ALT), 233 U/l (range 0–40); creatinine (Cr), 243.1 µmol/l (range 44–133); creatine kinase (CK), 36 762 U/l (range 26–174); plasma glucose, 49.1 mmol/l; fasting C-peptide, 0.01 ng/ml (range 0.7–1.9); two-hour postprandial C-peptide, 0.15 ng/ml; glycosylated haemoglobin (HbA1c), 8.4%; and C-reactive protein (CRP), 33.7 mg/l (range 0–5). The patient’s creatine kinase-MB (CK-MB) concentration was > 500 ng/ml, and his troponin I concentration was > 180 ng/ ml. Arterial blood gas analysis results showed the following: pH, 7.299; PO2, 16.80 kPa; PCO2, 4.01 kPa; base excess (BE), –10.8 mmol/l. A chest X-ray revealed a pneumonia infection of the lower right lung. An ECG showed ST-segment elevation in leads II, III, aVF and V7–V9 (Fig. 1A, B). Echocardiography revealed decreased left ventricular systolic function (ejection fraction: 32%) with left ventricular inferior and posterior wall motion abnormalities. Coronary angiography indicated no luminal narrowing in the left main coronary artery, circumflex or right coronary arteries, although atherosclerosis was apparent in the left anterior descending artery, with stenosis of 30% (Fig. 2A–C). Intravascular ultrasound results showed a local plaque load of 43% in the middle of the anterior descending artery, with a minimum vessel lumen area of 7.34 mm2 (Fig. 2D). Thus, myocardial infarction induced by coronary atherosclerosis and plaque rupture was excluded. From the above findings, the patient was diagnosed with SIRS and MODS, which included acute inferior and posterior
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wall myocardial infarction with acute heart failure, fulminant diabetes, acute liver dysfunction, acute kidney dysfunction and rhabdomyolysis. The patient received a series of powerful treatments, including insulin intravenous infusion, antiplatelet therapy and anticoagulation therapy with aspirin, clopidogrel and low-molecular-weight heparin, diuretics, urine alkalisation, and anti-inflammatory antibiotic therapy. The patient’s condition improved after treatment for one week; each organ regained normal function and the patient was discharged in a good clinical state after a total hospitalisation of 14 days. The follow-up visit in out-patient service one month after discharge showed that the patient’s blood test, ECG and echocardiography results were all normal.
Discussion Studies have shown that SIRS may produce stress hyperglycaemia, which has possible detrimental effects on the prognosis of patients.5 Elevated blood glucose levels may also predict mortality and length of intensive care unit (ICU) and hospital stay for trauma patients, and have been associated with infectious morbidity and prolonged need for mechanical ventilation.6,7 A strong link has been described between elevated blood glucose levels and the risk of critical illness in sepsis and SIRS.8 So, for this patient, whose blood glucose was reported out of range at 49.1 mmol/l, early active glycaemic control was extremely important. Two large randomised, controlled clinical trials A
B
C
D
A
B
Fig. 1. An electrocardiogram showing ST-segment elevation in leads II, III and aVF (A), and in leads V7–V9 (B).
Fig. 2. Results of coronary artery angiography and an intravascular ultrasound. (A) the arrow indicates the presence of atherosclerosis, with a 30% stenosis in the middle of the left anterior descending artery. (B) and (C) normal blood flow in the circumflex and right coronary arteries. (D) the arrow indicates a local plaque load of 43% in the middle of the anterior descending artery and a minimum vessel lumen area of 7.34 mm2, as revealed by an intravascular ultrasound.
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Table 1. Clinical classification of myocardial infarction (MI), as proposed at the 2007 ESC/ACCF/AHA/WHF consensus conference Type of MI Description Type 1 Spontaneous MI related to ischaemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring or dissection Type 2 MI secondary to ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension or hypotension Type 3 Sudden unexpected cardiac death Type 4a MI associated with primary percutaneous coronary intervention (PPCI) Type 4b MI associated with stent thrombosis as documented by angiography or at autopsy MI associated with coronary artery bypass grafting (CABG) Type 5
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artery disease mimicking acute myocardial infarction. Urgent diagnosis by angiography is required. To enable prompt diagnosis and effective treatment in similar cases, clinicians should be aware of this type 2 myocardial infarction. Patients who smoothly obtain an inflammatory reaction peak under active treatment will likely experience good results. No external financial support was provided. We thank the patient for his cooperation and for providing the photographic material.
References 1.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical
have demonstrated that maintenance of normoglycaemia with intensive insulin therapy may reduce morbidity and mortality rates in critically ill patients.9,10 The case reported here represents true myocardial infarction, based on the changes in cardiac enzyme levels, as well as echocardiographic and ECG findings. To our knowledge, this is the first reported case of SIRS-induced myocardial infarction. Different from previous reports, there was no relevant coronary stenosis in this case, as shown by the coronary angiography and IVUS (Fig. 2). A new clinical classification of myocardial infarction was proposed in the 2007 ESC/ACCF/AHA/WHF consensus conference,11 and clinically various types of myocardial infarction were classified by pathogenesis, as described in Table 1. In the present case, the myocardial infarction should be classified as type 2, and cardiac damage induced by SIRS is likely to be the most probable mechanism of acute myocardial infarction. Additionally, a hypodynamic circulation, especially one reflected in a notable reduction in the ejection fraction (32%) by echocardiography, as in this case, may also be related to myocardial infarction. In recent years, many researchers have suggested that local and systemic inflammation may play an important role in the occurrence, development and complications of acute coronary syndrome (ACS).12 However, coronary angiography is essential to avoid the potentially lethal consequences of thrombolytic therapy in this type of myocardial infarction. In summary, according to the results of glycated haemoglobin and the patient’s medical history, we may infer that the patient had a medical history of diabetes that was not well controlled. Pneumonia infection was induced by diabetes; therefore, we speculated that the patient developed SIRS secondary to diabetes-induced infection. As a result, a large number of inflammatory factors, including C-reactive protein, may have damaged the patient’s pancreas, heart, liver, kidney and skeletal muscle, leading to MODS.
Care Medicine. Chest 1992; 101: 1644–1655. 2.
Baue AE, Durham R, Faist E. Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle? Shock 1998; 10: 79–89.
3.
Samimi-Fard S, Dominguez-Rodriguez A, Abreu-Gonzalez P, EnjuanesGrau C, Blanco-Palacios G, Hernandez-Baldomero IF, et al. Role of myeloperoxidase as predictor of systemic inflammatory response syndrome in patients with ST-segment elevation myocardial infarction after primary percutaneous coronary intervention. Am J Cardiol 2009; 104: 634–637.
4.
Van Diepen S, Vavalle JP, Newby LK, Clare R, Pieper KS, Ezekowitz JA, et al. The systemic inflammatory response syndrome in patients With ST-segment elevation myocardial infarction. Crit Care Med 2013; 41: 2080–2087.
5.
Vanhorebeek I, Langouche L, van den Berghe G. Tight blood glucose control with insulin in the ICU: facts and controversies. Chest 2007; 132: 268–278.
6.
Bochicchio GV, Sung J, Joshi M, Bochicchio K, Johnson SB, Meyer W, et al. Persistent hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma 2005; 58: 921–924.
7.
Jacobi J, Bircher N, Krinsley J, Agus M, Braithwaite SS, Deutschman C, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. Crit Care Med 2012; 40: 3251–3276.
8.
Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001; 32: 2426–2432.
9.
Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–1367.
10. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354: 449–461. 11. Thygesen K, Alpert JS, White HD, Joint ESCAAHAWHFTFftRoMI. Universal definition of myocardial infarction. Eur Heart J 2007; 28: 2525–2538.
Conclusion The present case demonstrates that SIRS may lead to multiple organ damage, and even to a clinical performance of coronary
12. Fiechter M, Ghadri JR, Jaguszewski M, Siddique A, Vogt S, Haller RB, et al. Impact of inflammation on adverse cardiovascular events in patients with acute coronary syndromes. J Cardiovasc Med (Hagerstown) 2013; 14: 807–814.
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Case Report Treatment of right ventricular perforation during percutaneous coronary intervention Guoqiang Gu, Jidong Zhang, Wei Cui
Abstract Percutaneous coronary intervention (PCI) is widely used to treat stenotic coronary arteries caused by coronary heart disease. Coronary artery perforation is a rare but dreaded complication of PCI. Here, we report the successful treatment of a patient with coronary perforation of the right ventricular cavity. To our knowledge, this is the first report of its kind. The patient was a 69-year-old woman with intermittent chest tightness and chest pain of about five years’ duration who was hospitalised for severe chest tightness and pain persisting for three days. She had a history of hypertension and hyperlipidaemia; routine admission examination showed no other abnormalities. Results of routine blood, urine and stool tests, liver and kidney function, clotting time, electrocardiogram, chest radiography and echocardiography were normal. Although coil embolisation rather than balloon is safe and effective for treating coronary artery perforation, it may be not the best choice overall. If the perforation breaks through into the right ventricle, we may just monitor closely rather than treat. That course may be beneficial for patients in that it reduces the risk of myocardial cell necrosis. This case provides useful information for the treatment of such patients in the future. Keywords: percutaneous coronary intervention (PCI), coronary artery perforation, myocardial cell necrosis, right ventricle, cardiac tamponade Submitted 24/6/14, accepted 27/11/14 Cardiovasc J Afr 2015; 26: e4–e6
www.cvja.co.za
DOI: 10.5830/CVJA-2014-072
Percutaneous coronary intervention (PCI) is a widely used non-surgical procedure to treat stenotic coronary arteries caused by coronary heart disease.1,2 The benefit of PCI to the patient
Department of Cardiology, Hebei Institute of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China Guoqiang Gu, MD Jidong Zhang, MD Wei Cui, MD, cuiwei21c@hotmail.com
is great, but the procedure is accompanied by risk. Coronary artery perforation is a rare but dreaded complication of PCI, with a reported incidence from 0.12–0.93% and a mortality rate of about 7–41%.3–14 In most cases, the perforation breaks through into the pericardium, which may cause cardiac tamponade.15 Coronary perforation can also involve the cardiac chambers.16 Here we report the successful treatment of a patient with coronary perforation of the right ventricular cavity and provide a brief review of the literature on the treatment of coronary perforation during PCI.
Case report The patient was a 69-year-old woman with intermittent chest tightness and chest pain over the previous five years. She was hospitalised for severe chest tightness and chest pain persisting for three days. She had a history of hypertension and hyperlipidaemia; the admission examination showed no other abnormalities. Routine blood, urine and stool tests, liver and kidney function, clotting time, electrocardiogram, chest radiography and echocardiography were normal. A diagnosis of coronary artery disease was considered. Coronary angiography showed a right coronary arterydominant circulation. The left main coronary artery was normal, 80% of the middle segment of the left anterior descending (LAD) coronary artery showed stenosis, and the diagonal branch issuing from the site of the stenosis was thicker than the LAD artery. Plaques, but no obvious stenosis, were found in the circumflex and right coronary arteries (Fig. 1A–C). After discussing treatment with the patient, it was decided to perform PCI of the LAD artery. Because of the narrow opening of the diagonal branch, and because the diagonal branch was thicker than the LAD artery, we planned to implant a stent at A
B
C
Fig. 1. (A) Stenosis is shown in 80% of the middle segment of the LAD artery. (B) A diagonal branch issuing from the site of stenosis is thicker than the LAD artery. (C) The circumflex and the right coronary arteries showing visible plaques but no obvious stenosis.
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the juncture of the diagonal branch and the LAD artery, and to position a guide wire in the artery to protect it (Fig. 2A). After stent implantation, the guide wire was set for expansion (Fig. 2B). After expansion, angiography showed no mezzanine, side branch occlusion or residual stenosis at the implantation site, and forward blood flow was TIMI grade 3. However, contrast agent overflow was seen at the distal left LAD artery (Fig. 2C). The patient did not experience discomfort and had normal blood pressure with a steady heart rate. As the guide wire did not reach the distal vessel through the perforation site even after several attempts, it was positioned proximal to the perforation site, and a balloon was used for compression (Fig. 2D). Because this did not successfully close the perforation (Fig. 2E), a coil was used to achieve successful closure (Fig. 2F), after obtaining the consent of family members.
Discussion The incidence of coronary perforation during PCI is low, but it has a relatively high mortality rate. The available data show that the female gender, increasing age, treatment of a chronic total occlusion, angiographic evidence of calcification, and use of a cutting balloon or rotational atherectomy are associated with increased risk of coronary perforation.3–14 In a randomly assigned case–control study conducted between 2001 and 2008, Shimony and colleagues found that the strongest predictor of coronary perforation was treatment of a chronic total occlusion.9 Gruberg et al. identified age and cardiac tamponade as predictors of mortality among patients with coronary perforation.11 A classification scheme has been developed to help in the management of patients with perforation and to assist in delivery of optimal care.10 Coronary perforation is divided into three classes based on angiographic appearance: I, extraluminal crater without extravasation; II, pericardial or myocardial blushing; III, perforation ≥ 1 mm in diameter with contrast streaming and cavity spilling, i.e. perforation into an anatomical cavity, chamber, or coronary sinus (Ellis type III CS). A
B
C
D
E
F
G
H
Managing coronary perforation during PCI requires an accurate diagnosis of the type of perforation that has occurred. Adverse clinical outcomes (e.g. death or emergency surgical exploration) are associated with angiographic classification of the perforation, and have been more frequently observed in patients who experienced a class III coronary perforation.8–10,14 The management of coronary perforation often includes heparin reversal, discontinuation of glycoprotein IIb/IIIa inhibitors, platelet transfusion, pericardiocentesis, and emergency cardiac surgery. Additional treatment strategies include prolonged balloon inflation, covered stents, injection of polyvinyl alcohol, coil embolisation, and intracoronary administration of autologous blood.17–21 This patient had normal blood pressure, a steady heart rate and no manifestations of cardiac tamponade during the threehour procedure. Although balloon occlusion was used within an hour to apply pressure, rapid outward bleeding continued for more than two hours. Ultrasound monitoring of the pericardial cavity was performed during the entire procedure, and overflow into the pericardial fluid was not observed. Imaging showed that the contrast agent overflow visible at the base of the heart in the systolic phase (Fig. 2G) dissipated quickly during diastole (Fig. 2H). Overall, the evidence indicated that this was an Ellis type III CS coronary perforation that penetrated a ventricular cavity. Evidence for perforation of the right ventricle included the following reasons. First, overflow of contrast agent occurred in both systole and diastole, which is consistent with the haemodynamic properties of the coronary artery and right ventricle. If the left ventricle had been perforated, the contrast agent would have been much more evident in diastole than in systole. Second, images from the left anterior oblique position showing the anatomy of the right ventricle support this interpretation (Fig. 3A). Third, the velocity of the contrast agent overflow was similar to the right ventricular flow velocity, but much slower than the intra-aortic flow velocity (Fig. 3A). This patient was a 69-year-old woman. The hydrophilic coated guide wire used for expansion and the V-shaped anatomical structure proximal to the perforation site may also have contributed to the perforation (Fig. 3B). Others have found that LAD arteries and tortuous lesions were vulnerable to perforation, and that the guide wire was frequently responsible for the perforation.8,14 Therefore special care should be exercised to avoid perforation when performing PCI in older females with special anatomical structures. In the treatment of this patient, balloon compression was unsuccessful. Stent implantation was not considered because the A
Fig. 2. (A) A guide wire positioned at the junction of the diagonal branch and the LAD artery. (B) Resetting the guide wire for expansion. (C) Contrast agent overflow is shown at the distal LAD artery. (D) Balloon for compression. (E) Perforations that have not been successfully closed by the balloon. (F) Successful closure achieved using a coil. (G) Contrast agent overflow to the base of the heart in the systolic phase. (H) Dissipation of the contrast agent in the diastolic phase.
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B
Fig. 3. (A) Images from the left anterior oblique position showing the anatomy of the right ventricle. The velocity of the contrast agent overflow was similar to the velocity of the right ventricular flow but much slower than the intra-aortic velocity. (B) The atypical V-shaped anatomical structure proximal to the perforation site.
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vessel lumen was too small. Although it was concluded that the ventricle had been penetrated, for safety reasons, we carried out a block by coil embolisation. We did not use a gelatin sponge because of the risk of pulmonary embolism. The long- and short-term safety and effectiveness of coil embolisation are good, but it might be not the best choice in all cases. If perforation does involve the right ventricle, close monitoring without any treatment may be beneficial for the patient because of reduction in myocardial cell necrosis. We did not use glycoprotein IIb/IIIa inhibitors during treatment, therefore the question of discontinuation did not arise. The data show that the more patients who were given a glycoprotein IIb/IIIa inhibitor required the placement of a covered stent or emergency cardiac surgery than those who did not receive it (33.3 vs 3.2%). Clinical outcomes (tamponade, myocardial infarction, death) were similar for patients who had and had not received a glycoprotein IIb/IIIa inhibitor.8 Reversal of heparin was considered in our case but was not adopted because of the risk of coronary thrombosis and the patient’s haemodynamic stability. Al-Lamee et al. recommend the use of protamine ‘as necessary’ in the setting of coronary perforation if heparin or glycoprotein inhibitors have been administered.22
6.
Conclusion
14. Hendry C, Fraser D, Eichhofer J, et al. Coronary perforation in
Javaid A, Buch AN, Satler LF, et al. Management and outcomes of coronary artery perforation during percutaneous coronary intervention. Am J Cardiol 2006; 98: 911–914.
7.
Gunning MG, Williams IL, Jewitt DE, et al. Coronary artery perforation during percutaneous intervention: incidence and outcome. Heart 2002; 88: 495–498.
8.
Fasseas P, Orford JL, Panetta CJ,et al. Incidence, correlates, management, and clinical outcome of coronary perforation: analysis of 16,298 procedures. Am Heart J 2004; 147: 140–145.
9.
Shimony A, Zahger D, Van SM, et al. Incidence, risk factors, management and outcomes of coronary artery perforation during percutaneous coronary intervention. Am J Cardiol 2009; 104: 1674–1677.
10. Ellis SG, Ajluni S, Arnold AZ, et al. Increased coronary perforation in the new device era. Incidence, classification, management, and outcome. Circulation 1994; 90: 2725–2730. 11. Gruberg L, Pinnow E, Flood R, et al. Incidence, management, and outcome of coronary artery perforation during percutaneous coronary intervention. Am J Cardiol 2000; 86: 680–682. 12. Ben-Gal Y, Weisz G, Collins MB, et al. Dual catheter technique for the treatment of severe coronary artery perforations. Cathet Cardiovasc Diagn 2010; 75: 708–712. 13. Fukutomi T, Suzuki T, Popma JJ, et al. Early and late clinical outcomes following coronary perforation in patients undergoing percutaneous coronary intervention. Circ J 2002; 66: 349–356.
Coronary artery perforation is a rare but dreaded complication of PCI. Coronary perforation of the right ventricular cavity is less severe than perforation at other sites. Although coil embolisation is a safe and effective alternative to balloon treatment of coronary artery perforation, it might be not the best choice in the short and long term. If the perforation does break through into the right ventricle, we suggest close monitoring rather than treatment, which may be beneficial for patients in that it reduces the risk of myocardial cell necrosis.
the drug-eluting stent era: incidence, risk factors, management and outcome: the UK experience. Euro Intervention 2012; 8(1): 79–86. 15. Urbanyi B, Rieckmann C, Hellberg K, et al. Myocardial echinococcosis with perforation into the pericardium. J Cardiovasc Surg (Torino) 1991; 32(4): 534–538. 16. Tamura M, Oda H, Miida T, et al. Coronary perforation to the left ventricular cavity by a guide wire during coronary angioplasty. Jpn Heart J 1993; 34(5): 633–637. 17. Briguori C, Nishida T, Anzuini A, et al. Emergency polytetrafluoroethylene-covered stent implantation to treat coronary ruptures. Circulation 2000; 102: 3028–3031.
References 1.
Teirstein PS, Price MJ. Left main percutaneous coronary intervention. J Am Coll Cardiol 2012; 60(17): 1605–1613.
2. 3.
Catheter Cardiovasc Interv 1999; 48: 382–386. 19. Campbell PG, Hall JA, Harcombe AA, et al. The Jomed covered stent graft for coronary artery aneurysms and acute perforation: a successful
nary intervention. N Engl J Med 2011; 364(5): 453–464.
device which needs careful deployment and may not reduce restenosis. J
Ajluni SC, Glazier S, Blankenship L, et al. Perforations after percutaobservations. Cathet Cardiovasc Diagn 1994; 32: 206–212. Dippel EJ, Kereiakes DJ, Tramuta DA, et al. Coronary perforation during percu taneous coronary intervention in the era of abciximab platelet glycoprotein IIb/IIIa blockade: an algorithm for percutaneous management. Cathet Cardiovasc Diagn 2001; 52: 279–286.
5.
saphenous vein graft perforation with an autologous vein-covered stent.
Prasad A, Herrmann J. Myocardial infarction due to percutaneous coro-
neous coronary interventions: clinical, angiographic, and therapeutic 4.
18. Caputo RP, Amin N, Marvasti M, et al. Successful treatment of a
Invasive Cardiol 2000; 12: 272–276. 20. Mahmud E, Douglas JS Jr. Coil embolization for successful treatment of perforation of chronically occluded proximal coronary artery. Catheter Cardiovasc Interv 2001; 53: 549–552. 21. Cordero H, Gupta N, Underwood PL, et al. Intracoronary autologous blood to seal a coronary perforation. Herz 2001; 26: 157–160. 22. Al-Lamee R, Ielasi A, Latib A, et al. Incidence, predictors, management,
Friedrich SP, Berman AD, Baim DS, et al. Myocardial perforation in the
immediate and long-term outcomes following grade III coronary perfo-
cardiac catheterization laboratory: incidence, presentation, diagnosis,
ration. J Am Col Cardiol Cardiovasc Interv 2011; 4: 87–95.
and management. Cathet Cardiovasc Diagn 1994; 32: 99–107.
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Case Report An unusual cause of a large fibrinous pericardial effusion Noleen Chengetai Tembani-Munyandu, Rudo Makunike-Mutasa, Leolin Katsidzira, Andrew Chinogureyi Case report
Abstract The commonest cause of a large fibrinous pericardial effusion in sub-Saharan Africa is tuberculosis. There are, however, limited resources available for making a definitive diagnosis of tuberculous pericarditis. The diagnosis is largely based on clinical criteria. There is a risk of misdiagnosing lesscommon causes of large fibrinous pericardial effusions. We present a patient who had a pericardial angiosarcoma that was initially thought to be a tuberculous pericardial effusion, and discuss the challenges in making a definitive diagnosis of tuberculosis. Keywords: fibrinous pericardial effusion, tuberculosis (TB), angiosarcoma Submitted 3/7/14, accepted 1/12/14 Cardiovasc J Afr 2015; 26: e7–e10
www.cvja.co.za
DOI: 10.5830/CVJA-2014-075
The majority of fibrinous pericardial effusions in sub-Saharan Africa are caused by tuberculosis (TB), which accounts for such effusions in more than 80% of HIV-positive patients, and 50 to 70% of HIV-negative patients in the region.1-4 Consequently, it is a common clinical practice to commence patients on TB treatment on the basis of a fibrinous pericardial effusion seen on echocardiogram. While this strategy may have merit, there is the risk that patients with less-common causes of a fibrinous effusion may have their diagnosis and treatment unduly delayed. We present a patient who had a large fibrinous pericardial effusion, which was managed as tuberculosis, but this turned out not to be the case. Department of Medicine, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe Noleen Chengetai Tembani-Munyandu, MB ChB, MMed Medicine, nmbuwayesango@yoafrica.com Leolin Katsidzira, MB ChB, MMed Medicine
Department of Histopathology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe Rudo Makunike-Mutasa, MB ChB, MMedSci, FRCPath
Department of Radiology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe Andrew Chinogureyi MB ChB, FCRad, FRCR
A 24-year-old male was referred from a peripheral hospital complaining of two months’ history of shortness of breath on exertion, left-sided pleuritic chest pain, a non-productive cough and significant weight loss. He had lost 17 kg over two months and had drenching night sweats. He had drunk at least 40 units of alcohol per week and smoked two packs of cigarettes per week for a year. He had no significant medical history and had tested HIV negative a month prior to presentation. On examination he was wasted, had no significant lymphadenopathy and had a temperature of 37.2°C. His blood pressure was 96/50 mmHg and he had a low-volume tachycardia of 116 beats per minute. The jugular venous pressure was 7 cm and the apex beat could not be localised. The heart sounds were muffled and he had a tender hepatomegaly 4 cm below the costal margin. The chest X-ray showed a large globular heart shadow but no pulmonary congestion. The electrocardiogram showed a sinus tachycardia and echocardiography revealed a large fibrinous pericardial effusion about 5 cm in maximum depth. There was early right ventricular diastolic collapse and the inferior vena cava was 2.5 cm and not collapsing with inspiration. The full blood count showed a white cell count of 6.4 × 103 cells/μl, haemoglobin 14.6 g/dl and platelet count 275 × 103 cells/ μl. Urea and electrolytes were sodium 126 mmol/l, potassium 3.4 mmol/l, urea 9.1 mmol/l and creatinine 88 μmol/l. Serum albumin was 28 g/l, total protein was 81 g/l and serum globulin was 53 g/l. A probable diagnosis of TB pericardial effusion was made on the basis of a Tygerberg score5 of 8: night sweats = 1, weight loss = 1, fever > 37.8°C = 0, white cell count < 10 cells/μl = 3, serum globulin > 40 g/l = 3, total score = 8. The patient underwent urgent pericardiocentesis and 1 000 ml of haemorrhagic pericardial effusion were drained. The fluid microscopy showed a negative Ziehl Nielsen stain, a few leucoytes, many red blood cells, protein of 55 g/l, lactate dehydrogenase was 1 456 U/l and adenine deaminase was 24 U/l. He was commenced on TB therapy (isoniazid, rifampicin, pyrazinamide and ethambutol). Despite treatment, he continued to have severe chest pain and progressive loss of weight. On review at six weeks, there was echocardiographic evidence of re-accumulation of the fluid and he was experiencing severe pain in the thoracic spine. A computed tomography scan was requested and it showed a tumour in the pericardium compressing the cardiac chambers and extending posteriorly into the thoracic spine and upper lumbar spine (Fig. 1).
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Fig. 1. CT images of pericardial tumour and vertebral invasion. (A, B) Tumour surrounding all cardiac chambers. (C, D) Thoracic and lumbar vertebral invasion by tumour.
A pericardial biopsy showed a cellular tumour comprising vasoformative spindle cells with extravasation of red blood cells and eosinophilic bodies. Moderate nuclear pleomorphism and a brisk mitotic count were seen. This was consistent with an angiosarcoma (Fig. 2). The patient was referred to oncology care after debulking and he received a pulse of chemotherapy (vincristine, doxorubicin and cyclophosphamide). He became paraplegic and eventually died five months after his initial presentation.
Discussion Primary cardiac tumours are rare and angiosarcoma is the most frequent primary malignant cardiac tumour.6 Angiosarcomas of the pericardium are rare but there have been several case reports.7-10 They usually occur in the third to the fifth decade of
life and are more common in males. By the time these tumours are diagnosed, 66 to 89% have metastases. They have a poor prognosis. The mean survival is six to 11 months. Metastatic disease is frequent at the time of presentation, mainly to the mediastinal lymph nodes, lung and vertebrae. Our patientâ&#x20AC;&#x2122;s tumour was quite invasive and had metastases to several vertebrae. In this patient, the initial radiological investigation was an echocardiogram, which revealed a fibrinous pericardial effusion. Echocardiography is usually the initial diagnostic tool for cardiac tumours. Transthoracic and transoesophageal echocardiography have a sensitivity of 93 and 97%, respectively, for detecting cardiac masses.11 These however are operator and technique dependant. CT and magnetic resonance imaging reveal more detail in terms of cardiac soft tissue as well as extracardiac extension
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Fig. 2. (A) Pericardium (x 4). Micrograph shows thickened and fibrosed pericardium with a cellular spindle cell proliferation. (B) Pericardium (x 20). Photomicrograph shows a nodular and cellular spindle cell proliferation with large pools of blood. (C) Pericardium (x 40). Micrograph shows a sieve-like pattern with spindle cells forming vascular spaces in which there is red blood cell extravasation.
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of cardiac tumours. In this patient it was the transthoracic echocardiogram at six weeks, followed by the CT scan that suggested a malignant cause for the pericardial effusion. Pericardial fluid cytology is unreliable and is not diagnostic in the majority of patients. Pericardial or endomyocardial biopsy will be diagnostic in 23 to 50% of samples.11 The microscopy of cardiac angiosarcoma is characterised by anastomotic vascular channels formed by malignant cells, solid areas of spindle cells and areas of anaplastic cells. This patient’s biopsy specimens showed the typical histological features. This case illustrates the challenges of making a definitive diagnosis of TB pericarditis in resource-poor settings and that clinical index can be found wanting when faced with alternative pathology, as in this patient. The definitive diagnosis of TB pericarditis is known to be challenging. The symptoms, chest pain, shortness of breath, fever and night sweats, are not specific. The signs of a large effusion include a small-volume pulse, raised jugular venous pulsations, diffuse apex beat, muffled heart sounds and hepatomegaly. The presence of fever and a supraclavicular lymph node makes TB a most probable cause of the effusion. Chest X-ray, ECG and echocardiography are not specific for TB. There are other causes of fibrinous pericardial effusions, such as viral and bacterial infections, uraemia and malignancy. The definitive diagnosis hinges on finding mycobacteria on pericardial fluid microscopy or culture as well as histological examination of a pericardial biopsy. Finding mycobacteria in other specimens, such as sputum, gastric washings and pleural fluid in a patient with a fibrinous pericardial effusion makes TB the most likely cause of the effusion.12 However, direct smear is only positive in 0–42% of cases of TB pericarditis. Conventional culture is positive in up to 53% and this can be improved if direct culture onto liquid Kirchner culture medium is done. The rate of positive culture goes up to 75%. In resource-poor settings, microbiology services are limited so both direct smear and culture are not always available. The other problem with TB culture is the long delay in getting the results and for a condition where immediate therapy is needed, treatment is usually commenced before these results are available. Pericardial biopsy is invasive and requires the expertise of a surgeon and this is not usually available where TB is most common. Pericardial biopsy is diagnostic in 10–64% of cases.7 Other methods to make a diagnosis of probable pericardial TB include finding a lymphocyte predominance and a high protein level in the fluid, clinical index (Tygerberg score), PCR and indirect tests such as ADA, lysozyme and IFN gamma. The Tygerberg score comprises weight loss = 1, night sweats = 1, fever of ≥ 38°C = 2, peripheral white cell count < 10 cells/μl = 3, and serum globulin > 40 g/l = 3. A total score ≥ 6 has a sensitivity of 86% and a specificity of 85%. This is a reasonable approach in a resource-poor setting. PCR tends to be expensive, unavailable, and has a high rate of false-positive results. Adenine deaminase > 40 IU/l has a sensitivity of 87% and a specificity of 83%, IFN gamma > 50 pg/l has a sensitivity of 92% and specificity of 100% and lysozyme > 6.6 μg/dl has 100% sensitivity and 91% specificity. These three tests are very good but cost and availability are the limiting factors in sub-Saharan Africa where TB is very common. This patient had a low ADA of 24 IU/l; an ADA of > 35 IU/l has a sensitivity of > 95%.13 The low ADA should have been
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used much earlier as a rule-out test for TB pericarditis and an alternative cause could have been sought earlier. In most cases that are treated as TB pericarditis in sub-Saharan Africa, the clinical criteria are used to make a decision to treat. In the majority of patients, this is the correct decision, but it is that occasional patient such as the one described, where the special tests to make a definitive diagnosis would have clinched the alternative diagnosis earlier. This patient illustrates the need to be aware of the rarer causes of fibrinous pericardial effusion and the need to perform more tests, such as CT or MRI scans and pericardial biopsy to make a definitive diagnosis, even in our setting of high TB prevalence. Unfortunately however, most cases of angiosarcoma present with metastatic deposits and the options for therapy may not be available, as it was for this patient. The prognosis tends to be poor.
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1994; 75: 429–434. 5.
Reuter H, Burgess L, van Vuuren W, Doubel A. Diagnosing tuberculous pericarditis. Q J Med 1999; 12: 827–839.
6.
Timoteo AT, Brancho LM, Bravio I, et al. Primary angiosarcoma of the pericardium: case report and review of the literature. Kardiol Pol 2010; 68(7): 802–805.
7.
Ong P, Greulich S, Schumm J. et al. Images in Cardiovascular Medicine: Favorable course of pericardial angiosarcoma under paclitaxel followed by pazopanib treatment documented by cardiovascular magnetic resonance imaging. Circulation 2012; 126: e279–e281.
8.
Mayer F, Aebert H, Rudert M, et al. Primary malignant sarcomas of the heart and great vessels in adult patients – a single-center experience. Oncologist 2007; 12: 1134–1142.
9.
Brinckman SL, van der Wouw P. Images in Cardiovascular Medicine: Angiosarcoma of the pericardium: a fatal disease. Circulation 2005; 111(23): e388–389.
10. Kiyohiro O, Akio O, Motoi K, et al. Primary cardiac angiosarcoma
References 1.
Ntsekhe M, Mayosi BM. Tuberculous pericarditis with and without HIV. Heart Fail Rev 2013; 18(3): 367–373.
2.
Reuter H, Burgess LJ, Doubel AF. Epidemiology of pericardial effusions at a large academic hospital in South Africa. Epidemiol Infect 2005; 133: 393–399.
3.
4.
associated with cardiac tamponade. Case report. Japan Circ J 1999; 63(10): 822–824. 11. Riles E, Gupta S, Wang D, Tobin K. Primary cardiac angiosarcoma: a diagnostic challenge in a young man with recurrent pericardial effusions. Exp Clin Cardiol 2012; 17(1): 39–42. 12. Syed FF, Mayosi BM. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis 2007; 50(3): 218–236.
Maher D, Harries AD. Tuberculous pericardial effusion: a prospective
13. Pandie S, Peter JG, Kerbelker ZS, et al. Diagnostic accuracy of quan-
clinical study in a low resource setting – Blantyre, Malawi. Int J Tuberc
titative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared
Lung Dis 1997; 1: 358–364.
to adenosine deaminase and unstimulated interferon g in a high burden
Cegielsk JP, Lwakatare J, Dukes CS, et al. Tuberculous pericarditis in
setting: a prospective study. BMC Med 2014; 12: 101. doi: 10.1186/1741-
Tanzanian patients with and without HIV infection. Tuberc Lung Dis
7015-12-101.
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Case Report A fatal complication after repair of post-infarction ventricular septal rupture: heparin-induced thrombocytopenia with thrombosis Yunus Nazli, Necmettin Colak, Bora Demircelik, Mehmet Fatih Alpay, Omer Cakir, Kerim Cagli
Abstract Heparin-induced thrombocytopenia (HIT) is a rare but potentially devastating and life-threatening complication from using heparin. HIT not only causes thrombocytopenia, but it also carries an increased risk for fatal thrombotic complications. In this report, we describe the case of a patient in whom fatal HIT developed after successful surgical repair of a posterior post-infarction ventricular septal rupture with cardiopulmonary bypass. Keywords: heparin, thrombocytopenia, thrombosis, post-infarction ventricular septal rupture Submitted 25/2/14, accepted 10/1/15 Cardiovasc J Afr 2015; 26: e11–e15
www.cvja.co.za
DOI: 10.5830/CVJA-2015-001
Heparin-induced thrombocytopenia (HIT) is a rare but potentially devastating and life-threatening complication of heparin therapy. HIT not only causes thrombocytopenia, but it also carries an increased risk for both arterial and venous thrombotic complications, despite the administration of heparin as an anticoagulating agent.1 HIT is associated with antibodies to a complex of heparin– platelet factor 4 (H-PF4). HIT-associated antibodies are generally detected after open-heart surgery.2,3 Post-infarction ventricular septal rupture (PI-VSR) following acute myocardial infarction has a high mortality rate and surgical repair also presents a high risk of mortality. Department of Cardiovascular Surgery, Faculty of Medicine, University of Turgut Ozal, Ankara, Turkey Yunus Nazli, MD, yunusnazli@gmail.com Necmettin Colak, MD Mehmet Fatih Alpay, MD Omer Cakir, MD
Department of Cardiology, Faculty of Medicine, University of Turgut Ozal, Ankara, Turkey Bora Demircelik, MD
Department of Cardiovascular Surgery, Turkiye Yuksek Ihtisas Hospital, Ankara, Turkey Kerim Cagli, MD
In this report, we describe the case of a patient in whom fatal HIT developed after successful surgical repair of a posterior PI-VSR on cardiopulmonary bypass (CPB). This is rare, and a limited number of cases have been reported following surgical repair of a PI-VSR.
Case report A 74-year-old man presented with chest pain to a local hospital, from where he was transferred to our institution, with a PI-VSR. He had been anticoagulated with unfractioned heparin (UFH) (1 000 IU/h daily) for three days since the myocardial infarction (MI) had occurred. On admission, his heart rate was 92 beats/min, blood pressure was 90/50 mmHg and weight was 85 kg. Physical examination showed a systolic murmur at the left sternal border. Cardiac catheterisation was performed, during which a single intravenous dose of 2 500 units of heparin was administered. Coronary angiography showed critical stenoses in the mid segment of the left anterior descending artery and ostium of the second diagonal branch, and occlusion in the distal segment of the right coronary artery (Fig. 1A, B). The time between the onset of acute MI and surgery was three days. Transthoracic echocardiography revealed poor left ventricular wall motion and a large postero-inferior ventricular septal rupture (Fig. 1C). To prevent cardiogenic shock, intra-aortic balloon pump assistance was initiated and anticoagulation was continued with a heparin infusion of 500 IU/h over three hours. Thereafter, the patient was taken to the operating room for emergency surgery because of haemodynamic deterioration. After induction of general anaesthesia, transoesophageal echocardiography (TEE) was performed to evaluate the repair of the VSR. A median sternotomy was performed. Cardiopulmonary bypass was instituted with ascending aortic and bicaval venous cannulation. Heparin (300 U/kg) was given to obtain an activated clotting time of more than 400 s. Firstly, a longitudinal transinfarction incision was made in the left ventricular myocardium parallel to and 1 cm away from the posterior descending artery. The post-infarction VSR was closed with a double velour fabric polyester patch (Bard® Debakey®, IMPRA, Inc) using a 3-0 polypropylene suture (Ethicon, Inc, Somerville, NJ) with a teflon pledget through the left ventricle (Fig. 1D). The posteromedial papillary muscle was carefully inspected and the basal portion of the posteromedial papillary muscle
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Fig. 1. (A, B) Coronary angiography showing critical stenoses of the left anterior descending artery and ostium of the second diagonal branch, and occlusion of the right coronary artery. (C) Transthoracic echocardiography showing post-infarction postero-inferior ventricular septal rupture (VSR) (white arrow). (D) Surgery photograph showing VSR (white asterisk) and (E) necrotic and decayed basal portion of the postero-medial papillary muscle (white arrow). (F) Surgery photograph showing that the VSR was closed (black asterisk) with a patch and the posteromedial papillary muscle was attached to the left ventricular wall with polytetrafluoroethylene sutures (black arrow). LV: left ventricle, RV: right ventricle.
appeared to be necrotic (Fig. 1E). The decayed base of the posteromedial papillary muscle was attached to the left ventricular wall using two interrupted mattress 4-0 polytetrafluoroethylene (goretex) sutures with a teflon pledget (Fig. 1F). The posterior left ventriculotomy was closed in two layers over two teflon felt strips using 2-0 polypropylene sutures (Ethicon, Inc, Somerville, NJ). CABG was then performed with sequential grafting of the saphenous vein to the left anterior descending artery and second diagonal branch. Peri-operative transoesophageal echocardiography demonstrated well-preserved left ventricular wall contraction except for the infarcted area, with no evidence of residual leak. Successful weaning from cardiopulmonary bypass was achieved with an intra-aortic balloon pump (IABP) and low-dose inotropic support. The patient tolerated the surgical procedure well, and his initial postoperative course was uneventful. He remained intubated for 13 hours in ICU with a 24- and 48-hour postoperative blood loss of 750 and 300 ml, respectively. For 48 hours during the immediate postoperative period, the patient was managed with intra-aortic balloon counter pulsation and small doses of inotropic drugs. He was weaned off IABP on the third postoperative day. A total dose of 98 500 IU of heparin was given before (72 000 IU) and during (26 500 IU) cardiopulmonary bypass (CPB) at
our hospital. Anticoagulation was reversed by protamine at the end of the operation. Following separation from bypass, the patient was given a total of six units of fresh frozen plasma and eight units of packed red cells. Blood tests were done regularly and the platelet count was monitored daily. Laboratory findings on admission showed a normal platelet count (210 × 103 cells/μl). Thrombocytopaenia developed postoperatively on day four with falls in platelet count of more than 50%, with a platelet level of 64 × 103 cells/μl, from an initial admission count of 210 × 103 cells/μl. The nadir platelet count was 25 × 103 cells/μl on the seventh postoperative day (Fig. 2). Fig. 2 summarises the patient’s platelet counts and key clinical events during hospitalisation. On postoperative day five, right-hand cyanosis was noted with absent radial pulses and was attributed to the presence of a right radial arterial catheter. The radial arterial catheter was removed the same day without improvement. Doppler ultrasound showed an occlusion of the radial artey and a patent ulnar artery. Also, a superficial venous thrombosis (cephalic and basilic vein) was detected in the right arm by Doppler ultrasound. On postoperative day six, ischaemic changes developed on the front of both feet (Fig. 3). The ischaemic changes in the right hand worsened from that of the previous day. Additionally, an occlusion of the right ulnar artery was detected by Doppler ultrasound. A brachial artery thrombectomy was performed
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Fig. 2. Platelet counts and key clinical events during hospitalisation. ARF: acute renal failure, IABP: intra-aortic balloon pump, OR: operating room.
three times on the same day because of increased ischaemic changes. The thrombectomy was not successful. We suspected type 2 HIT. Heparin therapy was immediately discontinued on postoperative day three, including all intravenous fluids and lines. On the basis of the clinical symptoms, we used the ‘4 Ts’ clinical scoring system to test for the possibility of HIT, and found a high probability of heparin-induced thrombocytopenia. A laboratory test was performed on postoperative day six, and a definitive diagnosis of HIT was made by serological test, confirming positive antibodies to the heparin–PF4 complexes with a slow turnaround time. Complete thrombophilic studies were unremarkable for other hypercoagulable conditions. Anticoagulation was immediately started with fondaparinux, which is the only alternative anticoagulant agent in our country, at the recommended dose for these patients (7.5 mg/day, subcutaneous) on postoperative day four because of a fall in platelet count of more than 50%. The patient’s platelet count had not increased during therapy with fondaparinux after seven days. The patient developed acute renal insufficiency requiring haemodialysis on postoperative day nine. Fondaparinux (2.5 mg) was also instilled directly into the dialysis circuit on dialysis days. On the 11th day postoperatively, the patient died of multiple organ failure despite intensive care.
Discussion Unfractionated heparin (UFH) is routinely used worldwide during CPB procedures and other various conditions for systemic anticoagulation.4 However, a small percentage of patients treated with UFH or low-molecular weight heparin (LMWH) suffer complications caused by side effects of the drug, the most serious of which is HIT.1 HIT is an adverse effect of the drug causing potentially fatal thrombotic or thromboembolic complications. HIT is a clinicopathological condition initiated with heparin exposure and characterised by a fall in the platelet count and paradoxical thrombophilia.5,6 HIT syndrome may be classified into two distinct subtypes based on differences in the pathophysiology and clinical features:
type 1 and type 2. Type 1 HIT is non-immune and typically occurs as a fall in platelet count within the first two days after starting heparin. Platelet levels generally decrease by 10–20%.7 This condition usually resolves spontaneously without treatment or complications within days, even with continued heparin use. It is a non-immune-mediated disorder and appears to be due to a direct activation of the platelets by heparin, leading to platelet aggregation and, as a result, thrombocytopenia. By contrast, the less common and more severe form, type 2 HIT is an immune-mediated disorder caused by antibody formation against the circulating H-PF4 complexes. This type can be associated with thrombotic or thromboembolic complications. It is also known as heparin-induced thrombocytopenia and thrombosis (HITT) and white clot syndrome due to platelet-rich arterial thrombosis.5 In most cases, thrombocytopenia develops on approximately the fifth day of initiation of heparin.8 The incidence of type 2 HIT is significantly higher after exposure to UFH versus LMWH (2.6 vs 0.2%).9 Surgical patients (especially cardiac surgery) are also more likely to develop HIT than medical patients.5 The incidence of HITT in patients who have undergone cardiac surgery has been estimated at between 0.12 and 1.3%.10 Cardiac surgical patients are at a greater risk for postoperative HITT due to several factors. First, most of these patients have had previous exposure to heparin for diagnostic, prophylactic and therapeutic purposes. Second, they are exposed to high-dose intra-operative heparin during CPB, and platelet activation is associated with surgery and CPB. Third, this exposure is usually continued in the postoperative period (either prophylactically or for flushing the lines).11 The common clinical presentation of HIT involves thrombocytopenia and thrombosis. Thrombocytopenia is the primary manifestation of HIT, but the degree and onset of the fall in platelet count may be variable. Type 1 HIT is often characterised by a fall in platelet count within one and four days after heparin exposure, with a nadir level of 100 000 cells/μl, spontaneous normalisation despite continued heparin use, and no other clinical sequelae. On the other hand, type 2 HIT occurs within five to 10 days after the administration of heparin. The platelet counts fall more significantly by ≥ 50% or ≥ 100 000 cells/μl, with a median nadir of ~ 60 000 cells/μl.7 However, even when platelet counts in type 2 HIT are typically < 20 000/μl, spontaneous bleeding is uncommon. Thrombosis is the main contributor to morbidity and mortality associated with type 2 HIT, and HIT is fatal in an estimated 5–10% of patients, typically due to thrombotic or thromboembolic events. Thrombosis may accompany thrombocytopenia in 30–60%
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of patients. Although thrombosis may occur in any vascular bed, venous thrombosis is more common than arterial thrombosis and often presents as deep-vein thrombosis or pulmonary embolism. However, arterial thrombosis can be predominant in cardiac and vascular surgical patients.5 Major complications of arterial thrombosis are acute limb ischaemia, stroke and acute myocardial infarction. Arterial thrombi are uncommonly seen in the renal, mesenteric or spinal arteries.4 The diagnosis of HIT is essentially made on the basis of clinical grounds and a decrease in platelet count in a patient receiving heparin, for which there are no obvious causes. Laboratory assays (frequently with slow turnaround times) play a supportive role and involve functional and non-functional tests.12 Most laboratory tests are not readily available in the acute setting.8 HIT should be suspected in the setting of absolute thrombocytopenia (platelet count < 150 000 cells/μl) as well as relative thrombocytopenia (fall in platelet count of at least 50% from baseline value). However, this syndrome should also be considered in patients with the unexplained development of new or progressive thrombosis while receiving a heparin product. To aid in the diagnosis of HIT, a specific scoring system for clinical diagnosis, called the 4 Ts score was developed and validated by Lo et al.13 A score is calculated based on the following four categories: degree of thrombocytopenia, timing of onset of thrombocytopenia, clinical sequelae such as the development of venous or arterial thrombosis, and presence of other aetiologies of thrombocytopenia.5 Functional and immunological tests for HIT involve the platelet aggregation test (PAT), serotonin release assay (SRA), heparin-induced platelet aggregation (HIPA) test, the anti-HPF4 complex antibody enzyme-linked immunosorbent assays (ELISA), and flow cytometry studies.8 The sensitive (> 90%) but less specific (~ 71%) H-PF4 ELISA test is often used as a screening test, and the SRA (sensitivity and specificity 100 and 97%, respectively) can be performed as a confirmatory test, but is not universally available and utilised.12 The HIT-associated mortality rate in cardiac surgery patients is 35–42%.7 About 20% of patients developing HIT syndrome may require limb amputation because of peripheral arterial thrombosis. This syndrome is associated with a myriad of complications, including multiple organ systems: mesenteric ischaemia, renal insufficiency and stroke.8 Delays in the availability of diagnostic assay results frequently necessitate initiation of treatment for HIT based on clinical evaluation alone. When HIT with or without thrombosis is suspected postoperatively, the first step in treatment is immediate discontinuation of all heparin exposure, including heparin flushes and LMWH.12 In addition to heparin discontinuation, patients with either HIT with thrombosis or isolated HIT (type 2 HIT without thrombosis) require further treatment with an alternative anticoagulant agent. Heparin discontinuation alone is insufficient, because patients (even type 2 HIT without thrombosis) remain in a prothrombotic state. In light of the sustained thrombus propagation that occurs with HIT, current treatment is focused on reduction of thrombin generation via direct thrombin inhibition (e.g. bivalirudin, lepirudin, argatroban) or indirect factor Xa inhibition (e.g. danaparoid, fondaparinux).5 Prophylactic and therapeutic fondaparinux failed to prevent the development of and to treat HIT in our case, but we used
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fondaparinux because it is the only alternative anticoagulant agent in our country. Although successful results have been reported in the treatment of HIT with the use of fondaparinux, it was recommended as grade 2C at the 9th ACCP Conference on Antithrombotic Therapy and Prevention of Thrombosis.14 There are often plausible alternative explanations in critical patients with thrombocytopenia. CPB and the use of the IABP are clearly associated with thrombocytopenia. However, in our patient, the decreased platelet count was not attributed to these devices and conditions because there was no drop (> 50%) in platelet count within the first three postoperative days. It is also essential to differentiate HIT from other conditions causing thrombocytopenia, such as haemodilution, disseminated intravascular coagulation and sepsis. In our patient, these conditions were excluded by several examinations and laboratory tests.
Conclusion HIT is a clinicopathological syndrome in which one or more clinical events occur, usually thrombocytopenia or thrombosis. Patients undergoing cardiac surgery can be at risk of HIT in the early postoperative period, therefore daily platelet counts should be performed during this period. If signs of HIT develop in a patient receiving heparin, it must be stopped immediately and alternative anticoagulant agents started. In our case, we did not have success with fondaparinux as the alternative anticoagulant. Despite discontinuation of heparin and initiation of alternative anticoagulant agents, high morbidity and mortality rates are associated with HIT.
References 1.
Ishida K, Imamaki M, Ishida A, Shimura H, Miyazaki M. Heparininduced thrombocytopenia after coronary artery bypass grafting with cardiopulmonary bypass: report of a case. Surg Today 2004; 34: 1041–1043.
2.
Bauer TL, Arepally G, Konkle BA, et al. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997; 95: 1242–1246.
3.
Yoon JH, Jang IK. Heparin-induced thrombocytopenia in cardiovascular patients: pathophysiology, diagnosis, and treatment. Cardiol Rev 2011; 19: 143–153.
4.
Mitchell C, Riley CA, Vahid B. Unusual complication of heparininduced thrombocytopenia after mitral valve surgery: spontaneous rupture of spleen. Ann Thorac Surg 2007; 83: 1172–1174.
5.
Hess CN, Becker RC, Alexander JH, Lopes RD. Antithrombotic therapy in heparin-induced thrombocytopenia: guidelines translated for the clinician. J Thromb Thrombolysis 2012; 34: 552–561.
6.
Smythe MA, Forsyth LL, Warkentin TE, Smith MD, Sheppard JA, Shannon F. Progressive, fatal thrombosis associated with heparinınduced thrombocytopenia after cardiac surgery despite “therapeutic” anticoagulation with argatroban: Potential role for PTT and ACT confounding. J Cardiothorac Vasc Anesth 2014 Aug 25. doi: 10.1053/j. jvca. 2014.04.029.
7.
Yamamoto N, Nie M, Hari Y, Ohara K, Miyaji K. Death due to undetected heparin-induced thrombocytopenia after cardiac surgery. Gen Thorac Cardiovasc Surg 2012; 60: 511–513.
8.
DuBose J, Sutherland M, Moulton M, Krishnan B, Cohn J, Pratt JW. Heparin-induced thrombocytopenia and thrombosis syndrome after
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cardiac surgery. Curr Surg 2004; 61: 209–212. 9.
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106: 2710–2715.
10. Aouifi A, Blanc P, Piriou V, et al. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin induced thrombocytopenia. Ann Thorac Surg 2001; 71: 678–683.
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nia: when the obvious is not obvious, a case report. J Med Case Rep 2007; 1: 13. 13. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparininduced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759–765. 14. Linkins LA, Dans AL, Moores LK, et al. Treatment and preven-
11. Antoniou TH, Stavridis G, Daganou M, Melissari E, Gatzonis S.
tion of heparin-induced thrombocytopenia: antithrombotic therapy
Heparin-induced thrombocytopenia thrombosis after cardiac surgery. A
and prevention of thrombosis, 9th edn. American College of Chest
case report. Acta Anaesthesiol Scand 2000; 44: 991–993.
Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;
12. Cormack GM, Kaufman LJ. Severe heparin-induced thrombocytope-
141: e495–530.
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