CVJA Volume 24, Issue 8 by Clinics Cardive Publishing

SEPTEMBER 2013 VOL 24 NO 8

www.cvja.co.za

CardioVascular Journal of Africa (official journal for PASCAR)

• Journal impact factor and PubMed Central • Analysis of South African fish oil supplements • Management of effusive constrictive pericarditis • Carotid and popliteal artery IMT and poor oral hygiene • Tumescentless endovenous radiofrequency ablation • Alpha lipoic acid during extracorporeal circulation • Results of the DYSlipidaemia International Study

Cardiovascular Journal of Africa . Vol 24, No 8, September 2013

Printed by Tandym Printers

PUBLISHED ONLINE: • Mitral valve and CABG surgeries after pneumonectomy • Left ventricular rupture after double valve replacement

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

Vol 24, No 8, SEPTEMBER 2013

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

Editorial

295 Article visibility: journal impact factor and availability of full text in PubMed Central and open access PA Brink

Cardiovascular Topics

297 Analysis of the omega-3 fatty acid content of South African fish oil supplements: a follow-up study M Opperman • S Benade 303 Surgical management of effusive constrictive pericarditis F Buyukbayrak • E Aksoy • S Tas • K Kirali 308

Carotid and popliteal artery intima–media thickness in patients with poor oral hygiene and the association with acute-phase reactants IS Uyar • MB Akpinar • V Sahin • EF Yasa • F Abacilar • V Yurtman • FF Okur

313 Tumescentless endovenous radiofrequency ablation with local hypothermia and compression technique K Korkmaz • AÜ Yener • HS Gedik • AB Budak • Ö Yener • SB Genç • A Lafçi 318

Clinical experience of repair of pectus excavatum and carinatum deformities M Oncel • B Tezcan • KG Akyol • Y Dereli • GS Sunam

322 Alpha lipoic acid attenuates inflammatory response during extracorporeal circulation IS Uyar • S Onal • MB Akpinar • I Gonen • V Sahin • AC Uguz • O Burma 330

Prevalence of dyslipidaemia in statin-treated patients in South Africa: results of the DYSlipidaemia International Study (DYSIS) FJ Raal • DJ Blom • S Naidoo • P Bramlage • P Brudi

327

William Nelson ECG quiz

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

SUBJECT Editors

Acting Editor in Chief (South Africa) Prof PA Brink

Nuclear Medicine and Imaging DR MM SATHEKGE

Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie

Heart Failure Dr g visagie Paediatric dr s brown Renal Hypertension dr brian rayner

Regional Editor (Kenya) Dr F Bukachi

Surgical dr f aziz

Regional Editor (South Africa) PROF R DELPORT

Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne

Editorial Board prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

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

PROF DP NAIDOO Echocardiography PROF B RAYNER Hypertension/Society

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology)

PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology) DR GEORGE A MENSAH USA (General Cardiology) PROF WILLIAM NELSON USA (Electrocardiology)

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

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

CONTENTS Vol 24, No 8, SEPTEMBER 2013

Letter to the Editor

329

Cardiomyopathies and myocardial disorders in Africa: present status and the way forward. Response to Prof Bongani Mayosi A Falase • O Ogah

340

Novo Nordisk Incretin and Cardiovascular Summit P Wagenaar

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

Mitral valve and coronary artery bypass surgeries 13 years after pneumonectomy for lung cancer O Dag • MA Kaygin • U Arslan • A Kiymaz • N Kahraman • B Erkut

Drug Trends in Cardiology

Case Reports

e5 Left ventricular rupture after double valve replacement in a patient with myocarditis due to myasthenia gravis M Argiriou • V Patris • N Lama • S Katsaridis • O Argiriou • C Charitos e8 Diffuse giant tendon xanthomas in a patient with familial hypercholesterolaemia S Yuksel • EP Yuksel e10 Acute aortic dissection with a dangerous duo in an adolescent boy T Bezgin • C Doğan • A Elveran • A Karagöz • CY Karabay • AM Esen

managing editor

GLENDA HARDY Tel: 021 976 8129 Cell: 071 819 6425 e-mail: glenda@clinicscardive.com

financial & production co-ordinator ELSABÉ BURMEISTER Tel: 021 976 8129 Fax: 086 664 4202 Cell: 082 775 6808 e-mail: elsabe@clinicscardive.com

Production Editor

SHAUNA GERMISHUIZEN Tel: 021 785 7178 Fax: 086 628 1197 e-mail: shauna@clinicscardive.com

CONTENT MANAGER

Michael Meadon (Design Connection) Tel: 021 976 8129 Fax: 0866 557 149 e-mail: michael@clinicscardive.com

GAUTENG CONTRIBUTOR

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. Layout: Martingraphix

Printer: Durbanville Commercial Printers/ Tandym Print ONLINE SERVICES: Design Connection

Full text articles available on: www.cvja. co.za or via www.sabinet.co.za; for access codes contact elsabe@clinicscardive.com

All submissions to CVJA are to be made online via www.cvja.co.za

Subscriptions for 10 issues: To subscribe to the journal or change your postal address, e-mail elsabe@clinicscardive.com

Electronic submission by means of an e-mail attachment may be considered under exceptional circumstances.

South Africa: R650 (excl VAT) Overseas: R1306 Online subscription: R200

Postal address: PO Box 1013, Durbanville, RSA, 7551 Tel: 021 976 8129 Fax: 0866 644 202 Int.: +27 21 976 8129 e-mail: info@clinicscardive.com Electronic abstracts available on Pubmed Audited circulation

The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

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Editorial Article visibility: journal impact factor and availability of full text in PubMed Central and open access Both the impact factor of the journal and immediate full-text availability in Pubmed Central (PMC) have featured in editorials before.1-3 In 2004, the editor of the Cardiovascular Journal of Africa (CVJA) lamented, like so many others, the injustice of not having an impact factor, its validity as a tool for measuring science output, and the negative effect of a low perceived impact in drawing attention from publications from developing countries.1,4 Since then, after a selection process, we have been indexed by the Web of Science® (WoS) and Thomson Reuters (Philadelphia, PA, USA), and have seen a growing impact factor. In the case of PMC, our acceptance to this database was announced in 2012,2 and now we are proud that it is active and full-text articles are available dating back to 2009. The journal opted for immediate full open access (OA), which means that full-text articles are available on publication date for anybody with access to the internet.

The journal impact factor (JIF) The impact factor is one measurement of visibility of articles in specific journals and is more appropriately called the journal impact factor (JIF). It was originally developed by Eugene Garfield as a help to librarians in selecting journals to which to subscribe.5,6 However, it acquired iconic status as a single measure of the quality of science published in a journal and by extension, the scientific standing of authors, affecting, among others, grant allocation and career advancement. The classic JIF is defined as the ratio of the number of cites in a given year as a ratio of the number of ‘citable’ articles published in the previous two years. Information comes from the approximately 11 000 journals indexed by the WoS, which is published in the Journal Citation Report® (JCR).5,6 Cites, counted in the numerator, can be from any type of article from journals within the database, whereas only articles designated as research or review count in the denominator. Factors that can be correlated with the JIF have been much researched and debated. To name but a few, the country of the journal and its socio-economic status,7 the field of publishing, number or reviews versus original research articles, and the effect of a blockbuster article.5,6 The New England Journal of Medicine (NEJM) with a JIF of 52.658 (JCR 2012) and then Lancet with a JIF of 39.060 (2012) are probably the world’s most read medical journals. South Africa’s general medical journal, the South Africa Medical Journal, comes in at a JIF of 1.702. Surprisingly, the highest JIF belongs to a journal that most readers of CVJA may not even have heard off, a clinical oncology journal, Cancer Journal for Clinicians, with a JIF of

153.459 (2012). It publishes few articles, 37 in 2010 and 11, but with 5 678 cites in 2012. It went from a JIF of 101.78 in 2011 to 153.459 in 2012, the highest jump ever recorded. This can mostly be attributed to an extraordinary number of cites, 1 787 to one article (26% of cites).8 From this, one can calculate a contribution to the JIF of 39.945, which is more than the JIF of the Lancet, which had 21 366 cites for 547 articles, translating into its JIF of 39.060. Of course, when working in the cardiovascular field, one will not publish in a cancer journal. In the JCR field of cardiac and cardiovascular systems, where the CVJA resides, Circulation is top, with a JIF of 15.202. However, the CVJA is from Africa. Of the 46 African countries in the JCR, a non-medical journal the International Journal of Photoenergy from Egypt but domiciled in New York, has the highest JIF of 2.663. Second is the South African Medical Journal, which forms part of the medical group of 14 African journals within the JCR, with a JIF of 1.702. Of these, the CVJA with a JIF of 0.848 ranks a close third after the African Journal of Psychiatry, with a JIF of 0.871. Within the 14 titles, CVJA is the only journal from Africa in the field of cardiac and cardiovascular systems. Having publications accepted in journals with a high JIF does not necessarily reflect an interest in local problems, but often current interest in developed economies. For example, in the NEJM over the eight-year period from 1997 to 2004, less than 3% of published articles addressed health issues of developing countries. Furthermore, there was a bias towards HIV/AIDS and infective disease. Of 202 articles addressing issues of developing countries, 135 (almost 50% HIV/AIDS related) were about infectious disease. Only 23 were about non-communicable disease, of which one, a book review, discussed heart disease.9 So, in principle, it is possible that exhortation to publish in highimpact journals, as is often the practice, may skew research to improve visibility in the developed world. Then there is also the excessive emphasis on a single metric, the ‘number that’s devoured science’, the JIF.10 Who in clinical medicine relies on a single sign or a single test to make a diagnosis? The astute physician usually considers a constellation of findings and tests in coming to a diagnostic conclusion. This should be the same in the bibliometric evaluation of science, and in the San Francisco Declaration on Research Assessment, a group of editors and publishers made a plea for a more broadbased approach.11 The group suggests a reduction in emphasis on the journal impact factor and to create context by using a variety of journal-based metrics, e.g. five-year impact factor, EigenFactor, SCImago, h-index, editorial and publication times, all of which are available for the CVJA. A description of these metrics, their use and citation databases other than WoS, such as Scopus and

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Google Scholar can be read in Bornman, et al. and Pendlebury.5,6 The group also recommends consideration of non-journal factors, such as effect on health policy and to develop metrics for measuring scientific content rather than only publication metrics.

The journal and Pubmed Central With CVJA, the other important development has been listing in PMC. PMC is a free full-text archive of biomedical and life sciences journal literature at the US National Institutes of Health’s National Library of Medicine (NIH/NLM). Advantages and disadvantages have been discussed.2,12 One can access PMC-listed CVJA articles directly (http://www.ncbi.nlm.nih. gov/pmc/journals/1961/) where all the issues from 2009 to current are available in three formats: HTML, PDF and tablet friendly, the latter very user friendly. Note that only primary research and review articles are listed on PMC. In a sense, one is using more than a belt and braces in using multiple repositories. This ensures that articles published in the journal will survive for a long time in cyberspace. The same articles, in addition to editorial and other content in the journal, can also be accessed through Pubmed (http://www.ncbi.nlm.nih. gov/pubmed) by an article search. Here one can access full text in addition to case studies published online through SAePub (Sabinet). Then there is the website of CVJA (http://www.cvja.co.za/) where one can read articles in a number of formats, including an e-reader format or, even better, browse through a facsimile of the journal as it appears in print, with everything, adverts included. Advertising income plays an important role in sustainability of the CVJA and it is therefore important to maximise traffic through the website of the CVJA. In this regard, PMC has been shown to divert traffic from PMC-listed journals’ websites or other repositories.12 The ability to cross-reference data from diverse sources, clinical, genetic, DNA sequence, and protein is potentially very useful. For example, accessing a recent article on long QT syndrome brings up references to DNA sequences coding for cardiac ion channels (a cause of LQTS) and also information on the channel proteins contained within the NIH/NLM databases.13 However, this easy networking within PMC may create less of an impetus to use the website of the CVJA. In accessing OA articles, albeit through the journals’ websites, Pubmed, PMC or Sabinet, one needs only access to the internet. This is good news for readers from low-resource settings. No personal, departmental and library subscription is necessary. There is however no such thing as a free lunch. The publication bill needs to be settled. With OA, distribution costs can be very low if a journal chooses to publish only online, but there are still high costs involved for proper peer review and editorial quality control. Production costs are not necessarily cheaper and cost falls to the author or institution.12,14 For example, publishing in PLOS Medicine, an OA journal with high impact, it will cost the author(s) $1 900 (graded according to the economic status of a country). In the case of CVJA, the up-front cost is $50 to have a submission reviewed and the rest of the costs are covered by

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advertisements, special projects and subscriptions. As indicated, however, the last modality may be under threat. For the other sources of income, using the CVJA website as a portal of entry is very important. It may well happen that institutions limit subscriptions to journals not OA but deemed very important, such as Circulation and NEJM. It is interesting that a number of high-impact journals with content perceived to be commercially of value have not embraced PMC or OA, such as the NEJM and Circulation. Other funds may be needed to carry publication costs on the authorpay principle. All research is not backed by strong institutional funding, especially not in Africa. This does provide challenges!

Conclusion The CVJA is from Africa, but also part of the global environment. Within Africa, the journal is well placed and a portal to the world. Articles within the journal are visible, as the journal is indexed in the major databases. Content is freely available on date of publication, but the OA environment has created new challenges. A last thought: Is there not a place for an African journals database so that we can unlock synergies within Africa? PAUL A BRINK, MB ChB, PhD, paul@clinicscardive.co.za Department of Internal Medicine, Faculty of Health Sciences, University of Stellenbosch and Tygerberg Hospital, Tygerberg

References 1. 2. 3. 4.

6. 7.

8. 9. 10. 11. 12. 13.

14.

Brink AJ. Impact factor: use and abuse. Cardiovasc J S Afr 2004; 15(1): 5–7. Brink AJ. New impact factor and PubMed Central service from the Cardiovascular Journal of Africa. Cardiovasc J Afr 2012; 23(7): 364. Brink AJ. Electronic innovation and readership. Cardiovasc J Afr 2012; 23(3): 125. Rossner M, Van EH, Hill E. Show me the data. Cardiovasc J Afr 2008; 19(1): 3–4. (Reprinted with permission from the Journal of Experimental Medicine). Bornmann L, Marx W, Gasparyan AY, Kitas GD. Diversity, value and limitations of the journal impact factor and alternative metrics. Rheumatol Int 2012; 32(7): 1861–1867. Pendlebury DA. The use and misuse of journal metrics and other citation indicators. Arch Immunol Ther Exp (Warsz ) 2009; 57(1): 1–11. Yousefi-Nooraie R, Shakiba B, Mortaz-Hejri S. Country development and manuscript selection bias: a review of published studies. BMC Med Res Methodol 2006; 6: 37. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69–90. Lown B, Banerjee A. The developing world in the New England Journal of Medicine. Globalization Health 2006; 2(1): 3. Monastersky R. The number that’s devouring science (grading system for scholarly journals). Chron Higher Ed 2005; 52(8): NA. Way M, Ahmad SA. The San Francisco Declaration on Research Assessment. J Cell Sci 2013; 126(9): 1903–1904. Frank M. Open but not free – publishing in the 21st Century. New Engl J Med 2013; 368(9): 787–789. Hedley P, Durrheim G, Hendricks F, et al. Long QT syndrome in South Africa: the results of comprehensive genetic screening. Cardiovasc J Afr 2013; 26(6): 231–237. Haug C. The Downside of Open-Access Publishing. New Engl J Med 2013; 368(9): 791–793.

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Cardiovascular Topics Analysis of the omega-3 fatty acid content of South African fish oil supplements: a follow-up study MARETHA OPPERMAN, SPINNLER BENADE Introduction: Globally the omega-3 (n-3) fatty acid supplement industry is expanding rapidly while consumers are becoming more aware of the health benefits of n-3 fatty acids. Our group conducted a survey in 2009 on 45 commercially available fish oil supplements on the South African market. The aim of the study was to determine the fatty acid composition and content of supplements for comparison with the claimed contents on the product label. The survey was repeated in 2012 on 63 supplements. Methods: Sixty-three commercially available n-3 fatty acid supplements were analysed using gas–liquid chromatography to determine their fatty acid composition and content. Results: This analysis has shown an improvement in the accuracy of EPA content (44% in 2009) declared on supplement labels compared to the 2012 (52%) survey. It was also evident that a higher percentage of supplements (13% in 2009 vs 35% in 2012) contained DHA levels higher than declared. In 2009, 64% of supplements cost R2.01 to R5.00 or more to achieve a daily intake of 500 mg EPA + DHA, compared to 81% in 2012. Forty-four per cent of supplements were found to be in the early stages of rancidity [conjugated diene (CD) levels] compared to 73% in 2009. More than 80% of supplements had peroxide levels higher than the recommended content as specified by the Global Organisation for EPA and DHA Omega-3 (GOED). The majority (81%; n = 51) of the supplements under study in 2012 had a 1.1–1.5:1 EPA-toDHA ratio or less, compared to 56% in 2009. Almost a third (32%) of the supplements in the 2012 survey contained ethyl esters (EE) or a combination of ethyl esters and triglycerides. Conclusion: Although the results of the 2012 versus the 2009 analysis were encouraging in terms of the accuracy of EPA declared on the supplement labels, the high peroxide levels found in the supplement oils are of concern. High peroxide levels are associated with potential health implications. EE were present in some of the supplements, even though the safety of EE has not been confirmed in vulnerable groups such as pregnant women and children. Keywords: omega-3 fatty acids, supplement labels, conjugated dienes, peroxides, ethyl esters

Functional Foods Research Unit, Department of Agriculture and Food Science, Cape Peninsula University of Technology, Cape Town, South Africa MARETHA OPPERMAN, PhD, oppermanm@cput.ac.za SPINNLER BENADE, DSc

Submitted 26/9/12, accepted 16/4/13 Cardiovasc J Afr 2013; 24: 297–302

www.cvja.co.za

DOI: 10.5830/CVJA-2013-074

Scientific research and media exposure as well as raising health and nutritional awareness among consumers have led to a substantial rise in fish oil supplementation over the past five years. It is predicted that sales of omega-3 (n-3) fatty acid products in the United States (US) will increase from $25.4 billion in 2011 to $34.7 billion in 2016 (pers commun). Even though n-3 fatty acid supplements capture only 13% of the US n-3 product market, the highest retail dollar value of the supplements is in the fish oil as opposed to packaged food, beverages and infant formulas where the n-3 content is relatively small. The South African market for fish oil capsules over the past 12 months is estimated to be worth about R65 million (pers commun), however this figure only includes data from large retail store groups and not from privately owned businesses. A whole array of health benefits are attributed to the long-chain polyunsaturated n-3 fatty acids found in fish oil. The n-3 fatty acids of particular interest are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids are eminent as anti-thrombotic, anti-arrhythmic and antiaggregatory compounds.1 Routine intake of oily fish and fish oil are now widely acknowledged for their role in decreasing the risk of cardiovascular diseases (CVD) such as fatal coronary heart disease and stroke. N-3 fatty acids are also renowned for their anti-inflammatory properties and may be beneficial in reducing the risk of inflammatory-related conditions including obesity, Crohn’s disease, ulcerative colitis, type 2 diabetes, asthma, psoriasis, multiple sclerosis, cystic fibrosis and chronic obstructive pulmonary disease.2 The significance of EPA and DHA in neural and visual development is also well documented.3 In a typical Western diet there are only a few food sources contributing to dietary n-3 fatty acid intake. Research indicates that plant-derived n-3 fatty acids in the form of alpha-linolenic acid (ALA) are poorly converted to EPA and DHA,4 while preformed EPA and DHA from fish oil is readily available for metabolism. Several clinical trials have shown that baseline EPA and DHA blood levels can be increased by means of goodquality fish oil supplements. Clinical trial results from our group indicated low dietary EPA and DHA intakes, as reflected in the baseline blood levels of healthy, normo-lipidaemic, non-smoking research participants residing in Cape Town. Typical baseline red blood

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cell values varied between 3 and 5%.5 According to Harris’s proposed n-3 index,6 these levels position participants in a high- to intermediate- risk zone for the development of CVD. As Cape Town is located on the west coast of South Africa with its cold sea currents, one could expect that cold-water fatty fish consumption will be higher among people residing here compared to residents living in the provinces without a coastline. Consumers further away from the coast may therefore experience even lower n-3 fatty acid levels in their blood. However, canned fatty fish such as pilchards, sardines, salmon and mackerel are rich in n-3 fatty acids. These products are readily available to the majority of consumers and should theoretically help them to obtain their daily n-3 fatty acid intakes. Unfortunately the affordability of the products as well as some consumers’ preferences for red meat as a protein source may prevent them from purchasing these products. It therefore seems that progressively more consumers turn to fish oil supplements to augment their n-3 fatty acid intakes, as it is perceived to be an easy, effective and safe method to rectify poor dietary intakes. Yet controversy exists whether n-3 fatty acids consumed via supplementation is the best way to combat disease. Some reviews investigating the risk of major cardiovascular events reported no association between n-3 fatty acid supplementation and a reduced risk of all-cause mortality, cardiac death, sudden death, myocardial infarction or stroke,7 or for the secondary prevention of cardiovascular disease.8 On the other hand, other reviews9,10 did indicate associations between risk reduction of cardiovascular disease and n-3 fatty acid dietary supplements. According to Jump et al.,9 conflicting results may be attributed to people at risk for cardiovascular disease who take medications such as statins and fibrates as well as drugs with anti-inflammatory, anti-arrhythmic and anti-thrombotic effects, minimising the detectable effect of supplemental n-3 fatty acids. Dietary recommendations and advice for the intake of n-3 fatty acids have progressed notably during the past five years. No formal dietary reference intakes (DRIs) currently exist for EPA and DHA but intakes that vary from 250 to 600 mg EPA + DHA are recommended; however there are still many gaps in research7. Achieving these amounts through fish intake alone might be problematic without supplementation. To reach a 500-mg/day EPA + DHA as recommended by the International Society for Fatty Acids and Lipids (ISSFAL12) with purified fish oil, about 2 000 mg of oil with a 180-mg EPA to 120-mg DHA content ratio would be required. To consume these amounts of EPA + DHA through diet/non-supplementation, approximately 79 g/day of tuna or 60 g/day of pilchards or 52 g/day of salmon should be consumed. In addition, fish is not the dietary protein of choice for many South Africans. For an n-3 fatty acid supplementation to be effective, goodquality fish oil is essential. The quality of fish oil supplements is highly affected by the storage conditions of the refined oil before encapsulation, the nature of the preservative added to prevent oxidation, the time period of storage and light exposure. The EPA and DHA content of fish oil is also subjective to the fluctuation of long chain n-3 fatty acids even within single fish species and is further dependent on geographic origin, season and preparation of the oil. In a survey13 conducted in 2009 by our research group, where we studied the quality of 45 fish oil supplements available on the South African market, it appeared that supplements varied to a

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large extent in terms of the measured versus the claimed content of EPA and/or DHA, the level of lipid peroxidation, the EPA-toDHA ratios as well as the number of capsules and price to meet international dietary recommendations. These findings are of concern since no regulatory structure to monitor the quality of dietary supplements currently exists in South Africa. Consumers therefore depend on self-regulation within the neutraceutical industry for assurance of product quality, consistency, potency and purity of fish oil supplements. Since the survey was conducted in 2009, no new labelling and quality-assurance regulations have been published. It was therefore decided to repeat the survey, this time on 63 supplements, to assess if there were any improvements in the quality of fish oil supplements available to the South African consumer. Specific objectives for the survey included analysis and comparison of the EPA and DHA contents of the supplements with the contents claimed on the product label; number of capsules and price to achieve international n-3 fatty acid intake recommendations; to determine the conjugated diene (CD) and peroxide content of the supplement oils; and to determine whether the long-chain n-3 fatty acids present in the capsules were in the form of triglycerides (TG) or ethyl esters (EE) or a combination of TG and EE.

Methods Sixty-three n-3 fatty acid supplements were analysed for fatty acid composition and content, CD and peroxide values as well as EE content. Two independent researchers de-identified the supplements and stored them in numbered containers until commencement of analyses, hence a blind sample of supplements was received by the researchers conducting the analyses. Products from various brands were analysed, and in no particular order included: Pharmamark, ReVite, ADD Vance, Bettaway, Vitaforce, Biogen, Amipro Metagenics, Keynote Health, Dis-Chem, Holistix, Naturelle, Natrodale, SOLAL Technologies, Medi+Rite Pharmacy, Nativa, Pharmafrica, Clicks Group Limited, Georen Preg, Bioharmony, Rejuvenesse, Solgar, Amway, Pinnacle, Scientific Sports Nutrition, Equazen, Patrick Holford, The Real Thing, Durbell, Vital, Holgoun Healthcare, Absolute Organix, Vitabiotics, Kenzahealth, Annique, Bioter, Ocean Gold Fish Liver Oil, and TNP Healthcare. To determine the CD content of the fish oil supplements, a spectrophotometric method was used as described by Recknagel and Glende.14 CD values were compared against reference values as described by Opperman et al.13 Peroxide levels were determined spectrophotometrically as described by Khodaparast et al.15

Fatty acid composition and content of fish oil capsules The oil content of each capsule was determined by the difference in weight between the whole capsule and the weight of the capsule gelatin. An aliquot of oil, about 600 mg, was weighed in a 25-ml volumetric flask and made up to volume with chloroform–methanol (2:1) containing butylated hydroxyl toluene as anti-oxidant. To 50 μl of this stock solution was added 100 μl of heptadecanoic acid as internal standard (100 μl in chloroform-methanol 2:1).

After drying under a stream of nitrogen, fatty acids were trans-methylated with methanol-sulphuric acid (5% sulphuric acid in anhydrous methanol) for two hours at 70°C. Fatty acid methyl esters were extracted with hexane and analysed by gas– liquid chromatography (GLC, Thermo, Focus) equipped with a flame ionisation detector and a 60-meter BPX 70 capillary column. Oven temperature was programmed at 2°C per minute from 160 to 220°C. Fatty acids were quantified by comparing the areas of a specific fatty acid with that of the internal standard and correcting for the relative response factor for the specific acid. Total fatty acids were calculated and each fatty acid was expressed as a percentage of the total fatty acids. The values so obtained were then translated into the amount of fatty acid per capsule.

Determination of triglyceride and ethyl ester contents The content of all fish oil capsules were screened for neutral lipid and EE content by high-performance thin-layer chromatography (HPTLC) using 10 × 10-cm silica gel 60 plates (Merck). Plates were developed with hexane–diethyl ether–acetic acid (85:15:2 by volume).16 Ten micro-samples (10 μl), prepared for GLC analysis of fatty acid, were applied to plates as a single spot. Samples of EE of fatty acids and fatty acid TG were applied for identification. Lipids were identified by spraying with 2,5-Bis (5-tert-butyl-benzoxazol-2-yl) thiophene and visualised under UV light. Individual spots were scraped off the plate and eluted with chloroform methanol. TG spots were transmethylated with methanol sulphuric acid, where after EE spots were confirmed by GC-MS analysis.

Results Measured EPA and DHA contents of fish oil supplements were compared to the contents claimed on the product labels. A reference range between 90 and 110% of the manufacturers’ claimed contents for EPA and DHA was proposed. Supplements containing ≤ 89% of the claimed EPA and/or DHA were considered substandard, while those containing ≥ 110% EPA and/or DHA were considered to be in surplus.

100 80 60

24%

29%

< 89%

90–99%

% claimed EPA 2009

13%

100–110%

Ranges

13%

10%

> 110%

% claimed EPA 2012

Fig. 1. Measured versus claimed contents of EPA (*acceptable range 90–110%).

90–99%

35% 16%

15%

13%

100–110%

Ranges

> 110%

% claimed DHA 2012

Fig. 2. Measured versus claimed contents of DHA (*acceptable range 90–110%).

CD contents of the fish oils were compared to levels as described by Opperman et al.13 For peroxide contents, values ≤ 5 meq O2/kg oil were deemed acceptable as recommended by the Global Organisation for EPA and DHA Omega-3 (GOED).17 Results of the 2012 study were compared to the results of a similar study conducted in 2009 to determine if there was any improvement in the accuracy of labelling information, the level of rancidity, and the EPA-to-DHA ratios of the supplements. Comparison of measured versus claimed contents against the acceptable ranges (Fig. 1) indicated that almost half (n = 30; 48%) of the studied supplements failed to meet the claimed EPA requirements (2012). This is a small improvement compared to the 2009 analysis. For DHA, 31% (n = 19) of the supplements did not meet the proposed DHA requirements (Fig. 2) compared to the 51% in the 2009 study. Thirty-five per cent (n = 22) of the supplements contained more than 110% of the DHA claimed on the product label. For the current EPA and DHA analysis, data of only 62 supplements could be recorded because one of the supplements did not provide any information on the label about the EPA and DHA content of the product. In the absence of n-3 fatty acid dietary recommendations for South Africa, we used the ISSFAL18 recommended intake of 500 mg/day EPA + DHA for the prevention of cardiovascular

Percentage (%)

< 89%

19%

% claimed DHA 2009

20%

48%

31%

100

56%

51%

100

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Percentage (%)

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60 46%

31%

18% 19%

17%

20 0

38%

4% 6%

< R1.00

R1.01– R2.00

R2.01– R5.00

R5.01– R10.00

Price range (R)

Prices in 2009

10%

R10.01– > R15.00 R15.00

Prices in 2012

Fig. 3. Price to attain 500 mg/day EPA + DHA.

300

80 Percentage (%)

100

Percentage (%)

100

60 41%

40 20 0

15%

< 10

39%

32%

18%

16%

11–20

21–30

10%

31–40

18%

> 41

39%

40 20

59%

13%13% 4%

35%

10%

10% 0% 2%

2009

disease, as reference. The majority (46%; n = 29) of the surveyed supplements cost between R2.01 and R5.00 to attain a 500-mg/ day EPA + DHA intake. Thirty-five per cent (n = 22) of the supplements cost more than R5.00 per day to reach the proposed n-3 fatty acid intake (Fig. 3). Prices between R26.79 and R61.77 to achieve the daily recommended intake were recorded. Price increases seem to have been substantial between 2009 and 2012. The CD levels of oils are an indication of the early stages of rancidity of oils. CD levels of ≤ 20 μmol/g were considered acceptable. During the 2012 study, 56% (n = 33) of the analysed fish oil supplements contained CD levels within the acceptable ranges, while 44% (n = 26) had CD levels of > 20 μmol/g (Fig. 4). CD levels of only 59 of the 63 supplements could be determined due to colour interference with the assay, as CD levels were determined spectrophotometrically. From the current analysis it seems that fewer supplements were in the early stages of rancidity during the 2012 study compared to the 2009 study. Peroxide levels of < 5 meq O2/kg oil for edible oils are deemed acceptable, however, the majority (84%; n = 48) of the tested supplements contained peroxide levels higher than the acceptable range. Merely 16% (n = 9) of the fish oil supplements had peroxide levels within the proposed range (Fig. 5). Peroxide levels of only 57 of the supplements could be determined due to colour interference with the assay, as peroxide levels were determined spectrophotometrically. Peroxide levels were not determined during the 2009 study. 100

Percentage (%)

n=1

Ranges (meq O2/kg oil)

Fig. 5. Peroxide levels of fish oil supplements.

> 30

2012

The choice of n-3 fatty acid supplements is expanding annually as more and more manufacturers enter the market. Some fish oil supplements sold in South Africa are encapsulated locally while all fish oil or fish oil concentrates are imported from different countries. Without proper local and international labelling legislation, in combination with strictly enforced manufacturing standards, the quality of fish oil supplements as well as the credibility of their labels remains questionable. Other countries, for example the US and countries of the European Union (EU), have strict dietary supplement labelling legislation but in the US supplements are not subject to safety and efficacy testing requirements.18 The EU’s Food Supplements Directive19 requires that supplements are obliged to be demonstrated safe in terms of purity as well as the dosages recommended. Only supplements proved to be safe may be sold without a prescription. However, South Africa imports dietary

n = 43 68%

n=9

11–30

Discussion

n=7 11%

n = 17

6–10

The majority (81%; n = 51) of the supplements under study had a 1.1–1.5:1 EPA-to-DHA ratio or less (Fig. 6). Only a few supplements had a 1.5–2.0:1 ratio compared to the results reported in the 2009 survey. Fig. 7 shows that almost a third (32%; n = 20) of the analysed fish oil supplements available on the South African market contained EE or a combination of TG and EE. The form of the fatty acids was not determined during the 2009 study.

n = 30

0% 2%

Fig. 6. EPA-to-DHA ratio in the surveyed n-3 fatty acid supplements.

Ratio EPA:DHA

2012

Fig. 4. Conjugated diene levels of fish oil supplements.

< 0.5 0.6–1.0 1.1–1.5 1.6–2.0 2.1–2.5 2.6–3.0 3.0–3.5

Ranges (µmol/g)

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n = 13 21%

TG EE TG + EE n = 63

Fig. 7. Form of n-3 fatty acids present in the surveyed supplements.

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supplements from many other countries that do not have to adhere to such strict regulations. There was an improvement in the percentage (42% in 2012) of supplements that met the arbitrary range of 90–110% for EPA compared to the results of the previous survey (31% in 2009). With regard to DHA, there was a substantial increase in the percentage of supplements with DHA content > 110% (13% in 2009 vs 35% in 2012). This might be attributed to increased awareness of consumers regarding n-3 fatty acid intake and the emphasis on the importance of DHA for neural and brain development. To increase the level of n-3 fatty acids in the diet with a fish oil supplement may be expensive for the average South African consumer. The current analysis shows that the majority of the surveyed supplements will cost the consumer R60 to R150 (R2.01 to R5.00/day) per person per month to attain the daily recommendation of 500 mg/day EPA + DHA, as stipulated by ISSFAL. For a family of four it will cost R240 to R600 per month, which makes fish oil supplementation unaffordable for the average South African household. Rancidity is a concern, especially in polyunsaturated fatty acid oils such as fish oil. CDs were measured as an early indicator of rancidity. Almost half of the supplements tested were in the early stages of rancidity. Another concern is the peroxide levels of the majority of supplements, which were higher than the levels recommended by GOED17 (≤ 5 meq O2/kg oil). Peroxide levels are a measure of the oxidative rancidity of fats by determination of the lipid peroxides present. Rancidity or oil degradation occurs when unsaturated fats are exposed to oxygen and become oxidised.20 Fish oil is prone to oxidation because of the presence of very longchain polyunsaturated fatty acids compared to saturated fat or vegetable oils.21 Research21-23 has shown that dietary oxidised fatty acids pose an increased atherogenic risk. According to Turner et al.,20 the deleterious effects of oxidised fats on lipid and chylomicron metabolism, oxidative stress, inflammation, as well as vascular function contribute to the increased risk of atherosclerosis. On average, fish oils contain 180 mg EPA and 120 mg DHA (ratio of 1.5:1) per 1 000 mg. In our previous analysis, the majority of EPA-to-DHA ratios of oils in the analysed supplements were 1.51–2.5:1, while in the current analysis more DHA was included in the supplements to supply oils with a 1.1–1.5:1 ratio. It is also evident that some of the surveyed supplements contained substantially more EPA and DHA per 1 000 mg oil compared with the 180 mg EPA + 120 mg DHA of standard fish oil. These so-called concentrated fish oils consist of EE which are the esterified products of fatty acids and ethanol. This chemical process is known as trans-esterification and involves the removal of the glycerol backbone of the TG in fish oil by substituting it with ethanol. By using fractional distillation, which removes short-chain and saturated fatty acids from fish oil, it is now possible for manufacturers of supplements to allow for selective concentration of EPA and DHA to levels in excess of those found in natural fish oils. Esterification is also applied to deodorise the fish oil. These preparations are typically marketed as fish oil concentrates. Through the process of glycerolysis it is possible to convert EE back to TG. This process removes the ethanol molecule and re-esterifies the EPA and DHA fatty acids back to a glycerol

301

backbone, resulting in the formation of re-esterified TG. The digestion of EE is altered as a result of the absence of a glycerol backbone. Enzymes such as pancreatic lipase hydrolyse the fatty acids from the ethanol backbone in the small intestine. Since the fatty acid–ethanol bond of EE is much more resistant to hydrolysis by pancreatic lipase compared to the hydrolysis of TG in the natural form, this may explain the reduced bioavailability of EE. Because of the resistance to hydrolysis the digestion and absorption of EE is significantly lower compared to TG and phospholipids. It is concerning that about a third of the surveyed n-3 fatty acid supplements analysed contained EE. Pregnant women are advised against the use of EE since the safety of EE during pregnancy has not been established. In this study, we analysed one supplement containing EE that specifically recommended it to be used during pregnancy. During the digestion of EE, they are converted back to TG and alcohol is released. Even though the quantity of ethanol released in a typical dose of fish oil via supplementation is small, at-risk groups such as alcoholics, pregnant women and young children should refrain from using n-3 fatty acid supplements that contain EE. EE of fatty acids have shown toxicity in vivo24 and in vitro25 and are known to accumulate in major organs such as the heart, liver, pancreas and potentially the placenta.26 In a rat study,27 it was observed that efficient fatty acid EE digestion in the gastrointestinal tract may prevent toxicity, however, this was not confirmed in humans. At present no manufacturers indicate the form (EE, TG and or rTG) in which n-3 fatty acids are present in capsules. The safety of daily intakes of EE and/or rTG via n-3 fatty acid supplements has not been confirmed in humans. EE and rTG are synthetic molecules and are not found naturally in food or the human body. In some countries (not in South Africa) fatty acid EEs are used as prescription medication to reduce very high blood TG levels (≥ 5.65 mmol/l). However, these preparations provide pharmacological amounts of n-3 fatty acid EE and are used under strict supervision of a physician who should be well informed about the adverse effects the medicine might display. These drugs are also subjected to rigorous testing through three phases of clinical trials, as specified by the Federal Drug Administration. However, the same procedures are not applied to ensure quality, consistency and purity in dietary supplements. By presenting n-3 fatty acid supplements in the form of EE or rTG, it enables manufacturers to increase the concentration of EPA and DHA in supplements. Our analysis has shown that manufacturers are increasing the DHA content of fish oil supplements to entertain the consumer’s demands for higher DHA intakes. The benefit of such higher DHA intakes needs further investigation. A recent meta-analysis and systematic review28 reported that treatment with EPA or DHA showed diverse effects on high- and low-density lipoprotein cholesterol (HDL-C and LDL-C). Both treatments induced lower blood TG levels. However, DHA was more often associated with both elevated HDL-C levels and LDL-C levels. The increase in LDL-C is undesirable. On the other hand, clinical trials elsewhere29,30 indicated that fish oil supplementation is associated with increased LDL-C particle size or a shift in LDL-C particle distribution from small, dense particles to larger less dense LDL-C particles, which are known to be less atherogenic.

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Conclusion Fish oil supplementation is a useful tool to increase the dietary intake of n-3 essential fatty acids. However, due to the absence of a food supplement regulatory structure in South Africa, there is concern about the safety, purity and quality of the fish oil supplements surveyed. This analysis has shown a small improvement in the accuracy of EPA content declared on supplement labels compared to the 2009 survey. It was also evident that a higher percentage of supplements contained DHA levels higher than declared. Fish oil supplements remain expensive and are deemed to be unaffordable for the majority of South African consumers. A relatively large number of supplements were found to be in the early stages of rancidity. Of greater concern was the peroxide (rancidity) level of more than 80% of supplements, which were higher than the recommended content as specified by GOED.17 Dietary intakes of oxidised fatty acids may pose deleterious health effects. Compared to the previous survey, it seems that manufacturers have increased the DHA-to-EPA ratio as well as the concentration of these two components. Some of the surveyed supplements had EPA and DHA contents much higher than the standard 180 mg EPA and 120 mg DHA per 1 000 mg fish oil. This can be attributed to the EE and/or rTG content of these preparations. The safety of EE and rTG has not been confirmed in humans. The authors thank Mr Alfred Hlabana from the CPUT Functional Foods Research Unit for his assistance in analysing the fish oil supplement samples and the South African Cancer Association (CANSA) for financial support to conduct the survey.

References 1.

2. 3.

4. 5.

Calzolari I, Fumagalli S, Marchionni N, Di Bari M, et al. Polyunsaturated fatty acids and cardiovascular disease. Curr Pharm Des 2009; 15(36): 4094–4102. Calder PC. Fatty acids and inflammation: The cutting edge between food and pharma. Eur J Pharmacol 2011; 668: S50–58. Birch EE, Carlson SE, Hoffman DR, Fitzgerald-Gustafson KM, Fu VL, Drover JR, Castañeda YS, et al. The DIAMOND (DHA Intake And Measurement Of Neural Development) study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid. Am J Clin Nutr 2010; 91(4): 848–859. DeFilippis AP and Sperling LS. Understanding omega-3s. Am Heart J 2006; 151:564–570. Opperman AM, Marais DW, Benadé AJS. Washout kinetics of eicosapentanoic and docosahexanoic acid from human plasma after supplementation with salmon oil. S Afr J Clin Nutr 2010; 29: S8. Harris WS. Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor. Pharmacol Res 2007; 55(3): 217–223. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. J Am Med Assoc 2012; 308(10): 1024–1033. Kwak SM, Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebocontrolled trials. Arch Intern Med 2012; 172(9): 686–694. Jump DB, Depner CM, Tripathy S. Omega-3 fatty acid supplementation and cardiovascular disease. J Lipid Res. jlr.R027904. First Published on

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August 17, 2012. 10. Marik PE, Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol 2009; 32(7): 365–372. 11. Aranceta J, Pérez-Rodrigo C. Recommended dietary reference intakes, nutritional goals and dietary guidelines for fat and fatty acids: a systematic review. Br J Nutr 2012; 107 Suppl 2: S8–22. 12. International Society for the Study of Fatty Acids and Lipids. Recommendations for the intake of polyunsaturated fatty acids in healthy adults. 2004. http://www.issfal.org.uk/ (accessed 12 December 2012). 13. Opperman AM, Marais DW, Benadé AJS. Analysis of omega-3 fatty acid content of South African fish oil supplements. Cardiovasc J Afr 2011; 22: 324–329. 14. Recknagel RO, Glende EA. Spectrophotometric detection of lipid conjugated dienes. Meth Enzymol 1984; 105: 331–337. 15. Khodaparast MHH, Haghdoost A and Movahhed GG. New source of butein in root of Salvia leriifolia (Nowroozak). J Agric Environ Sci 2008; 4(6): 731–736. 16. Benadé AJ, Fincham JE, Smuts CM, Tung MT, Chalton D, Kruger M, et al. Plasma low density lipoprotein composition in relation to atherosclerosis in nutritionally defined Vervet monkeys. Atherosclerosis 1988; 74(1–2): 157–168. 17. Global Organization for EPA and DHA Omega-3. 2012. GOED voluntary monograph (v. 4). http://www.goedomega3.com [15 February 2013]. 18. Food and Drug Administration. New Dietary Ingredients in Dietary Supplements – Background for Industry. FDA. [10 March 2013]. 19. European Union’s Food Supplements Directive. Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements. [10 March 2013]. 20. Turner R, McLean CH, Silvers KM. Are the health benefits of fish oils limited by products of oxidation? Nutr Res Rev 2006; 19(1): 53–62. 21. Spiteller G. The relation of lipid peroxidation processes with atherogenesis: a new theory on atherogenesis. Mol Nutr Food Res 2005; 49(11): 999–1013. 22. Penumetcha M, Khan N, Parthasarathy S. Dietary oxidized fatty acids: an atherogenic risk? J Lipid Res 2000; 41(9): 1473–1480. 23. Staprans I, Pan XM, Rapp JH, Feingold KR. The role of dietary oxidized cholesterol and oxidized fatty acids in the development of atherosclerosis. Mol Nutr Food Res 2005; 49(11): 1075–1082. 24. Yoerger DM, Best CA, McQuillan BM, Supple GE, Guererro JL, Cluette-Brown JE, Hasaba A, Picard MH, Stone JR, Laposata M. Rapid fatty acid ethyl ester synthesis by porcine myocardium upon ethanol infusion into the left anterior descending coronary artery. Am J Pathol 2006; 168: 1435–1442. 25. Alhomsi K, Selig M, Sustic T, Katrangi E, Weissig V, Laposata M. Induction of apoptosis and necrosis in human peripheral blood mononuclear cells by fatty acid ethyl esters. Alcohol Clin Exp Res 2008; 32: 534–543. 26. Bearer CF, Gould S, Emerson R, Kinnunen P, Cook CS. Fetal alcohol syndrome and fatty acid ethyl esters. Pediatr Res 1992; 31: 492–495. 27. Saghir M, Werner J, Laposata M. Rapid in vivo hydrolysis of fatty acid ethyl esters, toxic nonoxidative ethanol metabolites. Am J Physiol 1997; 273: G184–190. 28. Lopez-Huertas E. The effect of EPA and DHA on metabolic syndrome patients: a systematic review of randomised controlled trials. Br J Nutr 2012; 107: S185–194. 29. Mori TA, Burke V, Puddey IB, et al. Purified eicsapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr 2000; 71: 1085–1094. 30. Griffin MD, Sanders TA, Davies IG, et al. Effects of altering the ratio of dietary n-6 to n-3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45-70 y: the OPTILIP Study. Am J Clin Nutr 2006; 84: 1290–1298.

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Surgical management of effusive constrictive pericarditis FUAT BUYUKBAYRAK, ERAY AKSOY, SERPIL TAS, KAAN KIRALI

Abstract Background: The surgical approach for effusive constrictive pericarditis (ECP) has not been extensively studied. We present our institution’s early and long-term results of pericardiectomy in our cohort of patients with ECP. Methods: Diagnosis was made primarily by echocardiography. Right heart catheterisation was performed in eight patients. Pre-operatively, 10 patients had undergone at least one previous attempt at therapeutic pericardiocentesis. Pericardiectomy was performed where appropriate (thickened or inflamed). Results: Of our 12 patients (50% male, median age 48 years, range 17–72 years), the underlying aetiology included idiopathic in five (41.6%), tuberculosis in four (33%), and malignancy in three patients (25%). Elective surgery was performed in nine patients. Median values of both central venous pressure and pulmonary capillary wedge pressure decreased markedly postoperatively (from 16.5 to 11.0 mmHg, p = 0.02; 20.0–15.0 mmHg, p = 0.01, respectively). There was no in-hospital mortality. Follow up ranged from three months to nine years (median three years). Five (41.6%) patients died during the follow-up period, and cumulative two-year survival was 55.6 ± 1.5%. Conclusion: Pericardiectomy for ECP was effective, in terms of our early results, in patients unresponsive to medical therapy. Long-term survival depends on the underlying disease. Keywords: effusive constrictive pericarditis, surgery, pericardiectomy Submitted 6/2/13, accepted 7/6/13 Published online 17/9/13 Cardiovasc J Afr 2013; 24: 303–307

www.cvja.co.za

DOI: 10.5830/CVJA-2013-042

Effusive constrictive pericarditis (ECP) is a distinct entity in which diastolic filling is compromised by two combined mechanisms. First, increased intrapericardial pressure adversely affects volumetric expansion by causing external chamber compression. Second, loss of epicardial elasticity precludes myocardial relaxation. ECP is defined, on the basis of simultaneous catheterisation and pericardiocentesis findings, as the persistence of high intracardiac pressures despite percutaneous drainage of the pericardial fluid. The definition should not be misinterpreted, Kartal Kosuyolu Heart and Research Hospital, Istanbul, Turkey FUAT BUYUKBAYRAK, MD ERAY AKSOY, MD, surgerayaksoy@yahoo.com SERPIL TAS, MD KAAN KIRALI, MD, PhD

as ECP differs from CP only in being accompanied by fluid collection around the heart. Rather, what makes ECP a distinct entity is the involvement of the visceral pericardium. The fluid collection is a consequence of the underlying inflammatory process, and may directly relate to treatment outcomes.1,2 The prevalence of ECP ranges from 1.4–14.8%,3 and as high as 24% in patients requiring pericardiectomy.4 Although ECP has commonly been linked with tuberculosis, numerous case reports associate it with a variety of clinical conditions, including cancer, renal failure, connective tissue disease, previous cardiac surgery and mediastinal radiation.5-10 Although the risk of developing CP is higher after tuberculous pericarditis,11 and ECP has been assumed to be a precursor to permanent constriction, the prevalence of tuberculous ECP is lower than that of idiopathic ECP.3 Although most patients with pericardial effusion respond well to medical therapy (especially of tuberculous aetiology),12 more than half of patients with ECP eventually need pericardiectomy due to persistent heart failure. The purpose of pericardiectomy (removal of the visceral pericardium) is to improve ventricular contractility; however, the early results and prognosis are still unknown in the surgical treatment of ECP.

Methods Twelve patients who underwent pericardiectomy and evacuation of pericardial fluid for ECP were included. These patients were among a total of 62 (19.2%) patients (50% male, median age 48 years, range 17–72) who underwent pericardiectomy for CP (15.8%) between November 2004 and March 2012. Patient registry information, medical records and hospital archives were systematically reviewed. The underlying aetiology was idiopathic in five patients (41.6%), tuberculosis in four (33%), and malignancy in three (25%). Pre-operatively, all patients were receiving optimal medical therapy for congestive heart failure and non-steroidal anti-inflammatory drugs to decrease the pericardial effusion (Table 1). Diagnosis was made primarily by echocardiography. ECP was diagnosed when widely accepted criteria for CP were met (thickening of parietal or visceral pericardium, asymmetric septal movement, plethored inferior vena cava, and variation in mitral or tricuspid inflow), accompanied by pericardial effusion. All patients met these echocardiographic criteria. Right heart catheterisation (RHC) was performed in eight patients and equalisation of end-diastolic pressures within both ventricles was considered to be definitive for the presence of pericardial constriction. RHC was not performed in four patients; three who presented with acute cardiac tamponade underwent emergency surgery, and one patient had clear evidence of parietal pericardial thickening on transthoracic echocardiography. Operative indications were advanced heart failure (i.e. NYHA class ≥ III) in eight patients (66.6%), acute cardiac tamponade in

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TABLE 1. BASELINE CHARACTERISTICS Variable

TABLE 2. DETAILS OF OPERATIONS PERFORMED

Value (%)

Clinical parameters NYHA class III or IV

9 (75.0)

Jugular venous distension

10 (83.3)

Ascites

9 (75.0)

Hepatomegaly

6 (50.0)

Hypertension

2 (16.7)

Diabetes

4 (33.3)

COPD

2 (16.7)

Creatinine > 1.5 µmol/l

4 (33.3)

Tobacco use

3 (25.0)

Pleural effusion

5 (41.7)

Echocardiography Ejection fraction (%)

Aeti- Clinical status: indication for Patient ology operation

Operation

Pericardiectomy

Advanced heart failure (NYHA IV) unresponsive to medical treatment

Elective

TP + epicardial fragmentation

Heart failure (NYHA III)

Elective

TP + epicardial peeling

MG† Cardiac tamponade – CPR

MG‡ Advanced heart failure (NYHA IV) unresponsive to medical treatment

Cardiac tamponade

Heart failure (NHYA III)

5 (41.7)

Mitral insufficiency

4 (33.3)

Septal bounce

11 (91.6)

Plethora in IVC

10 (83.3)

Pericardial effusion

12 (100) 9 (75)

NYHA: New York Heart Association

three (25%), and decreased effort capacity in one (8.3%) who had a recurrence of pericardial fluid accumulation. Overall, failure of therapeutic pericardiocentesis combined with medical treatment was the indication for surgery in 10 of the 12 patients (Table 2). Therapeutic pericardiocentesis was defined as percutaneous evacuation of the pericardial fluid to relieve cardiac functions. Pre-operatively, 10 patients had undergone at least one previous attempt at therapeutic pericardiocentesis. The procedure was routinely performed under echocardiographic guidance using a 5-F pigtail catheter inserted via the left infrasternal angle. On admission, five patients underwent pericardiocentesis under transthoracic echocardiographic guidance and were referred for surgery because the constriction persisted despite evacuation of the fluid. For the remaining patients, pericardiocentesis was not re-attempted in five patients because the effusion had recurred after previous attempts (two attempts in four patients and one attempt in one patient), and it was not attempted at all in two patients due to multiple, dense septations observed on echocardiography. Pericardiocentesis was always combined with medical therapy, which consisted of oral administration of antiinflammatory agents. The use of corticosteroids was avoided. During surgery, a median sternotomy was made in all patients. Beginning at the ascending aorta and anterolateral portion of the left ventricle, the anteroposterior extent of dissection was extended between the two phrenic nerves and included the superior vena cava–right atrium junction superiorly. The diaphragmatic surface and the inferior vena cava–right atrium junction defined the inferior extent of the excision. The atria and vena cavae were decorticated, if it could be performed without risk of haemorrhage. For most patients, multiple sharp dissections were required to establish a true dissection plane. In some situations, when both layers were thickened without a clear boundary, some areas of fragmented and firm adhesions were left in situ unless ventricular motion was compromised. When ventricular motion was not improved, the thickened visceral pericardium was further

Emergency PP + epicardial fragmentation Elective

Emergency PP + epicardial peeling Elective

TP + epicardial fragmentation

MG§ Advanced heart failure (NYHA IV) unresponsive to medical treatment

Elective

Heart failure (NYHA III)

Elective

TP + epicardial fragmentation

Dyspnea, decreased effort capacity (NYHA II)

Elective

Cardiac tamponade

Heart failure (NYHA III)

Elective

Heart failure (NYHA III)

Elective

60 (51.25–65)

Tricuspid insufficiency

Biatrial dilatation

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Emergency PP + epicardial fragmentation

ID: idiopathic, TB: tuberculosis, MG: malignancy, NYHA: New York Heart Association, HF: heart failure, TP: total pericardiectomy, PP: partial pericardiectomy. † Neoplastic cell invasion without definitive diagnosis, ‡ Pericardial involvement of malignant mesothelioma (epitolid type), § Pericardial involvement of high-grade diffuse β-type cell lymphoma.

divided into smaller fragments by electrocautery (epicardial fragmentation). Total pericardiectomy was defined as wide excision of the anterior pericardium. Pericardiectomy was considered partial if both ventricles could not be decorticated because of dense adhesions.

Statistical analysis All statistical analysis was performed using SPSS version 15.0 software. Continuous variables were defined by the median ± interquartile ranges. Multiple measurements regarding the same parameter were compared using the Friedmann test. Values obtained pre- and postoperatively were compared using the Wilcoxon signed-ranks test. Survival was calculated using the lifetable method. A p-value of less than 0.05 was considered to be statistically significant.

Results Overall, four of 19 (21%) tuberculous patients, three of 10 (30%) malignancy patients, and five of 33 (15%) idiopathic patients had ECP. Nine patients had NYHA class > II symptoms, with the duration of heart failure ranging from two to 15 months (median nine months). All except one patient were admitted for the first time, with duration of symptoms lasting between two and 12 months, with no identifiable cause of disease. The patient who had been admitted previously had undergone pericardiocentesis one month prior to the present admission. In this patient, histopathology revealed non-specific inflammation. Of three patients with cancer, one had a six-year history of diffuse B-type cell lymphoma and one had a five-year history of both gastric lymphoma and pulmonary malignant

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TABLE 3. PRE-OPERATIVE AND INTRA-OPERATIVE DATA Echocardiography AetiPatient ology Age

Presentation

Catheterisation

Operation

ELVS (cm)

ERVS (cm)

EPWS (cm)

mRAP (mmHg)

RVEDP (mmHg)

LVEDP (mmHg)

mPAP (mmHg)

CVP 1 (mmHg)

PCWP 1 (mmHg)

Fluid removed (ml)

CVP 2 PCWP 2 (mmHg) (mmHg)

2.5

2.6

2.8

500

1.2

1.8

1.5

1400

2.8

3.6

2.2

1000

4.1

3.5

2.4

1000

3.2

2.4

4.1

1500

1.8

2.6

2.1

500

1.5

3.6

2.2

750

2.8

3.0

2.1

1500

Dyspnoea

1.8

1.9

1.2

250

2.1

2.4

1.8

1200

3.5

2.2

1.0

600

2.2

2.1

1.2

400

ID: idiopathic, TB: tuberculosis, MG: malignancy, NYHA: New York Heart Association, CT: cardiac tamponade, CP: constrictive pericarditis, ELVS: effusion along left ventricle side, ERVS: effusion along right ventricle side, EPWS: effusion along posterior wall side, mRAP: mean right atrial pressure, RVEDP: right ventricular end-diastolic pressure, LVEDP: left ventricular end-diastolic pressure, mPAP: mean pulmonary artery pressure, CVP 1: central venous pressure before operation, CVP 2: central venous pressure after operation, PCWP 1: pulmonary capillary wedge pressure before operation, PCWP 2: pulmonary capillary wedge pressure after operation. CVP and PCWP measurements were performed using a Swan-Ganz catheter introduced via the internal jugular vein.

mesothelioma. Both these patients had advanced heart failure and were unresponsive to medical treatment. An independent oncologist and lung specialist confirmed that expected lifespan was more than one year for both patients. The remaining patient had malignant cells on pericardial biopsy, indicative of metastatic disease of unknown origin. This patient had emergency surgery. All tuberculous patients had a history of previous pulmonary involvement for a period of one to six years. All patients had documentation of completion of antituberculous treatment prior to admission. Acid-fast bacterial testing was negative pre-operatively on three separate occasions in all study patients. Pre-operative echocardiography demonstrated a thickened parietal or visceral pericardium in 10 patients (83.3%), plethored inferior vena cava in 10 (83.3%), asymmetric septal movement in 11 (91.6%), and variation in mitral inflow in seven (58.3%). Overall, at least two criteria for CP were present, accompanied by varying amounts of pericardial effusion in all patients. The amount of pericardial effusion was slightly higher on the right ventricular side (median 2.5 cm, interquartile range 2.1–3.3) than on the left ventricular side (median 2.3 cm, interquartile range 1.8–3.1 cm) and posterior wall (median 2.1 cm, interquartile range 1.2–2.3 cm). However, this difference was not found to be statistically significant (p = 0.076). Five patients (41.7%) had tricuspid insufficiency, four (33.3%) had mitral insufficiency, and seven (58.8%) had bi-atrial dilatation. The left ventricular systolic function was within normal ranges in all patients (median ejection fraction 60%, interquartile range 51.25–65%). The operation was elective in nine patients and emergency in three patients who presented with acute tamponade. The pericardial effusion consisted of free defibrinated blood in seven patients and was serofibrinated or loculated in the others. Samples of pericardial tissue and fluid were first sent for culture, histopathology and other testing prior to evacuation and volume measurement. Details of the operations performed are given in Table 2. Acute haemorrhage and conversion to urgent cardiopulmonary bypass occurred in one patient. The bleeding was close to the

posterolateral wall of the left ventricle and was treated with multiple pledgeted 4.0 polyprolene sutures. During peeling, minor haemorrhages occurring in the ventricular and right atrial wall were sutured using 5.0 polyprolene sutures. No coronary artery rupture or any additional complications were observed during the operation. Pre-operatively, central venous pressure and pulmonary capillary wedge pressure were both high (median 16.5 mmHg, interquartile range 11.0–27.5; median 20.0 mmHg, interquartile range 16.0–23.5, respectively). Postoperatively, both showed a marked decrease. Central venous pressure decreased in seven patients, increased in two, and was unchanged in three (median 11.0 mmHg, interquartile range 10.0–16.0, p = 0.021). Pulmonary capillary wedge pressure decreased in eight patients and remained unchanged in four (median 15 mmHg, interquartile range 12.5–17.5, p = 0.011) (Table 3). There was no in-hospital mortality. Respiratory distress was the most common postoperative complication, followed by low-cardiac output syndrome and renal failure. Two patients underwent re-operation for bleeding, although no particular site of bleeding was found in either one (Table 4). The follow-up period ranged from three months to nine years (median three years). Overall, five patients (41.6%) died from various causes. The three cancer patients died from disease progression within two years postoperatively, whereas all five tuberculous patients survived to the end of the follow-up period. Cumulative survival was 55.6 ± 1.5% at the end of the two-year follow-up period (when the last death occurred). Seven patients survived with a median follow up of five years (range nine months to eight years) postoperatively (Table 5, Fig. 1).

Discussion Our study emphasises the clinical importance of ECP. Survival after pericardiectomy for ECP was lower than previously reported.13,14 Although ECP has been observed in only a minority of pericarditis patients, we found that it represented a higher proportion in pericardiectomy patients. Moreover, we found that surgery for ECP was associated with substantial morbidity,

306

TABLE 4. OPERATIVE AND POSTOPERATIVE PARAMETERS Operative parameter

9 (75.0)

Time of operation (min)*

90 (90–120)

Ventilation > 8 hours

Date of Pat- Aetiol- opera- Intensive care unit ient ogy tion stay

4 (33.3)

24 hours bleeding (ml)*

2 (16.6)

Fluid removed (ml)*

875 (500–1350)

Transfusion (1 unit of ES)

5 (41.7)

Arrhythmia

3 (25.0)

LCOS

7 (58.3)

ICU stay > 3 days

7 (58.3)

ICU stay > 7 days

3 (25)

Peri-operative mortality

0 (0)

ES: erythrocyte suspension; LCOS: low-cardiac output syndrome; ICU: intensive care unit. *Data represented as medians with interquartile ranges.

Cum survival

without early mortality. Various complications occurred in 41.6% (n = 5) of patients, with more than half the patients having a prolonged intensive care unit stay. Total pericardiectomy, which we defined as peeling the parietal pericardium between the phrenic nerves anteriorly and peeling its diaphragmatic surface inferiorly, was achieved in nine patients. Pericardiectomy was limited (partial) in three patients in whom the decortication border could not satisfactorily be extended through the lateral aspect of the left ventricle because of dense calcific adhesions. Also, fragmented areas of the epicardium had to be left without peeling and could not be included within the decortication border in five patients. Although pre-operative ejection fractions of the patients were within normal ranges, postoperative LCOS was observed in seven patients. High rates of LCOS may partly have been due to structural alterations within the ventricle myocardium, which had developed due to long-lasting constriction during the chronic disease period. However, inadequate decortication of the left ventricle was the most probable reason for the development of high rates of LCOS, but this could not be totally proven. The initial approach should include a thorough clinical evaluation, with pericardiocentesis under echocardiographic guidance, and heart catheterisation available. The existence of persistent high intracardiac pressures, despite evacuation of the effusion, is essential for an accurate diagnosis; ECP was present in only 6.8% of patients undergoing pericardiocentesis in SagristaSauleda and co-workers’ study.2 Effective pericardiocentesis is of therapeutic importance, especially in the setting of pericardial tamponade. 1.0 0.9 0.8 0.7 n = 12

Time (months)

100

Fig. 1. Survival function of the entire group. The ﬁgure displays the survival curve by lifetable analysis. The overall mortality rate was 41.6%. Cumulative survival was 55.6 ± 1.5% at the end of the two-year follow-up period.

Pericardial biopsy

Follow up (months) Outcome

2004

8 days, LCOS, RF, RDS

Non-specific inflammation

4.04

Death from pneumonia + sepsis

2004

1 day, uneventful

Granulomatous inflammation

95.0

NYHA class I

2005

7 days, LCOS, RF, RDS

Neoplastic involvement†

2.9

Death from disease progression

2005

2 days, uneventful

Neoplastic involvement‡

19.7

Death from disease progression

2006

8 days, re-operation Granulomatous for bleeding, RF, RD inflammation

79.9

NYHA class III

2006

6 days, re-operation Non-specific for bleeding, RF, RD inflammation

25.7

Death from advanced HF

2007

2 days, uneventful

Neoplastic involvement§

25.6

Death from disease progression

2007

8 days, LCOS, RD

Non-specific inflammation

66.4

NYHA class II

2007

1 day, uneventful

Non-specific inflammation

62.5

NYHA class I

2008

5 days, low-dose inotrope

Non-specific inflammation

51.3

NYHA class I

2008

2 days, uneventful

Granulomatous inflammation

48.2

NYHA class II

2012

3 days, low-dose inotrope

Non-specific inflammation

8.9

NYHA class II

525 (362.5–837.5)

Re-operation for bleeding

0.5

TABLE 5. RESULTS OF PERICARDIAL TISSUE BIOPSY AND FOLLOW-UP DATA

Value (%)

Complete pericardiectomy

0.6

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ID: idiopathic, TB: tuberculous, MG: malignancy, LCOS: low-cardiac output syndrome, RF: renal failure, RD: respiratory distress, NYHA: New York Heart Association, HF: heart failure. † Neoplastic cell invasion without definitive diagnosis, ‡ Pericardial involvement of malignant mesothelioma (epitolid type), § Pericardial involvement of high-grade diffuse B-type cell lymphoma.

ECP has increasingly become a subject of intense research. Hancock was the first to describe the condition as a particular form of pericardial constriction, which persists despite evacuation of the compressive pericardial effusion.1 Although its prevalence ranged between 2.4 and 14.8%,3 Cameron reported the proportion of ECP to be as high as 24% in patients requiring pericardiectomy.4 The first prospective study by Sagrista-Sauleda and co-workers identified 15 ECP patients among 190 with tamponade over a period of 16 years.2 In this study, an accurate diagnosis of ECP was made with combined pericardiocentesis and cardiac catheterisation. The aetiological spectrum was similar to that reported in previous studies, with a predominance of idiopathic cases. Other less-frequent causes included post-cardiac surgery, tuberculosis, post-radiation and neoplasia. Seven of 15 (46%) patients underwent pericardiectomy within four months after pericardiocentesis and two patients died in the early postoperative period. Patients with cancer were found to have a high mortality and low pericardiectomy rate, whereas patients with idiopathic causes of ECP had a low mortality but high pericardiectomy rate. Also, four of the six survivors ultimately required pericardiectomy.2 We concluded that the development of persistent constriction is frequent in ECP and extensive epicardiectomy is the procedure of choice in patients with persistent heart failure. A recent systematic review by Ntsekhe et al.3 identified a pooled prevalence of 4.5% by applying a random-effects model. The aetiological spectrum was similar to that of previous ECP and CP series, although neoplastic and traumatic cases were excluded from the analysis; 26 ECP patients were identified among 642 subjects derived from five observational studies. The

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series reported by Sagrista-Sauleda et al. was also included in this review with its 11 non-neoplastic patients.2 In our study, pre-operative echocardiography of all ECP patients met the widely accepted criteria for ECP. Cardiac catheterisation was performed without concomitant pericardiocentesis and revealed equalisation of interventricular pressures in eight patients. However, we lacked intra-operative haemodynamic data regarding the effect of the presence and evacuation of pericardial fluid. Histopathology of the pericardial fluid and tissue were consistent with the underlying disease (Table 5). Five patients died during follow up; two of these deaths occurred within the first four months. Similar to previous reports, our patients were unresponsive to pericardiocentesis and subsequent aggressive medical therapy. Although early mortality did not occur, the majority of our patients had a complicated postoperative course. ECP has a relatively long duration of symptoms and failure of repeated pericardiocentesis attempts; therefore, echocardiography should not be seen as a misleading diagnostic tool. The presence of signs consistent with ECP should prompt early surgical intervention, especially in patients with known underlying disease, such as cancer or tuberculosis. The prognosis depends on the underlying disease in cancer patients, whereas patients with idiopathic ECP may respond to subsequent medical treatment after pericardiocentesis. Patients should be closely observed for the recurrence of symptoms; re-accumulation of fluid should be considered as indicative of disease persistence.

307

References 1. 2.

4. 5. 6.

9. 10. 11. 12.

Conclusion

13.

Pericardiectomy for ECP was effective, in terms of our early results, in patients unresponsive to medical therapy. Long-term survival depends on the underlying disease. The decision to delay or not to delay surgery in specific aetiological subgroups should be one of the main considerations for future studies on ECP.

14.

Hancock EW Subacute effusive-constrictive pericarditis. Circulation 1971; 43: 183–192 Sagrista-Sauleda J, Angel J, Sanchez A, Permanyer-Miralda G, Soler– Soler J. Effusive-constrictive pericarditis. N Engl J Med 2004; 350: 469–475. Ntsekhe M, Shey Wiysonge C, Commerford PJ, Mayosi BM. The prevalence and outcome of effusive constrictive pericarditis: a systematic review of the literature. Ntsekhe M, Shey Wiysonge C, Commerford PJ, Mayosi BM. Cardiovasc J Afr 2012; 23: 281–285 Cameron J, Oesterle SN, Baldwin JC, Hancock EW. The etiologic spectrum of constrictive pericarditis. Am Heart J 1987; 113: 354–360. Calvert PA, Bell AD, Lynch. Effusive constrictive pericarditis secondary to undifferentiated pericardial sarcoma. Heart 2006; 92: 1034. Sharma PS, Katechis D. Primary malignant pericardial mesothelioma presenting as effusive-constrictive pericarditis. J Invasive Cardiol 2011; 23: 197–199. Nakayama Y, Ohtani Y, Kobayakawa N, Kobayashi J, Kaneko Y, Aoyagi T. A case of early phase dialysis associated effusive constrictive pericarditis with distinct surgical findings. Int Heart J 2009; 50: 685–691. Harada T, Aoyagi T, Endo Y, et al. Effusive constrictive pericarditis due to rheumatoid arthritis revealed by pericardiocentesis with simultaneous pressure recording – a case report. Angiology 2002; 53: 105–108. Ito M, Tanabe Y, Suzuki K, et al. A case of effusive-constrictive pericarditis after cardiac surgery. Mayo Clin Proc 2001; 76: 555–558. Garg R, Singh A, Chockalingam. Effusive constrictive pericarditis. Congestive Heart Fail 2009; 15: 199–201. Imazio M. Risk of constrictive pericarditis after acute pericarditis. Circulation 2011; 124: 1270–1275. Reuter H, Burgess LJ, Louw VJ, Doubell AF. The management of tuberculous pericardial effusion: experience in 233 consecutive patients. Cardiovasc J S Afr 2007; 18: 20–25. Chowdhury UK, Subramaniam GK, Kumar AS, et al. Pericardiectomy for constrictive pericarditis: a clinical, echocardiographic, and hemodynamic evaluation of two surgical techniques. Ann Thorac Surg 2006; 81: 522–529. Gongora E, Dearani JA, Orszulak TA, et al. Tricuspid regurgitation in patients undergoing pericardiectomy for constrictive pericarditis. Ann Thorac Surg 2008; 85: 163–170.

Cardiovascular congress diary 2013/2014 DATE

CONFERENCE

PLACE

CONTACT DETAILS TO REGISTER

10–12 October

Federation of Infectious Disease Society in South Africa (FIDSSA)

Drakensberg, SA

www.fidssa.co.za

13–16 October

10th international congress on coronary and artery disease from prevention to intervention (ICCAD)

Florence, Italy

www.kenes.com/iccad

Dallas, Texas, USA

http://my.americanheart.org/

www.criticalcare.org.za

OCTOBER 2013

NOVEMBER 2013 16–20 November 86th American Heart Association scientific sessions (AHA) Critical care refresher course 2013

21–24 November 5th international conference of fixed combination in the treatment of Bangkok, Thailand hypertension, dyslipidaemia and diabetes mellitus

www.fixedcombination.com/2013

FEBRUARY 2014 20–23 February

UCT Department of Medicine General Physicians Conference

Cape Town, SA

www.physicians2014.co.za

To advertise your conference/meeting, e-mail details and half-page high-resolution PDF advert to info@clinicscardive.com

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Carotid and popliteal artery intima–media thickness in patients with poor oral hygiene and the association with acute-phase reactants IHSAN SAMI UYAR, MEHMET BESIR AKPINAR, VEYSEL SAHIN, ELIF FILIZ YASA, FEYZI ABACILAR, VOLKAN YURTMAN, FAIK FEVZI OKUR

Abstract Purpose: The aim of this study was to evaluate whether poor oral hygiene is associated with carotid and popliteal arterial intima–media thickness, which is one of the predictors of future progression of sub-clinical atherosclerosis, and highsensitivity C-reactive protein (hsCRP) and fibrinogen levels. Methods: A specialised dentist checked the patients and selected 550 patients during periodontal examinations, according to their oral hygiene. The patients had no history of atherosclerotic disease. Carotid and popliteal artery B-mode ultrasonographic examinations and hsCRP and fibrinogen levels were analysed at baseline and after a mean of 6.2 months. The patients were scored on the DMFT index for the number of decayed (D), missing (M), and filled (F) teeth (T). We also used the Silness-Loe plaque index (SLI) to evaluate oral hygiene and dental plaque. The patients were divided into two groups using the DMFT and SLI criteria. Group I had a DMFT index score from 0 to 3 and SLI index score of 0 or 1. Group II had a DMFT index score from 4 to 28 and SLI index score of 2 or 3. Results: A significant association was observed between dental status, oral hygiene, carotid and popliteal artery intima–media thickness and hsCRP level. Patients with increasing DMFT and SLI scores correlated with increasing carotid artery intima–media thickness. Conclusions: The results clearly showed that chronic poor oral hygiene and tooth loss are related to sub-clinical atherosclerotic changes in the carotid arteries and may be indicative of future progression of atherosclerosis. Keywords: tooth loss, periodontal disease, infection, atherosclerosis Submitted 15/5/13, accepted 19/6/13 Published online 12/8/13 Cardiovasc J Afr 2013; 24: 308–312

www.cvja.co.za

DOI: 10.5830/CVJA-2013-051

Department of Cardiovascular Surgery, Medical Faculty, Sifa University, Izmir, Turkey IHSAN SAMI UYAR, MD, ihsansami@hotmail.com MEHMET BESIR AKPINAR, MD VEYSEL SAHIN, MD FEYZI ABACILAR, MD VOLKAN YURTMAN, MD FAIK FEVZI OKUR, MD

Faculty of Dentistry, Sifa University, Izmir, Turkey ELIF FILIZ YASA, BDS

Cardiovascular diseases (CVDs) have been the most common cause of death and disability in recent decades. It is not true that conventional risk factors for atherosclerosis account for all atherosclerotic entities, and it has been postulated that novel risk factors such as poor oral hygiene and dental or periodontal disease are potentially associated with atherosclerosis.1-3 Several studies have reported a close association between CVDs and poor oral hygiene.4,5 In particular, it has been speculated that chronic inflammation triggered by poor oral hygiene pathophysiologically plays a role in the aetiology of atherosclerosis.6,7 In this study, we investigated whether poorer oral hygiene and/or periodontal disease indicated sub-clinical atherosclerosis and whether there was any relationship between periodontal disease and poor oral hygiene, and carotid–popliteal arterial intima–media thickness, and hsCRP and fibrinogen levels.

Methods In this study, out-patients were evaluated for oral hygiene and dental status at Sifa University Hospital’s School of Dentistry. DMFT index scores, which describe dental status, were obtained by calculating the number of decayed (D), missing (M) and filled (F) teeth (T). We also used the Silness-Loe plaque index (SLI index) to evaluate oral hygiene and dental plaque.1-4 The mean index was calculated after the evaluation of all teeth and surfaces. A specialised dentist checked patients and decided who could join the study. Ultimately, 550 out-patients with chronic poor oral hygiene were included in the study. The patients were divided into two groups using the DMFT and SLI index scores as criteria. Group I had a DMFT index score from 0 to 3, no to mild periodontal disease, a SLI index score of 0 or 1, good to mild oral hygiene (n = 125; mean DMFT 1.1 ± 1.56; mean SLI 0.56 ± 0.32; 74 males, 51 females, mean age 48.75 ± 9.72 years, range 29–78 years). Group II had a DMFT index score from 4 to 28, severe periodontal disease, a SLI index score from 2 to 3, and poor oral hygiene (n = 425; mean DMFT 19.82 ± 6.44; mean SLI 2.76 ± 3.42; 262 males, 163 females, mean age 50.15 ± 9.80 years, range 30–78 years). The mean follow-up time for all patients was 6.2 months (range 4.1–8.6 months). Patients were assessed after diagnosis, post treatment, and six months later. All patients were treated conservatively for two months with systemic antibiotics and local treatment. The carotid and popliteal arteries were examined with B-mode ultrasonography, and a carotid or popliteal arterial intima–media thickness of 1 to 2 mm was considered positive, and of up to 2 mm strongly positive for sub-clinical early atherosclerosis. We also measured hsCRP and fibrinogen levels in the blood. An

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hsCRP level above 3 mg/l and a fibrinogen level above 5 g/l were accepted as significant. The study also enrolled patients with atherosclerotic carotid and/or popliteal artery disease, as defined by the presence of non-stenotic plaques or carotid stenosis to some degree, who were clinically asymptomatic or symptomatic at the time of screening. For a variety of reasons, 135 patients could not finish the study and were excluded from the study. Data was collected from the patients between May 2011 and November 2012. Also excluded from the study were patients with diabetes mellitus, high cholesterol or triglyceride levels, hypertension, angina pectoris, a history of myocardial infarction and stroke, a history of rehabilitation, heart surgery, congestive heart failure, peripheral vascular disease, alcohol use, active malignant disease, or any immunological or known chronic inflammatory condition or were currently smoking. The study was approved by the institutional review board of the University of Sifa, and all patients gave signed, written informed consent before enrollment.

Dental examination In this study, we used the World Health Organisation-approved dental indices to quantify dental disease: DMFT as a measure of dental status and SLI as a measure of oral hygiene and dental plaque. All dental examinations were performed by specifically trained dentists blinded to the patients’ clinical and ultrasound data. Dental examinations took place one week before the initial ultrasound examination. The oral health parameters of all subjects were recorded at the beginning of the study. We evaluated all 28 teeth according to the DMFT index, excluding the third molar teeth from the study. DMFT used dental status and the amount of dental caries in an individual to numerically express the caries prevalence. SLI assessed the state of oral hygiene and dental plaque accumulation by measuring both soft and mineralised deposits at four sites per tooth (mesio-buccal, mid-buccal, disto-buccal and mid-lingual). All periodontal findings were taken using the half-mouth method at all four gingival areas of the tooth and marked with a score from 0 to 3. Dental plaque was scored as: • 0: no plaque • 1: a film of plaque adhering to the free gingival margin and adjacent area of the tooth, which can be seen in samples from the tooth surfaces • 2: moderate accumulation of soft deposits within the gingival pocket or the tooth and gingival margin, which can be seen with the naked eye • 3: abundance of soft matter within the gingival pocket and/or the tooth and gingival margin. In patients who were completely toothless, SLI was obtained from the prosthesis. SLI of 0 and 1 was defined as absent or mild, and 2 to 3 as serious.

Carotid B-mode ultrasonography The carotid and popliteal arterial intima–media thickness and/ or stenosis measurements were performed by experienced radiologists using B-mode ultrasonography. The extracranial carotid arteries were examined bilaterally using a 7.5-MHz linear array transducer (Siemens Antares, Germany). The operators were blinded to the patients’ clinical data and dental status.

309

The patients were in a supine position with their heads turned slightly away from the operator. Measurements were taken in longitudinal and transverse planes on the common carotid artery (CCA) far wall, 1 cm from the bulb, the bifurcation, the internal carotid artery (ICA), external carotid artery (ECA), and popliteal artery. The intima–media thickness was defined as the distance between the leading edges of the lumen–intima echo and media– adventitia echo. Sub-clinical atherosclerosis was defined as mean carotid and/or popliteal artery intima–media thickness of more than 1 mm, as assessed by B-mode ultrasound. The 1-mm cut-off point was chosen because it has clinical and prognostic significance and has been associated with the subsequent development of coronary artery disease. Carotid plaque was defined as a localised intima–media thickening of more than 1 mm, with at least 100% increase in thickness compared with adjacent wall segments. If a plaque occurrence was diagnosed during the examination, it defined early atherosclerosis. Plaques were present if they protruded into the lumen or localised roughness with an increased echogenicity or an area of increased thickness of the intima–media layer. Plaque presence was defined as one plaque in any of the carotid arteries. In order to compensate for the stretching effect of arterial distension secondary to increased arterial pressure on the wall thickness, the patients’ systolic arterial pressures were below 140 mmHg.

Statistical analysis Continuous data are displayed as means with standard deviation. Categorical data are expressed as proportions. Categorical variables were analysed using the chi-squared test or Fisher’s exact test when appropriate. In all studies, p < 0.05 were considered statistically significant.

Results The two groups of patients had similar baseline demographics and clinical characteristics. The mean age of the groups was not significantly different (Table 1). Baseline measurements in group II of the mean carotid and popliteal artery intima–media thickness and mean hsCRP levels were significantly higher than that of group I (p = 0. 001). However, there was no correlation with dental status, oral hygiene and fibrinogen levels (Table 2). The mean DMFT index scores were 1.1 ± 4.56 in group I and 19.82 ± 6.44 in group II, while the mean SLI index scores were 0.56 ± 2.32 and 2.76 ± 3.42, respectively. Figs 1 and 2 depict carotid artery intima–media thickness measured in B-mode ultrasonography. This examination revealed that patients with an intima–media thickness more than 1 mm numbered 15 (12%) in group I, and 349 (82.12%) in group II (Table 2). This proportion was 92% in patients who were toothless. Increasing DMFT and SLI scores were correlated with intima–media thickness of the carotid artery. Intima–media thickness was more than 1 mm in 88% of patients with a DMFT index higher than 20, and in 69% of patients with an SLI index of more than 2, but in only 12% of patients with a DMFT index below 3, and in 6.8% of patients with an SLI score of 0 or 1. Significantly more patients with an intima–media thickness greater than 2 mm had a DMFT index more than 20.

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TABLE 1. DEMOGRAPHIC AND CLINICAL DATA OF THE STUDY PATIENTS Group I, Group II, n = 125 n = 425 (DMFT: 0–3, (DMFT: 4–28, SLI: 0–1) SLI: 2–3) 48.75 ± 9.72 50.15 ± 9.80 74 (59.2) 262 (61.64) 27 ± 4 28 ± 6 136 ± 21 139 ± 24

Parameters p-value Age (mean ± SD) 0.160 Males, n (%) 0.766 0.08 BMI (kg/m2) (mean ± SD) Systolic blood pressure (mmHg) 0.207 (mean ± SD) Diastolic blood pressure (mmHg) 79 ± 12 78 ± 16 0.51 (mean ± SD) Family history, n (%) 23 (18.4%) 85 (20%) 0.713 Fasting plasma glucose (mg/dl) 92 ± 12 94 ± 15 0.172 (mean ± SD) Total cholesterol (mg/dl) 204 ± 28 212 ± 32 0.012 (mean ± SD) Triglycerides (mg/dl) (mean ± SD) 185 ± 18 187 ± 22 0.35 Uric acid (mg/dl) (mean ± SD) 5.1 ± 2.2 5.2 ± 2.6 0.69 DMFT index (mean ± SD) 1.1 ± 4.56 19.82 ± 6.44 0.001 Mean SLI (mean ± SD) 0.56 ± 2.32 2.76 ± 3.42 0.001 Mean CA IMT (mm) (mean ± SD) 0.63 ± 0.1 1.79 ± 0.14 0.001 HsCRP (mg/l) (mean ± SD) 2.8 ± 3.4 4.7 ± 3.8 0,001 Fibrinogen (g/l) (mean ± SD) 2.9 ± 4.2 4.1 ± 4.4 0.06 Mean ± SD; mean ± standard deviation; BMI, body mass index; DMFT, decayed, missing, filled teeth; SLI, Silness-Loe plaque index; CA IMT, carotid artery intima–media thickness; HsCRP, high-sensitivity C-reactive protein.

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TABLE 2. CAROTID AND POPLITEAL ARTERIAL ULTRASOUND RESULTS AND ACUTE-PHASE REACTANT LEVELS IN TWO GROUPS OF PATIENTS

Beginning Carotid intima–media thickness 1–2 mm > 2 mm Popliteal artery 1–2 mm > 2 mm HsCRP (≤ 3 mg/l) Fibrinogen (≤ 5 g/l)

Group I, Group II, n = 125 n = 425 (DMFT: 0–3, (DMFT: 4–28, SLI: 0–1) SLI: 2–3) p-value n (%) n (%) 15 (12) 2 (1.6)

349 (82.12) 76 (17.88)

0.0001 0.0001

9 (7.2) 3 (2.4) 10 (8) 9 (7.2)

238 (56) 183 (43) 391 (92) 36 (8.3)

0.0001 0.0001 0.0001 0.09

After six months Carotid intima–media thickness 1–2 mm 18 (14.4) 369 (86.82) 0.001 > 2 mm 3 (2.4) 204 (48) 0.0001 Popliteal artery 1–2 mm 11 (8.8) 259 (60.94) 0.0001 > 2 mm 3 (2.4) 208 (48.94) 0.0001 HsCRP (≤ 3 mg/l) 5 (4) 315 (74.11) 0.0001 Fibrinogen (≤ 5 g/l) 6 (4.8) 26 (6.11) 0.06 DMFT, decayed, missing, filled teeth; SLI, Silness-Loe plaque index; HsCRP, high-sensitivity C-reactive protein.

The intima–media thickness was greater than 1 mm in 9% of patients with just tooth fillings, significantly lower than the ratio for patients with decayed and missing teeth (p = 0.0001). The number of missing teeth was significantly associated with the baseline degree of carotid artery intima–media thickness. Toothless patients also had a significantly higher baseline degree of thickness (p = 0.007). In group II, patients who were completely toothless (11%) and had a dental prosthesis were included as a separate category in the calculations of the SLI. Analysing these patients, we found that toothless patients had a significantly higher risk for disease progression compared to patients in group I (p = 0.001).

The hsCRP values were significantly higher in group II than in group I both at baseline and after six months (p = 0. 001). The hsCRP levels were higher than 3 mg/l in 8% of patients in group I, and in 92% of patients in group II. The mean levels of fibrinogen were minimally higher in group II than in group I but the difference was not statistically significance (p = 0.06). Both DMFT and SLI indices were significantly associated with hsCRP levels at baseline and the six-month follow up. Among patients who received treatment, the intima–media thickness was similar after six months but the hsCRP and fibrinogen levels were significantly lower (p = 0.001). During a mean of 6.2 months (4.1–8.6 months), no deaths were recorded. During the follow-up period, only three patients

Fig. 1. Carotid artery intima–media thickness measured with B-mode ultrasonography.

Fig. 2. The intima–media thickness is seen in the bifurcation of the carotid artery, measured with B-mode ultrasonography.

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(2.4%) in group I showed progression of carotid artery intima– media thickness. On the other hand, 47 patients (11%) in group II showed progression of carotid artery intima–media thickness. Patients with progressive atherosclerosis had significantly higher DMFT and SLI indices than patients with stable disease. Further analysing the sub-categories of DMFT, six-month follow-up measurements revealed that the number of missing teeth was strongly associated with disease progression (p = 0.001). However the significance of the number of decayed teeth (p = 0.02) and filled teeth (p = 0.09) were not significantly associated with disease progression.

Discussion Cardiovascular disease is a major cause of morbidity and mortality worldwide. In the last 10 years, a rising number of epidemiological investigations have studied the possible association between inflammatory diseases or chronic infections (i.e. periodontal infections) and cardiovascular diseases.8-10 According to these studies, atherosclerosis is considered a process closely related to inflammation. We know that infectious or inflammatory diseases elevate levels of inflammatory markers, and autoimmune processes can contribute to the development of atherosclerosis.8 In addition, several studies published during the last two decades indicate that oral diseases, periodontal inflammation, and especially poor oral hygiene may act as risk factors for the development of atherosclerosis via chronic inflammation.11-13 In particular, chronic microbial infection, including several periodontal pathogens, may play an important role in the development of atherosclerotic disease.6,14,15 It is unclear how periodontal disease causes thickening of the arterial intima–media wall, which is a predictor of sub-clinical atherosclerosis.16,17 It is uncertain whether an immune response to the pathogens or the pathogen itself triggers progression of atherosclerotic disease.4,18 We could confirm that missing and decayed teeth were significantly associated with progression of atherosclerosis rather than filled teeth. Treated caries, where the hsCRP level was low, did not seem to play a major role in promoting atherosclerosis. Infectious, poor oral hygiene, a trigger for systemic inflammation, was previously suggested to correlate with carotid intima–media thickness, which is a surrogate marker of atherosclerosis.2 Elter et al.19 proposed a potential mechanism responsible for vascular dysfunction in the presence of periodontal disease. A study by Tonetti et al.20 concluded that intensive periodontal infection resulted in acute, short-term systemic inflammation and endothelial dysfunction. In addition, periodontal disease has been shown to be a strong predictor of mortality from ischaemic heart disease and diabetic nephropathy in Pima Indians with type 2 diabetes.21 Another study postulated that poor oral hygiene may be an insidious cause of endothelial dysfunction and future cardiovascular events.22

Conclusion The present study has clearly demonstrated a significant relationship between dental diseases, especially tooth loss, and sub-clinical atherosclerosis. We concluded that high DMFT index is associated with increased carotid intima–media wall thickness, and is a marker of early initiation of atherosclerotic lesions. Clinical implications derived from our study are that

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once a dentist diagnoses advanced dental disease or signs of poor oral hygiene, the patient should be referred to an internist for further screening and, if necessary, the treatment of cardiovascular risk factors. To demonstrate an association between inflammation, dental indices, poor oral hygiene and disease progression however, longer-term studies are needed. The mean six-month follow-up period was a limitation in this study. Therefore, we will continue to follow the investigation for two years to observe disease progression. There were other limitations to our study. Pathogen levels or immune responses to the pathogens were not available in our patient population. We could not determine the individual’s propensity to develop inflammatory reaction. Microbial aspects, which have been shown to be more specific than clinical signs of poor oral hygiene, were not evaluated in our study. In addition, the periodontal long-term status was not known. We only investigated clinical measures of dental and periodontal disease.

References 1.

10.

11.

12. 13.

14.

Desvarieux M, Schwahn C, Vo¨Lzke H, et al. Gender differences in the relationship between periodontal disease, tooth loss, and atherosclerosis. Stroke 2004; 35: 2029–2035. Schillinger T, Kluger W, Exner M, et al. Dental and periodontal status and risk for progression of carotid atherosclerosis: the Inflammation and Carotid Artery Risk for Atherosclerosis study dental substudy. Stroke 2006; 37: 2271–2276. Southerland JH, Moss K, Taylor GW, et al. Poor oral hygiene and diabetes associations with measures of atherosclerosis and CHD. Atherosclerosis 2012; 22: 196–201. Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs JR, Papapanou PN. Relationship between periodontal disease, tooth loss, and carotid artery plaque: the Oral Infections and Vascular Disease Epidemiology study (INVEST). Stroke 2003; 34(9): 2120–2125. Holland Z, Ntyintyane L, Gill G, Raal F. Carotid intima–media thickness is a predictor of coronary artery disease in South African black patients. Cardiovasc J Afr 2009; 20(4): 237–239. Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs DR, Sacco RL. Periodontal microbiota and carotid intima–media thickness: the Oral Infections and Vascular Disease Epidemiology study (INVEST). Circulation 2005; 111(5): 576–582. Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, et al. Chronic infections and the risk of carotid atherosclerosis – prospective analysis from a large population study. Circulation 2001; 103: 1064–1070. Larissa Pessoa L, Virgilio Galvão V, Leopoldo Santos L. Periodontal disease as a risk factor for cardiovascular disease: suggestion of a further link in systemic lupus erythematosus. Med Hypoth 2011; 77: 286–289. Cotti E, Dessi C, Piras A, Mercuro G. Can a chronic dental infection be considered a cause of cardiovascular disease? A review of literature. Int J Cardiol 2011; 148: 4–10. Sanz M, D’aiuto F, Deanﬁeld J, Fernandez-Avile F. European workshop in periodontal health and cardiovascular disease. Scientiﬁc evidence on the association between periodontal and cardiovascular diseases: a review of the literature. Eur Heart J 2010; Suppl 12: B3–B12. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima–media thickness: a systematic review and meta-analysis. Circulation 2007; 117: 459–67. Beck JD, Pankow J, Tyroler HA, et al. Dental infections and atherosclerosis. Am Heart J 1999; 138: 528–533. Anilo S, Al-Ghamdi HS. The impact of periodontal infections on systemic diseases. An update for medical practitioners. Saudi Med J 2006; 6: 767–776. Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction:

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the early predictor of atherosclerosis. Cardiovasc J Afr 2012; 23(4): 222–231. 15. Du Plessis A, Malan L, Malan NT. Coping and metabolic syndrome indicators in urban black South African men: the SABPA study. Cardiovasc J Afr 2010; 21(5): 268–273. 16. Schillinger M, Exner M, Mlekusch W, Sabeti S, Amighi J, Rumpold H, et al. Inflammation and Carotid Artery Risk for Atherosclerosis Study (ICARAS). Circulation 2005; 111: 2203–2209. 17. Sabeti S, Exner M, Mlekusch W, Amighi J, Rumpold H, Maurer G, et al. prognostic impact of fibrinogen in carotid atherosclerosis: unspecific indicator of inflammation or independent predictor of disease progression. Stroke 2005; 36: 1400–1404.

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18. Beck JD, Eke P, Heiss G, Madianos P, Couper D, Lin D, et al. Periodontal disease and coronary heart disease: a reappraisal of the exposure. Circulation 2005; 112: 19–24. 19. Elter JR, Hinderliter AL, Offenbacher S, et al. The effects of periodontal therapy on vascular endothelial function: a pilot trial. Am Heart J 2006; 151(1): 47. 20. Tonetti MS, D’aiuto F, Nibali L, et al. Treatment of poor oral hygiene and endothelial function. N Engl J Med 2007; 356(9): 911–920. 21. Saremi A, Nelson RG, Tulloch-Reid M, et al. Periodontal disease and mortality in type 2 diabetes. Diabetes Care 2005; 28: 27–32. 22. Blum A, Kryuger K, Eizenberg MM, et al. Periodontal care may improve endothelial function. Eur J Int Med 2007; 18: 295–298.

CardioVascular Journal of Africa

PROGRAMME LEADERS Dr Landi Lombard

Professor James Ker

Specialist endocrinologist and editor, South African Journal of Diabetes & Vascular Disease

Emeritus professor and professor in charge of education programmes at the University of Pretoria

A UNIQUE E-LEARNING OPPORTUNITY Learning objectives To enable participants to review and understand recent evidence demonstrating the residual risk of macro- and microvascular events that exists in patients with type 2 diabetes, even when their blood pressure is controlled and low-density lipoprotein cholesterol (LDL-C) targets are achieved; and to realise that additional therapeutic interventions are required to address this issue, particularly in those with atherogenic dyslipidaemia (low high-density lipoprotein cholesterol, and raised triglyceride and small, dense LDL-C particle levels).

Needs analysis Patients with type 2 diabetes have a two- to three-fold increased risk of cardiovascular disease compared with non-diabetics at any age. Indeed, about 65% of people with diabetes die as a result of a stroke or other cardiovascular event, such as a myocardial infarction. Microvascular disease is also common in this population and type 2 diabetes is a major cause of blindness, end-stage renal disease and non-traumatic limb amputation. The risk of these events remains high despite effective interventions to control blood pressure and lower LDL-C levels with statin therapy. Recent research has shown that many people with type 2 diabetes have atherogenic dyslipidaemia, which includes low levels of HDL-C as well as raised levels of triglycerides and atherogenic small, dense LDL-C particles. Statins have only limited effects on these elements of dyslipidaemia. However, when the statin is combined with a fibrate, cardiovascular risk can be significantly reduced. Additional fibrate therapy significantly reduces microvascular events, and prevents the risk of blindness, renal disease and peripheral vascular disease, resulting in limb amputation. Clinical trials have confirmed the clinical benefits of this treatment strategy in patients with type 2 diabetes.

ABOUT THIS PROGRAMME This modular and fully accredited education programme offers you opportunities to: • evaluate the importance of residual macro- and microvascular risk in your patients with type 2 diabetes • review discussions on the clinical issues with a distinguished international panel of experts • consider the clinical evidence for enhancing your current treatment strategies in patients with dyslipidaemia and type 2 diabetes. The programme will be available until 1 May 2014 and includes five interrelated modules, which provide an easily accessible but comprehensive review of this important clinical issue.

Each module offers: • a brief educational summary of key learning points • a 10-minute expert discussion (video) • 10 questions for you to obtain three CPD points per module.

website: http://www.cvja.co.za/dream/dream-landing.php

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Tumescentless endovenous radiofrequency ablation with local hypothermia and compression technique KEMAL KORKMAZ, ALİ ÜMİT YENER, HİKMET SELÇUK GEDİK, ALİ BARAN BUDAK, ÖZLEM YENER, SERHAT BAHADIR GENÇ, AYŞE LAFÇI

Abstract Introduction: Modern surgical management of chronic venous insufficiency is possible since the development of catheter-based minimally invasive techniques, including radiofrequency ablation (RFA) and the application of colour Doppler sonography. RFA technology requires the use of tumescent anaesthesia, which prolongs the operating time. Instilling tumescent anaesthesia percutaneously below the saphenous fascia is the steepest part of the learning curve. In our study, we compared operative and postoperative results of tumescentless RFA and RFA with tumescent anaesthesia, to investigate the necessity of tumescent anaesthesia. Methods: A total of 344 patients with Doppler-confirmed great saphenous vein insufficiency underwent RFA between January and December 2012. Patients were divided into two groups according to anaesthetic management. Group 1 consisted of 172 patients: tumescent anaesthesia was given before the ablation procedure, and group 2 contained 172 patients: a local hypothermia and compression technique was used; no tumescent anaesthesia was administered. The visual analogue scale (VAS) was used and ecchymosis scores of the patients were recorded. Clinical examinations were performed at each visit and Doppler ultrasonography was performed in the first and sixth month. Results: Mean ablation time was significantly lower in group 2 compared to group 1 (7.2 vs 18.9 min; p < 0.05). Skin burn and paresthesia did not occur. The immediate occlusion rate was 100% for both groups. No significant difference was found between the groups in terms of VAS and ecchymosis scores. All patients returned to normal activity within two days. The primary closure rate of group 1 was 98.2% and group 2 was 98.8% at six months, and there was no significant difference between the groups (p > 0.05). Conclusion: Eliminating tumescent infusion is a desirable goal. Tumescentless endovenous RFA with local hypothermia and compression technique appears to be safe and

Department of Cardiovascular Surgery, Numune Research and Training Hospital, Ankara, Turkey KEMAL KORKMAZ, MD, kemalkorkmaz44@hotmail.com ALİ ÜMİT YENER, MD HİKMET SELÇUK GEDİK, MD ALİ BARAN BUDAK, MD SERHAT BAHADIR GENÇ, MD

Department of Radiology, Ankara Yuksek Ihtisas Research and Training Hospital, Ankara, Turkey ÖZLEM YENER, MD

Department of Anaesthesiology, Numune Research and Training Hospital, Ankara, Turkey AYŞE LAFÇI, MD

efficacious. Our technique shortens the operation time and prevents patient procedural discomfort. Keywords: radiofrequency ablation, tumescentless, insufficiency of great saphenous vein Submitted 1/6/13, accepted 13/8/13 Cardiovasc J Afr 2013; 24: 313–317

www.cvja.co.za

DOI: 10.5830/CVJA-2013-053

Chronic venous insufficiency (CVI) is a frequent disease affecting approximately 20 to 40% of people in Western society.1 Generally, venous reflux at the great saphenous vein (GSV) and/or saphenofemoral junction (SFJ) is the commonest cause, leading to varicose veins and associated symptoms such as leg pain, itching, fatigue, night cramps and a burning sensation.2,3 In severe cases, swelling, skin changes and venous ulceration may develop. CVI has also been related to thrombophlebitis and pulmonary embolism.4 The GSV ligation and stripping (L/S) operation was the only treatment of choice from 1950 until recently.5 However, it is invasive, has a recurrence rate of approximately 30%, and is not conservative.3,6 Furthermore, Wood et al. reported the rate of cutaneous nerve injury as 27% after L/S.7 Modern surgical management of insufficiency of the GSV is possible because of the development of catheter-based minimally invasive techniques, including radiofrequency ablation (RFA) and the application of colour Doppler sonography (CDS). RFA is an alternative technique to L/S, working by ablating the vein using thermal energy delivered through an RF catheter which is inserted into the target vein under CDS guidence. It has been recognised that RFA reduces postoperative recovery time, postoperative pain, wound-related complications, and enables earlier return to normal activities.8-10 RFA technology requires the use of tumescent anaesthesia before the delivery of thermal energy through the catheter. Tumescent anaesthesia provides a heat sink to prevent the radiation of thermal energy to the surrounding tissues and increases contact between the RF catheter and the vein wall by mechanically reducing the luminal diameter.11,12 However, it prolongs the operation time and can be a source of patient procedural discomfort. Furthermore instilling tumescent anaesthesia percutaneously below the saphenous fascia under CDS guidance is the steepest part of the learning curve. In our study, we compared the operative and postoperative results of tumescentless RFA and RFA with tumescent anaesthesia to investigate the necessity of tumescent anaesthesia.

Methods Patients underwent a physical examination by a vascular surgeon. All the treated patients were symptomatic. Symptoms

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included pain, itching, limb heaviness, cramps, restless leg and distress about cosmetic appearance. CEAP (Clinical, aEtiology, Anatomical and Pathology) class was determined. All the patients’ height and body weights were measured. The body mass index was verified with the following formula: weight (kg)/ height2 (m).13 In all patients, the potential risks and benefits of endovenous radiofrequency ablation therapy were explained, and written informed consent was obtained. Additionally, throughout the study the principles of the Helsinki Declaration were strictly followed. Doppler venous scanning was performed on all patients in order to document the extent and severity of the reflux in the great saphenous vein and to evaluate the deep venous system. Doppler imaging of the patients was performed by Aloka Prosound Alpha 7 (Hitachi Aloka Medical, Japan) using 5- and 7-mHz linear probes. Reflux was determined at the saphenofemoral and saphenopoliteal junctions in the standing position using the Valsalva manoeuvre or manual distal compression with rapid release. Pathological venous reflux was defined as a reverse flow extending for 0.5 seconds or longer. The localisation and severity of the venous reflux and sonographic distribution of the varicose veins were recorded. Other parameters measured using grey-scale ultrasound in the standing position are as follows: • the diameter of the GSV in the SFJ • the diameter of the GSV above the knee • the distance of the GSV from the skin above the knee • the distance of the GSV from the skin in the middle of the thigh • the length of the GSV that was to be ablated. Only patients with documented GSV reflux with Doppler ultrasonography and in CEAP class 2 or above were recruited into the study. Patients were excluded if there was a significant reflux in the deep venous system, small saphenous vein or perforators. Other exclusion criteria included: deep-vein thrombosis, superficial thrombophlebitis, peripheral arterial vascular disease, immobility, pregnant or breast-feeding patients, and previous history of allergy to local anaesthesia. All cases in this study were performed under general anaesthesia using a laryngeal mask combined with either tumescent anaesthesia or a local hypothermia and compression technique. Electrocardiogram, arterial pressure and oxygen saturation of the patients were continously monitored. Induction was achieved with midazolam (0.03 mg/kg), lidocain (1 mg/kg) and propofol (2 mg/kg). Anaesthesia was maintained with 2% sevoflurane. Between January and December 2012 we treated 344 patients in CEAP clinical class 2–6 with endovenous radiofrequency ablation. These patients were divided into two groups according to the anaesthetic management as follows. Group 1: 58 males, 114 females (n = 172). Tumescent anaesthesia was given before the ablation procedure. Group 2: 42 males, 130 females (n = 172). The procedure was performed without tumescent anaesthesia. Local hypothermia and compression technique was used. Patients were placed in the supine position. Prior to performing RFA, Doppler ultrasonography was used to confirm the important parameters, including imaging of the GSV and

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SFJ, perforators, tributaries, and diameter and treatment length, to devise an effective operative plan. A linear 5- or 7-MHz probe was inserted into a sterile cover and using ultrasound guidance, the GSV was cannulated below or just above the knee. Following the introduction of a 0.025inch guidewire into the GSV, a 4- or 5-Fr intraducer sheath was advanced over it. The RFA catheter (ClosureFast radiofrequency ablation catheter, NYSE:COV) was then placed through the sheath, the guidewire was removed and the tip of the catheter was placed 2–3 cm distal to the SFJ, just below the superficial epigastric vein, under ultrasound guidance. Once proper positioning was confirmed with ultrasound, a tumescent anaesthetic solution was instilled percutaneously below the saphenous fascia to surround the vein in group 1 patients. This solution consisted of 500 ml saline, 20 ml 2% prilocaine, 20 ml 8.4% sodium bicarbonate and 0.5 ml epinephrine. In group 2, instead of local tumescent anaesthesia, we used a local hypothermia technique (external compression with ice and dampening the skin with saline (+4°C) in order to prevent skin burn) (Fig. 1). The RF generator (VNUS Medical Technologies) was then activated and delivery of radiofrequency energy was maintained at 120°C. Radiofrequency ablation was performed at a rate of 40 W per 7 cm. During the procedure, in both groups, sufficient pressure was exerted with the ultrasound probe to occlude the SFJ and CFV. Following completion of the procedure, closure of the GSV and patency of the common femoral vein and superficial epigastric vein was checked with Doppler ultrasound. As the last step of the treatment, all varicose veins were removed by phlebectomy in both groups (Figs 2, 3). A compression bandage was wrapped around the treated limb and the patient was encouraged to walk immediately. This remained in place for three hours. The patients wore class II (30–40 mmHg) thigh-high compression stocking continously for the next 24 hours. They then wore the compression stocking only during the day for the next 15 days. The patients were prescribed a non-steroidal anti-inflammatory drug, an antibiotic and a venoactive drug during the postoperative period.

Fig. 1. Local hypothermia and compression technique: external compression with Doppler probe for preventing extension of the thrombus to the deep venous system, and external compression with ice and dampening of the skin with saline (+4°C) in order to prevent skin burn.

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Fig. 2. Phlebectomy incision.

Fig. 3. Varicose veins.

Patients were followed up in the third hour, seventh day, and first and sixth month post-procedure. The patients registered a pain score on a visual analogue scale (VAS) from 0 (no pain) to 10 (worst pain ever). Also the ecchymosis scores of the patients were scaled from 0 (light bruise) to 5 (critical bruise). Clinical examination was performed at each visit and Doppler ultrasonography was performed on the first and sixth months postoperatively. The initial clinical result were assessed, GSV diameters were measured and occlusion of GSV was confirmed with ultrasonography.

A total of 344 patients were treated with endovenous radiofrequency ablation. In group 1, tumescent anaesthesia was given before the ablation procedure while in group 2, a local hypothermia technique was used. The demographic data of the patients are shown in Table 1. There was no significant intergroup differences in terms of age, gender, body weight and height, and body mass index (p > 0.05) No statistically significant difference was found between the groups in the pre-operative grey-scale measurements of GSV,

including diameter of the GSV in the SFJ, the diameter of the GSV above the knee, the distance of the GSV from the skin above the knee, and the length of the GSV that was to be ablated (p > 0.05). However, the distance of the GSV from the skin in the middle of the thigh was shorter in group 1 patients (p = 0.017) (Table 2). Mean ablation time was significantly lower in group 2 compared to group 1 (7.2 vs 18.9 min; p < 0.05). Skin burn and paresthesia did not occur. Immediate occlusion rate was 100% for both groups. All patients returned to normal activity within two days. All patients have reached the six-month follow-up point. We recognised recanalisation in three patients in group 1 and two in group 2 by Doppler ultrasound scanning. The primary closure rate of group 1 was 98.2% and group 2 was 98.8% at six months and there was no significant difference between the groups (p > 0.05). Endovenous heat-induced thrombosis and deep-vein thrombosis were not observed in any of the patients. The patients’ VAS scores were measured in the third hour, seventh day, first month and sixth month (Table 3). We observed there was no statistically significant difference between the pain score for the patients who recieved tumescent anesthesia and the patients on whom a local hypothermia and compression technique was used (p > 0.05). The patients’ ecchymoses scores were measured in the third hour, seventh day, first month and sixth month (Table 4). There was no significant difference between the groups in terms of ecchymoses scores (p > 0.05). At the one-month and six-month Doppler ultrasonography follow up, the diameter of the GSV at the SFJ and above the knee were measured. In both groups, GSV had decreased in diameter but no significant difference was found between the groups (Table 5).

TABLE 1. DEMOGRAPHIC DATA OF THE PATIENTS

TABLE 2. PRE-OPERATIVE GREY-SCALE MEASUREMENTS OF THE GSV

Statistical analysis Data analysis was performed using the SPSS for Windows 11.5 package program. The Shapiro Wilk test was used in order to investigate whether the distribution of continous variables was close to normal. Measurable parameters were expressed as mean ± standard error of the mean. Intergroup comparisons were made with the Student’s t-test or Mann-Whitney U-test, as appropiate, for normally and non-normally distributed data, respectively. Nominal variables were evaluated with Pearson’s chi-square test. A p value < 0.05 was considered statistically significant.

Results

Group 1 (n = 172)

Group 2 (n = 172)

p-value

Age (years)

46.1 ± 10.2

44.0 ± 10.6

0.178

Diameter of GSV above the knee

5.0 (4.0–12.1)

4.8 (4.0–11.9)

Gender (f/m)

114/58

130/42

0.179

Diameter of GSV in SFJ

9.2 (6.2–23.0)

9.2 (4.9–23.0)

0.952

Height (cm)

167.2 ± 7.6

165.4 ± 8.1

0.146

Length of GSV treated

44.0 (30.0–70.0)

42.5 (20.0–64.0)

0.147

Weight (kg)

79.0 ± 10.9

76.5 ± 13.4

0.173

GSV-skin distance above the knee

8.0 (1.3–28.8)

9.2 (1.0–32.2)

0.099

Body mass index (kg/m2)

28.3 ± 3.8

28.0 ± 4.7

0.592

GSV-skin distance mid-thigh

11.3 (2.6–32.5)

14.0 (1.0–34.7)

0.017

Variables

Measurement (cm)

Group 1 (n = 172) Group 2 (n = 172) p-value 0.532

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TABLE 3. POSTOPERATIVE VISUAL ANALOGUE SCALE SCORES OF THE PATIENTS

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TABLE 5. DIAMETER OF GSV AT SFJ AND ABOVE THE KNEE AT ONE-MONTH AND SIX-MONTH DOPPLER ULTRASOUND FOLLOW UP

Postoperative time

Group 1

Group 2

p-value

Group 1

Group 2

p-value

3rd hour

2 (0–7)

2 (0–8)

0.231

1st month above the knee

4.2 (0.0–10.5)

4.2 (2.7–10.5)

0.753

7th day

0 (0–1)

0.189

1st month at SFJ

8.3 (4.7–21.7)

8.4 (4.1–22.1)

0.480

1st month

0 (0–5)

0.5 (0–6)

0.105

6th month above the knee

3.5 (2.4–8.8)

3.7 (2.2–8.1)

0.960

6th month

0 (0–1)

1.000

6th month at SFJ

7.0 (3.8–18)

7.0 (3.8–20.1)

0.971

Discussion Until recently, conventional treatment for insufficiency of the GSV was ligation over the saphenous–femoral arch and stripping of the GSV. However this surgical operation has a long postoperative recovery time, a high incidence of postoperative paresthesias, haematoma formation and pain, a high recurrence rate, and is associated with wound-related complications such as infection.8,9,14,15 Understanding the pathophysiology of venous insufficiency, and technological advancement have enabled minimally invasive methods to be used for ablation of the GSV. RF consists of electric and magnetic waves that transform into thermal energy after contact with tissue.16 The increased luminal temperature induces vein wall contraction via denaturation of the collagen matrix. Various macro- and microscopic changes occur, including endothelial destruction, shortening and thickening of the venous wall and fibrotic sealing of the vessel lumen.16,17 Lohr et al. pointed out that the temperature gradient between the intima and adventitia and duration of the time of heating determines the total injury to the vein wall collagen and subsequently the total shrinkage of the vein wall.11 Earlier studies using first-generation RF devices and catheters17,18 maintained a set point temperature of 90°C and a slow incremental pull-back catheter technique with a speed of 2–3 cm/min. Merchant et al.19 pointed out the importance of the pull-back speed and its effect on the success of the venous closure. They also reported a higher incidence of clot formation, early vessel recanalisation and thermal injury with this technique.19 These issues are not considered to be relevant with the development of the latest generation catheters such as ClosureFast. Kapoor et al. retrospectively analysed the data of 100 patients treated with ClosureFast and showed that the new technique offsets the limitations of previous RF techniques, leads to good venous closure with minimal complications and improves patient comfort.20 This was the reason for us using the latest generation catheter in our study. The ClosureFast catheter treats a 7-cm segment of vein, providing an improved segmental contact with the vessel wall and has a lubricious jacket to ease guidance and decrease the formation of clotting.17 There is a temperature sensor near the catheter tip. The RF generator provides transmural heating of the venous wall and limits heating up of the surrounding tissue by using minimum energy (15–40 W) to reach and maintain a temperature set point of 120°C during the 20-s cycles.11,16 TABLE 4. POSTOPERATIVE ECCHYMOSIS SCORES OF THE PATIENTS Postoperative time

Group 1

Group 2

p-value

3rd hour

0 (0–2)

0 (0–3)

0.405

7th day

0 (0–0)

1.000

1st month

0 (0–0)

1.000

6th month

0 (0–0)

1.000

Diameter of GSV (cm)

Tumescent anaesthesia isolates the GSV from the surrounding soft tissue and by creating a heat sink, it prevents transfer of the thermal effects of intravascular energy to non-target tissues. Furthermore, it mechanically decreases the luminal diameter of the vein to better contact the laser or RF catheters, and drains the blood from inside the lumen to decrease thrombus formation.11,12,21 Merchant et al. showed a reduction in the incidence of paresthesia and rate of skin burn after the use of tumescent infiltration.22 However, it increases the operation time, its placement requires multiple patient needle-sticks, causing brusing, and it is the most difficult part of the learning curve.12 Besides Gibson et al. drew attention to the difficulty of adjusting the correct amount of tumescent solution.23 Technological advances in RF catheters have decreased the risk of pain, bruising and thermal injury to the nerve, muscle or skin. The aim of our study was elimination of tumescent infusion. Avoiding tumescent anaesthesia in group 2 reduced the ablation time significantly, as expected. Most importantly, however, the primary closure rates were similar at six months and no significant difference was found between the groups in terms of VAS and ecchymosis scores, postoperative measured GSV diameters, and the time needed to return to daily activities. The great saphenous nerve is very close to the GSV below the knee. We aimed to avoid nerve injury by performing venous puncture above the knee. With the technological advantages of the ClosureFast catheter, we did not encounter paresthesia in the tumescentless group. Our technique included external compression with ice and dampening of the skin with saline (+4°C), thereby cooling the skin and providing local hypothermia to prevent skin burn. In group 1, we used tumescent anaesthesia. No skin burn was found in either group. RFA of the GSV with a diameter greater than 12 mm has been another controversial issue, especially for first-generation catheters. Manfrini et al. reported that tumescent anaesthesia has a critical role to play in improving venous closure rates by compressing the vein wall into close contact with the catheter.24 Merchant et al. treated 59 limbs with GSV diameters greater than 12 mm and reported an occlusion rate of 96% at six months.22 ClosureFast fits through a 7-Fr sheath, improving the segmental contact with the vessel wall. Proebstle et al. treated 252 GSV with ClosureFast with diameters as large as 18 mm.25 They used tumescent anaesthesia and the primary venous closure rate was 99.6% at six months. Calcagno et al. retrospectively analysed 338 patients and concluded that vein diameter exceeding 12 mm had no effect on closure rate with the ClosureFast catheter, and using tumescent anaesthesia should allow for the succesful treatment of large veins.26 We did not find any reports investigating the effect of ClosureFast without tumescent anaesthesia on vein diameters > 12 mm. The mean diameter of GSV was 9.2 mm but the range

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extended up to 23 mm in both groups. Considering our results, we can claim that tumescentless RFA using a local compression and hypothermia technique was as succesful as RFA using tumescent anaesthesia for GSV diameters exceeding 12 mm. Deep-vein thrombosis after varicose vein surgery is a wellknown risk.27 With the development of special endoluminal catheters, a potential complication of the new techniques was reported: endovenous heat-induced thrombosis (EHIT).28 This can briefly be described as a thrombus extending from the superficial venous system to the deep venous system. In our technique, we externally compress the SFJ with the Doppler probe in order to prevent extension of the thrombus. Marsh et al. performed RFA on 2 470 limbs and identified deepvein thrombosis (DVT) in 17 limbs (0.7%).27 Of these, four were EHIT. Neither EHIT nor DVT was seen in our study, possibly due to keeping the tip of the catheter 2 cm distal to the SFJ and avoidance of the propagation of thrombus by compression of the SFJ.

11. 12.

13.

14. 15.

16.

17.

Conclusion

18.

Eliminating tumescent infusion is a desirable goal. Tumescentless endovenous RFA with a local hypothermia and compression technique appears to be safe and efficacious. Our technique shortens the operating time and prevents patient procedural discomfort.

19.

References Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol 2005; 15(3): 175–184. 2. Weiss RA, Feied CF, Weiss MA. Vein Diagnosis and Treatment: a Comprehensive Approach. New York: McGraw-Hill, 2001. 3. Xenos ES, Bietz G, Minion DJ, Abedi NN, Sorial EE, Karagiorgos N, Endean ED. Endoluminal thermal ablation versus stripping of the saphenous vein: Meta-analysis of recurrence of reflux. Int J Angiol 2009; 18(2): 75–78. 4. Yilmaz S, Ceken K, Alparslan A, Sindel T, Lüleci E. Endovenous laser ablation for saphenous vein insufficiency: immediate and short-term results of our first 60 procedures. Diagn Interv Radiol 2007; 13(3): 156–163. 5. Whiddon LL. Advances in the treatment of superficial venous insufficiency of the lower extremities. Proc Bayl Univ Med Cent 2007; 20(2): 136–139. 6. Teruya TH, Ballard JL. New approaches for the treatment of varicose veins. Surg Clin North Am 2004; 84(5): 1397–417, viii–ix. 7. Wood JJ, Chant H, Laugharne M, Chant T, Mitchell DC. A prospective study of cutaneous nerve injury following long saphenous vein surgery. Eur J Vasc Endovasc Surg 2005; 30(6): 654–658. 8. Glass GM. Neovascularization in recurrence of the varicose greta saphenous vein following transaction. Phlebology 1987; 2: 81–91. 9. Stonebridge PA, Chalmers N, Beggs I, Bradbury AW, Ruckley CV. Recurrent varicose veins: a varicographic analysis leading to a new practical classification. Br J Surg 1995; 82(1): 60–62. 10. Rasmussen LH, Lawaetz M, Bjoern L, Vennits B, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation, radi-

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26.

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28.

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ofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Br J Surg 2011; 98(8): 1079–1087. Lohr J, Kulwicki A. Radiofrequency ablation: evolution of a treatment. Semin Vasc Surg 2010; 23(2): 90–100. Elias S, Raines JK. Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial. Phlebology 2012; 27(2): 67–72. Wilburn SQ, Eijkemans G. Preventing needlestick injuries among healthcare workers: a WHO-ICN collaboration. Int J Occup Envir Health 2004; 10: 451–456. Winterborn RJ, Earnshaw JJ. Crossectomy and great saphenous vein stripping. J Cardiovasc Surg (Torino) 2006; 47(1): 19–33. Leopardi D, Hoggan BL, Fitridge RA, Woodruff PW, Maddern GJ. Systematic review of treatments for varicose veins. Ann Vasc Surg 2009; 23(2): 264–276. García-Madrid C, Pastor Manrique JÓ, Gómez Blasco F, Sala Planell E. [New advances in the treatment of varicose veins: endovenous radiofrequency VNUS Closure®]. Cir Esp 2011; 89(7): 420–426. Zikorus AW, Mirizzi MS. Evaluation of setpoint temperature and pullback speed on vein adventitial temperature during endovenous radiofrequency energy delivery in an in-vitro model. Vasc Endovascular Surg 2004; 38(2): 167–174. Dunn CW, Kabnick LS, Merchant RF, Owens R, Weiss RA. Endovascular radiofrequency obliteration using 90 degrees C for treatment of great saphenous vein. Ann Vasc Surg 2006; 20(5): 625–629. Epub 2006 Jul 25. Merchant RF, Pichot O. Endovenous radiofrequency ablation of superficial and perforator veins. Vasc Surg 2005; 42(3): 502–509. Kapoor A, Kapoor Ai Mahajan G. Endovenous Ablation of Saphenofemoral Insufficiency: Analysis of 100 Patients Using RF Closure Fast Technique. Indian J Surg 2010; 72(6): 458–462. Memetoglu ME, Kurtcan S, Kalkan A, Özel D. Combination technique of tumescent anesthesia during endovenous laser therapy of saphenous vein insufficiency. Interact Cardiovasc Thorac Surg 2010; 11(6): 774–777. Merchant RF, Pichot O, Myers KA. Four-year follow-up on endovascular radiofrequency obliteration of great saphenous reflux. Dermatol Surg 2005; 31(2): 129–134. Gibson KD, Ferris BL, Polissar N, Neradilek B, Pepper D. Endovenous laser treatment of the small [corrected] saphenous vein: efficacy and complications. J Vasc Surg 2007; 45(4): 795–801; discussion 801–803. Manfrini S, Gasbarro V, Danielsson G, Norgren L, Chandler JG, Lennox AF, et al. Endovenous management of saphenous vein reflux. Endovenous Reflux Management Study Group. J Vasc Surg 2000; 32(2): 330–342. Proebstle TM, Vago B, Alm J, Göckeritz O, Lebard C, Pichot O. Treatment of the incompetent great saphenous vein by endovenous radiofrequency powered segmental thermal ablation: first clinical experience. J Vasc Surg 2008; 47(1): 151–156. Calcagno D, Rossi JA, Ha C. Effect of saphenous vein diameter on closure rate with ClosureFAST radiofrequency catheter. Vasc Endovascular Surg 2009; 43(6): 567–570. Marsh P, Price BA, Holdstock J, Harrison C, Whiteley MS. Deep vein thrombosis (DVT) after venous thermoablation techniques: rates of endovenous heat-induced thrombosis (EHIT) and classical DVT after radiofrequency and endovenous laser ablation in a single centre. Eur J Vasc Endovasc Surg 2010; 40(4): 521–527. Mozes G, Kalra M, Carmo M, Swenson L, Gloviczki P. Extension of saphenous thrombus into the femoral vein: a potential complication of new endovenous ablation techniques. J Vasc Surg 2005; 41(1): 130–135.

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Clinical experience of repair of pectus excavatum and carinatum deformities MURAT ONCEL, BEKIR TEZCAN, KAZIM GUROL AKYOL, YÜKSEL DERELI, GÜVEN SADI SUNAM

Abstract Background: We present the results of surgical correction of pectus excavatum (PE) and pectus carinatum (PC) deformities in adults, and also report a new method of sternal support used in surgery for PE deformities. Methods: We present the results of 77 patients between the ages of 10 and 29 years (mean 17) with PE (n = 46) or PC (n = 31) deformities undergoing corrective surgery from 2004 to 2011, using the Ravitch repair method. Symptoms of the patients included chest pain (15%) and tachycardia (8%). Three patients underwent repair of recurrent surgical conditions. Results: All of the patients with dyspnoea with exercise experienced marked improvement at five months post operation. Complications included pneumothorax in 5.1% (n = 4), haemothorax in 2.6% (n = 2), chest discomfort in 57% (n = 44), pleural effusion in 2.6% (n = 2), and sternal hypertrophic scar in 27% (n = 21) of patients. Mean hospitalisation was eight days. Pain was mild and intravenous analgesics were used for a mean of four days. There were no deaths. Results after surgical correction were very good or excellent in 62 patients (80%) at a mean follow up of three years. Three patients had recurrent PE and were repaired with the Nuss procedure. In three patients who underwent the Ravitch procedure, a stainless steel bar was used for sternal support instead of Kirschner wire. Conclusions: Pectus deformities may be repaired with no mortality, low morbidity, very good cosmetic results and improvement in cardiological and respiratory symptoms. Keywords: pectus excavatum, pectus carinatum, modified Ravitch procedure, internal bar Submitted 24/3/13, accepted 4/9/13 Cardiovasc J Afr 2013; 24: 318–321

infancy but adult patients may suffer from poor chest movement in areas of the deformed cartilage, often resulting in serious exercise intolerance. The heart is often displaced to the left chest by the depressed sternum. Posterior displacement of the sternum can produce a deformity of the heart, specifically the anterior of the right ventricle.2 Exercise tolerance is usually improved after operation for PE. Pectus carinatum (PC) is the best recognised and most frequent protrusion deformity of the chest wall.1 PC is usually identified up to the 11th birthday. Mixed deformities have a carinate deformity on one side and a depression or excavatum deformity on the contralateral side. This study aimed to determine the results of surgical correction of PE and PC deformities in adults. We also report a new method of sternal support used in surgery for PE deformities.

Methods Patients between the ages of 10 and 22 years who underwent correction of PE and PC deformities at the Konya State Hospital and Faculty of Medicine, Selcuk University, between January 2004 and December 2010, were reviewed (Figs 1, 2). Indications for the operation included Haller index of 3.25 or greater, abnormal respiratory function test, or concerning findings after cardiological evaluation. Computed tomography (CT) of the chest was used to evaluate the severity of the deformity. The pectus index was calculated as A divided by C, where A is the greatest latero-lateral distance and C is the shortest antero-posterior distance.3 Chest X-ray, ECG, respiratory function tests and CT were routinely performed on all patients before operating (Fig. 3). All patients were examined by cardiological consultation, and

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DOI: 10.5830/CVJA-2013-065

Pectus excavatum (PE) may be as common as one in 300 live births.1 It is usually noticed within the first year of life. Sternal depression becomes much more pronounced in early adolescence during rapid skeletal growth. PE is well tolerated in Department of Thoracic Surgery, Faculty of Medicine, Selcuk University, Konya, Turkey MURAT ONCEL, MD, moncel01@hotmail.com GÜVEN SADI SUNAM, MD

Department of Thoracic Surgery, Konya State Hospital, Konya, Turkey BEKIR TEZCAN, MD KAZIM GUROL AKYOL, MD

Department of Cardiovascular Surgery, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey YÜKSEL DERELI, MD

Fig. 1. A patient with pectus excavatum.

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Fig. 3. Computed tomography of the chest showing the severity of the deformities.

Fig. 2. A patient with pectus carinatum.

ECG evidence of right ventricular strain was noted in 12% of deformities. Echocardiography showed mitral valve prolapse in 7.3% of the patients. The Rawitch repair operative technique was used for all 77 patients. General anaesthesia was given and a Foley catheter was placed in all patients. Intravenous cefazolin (1 g) was administered pre-operatively. A mid-sternal incision was made, and short skin flaps were elevated superiorly and inferiorly using electrocautery. The pectoralis major muscle on each side was then reflected laterally to expose all costal cartilages. The lower costal cartilages are often covered by the rectus muscles. The deformed costal cartilages were bilaterally resected sub-perichondrially for the full length of the deformed segments. After removal of the costal cartilages, the xiphosternal joint was transacted to enable a finger to pass below the sternum through the mediastinum. When the pleural space was opened, a small chest tube was inserted for drainage. A transverse wedge osteotomy was made across the anterior sternum where the sternum angled down to the depressed posterior region. The sternum of the posterior region was fractured at the wedge osteotomy without detachment. Prepared bone or costal cartilage was used to fix the deformity. It was placed in the osteotomy and secured by two transferral monofilament, non-absorbable sutures, and in some cases, a 5-mm stainless steel wire. The perichondrial sheaths were sutured together over the sternal and costal cartilage repair; this is termed plication. Haemostasis was achieved with cautery after a haemovac drain had been placed between the muscle layer and the cartilaginous repair. The skin was closed with absorbable subcuticular sutures. For three patients with very extensive resection of the costal

cartilage, we used stainless steel bars to support the sternum and prevent flail chest, instead of the standard Kirschner wires (Fig. 4). This method provided excellent mechanical stabilisation of the chest. In all 77 patients, the endotracheal tube was removed in the operating room. The chest tube and haemovac drain were routinely removed within 48 hours. Intravenous analgesics were giving for the first three postoperative days and then no narcotic medications thereafter. Intravenous cefazolin was given for five additional days. Three patientsâ&#x20AC;&#x2122; sternal support bar was removed six months later under general anaesthesia.

Results A total of 77 patients underwent repair of PE and PC deformities. Their ages ranged from 10 to 22 years (mean 17 years) (Table 1). The mean duration of the operation was 2.5 hours. Mean hospitalisation time was seven days and all patients returned to work or school about 15 days after the operation. Before the operation, the most frequent symptoms were aesthetic and cosmetic. Physiological disorders were present in 52%, and other symptoms, which were present to varying degrees, were common: dyspnoea occurred in 20%, and a compression type of discomfort in the lower anterior chest or chest pain occurred in 15%. Palpitations and/or tachycardia were experienced by 8%. Exercise-induced wheezing was reported in

Fig. 4. Stainless steel bars were used to support the sternum in three patients with very extensive resection of the costal cartilage.

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TABLE 1. AGE OF PECTUS PATIENTS Age (years) 10–14 14–17 17–22 Total

Number of patients 12 28 37 77

3%, and 2% of patients had an increased frequency of respiratory infections. Three patients had a sternal bar supporting the sternum using a modified Ravitch technique. One patient had Ehler-Danlos syndrome, and in another we removed a large amount of costal cartilage and the patient needed support to stabilise a flail chest. A third needed extra support because he underwent repair of a second recurrence of PE deformities. Each of the 77 patients was contacted by telephone, from three months to three years after the operation. Fifteen patients (19%) could not be located and were lost to follow up. In the remaining 62 patients, repair was judged by the patient to be very good or excellent. Each stated he/she would recommend repair of pectus deformities to other patients. All patients reported marked improvement in exercise tolerance with much less dyspnoea. Most patients were able to participate in exercise such as running, swimming or cycling. All but three patients who had only limited exercise ability before the repair, showed good physical activity six months after the operation. Three patients (3.8%) experienced recurrence, one after PC, and two after PE repair.

Discussion The pathophysiology of congenital pectus deformities is poorly understood. It is generally thought that abnormal cartilage growth results in displacement of the sternum either anteriorly in PC or posteriorly in PE.3 The majority of children and their parents related to cosmesis and public exposure of the body. A significant number of patients, however, presented with easy fatigue, decreased stamina and wheezing during physical activity, pain and palpitations. Physiological testing is often normal, but both the cardiac index and pulmonary function may be affected, particularly with exercise conditions.4 Symptoms of PE and PC are recognised infrequently during early childhood, apart from a child not wanting to go without a shirt while swimming or participating in other athletic or social activities.5 Pectus patients commonly try harder to keep up with their peers, using wider diaphragmatic excursions to compensate for diminished chest wall excursions caused by the PE or PC deformity; however, almost all patients experience a worsening of their symptoms with time. A careful history is important in identifying appropriate operative candidates. Symptoms such as chest pain, palpitations and dyspnoea may indicate underlying cardiac or pulmonary pathology. Inquiring about participation in athletic, physical and social activities provides descriptive information regarding limitations caused by the deformity on cardiopulmonary performance as well as lifestyle.5 The deformity gradually worsens, until skeletal growth is complete in late adolescence, and then changes little throughout adult life. The results of PE repair should be excellent. Peri-operative

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risks must be limited. The most significant complication is a recurrence, which has been described in a large series as occurring in 5–10% of patients.6 A minimal pneumothorax requiring aspiration is infrequent and sometimes needs a thoracostomy tube. Wound infection should be rare with the use of peri-operative antibiotics, especially with protective coverage of the skin during the operative procedure to minimise any contamination by skin flora.4 Many improvements in the technique for surgical correction of PE and PC have evolved during the eight decades since the first repairs were performed. Adults with severe pectus deformities and asymmetric defects are at a greater risk of recurrence after a Nuss procedure. These patients may be better repaired initially with a modified Ravitch repair.7 A modification of the Ravitch technique for pectus repair was originally described in 1949.2 For example, for PE, the surgical technique includes conservative sub-perichondrial resection of the deformed costal cartilages and detachment of the xiphoid process. The initial steps of the PC correction procedure are similar to that for PE. The sternum, however, is not freed of its environment. A length of 3–4 cm is resected from the distal sternum and the xiphoid process is restored in the proper anatomical direction.8 Although the technical aspect of pectus repair is more tedious in adults than in children, postoperative recovery and long-term results have been similar.9 The costal cartilages are usually thicker in adults and occasionally they must be scooped out from the perichondrial sheaths with a rongeur rather than being removed with a small elevator. Minimising injury to the perichondrial sheaths during removal of cartilage segments is considered essential in order to permit maximum cartilage regeneration.10 Placing minor fragments of fresh autologous cartilage into the empty perichondrial sheaths appears to support costal cartilage regeneration and does not increase the risk of infection.11 The Nuss procedure is a minimally invasive technique with a small wound size. The Ravitch procedure provides good correction of pectus deformities. We described here a modification of the Ravitch procedure for PE correction, adding a steel bar under the sternum for support. This procedure has the advantage of preventing postoperative flail chest and mediastinal disorders with severe PE. Placement of the sternal support across the lower anterior chest appears to provide optimal support for the sternum and may reduce late depression of the upper chest.12 In three patients with PE, we noted that placing the bar posterior to the costal cartilages or perichondrial sheaths before attaching it to the appropriate rib on each side elevated the anterolateral chest as well as the sternum to provide optimal cosmetic as well as physiological reconstruction. This technique is used for patients with a higher level of pectus index, who would have developed flail chest with respiratory stress after the postoperative period. It prevents paradoxical respiration, reduces pain, permits early movement, permits deeper inhalation, reduces hospitalisation time and cost, and provides very good long-term results.13 Minimal costal cartilage resection provides more stability to the chest during the early postoperative period and more consistent elevation of the anterior chest lateral to the sternum than when more extensive cartilage excision is performed.3 Furthermore, there is only moderate postoperative pain, few complications, rapid recovery with early discharge, easy return

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to physical activities, and consistently good to excellent results compared to the techniques used previously.14 Repair of pectus deformities is technically easier and is therefore encouraged during childhood. However, for those patients who have not undergone operations as children, repair during the adult years should be considered by the recommended treatment option of MIRPE (minimal invasive repair of pectus excavatum), as described by Dr Nuss.15 MIRPE does not require resection of the cartilage. Firstly the heart and mediastinum are slowly and carefully pushed down by the specific introducer, and the prepared convex steel bar is inserted under the sternum and across the bilateral thoracic incisions. The bar is turned, and the deformed sternum and costal cartilages are then brought into the correct position. The bar is left in place for at least two to three years, depending on the patient and the severity of the deformity. MIRPE is a minimally invasive procedure with shorter operating time, minimal complication rate, short length of hospitalisation and minimal postoperative pain.15 This technique requires neither cartilage incision nor resection.16 However, in Turkey, the bar has not been available in state hospitals, which has limited its adoption. Nowadays, thoracoscopic costal cartilage resection is described for unilateral pectus deformities. This procedure is performed by cutting the anomalous costal cartilages under thoracoscopic imaging, with excellent visibility. The anomalous cartilages are removed with the thoracoscopic view. The anomalous cartilages are identified, and the posterior perichondrium is incised using a hook. Both superior and inferior margins of the cartilage are prepared using a thoracoscopic cautery hook, taking care not to damage the intercostal vessels and nerves.8 During the adolescent years of rapid skeletal growth, both PE and PC deformities almost always become much more severe at a time that coincides with increasing athletic activity. The recognition of symptoms and the recommendation for surgical correction remain controversial, with strongly divergent opinions being expressed regarding whether PE and PC are primarily cosmetic disorders, or if they cause physiological impairment and limitations to the patient.

Conclusion This retrospective clinical study confirms that pectus deformities can be repaired with a low rate of complications and short hospital stay. The improvement in respiratory symptoms, exercise tolerance and endurance, as well as the cosmetic appearance of more than 97% of the patients in this study supports the view that symptomatic patients of all ages should undergo repair, preferably during the pre-adolescent years. Routine use of substernal support with minimal pre-operative testing has provided excellent long-term clinical results at a low cost. The most important aspect of pectus correction is to achieve long-term stability of the sternum and thorax after the removal of large amounts of cartilage and sternal osteotomy.16

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In three cases, use of a sub-sternal steel bar to stabilise the chest proved advantageous compared to the standard Kirschner wire technique. It is secure, reduces the risk of postoperative complications and provides good cosmetic results. Kim et al. reported successful sub-perichondrial resection, sternal osteotomy and pectus bar insertion placed under the depressed sternum after trauma, followed by internal bar rotation for elevation of the chest wall. This case illustrates that a modified Ravitch procedure using a pectus bar may be an alternative for post-traumatic pectus excavatum.17 The authors thank Dr Robert E Kelly (jun) for review of the manuscript and assistance with its preparation.

References 1.

5. 6. 7. 8. 9. 10. 11. 12. 13.

14.

15.

16.

17.

Molik KA, Engum SA, Rescorla FJ, et al. Pectus excavatum repair: experience with standard and minimal invasive techniques. J Pediatr Surg 2001; 36: 324–328. Fonkalsrud EW, Beanes S, Hebra A, Adamson W, Tagge E, Comparison of minimally invasive and modified Ravitch pectus excavatum repair. J Pediatr Surg 2002; 37: 413–417. Haller JA, Kramer SS, Lietman SA. Use of CT scans in selection of patients for pectus excavatum surgery: a preliminary report. J Pediatr Surg 1987; 22: 904–906. Davis JT, Weinstein S. Repair of the pectus deformity: results of the Ravitch approach in the current era. Ann Thorac Surg 2004; 78: 421–416. Lopushinsky SR, Fecteau AH. Pectus deformities: a review of open surgery in the modern era. Semin Pediatr Surg 2008; 17: 201–208. Swanson JW, Colombani PM. Reactive pectus carinatum in patients treated for pectus excavatum. J Pediatr Surg 2008; 43: 1468–1473. Robicsek F, Fokin A. Surgical correction of pectus excavatum and carinatum. J Cardiovasc Surg (Torino) 1999; 40: 725–731. Kuenzler KA, Stolar CJ. Surgical correction of pectus excavatum. Paediatr Respir Rev 2009; 10: 7–11. Luu TD, Kogon BE, Force SD, Mansour KA, Miller DL. Surgery for recurrent pectus deformities. Ann Thorac Surg 2009; 88: 1627–1631. Robicsek F, Watts LT, Fokin AA. Surgical repair of pectus excavatum and carinatum. Semin Thorac Cardiovasc Surg 2009; 21: 64–75. Robicsek F, Watts LT, Fokin AA. Surgical repair of pectus excavatum and carinatum. Semin Thorac Cardiovasc Surg 2009; 21: 64–75. Fonkalsrud EW. Open repair of pectus excavatum with minimal cartilage resection. Ann Surg 2004; 240: 231–235. Fonkalsrud EW. 912 open pectus excavatum repairs: changing trends, lessons learned: one surgeon’s experience. World J Surg 2009; 33: 180–190. Fonkalsrud EW, Mendoza J, Finn PJ, Cooper CB. Recent experience with open repair of pectus excavatum with minimal cartilage resection. Arch Surg 2006; 141: 823–829. Nuss D, Kelly RE Jr, Croitoru DP, Katz ME. A 10-year review of a minimally invasive technique for the correction or pectus excavatum. J Pediatr Surg 1998; 33: 545–552. Varela P, Torre M. Thoracoscopic cartilage resection with partial perichondrium preservation in unilateral pectus carinatum: preliminary results. J Pediatr Surg 2011; 46: 263–266 Kim HK, Choi YH, Shim JH, et al. Modified Ravitch procedure: using a pectus bar for posttraumatic pectus excavatum. Ann Thorac Surg 2007; 84: 647–648

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Alpha lipoic acid attenuates inflammatory response during extracorporeal circulation IHSAN SAMI UYAR, SULEYMAN ONAL, M BESIR AKPINAR, IBAK GONEN, VEYSEL SAHIN, ABDULHADI CIHANGIR UGUZ, OKTAY BURMA

Abstract Aim: Extracorporeal circulation (ECC) of blood during cardiopulmonary surgery has been shown to stimulate various proinflammatory molecules such as cytokines and chemokines. The biochemical oxidation/reduction pathways of a-lipoic acid suggest that it may have antioxidant properties. Methods: In this study we aimed to evaluate only patients with coronary heart disease and those planned for coronary artery bypass graft operation. Blood samples were obtained from the patients before the operation (P1) and one (P2), four (P3), 24 (P4) and 48 hours (P5) after administration of a-lipoic acid (LA). The patients were divided into two groups, control and LA treatment group. Levels of interleukin-6 (IL-6) and -8 (IL-8), complement 3 (C3) and 4 (C4), anti-streptolysin (ASO), C-reactive protein (CRP) and haptoglobin were assessed in the blood samples. Results: Cytokine IL-6 and IL-8 levels were significantly higher after surgery. Compared with the control groups, LA significantly decreased IL-6 and IL-8 levels in a time-dependent manner. CRP levels did not show significant variation in the first three time periods. CRP levels were higher after surgery, especially in the later periods. These results demonstrate that CRP formation depends on cytokine release. C3 and C4 levels were significantly higher after surgery than in the pre-operative period. LA treatment decreased C3 and C4 levels. Therefore, LA administration may be useful for the treatment of diseases and processes where excessive cytokine release could cause oxidative damage. Conclusions: Our findings suggest a possible benefit of using LA during cardiac surgery to reduce cytokine levels.

Department of Cardiothoracic Surgery, Faculty of Medicine, Şifa University, İzmir, Turkey IHSAN SAMI UYAR, MD, ihsansami@hotmail.com M BESIR AKPINAR, MD VEYSEL SAHIN, MD ABDULHADI, MD

Department of Microbiology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey SULEYMAN ONAL, MD

Department of Infectious Diseases, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey IBAK GONEN, MD

Department of Biophysics, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey ABDULHADI CIHANGIR UGUZ, MD

Department of Cardiothoracic Surgery, Faculty of Medicine, Firat University, Elazig, Turkey OKTAY BURMA, MD

Keywords: extracorporeal circulation, systemic inflammatory response, oxidative stress, a-lipoic acid Submitted 2/6/13, accepted 4/9/13 Cardiovasc J Afr 2013; 24: 322–326

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DOI: 10.5830/CVJA-2013-067

Nowadays, extracorporeal circulation (ECC) is commonly employed by surgeons in many cardiac surgical procedures, with the aim of keeping patients’ circulatory parameters at steady levels. ECC is therefore a vital tool for good execution of cardiac surgery. However, ECC is also associated with some disadvantages. The immune system generates a systemic inflammatory response to the artificial surfaces of the ECC circuit.1 ECC-related inflammation can result in adverse effects, including dysfunction of the myocardium, lung, kidney and liver, which may cause multi-organ failure, stroke and significant death rates.2-4 The molecular mechanism of ECC-induced inflammation needs clarification.2 Inflammation is a defensive mechanism of vascularised tissue, which functions as part of the normal host inspection mechanisms to destroy or quarantine both harmful agents and damaged tissue resulting from physiological processes.5 As a result of inflammation, levels of different cytokines either rise or fall. These changes in cytokine levels and activation of the complement system are well-known parameters used in the laboratory to determine the inflammatory response. α-Lipoic acid (LA) is an essential antioxidant that plays a crucial role in the mitochondrial respiratory pathway, including dehydrogenase reactions. It acts with reactive oxygen species (ROS) such as hydroxyl, peroxyl and superoxide radicals and also protects the cellular membrane structure by interacting with glutathione (GSH), which is the preferred substrate of vitamin E.6,7 The biochemical oxidation/reduction pathways of LA suggest that it may have potent antioxidant properties. Cardiopulmonary bypass (CPB) -triggered systemic inﬂammatory response is associated with increased cytokine levels, namely interleukin-6 (IL-6) and interleukin-8 (IL-8). These cytokines may be responsible for many undesirable sequelae associated with CPB.8 The main target of our current study was to investigate whether LA administration could modulate the ECC-triggered inflammatory response during ex vivo ECC. Standard procedures were used and 1 200 mg LA was administered into the ECC circuit. The effects of LA on IL-6, IL-8, ASO, CRP and haptoglobulin release were investigated.

Methods The study protocol was approved by the ethics committee of the Faculty of Medicine, Firat University, and it adheres to

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the Declaration of Helsinki. Individuals were informed about the aims, procedures and possible risks of the study and gave informed, written approval. Inclusion criteria were clinically diagnosed coronary artery disease requiring coronary artery bypass operation (CABG), age between 41 and 70 years and body mass index > 25 kg/m2. Thirty patients with coronary artery disease undergoing CABG were included in this study. Patients were randomly divided into two groups, the control and LA treatment group. Data obtained from 15 patients who were operated on in the standard manner were evaluated in the control group (n = 15; eight males, seven females; mean age 63.43 ± 6.12 years, range 41–69 years). During the same dates, another 15 patients who had undergone coronary bypass surgery and received LA in the prime solution of the cardiopulmonary bypass were evaluated within the LA group (n = 15; seven males, eight females; mean age 61.16 ± 4.72 years, range 42–70 years). Blood samples (10 ml) were taken 24 hours before (P1), and one (P2), four (P3), 24 (P4) and 48 hours (P5) after the operation. Five blood samples were taken from each patient by venipuncture. The mean follow-up time for all patients was 24 ± 9.4 months (range 12–48 months). Patients were followed postoperatively after the first month, and then every six months. Levels of IL-6 and IL-8 were evaluated by enzyme-linked immunosorbent assay (ELISA) using PeliKine compact human ELISA (Amsterdam, Netherlands) kits according to the manufactuter’s instructions. Results are presented in pg/ml. C3 and C4 levels in the serum were analysed nephelometrically with Dade Behring C3 and Dade Behring C4 kits (Marburg, Germany) using a Behring nephelometer 100 (Illinois, USA). Results are presented in g/l. C-reactive protein (CRP) and anti-streptolysin O (ASO) levels were analysed with the Schiapparelli biosystems (Columbia, USA) turbidimetric method. Results are presented in IU/ml for ASO and mg/l for CRP as described elsewhere.9 Haptoglobin levels were evaluated with the Space Schiapparelli Inc (Columbia, USA) turbidimetric method, and results are given in g/l.

Statistical significance was analysed using the SPSS program (SPSS, 10.0; Inc, Chicago, IL, USA). To compare the difference between groups, statistical significance was calculated by the Mann–Whitney U-test with Spearman rank order correlation test. A p-value lower than 0.05 was defined to indicate statistically significant differences. Since the ECC circuit causes haemodilution, correction was done according to the haematocrit for concentrations of cytokines obtained by the ELISA method. A correction factor for the haematocrit was calculated by dividing the baseline haematocrit by the haematocrit values measured at the sampling time points during ECC.10 Values were multiplied by this factor to adjust for haemodilution.

Results

Data are expressed as means ± SEM of the numbers of analyses.

To examine the effect of LA on synthesis of IL-6, IL-8, C3, C4, ASO, CRP and haptoglobulin, LA was introduced into the ECC and blood samples were drawn before and after CPB at different time periods (Figs 1–5). As shown in Fig. 1A, IL-6 levels initially increased and then decreased after LA administration. There was a detectable cytokine release after one hour of surgery, with the maximum effect obtained after one hour of ECC (p < 0.05). Thereafter IL-6 levels decreased in a time-dependent manner, compared with the controls and samples taken before surgery. Therefore, treatment with LA caused reduced IL-6 levels, compared with controls. Similarly, LA decreased IL-8 levels significantly (p < 0.05), compared with the controls (Fig. 1B). IL-8 levels were highest in the P3 period. C3 levels were high pre-operatively. LA administration decreased C3 levels in the post-operative period compared to P1 (Fig. 2A). The effect of LA was clearly seen in C4 levels (Fig. 2B), which were lower in P2, P3, P4, P5 samples than in P1 (p < 0.05). CRP levels did not show any significant change in the first three time periods (Fig. 3). Interleukin release was associated with CRP levels. After interleukins were released, CRP was synthesised and increased significantly in the P4 and P5 periods (p < 0.05).

Statistical analysis

IL-6 (pg/ml)

100

80 60

20 0

100

Time periods Control

IL-8 (pg/ml)

120

60 40

Time periods LA

Control

Fig. 1. ECC with LA administration had a significant effect on Il-6 (A) and Il-8 (B) release. Mean values of all baseline samples were transformed to 100% and data measured during ECC are given in relation to the adjusted baseline value in each treatment group. *p < 0.05 indicates statistical significance versus the respective baseline value in each group. # p < 0.05 indicates statistical significance between the two groups at each time point.

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2.0

C3 (g/l)

1.5 1.0

# *

* *

0.5 0.0

# *

0.4

0.5

0.3

C4 (g/l)

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0.2

0.0

Time periods Control

0.1

Time periods LA

Control

Fig. 2. ECC with LA treatment had a significant effect on activation of C3 (A) and C4 (B) release. *p < 0.05 indicates statistical significance versus the respective baseline value in each group. #p < 0.05 indicates statistical significance between the two groups at each time point.

Discussion The main purpose of the current study was to investigate the preventive effects of LA on ECC-triggered inflammatory events. We systematically investigated the generation of pro-inflammatory cytokines IL-6 and IL-8, and ASO, CRP and haptoglobulin after ECC. Recent studies on inflammatory reactions occurring during and after CPB have improved our understanding of the contribution of inflammatory pathways to disease. Our results clearly demonstrate that ECC triggered a pro-inflammatory cytokine release during CPB, which was significantly inhibited by LA administration into the ECC circuit. Warren et al. found that contact of the patient’s blood with the artificial surfaces of the ECC circuit triggered a systemic inflammatory response related to increased secretion of IL-1β, IL-6 and IL-8.4 The inflammatory response is associated with the production of reactive oxygen species (ROS). The primary source of ROS during ECC is thought to be neutrophil granulocytes,11 which also release enzymes. ECC activates neutrophil

180 160 CRP (mg/l)

140

120

3.0

* *

100

2.0 1.5

1.0

Time periods Control

0.0

* *

0.5

20 0

2.5

Haptoglobulin (g/l)

200

granulocytes,12 which then trigger an inflammatory response with complement activation after cytokine release. This may stimulate further cardiac injury.13 The activation of neutrophil granulocytes may occur following complement activation by both immunological or non-immunological (heparin-protamine, endotoxin) pathways.14 Up-regulation of adhesion molecules may be stimulated by cytokines on the cardiac cells, which allow neutrophil granulocytes to discharge ROS products.15 More recently, Salinthone et al. have shown that LA displays a non-redox anti-inflammatory role16 by moderating a diverse range of signaling cascades, which mediate these processes. Moreover, LA induces the production of the immunomodulator cAMP in human inflammatory cells by activating the prostaglandin E2 (PGE2), EP2 and EP4 receptors.17 In addition, in Wang and co-workers’ ECC model for CPB, the myocardium produced inflammatory mediators and ROS during ischaemia–reperfusion, which would contribute to cardiac functional reduction and apoptosis.18 Similarly, Sawa et al. reported that cardiac myocytes exposed

Time periods LA

Fig. 3. C-reactive protein (CRP) in serum analysed using a turbidimetric method. *p < 0.05 indicates statistical significance versus the respective baseline value in each group. #p < 0.05 indicates statistical significance between the two groups at each time point.

Control

Fig. 4. Haptogloubulin levels in the serum were analysed using a turbidimetric method. *p < 0.05 indicates statistical significance versus the respective baseline value in each group. #p < 0.05 indicates statistical significance between the two groups at each time point.

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200 ASO (IU/ml)

150

# * *

100

# *

50 0

Time periods Control

Fig. 5. Anti-streptolysin (ASO) levels in serum were analysed using a turbidimetric method. *p < 0.05 indicates statistical significance versus the respective baseline value in each group. #p < 0.05 indicates statistical significance between the two groups at each time point.

to ischaemia–reperfusion were shown to produce IL-6 in several experimental models.19 In order to improve clinical outcomes in open-heart surgery with CPB, oxidative stress should be prevented by decreasing reperfusion injury and inflammation. Despite improvements in surgical techniques, inflammation continues to be an important problem during these procedures. Wan et al. have shown that CPB may induce complement or leukocyte activation, endotoxin release, the expression of adhesion molecules, and the release of inflammatory mediators.2 Moreover, the heart itself is a major source of inflammatory mediators and oxygen-derived free radical species that are likely to contribute to the impairment of cardiac pump function.20 LA administration has been shown to be advantageous in a number of oxidative stress models such as ischaemia– reperfusion injury, diabetes and cataract formation. In the present study, the beneficial effects of LA were manifested by statistically significant decreases in plasma IL-6, IL-8, C3, C4, CRP and haptoglobulin levels. LA decreased levels of IL-6 in the P2, P3 and P4 periods and decreased levels of IL-8 in the P2 and P3 periods. When compared with the controls, LA significantly decreased IL-6 and IL-8 synthesis in a time-depended manner. LA may act as extra- and intracellular redox signaling couples and a powerful free radical scavenger, suggesting that LA has a possible therapeutic agent in surgeries where ECC is used.21 Similarly, Steinberg et al. reported that IL-6 levels increased after protamine administration and reached a maximum level three hours after bypass. At 24 hours after bypass, IL-6 levels remained above the levels measured at initiation. Our results showed that IL-6 levels in both groups were above the P1 levels at P2, P3 and P4. It has been previously reported that LA was able to increase intracellular GSH levels, which is the most abundant cellular antioxidant, by acting as a buffer system for the thiol redox state.6,22 Nowadays, there is strong evidence that LA is one of the modifiers of critical protein thiolates and therefore may influence the pathways of thiol redox state.23,24 Furthermore, GSH is implicated in the recycling of antioxidant vitamins such as vitamins E and C, which participate in modulating the activity of superoxide dismutase enzyme. Currently, there is mounting evidence that LA increases the levels of the cellular antioxidant enzyme GSH by acting as a

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transcriptional inducer of genes governing GSH synthesis.25 Glutathione peroxidase (GSH-Px) and GSH act as antioxidant molecules and have protective effects against reactive oxygenderived molecule-triggered degeneration. GSH is one of the most important antioxidant molecules for removing lipid hydroperoxides and hydrogen peroxide.26,27 It is one of the precursors for catalysing hydrogen peroxide to water. The two major sources of intracellular ROS production are mitochondria and the plasma membrane-bound multicomponent enzyme complex NADPH oxidase.28 Kagan et al. also mentioned that LA interacts with NADPH or NADH-dependent electron transport chains to recycle vitamin E.29 LA is well known as an inhibitor of nuclear factor (NF-kβ).7 LA decreases TNF-αinduced NF-kβ activation and the expression of adhesion molecules in endothelial cells, and thereby it may reduce the inflammatory response.25,30,31 In inflammatory diseases, membrane damage appears frequently in cells that incite lipid peroxidation and disturbances in membrane structure.32 When lipid peroxides aggregate to a certain level, they leak from the cells into the blood and increase lipid peroxidation in the blood plasma. Melek et al. determined increased levels of CRP during ECC.33 CRP is one of the indicators of inflammation activated by cytokines in the liver. In our study, the levels of CRP increased in the P4 period, following IL-6 and IL-8 increase. This demonstrated that CRP activation is depended on LA synthesis. These changes are also considered to be a consequence of imbalance between oxidant products and antioxidant defense mechanisms. This kind of systemic inflammatory response to CPB has the potential of bringing about clinical and cellular disorders. Maulik et al.34 demonstrated that oxidative stress triggered apoptosis in re-perfused hearts in swine. This relatively unknown anti-inflammatory effect of LA may contribute to the inhibition of ECC-induced inflammation in vivo and reduce ECC-related adverse effects.

Conclusion ECC is an important innovation in CPB, but its safety is not guaranteed due to the inflammatory reaction generated by ECC.35,36 Systemic inflammatory reactions cause serious complications, which may affect postoperative mortality in cardiac surgery patients. Therefore the originality of our findings and the potential benefits of using LA during cardiac surgery could be useful.37,38 Future research will be directed at finding the unique pharmacological and biological agents or their combinations, which may effectively reduce ECC-caused inflammatory responses. An appropriate strategy to inhibit ECC-triggered inflammation could be beneficial for patients undergoing cardiac surgery using ECC.

References 1.

Schmid E, Krajewski S, Bachmann D, et al. The volatile anesthetic sevoflurane inhibits activation of neutrophil granulocytes during simulated extracorporeal circulation. Int Immunopharmacol 2012; 14: 202–208. Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: Mechanisms involved and possible therapeutic strategies. Chest 1997; 112: 676–692. Edmunds LH,Jr. Inflammatory response to cardiopulmonary bypass.

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6. 7.

10.

11.

12.

13.

14. 15.

16.

17.

18.

19.

20.

21.

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Ann Thorac Surg 1998; 66: S12, 6; discussion S25–28. Warren OJ, Smith AJ, Alexiou C, et al. The inflammatory response to cardiopulmonary bypass: Part 1--mechanisms of pathogenesis. J Cardiothorac Vasc Anesth 2009; 23: 223–231. Marcus AJ. Thrombosis and inflammation as multicellular processes: Significance of cell-cell interactions. Semin Hematol 1994; 31: 261–269. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 1997; 22: 359–378. Packer L. Alpha-lipoic acid: A metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev 1998; 30: 245–275. Yilmaz M, Ener S, Akalin H, et al. Effect of low-dose methyl prednisolone on serum cytokine levels following extracorporeal circulation. Perfusion 1999; 14: 201–206. Wei TQ, Kramer S, Chu VP, et al. An improved automated immunoassay for C-reactive protein on the dimension clinical chemistry system. J Autom Methods Manag Chem 2000; 22: 125–131. Wendel HP, Philipp A, Weber N, et al. Oxygenator thrombosis: Worst case after development of an abnormal pressure gradient--incidence and pathway. Perfusion 2001; 16: 271–278. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 2004; 61: 481–497. Petzelbauer P, Zacharowski PA, Miyazaki Y, et al. The fibrin-derived peptide Bbeta15-42 protects the myocardium against ischemia-reperfusion injury. Nat Med 2005; 11: 298–304. Franke A, Lante W, Fackeldey V, et al. Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: Is what we see what we know? Eur J Cardiothorac Surg 2005; 28: 569–575. Wu CC, Sytwu HK, Lin YF. Cytokines in diabetic nephropathy. Adv Clin Chem 2012; 56: 55–74. Ren G, Dewald O, Frangogiannis NG. Inflammatory mechanisms in myocardial infarction. Curr Drug Targets Inflamm Allergy 2003; 2: 242–256. Salinthone S, Schillace RV, Marracci GH, et al. Lipoic acid stimulates cAMP production via the EP2 and EP4 prostanoid receptors and inhibits IFN gamma synthesis and cellular cytotoxicity in NK cells. J Neuroimmunol 2008; 199: 46–55. Schillace RV, Pisenti N, Pattamanuch N, et al. Lipoic acid stimulates cAMP production in T lymphocytes and NK cells. Biochem Biophys Res Commun 2007; 354: 259–264. Wang M, Baker L, Tsai BM, et al. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 2005; 288: E321–326. Sawa Y, Ichikawa H, Kagisaki K, et al. Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium. J Thorac Cardiovasc Surg 1998; 116: 511–517. Suleiman MS, Zacharowski K, Angelini GD. Inflammatory response and cardioprotection during open-heart surgery: The importance of anaesthetics. Br J Pharmacol 2008; 153: 21–33. Hussein A, Ahmed AA, Shouman SA, et al. Ameliorating effect of DL-alpha-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals. Drug Discov Ther 2012; 6: 147–156. Aly HA, Lightfoot DA, El-Shemy HA, et al. Modulatory role of lipoic acid on lipopolysaccharide-induced oxidative stress in adult rat sertoli

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cells in vitro. Chem Biol Interact 2009; 182: 112–118. 23. Steinberg BM, Grossi EA, Schwartz DS, et al. Heparin bonding of bypass circuits reduces cytokine release during cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 525–529. 24. Nakashima I, Kato M, Akhand AA, et al. Redox-linked signal transduction pathways for protein tyrosine kinase activation. Antioxid Redox Signal 2002; 4: 517–531. 25. Zhang WJ, Frei B. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J 2001; 15: 2423–2432. 26. Ozkaya MO, Naziroglu M. Multivitamin and mineral supplementation modulates oxidative stress and antioxidant vitamin levels in serum and follicular fluid of women undergoing in vitro fertilization. Fertil Steril 2010; 94: 2465–2466. 27. Ozkaya D, Naziroglu M, Armagan A, et al. Dietary vitamin C and E modulates oxidative stress induced-kidney and lens injury in diabetic aged male rats through modulating glucose homeostasis and antioxidant systems. Cell Biochem Funct 2011; 29: 287–293. 28. Infanger DW, Sharma RV, Davisson RL. NADPH oxidases of the brain: Distribution, regulation, and function. Antioxid Redox Signal 2006; 8: 1583–1596. 29. Kagan VE, Shvedova A, Serbinova E, et al. Dihydrolipoic acid – a universal antioxidant both in the membrane and in the aqueous phase. reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem Pharmacol 1992; 44: 1637–1649. 30. Bogani P, Canavesi M, Hagen TM, et al. Thiol supplementation inhibits metalloproteinase activity independent of glutathione status. Biochem Biophys Res Commun 2007; 363: 651–655. 31. Petersen Shay K, Moreau RF, Smith EJ, et al. Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity. IUBMB Life 2008; 60: 362–367. 32. Naziroglu M, Kilinc F, Uguz AC, et al. Oral vitamin C and E combination modulates blood lipid peroxidation and antioxidant vitamin levels in maximal exercising basketball players. Cell Biochem Funct 2010; 28: 300–305. 33. Melek FE, Baroncini LA, Repka JC, et al. Oxidative stress and inflammatory response increase during coronary artery bypass grafting with extracorporeal circulation. Rev Bras Cir Cardiovasc 2012; 27: 61–65. 34. Maulik N, Yoshida T. Oxidative stress developed during open heart surgery induces apoptosis: Reduction of apoptotic cell death by ebselen, a glutathione peroxidase mimic. J Cardiovasc Pharmacol 2000; 36: 601–608. 35. Nee L, Giorgi R, Garibaldi V, et al. Ischemia-modified albumin and adenosine plasma concentrations are associated with severe systemic inflammatory response syndrome after cardiopulmonary bypass. J Crit Care 2013; 13: 57–59. 36. Chen TT, Jiandong-Liu, Wang G, et al. Combined treatment of ulinastatin and tranexamic acid provides beneficial effects by inhibiting inflammatory and fibrinolytic response in patients undergoing heart valve replacement surgery. Heart Surg Forum 2013; 16(1): E38–47. 37. Kallel S, Jmel W, Jarraya A, et al. The role of procalcitonin and N-terminal pro-B-type natriuretic peptide in predicting outcome after cardiac surgery. Perfusion 2012; 27(6): 504–511. 38. Wang S, Palanzo D, Ündar A. Current ultrafiltration techniques before, during and after pediatric cardiopulmonary bypass procedures. Perfusion 2012; 27(5): 438–446.

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William Nelson ECG quiz Question This is the ECG of a 54-year-old woman. What are your observations?

Is there a conduction abnormality or any evidence of MI?

Answer What happened to the MI?

Here is an interesting sequence of tracings that may provide a modicum of humility! The top one is abnormal showing generalised T-wave flattening and a long QT interval… ho-hum … The bottom one shows that the QRS duration has increased and the tiny Q waves in leads I and AVL are no longer present – the pattern of incomplete LBBB. The QT remains prolonged and now the R waves in VI3 have vanished… new anterior MI? The tracing below is the next day. The incomplete LBBB has resolved and the R waves have returned, removing concern about the anterior infarction. Explanation: normally left-to-right septal activation results in an initial vector that is directed anteriorly and is dependent on the integrity of the left bundle branch. In the presence of incomplete LBBB, this wave front can change direction and proceed from right to left (anterior to posterior), removing the R waves that should be present in V1, 2, 3. If you anticipated this possibility, you will be awarded a gold star …if not, stay alert.

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Reviewers With great appreciation, the Cardiovascular Journal of Africa extends thanks to those reviewers who have contributed their time and expertise during the course of this year. Sejran Abdushi, Serbia and Montenegro M Abelson, South Africa Gurkan Acar, Turkey Adedeji Adebayo, Nigeria Peter Adeoye, Nigeria Anicet Adoubi, Ivory Coast Temilola Akande, Nigeria Ahmet Akcay, Turkey Nermin Akdemir, Turkey Cagdas Akgullu, Turkey Adeseye Akintunde, Nigeria Ersin Akpinar, Turkey Ibrahim Faruk Akturk, Turkey Chizindu Alikor, South Africa El Fatih Alsamani, Sudan Munir Alsuwaimel, Saudi Arabia Burak Altun, Turkey Basri Amasyali, Turkey Adeola Animasahun, Nigeria Victor Ansa, Nigeria Akif Ãœndar, United States Ejikeme Arodiwe, Nigeria Mehmet Ates, Turkey Azman Ates, Turkey Ganesh Athappan, United States Paschal Awah, United Kingdom Abolade Awotedu, United States Fatih Aygun, Turkey Ahmet Aykan, Turkey Olugbenga Ayodele, Nigeria Mustafa Ãzbaran, Turkey Fahad Aziz, United States Turgut Ãzkan, Turkey Fatimata Ba, Senegal Madhu Badireddy, United States Eric Balti, Cameroon Osman Baspinar, Turkey Tahir Bezgin, Turkey Lori Blauwet, United States Cengiz Bolcal, Turkey Aimee Bonny, Cameroon Francisco R Breijo-Marquez, Spain Onursal Bugra, Turkey Gene Bukhman, United States Huseyin Cakmak, Turkey Jasmin Caluk, Bosnia and Herzegovina Alp Burak Catakoglu, Turkey Atac Celik, Botswana Mustafa Cetin, Turkey Parag Chevli, United States Ashley Chin, South Africa Hyunmin Choi, Korea Solomon Choma, South Africa Simeon-Pierre Choukem, Cameroon Antoinette Cilliers, South Africa Pat Commerford, South Africa Valery Corfield, United States Gholamreza Davoodi, Iran Vida Demarin, Botswana Daneel Dietrich, South Africa Adem Älkay Diken, Turkey Georgios Dimitrakakis, United Kingdom Pawel Dimitrow, Poland Suat Doganci, Turkey Eugene du Toit, Australia

Miranda Durand, Canada Ahmet Baris Durukan, Turkey Simanta Dutta, United States Anastase Dzudie, Cameroon Ashraf Eissa, Australia Emmanuel Ejim, Botswana Chijioke Enweluzo, United States Bilgehan Erkut, Turkey M Faadiel Essop, South Africa Mieke Faber, South Africa Ayodele Falase, Nigeria Oluranti Familoni, Nigeria Bora Farsak, Turkey Seyed-Mohammad Fereshtehnejad, Iran James D Fett, United States Marcus Fokou, Cameroon Carla Fourie, South Africa Binita Goswami, India Vladimir Grigorov, South Africa Antonio Grimaldi, Italy George Hahalis, Botswana James Hakim, Zimbabwe Hashim Hanif, Pakistan Hee-Hwa Ho, Singapore Tian Hu, United States Barbara Huisamen, South Africa M Mohsen Ibrahim, Egypt Abdelmoniem Ismail, Kuwait Scott Reza Jafarian Kerman, Iran Islam Kaklikkaya, Turkey Guikahue Kakou, Botswana Oäÿuz Karahan, Turkey Hekim Karapanar, Turkey Kamilu Karaye, Nigeria Ganesan Karthikeyan, India Nurkay Katrancioglu, Turkey James Kayima, Uganda Andre Pascal Kengne, South Africa James Ker (jun), South Africa James Ker (sen), South Africa Dogu Kilic, Turkey Yogan Kisten, South Africa Joseph F Knapp, Botswana Kemal Korkmaz, Turkey Tolga Kurt, Turkey Tunay Kurtoglu, Turkey Pierre Lantelme, France John Lawrenson, South Africa Alain Lekoubou, France Salvatore Lentini, Italy Åžerife Tuba Liman, Turkey Anthony Linegar, South Africa TK Luqman-Arafath, United States Catarina Lundin, Sweden Enguerran Macia, France Jude Madu, Nigeria Eloi Marijon, France Amam Mbakwem, Nigeria Jean Claude Mbanya, Cameroon Amir Mohamed, Switzerland Charles Mondo, Uganda Jane Moses, South Africa Martin Mpe, South Africa Cephas Musabayane, South Africa Kathryn H Myburgh, South Africa

Rodolfo Neirotti, United States Theo Nell, South Africa Yves Ngoran Nda , Ivory Coast Kathleen Ngu Blackett, Cameroon Deliwe P Ngwezi, South Africa Jonathan Nwiloh, United States Augustine Odili, Botswana Okechukwu Ogah, Nigeria Nelson Oguanobi, Nigeria Oluwatoyin Ogunkunle, Nigeria Suraj Ogunyemi, Nigeria Emmy Okello, Uganda Kelechi Okonta, Nigeria Ikechi Okpechi, South Africa Beda Olabu, Kenya Brian Olshansky, United States Samuel Omokhodion, Nigeria Cihan Orem, Turkey Barbara Otaigbe, Nigeria Fredrick Otieno, Botswana Osa Oviawe, Nigeria Bilgehan Oz, Turkey Sedat Ozcan, Turkey Prashanth Panduranga, Oman Hasan Pekdemir, Turkey Lungile Pepeta, South Africa Soulemane Pessinaba, Senegal Adil Polat, Turkey Katja Prokselj, Slovenia Xue Qin, United States Camilla N Rathcke, Denmark Paul Rheeder, South Africa Daniel Ricklin, Botswana Saartjie Roux, South Africa Suzan Sacar, Turkey Mustafa Sacar, Turkey Tayfun Sahin, Turkey Timothy Sakellaridis, Greece Mudasiru, Salami, Nigeria Michael Sander, Germany Ismail Sapmaz, Turkey Ibrahim Sari, Botswana Ulrik Sartipy, Sweden Mike Sathekge, South Africa Aletta Schutte, South Africa Amine Sekhri, Morocco Yavuz Simsek, Turkey Karen Sliwa, South Africa Harris Steinman, South Africa Faisal Syed, United States Talat Tavli, Turkey Devika Tayal, India Ahmet Temiz, Turkey Kemi Tibazarwa, South Africa Vitor Valenti, Brazil Jacques van Rooyen, South Africa Enrico Vizzardi, Italy Mariza Vorster, South Africa Mostafa Yakoot, Egypt Adnan Yalcinkaya, Turkey Komlavi Yayehd, Togo Ali Umit Yener, Turkey Amir Farhang Zand Parsa, Iran Y Zorman, Switzerland

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Letter to the Editor Cardiomyopathies and myocardial disorders in Africa: present status and the way forward Response to Prof Bongani Mayosi

Dear Sir We are grateful to Prof Bongani Mayosi1 for his comments on our article ‘Cardiomyopathies and myocardial disorders in Africa’.2 We thank him for bringing to our attention previous publications from Africa on left ventricular non-compaction and ion channelopathies. These publications were not available to us when we wrote the article. It however shows that these diseases also exist in Africa. Interestingly we have, since our publication, encountered a case of Brugada syndrome in our practice, although we are yet to report the case. We therefore agree that many of the myocardial diseases reported from the rest of the world probably also exist here in Africa. The current problem however is how to define and classify the cardiomyopathies. One of us (AF) was part of the group that first proposed the name cardiomyopathy for this group of diseases.3,4 We also classified them at the time, based on existing knowledge. The key principle we agreed upon at our meeting was to name any disease of the myocardium according to the disease that caused it. Those that we did not know the cause or causes of were the ones we regarded as cardiomyopathies. In our view, subsequent attempts at classifying these disorders of the myocardium have disregarded this basic principle and have labelled virtually all diseases of the myocardium as cardiomyopathy. Such assumptions have made classification of the diseases more complex and difficult to use in routine clinical practice. They also ignore geographic differences in the causation and presentation of the diseases, especially in Africa where the problem of the cardiomyopathies is most profound. We do not think that the current European Society of Cardiology classification is suitable for clinicians working in

Africa.5 We therefore believe that it is time for Africa to develop its own classification based on the realities on the continent. Our classification was designed to trigger a debate in Africa towards this end and in so doing we have continued to maintain that basic philosophy of calling every disorder of the myocardium by the disease that caused the disorder. We have through that avoided the unending controversies surrounding the definition of cardiomyopathy and have attempted to bring all the disorders of the myocardium under one classification. We agree that the Pan-African Society of Cardiology (PASCAR) should take further steps to either adopt or modify this classification to suit the clinical realities of Africa. AYODELE FALASE, MD, FMCP, FWACP, FRCP, FAS, NNOM, aofalase@gmail.com OKECHUKWU OGAH, MBBS, MSc, FWACP Division of Cardiology, Department of Medicine, University College Hospital, Ibadan, Nigeria

References 1. 2.

3. 4. 5.

Mayosi BM. Cardiomyopathies and myocardial disorders in Africa: present status and the way forward. Cardiovasc J Afr 2013; 24: 65–71. Falase AO, Ogah OS. Cardiomyopathies and myocardial disorders in Africa: present status and the way forward. Cardiovasc J Afr 2012; 23: 552–62. Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. Br Heart J 1980; 44: 672–673. Cardiomyopathies. Report of a WHO Expert Committee. World Health Organization technical report series 1984; 697: 7–64. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29: 270–276.

EXAMINE Cardiovascular Safety Outcomes Trial Data from the global EXAMINE (Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) cardiovascular safety outcomes trial was recently presented at the European Association for the Study of Diabetes: 49th annual meeting, 23–27 September 2013, in Barcelona, Spain. Results indicated that alogliptin did not increase cardiovascular ischaemic events including all-cause mortality, non-fatal myocardial infarction, non-fatal stroke and urgent revascularisation due to unstable angina. Exploratory data also showed that rates of hospitalisation for heart failure were

comparable across alogliptin and placebo groups. The EXAMINE trial evaluated a total of 5 380 patients with type 2 diabetes and a recent acute coronary syndrome (within 15 to 90 days prior to randomisation). Alogliptin doses were adjusted according to renal function and the median duration of alogliptin exposure was 533 days. At study end, mean HbA1c change in level from baseline was –0.33 and 0.03% in the alogliptin and placebo groups, respectively. http://www.medscape.com/viewarticle/811921

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Prevalence of dyslipidaemia in statin-treated patients in South Africa: results of the DYSlipidaemia International Study (DYSIS) FREDERICK J RAAL, DIRK J BLOM, SHANIL NAIDOO, PETER BRAMLAGE, PHILIPPE BRUDI

Abstract Introduction and objectives: Cardiovascular disease (CVD) is the leading cause of mortality worldwide and increased levels of low-density lipoprotein cholesterol (LDL-C) are an important modifiable risk factor. Statins lower LDL-C levels and have been shown to reduce CVD risk. Despite the widespread availability of statins, many patients do not reach the lipid targets recommended by guidelines. We evaluated lipid goal attainment in statin-treated patients in South Africa and analysed variables contributing to poor goal attainment as part of the DYSlipidaemia International Study (DYSIS). Methods: This cross-sectional, observational study enrolled 1 029 consecutive South African patients consulting officebased physicians. Patients were at least 45 years old, had to be treated with a stable dose of statins for at least three months and had been fasting for 12 hours. We evaluated lipid goal attainment and examined variables associated with residual dyslipidaemia [abnormal levels of LDL-C, highdensity lipoprotein cholesterol (HDL-C) and/or triglycerides (TG)]. Results: We found that 50.3% of the patients overall did not achieve target LDL-C levels and 73.5% of patients were at very high cardiovascular risk. In addition, 33.7% had low levels of HDL-C, while 45.3% had elevated TG levels despite statin therapy. Asian and mixed-ancestry patients but not black (vs Caucasian ethnicity), as well as obese individuals in South Africa were more likely to still have dyslipidaemia involving all three lipid fractions. Conclusions: We observed that many patients in South Africa experienced persistent dyslipidaemia despite statin treatment, supporting the concept that there is a need for more intensive statin therapy or the development of novel treatment strategies. Measures aimed at combating obesity and

Carbohydrate and Lipid Metabolism Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa

FREDERICK J RAAL, MBBch, MMed, PhD, frederick.raal@wits.ac.za

Division of Lipidology, Department of Medicine, University of Cape Town, Cape Town, South Africa DIRK J BLOM, MBBCh, MMed, PhD

MSD South Africa, Midrand, South Africa

SHANIL NAIDOO, MB ChB, Dip HIV, MAN (SA), PDM

Institut für Pharmakologie und präventive Medizin, Mahlow, Germany PETER BRAMLAGE, MD

Merck, Sharp & Dohme Corp, Whitehouse Station, NJ, USA PHILIPPE BRUDI, MD

other lifestyle-related risk factors are also vital for effectively controlling dyslipidaemia and reducing the burden of CVD. Keywords: cardiovascular disease (CVD), dyslipidaemia, lipid abnormalities, statins, low-density lipoprotein cholesterol (LDL-C) Submitted 16/5/13, accepted 18/9/13 Cardiovasc J Afr 2013; 24: 330–338 DOI: 10.5830/CVJA-2013-071

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. In 2008, World Health Organisation (WHO) estimates suggested that 30% (17.3 million) of all deaths worldwide could be attributed to CVD.1 In 2008 and 2009, the two most recent years for which South African data are available, CVD was responsible for 13.7 and 14.0% of total deaths, respectively.2-4 However, CVD mortality rates are expected to rise in South Africa as unhealthy lifestyle trends associated with urbanisation spread to the countryside, and the population of people surviving life-threatening infections continues to grow.5,6 Well-known risk factors for CVD include age, gender, dyslipidaemia, tobacco smoking, high blood pressure and diabetes mellitus (DM). Other lifestyle behaviours such as excessive alcohol consumption, sedentary lifestyle and poor diet with resultant obesity further contribute to CVD risk.7,8 The WHO 2008 estimates indicated that the prevalence of obesity, tobacco smoking and physical inactivity in South Africa were 31.3 (≥ 20 years old), 14 and 51.1%, respectively.9 Furthermore, in 2010 the prevalence of DM was 4.5% for individuals ≥ 15 years old,10,11 and the WHO estimated the rate of high blood pressure at 42.2% in 2008.9 As the prevalence of these risk factors rise in South Africa,5 so will the rate of CVD. The main effect of statins is to lower LDL-C levels and they are used extensively in both primary and secondary prevention of CVD.12-14 Importantly, several large clinical trials have indicated that for every 1-mmol/l reduction in LDL-C levels there is a 23% reduction in CVD risk.15-18 In a further meta-analysis of studies comparing high and low statin doses, more intensive lowering of LDL-C (0.51 mmol/l additional reduction) in the high-dose statin arm was associated with a further 15% reduction in CVD risk.19 In the most recently published statin cardiovascular outcomes trial (JUPITER study: men and women free of overt cardiovascular disease over the ages of 50 and 60 years, respectively; baseline LDL-C < 3.37 mmol/l and high-sensitivity C-reactive protein of 2 mg/l or more; randomised to rosuvastatin 20 mg/day or placebo), statin treatment was associated with a 39% reduction in primary endpoints (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularisation or CV death) in patients with at least one risk factor for DM.20 The results of these and other studies have resulted in treatment guidelines recommending progressively lower LDL-C

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targets.21-23 However, studies from all over the world have demonstrated that many patients on lipid-lowering therapy do not reach their recommended lipid targets.24-26 The South African Heart Association (SA Heart) together with the Lipid and Atherosclerosis Society of Southern Africa (LASSA) therefore recently emphasised that intensive management of dyslipidaemia could significantly reduce the South African CVD health burden.21 The DYSlipidaemia International Study (DYSIS) is a crosssectional, observational study that has examined the efficacy of lipid-lowering therapies in patients from various regions of the world, including Canada and Europe (11 countries), in order to better characterise predictive factors for dyslipidaemia and CVD.24,25 Here, as part of DYSIS, we have analysed residual dyslipidaemia in statin-treated South African patients.

Methods As part of DYSIS, this epidemiological, observational, crosssectional study was conducted in South Africa between 1 November and 9 December 2011. Data for the study were collected in the South African private healthcare sector by 16 physicians; 50% were primary-care physicians and 50% were specialised office-based physicians (e.g. cardiologists). Prior to study initiation, the relevant local ethical review committees approved the study protocol and all patients gave written informed consent before enrolling in the study. Key eligibility criteria were: (1) age of at least 45 years, (2) receiving stable statin therapy for at least 3 months, and (3) fasting for at least 12 hours at the time of visit while on statin therapy. Participating physicians were instructed to include all eligible and consenting patients consecutively. Patient demographic, lifestyle and clinical characteristics were documented. Lipid levels (total cholesterol, LDL-C, HDL-C and triglycerides) were measured using the CardioChek® device (http://www.cardiocheck.com) at the time of patient enrollment to reliably collect lipid measurements uniformly at all sites. The LDL-C test strip provided measures LDL-C directly across a range of 1.29–5.18 mmol/l in about two minutes. Additionally, the lipid-lowering regimen at the time of the most recent blood sample was recorded for each patient (in particular, statin type and daily dose) as well as any information regarding other lipid-modifying therapies. The potency of different types of statins was normalised using a calculation that allows benchmarking against six different simvastatin dose levels (5, 10, 20, 40, 80 and 160 mg/day), with potency scores ranging from 1 (5 mg/day simvastatin) to 6 (160 mg/day simvastatin).23,27 The 2011 ESC guidelines were used to classify CV risk, LDL-C level treatment goals, and sub-optimal HDL-C and triglyceride levels.21,28 Variables independently associated with dyslipidaemia were evaluated with logistic regression modelling using the following variables: age (≥ 70 years), female gender, family history of premature coronary heart disease (CHD), current tobacco smoker, sedentary lifestyle, alcohol consumption (> 2 units/week), body mass index (BMI) ≥ 30 kg/m2, large waist circumference (> 102 cm in men, > 88 cm in women29), hypertension, DM, coronary heart disease, cerebrovascular disease, heart failure, peripheral artery disease, systolic/diastolic blood pressure ≥ 140/90 mmHg, simvastatin equivalent dose of either 20 to 40 versus 10 mg/day, or > 40 mg versus 10 mg/

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day, ezetimibe use, and physician’s specialty (cardiologist, endocrinologist, diabetologist, internal medicine or other).

Statistical analysis To estimate the sample size needed for South Africa we assumed a prevalence of residual lipid abnormalities between 20 and 60% in patients fulfilling the entry criteria for this study and a design effect of 20% (variance inflation due to cluster sampling design). We calculated that, within this range, a sample size of 1 000 would be sufficient to estimate the prevalence of residual dyslipidaemia with a given precision of ± 3.4% (range of 95% confidence interval: 6.8%). Furthermore we determined that this size guaranteed enough information for estimating the prevalence in smaller subgroups (representing one-quarter or more of the population) with a precision of ± 6.8% (95% CI: 13.6%). Following data collection, patient information was entered into a central web-based database housed and managed at the Institut für Herzinfarktforschung, Ludwigshafen, Germany. Real-time quality control (internal logic checks) occurred during web-based data entry. Continuous variables are presented as means with standard deviations or medians with 25th and 75th percentiles [interquartile range (IQR)] as indicated, and categorical variables are reported as absolute numbers and percentages. Kernel density estimation was used to analyse the distribution of total cholesterol, LDL-C, HDL-C and triglyceride levels. The value of a kernel density and its slope at the lipid value equal to the ESC goal provides a crude indicator of the change in the proportions of patients meeting the goal from a small improvement or deterioration in lipid level starting from the ESC goal. This approach thus provides a sensitivity analysis for either changes in the ESC goals or changes in lipid levels for people whose levels are near the goals. Multiple logistic regression analyses with backward selection (α = 0.05) were used to identify variables independently associated with LDL-C, HDL-C and triglyceride irregularities. Two-tailed statistical comparisons were used (p < 0.05 was significant) and patients lacking the appropriate lipid parameters were not included within the analyses. All analyses were performed using SAS v 9.1 (SAS Institute Inc, USA).

Results Patient characteristics, risk categories and lipid parameters are presented in Table 1. The study enrolled 1 029 patients (429 men, 600 women). The mean age of patients was 65.4 years, and 58.3% were female. The study population was of mixed ethnic (multi-racial) origin, including Caucasians (56.6%), blacks (22.0%), Asians (9.5%) and patients of mixed ancestry (12.0%). Patient characteristics and cardiovascular risk profile differed by ethnic group. A family history of premature CVD was reported by 34% of Caucasian patients while the diabetes prevalence of 25.6% was the lowest of all the ethnic groups studied. Hypertension was found in 69.8% and CVD in 41.1% of Caucasian patients. Black patients were least likely (1.8%) to report a family history of premature CHD and had the lowest (5.3%) smoking rates. However, hypertension was almost universal (93.3%) and diabetes and obesity were highly prevalent at 71.2 and 61.9%, respectively. Despite the high prevalence

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of hypertension and obesity, only 9.7% of black patients had clinically overt CVD. Asian patients had the highest rates of CVD (51.5%) among all ethnic groups studied and also the highest reported rate of a family history of premature CVD (44%). Diabetes was highly prevalent at 44.4% while the hypertension prevalence of 64.6% was similar to that observed in Caucasian patients. Mixedancestry patients had the highest smoking rates (18%) while the diabetes and hypertension prevalences were 50.8 and 89.3%, respectively. CVD was documented in 49.2% of mixed-ancestry patients. CVD was almost twice as common in men (49.9%) than women (26.3%). DM was more common in men than women (45.7 vs 36.7%), while obesity was more frequent in women (46.8 compared with 35.7%). Additionally, using the 2011 ESC criteria, 73.5% of patients (83.9% men and 66.0% of women) were classified as very high risk for CV complications [defined as having CVD, DM and/or an ESC systematic coronary risk evaluation (SCORE) risk of ≥ 10% on chronic statin therapy].

lovastatin (0.2%). Other lipid-lowering agents were used by only 2% of patients, including ezetimibe (1.2%), fibrates (0.9%) and bile acid sequestrants (0.2%). The most frequently used statin dose potency was 3 (equivalent to 20 mg simvastatin per day) for both very high-risk patients (40.2%) and non-very high-risk patients (47.6%), while the second most-frequent dose potency was 2 (equivalent to 10 mg simvastatin per day) in 32.4 and 25.6% of very high-risk patients and non-very high-risk patients, respectively (Fig. 1). While a statin dose potency of 3 was most frequently used in Caucasian, Asian and mixed-ethnicity patients, a dose potency of 2 was most common in black patients.

Lipid abnormalities Data on the frequency of lipid abnormalities, including sub-analyses by CVD risk level, are provided in Tables 2 and 3. Among all patients (n = 1 029), 50.3% had LDL-C levels not at goal. We defined ‘not at LDL-C goal’ as LDL-C ≥ 1.8 mmol/l and LDL-C reduction of < 50% for patients with CVD, DM and/ or a SCORE risk of ≥ 10% (very high risk), and as ≥ 2.5 mmol/l and ≥ 3 mmol/l for patients with a SCORE risk of 5 to 9% (high risk) and 1 to 4% (moderate risk), respectively. Elevated TG levels (defined as > 1.7 mmol/l) were seen in 45.3% of patients, and 33.7% had low HDL-C levels (defined as < 1.0 mmol/l for men and < 1.2 mmol/l for women).

Lipid-modifying regimens and statin potency Prior to enrollment in DYSIS, patients had been treated with various lipid-lowering therapies. The most commonly prescribed statin was simvastatin (64.6%), followed by atorvastatin (22.2%), rosuvastatin (10.9%), pravastatin (1.6%), fluvastatin (0.6%) and

TABLE 1. PATIENT CHARACTERISTICS, RISK CATEGORIES AND LIPID PARAMETERS IN DIFFERENT ETHNIC GROUPS

Age (years) (mean ± SD)

All patients (n = 1 029)

Caucasian (n = 582; 56.6%)

Black (n = 226; 22.0%)

Asian (n = 99; 9.6%)

Mixed ancestry (n = 122; 11.9%)

65.4 ± 10.8

69.0 ± 11.0

60.0 ± 8.9

61.8 ± 9.0

60.9 ± 7.4

Family history of premature CHD (%)

26.7

34.0

1.8

44.4

23.0

Current smokers (%)

10.7

11.2

5.3

11.1

18.0

Hypertension (%)

76.8

69.8

93.3

64.6

89.3

134.4 ± 20.0

134.9 ± 20.4

135.2 ± 19.4

129.0 ± 17.1

134.9 ± 20.7

Diastolic BP (mmHg) (mean ± SD)

79.7 ± 11.0

79.6 ± 11.1

79.6 ± 11.5

78.3 ± 9.6

81.2 ± 10.5

Waist circumference (cm) (mean ± SD)

100.7 ± 15.1

99.5 ± 16.5

105.0 ± 13.4

96.1 ± 9.6

101.8 ± 12.5

Systolic BP (mmHg) (mean ± SD)

29.6 ± 6.4

28.6 ± 6.4

32.8 ± 6.5

27.0 ± 4.5

30.4 ± 5.6

BMI > 30 kg/m2 (%)

BMI (kg/m2) (mean ± SD)

42.2

36.8

61.9

22.2

47.5

CVD (%)

36.2

41.1

9.7

51.5

49.2

Diabetes mellitus (%)

40.4

25.6

71.2

44.4

50.8

Metabolic syndrome (IDF) (%)

67.2

59.8

83.2

59.8

78.7

Very high-risk patient (%)

73.5

69.9

77.9

73.7

82.0

High-risk patient (%)

8.9

11.2

4.0

11.1

5.7

Moderate-risk patient (%)

13.5

15.6

11.5

9.1

10.7

Low-risk patient (%)

4.1

3.3

6.6

6.1

1.6

Very high-risk patient (%)

68.6

61.2

77.9

73.5

82.8

High-risk patient (%)

9.2

11.7

6.2

8.2

3.3

Moderate-risk patient (%)

21.6

26.6

15.9

15.3

13.9

Low-risk patient (%)

0.6

0.5

0.0

3.1

0.0

LDL-C

2.3 ± 1.1

2.2 ± 1.0

2.1 ± 1.0

2.6 ± 1.2

2.7 ± 1.1

HDL-C

1.3 ± 0.4

1.4 ± 0.4

1.3 ± 0.4

1.3 ± 0.5

Total cholesterol

4.4 ± 1.3

4.4 ± 1.2

4.4 ± 1.4

4.7 ± 1.6

4.7 ± 1.3

1.6 (1.1–2.3)

1.5 (1.1–2.2)

1.7 (1.2–2.4)

1.7 (1.2–2.7)

1.5 (1.1–2.4)

ESC risk level (2011)*

South African guidelines

Lipids (mmol/l) (mean ± SD)

Triglycerides [median (IQR)] Blood glucose FBG (mmol/l) [median (IQR)]

4.9 (4.3–6.4)

4.6 (4.2–5.4)

6.2 (4.7–9.0)

5.3 (4.2–7.0)

5.6 (4.7–7.2)

HbA1c (%) diabetics [median (IQR)]

7.4 (6.6–8.8)

7.1 (6.0–8.0)

8.2 (6.8–9.9)

7.8 (7.0–8.7)

7.4 (7.0–8.8)

CHD, coronary heart disease; BP, blood pressure; BMI, body mass index; CVD, cardiovascular disease; DM, diabetes mellitus; IDF, International Diabetes Federation.

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TABLE 2. LIPID ABNORMALITIES ACCORDING TO ESC GUIDELINES (2011) ON RISK STRATIFICATION

Percentage of patients

45 35

LDL-C not at target (%)†+ Low HDL-C [< 1.0 (men)/1.2 (women) mmol/l) (%)‡

19.8

20 10

4.6

0.8

Percentage of patients

Non-very high risk

47.6

Very high risk

40.2

40 35

2.0

Statin dose potency

18.7

20.2

Low HDL-C [< 1.0 (men)/1.2 (women) mmol/l] (%)†

Elevated TG (> 1.7 mmol/l) (%)

‡

10 0

3.3

Statin dose potency

1.6

Caucasian Black

67.3

Asian 44.7

Mixed ancestry

50.5 46.7

38.5 29.6

20 0

5.0

3.3

1.5 0.5

17.2

16.2

12.3 2.7

1.2 0.4 0.0 0.0

29.3

26.5

Statin dose potency

7.0 0.0

3.0 2.5

3.4

0.0 1.0 0.0

Fig. 1. Statin dose potency overall (A), according to patients’ risk status (B), and by ethnicity (C) calculated according to references 22, 23. *Statin dose potency 1 is equivalent to simvastatin 5 mg/day, potency 2 is equivalent to simvastatin 10 mg/day, potency 3 is equivalent to simvastatin 20 mg/day, potency 4 is equivalent to simvastatin 40 mg/day, potency 5 is equivalent to simvastatin 80 mg/day, and potency 6 is equivalent to simvastatin ≥ 160 mg/day.

The most prevalent lipid disorder (either alone or in combination) in very high-risk patients was above-target LDL-C levels (60.1%), followed by elevated TG levels (45.8%), and low HDL-C levels (36.0%). By contrast, in both high- and moderate-risk patients, elevated TG levels were observed more frequently (46.7 and 40.1%, respectively in the two risk groups) than above-target LDL-C levels (33.3 and 24.1%, respectively)

60.1

33.3

24.1

33.7

36.0

25.0

26.3

34.1

45.3

45.8

46.7

40.1

50.0

TABLE 3. LIPID ABNORMALITIES ACCORDING TO ESC GUIDELINES (2011) IN VERY HIGH-RISK PATIENTS

LDL-C ≥ 1.8 mmol/l and LDL-C reduction < 50% (%)*

25.6

50.3

*Very high risk = CVD, diabetes, and/or SCORE risk ≥ 10% (chronic kidney disease was not documented in DYSIS) † LDL-C ≥ 3.0 mmol/l in patients with SCORE risk 1–4%, LDL-C ≥ 2.5 mmol/l in patients with SCORE risk 5–9%, LDL-C ≥ 1.8 mmol/l in patients with CVD, DM, and/or SCORE risk ≥ 10%; LDL-C ≥ 1.8 mmol/l + Data on 987 patients were available ‡ Data on 1 025 patients were available § Data on 1 027 patients were available In the ESC 2011 guidelines, no LDL-C goal was specified for the low-risk group.

32.4

Percentage of patients

Elevated TG (> 1.7 mmol/l) (%)

All Very high High Moderate Low patients risk* risk risk risk (n = 1 029) (n = 756) (n = 92) (n = 139) (n = 42)

30.6

42.2

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CVD + DM (n = 131)

CVD (w/o DM) (n = 241)

DM (w/o CVD) (n = 285)

SCORE ≥ 10% (n = 99)

57.9

68.0

53.8

61.9

39.7

33.8

37.9

31.3

54.2

38.2

51.9

35.4

*Data on 722 of a total of 756 high-risk patients were available † Data on 755 patients were available ‡ Data on 756 patients were available.

and low HDL-C levels (25.0 and 26.3% for both risk groups, respectively). We next performed a sub-analysis of lipid abnormalities for only very high-risk patients (756 of all patients, Table 3), which we stratified as indicated. Of those with CVD and DM, 57.9% displayed off-target LDL-C levels (≥ 1.8 mmol/l and a decrease in LDL-C levels of < 50%), 39.7% showed low HDL-C levels, and 54.2% had elevated TG levels. In comparison, patients in the CVD without DM group showed a higher rate of LDL-C not at target (68.0%), decreased rates of low HDL-C (33.8%), and elevated TG levels (38.2%). Interestingly, the ESC SCORE group with risk of ≥ 10% showed a lower proportion of patients with low HDL-C and elevated TG levels. Overall, we found that LDL-C not at goal was the most common lipid abnormality observed in each of the four sub-sets. Additionally, we analysed patient lipid abnormalities using kernel density curves for the empirical distributions of very highrisk and non-very high-risk patient groups with regard to total cholesterol, LDL-C, HDL-C (separately for men and women), and TG levels (ESC guidelines indicated as superimposed vertical lines) (Fig. 2). Overall, we found that the density curves were unimodal and positively skewed, and the data indicated that the very high-risk group showed slightly lower overall LDL-C levels than non-very high-risk patients. Moreover, we observed that women maintained higher overall HDL-C levels than men in both the very high and non-very high-risk groups, while TG levels were similar between the two risk groups.

Distributions of lipid abnormalities Distributions of single and multiple combined lipid abnormalities for our study are shown in Figs 3–5. Here, we present the joint

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Non-very high-risk patients

0.6

Density

0.5

Very high-risk patients

0.4 0.3 0.2 0.1 0

Density

0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0

1.4 1.2 1 0.8 0.6 0.4 0.2 0

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

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Total cholesterol (mmol/l)

Non-very high-risk patients Very high-risk patients

LDL-C (mmol/l)

Non-very high-risk patients Very high-risk patients

0.5

1.5

2.5

HDL-C (mmol/l) in men

Non-very high-risk patients Very high-risk patients

0.5

1.5

HDL-C (mmol/l) in women

2.5

distribution of lipid abnormalities for the entire sample and then for sub-samples of very high-risk and non-very high-risk patients. Additionally, joint distributions that either include or exclude patients with no lipid abnormalities are provided for each patient group. Fig. 3 shows that in 39.4% of patients with a total lipid profile, there was only one single-lipid abnormality, 32.8% had two abnormalities, and the remaining 7.3% had abnormalities in all three assessed components of the lipid profile. Among statin-treated patients, the most common abnormality was high LDL-C levels (18.8% of all cases), accounting for 47.7% of all single-lipid abnormalities. Among the 983 patients, 20.4% had no lipid abnormalities. Figs 4 and 5 present the joint distribution for non-very high-risk and very high-risk patients, respectively, and indicate different patterns of prevalence for these sub-groups. For the 261 non-very high-risk patients with at least one abnormality depicted in Fig. 4, 37.2% had only one lipid abnormality, 21.5% had two lipid abnormalities and the remaining 4.2% had all three lipid abnormalities. By contrast, for the 826 very high-risk patients depicted in Fig. 5, the majority, 45.4%, had two or more lipid abnormalities (40.2% had one, 37.0% had two, and the remaining 8.4% had all three). For non-very high-risk patients, elevated triglycerides were the largest single abnormality present, appearing in 42.2% of all non-very high-risk patients. By contrast, among very high-risk patients, high LDL-C level was the most frequent abnormality, at 60.1% of all very high-risk patients.

Variables independently associated with dyslipidaemia Multivariate logistic regression analyses indicated that among the 19 risk factors incorporated into the model, mixed ancestry, along with history of hypertension, DM and cerebrovascular disease were among the risk factors strongly, positively and LDL-C not at goal (≥ 1.8 / ≥ 2.5 / ≥ 3.0 mmol/l)

Non-very high-risk patients

No lipid abnormalities

18.8% (185)

Very high-risk patients 8.6% (85)

20.4% (201) 8.9% (87) 0

TG (mmol/l) in men

Fig. 2. Kernel density curves of lipids. Density curves were unimodal and positively skewed throughout. The data indicate that the very high-risk group (B) showed slightly lower overall LDL-C levels than non-very highrisk patients. Moreover, we observed that women (D) maintained higher overall HDL-C levels than men (C) in both the very-high and non-very high-risk groups, while triglyceride levels were similar between the two risk groups (E). Density curves for total cholesterol were mostly overlapping (A). Vertical lines mark the cutoff point of ESC guidelines (2011); LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

7.3% (72) 8.5% (84)

Low HDL-C (< 1.0 male / < 1.2 female mmol/l)

15.7% (154) 11.7% (115)

Elevated TG (≥ 1.7 mmol/l)

Fig. 3. Distribution of no, single and multiple combined lipid abnormalities for the total study population. TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; proportions add up to 99.9% because of rounding; thresholds for LDL-C are based on the ESC guidelines (2011): SCORE risk 1–4%: LDL-C ≥ 3.0 mmol/l; patients with SCORE risk 5–9%: LDL-C ≥ 2.5 mmol/l; patients with CVD, DM, and/or SCORE risk ≥ 10%: LDL-C ≥ 1.8 mmol/l.

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LDL-C not at goal (≥ 1.8 mmol/l) No lipid abnormalities

No lipid abnormalities

22.9% (165) 10.8% (78)

14.4% (104)

LDL-C not at goal (≥ 1.8 mmol/l)

8.3% (60)

8.4% (61)

18.0% (130)

10.8% (78)

14.4% (104) 9.0% (65)

8.2% (59)

8.3% (60)

Elevated TG (≥ 1.7 mmol/l)

Low HDL-C (< 1.0 male / < 1.2 female mmol/l)

22.9% (165)

Fig. 4. Distribution of no, single and multiple combined lipid abnormalities in non-very high-risk patients (ESC 2011, SCORE < 10%). TG, triglycerides; HDL-C, highdensity lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; thresholds for LDL-C are based on the ESC guidelines (2011): SCORE risk 1–4%: LDL-C ≥ 3.0 mmol/l; patients with SCORE risk 5–9%: LDL-C ≥ 2.5 mmol/l; patients with CVD, DM, and/or SCORE risk ≥ 10%: LDL-C ≥ 1.8 mmol/l.

independently associated with LDL-C levels not being at goal. Having low HDL-C levels was negatively associated with female gender and increased alcohol consumption, but positively associated with being treated by a specialist, increased waist circumference, and presence of DM. Having elevated triglyceride levels was negatively associated with age above 70 years, but positively associated with female gender, obesity, history of DM and peripheral artery disease. The three variables independently associated with having all three lipid abnormalities were Asian and mixed-ancestry ethnicity versus Caucasian ethnicity, and obesity, all of which were positively associated with not reaching goal (Table 4).

8.4% (61)

18.0% (130) 9.0% (65)

8.2% (59)

Low HDL-C (< 1.0 male / < 1.2 female mmol/l)

Elevated TG (≥ 1.7 mmol/l)

Fig. 5. Distribution of no, single and multiple combined lipid abnormalities in very high-risk patients (ESC 2011, SCORE ≥ 10%). TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; proportions add up to 100.1% because of rounding; thresholds for LDL-C are based on the ESC guidelines (2011): SCORE risk 1–4%: LDL-C ≥ 3.0 mmol/l; patients with SCORE risk 5–9%: LDL-C ≥ 2.5 mmol/l; patients with CVD, DM, and/or SCORE risk ≥ 10%: LDL-C ≥ 1.8 mmol/l.

Discussion In the DYSIS South Africa study we observed marked ethnic differences in cardiovascular risk profiles and the primary indication for statin therapy. While about half of Asian and mixed-ancestry patients had clinically overt CVD, the rate in black patients was less than 10%. The major indication for statin therapy in black patients was diabetes, which was present in 71.2% of patients. A family history of premature CVD was very uncommon (1.8%) in black patients. These data are reflective of the epidemiological transition, which the South African black population is currently undergoing,6 with increasing urbanisation and transition to a

TABLE 4. FACTORS INDEPENDENTLY ASSOCIATED WITH LDL-C, HDL-C AND TG ABNORMALITIES: RESULTS FROM MULTIPLE REGRESSION ANALYSES (OR, 95% CI) LDL-C not at target*† (≥ 1.8/2.5/3.0 mmol/l)

Low HDL-C* [< 1.0 (m)/1.2 (w) mmol/l]

Elevated TG* (> 1.7 mmol/l)

LDL-C not at target, low HDL-C, elevated TG* ns

Age ≥ 70 years

0.57 (0.43–0.77)

Female

0.43 (0.32–0.58)

1.33 (1.02–1.74)

Asian vs Caucasian

2.48 (1.19–5.16)

Black vs Caucasian

2.12 (1.36–3.32)

2.78 (1.50–5.19)

Alcohol consumption > 2 units/week

0.50 (0.31–0.79)

BMI ≥ 30 kg/m2 (obesity)

1.74 (1.33–2.29)

2.11 (1.27–3.50)

Mixed ancestry vs Caucasian

WC > 102 (m)/> 88 cm (w) Hypertension

1.71 (1.26–2.32)

1.55 (1.12–2.13)

Diabetes mellitus

1.36 (1.01–1.82)

1.58 (1.17–2.15)

1.49 (1.12–1.98)

Cerebrovascular disease

1.89 (1.39–2.57)

Peripheral artery disease

2.35 (1.09–5.07)

Specialist (Card/Endo/Dia/Int/Oth)

2.01 (1.46–2.76)

*Models contained the following variables: age, gender, ethnicity, 1st-grade family history of premature CVD, current smoker, sedentary lifestyle, alcohol consumption > 2 units/ week, BMI ≥ 30 kg/m2 (obesity), waist circumference > 102 cm in men/> 88 cm in women, hypertension, diabetes mellitus, coronary heart disease, cerebrovascular disease, heart failure, peripheral artery disease, RR ≥ 140/90 mmHg (systolic/diastolic), 20–40 vs 10 mg/day simvastatin equivalent, ≥ 80 vs 10 mg/day simvastatin equivalent, ezetimibe. Backward selection (alpha = 0.05) was done. † Patients with SCORE risk 1–4%: LDL-C ≥ 3.0 mmol/l; patients with SCORE risk 5–9%: LDL-C ≥ 2.5 mmol/l; patients with CVD, DM, and/or SCORE risk ≥ 10%: LDL-C ≥ 1.8 mmol/l Card = cardiologist, Endo = endocrinologist, Dia = diabetologist, Int = internist, Oth = other speciality, ns = not significant (p > 0.05), OR = odds ratio, CI = confidence interval.

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Westernised lifestyle. Hypertension, obesity and diabetes are highly prevalent in black patients while CVD, which results from prolonged exposure to cardiovascular risk factors, is still relatively uncommon. With further progression of the epidemiological transition, CVD rates in black patients are likely to rise and may well match or exceed those observed in the other ethnic groups if cardiovascular risk factors are not addressed intensively, both on a population and an individual level. The DYSIS South Africa study identified a group of patients at high cardiovascular risk, with 73.5% of statin-treated patients assessed to be at very high risk for CVD. Within this very high-risk group, despite statin therapy, 85.6% had at least one lipid abnormality, of which a majority had two or more lipid abnormalities. The most common lipid abnormality was high LDL-C levels, which was diagnosed in 60.1% of all very highrisk patients. Moreover, for all patients in the study, 50.5% had LDL-C levels not at goal, which is comparable with the findings from the recently published CEPHEUS-SA study and the Canadian/ European cohort of the DYSIS study, and below the levels found in the Middle Eastern cohort (62%).24,26,30 Not surprisingly, the metabolic syndrome was present in 67.2% of the sample, since its components also contribute to elevated CVD risk. Statistically significant factors associated with high LDL-C levels included ethnicity, hypertension, DM, and the presence of coronary and cerebrovascular heart disease. Factors associated with low HDL-C levels were a high waist circumference, DM and being treated by a specialist. Elevated TG was associated with female gender, obesity, DM and peripheral artery disease. However, the only statistically significant factors independently associated with the presence of all three lipid abnormalities were obesity and Asian as well as mixed-ancestry ethnicity. Based on the current data, it is unclear whether the findings with regard to ethnicity are biologically or sociologically determined. Even though this study was conducted exclusively in the private healthcare sector in South Africa, Asian or mixedancestry ethnicity most likely still correlates partially with social deprivation, which has been shown to be a risk factor for cardiovascular disease. Social deprivation may also affect access to medical care, with less access to specialist care and a bias towards less aggressive treatment. Studies from other countries have shown that ethnic minorities or immigrants often receive less aggressive cardiovascular care,31 as also observed in this study, with black patients receiving lower-dose potency of statins, despite the majority of patients being at high risk. Socio-economic status has also been associated with statin adherence,32 as has ethnicity.33 In the South African context, lower socio-economic status would, for instance, often correlate with membership of a medical scheme option that restricts lipid-lowering treatment to less-potent (and less-costly) options. Lower income may also influence the willingness and ability to pay ‘co-payments’ that are often required to access more potent lipid-lowering therapy. However, factors such as provider bias, access to treatment and differential adherence do not completely explain the observed ethnic differences, as black patients generally still experience the highest level of socio-economic deprivation as a legacy of South Africa’s past history. Lesser goal attainment may also in part be due to differences in baseline lipids. In the Heart of Soweto study, there were significant differences in untreated lipid profiles by ethnicity in

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patients presenting for cardiovascular care34 at a tertiary referral centre. The odds ratio (compared to black patients) for elevated LDL-C levels in Asian and mixed-ancestry patients was 4.66 and 2.44, respectively. Indian and mixed-ancestry patients also had higher median TG levels (1.8 and 1.4 mmol/l, respectively) than black patients (1.1 mmol/l). In addition to identifying factors that are associated with dyslipidaemia in statin-treated patients, DYSIS in South Africa (along with previous DYSIS studies) also highlights the deficiencies of lipid-lowering therapy in clinical practice. Other researchers analysing the efficacy of lipid-lowering therapies have supported this conclusion,35,36 including another recent study analysing statin-treated South African patients.26 Together, these findings suggest that there is a need to improve upon existing treatment strategies (e.g. combination of current therapies for optimal patient efficacy, utilisation of more-potent statins, improving adherence) while also developing novel therapeutic approaches. Combination therapies were evaluated in the Austrian Cholesterol screening and Treatment (ACT) II study, which evaluated the effect of lipid-lowering therapies in high-risk, statin-treated patients with elevated LDL-C levels. Interestingly, combination therapy consisting of simvastatin and ezetimibe (used for 73% of patients in the ACT II study) resulted in 40.3% of patients meeting their LDL-C goals, with a decline in LDL-C levels from a baseline of 31.3% following 12 months of intensified therapy.37 High-dose statins are another option to achieve LDL-C targets in high-risk patients.38,39 Improving adherence is a challenge that physicians face every day, and some strategies that have shown promise include regular phone calls by a practice nurse, regular review by a community pharmacist and providing a medication calendar when patients filled their first prescription.40 There is likely no single strategy that will work for all patients but studies show that adherent patients have much better cardiovascular outcomes than non-adherent patients, although some of the improvement may also be ascribed to the correlation between adherence and other healthy behaviours.41-44 According to a mathematical model of statin use in a population, increasing statin adherence from 50 to 75% at five years would prevent more events than lowering the risk threshold for prescribing statins.45 Lastly, novel LDL-C-lowering therapies may be necessary for patients with very high baseline LDL-C levels, such as is seen in familial hypercholesterolaemia, and when patients are unable to tolerate adequate doses of potent statins.46 In South Africa, the modal statin dose potency prescribed to patients was 3, which was prescribed to 42.2% of the individuals. Interestingly, although the very high-risk patients had a disproportionately high share of the statin prescriptions with a potency of 4 and 5, they also had a disproportionately high amount of prescriptions with a potency of 2, and a disproportionately low share of the prescriptions with a potency of 6. In addition, although combination therapies may have the potential to benefit some patients,37 we found that the use of combination treatment with lipid-lowering therapies was rare in South Africa. Only seven patients were co-prescribed statins and ezetimibe in this study. DYSIS-South Africa had several limitations, including its cross-sectional design, which did not permit follow up to assess

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the effects of statins over time in either reducing CVD risk factors or their ultimate effects in reducing CVD. In addition, the cross-sectional nature of the study precludes us from drawing conclusions of temporality based on observed associations. The study was also only conducted in the private sector and does not therefore provide any information on the care provided in the public sector, which accounts for about 80% of patients in South Africa. As this study was conducted in the private sector, the ethnic make-up of the DYSIS study cohort is not representative of the South African population at large. Furthermore physicians were aware of the study purpose, possibly making the results prone to a selection bias towards patients with better-than-average lipid goal attainment. DYSIS by its design is also unable to provide data on the important public health question on what proportion of patients with an indication for lipid-lowering therapy is actually being treated. Analysing patients that return for follow-up consultation and are still taking statins is not reflective of the entire statin treatment experience, as patients discontinuing early and defaulting on follow up are not captured. However, in spite of these potential limitations, the data obtained during this cross-sectional, observational study of South Africa has furthered our knowledge of CV risk and the factors that contribute to persistent dyslipidaemia in statintreated patients.

Conclusions The DYSIS study for South Africa, like the DYSIS studies in other countries and regions, indicates that large proportions of statin-treated patients have persisting lipid abnormalities, which place them at ongoing risk for CVD. While some observations with regard to co-morbid conditions and demographics associated with lipid goal attainment were expected, observations also demonstrate a decreased likelihood of obtaining lipid goals among two ethnic minority groups, independent of treatment, demographics and other co-morbidities. These findings deserve further attention. As statins remain among the most effective agents for preventing CVD, the findings of this study emphasise the necessity for more aggressive therapy in order to achieve recommended lipid targets, so as to reduce the burden of cardiovascular disease, which is on the increase not only in South Africa but worldwide. The authors thank Dr Claus Jünger and Dr Steffen Schneider, Stiftung Institut für Herzinfarktforschung, Ludwigshafen, Germany, for performing the statistical analyses, Dr Myrga Zankel (MSD International) for general support of the study, and Dr Lori D Bash (Merck, Sharp & Dohme Corp) for critical content review. We are indebted to all investigators and patients in South Africa who participated in DYSIS. This study was funded by Sharp & Dohme Corp, a subsidiary of Merck & Co, Ltd (New Jersey, USA).

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For statin mono-therapy patients who are not at LDL-C Goal

Powerful LDL-C reduction through in a single tablet 1,2 10/10

10/20

10/40

… as demonstrated in a study conducted on patients with hypercholesterolaemia2

STUDY DESIGN: Goldberg et al: A multicentre double-blind, placebo-controlled, factorial study enrolled 887 patients with hypercholesterolaemia (low-density lipoprotein cholesterol [LDL-C], 3.7 – 6.5 mmol/L (145 - 250 mg/dL): triglycerides, <3.96 mmol/L (350 mg/dL)). Patients were randomised to 1 of 10 treatments – placebo, ezetimibe at 10 mg/d, simvastatin at 10, 20, 40, or 80 mg/d, or simvastatin at 10, 20, 40, or 80 mg/d plus ezetimibe at 10 mg/d for 12 weeks. The study began March 13, 2001, and ended January 8, 2002. The primary efficacy end-point was the mean percent change in LDL-C levels from baseline to study end-point (last available past baseline LDL-C measurement) for the pooled ezetimibe/ simvastatin group vs the pooled simvastatin monotherapy group. Co-administration of ezetimibe/simvastatin was significantly (p<0.001) more effective than simvastatin alone in reducing LDL-C levels for the pooled ezetimibe/simvastatin vs pooled simvastatin analysis and at each specific dose comparison. REFERENCE: 1. Shepherd J. The role of the exogenous pathway in hypercholesterolaemia. Eur Heart J Suppl. 2001;2(suppl E):E2–E5. 2. Goldberg AC, Sapre A, Liu J, et al. for The Ezetimibe Study Group. Efficacy and Safety of Ezetimibe Co-administered with Simvastatin in Patients With Primary Hypercholesterolaemia: A randomised, double-blind, Placebo-controlled trial. Mayo Clin Proc. 2004;79:620-629.

MSD (Pty) Ltd (Reg. No. 1996/003791/07), Private Bag 3, Halfway House 1685. Tel: (011) 655-3000. www.msd.co.za. INEGY S4 Each tablet contains 10 mg ezetimibe and 10, 20 or 40 mg simvastatin. Reg. No’s: 10/10 – A39/7.5/0031, 10/20 – A39/7.5/0032, 10/40 – A39/7.5/0033. Copyright © 2013 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, U.S.A. All rights reserved.

Before prescribing, please consult the full package insert. CARD-1098144-0000

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Drug Trends in Cardiology Novo Nordisk Incretin and Cardiovascular Summit, Durban, June 2013 Acute coronary syndrome in diabetes: how do we improve clinical outcomes? Dr Sajidah Khan, principal specialist in cardiology, Wentworth and Albert Luthuli central hospitals, Durban Acute coronary syndrome (ACS) in diabetics is associated with higher mortality rates, higher morbidity and more co-morbid conditions. ‘Type 2 diabetes is more than hyperglycaemia. The unified pathophysiology of oxidative stress and subclinical inflammation drives both diabetes and cardiovascular disease (CVD), and diabetics have accelerated rates of atherosclerosis, increased rates of stenosis/ re-occlusion and exaggerated inflammation.’ The only real difference between STEMI and non-STEMI ACS is that in the former, the thrombus occludes the vessel completely. This means that with STEMI every second counts, whereas one can wait before treating non-STEMI. ‘Symptoms of STEMI are unreliable in those with diabetes, and they may not present with classic chest pain’, said Dr Khan. ‘When performing primary percutaneous intervention (PCI), one should not use baremetal stents in diabetic patients, but rather second-generation drug-eluting stents. However, the “limos” drugs do not work as well in diabetics as in non-diabetics, failing to inhibit smooth muscle proliferation, so paclitaxel is a better option.’ With regard to adjunctive antiplatelet therapy, prasugrel is more effective than clopidogrel in diabetics. Many low- and middle-income countries have a shortage of PCI facilities and interventional cardiologists, which makes addressing ACS in these environments challenging, given that it requires prompt action. ‘If PCI is not an option, fibrinolysis is an alternative strategy. Further to this, the patient can be transferred to a PCI-capable facility for angiography and possible PCI if it is still appropriate.’ People living with diabetes are considered at high risk for non-STEMI and may be asymptomatic. ‘Thirty per cent of patients are hyporesponders to clopidogrel and in future, ticagrelor – which will be launched next year – will be a better option. As with diabetic therapies, antiplatelet and antithrombotic regimens are complex.’

People living with diabetes are also more likely to have adverse left ventricular remodelling, and this needs to be borne in mind. Hyperglycaemia during ACS is a powerful predictor of in-hospital survival, and complications and so-called ‘stress hyperglycaemia’ is common in both diabetics and non-diabetics. Blood glucose control is therefore imperative, but the challenge is to achieve this without inducing hypoglycaemia, which has its own cardiovascular risks in respect of being arrhythmogenic and a precipitator of ischaemia. Symptom status is not a reliable predictor of ischaemia and provocative testing is required to assess the total ischaemic burden, which in turn predicts prognosis. Summing up, Dr Khan observed that all STEMI patients should be taken to the catheterisation laboratory and that an early invasive strategy is also associated with better survival in non-STEMI. PCI with a drug-eluting stent should be followed by dual antiplatelet therapy for one year, and coronary artery bypass grafting should be undertaken when there is multi-vessel disease. ‘In developing countries, the progression of insulin resistance to diabetes parallels that of endothelial dysfunction to atherosclerosis. Primary prevention, in the form of early, aggressive diabetes therapy is therefore important.’

Hypoglycaemia and cardiovascular outcomes in diabetes Prof Wolfgang Schmidt, chief of GI/ Hepatology and Diabetes Services and director of the Department of Medicine, St Josef-Hospital, Ruhr-University Medical School, Bochum, Germany Hypoglycaemia is an important confounder in the management of diabetes, and glycaemic control is only part of the story. To achieve an overall favourable outcome also requires control of CVD risk factors and an avoidance of weight gain and hypoglycaemic episodes. Multiple studies have shown the benefits of good early glycaemic control and its association with a lower CHD event rate. Its legacy effect confers significant benefit 10 to 15 years later. The challenge in achieving

this favourable scenario lies in attaining glycaemic control, lowering lipid levels and blood pressure and avoiding hypoglycaemia while not doing harm. Intensive intervention in diabetes and better glycaemic control often come at the price of increased weight gain and more hypoglycaemic episodes, which is a bad risk–benefit ratio. Certain patients are at particular risk, including the elderly, those with diabetes of longer duration and/or a high baseline HbA1c level, and patients with renal dysfunction or peripheral neuropathy. Severe hypoglycaemic events are associated with a 2.5% higher mortality rate so therapy-induced hypoglycaemia must be avoided. ‘Why is it so dangerous?’ asked Prof Schmidt. ‘It has pro-arrhythmic effects, is associated with cognitive dysfunction and delayed recovery in the elderly and is both pro-thrombotic and pro-inflammatory. In addition it causes increased anxiety in patients, which in turn has a negative impact on compliance.’ So control needs to be both stringent and safe from the time of diagnosis. ‘In 2013, when managing diabetes, we need to avoid hypoglycaemia, especially in those with cardiovascular risk, avoid weight gain, reconstitute beta-cell function and stop their loss. Is GLP-1 incretin therapy an option?’ Prof Schmidt feels strongly that it is. ‘GLP-1 normalises glucose levels in poorly controlled patients, without causing hypoglycaemia. Liraglutide improves firstphase insulin secretion and maximal betacell insulin capacity. Importantly, it does not induce insulin secretion when glucose levels are low. Used in combination with metformin, the risk of hypoglycaemia is low, comparable with that of placebo. It also improves biomarkers of CVD risk, notably reducing systolic blood pressure.’ Liraglutide therefore has a favourable impact on the composite endpoint of optimal HbA1c concentration, weight loss and hypoglycaemia. ‘It shows great promise in helping us get our patients to their individualised HbA1c targets early, without weight gain and hypoglycaemia, while preserving beta-cell function’, Prof Schmidt concluded. P Wagenaar

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Case Report Mitral valve and coronary artery bypass surgeries 13 years after pneumonectomy for lung cancer OZGUR DAG, MEHMET ALI KAYGIN, UMIT ARSLAN, ADEM KIYMAZ, NAIL KAHRAMAN, BILGEHAN ERKUT

Abstract We successfully performed coronary artery bypass grafting and mitral valve replacement in a 72-year-old man who had undergone a left pneumonectomy 13 years previously due to a malignant mass. The patient was admitted to our clinic with symptoms of dyspnoea, palpitations, chest pain and fatigue. He was diagnosed with mitral valve disease and two-vessel coronary artery disease, as seen from echocardiography and catheterisation studies. Conventional cardiopulmonary bypass grafting was performed following sternotomy. The patient’s heart was completely displaced to the left hemithorax. Saphenous vein grafts were harvested. Distal anastomoses were performed with the use of the on-pump beatingheart technique without cross clamping. Afterwards a cross clamping was placed and a left atriotomy was performed. The mitral valve was severely calcific. A mitral valve replacement was performed using number 27 mechanical valve after the valve had been excised. The patient’s postoperative course was uneventful. Cardiac contractility was seen to be normal and the mitral valve was functioning on echocardiography done in the second postoperative month. Keywords: cardiac surgery after pneumonectomy, mitral valve replacement, coronary artery bypass grafting, lung mass Submitted 27/9/12, accepted 24/4/13 Cardiovasc J Afr 2013; 24: e1–e4

www.cvja.co.za

DOI: 10.5830/CVJA-2013-031

severe pulmonary complications that may develop after openheart surgery cannot be well tolerated due to the limited pumonary function and reserves of these patients.1,2 Pneumonectomy results in anatomical and physiological changes, which can have a deleterious effect on the performance of subsequent open-heart operations, especially where it involves multiple procedures. We report on a case of coronary artery disease with valvular heart disease in a 72-year-old patient who had undergone pneumonectomy 13 years before.

Case report A 72-year-old man, who had undergone left pneumonectomy 13 years earlier for epithelial squamous-cell carcinoma, presented with symptoms of unstable angina, palpitations and shortness of breath. However, he had no clinical symptoms at rest and had appeared fit for his age until the last six months. On chest examination, respiratory sounds could not be heard on the left hemithorax and precordial pulsation was detected on the left sternal border. The apex beat was displaced laterally. On auscultation, a mitral opening snap and diastolic rulman were heard at the fifth intercostal space at the apex. An electrocardiogram revealed atrial fibrillation of between 80 and 120 beats/min. Chest radiography and computed tomography of the chest revealed that the cardiac silhouette was displaced to the left hemithorax and there was intestinal gas in the left hemithorax (Figs 1, 2). The right lung was fully expanded and clear.

When open-heart operations are necessary in patients who have undergone pneumonectomy, the unavoidable shift of mediastinal structures should be carefully considered. Surgical access, revascularisation procedures, and the institution of cardiopulmonary bypass may all require approaches that differ from the usual. Pneumonectomy is a condition that may be problematic for future open-heart surgery, which may be fraught with anatomical and physiological problems. In patients with pneumonectomy,

Department of Cardiovascular Surgery, Erzurum Regional Training and Research Hospital, Erzurum, Turkey OZGUR DAG, MD MEHMET ALI KAYGIN, MD UMIT ARSLAN, MD ADEM KIYMAZ, MD NAIL KAHRAMAN, MD BILGEHAN ERKUT, MD, bilgehanerkut@yahoo.com

Fig. 1. Pre-operative chest X-ray study showing marked displacement of the heart shadow into the left pneumonectomy space.

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Fig. 2. Pre-operative computed tomography appearance of a marked shift of the heart and the great vessels into the left hemithorax with a hyperinflated right lung.

Echocardiography revealed critical mitral stenosis with a peak gradient of 33 mmHg and mean of 17 mmHg, a dilated left atrium (55 mm) with severe mitral regurgitation and severe pulmonary arterial hypertension (mean PAP 66 mmHg). The mitral valve area was 0.75 cm2. The left ventricular ejection fraction was 0.45. Cardiac catheterisation revealed two-vessel disease with stenosis in the left anterior descending artery (LAD) and right coronary artery (RCA). A pulmonary function test showed moderate restrictive and obstructive respiratory dysfunction. Arterial oxygen saturation was 89% when he was receiving 2 l/ min oxygen. On arterial blood gas examination, the partial oxygen pressure was 64 mmHg, partial carbon dioxide pressurewas 26 mmHg, pH was 7.30 and bicarbonate concentration was 21 mmol/l. He was accepted for surgery as a high-risk case in view of the complex nature of the cardiac surgery involving a valve procedure with coronary bypass grafting (CABG) surgery. A median sternotomy was performed and the right lung was found to be significantly prolapsing over to the left and the heart was markedly displaced into the left hemithorax. There were dense pericardial adhesions and moderate left ventricular hypertrophy. Stay sutures were required to hold the right lung away and exposure was quite satisfactory without having to extend the sternotomy incision laterally. Adequate exposure was provided for valve and coronary interventions (Fig. 3). A suitable segment of the saphenous vein was harvested. Cardiopulmonary bypass (CPB) was initiated with the classical method. Myocardial protection was provided through internal cold cardioplegic arrest (St Thomas Cardioplegic solution). Constant blood cardioplegy was given to the retrograde coronary sinus for maintenance of cardioplegy. Without cross clamping, a reversed saphenous vein was used to bypass the RCA and LAD with the beating-heart technique. Then cross clamping was placed on the ascending aorta. A left atriotomy was performed and the calcific mitral valve was excised. The mitral valve replacement was performed with a number 27 mechanical valve (St Jude Medical). The cross clamping was removed and proximal anastomoses were completed to the ascending aorta.

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Fig. 3. The right lung is seen to have shifted into the mediastinal space and the heart into the left hemithorax on intra-operative imaging.

The patient was weaned from CPB without problem. The total bypass time was 105 min and aortic cross-clamp time was 59 min. Temporary bipolar atrial and ventricular pacing wires were used and the chest was closed, leaving the pericardium open. His postoperative course was uneventful. Fluid administration was restricted during the peri-operative period. He could be extubated the next morning. Arterial oxygen saturation of the patient was 90–94% and partial oxygen pressure was 78 mmHg in the postoperative period. Warfarin sodium (Coumadin 5 mg) was started because of the mechanical valves and a dose adjustment was done so as to keep the INR value between 2.5 and 3.5. He was discharged from hospital on the ninth postoperative day. At the six-month follow up he remained in New York Heart Association class I.

Discussion Performing open-heart operations in patients who have undergone pneumonectomy presents several problems due to anatomical and physiological changes.3,4 This results in a much higher risk of surgery, especially in the elderly, and requires careful analysis and management from the pre-operative and intra-operative to the postoperative periods to have a successful outcome. Pulmonary dysfunction is a condition that may commonly be seen after open-heart surgery. Additionally, open-heart surgery performed on patients who have undergone pulmonary lobectomy or pneumonectomy may lead to pulmonary problems. First, a vital capacity reduction related to the previous pulmonary surgery and pericardial adhesions may be seen. Second, herniation of the lung to the opposite side may develop due to mediastinal shift. Besides, anatomical changes in the thoracic cavity may change the normal relationship and position of the heart, lungs and great vessels (such as the vena cava). Third, reduction in pulmonary functions may result in irregularity in oxygenation due to decreased pulmonary reserve, changes in ventilation–perfusion rates, pulmonary capillary pressure and airway pressure. Although these changes are less in patients who have undergone single lobectomy, they may be more severe in those who have undergone pneumonectomy.3-5 When open-heart operations are necessary in patients who have undergone pneumonectomy, the unavoidable shift of the mediastinal structures, exposure of the heart, and localisation of the great vessels and target coronary artery should be carefully

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considered. Alternative incisions such as a left posterolateral thoracotomy that would enable full exposure of the coronary arteries may be required. Besides, it may be difficult to institute standard CPB by means of aortic and right atrial cannulation. These standard cannulation techniques may need to be modified, for example by the use of direct bicaval cannulation, femoral vein cannulation, or cannulation through the pulmonary artery into the right ventricle. However, the off-pump technique is most commonly used, as in our patient, for only CABG. In patients who have multi-vessel lesions, hybrid myocardial revascularisation is another option.4-6 This approach involves the anastomosis of one venous graft to the LAD and the placement of stents in the left main coronary artery and in the ostial and proximal lesion of the circumflex artery. It is difficult to perform a proximal anastomosis to the ascending aorta due to displacement and rotation of the ascending aorta and severe adhesion to the thoracic cavity, so proximal anastomoses to the descending aorta may be more advisable. Consequent to displacement and rotation of the heart and to hyperinflation of the contralateral lung, the internal mammary artery (IMA) may not be useful as a graft for the target vessel because of the risk of IMA stress and tension. Then too, harvesting of the IMA may decrease pulmonary function and increase the risk of injury to the phrenic nerve.4,7,8 Therefore, venous grafts have reportedly been used in most CABG procedures after pneumonectomy. In our patient, we chose saphenous vein grafts, chiefly because the pedicle of the left IMA would not reach its target vessel (the LAD) without being subjected to substantial tension. Also the right lung was displaced to the mediastinal region and the heart had moved into the left hemithorax. This condition could make exposure of the coronary arteries and therefore CABG difficult by making exposure of the heart difficult. However we could fully expose the right coronary artery and LAD. Therefore alternative interventions such as a hybrid revascularisation or left thoracotomy were not required. Difficulty with cannulation could also have occurred due to the mediastinal shift, however we did not encounter any problems during the cannulation procedures of the aorta and right atrium. Although standard approaches are usually preferred in patients who have undergone pneumonectomy and who need to undergo open-heart surgery, sometimes different practices may be required.3-5 Observation of the mitral apparatus may be difficult because of the shifting of the heart to the right as a result of right pulmonary resection. In those cases, the mitral valve may be approached through the left atrial airucula. Transseptal and superior septal approaches may also be preferred.9-11 However, as our patient had undergone a left pneumonectomy previously and the heart had displaced towards the left hemithorax, no difficulties were encountered to access the valve. On the contrary, a left atriotomy was done and mitral valve replacement was performed. Physiological changes likely to occur are impaired lung function and poor pulmonary reserves where even minor atelectasis or pulmonary infection in the postoperative period can be disastrous, as the respiratory reserves decrease by over 50% in these cases; more so in cases of valvular heart disease with high pulmonary artery (PA) pressures.4,12 Mean PA pressures > 40 mmHg carry a higher risk for surgery and we use only glycerol trinitrate solution in the peri-operative period to lower

PA pressures.7,13 As pulmonary dysfunction is both common and frequently severe even after uncomplicated CPB, all possible measures must be taken to preserve the single functioning lung. Postoperative care includes careful fluid management, aggressive pulmonary care including bronchodilator therapy and nebulisation with chest physiotherapy.2,4,12 Pulmonary function, which is inherently reduced after pneumonectomy, becomes even worse after CABG. Although the risk of pulmonary complications increases, no deaths from respiratory failure have been reported in cases of CABG after pneumonectomy. Therefore, there is no general contraindication for open-heart surgery in these special circumstances. Nevertheless, it is prudent to give careful pre-operative consideration to pulmonary function. Forced vital capacity usually reduces approximately 70% on the first day after cardiac surgery compared to pre-operative values. Reduced forced vital capacity improves from the 10th postoperative day. However this increase is about 30% compared to the postoperative period.4,7,14 Such changes may be easily tolerated by patients with normal pulmonary reserve. However pnemonectomy patients have difficulty tolerating this change as their pulmonary reserve has reduced about 50â&#x20AC;&#x201C;55% due to pneumonectomy.4-7 Surgical morbidity is reduced through pulmonary rehabilitation in the early period and mainly with postoperative care. Pulmonary physical exercises and bronchodilator therapy should be started in the pre-operative period. We did this with our patient. In general, conditions to be considered in patients who have a single lung and will undergo open-heart surgery are as follows. The central venous line should be placed from the side that the pneumonectomy was performed because of the risk of pneumothorax. The intra-operative position of the coronary arteries and cannulation procedures should also be considered because of cardiac displacement.4,5,7 Cold topical applications should be avoided in patients with a single lung as diaphragm paralysis may develop. Besides, atelectasis and deep vein thrombosis can be avoided with early mobilisation. Chest physiotherapy and exercises should be done to reduce atelectasis. Bronchodilators, steriods and diuretics should be used in order to prevent pulmonary congestion and bronchospasm. Non-steroid anti-inflammatory drugs may be used, as pain may hinder pulmonary function in the postoperative period. Beta-adrenergic blockage should be avoided due to the risk of bronchospasm. Patients should be ventilated with low pressure in order to avoid postoperative pulmonary barotrauma and they should be extubated as early as possible in order to prevent complications from prolonged intubation.14

Conclusion Performing open-heart operations in patients who have undergone pneumonectomy may have potentially serious complications and these cases require proper pre-operative assessment. Patient selection regarding pulmonary function must be carefully done. The surgical procedure needs to be carefully planned and executed for a successful outcome. We believe that open-heart surgery can be safely performed in patients who have undergone pneumonectomy, with careful pre-operative assessment and preparation for surgery, and fluid infusion (with measurement of central venous pressure).

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References 1.

2. 3.

5. 6.

Taggart DP, el-Fiky M, Carter R, Bowman A, Wheatley DJ. Respiratory dysfunction after uncomplicated cardiopulmonary bypass. Ann Thorac Surg 1993; 56: 1123–1128. Medalion B, Elami A, Milgalter E, Merin G. Open heart operation after pneumonectomy. Ann Thorac Surg 1994; 58: 882–884. Berrizbeitia LD, Anderson WA, Laub GW, McGrath LB. Coronary artery bypass grafting after pneumonectomy. Ann Thorac Surg 1994; 58: 1538–1540. Unlu Y, Ceviz M, Erkut B, Becit N, Kocak H. Double valve replacement after pneumonectomy: a case report. Turkish J Thorac Cardiovasc Surg 2009; 17: 43–45. Izzat MB, Regragui IA, Angelini GD. Mitral valve replacement after previous right pneumonectomy. Ann Thorac Surg 1995; 59: 222–224. Vargas FS, Terra-Filho M, Hueb W, Teixeira LR, Cukier A, Light RW. Pulmonary functions after coronary artery bypass surgery. Respir Med 1997; 91: 629–633. Shanker VR, Yadav S, Hodge AJ. Coronary arteries bypass grafting

8. 9. 10. 11. 12. 13.

14.

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with valvular heart surgery after pneumonectomy. ANZ J Surg 2005; 75: 88–90. Kopec SE, Irwin RS, Umali-Torres CB, Balikian JP, Conlan AA. The postpneumonectomy state. Chest 1998; 114: 1158–1184. Smith CR. Septal-superior exposure of the mitral valve. The transplant approach. J Thorac Cardiovasc Surg 1992; 103: 623–628. Brawley RK. Improved exposure of the mitral valve in patients with a small left atrium. Ann Thorac Surg 1980; 29: 179–181. Zhao BQ, Chen RK, Song JP. Coronary arteries bypass grafting after pneumonectomy. Tex Heart Inst J 2008; 35: 470–471. Pezzella AT. Coronary artery bypass grafting after pneumonectomy. Eur J Cardiothorac Surg 2001; 20: 1273–1274. Kon ND, Tucker WY, Mills SA, Lavender SW, Cordell AR. Mitral valve operation via an extended transseptal approach. Ann Thorac Surg 1993; 55: 1413–1416. Rao V, Todd TR, Weisel RD, Komeda M, Cohen G, Ikonomidis JS, Christakis GT. Results of combined pulmonary resection and cardiac operation. Ann Thorac Surg 1996; 62: 342–346.

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Case Report Left ventricular rupture after double valve replacement in a patient with myocarditis due to myasthenia gravis MIHALIS ARGIRIOU, VASILIS PATRIS, NIKI LAMA, SOTIRIOS KATSARIDIS, ORESTIS ARGIRIOU, CHRISTOS CHARITOS

Abstract Myasthenia gravis is an autoimmune disease characterised by a weakness of the skeletal muscles, with remissions and exacerbations due to antibodies acting on the acetylcholine receptors. This leads to the characteristic defect transmission in the neuromuscular junction. Treatment includes anticholinesterase agents, thymectomy, and immunosuppression. Surgical thymectomy can induce remission or improvement, allowing for reduction in the immunosuppressive treatment. The case of an 84-year-old female patient with myasthenia gravis, aortic valve stenosis, mitral valve regurgitation and myocarditis is described. The development of myocarditis was related to inflammatory cell infiltration, and progressive and additive focal cellular necrosis associated with reactive myocardial fibrosis. After replacement of the mitral valve, complications arose whereby a rupture of the left ventricular posterior wall occurred, which caused massive bleeding and sudden death on the operating table.

who have heart disease.3 It is speculated that the heart and skeletal muscles are also autoimmune targets in MG.4 However, inflammatory myopathies, autoimmune-mediated myocarditis and/or myositis have developed in a few patients with MG, especially thymoma-associated MG.4 Treasure et al.5 classified the complications on the basis of the location of the tear: ruptures located in the posterior atrioventricular groove are type I, ruptures in the posterior wall of the left ventricle at the base of the papillary muscles are type II, and ruptures posterior to the atrio-ventricular area are type III. The ruptures have also been classified by time pattern of presentation: early, delayed and late rupture. This report presents a rare case of early left ventricular rupture after mitral–aortic valve replacement in a patient with MG and myocarditis. The exact rupture could not be classified on the basis of the location because it was not possible to determine its precise location. However, it is postulated that the rupture may be classified as a type III in accordance with Sersar et al.6

Keywords: left ventricular rupture, double valve replacement, myasthenia gravis, thymectomy, myocarditis

Case report

Submitted 6/1/13, accepted 14/8/13 Cardiovasc J Afr 2013; 24: e5–e7

www.cvja.co.za

DOI: 10.5830/CVJA-2013-056

Myasthenia gravis (MG) is an acquired autoimmune disease with remissions and exacerbations due to antibodies acting on the acetylcholine receptors (AChR). This leads to the characteristic defect transmission in the neuromuscular junction,1 usually resulting from a decreased number of active acetylcholine receptors (AChR) at the neuromuscular junction. It is characterised by a weakness of the voluntary skeletal muscles.2 MG patients have been suggested to have a higher-than-normal prevalence of heart disease. Antibodies against β-adrenergic receptors in patients with MG bind to both β1- and β2-adrenergic receptors and may be implicated in the few patients with MG Cardiac Surgery Department, Evaggelismos General Hospital, Athens, Greece MIHALIS ARGIRIOU, MD, mihalisargiriou@ath.forthnet.gr VASILIS PATRIS, MD NIKI LAMA, MD SOTIRIOS KATSARIDIS, MD ORESTIS ARGIRIOU, MD CHRISTOS CHARITOS, MD

An 84-year-old female patient with a history of MG who was on medication for over two years was admitted to our department with an echocardiographic diagnosis of severe aortic valve stenosis (max Gr 84 and AVA 0.65–0.7 cm2), mitral valve regurgitation (3+), the ECG showed T-wave abnormality, atrioventricular dissociation, arrhythmias [chronic atrial fibrillation (AF)], and wide QRS complex. It is important to note that the patient was not treated with Cox-Maze IV (ablation) due to her chronic AF. The patient’s clinical status was classified as NYHA class III and her MG status was Osserman IIB, so her symptoms were not further investigated considering her severe double valvular disease. She was scheduled for an elective aortic–mitral valve repair with simultaneous thymectomy. Initially, a trans-sternal thymectomy was carried out and the hyperplastic thymus tissues were completely removed and sent for histological analysis. The ascending aorta and both venae cavae were cannulated, and cardiopulmonary bypass was instituted. After aortic cross-clamping, myocardial protection was achieved with antegrade and retrograde intermittent cold blood cardioplegia. A longitudinal left atrial incision parallel to the atrial septum was performed to expose the mitral valve. The valve leaflets were fragile and myxomatous, and the chordal structures of the anterior leaflet were ruptured. After excision

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Fig. 1. Infiltration of cardiac muscle fibres by small lymphocytes; a focal aggregation consisting of approximately 25 lymphocytes (H-E stain, × 400).

of the anterior mitral leaflet, interrupted everting sutures were placed in the annulus and passed through the preserved posterior leaflet. The mitral valve was replaced with a 25-mm Sorin bileaflet (Sorin Group®) mechanical prosthesis. All interrupted sutures used for valve replacement were reinforced with Teflon (Bard®) felt pledgets to prevent dehiscence of the prosthesis. The aortic valve was replaced with a 19-mm Sorin (Sorin Group®) mechanical prosthesis. The atrial wall and aorta were sutured and the aortic cross-clamp was released. The procedure was straightforward, but after separation from cardiopulmonary bypass, the pericardium suddenly filled with blood and, on lifting the heart, bleeding was identified from the atrio-ventricular groove with swelling and haematoma in the posterior wall of the left ventricle. The patient was placed back onto bypass and cooled, and the heart was perfused with cold blood cardioplegia again. Teflon (Bard®) felt-buttressed interrupted sutures were placed, but considerable bleeding was continued. We used BioGlue (Cryolife®) to stick a Teflon (Bard®) felt patch approximately 5–6 cm over the involved area, but the bleeding was not stopped, and the condition of the patient deteriorated. All external repair methods were tried, but the sutures themselves also caused additional damages to the friable heart tissue. The patient died on the operating table. Due to the patient’s background we sent heart tissue for biopsy. The biopsy showed diffuse myocardial necrosis with infiltration by lymphocytes (Fig. 1). Immunohistochemistry showed that the lymphocytes were mostly CD3+ T cells (Fig. 2) and T-lymphocytes under the endocardium immune-expressing cytotoxic TIA-1 enzyme (Fig. 3).

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Fig. 2. Detection of T-lymphocytes by CD3 immunohistochemical staining (× 200).

• entrance of deeply placed sutures into the ventricular myocardium • apical venting of the left ventricle with dislocation of the heart and consequent distortion of the left ventricular posterior wall when a rigid mitral prosthesis is in place • forceful traction on the mitral annulus • mechanical injury to the ventricular endocardium caused by such devices as metal vents and cardiotomy suckers, scissors used during valve excision and retractors used to expose the chordae tendineae • forceful compression of the ventricle against the prosthesis during manual massage • positioning the strut of a bioprosthesis against the posterior left ventricular wall. In most cases it is difficult to define the causes of left ventricular rupture. All the above intra-operative events have been linked to left ventricular rupture, but none of these occurred in the present case. In patients with a fragile and myxomatous valve, to reduce the risk of rupture of the left ventricular posterior wall after mitral valve replacement, the posterior mitral leaflet with attached chordae is preserved.

Discussion Rupture of the left ventricular posterior wall, although infrequent, is one of the most life-threatening sequelae of prosthetic replacement of the mitral valve.7 Its cause is still controversial. Female gender, advanced age, intrinsic myocardial disease, mitral stenosis, small body size, and a small left ventricle have been considered as predisposing risk factors.8 A large number of intra-operative factors that initiate the primary tear and cause the transmural left ventricular rupture have been considered:9 • resection of excessive tissue during removal of the mitral valve and consequent injury of the annulus • inaccurate sizing of the annulus and insertion of an oversized prosthesis

Fig. 3. T-lymphocytes under the endocardium immunoexpressing cytotoxic TIA-1 enzyme (× 200).

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An MG patient is often the subject of cardiac disease, as was the case with our patient. According to Hofstad et al.,10 16% of patients with MG have signs of cardiac disease, which is a much higher frequency than that found in the general population. This strongly indicates that these otherwise unexplained signs of heart disease are related to or caused by MG. Such findings are more frequent among thymoma patients (50%) than among non-thymoma patients (12%). The histological changes in the striated muscle found in MG are muscle fibre atrophy and varying degrees of inflammation.10 The inflammatory lesions range from discrete accumulations of lymphocytes without tissue destruction to extensive myonecrosis with heavy inflammatory cell infiltration and signs of regeneration. Hearts microscopically examined by Hofstad et al. had inflammatory infiltrates in the myocardium, with varying degrees of muscle fibre degeneration or necrosis.10 The cardiac findings may be caused by mechanisms specific to MG or they may represent non-specific myocardial damage. The focal, spotty localisation of the myocardial changes indicates that the heart pathology has a causal relationship with MG. Moreover, clinical evaluation usually represents the first diagnostic step for a patient with suspected MG. The evaluation of MG-related symptoms could be difficult as the cardiac disease may mask them. In our case, the pre-operative clinical status was not correctly addressed as the cardiac symptoms were predominant. Hence, the diagnosis of myocarditis in this patient was guided by the intra-operative and histological findings, which led to revaluation of the pre-operative clinical conditions.

Conclusion A dynamic hypothesis concerning the correlation between myocarditis due to myasthenia gravis and left ventricular rupture after mitral valve replacement is presented. Additionally, we believe that endomyocardial biopsy should be considered in this group of patients.

References Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330(25): 1797–1810. 2. Vincent A, Palace J, Hilton-Jones D: Myasthenia gravis. Lancet 2001; 357: 2122–2128. 3. Xu BY, Pirskanen R, Lefvert AK. Antibodies against beta1 and beta2 adrenergic receptors in myasthenia gravis. J Neuroimmunol 1998; 91: 82–88. 4. Zamecnik J, Vesely D, Jakubicka B, et al. Muscle lymphocytic infiltrates in thymoma associated myasthenia gravis are phenotypically different from those in polymyositis. Neuromuscul Disord 2007; 17(11–12): 935–942. 5. Treasure RL, Rainer WG, Strevey TE, Sadler TR. Intraoperative left ventricular rupture associated with mitral valve replacement. Chest 1974; 66: 511–514. 6. Sersar SI, Jamjoom AA. Left ventricular rupture post mitral valve replacement. Clin Med Cardiol 2009; 3: 101–113. 7. Karlson KJ, Ashraf MM, Berger RL. Rupture of left ventricle following mitral valve replacement. Ann Thorac Surg 1988; 46: 590–597. 8. Otaki M, Kitamura N. Left ventricular rupture following mitral valve replacement. Chest 1993; 104: 1431–1435. 9. Reardon MJ, Letsou GV, Reardon PR, Baldwin JC. Left ventricular rupture following mitral valve replacement. J Heart Valve Dis 1996; 5: 10–15. 10. Hdkon H, Ole-Jsrgen O, Sverre J, Merrksand JAA. Acta Neurol Scand 1984: 70: 176–184. 1.

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Case Report Diffuse giant tendon xanthomas in a patient with familial hypercholesterolaemia SERKAN YUKSEL, ESRA PANCAR YUKSEL

Abstract Familial hypercholesterolaemia is a genetic disease that provides the best evidence for the causal role of low-density lipoprotein cholesterol in human atherosclerosis. The disease was ﬁrst described by Muller in 1939 and is characterised by high cholesterol levels from birth, and the subsequent development of tendon and cutaneous xanthomas and premature atherosclerosis. In this case report, we described an 18-yearold female patient who was admitted to the out-patient clinic with swellings on various parts of her body. Her family history, physical examination and laboratory evaluation revealed that these swellings were giant tendon xanthomas caused by familial hypercholesterolaemia. In this report we also discuss the pathogenesis, clinical manifestations, complications and treatment of familial hypercholesterolaemia. Keywords: familial hypercholesterolaemia, xanthelesma, xanthoma Submitted 9/1/13, accepted 14/8/13 Published online 9/10/13 Cardiovasc J Afr 2013; 24: e8–e9

www.cvja.co.za

DOI: 10.5830/CVJA-2013-057

The primary dyslipidaemias are associated with overproduction and/or impaired removal of lipoproteins. The defect can be induced by an abnormality in either the lipoprotein itself or the lipoprotein receptor, and it is often familial. Familial hypercholesterolaemia (FH) is a genetically modulated clinical syndrome in which the phenotype is characterised by high low-density lipoprotein cholesterol (LDL-C) levels from birth, a tendency to develop tendon xanthomas, and early onset coronary artery disease (CAD), which often develops in the absence of other risk factors. LDL receptor (LDL-R) gene mutations are most often the cause of this disease.1,2 Diagnosis requires the patient’s detailed family and personal history, physical examination, and chemical analysis of the blood. It is important not only for the prognosis of the patient, but also has implications for family members who may have the same inherited disorder.1

In this case report, we present a patient with giant tendon xanthomas, high cholesterol levels and a strong family history of early onset CAD caused by FH.

Case report An 18-year-old female patient was admitted to the dermatology clinic because of swellings on various parts of her body. These swellings were painless and had been present for about 10 years. Surgical excision had been tried but they had recurred soon thereafter. A family history of the patient revealed that both her mother and elder sister had early onset CAD. Her mother underwent a coronary artery bypass graft (CABG) operation when she was 35 years old and the elder sister had two separate CABG operations when she was younger than 30 years old. Furthermore, her elder sister had severe valvular aortic stenosis. In her dermatological examination there were xanthelasmas on the medial canthus of both eyes. Xanthomas were present in varying sizes on the lateral and medial sides of her fingers, both elbows, the lateral sides of both feet, the back of her ankles and both knees (Fig. 1). Blood biochemical evaluation revealed that the level of total cholesterol was 687 mg/dl, LDL-C was 635.9 mg/dl, triglycerides (TG) was 50 mg/dl and high-density lipoprotein (HDL) cholesterol was 41.1 mg/dl. Other laboratory tests, including thyroid function, were normal. In the histopathological examination of the punch biopsy specimen of the xanthomas,

Cardiology Department, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey SERKAN YUKSEL, MD, serkan.yuksel@omu.edu.tr

Dermatology Department, Faculty of Medicine, Ondokuz Mayis University Samsun, Turkey ESRA PANCAR YUKSEL, MD

Fig. 1. Xanthomas on the lateral and medial sides of the fingers, elbows, knees and Achilles tendons.

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Fig. 2. Histopathological examination of the punch biopsy specimen stained with haematoxylin and eosin. Histiocyte groups with vacuolated (foamy) cytoplasm between collagen bundles and fibrotic bands were seen.

histiocyte groups with vacuolated (foamy) cytoplasm between collagen bundles and fibrotic bands were seen (Fig. 2). Initially, 80 mg atorvastatin treatment was given. However, this treatment did not result in adequate decrease in LDL-C levels. A 40-mg rosuvastatin and 10-mg ezetimibe combination was then prescribed for the patient.

Discussion FH was ﬁrst described by Muller in 1939 and is characterised by hypercholesterolaemia from birth, the subsequent development of tendon and cutaneous xanthomas, and premature atherosclerosis.1,3 Myant documented that increase in total serum cholesterol was largely due to LDL-C levels, and Goldstein and Brown showed that FH results from defective catabolism of LDL-C caused by dominant mutations in the LDL-R gene.2,4 Heterozygous and homozygous variants have been described. The heterozygous form has a prevalence of approximately 1/500 individuals, whereas the homozygous form is very rare (1/1 000 000). In the homozygous form, high levels of LDL-C (600– 1 000 mg/dl) can be found between birth and five years of age. Clinically, this form is characterised by severe xanthomatosis developing in the first few years of life, multiple types of xanthomas can occur, and coronary atherosclerosis usually develops earlier, characteristically before the teenage years. In the heterozygous form, the cholesterol levels are approximately twice normal, with values usually in the 270–550 mg/dl range. In this form the xanthomatous lesions develop during the third to sixth decades.1,5 Our patient’s clinical characteristics with very high LDL-C levels, diffuse xanthomas at a young age, strong family history of hypercholesterolaemia and early onset CAD in family members were consistent with the homozygous form of FH. Xanthoma is a deposition of yellowish material formed by lipids. Tendon xanthomas are firm, skin-coloured subcutaneous nodules, localised over the proximal finger joints, insertions of the patellar tendons, and the Achilles tendons. Tendonitis, peritendonitis or bursitis, trauma, nodules of rheumatic arthritis, or gout tophi are other frequent conditions that may lead to

tendon thickening, and in such cases, a differential diagnosis may be difficult. A detailed family and medical history, serum lipid analysis, and ultrasound of the affected tendon may help in the differential diagnosis.5 The aim of the treatment of FH patients is reduction of plasma LDL-C concentrations to decrease the risk of CAD. Modern pharmacotherapy can achieve desirable concentrations of LDL-C in heterozygotes but treatment for homozygotes remains problematic.6-8 High-dose atorvastatin, rosuvastatin or simvastatin should be the initial regimen since these drugs are more effective than other statins as monotherapy in heterozygotes with FH.6,7 To retard the progression of premature coronary and/or aortic valvular disease, aggressive treatment must begin in early childhood in homozygotes.8 LDL-apheresis is the standard treatment for patients with homozygous FH because it can lower LDL-C levels in a safe and effective manner. However, the disadvantages of apheresis include limited availability, high cost, the duration of the procedure and the need to maintain adequate vascular access. Ezetimibe induces a complementary reduction in LDL-C concentrations. Therefore statins and ezetimibe are classically used in patients treated with LDL apheresis to achieve LDL-C goals.9 Liver transplantation and gene therapy have the potential for a radical cure but there are too many disadvantages for them to be the treatment of choice.6,9 It has been shown that effective LDL apheresis and statin treatment could prevent the onset of CAD and reduce the size of the xanthomas.10 We initiated a high-dose potent statin and ezetimibe treatment for our patient. However, LDL apheresis could not be started because of the unavailability of the technique in our hospital.

Conclusion The early diagnosis and treatment of FH is crucial, especially for the prevention of CAD and the development of xanthomas.

References Durrington P. Dyslipidaemia. Lancet 2003; 362(9385): 717–731. Goldstein JL, Brown MS. The LDL receptor locus and the genetics of familial hypercholesterolemia. A Rev Genet 1979; 13: 259–289. 3. Muller C. Angina pectoris in hereditary xanthomatosis. Arch Intern Med 1939; 64: 675–700. 4. Myant NB. The metabolic lesion in familial hypercholesterolaemia. Expos A Biochim Med 1977; 33: 39–52. 5. Rapp JH, Connor WE, Lin DS, Inahara T, Porter JM. Lipids of human atherosclerotic plaques and xanthomas: clues to the mechanism of plaque progression. J Lipid Res 1983; 24(10): 1329–1335. 6. Farnier M, Bruckert E. Severe familial hypercholesterolaemia: Current and future management. Arch Cardiovasc Dis 2012; 105(12): 656–665. 7. Naoumova RP, Thompson GR, Soutar AK. Current management of severe homozygous hypercholesterolaemias. Curr Opin Lipidol 2004; 15(4): 413–422. 8. Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE, et al. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J Cardiol 2008; 102(11): 1438–1443. 9. Thompson GR. Lipoprotein apheresis. Curr Opin Lipidol 2010; 21(6): 487–491. 10. Riche DM, East HE. Xanthomas associated with homozygous familial hypercholesterolemia. Pharmacotherapy 2009; 29(12): 1496. 1. 2.

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Case Report Acute aortic dissection with a dangerous duo in an adolescent boy TAHIR BEZGIN, CEM DOĞAN, ALI ELVERAN, ALI KARAGÖZ, CAN YÜCEL KARABAY, ALI METIN ESEN

Abstract Acute type II aortic dissection and aortic coarctation are rare combined disorders. This report is of a patient with coarctation, a bicuspid aortic valve and type II dissection, who underwent emergency repair for the dissection, with aortic valve preservation. Repair of the coarctation was planned for a future occasion. The optimal sequence and timing of the repair, the best surgical technique, adequacy of blood perfusion, and the most appropriate arterial cannulation site are important issues in the repair of aortic dissection secondary to aortic coarctation.

Bedside transthoracic echocardiography revealed an aneurysmal dilatation with an intimal flap in the ascending aorta, a bicuspid aortic valve, minimal pericardial effusion, and a mild degree of aortic regurgitation (Fig. 1). The diameter of the ascending aorta was 7.5 cm. Left ventricular function was within normal limits. Computed tomography with three-dimensional reconstruction demonstrated CoA and a dissection plane starting from the level of the aortic valve to the arcus aorta (Figs 2, 3). The patient was immediately taken to the operating room. Cardiopulmonary bypass was established with arterial

Keywords: aortic dissection, coarctation, bicuspid aortic valve Submitted 4/3/13, accepted 4/9/13 Cardiovasc J Afr 2013; 24: e10–e12

www.cvja.co.za

DOI: 10.5830/CVJA-2013-064

A combination of acute aortic dissection (AAD) associated with significant coarctation (CoA) of the aorta and other cardiac abnormalities is rarely seen. In a review of the literature, it was found that these combined disorders have been treated with multi- or single-stage surgery.1-4 In both conditions, there is a problem with sufficient blood flow to the upper and lower torso. We present a case of AAD associated with CoA and a bicuspid aortic valve, which we were able to treat successfully with a two-stage approach, first performing repair of the AAD, with correction of the CoA done in another session.

Case report A 16-year-old male was admitted to emergency because of transient loss of consciousness. On clinical examination, a 2/6 diastolic murmur was noted in the precordium, with muffled heart sounds. The blood pressure was 140/100 mmHg in his right arm, 110/70 mmHg in his left arm and 90/40 mmHg in his legs. The femoral pulses were weakly palpated. The body stature of the patient was not Marfanoid.

Cardiology Clinic, Kartal Koşuyolu Heart and Research Hospital, Istanbul, Turkey TAHIR BEZGIN, MD, bezgintahir3@yahoo.com CEM DOĞAN, MD ALI ELVERAN, MD ALI KARAGÖZ, MD CAN YÜCEL KARABAY, MD ALI METIN ESEN, MD

B Fig. 1. Transthoracic echocardiography with parasternal long- and short-axis images shows the dissection flap, aneurysm of the ascending aorta, pericardial effusion and bicuspid aortic valve (arrow).

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Fig. 2. Computed tomography of the chest demonstrates the dissection plane with double lumen.

cannulation in the right axillary artery, and venous cannula drainage. After median sternotomy, the ascending aorta was cross-clamped just proximal to the brachiocephalic artery. The mean blood pressure of the dorsalis pedis was not satisfactory, and another cannula was inserted into the femoral artery to adequately perfuse the lower body. The patient was slowly cooled to 24°C and aortotomy was performed. Antegrade direct blood cardioplegia was used selectively to each coronary ostium to arrest the heart and it was repeated every 20 minutes. Aortotomy confirmed an intimal tear situated just 2 cm above the non-coronary sinus with no extension of the flap beyond the ascending aorta. The aortic annulus was dilated and the valve was bicuspid, but the valves were anatomically normal. A total ascending aortic replacement was performed with a tube graft of 26 mm, suturing the proximal anastomosis at the sino-tubular junction and distally to the starting point of the aortic arch. The brachiocephalic artery was unclamped and cardiopulmonary bypass was maintained at 4.5 l/min/m2 to rewarm the patient. A mean perfusion pressure of 67 mmHg was maintained, with the lowest perfusion pressure being 55 mmHg at the initiation of cardiopulmonary bypass. Intra-operative transoesophageal echocardiography showed neither aortic regurgitation nor any residual valvular abnormalities. The total cardiopulmonary bypass duration was 130 minutes and total aortic cross-clamp time was 80 minutes. The patient’s postoperative course was uneventful and he was discharged on postoperative day 18. Computed tomography revealed satisfactory repair, and no aortic valve insufficiency was detected on echocardiograms two weeks and six months after surgery. Repair of the CoA was scheduled for as soon as possible.

Discussion AAD is a life-threatening disease. Complications such as aortic rupture, cardiac tamponade and acute aortic regurgitation require immediate surgical intervention. The combination of acute aortic dissection and CoA is a rare but a significant condition due to the choice of surgical timing and perfusion methods. Bicuspid aortic valve is common and occurs in 1–2% of the population.5

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Fig. 3. Computed tomography with three-dimensional reconstruction reveals coarctation (arrow) at the level of the aortic isthmus.

In addition, up to 40% of patients with CoA have an associated bicuspid aortic valve.6 As expected, surgery of the AAD combined with CoA can be more challenging than a simple aneurysm and CoA repair. Several surgical options are available. Reported treatment choices include simultaneous repair of an AAD and CoA by extra-anatomical bypass in a single operation, and sequential repair of an AAD followed by CoA repair. As a staged strategy, Sampath and colleagues advocated initial repair of the CoA to relieve proximal hypertension, so decreasing the risk of progressive dissection or rupture.7 This also permits safe perfusion during repair of the dissection in the second stage of an operation. On the other hand, replacement of the ascending aorta can be performed first, followed by repair of the CoA at a later time.8-10 Plunkett et al. reported a case of a pregnant patient in which the aneurysm was repaired first using femoral arterial cannulation, but they had to repair the CoA in the early postoperative period because of refractory heart failure.9 Single-stage surgical repair of this combination with successful outcomes has been reported.11,12 Correction of the CoA first can solve possible cannulation and perfusion problems. The most significant difficulties related to a dissected aortic aneurysm are arterial cannulation and perfusion problems because dissection impedes cannulation of the ascending and arcus aorta. If cannulation is performed via a femoral artery, this procedure can result in perfusion difficulties, especially to the upper extremities and brain. Lawson et al. reported a case in which they repaired the CoA first then the AAD.13 Percutaneous treatment of the CoA followed by repair of the aortic dissection is another choice of therapy sequence that may be preferred.14-15 When a combined single-stage procedure is undertaken, it can be difficult to provide adequate blood flow on cardiopulmonary bypass (CPB) to both the upper and lower body. This is because when the gradient across the coarctation is high, femoral artery cannulation can deliver adequate blood flow to only the lower torso and not to the upper torso proximal to the coarctation of the aorta. Similarly, establishing CPB with cannulation of the distal arch in patients with coarctation may result in inadequate blood flow to the lower torso. When a patient presents with a combination of acute dissection

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and CoA, establishing adequate blood flow to the upper body during CPB can be difficult, especially when the gradient across the coarctation is severe. The problem can be solved by putting a Y-graft into the arterial line, perfusing the lower body via a tube graft attached to the supracoeliac aorta, and perfusing the upper body and head via a cannula in the aortic arch. This allows for the maintenance of adequate flow to both areas of the body.7 Furthermore, using this approach, the two lesions can be treated in a single operation. Therefore bypass is performed from the ascending aorta beyond the coarctation, bypassing the stenosis and resulting in normal blood pressures. There is also a risk of inadequate blood flow to the organs beyond the coarctation, leading to end-organ failure, including spinal cord ischaemia, hepatic failure and bowel ischaemia when the coarctation is not relieved in the same session. When weaning the patient from cardiopulmonary bypass, there is a risk of detachment of the anastomosis to the acutely inflamed aorta because of the CoA. Valve-sparing aortic replacement for a root aneurysm with a morphologically intact valve has become a common procedure with acceptable results, but this operation for a dilated aorta with bicuspid valve remains challenging. However, some reports have demonstrated acceptable early and mid-term results of a valvesparing root replacement in patients with a bicuspid valve.16,17 Because of the patient’s haemodynamic instability, we did not consider either a single-stage procedure, due to the increased operating time and possible malperfusion, or percutaneous treatment of the CoA. Since the aortic valve was bicuspid and intact, valve-sparing replacement of the ascending aorta was performed, and repair of the CoA was planned for a second operation at a later stage.

Conclusion Repair of the AAD takes precedence over CoA repair. A two-stage surgical approach appears to be a safe choice, taking into account the feasibility of perfusing all arterial regions during replacement of the ascending aorta.

4. 5.

10.

11.

12.

13. 14.

15.

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Bricker DL, Parker TM, Mistrot JJ, Dalton ML. Repair of acute dissection of the ascending aorta, associated with coarctation of the thoracic aorta in a Jehovah’s Witness. J Cardiovasc Surg (Torino) 1980; 21(3):

17.

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374–378. Hovaguimian H, Aru GM, Floten HS. Acute type 1 aortic dissection with coarctation of the aorta: discussion of management and the report of a successful brain perfusion across an aortic coarctation. J Thorac Cardiovasc Surg 1990; 100: 152–153. Horai T, Shimokawa T, Takeuchi S, et al. Single-stage surgical repair of type II acute aortic dissection associated with coarctation of the aorta. Ann Thorac Surg 2007; 83: 1174–1175. Svensson LG. Management of acute aortic dissection associated with coarctation by a single operation. Ann Thorac Surg 1994; 58: 241–243. Furukawa K, Ohteki H, Cao ZL, et al. Does dilatation of the sinotubular junction cause aortic regurgitation? Ann Thorac Surg 1999; 68: 949–953; discussion 953–954. Sabet HY, Edwards WD, Tazelaar HD, Daly RC. Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991–1996) and a literature review of 2,715 additional cases. Mayo Clin Proc 1999; 74: 14–26 Sampath R, O’Connor WN, Noonan JA, Todd EP. Management of ascending aortic aneurysm complicating coarctation of the aorta. Ann Thorac Surg 1982; 34: 125–231. Rampoldi V, Trimarchi S, Tolva V, Righini P. Acute type A aortic dissection and coarctation of aortic isthmus. J Cardiovasc Surg 2002; 43: 701–703. Plunkett MD, Bond LM, Geiss DM. Staged repair of acute type I aortic dissection and coarctation in pregnancy. Ann Thorac Surg 2000; 69: 1945–1947. Erkut B, Koçoğullari CU, Ozyazicioğlu A, Koçak H. Two-stage successful surgery in an aortic coarctation case operated initially for ascending aortic aneurysm. Anadolu Kardiyol Derg 2007; 7(4): 445–448. Paparella D, Schena S, Schinosa LLT, Vitale N. One step surgical repair of type 2 acute aortic dissection and aortic coarctation. Eur J Cardiothorac Surg 1999; 16: 584–586. Ananiadou OG, Koutsogiannidis C, Ampatzidou F, Drossos GE. Aortic root aneurysm in an adult patient with aortic coarctation: a single-stage approach. Interact Cardiovasc Thorac Surg 2012; 15(3): 534–536. Lawson RA, Fenn A. Dissection of an aneurysmal ascending aorta in association with coarctation of the aorta. Thorax 1979; 34: 606–611. Imamura M, Aoki H, Eya K, Murakami T, Yasuda K. Balloon angioplasty before Wheat’s operation in a patient with Turner’s syndrome. Cardiovasc Surg 1995; 3: 70–72. Heper G, Yorukoglu Y, Korkmaz ME. Clinical and hemodynamic follow-up of a patient after operation for dissection of an ascending aortic aneurysm secondary to coarctation of the aorta. Int Heart J 2005; 46(6): 1123–1131. Aicher D, Langer F, Kissinger A, Lauberg H, Fries R, Schafers HJ. Valve-sparing aortic root replacement in bicuspid aortic valves: a reasonable option? J Thoracic Cardiovasc Surg 2004; 128: 662–668. Kallenbach K, Karck M, Pak D, et al. Decade of aortic valve sparing reimplantation: are we pushing limits too far? Circulation 2005; 112: I253–259.

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PUBLISHED ONLINE: • Mitral valve and CABG surgeries after pneumonectomy • Left ventricular rupture after double valve replacement