cvja volume 24, issue 6

JULY 2013VOL 24 NO 6

CardioVascular Journal of Africa (official journal for PASCAR)www.cvja.co.za

Cardiovascular Journal of A

frica . Vol 24, No 6, July 2013

• DuctalclosurewithAmplatzerductoccluder

• UncontrolledhypertensioninSudaneseadults

• AorticclampingtechniquesduringCABsurgery

• MyocarditisandcardiotropicvirusinfectioninAfricans

• Ventilationduringcardiopulmonarybypass

• LongQTsyndromeinSouthAfrica

• InsightsfromtheCEPHEUSSAstudy

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REFERENCES:1. South African Dyslipidaemia Guideline Consensus Statement. March 2012, Vol. 102, No. 3 SAMJ2. Department of Health website http://www.doh.gov.za – accessed 06/20133. IMS data March 20134. Data on file

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BY M ORE THAN

EditorsActing Editor in Chief (South Africa)Prof PA Brink

Assistant EditorProf JAMES kEr (JUn)

regional EditorDr A DzUDiE

regional Editor (kenya)Dr f BUkAChi

regional Editor (South Africa)Prof r DELPorT

sUBJECt Editorsnuclear Medicine and imagingDr MM SAThEkGE

heart failureDr G viSAGiE

PaediatricDr S Brown

renal hypertensionDr BriAn rAynEr

SurgicalDr f Aziz

Adult SurgeryDr J roSSoUw

Epidemiology and PreventionistDr AP kEnGnE

Editorial BoardProf PA BrinkExperimental & Laboratory Cardiology

Prof r DELPorTChemical Pathology

Prof Mr ESSoPhaemodynamics, heart failure & valvular heart Disease

Dr oB fAMiLoniClinical Cardiology

Dr v GriGorovinvasive Cardiology & heart failure

Prof J kEr (SEn)hypertension, Cardiomyopathy, Cardiovascular Physiology

Dr J LAwrEnSonPaediatric heart Disease

Prof A LoChnErBiochemistry/Laboratory Science

Prof BM MAyoSiChronic rheumatic heart Disease

Dr MT MPECardiomyopathy

Prof DP nAiDooEchocardiography

Prof B rAynErhypertension/Society

Prof MM SAThEkGEnuclear Medicine/Society

Prof yk SEEDATDiabetes & hypertension

Prof h DU T ThEroninvasive Cardiology

intErnational advisory BoardProf DAviD CELEMAJErAustralia (Clinical Cardiology)

Prof kEiTh CoPELin fErDinAnDUSA (General Cardiology)

Dr SAMUEL kinGUECameroon (General Cardiology)

Dr GEorGE A MEnSAhUSA (General Cardiology)

Prof wiLLiAM nELSonUSA (Electrocardiology)

Dr ULriCh von oPPELwales (Cardiovascular Surgery)

Prof PETEr SChwArTzitaly (Dysrhythmias)

Prof ErnST von SChwArzUSA (interventional Cardiology)

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

Cardiovascular Journal of Africa www.cvja.co.za

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Editorial199 Cardiotropic viral infection in HiV-associated cardiomyopathy: pathogen or innocent

bystander?LA Blauwet • LT Cooper

lEttEr to tHE Editor

201 left ventricular hypertrabeculation/non-compaction in a pregnant womanJ Finsterer • SZ Mahjoub

CardioVasCular topiCs202 ductal closure using the amplatzer duct occluder type two: experience in port Elizabeth

hospital complex, south africaL Pepeta • A Dippenaar

208 awareness of hypertension and factors associated with uncontrolled hypertension in sudanese adultsFA Babiker • LA Elkhalifa • ME Moukhyer

213 Effects of single aortic clamping versus partial aortic clamping techniques on post-operative stroke during coronary artery bypass surgeryIS Uyar • MB Akpinar • V Sahin • F Abacilar • V Yurtman • FF Okur • U Ozdemir • M Ates

218 prevalence of myocarditis and cardiotropic virus infection in africans with HiV-associated cardiomyopathy, idiopathic dilated cardiomyopathy and heart transplant recipients: a pilot studyG Shaboodien • C Maske • H Wainwright • H Smuts • M Ntsekhe • PJ Commerford • M Badri • BM Mayosi

managing editorGLENDA HARDYTel: 021 976 8129Cell: 071 819 6425e-mail: [email protected]

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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.

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224 Ventilation during cardiopulmonary bypass did not attenuate inflammatory response or affect postoperative outcomes AB Durukan • HA Gurbuz • N Salman • EU Unal • HI Ucar • CEM Yorgancioglu

231 long Qt syndrome in south africa: the results of comprehensive genetic screeningPL Hedley • GA Durrheim • F Hendricks • A Goosen • C Jespersgaard • B Støvring • TT Pham • M Christiansen • PA Brink • VA Corfield

238 Gender and ethnic differences in the control of hyperlipidaemia and other vascular risk factors: insights from the CEntralised pan-south african survey on tHE under-treatment of hypercholesterolaemia (CEpHEus sa) studyN Rapeport • CL Schamroth • DJ Blom

druG trEnds in CardioloGy243 anticoagulation: ‘putting new evidence into clinical practice’

G Hardy

puBlisHEd onlinE (Available on www.cvja.co.za and in Pubmed)

CasE rEportse1 new vascular ring connectors in surgery for intramural haematoma of the abdominal

aorta progressing to ruptureC-H Lee • L-W Ko • Y-C Lin • C-C Yen • H-Y Yang • C-H Kao • C-S Tsai • Y-T Tsai

e4 Endovascular stent-graft repair for abdominal aortic aneurysm in a patient with a short and severely angulated proximal aortic neckAE-Y Her • YH Kim

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 6, July 2013AFRICA 199

Editorial

Cardiotropic viral infection in HiV-associated cardiomyopathy: pathogen or innocent bystander?LORI A BLAUWET, LESLIE T COOPER

Clinical cardiovascular presentations associated with HIV infection include myocarditis, pericarditis, dilated cardiomyopathy (DCM), arrhythmias and vascular disease. The incidence of cardiomyopathy, myocarditis and pericardial diseases correlates with the severity of HIV infection as measured by low CD4 count or high viral titre. In retrospective series and autopsy studies performed in the pre-HAART (highly active antiretroviral therapy) era, the incidence of cardiac involvement in patients with HIV ranged from 6–79%.1-6 In areas where HAART is readily available, the incidence of primary cardiomyopathy in HIV-infected patients is decreasing, but the prevalence of all cardiac disease, including atherosclerosis, in these patients is increasing due to improved survival rates.

Myocarditis with lymphocytic infiltration has been reported to be present in 40–52% of patients who died of AIDS in the pre-HAART era.4 In countries where HAART has been readily available for a number of years, the prevalence of HIV-associated cardiomyopathy has been reduced by approximately 30% due to the prevention of opportunistic infections and a reduction in the incidence of myocarditis.7 However, in developing countries where HAART is not readily available and nutritional and environmental factors may have a greater impact on the pathogenesis of cardiac disease, the prevalence of HIV-associated cardiomyopathy is increasing.6 Many HIV-infected patients who do not receive HAART develop cardiac disease.8

The pathogenesis of HIV-associated cardiomyopathy is complicated by infection with pathogens that are associated with immunosuppression, nutritional deficiencies and other confounding factors. Although the mechanisms by which HIV infection is associated with cardiac dysfunction remain unclear, activation of cytokines and alteration of immune cells that affect cardiac function likely play a significant role.

Another potential confounding factor in the current era is that nucleoside reverse transcriptase inhibitors, a cornerstone among the HAART medications used to treat HIV/AIDS, have occasionally been implicated in the pathogenesis of HIV-associated cardiomyopathy, possibly through mitochondrial DNA toxicity.9,10

In this issue of the Cardiovascular Journal of Africa, Shaboodien et al. (page 218) report on associations between myocarditis, viral infection and HIV-associated cardiomyopathy. Endomyocardial biopsy specimens of 33 patients (14 with HIV-associated cardiomyopathy, eight with idiopathic DCM and 11 heart transplant recipients) were examined. Myocarditis was present in 44% (6/14) of the patients with HIV-associated cardiomyopathy (three acute and three chronic myocarditis), 25% (2/8) of the patients with DCM (both chronic myocarditis)

and 36% (4/11) of the heart transplant recipients (two acute and two chronic myocarditis). Cardiotropic viral infection was present in 90% of the heart transplant recipients and in all of the HIV-associated cardiomyopathy and DCM cases. Multiple viruses were present in most cases.

Several features of the study by Shaboodien et al. deserve comment. First of all, the HIV-positive patients in the study had not received antiretroviral therapy (ART) and their average CD4 count was only 246 cells mm3. Therefore these observations provide a contemporary and rare window into the pathogenesis and natural history of HIV-associated cardiomyopathy in patients who received no antiretroviral therapy.

Second, the distribution of cardiotropic viruses among the patients in this series differs from that observed in patients in more developed countries. The most common viruses present in the HIV-associated cardiomyopathy patients in this study were Epstein Barr and herpes simplex, while co-infection with cytomegalovirus or adenovirus is more common in patients with HIV-associated cardiomyopathy in North America and Europe. The most common virus detected in DCM patients in the study cohort was enterovirus, while Parvovirus B19 was among the least detected. Among patients with chronic DCM studied in North America and Europe, Parvovirus B19 is one of the most common viruses currently being detected. The reason(s) for these geographic differences is uncertain.

The observation that the number of viruses and the percentage of patients with myocarditis were numerically higher in the HIV-associated cardiomyopathy cases than in either heart transplant recipients with a normal ejection fraction on immunosuppression or patients with idiopathic DCM on no immunosuppression suggests that both the state of immunosuppression and the degree of damage to the left ventricle contribute to inflammation and cardiotropic viral infection in the HIV-infected population. Damaged myocardium from either direct HIV infection or co-infection with other viruses may provide a ‘danger signal’ to the immune system, triggering pro-inflammatory cytokine release through toll-like receptor activation by endogenous antigens such as cardiac myosin.

HIV-infected patients with advanced cardiomyopathy represent a high-risk cohort which may potentially benefit from both additional antiretroviral treatment and tailored therapy directed specifically at opportunistic viral infection, including immunisation and/or antiviral drug therapy. The results of the Shaboodien study are intriguing because they open the possibility for novel tailored therapy in patients with HIV-associated cardiomyopathy based on the results of endomyocardial biopsy.

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 6, July 2013200 AFRICA

One weakness of the study is that a few putative cardiotropic viruses, such as human herpes virus 6, hepatitis C and varicella virus, were not tested. If the cardiotropic virus panel investigated in this study had been more complete, the presence of cardiotropic viruses among the patients in this study may have been even higher than reported. Another weakness, as the authors rightly point out, is the small sample size, which limits the generalisability of the findings in this study.

Observations by Towbin et al.11 in children who underwent heart transplantation revealed that the presence of viral genomes in the allograft heart predicts a subsequent risk of allograft rejection. In the setting of HIV-associated cardiomyopathy where viral infection is also present in immunocompromised hosts, there may be a similar risk of progressive cardiomyopathy and end-stage heart failure as a result of viral co-infections. The hypothesis that opportunistic viral infection leads to end-stage cardiomyopathy in patients with untreated HIV could be tested in a prospective observational study performed in locations where HAART is currently not available.

There are a number of unmeasured variables that may have contributed to the development of cardiomyopathy and myocarditis in the populations assessed in Shaboodien’s study, including exposure to heavy metals and malnutrition. Exposure to low doses of mercury has been shown to increase chronic myocarditis and DCM in a murine model.12 Deficiencies of trace elements such as copper and selenium result in increased oxidative stress and foster active virus replication, while malnutrition results in increased oxidative stress as well as increased virulence of cardiotropic viruses. Any of these factors could contribute to a higher rate of myocarditis or viral infection among the patients included in the current study.

Myocarditis is not infrequently associated with other immunocompromised states such as rheumatological and inflammatory bowel diseases. Usually the pathogenesis is assumed to be related to epitope spreading or molecular mimicry from the original inflammatory response and the treatment is therefore augmented immunosuppression. However, there are no outcome data regarding the benefit of such a strategy, and the role of viral infection in the cardiomyopathies associated with these disorders has yet to be explored.

Shaboodien and co-workers’ observations on the association of viral genomes, myocarditis and cardiomyopathy should be extended to include longer term outcome data such as risk of death and recurrent heart failure in their population. We still do not know whether the cardiomyopathy associated with untreated HIV will improve with antiretroviral therapy. As antiretroviral agents are most likely now available to this cohort, the impact of these medications on left ventricular function, inflammation and infection should be prospectively assessed.

In addition, an investigation of the cardiovascular effects of treating opportunistic viral infections in patients with established HIV-associated cardiomyopathy is warranted.

LORI A BLAUWET, MD, [email protected] T COOPER (jun), MDDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, USA

References1. Cammarosano C, Lewis W. Cardiac lesions in acquired immune defi-

ciency syndrome (AIDS). J Am Coll Cardiol [Research Support, US Government, PHS]. 1985; 5(3): 703–706.

2. Anderson DW, Virmani R, Reilly JM, O’Leary T, Cunnion RE, Robinowitz M, et al. Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome. J Am Coll Cardiol 1988; 11(4): 792–799.

3. Lewis W. AIDS: cardiac findings from 115 autopsies. Prog Cardiovasc Dis 1989; 32(3): 207–215.

4. Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Cardiac involve-ment in the acquired immunodeficiency syndrome: a multicenter clinical-pathological study. Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. AIDS Res Hum Retroviruses 1998; 14(12): 1071–1077.

5. Pugliese A, Gennero L, Vidotto V, Beltramo T, Petrini S, Torre D. A review of cardiovascular complications accompanying AIDS. Cell Biochem Funct 2004; 22(3): 137–141.

6. Twagirumukiza M, Nkeramihigo E, Seminega B, Gasakure E, Boccara F, Barbaro G. Prevalence of dilated cardiomyopathy in HIV-infected African patients not receiving HAART: a multicenter, observational, prospective, cohort study in Rwanda. Curr HIV Res 2007; 5(1): 129–137.

7. Bijl M, Dieleman JP, Simoons M, van der Ende ME. Low prevalence of cardiac abnormalities in an HIV-seropositive population on antiret-roviral combination therapy. J Acquir Immune Defic Syndr 2001; 27(3): 318–320.

8. Longo-Mbenza B, Seghers KV, Phuati M, Bikangi FN, Mubagwa K. Heart involvement and HIV infection in African patients: determinants of survival. Int J Cardiol 1998; 64(1): 63–73.

9. Breuckmann F, Neumann T, Kondratieva J, Wieneke H, Ross B, Nassenstein K, et al. Dilated cardiomyopathy in two adult human immunodeficiency positive (HIV+) patients possibly related to highly active antiretroviral therapy (HAART). Eur J Med Res 2005; 10(9): 395–399.

10. Patel K, van Dyke RB, Mittleman MA, Colan SD, Oleske JM, Seage GR, 3rd. The impact of HAART on cardiomyopathy among children and adolescents perinatally infected with HIV-1. AIDS 2012; 26(16): 2027–2037.

11. Pietra BA, Kantor PF, Bartlett HL, Chin C, Canter CE, Larsen RL, et al. Early predictors of survival to and after heart transplantation in children with dilated cardiomyopathy. Circulation. [Multicenter Study. Research Support, N.I.H., Extramural]. 2012 Aug 28;126(9):1079-86.

12. Nyland JF, Fairweather D, Shirley DL, Davis SE, Rose NR, Silbergeld EK. Low-dose inorganic mercury increases severity and frequency of chronic coxsackievirus-induced autoimmune myocarditis in mice. Toxicol Sci 2012; 125(1): 134–143.


letter to the Editor

left ventricular hypertrabeculation/non-compaction in a pregnant woman

dear sirWe read with interest the article by Kilic et al. about a 19-year-old female who developed exertional dyspnoea, neck vein distension and pulmonary congestion shortly after delivery. Transthoracic echocardiography revealed a dilated left ventricle, an ejection fraction of 20%, pulmonary artery hypertension, and surprisingly, left ventricular hypertrabeculation/non-compaction (LVHT).1 We have the following comments and concerns.

LVHT is not only due to an arrest in the cardiac compaction process during embryogenesis, it may have another pathogenetic background as well. In acquired LVHT, which has occasionally been reported, LVHT is not present at birth but develops during the patient’s lifetime.2

Some studies show an increased frequency of stroke or embolism among patients with LVHT, and other studies do not confirm these findings. Did the presented patient have a history of stroke or embolism, or were thrombi detected within the intertrabecular spaces? Some studies report an increased risk of stroke or embolism only in association with systolic dysfunction or atrial fibrillation.3 Was a cerebral MRI carried out?

Despite a negative family history for heart failure, it could be useful to look for LVHT in other family members. In a study of 15 families, with at least a single index patient with LVHT, familial LVHT was detected in 27% of the cases.4

LVHT is frequently associated with neuromuscular disorders or chromosomal abnormalities, in particular muscular dystrophies, myotonic dystrophies, metabolic myopathies, inclusion body myositis, Barth syndrome, or 1q36 syndrome.5 Was the presented patient seen by a neurologist? Were there clinical indications of a neuromuscular disorder or a chromosomal defect? Was there facial or limb dysmorphism? What were the CK values and was an electro- myogram recorded? Since some of the neuromuscular disorders present with only mild manifestations, it is essential to refer each patient with LVHT to a neurologist specialised in neuromuscular disorders so as not to overlook associated muscle disease.

Altenberger et al. reported single patients with LVHT in whom LVHT had disappeared during their lifetime.6 Was echocardiography carried out after delivery? Was there ever a change observed in the morphology or extension of LVHT between initial and follow-up echocardiographic investigations?

The patient received treatment with beta-blockers, angiotensin-converting inhibitors, diuretics, and acetyl-salicylic acid.1 Did the morphology or extension of LVHT change on treatment?

LVHT is visible on ultrasound in foetuses during intra-uterine development.7 Was echocardiography carried out on the patient’s child during pregnancy or after delivery? Since LVHT can be detected during intra-uterine development, foetuses of mothers with LVHT should be screened for the abnormality, since isolated and non-isolated LVHT are associated with an increased risk of developing heart failure, severe arrhythmias, or stroke or embolism.

Overall, there are a number of points that need to be addressed before drawing final conclusions about LVHT. LVHT patients require close cardiological follow up so as not to overlook deterioration of systolic function or the development of ventricular arrhythmias. Patients with LVHT require neurological investigations to confirm or exclude the presence of a neuromuscular disorder or chromosomal abnormality.

JOSEF FINSTERER, MD, PhD, [email protected] Krankenanstalt Rudolfstiftung, Vienna, Austria

SINDA ZARROUK MAHJOUB, PhD Biochemistry Laboratory, UR Human Nutrition and Metabolic Disorders, Faculty of Medicine, Monastir, Tunisie

References 1. Kilic ID, Tanriverdi H, Evrengul H, Uslu S, Sungur MA. Left ventricu-

lar non-compaction in pregnancy. Cardiovasc J Afr 2013; 24: e1–2.2. Finsterer J, Stöllberger C, Bonner E. Acquired noncompaction associ-

ated with coronary heart disease and myopathy. Heart Lung 2010; 39: 240–241.

3. Stöllberger C, Blazek G, Dobias C, Hanafin A, Wegner C, Finsterer J. Frequency of stroke and embolism in left ventricular hypertrabecula-tion/noncompaction. Am J Cardiol 2011; 108: 1021–1023.

4. Finsterer J, Stöllberger C, Blazek G, Sehnal E. Familal left ventricular hypertrabeculation (noncompaction) is myopathic. Int J Cardiol 2013; 164: 312–317.

5. Finsterer J, Stöllberger C, Fazio G. Neuromuscular disorders in left ventricular hypertrabeculation/noncompaction. Curr Pharm Des 2010; 16: 2895–2904.

6. Altenberger J, Hasenauer G, Granitz M, Stöllberger C, Finsterer J. Disappearance of left ventricular hypertrabeculation/noncompaction and sudden death in a patient with Turner mosaic syndrome. Am J Cardiol 2012; 110: 314–315.

7. Gardiner H, Holder S, Karatza A. Prenatal diagnosis of fetal left ventricular non-compaction cardiomyopathy. Ultrasound Obstet Gynecol 2012; 40: 730–731.


Cardiovascular Topics

ductal closure using the amplatzer duct occluder type two: experience in port Elizabeth hospital complex, south africaLUNGILE PEPETA, ADELE DIPPENAAR

abstractObjective: To report outcomes in percutaneous ductal closure using the Amplatzer duct occluder type two (ADO II). Methods: Records of patients admitted for percutaneous closure of patent ductus arteriosus (PDA) were reviewed. Results: From May 2009 to July 2012, 36 patients were assigned to closure using the ADO II. There were 21 females and 15 males. The median age was 16.5 (2–233) months; median weight, 8 (3.94–39.2) kg; and median height, 75 (55–166) cm. The mean pulmonary artery pressure was 24.4 (± 10.4) mmHg, the pulmonary blood flow:systemic blood flow (Qp:Qs) ratio was 2.25 (± 1.97), and mean pulmonary resistance (Rp) was 1.87 (± 1.28) Wood units. The mean ductal size was 2.74 (± 1.3) mm. In 30 patients the device was delivered through the pulmonary artery. Thirty-three patients achieved complete closure by discharge (day one). Conclusion: The ADO II is capable of closing a wide range of ducts in carefully selected patients. Our findings are compa-rable with other studies regarding ductal closure rates.

Keywords: patent ductus arteriosus, Amplatzer duct occluder II, percutaneous ductal closure

Submitted 2/11/12, accepted 10/5/13

Published online 27/6/13

Cardiovasc J Afr 2013; 24: 202–207 www.cvja.co.za

DOI: 10.5830/CVJA-2013-033

The incidence of patent ductus arteriosus (PDA) accounts for 11.9 to 15.6% of all congenital heart diseases.1,2 This figure rises to about 31% in premature infants.3 Surgical closure of the PDA was first reported by Gross, et al. in 1938.4 However, it was not until 1967 when Porstmann, et al. reported the first percutaneous closure of the PDA in the cardiac catheterisation laboratory.5 Several devices have been introduced for transcatheter closure of the PDA over the years.6-16 In 2008, the Amplatzer duct occluder type two (ADO II) (St Jude Medical, Cardiovascular Division, St

Paul, MN) was introduced.17 We report on our experience from a single centre.

MethodsFollowing ethics clearance, a review of records of patients who underwent percutaneous closure of the PDA in the Port Elizabeth Provincial Hospital, Port Elizabeth, South Africa was performed. Patients’ age, gender, weight, pulmonary blood flow:systemic blood flow (Qp:Qs) ratios, and pulmonary resistance (Rp) were documented. Angiographic anatomy, including narrowest diameter (ductal size), ductal length and ductal ampulla; selection of ductal closure device; ductal closure approach; radiological screening time; complications and outcomes were also noted.

The Amplatzer duct occluder type two device is made of a meshwork of self-expandable nitinol wire. It consists of a central ‘lobe’, which measures 3–6 mm in diameter, and two retention disks on either side of the lobe (Fig. 1). The disks are 6 mm larger than the central lobe and range from 9–12 mm in diameter. The devices are designed in such a way that the central lobe is the one that is placed in the duct itself, with a retention disk on either side of the PDA.

The device is delivered using a TorqVue low-profile (LP) delivery system (Fig. 2). The reason these newer devices can be delivered using a low-profile delivery system is that they lack the polyester material that is present in the Amplatzer duct occluder

division of paediatric Cardiology, paediatrics and Child Health, dora nginza Hospital, port Elizabeth, Eastern Cape south africa LUNGILE PEPETA, FCPaed (SA), Cert Cardiol (SA), [email protected] DIPPENAAR, FCPaed (SA), MRCPCH (UK)

Fig. 1. amplatzer duct occluder type ii device. a. Central lobe diameter (3–6 mm), B. device length (4 or 6 mm), C. retention disks diameter (9–12 mm). (Figure used with permission from st Jude Medical, Cardiovascular division, st paul, Mn).

a

B

C


type one (ADO I) (St Jude Medical, Cardiovascular Division, St Paul, MN). The delivery system has delivery sheaths of 4- and 5-F in size, with a length of either 60 or 80 cm; delivery wire with a screw mechanism to attach the device; device loader; Y-connector and a plastic vise.

Informed consent is obtained before attempting percutaneous ductal closure. Under conscious sedation, the patient is scrubbed and draped to ensure a sterile environment. Femoral arterial and venous access is achieved using standard vascular-access short sheaths. About 50 IU/kg of heparin are then given through the arterial sheath. Descending aortography in the straight lateral view is performed.

The size and shape (type) of the PDA using the Krichenko classification are determined.18 Standard left and right cardiac catheterisation procedures are then performed. Calculations to ascertain the extent of left-to-right (or right-to-left) shunting, pulmonary vascular and systemic vascular resistances are done.

Following angiography and haemodynamic data, the decision whether or not to close the PDA is then made. If the PDA is amenable to percutaneous closure based on the size and length of the duct, an appropriate device is selected using the manufacturer’s device selection table (St Jude Medical, Cardiovascular Division, St Paul, MN) as a guide (Table 1). The delivery system is then flushed using heparinised saline.

A 0.035-inch guide wire is passed across the PDA using an end-hole catheter, either in an anterograde fashion through the pulmonary side or in a retrograde manner via the aortic route. The ADO II delivery sheath is passed across the PDA over the guide wire. Blood is allowed to flow from the back of the sheath to purge all air from the system. The delivery wire is passed through the loader. The device is attached to the delivery wire using a screw mechanism.

Under water, the device is retrieved into the loader so that its distal radiopague end is at the tip of the loader. The loader is firmly introduced into the delivery sheath. Under fluoroscopy, the device is advanced into the sheath using the delivery wire until it reaches the tip of the delivery sheath. At this stage the

whole assembly is repositioned until the operator is satisfied, to deploy the distal disk.

Once the distal disk is well positioned and conforms to the vessel wall, the middle lobe is deployed in the duct with the proximal disk deployed on the other end of the PDA. Angiography may be performed at any stage of device deployment using the Y-connector and an angiographic catheter to check for device positioning in the duct, pulmonary artery or aorta. The device is released or retrieved as the operator deems fit.

The patient receives an intravenous antibiotic and may receive prophylaxis for infective endocarditis for six months. The patient is followed up at one day, one month, three months, six months, one year and two years following transcatheter closure of the PDA, using this device, to look for complications that may arise from the catheterisation procedure or the device itself. After two years’ follow up, patients are discharged.

Complications relating to closure of PDA in our patients, including aortic and (left) pulmonary obstruction, and device embolisation are documented. Short-term outcomes are also reported.

Statistical analysisValues were reported as mean ± standard deviation (SD) and median (range). Statistical significance was not required, as data comparison was not done.

resultsBetween May 2009 and July 2012, 36 patients were selected for percutaneous closure of the PDA using the Amplatzer duct occluder II. Their median age was 16.5 months (range: 2–233), with a median weight of 8 kg (range: 3.9–39.2), and a median height of 75 cm (range: 55–166). There were 21 females and 15 males. Patients’ basic characteristics and haemodynamic data are presented in Table 2.

The mean pulmonary artery pressure was 24.4 (SD: ± 10.4) mmHg, while the mean systolic pulmonary artery pressure was 34.8 (SD: ± 14.5) mmHg (Table 2). The Qp:Qs ratio was 2.25 (SD: ± 1.97), while the Rp mean was 1.87 (SD: ± 1.28) Wood units.

Table 3 shows angiographic data and outcomes in ductal closure using the ADO II. According to the Krichenko classification, 16 PDAs were type A (conical), four were type B (A-P window like), five were type C (tubular and more than 3 mm in length), two were type D (complex, with more than one constriction site), and nine were type E (long with sudden tapering at the pulmonary end). In terms of size, the narrowest mean ductal diameter (PDA size) was 2.74 (SD: ± 1.3) mm, with a mean PDA length of 9.5 (SD ± 4.16) and mean aortic ampulla of 9.46 (SD: ± 4.1) mm.

In terms of device choice, nine patients were closed using a 3 × 6-mm device, two with a 4 × 4-mm device, seven with a 4 × 6-mm device, four with a 5 × 6-mm device, one with a 6 × 4-mm device, and 13 with a 6 × 6-mm device. Regarding the delivery of the device, in 30 patients, the device was delivered through the pulmonary artery, while in six it was in a retrograde fashion through the aorta.

The exposure to radiation had a median of 20.2 minutes (range of 7.1–88.7). In terms of closure rates, 33 patients (91.67%) achieved complete closure by discharge (day one) and

Fig. 2. a picture of the amplatzer duct occluder type ii torqVue low-profile delivery system. (Figure used with permission from st Jude Medical, Cardiovascular division, st paul, Mn).

TABLE 1. MANUFACTURER’S GUIDELINES REGARDING ADO II DEVICE SIZE CHOICE IN RELATION TO THE

PDA SIZE AND LENGTH

Ductal length

Ductal size < 5 mm 5.1–8 mm 8.1–10 mm 10.1–11 mm

< 2.5 mm 3 × 4 3 × 6 4 × 6 5 × 6

2.5–3.5 mm 4 × 4 4 × 6 5 × 6 6 × 6

3.6–4.5 mm 5 × 4 5 × 6 5 × 6 6 × 6

4.6–5.5 mm 6 × 4 6 × 6 6 × 6 6 × 6


one additional patient by one month’s follow up. Two patients had residual PDA by three months and these patients were lost to follow up, therefore achieving a closure rate of 94.44% by three months’ follow up.

There were two patients with other congenital heart defects. One patient had a single ventricle, common atrium, pulmonary artery (PA) band, Glenn shunt and stenosis at the origin of the left and right pulmonary arteries due to the PA band. The patient had percutaneous PDA closure and right pulmonary artery-to-left pulmonary artery stenting. This patient had the longest screening time (88 minutes) as there were complications associated with the stenting of the branch pulmonary arteries. The second patient had an atrioventricular septal defect with a tiny inlet ventricular

septal defect and a primum atrial septal defect, which would be attended to at a later stage.

When reviewing complications or outcomes; in one patient the device embolised to the left pulmonary artery following release. This device was successfully retrieved and the patient was sent for surgical closure of the PDA (Fig. 3). In another patient, there was mild left pulmonary artery (LPA) stenosis with a gradient of 15 mmHg. This gradient had not worsened on follow up. There were no other complications reported.

discussionPercutaneous closure of symptomatic PDA has become the preferred method over surgical closure. For moderate to large (> 3 mm) PDAs, the Amplatzer duct occludder type I has been the device of choice.15 However, there are limitations in using the ADO I device. The device is made of polyester material, which

TABLE 3. ANGIOGRAPHIC DATA, CLOSURE APPROACH AND OUTCOMES

Pat-ients

PDA type

Narr-owest diam-eter

PDA amp-ulla

PDA length

Radi-ation expo-sure

Mode of delivery

Closure device Outcome

1 A 3.6 7.4 5.6 22.4 Pulmonary 05 × 06 Immediate closure

2 A 0.6 7.8 15.3 18 Aortic 03 × 06 Immediate closure

3 A 2.2 4.78 4.08 10.21 Pulmonary 03 × 06 Closed in one month

4 A 2 10.5 8.4 17.5 Pulmonary 04 × 06 Closed on day one

5 C 2.8 4.2 6.4 21.8 Pulmonary 06 × 06 Closed on day one

6 E 1.65 6.96 7.85 21 Pulmonary 03 × 06 Lost to follow up

7 D 2 7.1 10.9 25.2 Pulmonary 06 × 06 Immediate closure

8 A 0.9 8.2 8.9 15.3 Pulmonary 03 × 06 Closed on day one

9 E 2.2 6.5 8.6 24.3 Pulmonary 04 × 06 Closed on day one

10 C 3.6 4.3 10 15.2 Pulmonary 05 × 06 Immediate closure

11 E 3.4 12.6 13.5 17.5 Pulmonary 06 × 06 Immediate closure


13 A 3 11.1 9.7 21.6 Pulmonary 06 × 06 Closed in one month

14 A 1.4 10.8 16.6 23.2 Aortic 05 × 06 Immediate closure

15 C 5.5 13.7 10.1 29.4 Pulmonary 06 × 06 Embolised, surgery

16 B 4 4.8 3.3 28.8 Pulmonary 04 × 06 Lost to follow up

17 A 2.1 12 9.2 17.5 Pulmonary 04 × 06 Closed on day one

18 A 2 12 7.4 42.1 Aortic 03 × 06 Immediate closure

19 E 4.2 15.1 14.9 14.8 Pulmonary 06 × 06 Immediate closure


21 C 1 5 8 79.21 Aortic 03 × 06 Immediate Closure

22 E 2.2 10 9.3 23.3 Pulmonary 06 × 06 Immediate Closure

23 E 1.8 5.6 11.5 88.7 Aortic 06 × 06 Immediate Closure

24 B 4 4.9 3.4 13.8 Pulmonary 04 × 04 Immediate Closure

25 D 3.5 11.8 14.5 8.5 Pulmonary 06 × 06 Immediate Closure

26 B 3 3 2.5 17 Pulmonary 04 × 04 Immediate Closure

27 A 1.86 12.56 6.07 11.1 Pulmonary 03 × 06 Closed on day one

28 A 4.5 14.6 12.7 21.2 Pulmonary 06 × 06 Immediate Closure


30 C 3.3 7.5 15.1 14.1 Pulmonary 04 × 06 Immediate closure

31 B 4.9 7.3 3.8 30.7 Pulmonary 06 × 04 Immediate closure


33 A 1.3 18.7 6 13.3 Pulmonary 04 × 06 Immediate closure

34 A 6.2 15.4 15.6 31.5 Aortic 06 × 06 Immediate closure


36 A 0.8 5.3 6 24.9 Pulmonary 03 × 06 Immediate closure

Mean 2.74 9.46 9.5

TABLE 2. PATIENT BASIC CHARACTERISTICS AND HAEMODYNAMIC DATA

PatientsAge

(months)Weight

(kg)Height (cm) Gender Qp:Qs

Rp (WU)

PA systolic (mmHg)

Mean PA

(mmHg)

1 18 7.6 74 M 2.68 2.77 46 31

2 9 6.4 65 F 1.18 0.789 18 9

3 5 8.1 76 F 1.5 1.4 34 27

4 47 18.7 99.5 F 1.31 1.41 27 22

5 5 3.94 58 M 8.72 0.59 43 31

6 6 5.3 62 F 3.47 0.51 30 17

7 48 18.3 103 M 1.38 0.54 28 20

8 5 4.7 64 M 1.48 2.47 23 12

9 5 5.1 62 M 1.82 2.75 28 20

10 6 4.88 55.5 M 1.08 4.59 40 29

11 3 5.9 55 M 1.57 1.7 20 16

12 8 5.2 56 F 1.18 3.84 32 24

13 38 11.1 91 F 1.72 1.5 31 27

14 19 12.4 83 M 2.2 1.8 38 26

15 9 6 62 F 2.8 2.02 57 48

16 8 5.7 63 M 1.21 1.96 38 27

17 54 22.5 107.5 M 1.34 0.27 26 19

18 73 17.2 109 M 1.29 1.95 31 18

19 39 13 92.3 F 3.34 1.37 31 17

20 80 20.3 117 F 1.74 0.1 18 15

21 81 20 112 F 1.1 0.74 20 17

22 35 14.2 91.5 M 1.04 1.17 24 17

23 40 12.4 94 F 1.46 1.12 75 23

24 9 7.9 61 F 3.54 4.46 78 61

25 42 11.9 101 F 2.48 1.25 29 22

26 7 4.48 68 F 1.62 3.19 48 36

27 28 13.9 85 F 1.4 0.56 21 14

28 4 4.3 59 M 1.8 2.96 36 29

29 233 59 166 F 1.56 1.39 24 18

30 7 5.2 67 F 1.2 5.53 44 31

31 3 4.6 56 M 9.65 2.69 31 23

32 47 14.9 103 F 1.13 1.13 19 16

33 156 39.2 152 F 1.1 0.71 23 16

34 190 63 158 F 1.46 2.8 47 37

35 2 3.9 56 F 1.5 1.96 40 26

36 15 5.9 73 M 5.95 1.47 55 38

Mean 2.25 1.87 34.80 24.4

QP:QS, pulmonary blood flow:systemic blood flow ratio; RP (WU), pulmo-nary resistance in Wood units; PA systolic, pulmonary artery systolic pres-sure; Mean PA, mean pulmonary artery pressure.


makes it cumbersome and it requires a large delivery system (5–7 F) (St Jude Medical, Cardiovascular Division, St Paul, MN). This large delivery system makes it difficult and rather challenging to close a moderate to large PDA in small infants (< 6 kg). The device may also cause coarctation of the aorta due to its large retention skirt, which is on the aortic side.19

While the ADO II has a low profile and low delivery system, it can also cause aortic and left pulmonary artery (LPA) obstruction like the ADO I.20-22 In this series, there was one patient who had mild LPA obstruction. Both devices have the potential to embolise.21

We had one device that embolised. The patient (patient 15) had a large PDA with its narrowest diameter being 5.5 mm, which is the upper limit for percutaneous closure using ADO II, according to the manufacture’s guidelines (see Table 1). This patient had a large left-to-right shunt with a Qp:Qs ratio of 2.8:1. The duct morphology itself was more tubular than conical. The ductal size and the shape of the PDA were high risk factors for embolisation in this patient. The device was successfully retrieved and the duct was deemed unsuitable for percutaneous closure and as a result was closed surgically.

Care should be taken when choosing a device for closure of large PDAs with less suitable anatomy, as in such patients, the device might embolise. There were no major catheterisation-related complications in this study, such as bleeding, requiring blood transfusion, loss of femoral arterial pulse or arterial avulsion, as reported elsewhere.21,22

The low-profile TorqVue delivery system of the ADO II (4–5 F) allows this device to be used to close PDAs in smaller infants (< 6 kg) with a limited risk of causing either aortic or pulmonary obstruction in carefully selected patients. In this series, there

were 10 patients weighing less than 6 kg who underwent ductal closure using the ADO II, contrary to the manufacturer’s recommendations. This device was also able to close ducts in patients less than six months of age. Eight patients in this study were younger than six months of age (range 2–5 months).

Another advantage of this device over the ADO I is that it may be introduced both in anterograde fashion through the pulmonary side and in retrograde approach through the arterial side to close the PDA. In this report, there were six patients who had their ducts closed through the arterial side. Except for one patient whose duct was 6.2 mm, PDAs less than 3 mm (range 0.6–2 mm) were closed through the aortic route.

Historically, smaller PDAs (≤ 3 mm) would be closed with Cook’s or Gianturco coils or the Nit Occlud device.21 The ADO II has offered an alternative to this mode of closure. It should be mentioned though that the ADO II remains more expensive than the Gianturco coils. It has also been shown that the coils have less screening time and have shown less use of contrast than the Amplatzer device.21

When it comes to ductal shape, other devices such as the ADO I, coils and Nit Occlud device would close Krichenko type A (conical) PDAs. The ADO II has been shown in this report (Fig. 4) and others to be able to close all anatomical types of PDAs, including tubular and long (type C), and tubular, AP-window like ducts with a shallow aortic ampulla (type B).17,20,21 Two patients had residual ducts at three months of follow up. Residual ducts have been reported in other studies.23,24 These were closed using coils or the Nit Occlud device.

In terms of the narrowest diameter of the PDA, the manufacturer recommends closure of the PDA using the ADO II up to 5.5 mm. In this series, there was one patient who had a

Fig. 3. large patent ductus arteriosus (pda) before closure (a); with device in the pda (B); dislodged device in the left pulmonary artery (C); and percutaneous retrieval of device (d).

a

C

B

d


Fig. 4. descending aortograms in straight lateral view, showing Krichenko type a, B, C, d, and E pdas before closure (a-E) and after closure (F-J) with the amplatzer duct occluder type ii. (Figures a and F, patient 13; B and G, patient 24; C and H, patient 10, d and i, patient 7; E and J patient 12).

a B

C

E

d

F

G H

i J


PDA that measured 6.2 mm, which was 0.7 mm more than the recommended upper limit. In favour of percutaneous closure in this patient was the shape of the PDA, which was more conical with a larger ampulla of 15.4 mm. This patient also had a small left-to-right shunt of 1.46:1. This may have been due to the fact that the patient had significant pulmonary hypertension with a pulmonary artery mean of 37 mmHg, thus limiting left-to-right shunting across the PDA. The duct was amenable to percutaneous closure though, as the Rp was high-normal at 2.8 Wood units.

The mean screening time of 23.4 (± 16.66) min was longer than in other studies.17,22 Limitations to the use of this device would include inability to close a very large PDA, as the largest size is 6 × 6 mm, with a retention disk of 12 mm; and inability to occlude a duct with a shallow ampula and a small aorta or pulmonary artery, as closure in such patients might cause significant aortic coarctation or left pulmonary artery stenosis. The introduction of ADO II additional sizes and the use of an Amplatzer vascular plug II for ductal closure, which has a much smaller profile with smaller retention disks, has offered hope for closure of PDAs in much smaller infants, including newborns.21,25,26

The major limitation of this study was that this was a retrospective analysis of records. There was no direct comparison between this device and other devices used for percutaneous ductal occlusion, including the ADO I.

ConclusionThe Amplatzer duct occluder II is able to close all types of PDAs in very small infants (< 6 kg). The device may be utilised to close PDAs historically closed using coils. Its ability to be delivered via both pulmonary and aortic approaches expands its use, including patients whose anatomy is difficult to approach either through the pulmonary side or the aorta.

References1. Dickinson D, Arnold R, Wilkinson J. Congenital heart disease among

160 480 liveborn children in Liverpool 1960 to 1969. Implications for surgical treatment. Br Heart J 1981; 46: 55–62.

2. Carlgren LE. The incidence of congenital heart disease in children born in Gothenburg 1941–1950. Br Heart J 1959; 21: 40–50.

3. Van Overmeire B, Smets K, Lecoutere D, van de Broek H, Weyler J, de Groote K, Langhendries JP. A comparison of ibuprofen and indo-methacin for closure of patent ductus arteriosus. N Engl J Med 2000; 343: 674–681.

4. Gross RE, Hubbard JP. Surgical ligation of a patent ductus arteriosus. Report of first successful case. J Am Med Assoc 1939; 112: 729–731.

5. Sievert H, Ensslen R, Fach A, Merle H, Scherer D, Schrader R, Spies H, Schulze R, Utech A. Transcatheter closure of patent ductus arteriosus with the Rashkind occluder. Acute results and angiographic follow-up in adults. Eur Heart J 1997; 18: 1014–1018.

6. Rashkind W, Mullins C, Hellenbrand W, Tait M. Non-surgical closure of patent ductus arteriosus: Clinical application of the Rashkind PDA occluder system. Circulation 1987; 75: 583–592.

7. Rao P, Sideris E, Haddad J, Rey C, Hausdorf G, Wilson A, Smith P, Chopra P. Transcatheter occlusion of patent ductus arteriosus with

adjustable buttoned device: Initial clinical experience. Circulation 1993; 88: 1119–1126.

8. Verin V, Saveliev V, Kolody S, Prokuborski V. Results of transcatheter closure of the patent ductus arteriosus with the Botalloocluder. J Am Coll Cardiol 1993; 22: 1509–1514.

9. Moore JW, George L, Kirkpatrick SE, Mathewson J, Spicer R, Uzark K, et al. Percutaneous closure of the small patent ductus arteriosus using occluding spring coils. J Am Coll Cardiol 1994; 23: 759–765.

10. Hijazi ZM, Geggel RL. Results of anterograde transcatheter closure of patent ductus arteriosus using single or multiple Gianturco coils. Am J Cardiol 1994; 74: 925–929.

11. Tometzki A, Chan K, de Giovanni J, Houston A, Martin R, Redel D, et al. Total UK multicenter experience with a novel arterial occlusion device (Duct Occlud pfm). Heart 1996; 76: 520–524.

12. Uzun O, Hancock S, Parsons JM, Dickinson D, Gibbs J. Transcatheter occlusion of the arterial duct with Cook detachable coil: Early experi-ence. Heart 1996; 76: 269–273.

13. Tometzki AJ, Arnold R, Peart I, Sreeram N, Abdulhamed J, Goodman M, et al. Transcatheter occlusion of the patent ductus arteriosus with Cook detachable coils. Heart 1996; 76: 531–535.

14. Podnar T, Masura J. Percutaneous closure of patent ductus arteriosus using special screwing detachable coil. Catheter Cardiovasc Diagn 1997; 41: 386–391.

15. Masura J, Walsh K, Thanopoulos B, Chan C, Bass J, Goussous Y, et al. Catheter closure of moderate- to large-sized patent ductus arteriosus using the new Amplatzer duct occluder: Immediate and short-term results. J Am Coll Cardiol 1998; 31: 878–882.

16. Masura J, Gavora P, Podnar T. Transcatheter occlusion of patent ductus arteriosus using a new angled Amplatzer duct occluder: Initial clinical experience. Catheter Cardiovasc Interv 2003; 58: 261–267.

17. Bhole V, Miller P, Mehta C, Stumper O, Reinhardt Z, de Giovanni JV. Clinical evaluation of the new Amplatzer duct occluder II for patent arterial duct occlusion. Catheter Cardiovasc Interv 2009; 74: 762–769.

18. Krichenko A, Benson LN, Burrows P, Moes CAF, McLaughlin P, Freedom RM. Angiographic classification of the isolated, persistently patent ductus arteriosus and implications for percutaneous catheter occlusion. Am J Cardiol 1989; 63: 877–880.

19. Duke C, Chan KC. Aortic obstruction caused by device occlusion of patent arterial duct. Heart 1999; 82: 109–111.

20. Thanopoulos B, Eleftherakis N, Tzannos K, Stefanadis C. Transcatheter closure of the patent ductus arteriosus using the new Amplatzer duct occluder: Initial clinical applications in children. Am Heart J 2008; 156: 917.e1–917.e6.

21. Baspinar O, Irdem A, Sivasli E, Sahin DA, Kilinc M. Comparison of the efficacy of different-sized Amplatzer duct occluders (I, II, and II AS) in children weighing less than 10 kg. Pediatr Cardiol 2012. (Epub ahead of print).

22. Park YA, Kim NK, Park S, Yun BS, Choi JY, Sul JH. Clinical outcome of transcatheter closure of patent ductus arteriosus in small children weighing 10 kg or less. Korean J Pediatr 2010; 53(12): 1012–1017.

23. Kusa J, Szkutnik M, Baranowski J, Adams E, Karwot B, Rycaj J, et al. Percutaneous closure of recanalised ductus arteriosus – a single-centre experience. Kardiol Pol 2007; 65(2): 125–129.

24. Beck C, Laser KT, Haas NA. Failure of the Amplatzer ductal occluder II: kinking of the aortic retention disk at 24 hours. Catheter Cardiovasc Interv 2010; 75(7): 1100–1103.

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awareness of hypertension and factors associated with uncontrolled hypertension in sudanese adultsFAWZI A BABIKER, LAMIA A ELKHALIFA, MOHAMED E MOUKHYER

abstractBackground: The incidence of hypertension (HTN) has increased rapidly in the Sudan in the last few years. The aim of this study was to determine the prevalence of uncontrolled HTN and the risk factors associated with it in Sudanese adults.Methods: This study was cross sectional. Data were collected using structured questionnaires filled in during interviews with subjects visiting referral clinics in Khartoum, the capi-tal city of Sudan. Blood pressure (BP) was measured using a digital sphygmomanometer. A digital balance was used for determination of body weight and a traditional cloth tape measure was used for measuring height, for calculation of body mass index.Results: This study included 200 subjects, 46% male and 54% female. In the whole study, 82% of subjects (p < 0.001) were on hypertension drug treatment. Of these, 64% had their BP controlled to normal standards set by the World Health Organistion (< 140/90 mmHg). The prevalence of uncontrolled BP was significantly (p < 0.001) higher in males (61%) compared to females (15%). When the risk factors of HTN were considered, 54% of the subjects had a positive family history of HTN and 52% were smokers. Uncontrolled BP was found to be significantly (p < 0.001) higher in smok-ing males (43%) compared to females (4%). It was also high in people with higher education (55%) and workers (41%). In these groups, when genders were considered separately, uncontrolled hypertension was significantly (p < 0.01) higher in males than females with higher education (67 and 40%, respectively), and in workers (86 and 10%, respectively). Uncontrolled HTN was associated with overweight and obesity in 45 and 29% of the subjects, respectively. Most of the interviewed subjects were not aware of the consequences of HTN and its associated risk factors.Conclusions: Uncontrolled HTN was associated with risk factors of HTN and lifestyle, and was more prominent in the male gender. The ignorance of the interviewed subjects about HTN, its associated risk factors, changes in lifestyle and adherence to taking the medication may have been a major factor in the prevalence of uncontrolled HTN.

Keywords: hypertension, blood pressure, awareness, risk factors, gender differences, stress, family history



DOI: 10.5830/CVJA-2013-035

Hypertension (HTN) is universally accepted as one of the most important risk factors in the development of cardiovascular disease (CVD), stroke and renal disease.1-3 There has been a considerable increase in the prevalence of HTN in the Middle East during the last few years. In some Arab countries HTN has become a major health problem.4 This drastic increase in incidence of HTN is specifically caused by a combination of many parameters, including family history,5 change in lifestyle, dietary habits and environmental factors.6

Sudan is considered one of the leading countries in Africa for the prevalence of HTN.7 However, a proper national registry on HTN is not available in Sudan and evaluation studies are rarely done.8 Nevertheless, a recent study showed an inreasing incidence of HTN in Sudan,9 which may result in serious health problems in the near future if no appropriate measures are taken.

The prevalence of HTN may be a result of the marked shift in the Sudanese diet, which has resulted in increased overweight and obesity.4 Some studies have claimed the prevalence of HTN is a cause of the tremendous increase in renal insufficiency.3

Increased awareness, follow up and control of HTN in industrialised countries has resulted in a decreased tendency to morbidity and mortality from cardiovascular disease.10 To reach the level of improvement attained in developed countries, epidemiological studies on the risk factors, control methods, control levels, lifestyle, adherence to medication, and awareness will be crucial for setting control strategies in Sudan.

In this study we investigated the prevalence of uncontrolled HTN in Sudanese adults and determined the factors that may be responsible for the poor control in the study participants. We also acquired essential information on risk factors and their effects on outcome of the control of HTN.

MethodsThis study was a clinic-based, cross-sectional study. The study population was a group of 200 hypertensive patients selected randomly from referral clinics in the teaching hospitals (Omdurman, Khartoum North and Khartoum). Subjects underwent interviews using a standard questionnaire, collecting data on personal information, presence of concomitant diseases such as diabetes and renal failure, family medical history, medication use, salt intake, and awareness of HTN and its control.

All the interviewed subjects were considered for the study except those who were diagnosed with kidney failure before the start of our study. These subjects were excluded because their HTN may have been secondary hypertension or influenced by the kidney failure and the subjects’ body fluid volumes. All subjects invited to participate in the study responded positively and participated, except three (two because of lack of time and one declined participation for no reason).

At the beginning of the study, blood pressure (BP) of the subjects was measured using digital sphygmomanometers

department of physiology, Faculty of Medicine, Kuwait university, KuwaitFAWZI A BABIKER, PhD, [email protected] of Community Medicine, Faculty of Medicine, Ahfad University for Women, SudanLAMIA A ELKHALIFA, MScMOHAMED E MOUKHYER, PhD


(Omron, MX3 Plus, Kyoto, Japan), which had been validated to the European Society of Hypertension’s international protocol.11 BP measurements were done on one occasion and repeated three times with five-minute intervals between them. The subjects were in a seated position. The averages of these measurements were used for further analysis. HTN was systolic blood pressure (SBP) above 140 mmHg and/or diastolic blood pressure (DBP) above 90 mmHg (WHO, Guidelines for the Management of Hypertension),12 or use of antihypertensive medication by the study subjects.

Body weight was measured using a digital balance and height was measured using a traditional cloth tape measure. Body mass index (BMI) was calculated from the weight and height using the formula, BMI = weight (kg)/height (m2). Overweight was defined as BMI = 25.0–29.9 kg/m2.

All subjects interviewed in this study were adults. All personal information and measurements were kept confidential. Authorisation was obtained from the ethics committee at Ahfad University for Women, Omdurman, Sudan before the start of the study and an informed consent was signed by the selected individuals before filling in the questionnaire.

Statistical analysisAll statistical analyses were done using the statistical package SPSS (version 17.0, SPSS Inc, USA). Results were summarised as percentage for all variables. Chi-squared (χ2) test was used for the analysis of factors associated with HTN. The data were analysed using the Student’s t-test to determine means for the variables; p < 0.05 was considered statistically significant.

resultsThe study population comprised 200 hypertensive patients selected randomly from those who were visiting referral clinics in Khartoum. All study subjects were adults, 20 years of age and older. The subjects interviewed were 92 (46%) males and 108 (54%) females. Of the study subjects, 148 (74%) were married, 44 (22%) were single, four (2%) were widows and four (2%) were divorced.

The education level of the subjects varied widely; 32 (16%) were illiterate, 44 (22%) had primary school level, 80 (40%) had secondary education and 44 (22%) higher education (university and graduate). The employment pattern was 68 (34%) unskilled manual workers, 88 (44%) government employees and 44 (22%) were self-employed or in the private business sector.

The majority of subjects (144, 72%, p < 0.001) were only hypertensive with no other non-communicable diseases such as stroke or diabetes. HTN in combination with diabetes was found in 48 (24%) patients and HTN, combined with stroke in eight (4%). There were 112 (56%) subjects with a family history of hypertension, 84 (42%) with diabetes, and four (2%) with other diseases among their direct blood relatives.

In this study HTN was found in 92 (46%) of the subjects during a routine general check-up. It was recognised in the other 108 (54%) after the start of complications. Although 56 (28%) of the subjects did not remember their BP readings during their last visit to the clinic, BP monitoring in the clinics showed controlled BP (120–140/60–90 mmHg) (self-referred) in 76 (38%) subjects, and 68 (34%) had uncontrolled BP (> 140/> 90 mmHg) (Table 1).

In our BP check-ups during this study, 128 (64%) subjects showed controlled and 72 (36%) uncontrolled BP and only 2% showed very high BB levels (Table 1). The uncontrolled BP was significantly (p < 0.001) higher in males (56, 61%) than females (16, 15%) when genders were analysed separately (Table 2). Marital status had no influence on the lack of BP control when the genders were pooled, however, a high prevalence of uncontrolled HTN was shown in 48 males (62%) compared to eight females (11%, p < 0.001) when they were considered separately (Table 2).

Although uncontrolled BP was found in eight (25%) of the illiterate subjects, surprisingly, the lack of control increased with increasing educational level, as it was found in 40 (50%, p < 0.01) subjects with secondary education and in 24 (55%, p < 0.01) of the higher educated subjects when both genders were considered together. The highest prevalence was found in males compared to females (32, 67% and eight, 25%, respectively) (p < 0.01) with secondary education, and 16 (67%) and eight (40%), respectively (p < 0.03) with higher education (Table 2) when genders were considered separately.

Uncontrolled HTN was found in 28 workers (41%), in 36 (41%) government employees and in eight (18%) self-employed subjects. However, a high prevalence of uncontrolled HTN was found in 24 (86%) (p < 0.01), 28 (50%) (p < 0.01) and four (50%) males compared to four (10%), eight (25%) and four (11%) females among workers, government employees and self-employed subjects, respectively, when genders were considered separately (Table 2).

In this study we also investigated awareness among the study subjects, their willingness and effort to control their BP, and their motivation to change their lifestyle. For the variable following up on their BP and monitoring it at home, 160 (80%) (p < 0.001) of the subjects did not monitor their BP at home, and 184 (82%) patients took their medication as prescribed by the doctors. Of all subjects studied, 172 (86%) (p < 0.001) showed a desire to normalise their BP. To follow up on their PB, 132 (66%) subjects visited doctors on a regular basis. Surprisingly, for control of BP and change of lifestyle, 104 (52%) subjects did not decrease their salt intake in their diet, and 120 (60%) still ate Faseekh, which contains large amounts of salt (Table 3).

TABLE 1. DATA REPRESENTING, HEALTH STATUS, FAMILY HISTORY, HOW HTN WAS DETECTED FOR THE FIRST TIME, HISTORICAL MEASUREMENT OF BLOOD PRESSURE IN THE

CLINICS AND BP MEASUREMENT DURING OUR STUDY (n = 200)

Variables n %

Health status Hypertension 144 72

Hypertension + diabetes 48 24

Hypertension + stroke 8 4

Family history Hypertension 112 56

Diabetes 84 42

Other 4 2

HTN detection Routine check-up 92 46

After complaint 108 54

BP monitoring 120–140/60–90 76 38

(mmHg) >140/>90 68 34

Do not know 56 28

BP measured in study 120–140/60–90 128 64

(mmHg) >140/>90 72 36


In the whole study group, the number of non-smokers was 104 (52%) compared to 96 (48%) smokers. Of these, smoking was found in 76 (83%) males and 21 (19%) females (p < 0.001). The number of subjects who were hypertensive and smokers was 40 (43%) males and four (4%) females (p < 0.001) (Fig. 1).

BMI estimation showed that 20 (10%) of the study subjects were of normal weight, 84 (42%) were overweight and 96 (48%) were obese (Fig. 2). In this study, the relationship of HTN control with overweight and obesity showed that a higher BMI had a more detrimental effect on HTN control than a normal BMI. With regard to BP control, there were 44 (52%) (p < 0.03) subjects in the overweight and 60 (71%) in the obese category compared to16 (80%) normal-weight subjects. Surprisingly, BP control in the overweight category was less compared to obese subjects (Fig. 2).

discussionIn this study, uncontrolled BP was found in 34% of the subjects, which is in line with studies in other countries where high levels of uncontrolled BP were recognised.13,14 However, the percentages of uncontrolled BP in this study were higher than that obtained in other studies.15,16 This tendency to have uncontrolled BP is common, even in developed countries such as the USA.17,18 Our study suggests a similar prevalence of uncontrolled HTN in Sudan compared to other countries. However, there has been a increase in incidence of uncontrolled HTN in Sudan over the last few years. Further studies are required to determine suitable methods of BP control to decrease the percentage of uncontrolled hypertension in the population.

When we considered the risk factors of HTN, this study revealed that HTN control was better in females than males. These results are similar to those from previous studies where females were better protected and achieved better BP control than males.19,20 The prevalence of uncontrolled HTN was also found to be higher in males than females, who were proven to be protected by the female gender due to the presence of the hormone oestrogen.21 Furthermore, male subjects are less likely to seek medical care.22

Surprisingly, the level of education showed a positive association with uncontrolled hypertension in our male subjects, as the presence of uncontrolled HTN increased with the educational level. These results are in line with a previous study done in Sudan.23 There is no explanation for this association but we can speculate that HTN in these subjects may have been complicated by other factors such as stress at work and a sedentary lifestyle.

Both marital status and employment were found in this study to be associated with uncontrolled BP in males, although there was no positive relationship between marriage and lack of control of HTN in all studies done to date.24 The negative impact of marriage on HTN control in our study may have been due

TABLE 2. COMPARISON OF GENDER, MARITAL STATUS, EDUCATIONAL LEVEL AND EMPLOYMENT AND THEIR

RELATIONSHIP WITH LEVEL OF CONTROL OF HTN IN SUBJECTS WITH CONTROLLED OR UNCONTROLLED HYPERTENSION (n = 200)

Blood pressureUncontrolled hypertension

Normal High Male Female

Variables n % n % n % n % n %

Gender

Male 92 46 36 39 56 61 – – – –

Female 108 54 92 85 16 15 – – – –

Marital status

Single 44 22 28 64 16 36 8 50 8 29

Married 148 74 92 62 56 38 48 62 8 11

Widows 4 2 4 100 0 0 0 0 0 0

Divorced 4 2 4 100 0 0 0 0 0 0

Education

Illiterate 32 16 24 75 8 25 8 50 0 0

Primary school 44 22 44 100 0 0 0 0 0 0

Secondary school 80 40 40 50 40 50 32 67 8 53

Higher education 44 22 20 45 25 55 16 67 8 40

Employment

Workers 68 34 40 59 28 41 24 86 4 10

Government-employed 88 44 52 59 36 41 28 50 8 25

Self-employed 44 22 36 82 8 18 4 50 4 11

TABLE 3. DATA REPRESENTING THE DESIRE OF PATIENTS TO CONTRIBUTE TO DECREASING THEIR BP BY MONITORING

IT AT HOME, ADHERING TO DRUG USE, CONTROL VISITS TO THE DOCTOR AND DIETARY CHANGES (n = 200)

Variables n %

BP monitoring at home Yes 40 20

No 160 80

Drug intake as prescribed Yes 164 82

No 36 18

Efforts to control BP Yes 172 86

No 28 14

Control visits to doctor Yes 132 66

No 68 34

Salt in daily meals Eat with family 104 52

Eat low salt 96 48

Eating salty food (extra salt) Yes 120 60

No 80 40

Fig. 1. Control of hypertension in smokers and non-smokers. the table and graph show prevalence of hyper-tension, and smoking and hypertension in male and female smokers (n = 200).

1009080706050403020100

Hypertensive smoker smoker and hypertensive

%

Males Females

NumberHypertension

n (%)Smoker n (%)

Smoker and hypertensive

n (%)

Males 92 56 (61) 76 (83) 40 (43)

Females 108 16 (15) 20 (19) 4 (4)


to complications from other stresses, risk factors and lifestyle changes. Low income in Sudan may also be an important stress factor in marriage. Stress at work could be due to work demands and low salaries, which would influence the outcome of BP control.10,25

The female subjects in all educational groups, marital and work categories showed better BP control than the males. This may have been because of the presence of oestrogen, which is protective against HTN.21 Moreover females were known to be better than males in adherence to medication.26

Other risk factors such as positive family history for HTN were also evident in this study. This is not surprising as Shehata et al.5 found relatives of hypertensive subjects to be more likely to have HTN early in life.5 The risk of occurrence of HTN was found to be greater in subjects with hypertensive first-order family members.27

When we evaluated the awareness of HTN and its control, our data showed a very poor appreciation of HTN and its associated risks in the study population. The study showed that 54% of our subjects discovered their HTN when the complications of the disease became apparent. In the rest of our subjects, HTN was detected by chance in a routine check-up. These finding suggest a poor healthcare system and health education programmes. These results confirm the lack of a national data registry on HTN in Sudan, which points to a low level of screening and follow up.28 Lack of awareness is very significant in the prevalence of HTN and uncontrolled high BP.10,16 More attention must be given to HTN as it is a common risk factor for stroke29 and kidney disease,30 which are recognised to be rapidly increasing in Sudan.

Lack of awareness was evident in our studied subjects. Compliance with drug usage as prescribed by the doctor was poor in our study subjects; 18% did not take their medication as prescribed. In other studies, 11% lack of compliance with drug use was considered a serious cause of poor treatment of HTN.31 Some researchers stated compliance with medication to be of

vital importance for good results in the control of HTN.18,32,33 Lack of awareness in our study subjects can be viewed in

several ways. Only 20% of the study participants went for check-ups or monitored their BP at home, 14% did not change their habits to achieve suitable pressure levels and 34% did not visit doctors on a regular basis. Green et al. found that follow up with doctors and monitoring BP at home resulted in better control.34 Control of HTN was also influenced by the high sodium intake found in our study subjects. Increased sodium intake and a high-salt diet has been proven to be an important aspect in the prevalence of HTN in the Sudanese population.35-37

In this study, uncontrolled HTN was found to be prevalent in smoking males compared to smoking females. In many other studies, smoking has been recognised as a risk factor for HTN.38,39 BP levels were found to be higher in hypertensive smokers than in hypertensive non-smokers.40 Gender differences with regard to smoking have not been examined before, but our data are in line with other studies,40,41 where smoking was shown to interfere negatively with the control of HTN.

Overweight and obesity were common among our study subjects. From this it is evident that overweight and obesity are among the important risk factors of HTN in the Sudanese population. Obesity was also noted by Elmahdi et al.42 in a Sudanese population. A large number of the subjects in our study who had uncontrolled HTN were overweight or obese. High BMI is proven to be an important risk factor for HTN.43,44 Indeed our finding supports the notion that persistent overweight and obesity can interfere with the efficacy of hypertension drugs.45,46

ConclusionUncontrolled HTN was associated with lifestyle and risk factors for HTN and was more prominent in the male gender. The lack of awareness in the subjects about HTN, its associated risk factors, changes in lifestyle and adherence to the medication may be a major factor in the prevalence of uncontrolled HTN in Sudan.

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Effects of single aortic clamping versus partial aortic clamping techniques on post-operative stroke during coronary artery bypass surgeryIHSAN SAMI UYAR, MEHMET BESIR AKPINAR, VEYSEL SAHIN, FEYZI ABACILAR, VOLKAN YURTMAN, FAIK FEVZI OKUR, UGUR OZDEMIR, MEHMET ATES

abstractBackground: The aim of this study was to compare the effects of single-clamping and partial-clamping techniques on post-operative stroke during coronary artery bypass surgery. Methods: Between December 2008 and December 2012, 2 000 patients who underwent coronary artery bypass grafting in two hospitals were analysed. Post-operative neurological complications were analysed retrospectively in these patients. The cases were divided into two groups: in group 1, 1 500 patients were analysed, in whom proximal anastomosis was performed with partial clamping in a beating heart (n = 1 500, 846 male, 654 female; mean age 63.25 ± 5.72 years; range 43–78 years). In group 2, 500 patients were analysed, in whom proximal anastomosis had been performed by other surgical teams in another hospital, with cross clamping in a resting heart with cardioplegia (n = 500, 296 male, 214 female; mean age 64.83 ± 8.12 years; range 41–81 years). During 30 days post-operatively, neurological deficits, stroke incidence and the relationship of the clinical situation to mortality were analysed. Results: For both groups, patients were similar in terms of patient characteristics. In group 2, cross-clamp duration and perfusion time were longer; however, time of hospital stay was similar in the two groups. Post-operative stroke was seen in 26 patients in group 1 (1.73%) and in nine in group 2 (1.8%). The difference between the two groups was not statistically significant (p = 0.92). All stroke patients were over the age of 55 years. Seven of the stroke patients died (21.1%). In total, 31 patients died because of multiple organ failure in the post-operative 30 days (group 1: 1.6%; group 2: 1.4%) (p = 0.91). Smoking, diabetes mellitus, hypertension, atrial fibrillation, peripheral vascular disease and hypercholesterolaemia were found to be factors that affected stroke development. Mean duration of hospital stay was 5.1 ± 2.8 days in group 1 and 4.9 ± 3.6 days in group 2 and the difference between the two groups was not statistically significant (p = 0.46). Conclusion: In patients without plaques in the aorta, perform-ing partial clamping did not increase stroke incidence.

Keywords: coronary bypass, stroke, partial clamp



DOI: 10.5830/CVJA-2013-038

Neurological complications are undoubtedly among the most important adverse outcomes of coronary artery bypass surgery. Neurological problems increase morbidity and mortality considerably. Although techniques performed during cardiac surgery have progressed, neurological complications have not disappeared completely. The real causes of these complications may be problems associated with atherosclerosis that is present before the operation or with surgical technical failure. Advanced age, carotid artery disease and severe calcification of the aorta are the main factors that increase the risk of neurological complications.1-3

There are many studies in the literature on the prevention of these problems, and they suggest technical solutions. However, concerns about the safety of these techniques and the neurological complications still exist.

Patients with similar demographic characteristics who were treated with coronary artery bypass grafting (CABG) at our clinic were evaluated retrospectively in this study. The results obtained by a team using a single aortic clamp for the proximal anastomosis were compared with those obtained by a team utilising partial clamping for the proximal anastomosis. The study sought to observe whether either of these techniques increased the incidence of post-operative stroke.

Methods In this study, 2 000 patients who had undergone CABG in two hospitals between December 2008 and December 2012 were evaluated retrospectively for neurological complications and mortality in the post-operative period. The cases were divided into two groups. Data from the 1 500 patients in whom proximal anastomosis had been performed with partial clamping were evaluated as group 1 (n = 1 500; 846 males, 654 females; age 63.25 ± 5.72 years; range of 43–78 years). The data from the patients (treated by another surgical team in another hospital) in whom proximal anastomosis had been performed in the stopped heart with cross clamping were evaluated as group 2 (n = 500; 296 males, 214 females; mean age 64.83 ± 8.12 years; range 41–81 years). The data for these two groups were compared.

The study was planned, and approval of the hospital ethics committee was obtained. The informed consent forms of all patients were seen in chart review, and cases that did not have an informed consent form were excluded. Patients with plaques in the aorta and with a history of corticosteroid, salicylate,

department of Cardiovascular surgery, Medical Faculty, sifa university izmir, turkeyIHSAN SAMI UYAR, MD, [email protected] BESIR AKPINAR, MDVEYSEL SAHIN, MDFEYZI ABACILAR, MDVOLKAN YURTMAN, MDFAIK FEVZI OKUR, MDUGUR OZDEMIRMEHMET ATES, MD


dipyridamole or anticoagulant use, those that had a coagulation or platelet dysfunction, and cases having simultaneous valve surgery, aortic surgery, ventricular aneurism resection or carotid endarterectomy were also excluded from this study. Cases in whom stenosis of the carotid artery was considered critical were excluded. Patients who had undergone re-operation were also excluded.

Patients older than 60 years of age, those with a history of stroke or transient ischaemic attack before the operation, and cases in whom a systolic murmur was detected over the carotid artery were all routinely examined by carotid Doppler ultrasonography.

The development of neurological deficits and strokes in the 30-day post-operative period, and the association of this clinical situation with mortality was assessed. These cases were followed up in co-operation with a neurologist. Cranial magnetic resonance imaging and computerised tomography were used in the diagnosis.

Midalozam 5 mg was administered intramuscularly to all patients one hour before the intervention as pre-medication. Cefazolin 1 g was administered intravenously before induction of anaesthesia and continued in repeated doses (twice a day) until chest tube removal. In case of infection, a swab was taken from the wound and following the outcome of cultures, targeted antibiotics were administered.

Internal thoracic artery (ITA) and saphenous vein grafts were prepared after median sternotomy. Cardiopulmonary bypass was started with arterial cannulation of the ascending aorta and two-stage venous cannulation from the right atrial auricle. Non-pulsatile extra-corporeal circulation (ECC) (cardiopulmonary bypass) was started with a Sarns roller pump (Sarns, Fort Myers, FL,USA) at 2.4–2.6 l/m2/min, and mild–moderate hypothermia (oesophageal temperature 26–28°C) was obtained. A membrane oxygenator (Dideco, Mirandola, Italy) was used for oxygenation during ECC.

The haematocrit values were kept between 20 and 25%, and mean perfusion pressure measured from the radial artery was kept between 50 and 80 mmHg during bypass. Multi-dose antegrade blood cardioplegia was used in both groups.

Before placement of the cross clamping, the arterial pressure was lowered to 30 mmHg for a few seconds in a controlled fashion with ECC support, and the aorta was evaluated manually in detail. Partial clamping was not used in patients in whom the presence of plaques in the aorta was suspected. For patients in whom no atherosclerotic plaques were found in the aorta, it was clamped at the aortic root.

Cardiac arrest was obtained by applying 1 500 ml isothermic blood cardioplegic solution antegradely from the aortic root, and topical cold saline was applied in all patients. Blood cardioplegic solution doses for maintenance were administered consequently. Cardioplegic solution at 37ºC, with the heater circulatory system in the cardioplegia set (Dideco, Mirandola, Italy), was administered to obtain a controlled reperfusion before the cross clamp was removed in both groups.

All of the proximal anastomoses were done with an aortic partial clamp in group 1. The clamp was removed when the last proximal anastomosis was completed, before the suture material was tied; bleeding of the aorta for at least 10 seconds was permitted before tying.

In group 2, each patient was warmed while the proximal

anastomoses were performed. The proximal anastomoses were done under cross clamping in the resting heart. The sutures were not tied after the last proximal anastomosis, and bleeding of the aorta was permitted for at least 10 seconds in this region after the clamp was removed. The patients were kept under observation in the intensive care unit for at least six hours with mechanical respiratory support.

Statistical analysisThe results are presented as mean ± standard deviation. The data were evaluated with multivariate logistic analysis, Student’s t-test and chi-square test. In all studies, p-values < 0.05 were considered statistically significant.

results There were no statistically significant differences between the two groups in terms of mean age, gender, morbid obesity, smoking habit, hypertension, diabetes mellitus, and chronic pulmonary or renal disease (p > 0.05). There were also no significant differences in terms of functional capacity according to New York Heart Association (NYHA) classification, blood cholesterol level, family history, accompanying peripheral artery disease and history of cerebrovascular disease (p > 0.05). The mean ejection fraction (EF) values of the patients at pre-operative echocardiographic evaluation were 45.4 ± 5.23 in group 1 and 46.4 ± 2.31 in group 2, and the difference was not statistically significant (p = 0.067). Comparisons of the demographic data of the patients are summarised in Table 1.

The operative data of the patients, such as time of cross clamp, time of perfusion, mean number of distal anastomoses, inotropic agent support, amount of post-operative drainage, intra-aortic balloon use, peri-operative myocardial infarction, duration of intubation, duration of stay in the intensive care unit (ICU), and post-operative complications were compared. The results of these comparisons are summarised in Table 2.

Post-operative stroke was seen in 26 patients in group 1 (1.73%), and in nine patients in group 2 (1.8%). The difference was not statistically significant (p = 0.92). All patients who suffered from stroke were older than 55 years. In a detailed analysis of the group of patients with stroke, the frequency of smoking was 24%, diabetes 67%, hypertension 72%, atrial fibrillation 35%, peripheral arterial disease 74%, and hypercholesterolaemia 68%. Echocardiographic left ventricular ejection fraction (LVEF) was lower than 45% in all patients (Table 3).

A total of 31 patients [24 patients from group 1 (1.6%) and seven patients from group 2 (1.4%)] were lost during the 30-day post-operative period due to multiple organ failure that had developed after low cardiac output. The difference between the groups was not significant (p = 0.91). The 30-day mortality rate in all patients included in this study was 1.55% (31 patients). The mean duration of stay in hospital was 5.1 ± 2.8 days in group 1 and 4.9 ± 3.6 days in group 2, and the difference was not significant (p = 0.46).

discussionMajor neurological problems are among the most feared complications after CABG with cardio-pulmonary bypass.


Neurological complications have a major effect on post-operative morbidity and mortality and the outcome may be catastrophic for both the patient and surgeon. The rate of stroke after cardiac surgery is reported to be between 1 and 5% in published studies and this may increase to 9% in patients over 75 years of age.1,4 Indeed, mortality may reach 28% in the latter cases.5-7

Cerebral damage and neurological complications due to this damage have many causes, including embolisations originating in the heart and aorta (air, particles from ruptured plaques, fatty particles), cerebral hypo-perfusion, bleeding, carotid artery disease, and metabolic causes such as toxic mediators and cytokines released during prolonged ECC.8,9 The dimensions of the neurological damage are dependent on the extent of embolisation and the affected region.

There are publications in which single aortic clamping is recommended for proximal and distal anastomosis in CABG surgery, in order to decrease the rate of such complications.4,8,10,11

Aranki et al. 12 reported a decrease in both hospital mortality and cerebral damage with the use of the single-clamp technique. Marshall et al.13 have shown that most of the embolisations occurred during manipulation of the aorta, especially when the clamp was removed from the aorta.

In the Framingham study, the rate of stroke was 3.5 times higher in patients over 65 years, with a calcification in their aorta. The rate of sudden death due to coronary artery disease was found to be twice as high in patients younger than 65 years, with radiological aortic calcifications, in comparison with patients without aortic calcifications in the same study.14,15

Akpınar et al.5 reported performing coronary artery bypass grafting with only arterial grafts, by inducing ventricular fibrillation with deep hypothermia in 23 patients who had advanced calcifications in the aorta. The mean age of these patients was 65 years, and major neurological complications

were not observed in any of them. We utilised this method in only one of our patients in this series, a patient on whom we had operated in the past five years. However, like other patients in whom plaques were detected in the aorta, this patient was not included in this study.

In a study by Orhan et al.,1 partial clamping was compared with single clamping during coronary bypass operations, and no statistical differences were observed between these groups in terms of stroke and neurological problems. In a study by Us et al.,8 neurological complications were not observed in patients in whom the single-clamp technique was used, whereas neurological complications were statistically significantly higher in those in whom partial clamping was used. Güden et al.16 recommend the single-clamp technique in CABG surgery, as this approach minimises possible embolisations from the aorta

TABLE 1. DEMOGRAPHIC, CLINICAL AND PROCEDURAL DATA FOR STUDY PATIENTS

Group 1 (n = 1500) Group 2 (n = 500)

p-valueParametersPatient number %

Patient number %

Age (mean ± SD) 63.25 ± 5.72 64.83 ± 8.12 0.079

Female gender 654 43.6 214 42.8 0.46

Cardiac data

Acute MI 93 6.2 29 5.8 0.065

Heart failure (pre-operative) 486 32.4 144 28.8 0.058

Risk factors

Smoking 564 37.6 191 38.2 0.95

Hypertension 768 51.2 254 50.8 0.73

Morbid obesity 276 18.4 96 19.2 0.66

Dyslipidaemia 1023 68.2 339 67.8 0.97

Family history 357 23.8 109 21.8 0.39

Peripheral vascular disease 192 12.8 56 11.2 0.38

MI (pre-operative) 648 43.2 214 42.8 0.73

DM 675 45.0 223 44.6 0.73

COLD 333 22.2 109 21.8 0.90

CRF 84 5.6 26 5.2 0.13

NYHA class (mean ± SD) 3.24 ± 7.1 3.18 ± 1.2 0.65

EF (mean ± SD) (pre-operative) 45.46 ± 5.23 46.41 ± 2.31 0.067

LMCA lesion 375 31.51 685 29.65 0.567

Mean ± SD, mean ± standard deviation; MI, myocardial infarction; DM, diabetes melli-tus; COLD, chronic obstructive lung disease; CRF, chronic renal failure; NYHA, New York Heart Association; EF, ejection fraction; LMCA, left main coronary artery.

TABLE 2. COMPLICATIONS AND MORTALITY AFTER CORONARY ARTERY BYPASS GRAFTING

Group 1 (n = 1500)

Group 2 (n = 500) p-value

Number of distal anastomoses (mean ± SD) 2.98 ± 1.9 (1–5) 3.12 ± 2.1 (1–4) 0.96

Time of cross clamp (min) (mean ± SD) 41 ± 4.3 69.6 ± 1.3 0.001

Time of perfusion (min) (mean ± SD) 67.3 ± 3.6 76.7 ± 2.2 0.001

Positive inotropic support (%) 31.2 29.4 0.43

IABP (%) 1.26 0.8 0.001

Time in operating room (min) (mean ± SD) 187.95 ± 2.32 185.25 ± 7.35 0.072

Using grafts

LITA, n (%) (for LAD coronary artery) 2275 (98.48) 483 (96.62%) 0.001

Blood transfusion (units) 3.1 ± 1.4 2.8 ± 2.7 0.001

Days in ICU (mean ± SD) 1.2 ± 2.1 1.8 ± 2.3 0.001

Total days in hospital (mean ± SD) 5.1 ± 2.8 4.9 ± 3.6 0.46

Post-operative bleeding (ml) 550 ± 2.6 490 ± 2.6 0.001

Intubation time (hour) (mean ± SD) 7.86 ± 9.2 12.67 ± 4.8 0.001

Re-operation for bleeding (%) 0.6 0.4 0.86

Peri-operative MI (%) 1.9 2.1 0.92

Stroke, n (%) 26, 1.73 9, 1.8 0.92

30-day mortality, n (%) 24, 1.6 7, 1.4 0.91

Mean ± SD, mean ± standard deviation; IABP, intra-aortic balloon counter pulsation; LITA, left internal thoracic artery; LAD, left anterior coronary artery; ICU, intensive care unit; CVE, cerebrovascular events; AF, atrial fibrillation.

TABLE 3. RISK FACTORS FOR STROKE AFTER CABG IN MULTIVARIATE LOGISTIC ANALYSIS

ParametersStroke patients

(n = 35)Populatıon (n = 2000) p-value

Age (mean ± SD) 65.26 ± 21.4 63.85 ± 5.72 0.14

LMCA disease (%) 17.9 18.4 0.85

IABP use (%) 1.23 1.15 0.925

Time of perfusion (min) (mean ± SD) 79.65 ± 48.12 71.15 ± 24.12 0.001

Time of cross clamp (min) (mean ± SD) 48.75 ± 29.12 36.14 ± 65 0.001

Post-operative hypotension (%) 79.8 12.4 0.001

Peripheral vascular disease (%) 74 16.5 0.001

Hypertension (%) 72 44.6 0.001

Smoking (%) 24 56.7 0.001

AF (%) 35 22.6 0.001

Dyslipidaemia (%) 68 94.5 0.001

DM (%) 67 86.7 0.001

CRF (%) 3.9 4.3 0.792

LVEF (mean ± SD) 38.27 ± 26.31 46.12 ± 12.31 0.001

Mean ± SD, mean ± standard deviation; LMCA, left main coronary artery; IABP, intra-aortic balloon counter pulsation; AF, atrial fibrillation; DM, diabetes mellitus; CRF, chronic renal failure; LVEF, left ventricular ejection fraction.


and neurological complications, and decreases the duration of ischaemia.

In the present study, we were not able to show that the single-clamping technique was superior to the partial-clamping technique during coronary artery bypass operations, in terms of frequency of neurological damage. We found that the mortality rate was the same in both groups.

The single-clamp technique may not be sufficient to minimise neurological complications by itself. Sequential anastomosis may be preferred in order to decrease the number of proximal anastomoses in patients with plaques in the aorta. As the sequential-anastomosis technique is not used routinely in our clinic, this was not included among the parameters evaluated in the present study. Also, replacement of the ascending aorta under hypothermic circulatory arrest, which was recommended by Kouchokos et al.17 for patients with severely calcific aortas, may be considered as an alternative method. The authors reported a mortality rate of 4.3%, without neurological complications.

Revascularisation with the ‘no-touch’ technique or ‘off-pump’ coronary bypass grafting, which were described by Mills et al.,18 may be applied to patients, especially those who have atherosclerotic plaques in their ascending aortas. Coronary bypass surgery with the beating heart technique may be an alternative method, if proximal anastomoses are used for a region outside the ascending aorta. Intra-operative ultrasonographic evaluation is recommended to detect the presence of plaques in the ascending aorta.13 This may be the best method for the prevention of neurological complications due to possible embolisations from the aorta. However, in our hospital, we could not use this method because of practical problems in the operating rooms.

Advanced age, carotid artery disease, aortic atherosclerosis, previous cerebrovascular disease, prolonged cardiopulmonary bypass, and peri-operative hypotension are reported as risk factors for stroke development after CABG.2,19 We detected prolonged cross-clamp duration, diabetes, hypercholesterolaemia, left ventricular dysfunction (EF < 40%), atrial fibrillation, peripheral arterial disease, and peri-operative hypotension as risk factors for stroke (Table 3). Partial clamping used during proximal anastomosis was not found to be a risk factor. Our observation of our patients was that the neurological damages seen after coronary artery bypass surgery were due to multiple factors; they cannot be decreased solely by means of the single-clamp technique.

Neurological problems may also occur during placement and replacement of total aortic cross clamp, aortic cannulation or aortic ‘punch’ application, as well as partial clamp use. Also, there are reports of embolidation even during manual examination of the aorta.16,18,20 It is known that thrombus material that was already present in the left atrium or ventricle may also cause embolism. Each of these factors may cause neurological problems.

At our clinic, we routinely created controlled hypotension for a few seconds with ECC support before replacement of an aortic clamp in patients undergoing CABG. During those few seconds, the surgeon evaluated the aorta carefully. Different techniques other than the routine could be used in patients in whom the presence of aortic plaques was detected. However, patients with aortic plaques were not included in the current study. It is probably for this reason that we found non-superiority of the

single-clamping technique in comparison with partial clamping, in terms of stroke development.

Grocott et al.21 found that the S100β protein was a good marker for showing cerebral damage and that the level of this protein was highest during aortic cannulation in coronary bypass surgery. These authors also detected that the serum levels of the S100β protein were lower during aortic cross-clamp placement or replacement. It was stressed in this study that cannulation was more important in terms of post-operative stroke risk than clamp placement on the aorta.

We believe that metabolic investigations such as protein C, protein S, and anti-thrombin deficiency should be done, as well as determining S100β protein levels for post-CABG stroke and cerebral damage. We could not investigate these parameters, given that the present study was retrospective. Also, the lack of echocardiographic examination of the aorta and the lack of a prospective design were limiting factors of the present study.

ConclusionWe believe that a surgical team may utilise either of the two techniques studied here, after the surgeon has evaluated the aorta at low aortic pressure and concluded that plaques are not present. We feel that both methods may be used safely in routine coronary artery bypass grafting.

References1. Orhan G, Sokullu O, Özay B, Biçer Y, Sargın M, Şenay Ş, et al. The

effect of single-clamp technique on stroke risk in coronary artery bypass surgery. Turk Gogus Kalp Dama 2007; 15(1): 45–50.

2. Christenson JT, Vala DL, Licker M, Sierra J, Kalangos A. intra-aortic filtration: capturing particulate emboli during aortic cross-clamping. Tex Heart Inst J 2005; 32(4): 515–521.

3. Blauth CI, Cosgrowe DM, Webb BW, et al. Atheroembolism from the ascending aorta: an emerging problem in cardiac surgery. J Thorac Cardiovasc Surg 1992; 103: 1104–1112.

4. Kengne AP, Ntyintyane LM, Mayosi BM. A systematic overview of prospective cohort studies of cardiovascular disease in sub-Saharan Africa. Cardiovasc J Afr 2012; 23(2): 103–112.

5. Akpınar B, Güden M, Polat B, Sağbaş E, Sanisoğlu I, Sönmez B, et al. Coronary artery surgery in patients with severe atherosclerosis of the ascending aorta. Turk Gogus Kalp Dama 1999; 7: 217–222.

6. Culliford AT, Colvin SB, Rohrer K, Brauman FG, Spencer FC. The atherosclerotic ascending aorta and transverse arch: a new technique to prevent cerebral injury during bypass: experience in 13 patients. Ann Thorac Surg 1986; 41: 27–35.

7. McKhann GM, Grega MA, Borowicz LM, Baumgartner WA, Selnes OA. Stroke and encephalopathy after cardiac surgery. An update. Stroke 2006; 37: 562–571.

8. Us MH, Süngün M, Caglı K, Yılmaz M, Pekedis A,Oztürk OY. Single clamp technique in elderly patients undergoing coronary artery surgery. Anadolu Kardiyol Derg 2003; 3: 291–295

9. Hammon JW, Stump DA, Kon ND, et al. Risk factors and solutions for the development of neurobehavioral changes after coronary artery bypass grafting. Ann Thorac Surg 1997; 63: 1613–1618.

10. Hammon JW, Stump DA, Butterworth JF, Moody DM, Rorie K, Deal DD, et al. Single crossclamp improves 6-month cognitive outcome in high-risk coronary bypass patients: the effect of reduced aortic manipu-lation. J Thorac Cardiovasc Surg 2006; 131(1): 114–121.

11. Furlan AJ, Breuer AC. Central nervous system complications after open heart surgery. Stroke 1984; 15: 912–915.

12. Aranki SF, Rizzo RJ, Adams DH, Couper GS, Kinchla NM, Gildea JS, et al. Single-clamp technique: an important adjunct to myocardial and cerebral protection in coronary operations. Ann Thorac Surg 1994; 58:


296–302.13. Marshall WG, Barzilai B, Kouchoukos NT, Saffitz J. Intraoperative

ultrasonic imaging of the ascending aorta. Ann Thorac Surg 1989; 48: 339–344.

14. Witteman JC, Kannel WB, Wolf PA, et al. Aortic calcified plaques and cardiovascular diseases (the Framingam Study). Am J Cardiol 1990; 66: 1060–1064.

15. Hatemi AC, Omay O, Baskurt M, Kücükoglu S, Öz B, Süzer K. Mobile atheromatous plaque of the aortic arch diagnosed by transthoracic echocardiography prior to coronary artery bypass surgery. Which one would you choose: skepticism or wishful thinking? Cardiovasc J Afr 2012; 23(4): 3–5.

16. Güden M, Sagbas E, Sanisoglu I, Akpınar B, Yılmaz O. The effects of single clamp technique on cardiac and neurologic outcomes in coronary surgery. Turk Gogus Kalp Dama 2001; 9: 1–3.

17. Kouchokos NT, Wareing TH, Murphy SF, Perrilo JB. Sixteen year experience with aortic root replacement. Results of 172 operations. Ann Thorac Surg 1991; 214: 308–320.

18. Mills NL, Everson CT. Atherosclerosis of the ascending aorta and coronary artery bypass. Pathology, clinical correlates, and operative management. J Thorac Cardiovasc Surg 1991; 102: 546–553.

19. Gardner TJ, Horneffer PF, Manolio TA, et al. Stroke following coronary artery bypass grafting: a ten year study. Ann Thorac Surg 1985; 40: 574–581.

20. Davila Roman VG, Phillips KJ, Daily BB, et al. Intraoperative TEE and epiaortic ultrasound for assessement of atherosclerosis of the thoracic aorta. J Am Coll Card 1996; 28: 942–927.

21. Grocott HP, Croughwell ND, Amory DW, White WD, Kirchner JL, Newman MF. Cerebral emboli and serum S100beta during cardiac operations. Ann Thorac Surg 1998; 65: 1645–1649.

A UNIQUE E-LEARNING OPPORTUNITY

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Dr Landi Lombard

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

Professor James Ker

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

Learning objectivesTo 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 analysisPatients 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 ampu-tation. 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.

CardioVascular Journal of Africa

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.

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


prevalence of myocarditis and cardiotropic virus infection in africans with HiV-associated cardiomyopathy, idiopathic dilated cardiomyopathy and heart transplant recipients: a pilot studyGASNAT SHABOODIEN, CHRISTOPHER MASKE, HELEN WAINWRIGHT, HEIDI SMUTS, MPIKO NTSEKHE, PATRICK J COMMERFORD, MOTASIM BADRI, BONGANI M MAYOSI

abstractBackground: The prevalence of myocarditis and cardiotropic viral infection in human immunodeficiency virus (HIV)-associated cardiomyopathy is unknown in Africa. Methods: Between April 2002 and December 2007, we compared the prevalence of myocarditis and cardiotropic viral genomes in HIV-associated cardiomyopathy cases with HIV-negative idiopathic dilated cardiomyopathy patients (i.e. negative controls for immunodeficiency) and heart trans-plant recipients (i.e. positive controls for immunodeficiency) who were seen at Groote Schuur Hospital, Cape Town, South Africa. Myocarditis was sought on endomyocardial biopsy using the imunohistological criteria of the World Heart Federation in 33 patients, 14 of whom had HIV-associated cardiomyopathy, eight with idiopathic dilated cardiomyopa-thy and 11 heart transplant recipients. Results: Myocarditis was present in 44% of HIV-associated cardiomyopathy cases, 36% of heart transplant recipients, and 25% of participants with idiopathic dilated cardiomyo-pathy. While myocarditis was acute in 50% of HIV- and heart transplant-associated myocarditis, it was chronic in all those with idiopathic dilated cardiomyopathy. Cardiotropic viral infection was present in all HIV-associated cardiomyopathy and idiopathic dilated cardiomyopathy cases, and in 90%

of heart transplant recipients. Multiple viruses were identi-fied in the majority of cases, with HIV-associated cardio-myopathy, heart transplant recipients and idiopathic dilated cardiomyopathy patients having an average of 2.5, 2.2 and 1.1 viruses per individual, respectively. Conclusions: Acute myocarditis was present in 21% of cases of HIV-associated cardiomyopathy, compared to none of those with idiopathic dilated cardiomyopathy. Infection with multiple cardiotropic viruses may be ubiquitous in Africans, with a greater burden of infection in acquired immunodefi-ciency states.

Keywords: HIV-associated cardiomyopathy, myocarditis, dilated cardiomyopathy, cardiotropic virus


Published online 14/6/13


DOI: 10.5830/CVJA-2013-039

Dilated cardiomyopathy is a common manifestation of HIV-associated cardiovascular disease in Africans.1 Little is known, however, about the cause of cardiomyopathy in HIV-infected people living in Africa, a continent with the largest number of people with HIV/AIDS in the world.2-4 A number of hypotheses regarding the pathogenesis of HIV-associated cardiomyopathy have been proposed including myocarditis due to direct infection with HIV or other cardiotropic viruses, genetic predisposition, and nutritional deficiencies.4-6

An autopsy study of 16 patients with HIV/AIDS from the Democratic Republic of the Congo reported histopathological changes of acute myocarditis in all cases, which were attributed to opportunistic infection with Toxoplasma gondii in three of 16 cases (18.75%), Cryptococcus neoformans in three of 16 cases (18.75%) and Mycobacterium avium intracellulare in two of 16 cases (12.5%), and to direct HIV infection in eight of 16 (50%) patients.7 This report raises the possibility that HIV-associated cardiomyopathy may be caused by potentially treatable opportunistic infections in up to 50% of patients living in the sub-Saharan region.2 By contrast, in Western series, opportunistic viral infections or idiopathic causes have been implicated in a significant proportion of cases of HIV-associated cardiomyopathy.8,9

To the best of our knowledge, there have been no ante-mortem studies on the prevalence of myocarditis and cardiotropic viral infection in patients with HIV-associated cardiomyopathy living in Africa.2-4 The aim of this study was to determine the prevalence and type of myocarditis and cardiotropic viral infection in

the Cardiac Clinic and the Hatter institute for Cardiovascular research in africa, department of Medicine, Groote schuur Hospital and university of Cape town, Cape town, south africaGASNAT SHABOODIEN, PhD MPIKO NTSEKHE, MD, PhDPATRICK J COMMERFORD, MB ChB, FCP (SA)MOTASIM BADRI, PhDBONGANI M MAYOSI, MB ChB, DPhil, [email protected]

division of anatomical pathology, department of Clinical laboratory sciences, national Health laboratory service and university of Cape town, Cape town, south africa CHRISTOPHER MASKE, MB ChB, DPhilHELEN WAINWRIGHT, MB ChB, FCPath (SA) Anat

division of Medical Virology, department Clinical laboratory sciences, national Health laboratory service and university of Cape town, Cape town, south africaHEIDI SMUTS, PhD

College of Medicine, King saud Bin abdulaziz university for Health sciences, riyadh, Kingdom of saudi arabia MOTASIM BADRI, PhD


patients with HIV-associated cardiomyopathy compared to those with idiopathic dilated cardiomyopathy and heart transplant recipients in Cape Town.

MethodsThis was a case-comparison study in which the frequency of myocarditis and cardiotropic viral infection in patients with HIV-associated cardiomyopathy was compared with those with idiopathic dilated cardiomyopathy without HIV infection (i.e. negative controls for acquired immunodeficiency state) and heart transplant recipients (i.e. positive controls for an acquired immunodeficiency state). The endomyocardial biopsy study was conducted in the cardiac catheterisation laboratory at Groote Schuur Hospital in Cape Town from April 2002 to December 2007, before anti-retroviral therapy became widely available in South Africa.

A minimum of four right ventricular endomyocardial biopsy specimens were obtained for all patients through the right internal jugular vein. The endomyocardial biopsy samples were immediately placed in formalin (for light microscopy) and snap frozen in liquid nitrogen (for the virological studies).

The study was approved by the Research Ethics Committee of the Faculty of Health Sciences of the University of Cape Town, and all participants gave written informed consent.

We recruited consecutive cases of HIV-positive and HIV-negative patients with a new-onset echocardiographically confirmed diagnosis of dilated cardiomyopathy (i.e. a left ventricular ejection fraction ≤ 45% and/or fractional shortening < 25%, plus a left ventricular end-diastolic diameter > 117% of the predicted value for age and body surface area by applying Henry’s formula)10 or isolated left ventricular systolic dysfunction (i.e. a left ventricular ejection fraction ≤ 45% and/or fractional shortening < 25% plus normal left ventricular dimensions).

Patients with secondary causes of cardiomyopathy or left ventricular systolic dysfunction (such as hypertension, valvular heart disease, diabetes, coronary artery disease, or prior AIDS defining opportunistic infection or malignancy) were excluded from the study. Coronary artery disease was excluded by coronary angiography in all cases with cardiomyopathy who participated in this study.

The HIV-positive patients with unexplained cardiomyopathy were categorised as HIV-associated cardiomyopathy, while the HIV-negative cases were labelled as idiopathic dilated cardiomyopathy. Heart transplant recipients who were undergoing routine endomyocardial biopsy to monitor rejection were also enrolled.

The diagnosis of myocarditis was based on the immunohistological criteria of the World Heart Federation.11,12 These criteria define an abnormal lymphocytic infiltrate as the presence of > 14 CD3

+ lymphocytes per high-power field (and up to four CD68

+ macrophages included in this total amount) (magnification, × 40) with use of a microscope with wide-field, 10 × eyepieces (diameter 550 m; area 2.4 × 105 m; Olympus BH-2, Hamburg, Germany).

Acute myocarditis was defined as a significant lymphocytic infiltrate with myocytolysis (i.e. necrosis or degeneration) on light microscopy, while chronic myocarditis was defined as a significant lymphocytic infiltration with no myocytolysis. Patients with no infiltrating cells or insignificant lymphocyte

infiltrate (< 14 leukocytes/mm2) and no myocytolysis were classified as having no evidence of myocarditis.

Immunohistochemistry was used to define the types of immune cells in the inflammatory infiltrate of myocarditis. Formalin-fixed, paraffin-embedded tissues were sectioned at 5µm for routine, single-label immunohistochemistry. Cell populations were characterised using antibodies specific for CD3 (rabbit polyclonal, A 0452, DakoCytomation, Carpinteria, CA), CD4 (clone 1F6, VP-C318, Vector Laboratories, Burlingame, CA), CD8 (clone 1A5, VP-C325, Vector) and CD68 (clone KP1, M 0814, DakoCytomation).

Two methods were used for the detection of cardiotropic viruses: viral antigen detection using immunohistochemical methods and identification of viral genome by PCR or reverse transcription (RT)-PCR. To evaluate the extent to which cardiotropic viral infections may contribute to induction of the myocardial inflammatory response in the heart tissue under study, specific virological immunoperoxidase screening was conducted for seven cardiotropic viruses using the following virus-specific antigens: cytomegalovirus (Dako, Carpenteria, California, M0854), adenovirus (Novocastra, NCL-ADENO), herpes simplex virus types 1 and 2 (Dako, Carpenteria, California, B0114 and B0116), HIV-1 p24 antigen (Dako, Carpenteria, California, M0857), Epstein-Barr virus (Dako, Carpenteria, California, M0897), enterovirus (Dako Carpenteria, California, M7064), and parvovirus B19 (Dako Carpenteria, California, B0091), along with reviews of haematoxylin and eosin (H&E)-stained sections and special staining for histological evidence of infective agents, such as Toxoplasma gondii, Cryptococcus neoformans and mycobacteria.

Sections were deparaffinised in xylene and rehydrated through graded ethanols, followed by blocking of endogenous peroxidase by incubation in 3% hydrogen peroxide in phosphate-buffered saline. Antigen retrieval in most cases consisted of microwaving in citrate buffer. Antigen retrieval for CD4 consisted of microwaving in EDTA buffer (Lab Vision, Fremont, CA), for adenovirus it consisted of five-minute digestion with proteinase K (Dako, Carpenteria, California), and for CD8 it consisted of 20-min pressure cooker treatment in Trilogy solution (Cell Marque, Hot Springs, AK). Sections were incubated with primary antibody followed by an avidin–biotin block (Vector) to block endogenous biotin, and sequential incubation with biotinylated secondary antibody and horseradish peroxidase-conjugated avidin (ABC Standard or ABC Elite, Vector), or the EnVision polymer system (Dako, Carpenteria, California) applied according to the manufacturer’s instructions.

Antigen–antibody complex formation was detected by use of 3,3′- diaminobenzidine (DAB) chromogen (Dako, Carpenteria, California) and tissues were counterstained with Mayer’s haematoxylin. Viral antigen was detected with viral antibodies to cytomegalovirus, Epstein-Barr virus, herpes simplex virus, parvovirus B19, adenovirus, enterovirus and HIV-1 (Dako, Carpenteria, California; Novocastra, UK Laboratories) in the three groups. Control lymph node tissue was used as positive controls for each virus under study.

Statistical analysisGroups were compared using the Mann-Whitney non-parametric test, Kruskal-Wallis test, χ2 test or Fisher’s exact test, as


appropriate. Statistical analysis of quantitative image analysis data was performed on pooled individual data points collected for each patient within the evaluated groups. All tests were two-sided and p < 0.05 was considered significant. Statistical analysis was performed using Statistica (version 7) and EpiInfo software.

resultsControl endomyocardial biopsy samples were obtained from HIV-negative individuals who were undergoing routine endomyocardial biopsy in the Cardiac Catheterisation Laboratory at Groote Schuur Hospital, either for the investigation of idiopathic dilated cardiomyopathy or for monitoring of rejection in heart transplant recipients. The heart transplant recipients served as positive controls for immunosuppression (which is also present in HIV-associated cardiomyopathy) and their likelihood of having a high frequency of myocarditis resulting from varying degrees of rejection, whereas the idiopathic dilated cardiomyopathy cohort acted as negative controls for absence of immunosuppression and a likely low prevalence of active myocarditis.

During the study period, a total of 40 participants (15 with HIV-associated cardiomyopathy, 10 with idiopathic dilated cardiomyopathy and 15 heart transplant recipients) met the inclusion criteria and were subjected to the endomyocardial biopsy study. Of these, seven were excluded due to inadequate amounts of endomyocardial biopsy tissue for the histological, immunohistochemical and virological analysis. The clinical characteristics of participants who were analysed are presented in Table 1. There was no significant difference in age and gender between the cases with HIV-associated cardiomyopathy, idiopathic dilated cardiomyopathy and heart transplant recipients.

Fifteen patients with HIV-associated cardiomyopathy underwent endomyocardial biopsy, but one patient with inadequate biopsy material was excluded from the analysis, resulting in 14 patients being entered into the analysis. All cases were of black African descent (mean age, 40.5 ± 10.7). A low CD4

+ T-cell count (mean cell count 246 ± 193 cells/mm3; normal range, 600–1000 cells/mm3) and left ventricular ejection fraction (mean range 27.9 ± 6.92%) were found in the patients with HIV-associated cardiomyopathy, as expected.6

Ten consecutive patients with idiopathic dilated cardiomyopathy were recruited and used for comparison with findings in the patients with HIV-associated cardiomyopathy. Two patients were excluded from the analysis due to inadequacy of endomyocardial biopsies, resulting in eight patients being

entered in the comparative analysis (mean age 43 ± 7.35 years; mean left ventricular ejection fraction 26.2 ± 10.39%).

Fifteen consecutive heart transplant recipients who were undergoing routine endomyocardial biopsy were used as controls for comparison with findings in the patients with HIV-associated cardiomyopathy. Due to tissue inadequacy, four patients were excluded from the analysis, resulting in 11 patients being entered into the analysis (mean age 47.1 ± 14.1 years; mean left ventricular ejection fraction 52.8 ± 7.7%).

Immunohistochemical analysis of the mononuclear infiltrates in the myocardium demonstrated a lymphocyte population expressing the pan T-cell marker CD3, CD4

+ T lymphocytes (helper/inducer), CD8

+ T lymphocytes (cytotoxic/suppressor), and monocytes and macrophages (CD68

+ cells). Using CD3 and CD68 immune cell counts, we determined that six of 14 (42.8%) of the HIV-associated cardiomyopathy cohort met the World Heart Federation criteria for myocarditis, displaying > 14 leukocytes/mm2; three cases of 14 had acute myocarditis (21.4%), while three of 14 had chronic myocarditis (21.4%) (Fig. 1A). The remaining eight cases did not display any myocarditis.

Two of the eight idiopathic dilated cardiomyopathy cases (25%) were classified as having chronic myocarditis; the other six samples were classified as having no myocarditis (Fig. 1B). None of the idiopathic dilated cardiomyopathy cases met the criteria for acute myocarditis.

Four heart transplant recipients met the criteria for myocarditis: two of 11 cases (18%) had acute myocarditis and two of 11 (18%) displayed chronic myocarditis (Fig. 1C). There was no significant difference in the prevalence of chronic myocarditis between the groups (p = 0.48).

All cases of HIV-associated cardiomyopathy were infected with at least one cardiotropic virus based on results of testing for viral genomes by PCR. No virus was detected by immunohistochemical methods, suggesting low levels of viral particles in the endomyocardial biopsies. The number of viruses per case ranged from one to four with a mean viral burden of 2.5 viruses per case irrespective of whether patients were classified as having myocarditis or no myocarditis. The biopsy tissues from patients with HIV-associated cardiomyopathy were dominated by the Epstein-Barr virus (64%) and herpes simplex virus (50%) with parvovirus B19 (14%) and cytomegalovirus (7%) having the lowest frequency. HIV-1 was detected in 29% of the HIV-associated cardiomyopathy cases (Fig. 2).

Similarly, all cases of idiopathic dilated cardiomyopathy were infected with at least one cardiotropic virus, with a mean viral burden of 1.1 viruses per case. Enterovirus was the commonest virus (56%), followed by Epstein-Barr virus (29%). Herpes

TABLE 1. CLINICAL CHARACTERISTIC OF PATIENTS WITH HIV-ASSOCIATED CARDIOMYOPATHY (HIVAC), IDIOPATHIC DILATED CARDIOMYOPATHY (IDCM) AND HEART TRANSPLANT RECIPIENTS (HTX)

WHO WERE STUDIED WITH ENDOMYOCARDIAL BIOPSY

HIVAC (n = 14) iDCM (n = 8) HTx (n = 11) p-value‡

Median age in years (range) 40 (27–63) 43.5 (31–54) 50 (26–69) NS*

Male (%) 58 75 82 0.44

Median CD4+ T-cell count (cells/mm3) 253 (200–344) not applicable not applicable

Median HIV load, (copies/ml) 155 000 (28 000-265 000) not applicable not applicable

Median LVEF (%) 30.6 (23–35) 27 (13.5–29) 56.5 (46.8–59.0) < 0.0001

Median duration of illness (weeks) 18 (14.5–26) 14 (7–18) 18.5 (6–21.8) 0.3‡p-value: Fisher’s exact test for categorical variables, Kruskal-Wallis test for continuous variables. LVEF, left ventricular ejection fraction, NS, not significant.


simplex virus, adenovirus and parvovirus B19 virus were each detected in 12% of the cases (Fig. 2). Cytomegalovirus infection was not detected in participants with idiopathic dilated cardiomyopathy.

A viral prevalence of 90% was found in the heart transplant recipients as 10 of the 11 cases were positive for at least one virus as detected by PCR. A mean viral burden of 2.2 viruses per case was found irrespective of whether patients were classified as having myocarditis or no myocarditis. The most prevalent viruses was the enterovirus (50%) and adenovirus (50%), followed by Epstein-Barr virus (32%) and herpes simplex virus (25%), with parvovirus B19 (18%) and cytomegalovirus (18%) being the least common agents (Fig. 2).

discussionIn this first report of the prevalence of myocarditis and cardiotropic viral infection in African patients with HIV-associated cardiomyopathy, we show that nearly half of the patients may

have had acute and chronic myocarditis. By contrast, idiopathic dilated cardiomyopathy was associated with myocarditis in a quarter of the cases, none of whom had acute disease.

The presence of genomes of cardiotropic viruses was almost universal in African patients with HIV-associated cardiomyopathy, idiopathic dilated cardiomyopathy, and heart transplant recipients. Furthermore, we observed that participants who were immunosuppressed by HIV infection or on immunosuppressive treatment for heart transplantation had double the number of cardiotropic viruses per case, compared to those with idiopathic dilated cardiomyopathy (2.2–2.5 viruses per case compared to 1.1 virus per case).

Because heart biopsy and viral genome analysis are rarely done in many regions of the world, the prevalence of viral myocarditis in much of Africa, Asia, the Middle East and South America is unknown.12 The few endomyocardial biopsy studies in African patients with cardiomyopathy were conducted in the pre-HIV era.13–16 These studies, which did not use modern techniques of immunohistochemistry and molecular characterisation of viral genomes, had conflicting findings on the prevalence of myocarditis.

In the largest endomyocardial biopsy study of 76 South African patients with idiopathic dilated cardiomyopathy, no evidence of myocarditis was found, leading to the conclusion that the cardiac failure of dilated cardiomyopathy was due to an unknown functional abnormality, such as a toxin or metabolic defect.13,14 However, endomyocardial biopsy studies of dilated and peripartum cardiomyopathy from Kenya revealed that about half of the patients had evidence of healed myocarditis but no serological evidence of a previous Coxsackie virus infection or any other common viral infections.15,16 The authors concluded that the myocarditis was due to an inappropriate immunological reaction to myocardial muscle.15,16

a: HiV-associated cardiomyopathy

B: idiopathic dilated cardiomyopathy

C: Heart transplant recipients

Fig. 1. prevalence of myocarditis in HiV-associated cardiomyopathy (a), idiopathic dilated cardiomyopathy (B), and heart transplant recipients (C).

Acute myocarditis

Chronic myocarditis

No myocarditis

Chronic myocarditis

No myocarditis

Acute myocarditis

Chronic myocarditis

No myocarditis

Fig. 2. prevalence of cardiotropic virus infection in patients with HiV-associated cardiomyopathy (HiVaC), idiopathic dilated cardiomyopathy (idCM), and heart transplant recipients (Htx). Entero, enterovirus; adeno, adenovirus; parvo, parvovirus B19; CMV, cytomegalovi-rus; EBV, Epstein-Barr virus; HsV, herspes simplex virus; HiV, human immunodeficiency virus.

Vira

l pre

senc

e (%

)

Viral infective status of three cohorts using EMB

CohortsidCM

HiVaC

8

6

4

2

0

Enteroadeno

parvoCMV

EBVHsV

HiV

Entero adeno parvo CMVEBV HsV HiV

57.2%

64%

75%

21.4%

18%

21.4%

18%

25%

Htx


The literature from developed countries on the presence of viral genomes in cardiomyopathy has pointed to enterovirus, adenovirus, cytomegalovirus and HIV-1 as the dominant opportunistic viral infections in the heart tissue of patients with HIV-associated cardiomyopathy.17–19 By contrast, our study revealed Epstein-Barr and herpes simplex viruses to be the most prevalent cardiotropic viruses in patients with HIV-associated cardiomyopathy.

Epstein-Barr virus and herpes simplex virus are common herpes viruses that have a latency stage; they are reactivated in immunocompromised individuals, causing tissue damage. Similarly, enteroviruses, which were common in our cases with HIV-associated cardiomyopathy and idiopathic dilated cardiomyopathy, are also known have a latency stage, which could have important consequences for the clinical course of the disease. Parvovirus B19 had the lowest prevalence in all groups of patients, whereas it is one of the commonest causes of viral myocarditis in North America and Europe.20,21 We found no obvious pattern of association with any of these viral genomes with myocarditis, in line with previous observations.22

While the phenomenon of multiple viral infections is known to occur in patients with end-stage dilated cardiomyopathy, the prevalence of cardiotropic viral infection is much higher in African patients (100%) compared to elsewhere in the world (~ 65%).22 It is of interest that the number of viruses per case ranged from one to four, with a mean viral burden of 2.3 types of viruses in HIV-associated cardiomyopathy, zero to four in heart transplant recipients with a mean viral burden of 2.2 types per case, and one to two in those with idiopathic dilated cardiomyopathy with a mean viral burden of 1.1 per case. These findings, which suggest an increased susceptibility to viral infection in immunosuppressed groups, point to the possibility that the damage to the myocardium in patients with cardiomyopathy is not only through post-viral autoimmune mechanisms but may also be as a result of repeated infections by different cardiotropic viruses.

The finding of myocarditis in a significant proportion of patients with idiopathic dilated cardiomyopathy may have prognostic implications. Kindermann and colleagues showed that the risk of death or need for cardiac transplantation in patients with myocarditis was worse in those with inflammation than in those without, as assessed by immunohistology.23 Significant inflammation was present in 25% of the participants who underwent endomyocardial biopsy testing as part of investigation of unexplained dilated cardiomyopathy.

It is essential to determine whether the cellular and imunohistological changes have prognostic effects in African patients with dilated cardiomyopathy. Furthermore, interferon-beta treatment may eliminate enterovirus and adenovirus and improve left ventricular function in immuno-competent patients with myocardial persistence of viral genomes and left ventricular dysfunction.20 There is a need to assess the effectiveness of interferon-beta treatment in African patients with cardiomyopathy, in the light of the discovery of the overwhelming presence of viral genomes in our patients.

The major weakness of the study was the small sample size. The number of analysed patients may have beeen insufficient to reliably determine the proportion of patients with HIV-associated cardiomyopathy with acute myocarditis, or to delineate differences between the HIV-infected and HIV-negative patients with dilated

cardiomyopathy. However, while the small sample size limits the generalisability of the findings, it provides a strong basis for the exploration of the findings in larger studies.

Furthermore, the use of a prospective consecutive design with two different types of controls has, however, ensured that the study has internal validity with regard to the diagnosis of myocarditis and patterns of viral infection in immunosuppressed hosts. The heart transplant recipients, as expected, had evidence of acute myocarditis due to varying degrees of rejection. It was also interesting to note that the burden of viral infection was higher in the immunosuppressed patients (by HIV and heart transplantation), with cytomegalovirus infection being observed, as expected, only in immunosuppressed individuals.24 We included all eligible patients with HIV-associated cardiomyopathy during the period of the study (five years), and the sample size was not different from that of similar studies.25

The prevalence of myocarditis in HIV-associated cardiomyopathy in our study is similar to the rates found in North America in the pre-HIV era, and the frequency of chronic myocarditis in idiopathic dilated cardiomyopathy is consistent with findings elsewhere in the world.8,26 The external validity of this study is confirmed by the finding of a high prevalence of enteroviruses in HIV-positive heart tissue, which corresponds with data that were reported by Herskowitz in patients with AIDS nearly two decades ago.8

ConclusionMyocarditis and cardiotropic viral infection appear to be common and may play a significant role in the pathogenesis of HIV-associated and idiopathic dilated cardiomyopathy in Africans. The results of this small pilot study need to be confirmed in larger studies to endorse these observations and determine the prognostic and therapeutic implications of our findings. If the pathogenetic role of cardiotropic viral infection in cardiomyopathy is confirmed in other studies, this might lead to the development of appropriate immunisation to aid the prevention of the disease and reduce the prevalence of cardiomyopathies, which are endemic in Africa.27

We thank Sisters Naomi Hare, Joanne Hartnick and Maitele Tshifularo for assistance with this research. We also greatly appreciate the Claude Leon Foundation for providing us with the sponsorship of Dr Gasnat Shaboodien. Funding was provided by the Medical Research Council and the National Research Foundation.

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3. Ntsekhe M, Hakim J. Impact of human immunodeficiency virus infection on cardiovascular disease in africa. Circulation 2005; 112: 3602–3607.

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5. Lemmer CE, Badri M, Visser M, Mayosi BM. A lower body mass index is associated with cardiomyopathy in people with HIV infec-tion: Evidence from a case comparison study. S Afr Med J 2011; 101: 119–121.


6. Twagirumukiza M, Nkeramihigo E, Seminega B, Gasakure E, Boccara F, Barbaro G. Prevalence of dilated cardiomyopathy in hiv-infected african patients not receiving haart: A multicenter, observational, prospective, cohort study in rwanda. Curr HIV Res 2007; 5: 129–137.

7. Longo-Mbenza B, Seghers KV, Phuati M, Nkiabungu Bikangi F, Mubagwa K. Heart involvement and hiv infection in african patients: Determinants of survival. Int J Cardiol 1998; 64: 63–73.

8. Herskowitz A, Wu TC, Willoughby SB, Vlahov D, Ansari AA, Beschorner WE, Baughman KL. Myocarditis and cardiotropic viral infection associated with severe left ventricular dysfunction in late-stage infection with human immunodeficiency virus. J Am Coll Cardiol 1994; 24: 1025–1032.

9. Anderson DW, Virmani R, Reilly JM, O’Leary T, Cunnion RE, Robinowitz M, et al. Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome. J Am Coll Cardiol 1988; 11: 792–799.

10. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation 1980; 62: 1054–1061.

11. Maisch B, Portig I, Ristic A, Hufnagel G, Pankuweit S. Definition of inflammatory cardiomyopathy (myocarditis): On the way to consensus. A status report. Herz 2000; 25: 200–209.

12. Sagar S, Liu PP, Cooper Jr LT. Myocarditis. Lancet 2012; 379: 738–747.13. Rose AG, Fraser RC, Beck W. Absence of evidence of myocarditis in

endomyocardial biopsy specimens from patients with dilated (conges-tive) cardiomyopathy. S Afr Med J 1984; 66: 871–874.

14. Rose AG, Beck W. Dilated (congestive) cardiomyopathy: A syndrome of severe cardiac dysfunction with remarkably few morphological features of myocardial damage. Histopathology 1985; 9: 367–379.

15. Sanderson JE, Olsen EG, Gatei D. Peripartum heart disease: An endo-myocardial biopsy study. Br Heart J 1986; 56: 285–291.

16. Sanderson JE, Olsen EG, Gatei D. Dilated cardiomyopathy and myocar-ditis in kenya: An endomyocardial biopsy study. Int J Cardiol 1993; 41: 157–163.

17. Poller W, Fechner H, Noutsias M, Tschoepe C, Schultheiss HP. Highly variable expression of virus receptors in the human cardiovascular system. Implications for cardiotropic viral infections and gene therapy. Z Kardiol 2002; 91: 978–991.

18. Wu TC, Pizzorno MC, Hayward GS, Willoughby S, Neumann DA,

Rose NR, et al. In situ detection of human cytomegalovirus imme-diate-early gene transcripts within cardiac myocytes of patients with HIV-associated cardiomyopathy. AIDS 1992; 6: 777–785.

19. Bowles NE, Ni J, Kearney DL, Pauschinger M, Schultheiss H-P, McCarthy R, et al. Detection of viruses in myocardial tissues by poly-merase chain reaction: Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003; 42: 466–472.

20. Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, et al. Interferon-{beta} treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocar-dial persistence of viral genomes and left ventricular dysfunction. Circulation 2003; 107: 2793–2798.

21. Kühl U, Lassner D, Pauschinger M, Gross UM, Seeberg B, Noutsias M, et al. Prevalence of erythrovirus genotypes in the myocardium of patients with dilated cardiomyopathy. J Med Virol 2008; 80: 1243–1251.

22. Kuhl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, et al. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with ‘idiopathic’ left ventricular dysfunction. Circulation 2005: 111: 887–893.

23. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, et al. Predictors of outcome in patients with suspected myocarditis. Circulation 2008; 118: 639–648.

24. Merigan TC, Stevens DA. Viral infections in man associated with acquired immunological deficiency states. Fed Proc 1971; 30: 1858–1864.

25. Rodriguez ER, Nasim S, Hsia J, Sandin RL, Ferreira A, Hilliard BA, et al. Cardiac myocytes and dendritic cells harbor human immunodefi-ciency virus in infected patients with and without cardiac dysfunction: Detection by multiplex, nested, polymerase chain reaction in individu-ally microdissected cells from right ventricular endomyocardial biopsy tissue. Am J Cardiol 1991; 68: 1511–1520.

26. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, et al. Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyo-pathy : Two-year follow-up results. Circulation 2001; 104: 39–45.

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Ventilation during cardiopulmonary bypass did not attenuate inflammatory response or affect postoperative outcomes AHMET BARIS DURUKAN, HASAN ALPER GURBUZ, NEVRIYE SALMAN, ERTEKIN UTKU UNAL, HALIL IBRAHIM UCAR, CEM YORGANCIOGLU

abstractIntroduction: Cardiopulmonary bypass causes a series of inflammatory events that have adverse effects on the outcome. The release of cytokines, including interleukins, plays a key role in the pathophysiology of the process. Simultaneously, cessation of ventilation and pulmonary blood flow contribute to ischaemia–reperfusion injury in the lungs when reperfusion is maintained. Collapse of the lungs during cardiopulmonary bypass leads to postoperative atelectasis, which correlates with the amount of intrapul-monary shunt. Atelectasis also causes post-perfusion lung injury. In this study, we aimed to document the effects of continued low-frequency ventilation on the inflamma-tory response following cardiopulmonary bypass and on outcomes, particularly pulmonary function. Methods: Fifty-nine patients subjected to elective coro-nary bypass surgery were prospectively randomised to two groups, continuous ventilation (5 ml/kg tidal volume, 5/min frequency, zero end-expiratory pressure) and no ventilation, during cardiopulmonary bypass. Serum interleukins 6, 8 and 10 (as inflammatory markers), and serum lactate (as a mark-er for pulmonary injury) levels were studied, and alveolar–arterial oxygen gradient measurements were made after the induction of anaesthesia, and immediately, one and six hours after the discontinuation of cardiopulmonary bypass. Results: There were 29 patients in the non-ventilated and 30 in the continuously ventilated groups. The pre-operative demographics and intra-operative characteristics of the patients were comparable. The serum levels of interleukin 6 (IL-6) increased with time, and levels were higher in the non-ventilated group only immediately after discontinuation of cardiopulmonary bypass. IL-8 levels significantly increased only in the non-ventilated group, but the levels did not differ between the groups. Serum levels of IL-10 and lactate also increased with time, and levels of both were higher in the

non-ventilated group only immediately after the discontinu-ation of cardiopulmonary bypass. Alveolar–arterial oxygen gradient measurements were higher in the non-ventilated group, except for six hours after the discontinuation of cardiopulmonary bypass. The intubation time, length of stay in intensive care unit and hospital, postoperative adverse events and mortality rates were not different between the groups. Conclusion: Despite higher cytokine and lactate levels and alveolar–arterial oxygen gradients in specific time periods, an attenuation in the inflammatory response following cardiopulmonary bypass due to low-frequency, low-tidal volume ventilation could not be documented. Clinical param-eters concerning pulmonary and other major system func-tions and occurrence of postoperative adverse events were not affected by continuous ventilation.

Keywords: cardiopulmonary bypass, respiration, artificial, lactic acid, interleukins



DOI: 10.5830/CVJA-2013-041

Since the development of the first heart–lung machine in the 1950s, cardiopulmonary bypass (CPB) has been the only way to provide a motionless and bloodless field. During CPB, circulation is maintained by mechanical pumps and venous blood is artificially oxygenated.1

Cardiopulmonary bypass is a non-physiological state where blood is exposed to artificial surfaces; laminar flow is employed instead of pulsatile flow, the heart is exposed to cold cardioplegic arrest and the body temperature is lowered. These key derangements lead to a series of inflammatory events involving the endothelium, leukocytes, platelets, complement system and the coagulation cascade, with the release of various cytokines.2 Surgical trauma, blood product transfusion and haemodilution also participate in this inflammatory process.3

During CPB, pulmonary arterial circulation and alveolar ventilation are ceased and only bronchial arterial circulation supply oxygen to the lungs.3 After weaning from CPB, pulmonary reperfusion leads to ischaemia–reperfusion injury (I/R), with the release of oxygen free radicals and the resultant lipid peroxidation and endothelial damage.4 Maintaining ventilation and pulmonary flow during CPB attenuates the inflammatory response.3,5

In this study, we aimed to compare ventilation and non-ventilation regimes during CPB in patients undergoing on-pump coronary artery bypass grafting (CABG). Its influence on pulmonary injury was evaluated using lactate levels and

department of Cardiovascular surgery, Medicana international ankara Hospital, ankara, turkeyAHMET BARIS DURUKAN, MD, [email protected] ALPER GURBUZ, MDHALIL IBRAHIM UCAR, MDCEM YORGANCIOGLU, MD

department of anesthesia, Medicana international ankara Hospital, ankara, turkeyNEVRIYE SALMAN, MD

department of Cardiovascular surgery, ankara yuksek ihtisas Hospital, ankara, turkeyERTEKIN UTKU UNAL, MD


measurement of alveolar–arterial oxygen gradients, and on postoperative cardiopulmonary functions using clinical parameters.

MethodsA prospective, randomised study was carried out. The study was approved by the local ethics committee and written informed consent was obtained from every patient. The study followed the Declaration of Helsinki 2008 on medical protocol.

Between October 2011 and February 2012, patients subjected to elective CABG surgery were studied. Patients undergoing redo surgery, and those with pre-operative renal failure (serum creatinine > 1.3 mg/dl) or hepatic dysfunction (serum aspartate/alanine amino transferase > 40 U/l), myocardial infarction within six weeks prior to surgery, any kind of pulmonary disease, pre-operative use of steroids and ejection fraction below 30% were excluded from the study.

A total of 59 patients were prospectively randomised into two groups as follows: in the operation room, each patient was numbered chronologically by the same perfusionist. He reviewed the patient’s file prior to the induction of anaesthesia, based on a form explaining the inclusion and exclusion criteria, and the anesthesiologist was informed about the proposed regimen. Odd-numbered patients (n = 30) were ventilated during CPB and the even-numbered patients (n = 29) were not ventilated.

Peri-operative management and anaesthesiaPre-operative acetylsalicylic acid 100 mg/day was continued in all patients prior to the day of surgery. All patients were pre-medicated with 10 mg of oral diazepam. Anaesthesia was induced with etomidate 2 mg/kg, fentanyl 1µg/kg, vecuronium 1 mg/kg, isofluorane 1 MAC with 50% oxygen and 50% air, and remifentanyl 1µg/kg bolus, followed by a 0.5-µg/kg/min infusion. Intra-operative arterial (through the radial artery catheter) and central venous pressure (through the right internal jugular vein catheter) monitoring was done.

The CPB circuit was primed with 1 500 ml Isolyte-S® (Eczacibaşi-Baxter, Istanbul), which is a balanced electrolyte solution, and 5 000 units of heparin were added. After anticoagulation with heparin (300 U/kg), CPB was established using a roller pump with a membrane oxygenator (Dideco Compactflo Evo, Sorin group, Mirandola Modena, Italy). The average flow rate varied from 2.3 to 2.4 l/min/m2. Surgery was performed under mild hypothermia (33°C). Mean arterial pressure was kept between 45 and 70 mmHg. All patients were rewarmed to 37°C (nasopharayngeal temperature) before weaning from CPB. Heparin was neutralised with 1:1 protamine sulfate.

Cold (4–8°C) blood cardioplegia (1 000 ml, 25 mEq/l potassium) was administered after aortic cross clamping, and 500-ml repeat doses were given every 15 to 20 minutes (antegrade and from the venous bypass grafts; retrograde in the case of left main stenosis). Terminal warm blood cardioplegia (36–37°C) was given prior to aortic clamp release. The operating room temperature was kept at 20–21°C.

Following surgery, the patients were taken to the intensive care unit (ICU), intubated, and intravenous propofol (1–2 mg/kg/h) and morphine (0.01–0.02 mg/kg/h) were given for the maintenance of analgesia and sedation.

Atrial fibrillation (AF) was diagnosed based on an electrocardiogram. All patients were ECG monitored continuously during the ICU stay and for the first 24 hours in the ward. An ECG was immediately performed in cases of irregular pulse, palpitations or symptoms related to possible AF.

Primary outcome variables included mean time to extubation, length of stay in ICU and postoperative hospital stay, incidence of renal dysfunction (based on the finding that the peak creatinine value was ≥ 1.5 times the pre-operative value), postoperative stroke, total amount of blood loss postoperatively, postoperative exploration for haemorrhage, amount of blood and blood products used, and in-hospital mortality.

Ventilation strategyAfter intubation, before and after CPB, all patients were ventilated with FiO2 of 0.4 to 0.5, at a tidal volume of 7 ml/kg and respiratory rate of 12/min. Positive end-expiratory pressure was not used, and no requirement for FiO2 over 0.5 was required to maintain adequate oxygen saturation. The variability in ventilation parameters was to maintain a partial arterial carbon dioxide pressure between 35 and 40 mmHg.

In the non-ventilated group (NV), following establishment of CPB, ventilation was stopped (open to atmospheric pressure). In the ventilated group (V) mechanical ventilation with 0.5 FiO2

at 5 ml/kg tidal volume and 5/min respiratory rate with zero end-expiratory pressure was maintained. In the ICU, patients had volume-controlled ventilation and were extubated when their haemodynamics were stable, and neurological and respiratory functions were noted.

Blood sampling and measurementsPeripheral arterial blood samples were collected from the radial artery catheter after the induction of anaesthesia (T0), and immediately after (T1), one (T2) and six hours (T3) after the discontinuation of CPB. The blood samples were put into citrated and EDTA anti-coagulated tubes, centrifuged, and the plasma was separated and stored at –70°C until the assay.

Plasma levels of IL-6, -8 and -10 were measured by commercially available enzyme-linked immunosorbent assays (AssayMax Human ELISA Kit, Assaypro, Missouri, USA). Plasma lactate levels were measured by blood gas analyser (ABL 700 series, Radiometer®, Brønshøj, Denmark).

Alveolar–arterial oxygen gradient (∆A–aO2) was calculated as follows:6

∆A–aO2 = PAO2 – PaO2

PAO2 = PiO2 – (PACO2/R)

PiO2 = (PB – PH2O) – FiO2

where PAO2 = alveolar oxygen tension; PaO2 = partial arterial oxygen pressure; PiO2 = partial pressure of inspired oxygen; PACO2 = alveolar carbon dioxide tension (assumed to equal the partial arterial CO2 pressure due to the ease of exchange of CO2); R = respiratory quotient (assumed at 0.8); PB = barometric pressure; PH2O = water pressure (6.2 kPa, as inspired air is fully saturated at the level of the carina); and FiO2 = fractional concentration of inspired oxygen.

Statistical analysisStatistical analyses were performed using SPSS software for


Windows version 17.0 (Statistical Package for the Social Sciences Inc, Chicago, IL, USA). Continuous variables were expressed as mean values ± standard deviation (SD). Categorical variables were expressed as number and percentages. Demographic characteristics and outcomes of the groups were compared using independent samples t-test for continuous variables, and chi-square and Fisher’s exact tests for categorical variables. Statistical significance was set as p < 0.05.

The changes in cytokine levels, lactate and ∆A–aO2 within the groups were compared using the Friedman test. In cases of significant difference, Wilcoxon signed ranks test was used to define the groups that made the difference. Comparison between the groups was done using the Mann-Whitney U-test.

resultsFifty-nine patients were included in the study. There were 29 patients in the NV group and 30 in the V group. The mean ages of the patients were 62.48 ± 6.42 in the NV group and 59.40 ± 11.10 in the V group (p = 0.19). The pre-operative demographic data and intra-operative characteristics of the patients are given in Table 1. The groups were comparable.

IL-6 levels were increased after induction of anaesthesia in both groups and remained higher than baseline levels six hours after discontinuation of CPB. When the two groups were compared, only IL-6 levels were higher immediately after discontinuation of CPB in the NV group than in the V group (p = 0.049) (Table 2, Fig. 1).

Interleukin-8 levels were increased in the NV group, they peaked one hour after discontinuation of CPB and decreased

at six hours to baseline levels (p = 0.005). In the V group, IL-8 levels increased, peaked immediately after discontinuation of CPB, decreased at one hour and increased again at six hours, but the change in IL-8 concentrations in this group was not significant (p = 0.99). When the two groups were compared, there was no statistically significant difference at any time period (Table 2, Fig. 2).

IL-10 levels were increased in the NV group, peaked immediately after discontinuation of CPB, decreased soon after

TABLE 1. PRE-OPERATIVE DEMOGRAPHIC CHARACTERISTICS OF PATIENTS

VariableNV group (n = 29)

mean ± SDV group (n = 30)

mean ± SD p-value*

Age 62.48 ± 6.42 59.40 ± 11.10 0.19

BMI (kg/m2) 32.51 ± 12.22 29.17 ± 3.44 0.15

LVEF (%) 52.48 ± 11.77 52.57 ± 10.14 0.97

Cross-clamp time (min) 54.66 ± 13.97 54.67 ± 13.11 0.99

CPB time (min) 83.41 ± 22.72 80.83 ± 22.23 0.66

No of grafts 3.21 ± 0.77 3.03 ± 0.85 0.41

n (%) n (%) p-value**

Male 23 (79.3) 26 (86.7) 0.45

Current/ex-smoker 22 (75.9) 22 (73.3) 0.82

Diabetes mellitus 16 (55.2) 12 (40.0) 0.24

Insulin dependenta 7 (46.7) 8 (58.3) 0.22

Hypertension 22 (75.9) 16 (53.3) 0.07

Dyslipidaemia 23 (79.3) 21 (70) 0.41

Statin therapyb 14 (60.9) 16 (76.2) 0.27

Pre-operative β-blocker use 17 (58.6) 12 (40.0) 0.15

Peripheral arterial diseasec 2 (6.9) 0 0.23***

Stroke 2 (6.9) 1(3.3) 0.49***

Carotid diseased 0 2 (6.7) 0.61***

SD: standard deviation, NV: non-ventilated, V: ventilated, BMI: body mass index, LVEF: left ventricular ejection fraction, CPB: cardiopulmonary bypass.*Independent samples t-test, **Chi-square test, ***Fisher’s exact test.aThe percentage values were calculated in diabetic patients. bThe percentage values were calculated in dyslipidaemic patients.cHistory of therapeutic vascular intervention, history of claudication, aniography/ non-invasive proven peripheral arterial disease. dHistory of carotid intervention or angiographic/non-invasive proven > 40% stenosis of either carotid artery.

TABLE 2. COMPARISON OF TWO GROUPS WITH CYTOKINE LEVELS AND ALVEOLAR–ARTERIAL OXYGEN GRADIENT

VariableNV group (n = 29)

mean ± SDV group (n = 30)

mean ± SD p-value*

IL-60 (pg/ml) 8.28 ± 1.06 8.03 ± 0.18 0.51

IL-61 (pg/ml) 16.0 ± 9.04 15.37 ± 17.21 0.049

IL-62 (pg/ml) 17.31 ± 10.34 13.97 ± 6.57 0.22

IL-63 (pg/ml) 22.83 ± 12.91 19.50 ± 6.88 0.38

p-value** < 0.001 < 0.001

IL-80 (pg/ml) 24.86 ± 48.30 25.03 ± 25.53 0.14

IL-81 (pg/ml) 30.79 ± 44.50 26.07 ± 30.35 0.85

IL-82 (pg/ml) 31.72 ± 44.71 21.67 ± 21.18 0.62

IL-83 (pg/ml) 20.34 ± 29.47 24.20 ± 23.63 0.33

p-value** 0.005 0.997

IL-100 (pg/ml) 15.30 ± 7.31 15.58 ± 9.36 0.87

IL-101 (pg/ml) 142.03 ± 55.20 85.74 ± 61.65 0.002

IL-102 (pg/ml) 120.00 ± 41.73 108.45 ± 68.13 0.62

IL-103 (pg/ml) 24.20 ± 24.98 26.16 ± 37.41 0.98

p-value** < 0.001 < 0.001

Lactate0 (mmol/l) 1.56 ± 0.73 1.38 ± 0.47 0.55

Lactate1 (mmol/l) 4.07 ± 1.68 2.95 ± 1.49 0.003

Lactate2 (mmol/l) 4.10 ± 1.90 4.04 ± 4.04 0.21

Lactate3 (mmol/l) 3.96 ± 2.16 4.10 ± 1.37 0.34

p-value** < 0.001 < 0.001

∆A–aO2(0) (kPa) 20.60 ± 6.16 11.84 ± 5.39 < 0.001

∆A–aO2(1) ( kPa) 24.91 ± 3.98 14.15 ± 5.77 < 0.001

∆A–aO2(2) (kPa) 26.47 ± 5.13 19.54 ± 4.05 < 0.001

∆A–aO2(3) (kPa) 18.95 ± 7.59 17.19 ± 6.77 0.31

p-value** < 0.001 < 0.001

SD: standard deviation, NV: non-ventilated, V: ventilated, IL: interleukin, ∆A–aO2: alveolar–arterial oxygen gradient.*Mann-Whitney U-test, **Friedman test.0After induction of anaesthesia, 1Immediately after discontinuation of CPB, 2One hour after discontinuation of CPB, 3Six hours after discontinuation of CPB.

Fig. 1. serum il-6 levels.

30

25

20

15

10

5nV V

Group

95%

Ci (

pg/m

l)

il-60 il-62il-61 il-63


and returned to baseline levels (p < 0.001). In the V group, IL-10 levels were increased following induction of anaesthesia, peaked at one hour after discontinuation of CPB, and decreased soon after (p < 0.001). When the two groups were compared, only IL-10 levels were higher immediately after discontinuation of CPB in the NV group than in the V group (p = 0.001) (Table 2, Fig. 3).

Pulmonary functionLactate release was significantly increased after the induction of anaesthesia in both groups; it peaked at one hour after discontinuation of CPB in the NV group and decreased at six hours, but remained higher than baseline levels (p < 0.001). In the ventilated group, levels of lactate progressively increased with time (p < 0.001) (Table 2, Fig. 4). However, in each time period there was no significant difference in lactate levels between the groups.

The alveolar–arterial oxygen gradient widened after the induction of anaesthesia, peaked at one hour after discontinuation of CPB, and decreased at six hours, but remained higher than baseline levels in both groups (p < 0.001). When the two groups were compared, the gradient was higher in the non-ventilated group after induction, and immediately after and at one hour after discontinuation of CPB (p < 0.001) (Table 2, Fig. 5).

In the ICU, the intubation time for the NV group was 9.67

± 3.29 h and 9.27 ± 2.86 h in the V group (p = 0.61) (Table 3). Prolonged intubation was not required in any patient.

Clinical parametersLength of stay in ICU and postoperative hospital length of stay were not statistically different in both groups. There was no significant difference when amount of drainage, amount of blood and blood products used, and incidence of postoperative exploration for haemorrhage were compared. Renal failure was defined as peak creatinine value ≥ 1.5 times the pre-operative value and there was no significant difference between the groups (Table 3).

When postoperative AF was studied, there were six patients (20.7%) with AF in the NV group, and three (10.0%) in the V group (p = 0.29). Normal sinus rhythm was maintained in all patients except one in the V group. There was no statistically significant difference when maintenance of sinus rhythm was compared. There was no postoperative stroke and mortality noted throughout the study.

discussionThe inflammatory response to CPB is acute, complex and can lead to significant morbidity and mortality. It involves the release of cytokines, which may have an impact on postoperative


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outcomes. The release of cytokines [tumour necrosis factor-alpha (TNF-α), interleukins and interferons] may negatively affect cardiac, renal and pulmonary functions.2 Cytokine release was shown to correlate with outcome after cardiac surgery. During and after CPB, serum levels of IL-6, IL-8 and TNF-α were increased.

TNF-α is a proximal mediator in the inflammatory cascade.7 It induces endothelial cells to produce cell adhesion molecules (E- and P-selectins), which bind to ligands on activated leukocytes to mediate ‘rolling’ of the leukocytes, and intracellular and vascular cell adhesion molecules, which facilitate leukocyte migration from the endothelium to the extravascular space.1 TNF-α also induces a second wave of cytokines such as IL-6, which is an important regulator of the hepatic acute-phase response, and IL-8, a cytokine with important neutrophil-activating and chemo-attractant properties.7 The neutrophilic effects of IL-8 lead to local release of proteolytic enzymes, with resultant pulmonary injury.8

Increased levels of IL-6 and IL-8 were also related to regional wall motion abnormalities following on-pump cardiac surgery.2 The release of IL-6 and -8 during CPB led to neutrophil entrapment in pulmonary capillaries. This in turn led to endothelial cell swelling, plasma and protein extravasation into the pulmonary interstitial tissue, together with the release of proteolytic enzymes and the resultant congestion of the alveoli.9 The clinical result was decreased PaO2 and increased PaCO2, indicating pulmonary injury.10

The negative effects of these cytokines are limited by the anti-inflammatory cytokine IL-10, which has protective effects against organ dysfunction following CPB.11 In a study of 13 patients, Deblier et al.12 reported increased IL-10 release, with a peak at the end of CPB in both ventilated and non-ventilated groups, but ventilation did not influence this increase and there was no significant difference between the groups. They failed to document a significant increase in IL-6 in both groups.

Beer et al.13 conducted a similar study and indicated that continued ventilation during CPB attenuated pro-inflammatory IL-6 concentrations and anti-inflammatory IL-10 concentrations. The levels of IL-6 and IL-10 peaked at the end of surgery (which corresponds to T2 in our study) in both groups.

Ng et al.3 documented higher IL-10 levels one hour after declamping the aorta in the ventilated group (which corresponds to sometime between T1 and T2 in our study). In our study, the levels of IL-6 were highest six hours after discontinuation of CPB in both groups, but there was no significant difference at any time interval between the ventilated and non-ventilated groups. In the NV group, IL-10 levels peaked immediately after discontinuation of CPB, and one hour after discontinuation of CPB in the V group. The serum IL-10 levels were only significantly higher in the NV group immediately after discontinuation of CPB.

Miranda et al.7 compared different ventilation strategies during CPB in their randomised, controlled clinical study: continuous ventilation, early and open-lung concepts. They observed that CPB caused a significant increase in IL-6, IL-8 and IL-10 levels. IL-6 levels did not differ significantly between the groups. The decrease in IL-10 levels was more pronounced in the early open-lung group. After discontinuation of CPB, they observed a more rapid decrease in IL-8 in the open-lung groups. They concluded that the open-lung concept attenuates the inflammatory response. It is not wise to compare our results with theirs since the design of the studies were completely different, but we can conclude that we did not observe an objective attenuation of the inflammatory response with ventilation.

Most of the studies comparing the effects of ventilation on the inflammatory response after CPB did not study serum IL-8 levels.12,13 IL-8 is a very important cytokine in the pathophysiology of myocardial ischaemia. Its levels correlate with complications following myocardial infarction, and anti-IL-8 antibodies prevented injury in experimental models.7 Its levels also correlated well with left ventricular wall motion abnormalities in the postoperative period.4 Furthermore, it was reported that cyclic alveolar stress due to mechanical ventilation led to increased IL-8 levels.14

Ng et al.3 studied IL-8 levels. They reported IL-8 levels were higher in the non-ventilated group four hours after declamping. In our study, in the ventilated group, we did not observe any significant change in IL-8 concentrations. They peaked at one hour after discontinuation of CPB in the non-ventilated group and then decreased to baseline levels. However, there was no statistically significant difference between the groups at any given time interval.

Lamarche et al.15 reported that CPB with reperfusion without aortic clamping induced a selective decrease in endothelial relaxation to acetylcholine, and normal ventilation during CPB prevented changes in endothelium-dependent relaxation of the endothelium. Similarly Gagnon et al.4 documented that continued ventilation during CPB correlated with an attenuated inflammatory and proteolytic process and better preserved pulmonary function. It was suggested that maintaining ventilation and pulmonary flow during CPB attenuated the inflammatory response.3,5,16 The continuation of pulmonary blood flow during CPB also led to reduction in serum IL-6 and -8 levels.10

The lungs depend on three separate sources of oxygen delivery: bronchial arterial and pulmonary arterial circulations, and alveolar ventilation.3 Two of these cease during CPB because

TABLE 3. COMPARISON OF TWO GROUPS BY POSTOPERATIVE VARIABLES

NV group (n = 29)

mean ± SD

V group (n = 30)

mean ± SD p-value*

ICU intubation time (h) 9.67 ± 3.29 9.27 ± 2.86 0.61

Length of stay

ICU (h) 47.90 ± 14.16 45.83 ± 2.15 0.43

Postoperative (days) 5.45 ± 0.87 6.07 ± 1.66 0.08

Drainage tubes removed (h) 36.03 ± 9.22 36.93 ± 20.64 0.94

Total amount of drainage (ml) 709.66 ± 541.21 720.00 ± 540.37 0.83

Number of FFP used 1.07 ± 2.18 1.10 ± 1.34 0.94

Number of packed RBC used 1.79 ± 1.67 1.60 ± 1.67 0.66

Number of PC used 0.45 ± 1.32 0.37 ± 1.21 0.80

n (%) n (%) p-value**

Postoperative exploration for haemorrhage

0 1 (3.3) 1.00

Postoperative AF 6 (20.7) 3 (10.0) 0.29

Renal dysfunctiona 5 (17.2) 4 (13.3) 0.73

Postoperative stroke 0 0 -

SD: standard deviation, NV: non-ventilated, V: ventilated, ICU: intensive care unit, FFP: fresh frozen plasma, RBC: red blood cells, PC: platelet concentrate, AF: atrial fibrillation.*Independent samples t-test, ** Fisher’s exact test.aDefined when peak creatinine value was ≥ 1.5 times the pre-operative value.


in standard CPB surgery, the lungs are deflated and pulmonary blood flow is shunted. After weaning from CPB, pulmonary reperfusion leads to I/R injury with the release of oxygen free radicals and the resultant lipid peroxidation and endothelial damage.4 As a consequence of I/R injury, pulmonary vascular endothelial dysfunction results in secondary vasoconstriction and increased vascular permeability, and finally pulmonary hypertension, oedema and hypoxia.15

The alveolar–arterial oxygen gradient is widened and lactate is released as a result of lung injury. The levels of pulmonary lactate release correlate well with systemic lactate levels. This lactate release is increased in procedures employing CPB and correlates with prolonged respiratory support.6 Furthermore, deflated/unventilated lungs during CPB induce atelectasis,12 which may further induce pro-inflammatory cytokine production.17 Atelectasis is also blamed for post-CPB pulmonary injury. Moreover, the degree of intrapulmonary shunt and atelectasis was found to be correlated.

Computed tomography studies also showed a correlation between atelactatic areas and intrapulmonary shunt.18 Based on this finding ventilation was suggested to protect lungs from ischaemic damage.

Gasparovic et al.6 studied pulmonary lactate release and changes in ∆A–aO2 during CPB. They reported that the lungs were a significant source of lactate release and there was a correlation between pulmonary lactate release and peripheral lactate concentrations. The duration of CPB correlated with increased pulmonary lactate release and widened ∆A–aO2. We also observed that lactate release was increased with CPB and ∆A–aO2 was widened in both groups, but unlike their study, we studied the effects of continued ventilation on ∆A–aO2 and peripheral lactate levels in order to document its effects on pulmonary functions.

The lactate levels were significantly lower only immediately after discontinuation of CPB in the ventilated group; in other determined time periods there was no difference. In each group, ∆A–aO2 widened with time. When the two groups were compared, ∆A–aO2 was lower in the ventilated group in all time periods, except for six hours following discontinuation of CPB, when there was no difference. We also report that ∆A–aO2 was higher following induction of anesthaesia in the non-ventilated group, and this may be the cause of differences in the following time periods.

In an experimental porcine study, Imura et al.19 documented that low-frequency ventilation caused reduction of ischaemic changes and lower rates of atelectasis. They also observed that lactate levels were lower in the ventilated group compared to the control. We also documented similar results with regard to ∆A–aO2, but lactate levels were higher only in the non-ventilated group immediately after discontinuation of CPB.

Schreiber et al.20 revealed that to date, there have been three trials that investigated the effects of continued ventilation during CPB on pulmonary functions. Gagnon et al.4 determined a tidal volume of 3 ml/kg during CPB and John et al.21 5 ml/kg. Boldt et al.22 continued normal ventilation during CPB. They all failed to document a significant difference with regard to ∆A–aO2. Only John et al.21 reported less extravascular lung fluid accumulation and a decreased period of ventilation.

In our study, we employed a modified ventilation strategy, the tidal volume was 5 ml/kg, but frequency was 5/min to avoid an

uncomfortable operating field. Different from these studies, we documented higher ∆A–aO2 in the non-ventilated group, except for six hours after discontinuation of CPB.

The effects of continued ventilation during CPB on pulmonary function are still controversial. This controversy is very briefly summarised by Schreiber et al.20 in a recent systematic review and meta-analysis comprising 814 participants of 16 randomised trials. They concluded that continued ventilation was beneficial when serum levels of inflammatory cytokines were considered. Moreover, oxygenation parameters were improved and shunt fraction was decreased. However, all these documented effects were short-lived, questionable, and did not influence the clinical course and final outcomes.

A similar review reported by Vohra et al.23 also concluded that no convincing results of any ventilation strategies were available. In our study, aside from the cytokine levels and other formula measurements, the clinical outcomes were not affected by continuous ventilation during CPB. The intubation time, length of stay in ICU and hospital, and occurrence of postoperative adverse events were not different between the groups.

ConclusionWe did not document an objective finding that continuous, low-frequency ventilation attenuated the inflammatory response and positively affected postoperative pulmonary functions, adverse events and outcomes. We believe that further studies with increased numbers of patients and more detailed investigation of inflammatory markers should be done to be able to draw any conclusions.

The IL kits were provided by Sanovel Pharmaceutical Company, Istanbul, Turkey.

References1. Warren OJ, Smith AJ, Alexiou C, Rogers PL, Jawad N, Vincent C,

et al. The inflammatory response to cardiopulmonary bypass: Part 1-Mechanisms of pathogenesis. J Cardiothorac Vasc Anesth 2009; 23: 223–231.

2. Larmann J. Inflammatory response to cardiac surgery: Cardiopulmonary bypass vs. non-cardiopulmonary bypass surgery. Best Pract Res Clin Anesthesiol 2004; 18: 425–438.

3. Ng CS, Arifi AA, Wan S, Ho AM, Wan IY, Wong EM, et al. Ventilation during cardiopulmonary bypass: Impact on cytokine response and cardiopulmonary function. Ann Thorac Surg 2008; 85: 154–162.

4. Gagnon J, Laporta D, Beique F, Langlois Y, Morin JF. Clinical rele-vance of ventilation during cardiopulmonary bypass in the prevention of postoperative lung dysfunction. Perfusion 2010; 25: 205–210.

5. De Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia reperfusion-induced lung injury. Am J Respir Crit Care Med 2003; 167: 490–511.

6. Gasparovic H, Plestina S, Sutlic Z, Husedzinovic I, Coric V, Ivancan V, et al. Pulmonary lactate release following cardiopulmonary bypass. Eur J Cardiothorac Surg 2007; 32: 882–887.

7. Reis Miranda D, Gommers D, Struijs A, Dekker R, Mekel J, Feelders R, et al. Ventilation according to open lung concept attenuates pulmo-nary inflammatory response in cardiac surgery. Eur J Cardiothorac Surg 2005; 28: 889–895.

8. Ng CS, Wan S, Yim AP, Arifi AA. Pulmonary dysfunction after cardiac surgery. Chest 2002; 121: 1269–1277.

9. Zhang R, Wang Z, Wang H, Song H, Zhang N, Fang M. Effective pulmonary artery perfusion mode during cardiopulmonary bypass. Heart Surg Forum 2011; 14: 18–21.

10. Yewei X, Liya D, Jinghao Z, Rufang Z, Li S. Study of the mechanism


of pulmonary protection strategy on pulmonary injury with deep hypo-thermia low flow. Eur Rev Med Pharmacol Sci 2013; 17: 879–885.

11. Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP. Avoiding cardio-pulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999; 68: 52–57.

12. Deblier I, Sadowska AM, Janssens A, Rodrigus I, Backer WA. Markers of inflammation and oxidative stress in patients undergoing CABG with CPB with and without ventilation of the lungs: a pilot study. Interact Cardiovasc Thorac Surg 2006; 5: 387–391.

13. Beer L, Szerafin T, Mitterbauer A, Debreceni T, Maros T, Dworschak M, et al. Continued mechanical ventilation during coronary artery bypass graft operation attenuates the systemic immune response. Eur J Cardiothorac Surg 2012 doi:10.1093/ejcts/ezs659.

14. Yamamoto H, Teramoto H, Uetani K, Igawa K, Shimizu E. Cyclic stretch upregulates interleukin-8 and transforming growth factor-beta1 production through a protein kinase C-dependent pathway in alveolar epithelial cells. Respirology 2002; 7: 103–109.

15. Lamarche Y, Gagnon J, Malo O, Blaise G, Carrier M, Perrault L. Ventilation prevents pulmonary endothelial dysfunction and improves oxygenation after cardiopulmonary bypass without aortic cross clamp-ing. Eur J Cardiothorac Surg 2004; 26: 554–563.

16. Hasegawa A, Iwasaka H, Hagiwara S, Koga H, Hasegawa R, Kudo K, et al. Anti-inflammatory effects of perioperative intensive insulin therapy during cardiac surgery with cardiopulmonary bypass. Surg Today 2011; 41: 1385–1390.

17. Kotani N, Hashimoto H, Sessler DI, Muraoka M, Wang JS, O’Connor MF, et al. Cardiopulmonary bypass produces greater pulmonary than systemic proinflammatory cytokines. Anesth Analg 2000; 90: 1039–1045.

18. Verheiji J, van Lingen A, Raijmakers PG, Spijkstra JJ, Girbes AR, Jansen EK, et al. Pulmonary abnormalities after cardiac surgery are better explained by atelectasis than increased permeability oedema. Acta Anaesthesiol Scand 2005; 49: 1302–1310.

19. Imura H, Caputo M, Lim K, Suleiman M, Shimizu K, Angelini G. Pulmonary injury after cardiopulmonary bypass: Beneficial effects of low frequency ventilation. J Thorac Cardiovasc Surg 2009; 137: 1530–1537.

20. Schreiber JU, Lancé MD, de Korte M, Artmann T, Aleksic I, Kranke P. The effect of different lung-protective strategies in patients during cardiopulmonary bypass: a meta-analysis and semiquantitative review of randomized trials. J Cardiothorac Vasc Anesth 2012; 26: 448–454.

21. John LCH, Ervine IM. A study assessing the potential benefit of contin-ued ventilation during cardiopulmonary bypass. Interact Cardiovasc Thorac Surg 2008; 7: 14–17.

22. Boldt J, King D, Scheld HH, Hempelmann G. Lung management during cardiopulmonary bypass: influence on extravascular lung water. J Cardiothorac Anesth 1990; 4: 73–79.

23. Vohra HA, Levine A, Dunning J. Can ventilation while on cardiopulmo-nary bypass improve post-operative lung function for patients undergo-ing cardiac surgery. Interact Cardiovasc Thorac Surg 2005; 4: 442–446.

annonce de la société Camerounaise de CardiologieCameroon Cardiac society announcement

Call for abstracts

Dear colleagues and friends,The 9th scientific congress of the Cameroon Cardiac Society (CCS) will take place from 12–14 March 2014, at the Yaounde Hilton Hotel. The organising committee invites you to come in numbers and contribute to the traditional success of this meeting, which registered about 450 specialists and general practitioners from 16 African and European countries in 2012. Cameroon is a bilingual country and the congress languages are both English and French.

The main theme of the meeting is investigation of cardiovascular diseases; however the diversity of secondary themes brings together cardiologists, surgeons, paediatricians, internists, epidemiologists, anaesthesiologists, nurses and paramedical technicians. Your abstracts from these areas of medical practice are welcome.

The updated scientific programme will be available on our website www.camcarsoc.org. You can also write to us at [email protected].

In addition to being the capital city of Cameroon, Yaounde is a lovely city with cultural and tourist attractions. It has a slight mountain relief and is therefore called ‘the town of seven hills’. We look forward to a positive response and to welcoming you in Yaounde,

Yours sincerely

Pr Samuel Kingué ([email protected]), president of the scientific committee

Dr Yves Monkam-Mbouendé ([email protected]), secretary general

Dr Anastase Dzudié-Tamdja ([email protected]), scientific secretary


long Qt syndrome in south africa: the results of comprehensive genetic screeningPAULA L HEDLEY, GLENDA A DURRHEIM, FIRZANA HENDRICKS, ALTHEA GOOSEN, CATHRINE JESPERSGAARD, BIRGITTE STØVRING, TAM T PHAM, MICHAEL CHRISTIANSEN, PAUL A BRINK, VALERIE A CORFIELD

abstractCongenital long QT syndrome (cLQTS) is a genetic disor-der predisposing to ventricular arrhythmia, syncope and sudden death. Over 700 different cLQTS-causing muta-tions in 13 genes are known. The genetic spectrum of LQTS in 44 South African cLQTS patients (23 known to carry the South African founder mutation p.A341V in KCNQ1) was established by screening for mutations in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A, the most frequently implicated cLQTS-causing genes (five-gene screening). Fourteen disease-causing mutations were identi-fied, eight (including the founder mutation) in KCNQ1, five in KCNH2 and one in KCNE1. Two mutations were novel. Two double heterozygotes were found among the 23 fami-lies (8.5%) carrying the founder mutation. In conclusion, cLQTS in South Africa reflects both a strong founder effect and a genetic spectrum similar to that seen in other popula-tions. Consequently, five-gene screening should be offered as a standard screening option, as is the case internationally. This will disclose compound and double heterozygotes. Five-gene screening will most likely be even more informative in other South African sub-populations with a greater genetic diversity.

Keywords: LQTS, mutation, ion-channels, sudden death, arrhythmia



DOI: 10.5830/CVJA-2013-032

The congenital long QT syndrome (cLQTS)1 is an inherited disorder characterised by prolongation of the QT interval on a surface electrocardiogram (ECG) and an increased risk for life-threatening ventricular arrhythmias,2 particularly ventricular tachycardia of the torsades de pointes type. cLQTS provides the archetypical monogenic disorder for studying the genetic basis of inherited arrhythmia syndromes in that it is relatively common (prevalence of 1:2 500 to 1:5 000),3 and more than 700 disease-causing mutations have been identified in 13 genes encoding different cardiac ion channels or membrane adaptors.4,5 The genetic and allelic heterogeneity results in subtly different clinical phenotypes.6

Several clinical syndromes have been described: Romano-Ward syndrome (RWS), an autosomal dominant form of cLQTS, which presents clinically with a pure cardiac phenotype; Jervell and Lange-Nielsen syndrome (JLNS), an autosomal recessive form of LQTS which is associated with congenital deafness;2 Andersen-Tawil syndrome (ATS), which is an autosomal dominant multisystem disorder where cLQTS is variably present; and Timothy syndrome (TS), which is characterised by severe cLQTS as well as cardiac and somatic malformations.

cLQTS is associated with loss-of-function mutations in genes encoding repolarising K+ ion channels, their subunits and certain interacting proteins, i.e. KCNQ1 encoding Kv7.1 (LQT1),6 KCNH2 encoding Kv11.1 (LQT2),7 ANK2 encoding Ankyrin B (LQT4),8 KCNE1 encoding MinK (LQT5),9,10 KCNE2 encoding MiRP1 (LQT6),11 KCNJ2 encoding Kir2.1 (LQT7),12 CAV3 encoding M-Caveolin (LQT9),13 SCN4B encoding Navβ3 (LQT10),14 AKAP9 encoding Yotiao (LQT11),15 SNTA1 encoding α1-Sytophin (LQT12)16 and KCNJ5 encoding Kir3.4 (LQT13).17 Furthermore, gain-of-function mutations in genes encoding depolarising Na+ and Ca2+ ion channels have also been associated with LQTS, i.e. SCN5A (LQT3)18 and CACNA1C (LQT8).19

The ion channel defects result in either decreased K+ efflux or increased Na+ or Ca2+ influx over the cardiomyocyte plasma membrane, leading to reduced repolarisation and increased frequency of after-depolarisations (ADs) and prolonged refractory period. The latter predisposes to re-entrant ventricular arrhythmia.4 Adrenergic stimulation, which increases the frequency of ADs, may precipitate fatal arrhythmia in asymptomatic mutation carriers.1,4 Drugs, e.g. amiodarone, cisapride, sotalol and haloperidol, which reduce the repolarisation reserve, may cause drug-related LQTS (dLQTS) or, likewise, precipitate arrhythmia in mutation carriers.1,4

Previously, de Jager et al. and Brink et al. reported on the Kv7.1 (encoded by KCNQ1) founder mutation, p.A341V, identified in 23 Afrikaner families.20,21 Little is known of the occurrence of other cLQTS-associated mutations in South Africa.

In order to describe the spectrum of mutations causing cLQTS in South Africa, we screened 44 apparently unrelated

us/MrC Centre for Molecular and Cellular Biology, department of Biomedical sciences, Faculty of Medicine and Health sciences, university of stellenbosch, south africaPAULA L HEDLEY, MScGLENDA A DURRHEIM, MScFIRZANA HENDRICKS, MB ChBVALERIE A CORFIELD, PhD, [email protected]

department of Clinical Biochemistry, immunology and Genetics, statens serum institut, denmark PAULA L HEDLEY, MScCATHRINE JESPERSGAARD, PhDBIRGITTE STØVRING, PhDTAM T PHAM, MScMICHAEL CHRISTIANSEN, MB ChB

department of internal Medicine, Faculty of Medicine and Health sciences, university of stellenbosch, south africaALTHEA GOOSEN, RNPAUL A BRINK, MD, PhD


South African cLQTS probands, including the 23 probands of the families that are carriers of the founder p.A341V mutation, for mutations in the five most frequently implicated cLQTS genes, KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2, by multiplex capillary electrophoresis single-strand conformation polymorphism (multi-CE-SSCP). A sub-group was further analysed by the direct sequencing of these genes.

MethodsForty-four LQTS probands (23 known founder mutation carriers and 21 unrelated patients shown not to carry the founder mutation) [77% female; mean (SD) age at first event 10 (6) years, were ascertained to have cLQTS, mean (SD) QTc 501 (59) ms]. See Table 1 for clinical and demographic information. The diagnosis was based on the 1993 standard diagnostic criteria22 and included a physical examination, a standard 12-lead ECG and a personal interview. All probands were of the RWS type. All patients provided written informed consent (parental in the case of minors). The study was approved by the Health Research Ethics Committee of the University of Stellenbosch.

Molecular genetic proceduresDNA was isolated from peripheral blood using a commercially available procedure (Qiagen GmBH, Germany). Primers were designed to amplify all the exons of the five LQTS-causing genes under investigation, including the intron/exon boundaries. The primers were synthesised by the Synthetic DNA Laboratory (University of Cape Town, Cape Town, South Africa) and Applied Biosystems (Copenhagen, Denmark).

PCR amplification was performed by published protocol for SCN5A.23 Primer sequences and PCR conditions for KCNQ1, KCNH2, KCNE1 and KCNE2 are available upon request ([email protected]). Primers used for generating PCR products for sequencing were tagged with M13 sequence. PCR products were qualitatively assessed on 2% agarose gels by standard procedures prior to multi-CE-SSCP and direct sequencing.

Multi-CE-SSCP PCR primers were labelled at their 5′ end with one of the following fluorophors: 6FAMTM, VIC®, NEDTM or PETTM (Applied Biosystems, Foster City, California, USA). The labelled PCR amplicons were mixed and diluted according to published protocol23 for SCN5A. Amplicons of KCNQ1, KCNH2, KCNE1 and KCNE2 were mixed and diluted in a similar manner; the specifics of these mixtures are available upon request.

Multi-CE-SSCP was performed on an ABI PrismTM 3100 Genetic Analyser (PE Applied Biosystems, Foster City, California, USA) with GeneScan polymer (Applied Biosystems,

Foster City, California, USA) at 18°C and 30°C. PCR amplicons were sequenced to identify the variants responsible for alterations in the electrophoretic mobility detected by multi-CE-SSCP analysis.

Direct sequencingA sub-group of 32 probands was additionally analysed by direct DNA sequencing. The probands of the founder families were included to assess the frequency of compound heterozygozity in our cohort. PCR products were purified by exonuclease 1 and shrimp alkaline phosphatase reaction.

Sequencing of both strands was performed using BigDye® Terminator v1.1 (Applied Biosystems, UK) and M13 primers (sense 5′-CAGTTCTCACAGGAGCCACA-3′) and (antisense 5′-AGGTGAACTGGAACCACAGG-3′) (Taq Copenhagen, Denmark). Sequences were analysed with the ABI 3730 DNA analyser (Applied Biosystem, UK).

Bio-informaticsNucleotide sequences were aligned to GenBank (http://www.ncbi.nlm.nih.gov/Entrez) reference sequences KCNQ1 (NM_000218.2/NP_000209.2), KCNH2 (NM_000238.2/NP_000229.1), SCN5A (NM_000335.2/NP_000326.2), KCNE1 (NM_000219.2/NP_000210.2) and KCNE2 (NM_172201.1/NP_75195.1). Multiple sequence alignments of multiple species were performed with Clustal W (version 1.82) (http://www.ebi.ac.uk/clustalw/#). SNPs were compared to the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP/) and the NHLBI Exome Sequencing Project Exome Variant Server (EVS) (http://evs.gs.washington.edu/EVS/). These data were used as in silico control.

Criteria for disease associationA genetic variant was considered a disease-causing mutation if it resulted in an amino acid substitution, interfered with a splice site or had previously been shown to be associated with cLQTS and was not found in in silico controls and had not previously been described as a polymorphism. Sequence variants also found in controls were considered polymorphisms and are not reported here.

resultsWe identified 14 different disease-causing mutations in 34 of the 44 probands tested (Table 2). Three mutations were identified among the 23 founder probands; all harboured the South African founder mutation KCNQ1:p.A341V, while two probands (8.5%) harboured an additional mutation in a second cLQTS-causing gene, which may contribute to disease. These are cases of double heterozygosity. Furthermore, 11 mutations were identified in 13 non-founder probands.

The multi-CE-SSCP results corroborated standard gel-based PCR-SSCP results (not shown), however, in 32 cases where the DNA concentration was sufficient, direct DNA sequencing led to the identification of four disease-causing mutations (KCNQ1:p.Y315C; KCNQ1:p.A344V; KCNH2:c.917-3T>C and KCNH2:p.R328C), which were missed by multi-CE-SSCP. In the case of KCNQ1:pA344V, two cases had been detected by SSCP, but an additional case was identified by direct sequencing.

TABLE 1. DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF 44 INDEX PATIENTS

Cohort % femaleQTc

mean (SD)Age at first event

mean (SD)

Total 77 501 (59) 10 (6)

A341V carriers 81 513 (48) 8 (4)

Other mutation carriers 73 507 (69) 11 (5)

No mutation detected 75 452 (35) 17 (7)


discussionWe have identified 14 mutations in 34 of 44 (77 %) South African probands screened; two (14%) of the mutations identified are novel. The disease-causing mutations of 33 probands were identified by multi-CE-SSCP (Table 2), which represents a detection rate of 75%. Additionally, applying direct DNA sequencing to a smaller cohort resulted in the detection of the disease-causing mutation in 30 of the 32 probands screened, which represents a total detection rate of 94%.

These results are comparable to those reported in other screening studies.22,24,25 Therefore, in comparison to just screening for the KCNQ1:p.A341V founder mutation in our cLQTS probands (which had a detection rate of 52%), the addition of other genes and the application of direct DNA sequencing for mutation screening resulted in manifest improvements in diagnostic efficiency.

Within the founder families, represented by 23 probands, two probands (8.5 %) were double heterozygotes. One case carried KCNQ1:p.A341V and KCNH2:p.R328C while the other carried KCNQ1:p.A341V and KCNE1:p.D91E. This is an important finding as one of the purposes of genetic screening in cLQTS probands is the identification of asymptomatic mutation carriers in family members (cascade screening) in order to clinically assess the need for prophylaxis.

In theory, half of the mutation carriers within a cLQTS family may be missed if only one of the mutations in a compound heterozygote or double heterozygote is identified through selective screening for only one mutation or the selective screening of only one of the involved genes. As the clinical presentation may be sudden death in cLQTS mutation carriers, this is a serious clinical problem. Our results demonstrate that the detection of compound and double heterozygotes is also an important consideration in clinical handling of cLQTS cases in South Africa.

KCNQ1 mutationsThe common South African founder mutation (p.A341V) was identified in 23 probands.20,21 p.V254M was first identified in a large LQT1-kindred6 and later associated with sudden death before 40 years of age.26 This mutation was found to exert a dominant negative effect on native IKs.27 Assessment of beta-blocker therapy was performed on a cLQTS family carrying p.V254M; treatment was determined to be effective and safe.28

p.Y315C has been shown to be a dominant negative mutation, which, while the protein was normally trafficked to the cell surface, produced no measurable current.29 This mutation has been shown to be associated with cisapride-induced QT prolongation.30

p.Y315S was first identified in a French LQTS family.26 Jongbloed et al. (1999) identified this mutation as a de novo cause of cLQTS, which appeared to be triggered by both physical and emotional stress.31 In both cases the mutation was associated with an onset of symptoms before 10 years of age.

p.L342F was previously reported by Donger et al. (1997) where it was identified in a single case; none of the other family members carrying the mutation presented with symptoms of LQTS.26 However, the proband had experienced onset of symptoms before the age of 10 years.

p.A341E was identified in the first double heterozygote-carrying cLQTS family identified in a French cLQTS cohort,32 where carriers of both mutations (KCNQ1:p.A341E and KCNH2:c.2592+1G>A) were reported to be severely symptomatic, with both stress- and rest-induced symptoms initiating in early childhood. The mutation was found to exert a dominant negative effect on native IKs.27

The p.A344V mutation was first identified as a forme fruste cause of LQTS.26 Later, Choi et al. (2004) discovered this mutation in a cohort of patients, which had suffered swimming-triggered arrhythmias.33 In addition to shifting the voltage

TABLE 2. DISEASE-CAUSING MUTATIONS IDENTIFIED IN THE SOUTH AFRICAN LQTS PROBANDS AS WELL AS AN INDICATION OF WHICH PLATFORM IDENTIFIED THE VARIANT

Gene/protein

MutationsMutation detection

technique Frequency in in silico controls Av QTc/additional info References

Coding substitution

Protein consequence SSCP sequencing total

KCNQ1/Kv7.1

c.760G>A p.V254M 1 ns 1 0 500 ms/ICD 4–6, 25–28, 33, 45, 55–58

c.944A>G p.Y315C 0 1 1 0 550 ms 4, 5, 25, 29, 33, 57, 59–62

c.944A>C p.Y315S 1 ns 1 0 512 ms 4, 26, 31, 57

c.1022C>A p.A341E 1 ns 1 0 502 ms/CA at 51 years 4, 5, 27, 32, 45, 57, 59, 63, 64

c.1022C>T p.A341V 23 23 23 0 513 ms/BB 4–6, 20, 21, 25–27, 45, 65–75

c.1024C>T p.L342F 1 1 1 0 527 ms 4, 5, 24, 26, 76, 77

c.1031C>T p.A344V 2 2 3# 0 557 ms 4, 5, 25, 26, 33, 34, 57, 68

c.1760C>T p.T587M 1 ns 1 0 400 ms 4, 5, 24, 35–37, 59, 78–80

KCNH2/ Kv11.1

c.208C>A p.R100W 1 1 1 0 437 ms 5

c.917-3T>Cdefective splicing/ protein degradation 0 1 1 0 450 ms This study

c.982C>T* p.R328C* 0 1 1 0 654 ms* 4, 5, 25, 30, 39, 40, 47, 48, 81–83

c.1714G>A p.G572S 1 1 1 0 402 ms/BB 4, 5, 24, 25, 39–44

c.1882C>G p.F627L 1 ns 1 0 462 ms 4, 45, 46

KCNE1/MinK c.273C>A* p.D91E* 1 1 1

0 (EA); 0.0002 (AA) 533 ms* This study

*Variants that co-occur with Kv7.1:p.A341V; #One of the probands in which p.A344V had been identified previously by SSCP was not available for sequencing. ns: not screened by sequencing; EA: 8 600 European-Americans screened by exome sequencing; AA: 4 406 African-Americans screened by exome sequencing; ICD: implantable cardioverter defibrillator; CA: cardiac arrest. BB: beta-blockers.


dependence of the IKs channel activation, the p.A344V mutation increased the sensitivity of the channel for bupivacaine (a local anaesthetic).34 KCNQ1:p.T587M was found to result in haplo-insufficiency as a consequence of being transport deficient.35,36 Furushima et al. (2010) identified a case of foetal atrio-ventricular block and unmasked maternal QT prolongation in the postpartum period in a mother and baby carrying this mutation.37

KCNH2 mutationsKCNH2:c.917-3T>C has not been previously reported; however, splice-site analysis suggests that the tentative consequence of this variant is disruption the splice acceptor of exon 5. Such a splice-site disruption would be expected to cause aberrant mRNA splicing and result in either the synthesis of a truncated protein or, more likely, haplo-insufficiency. In both cases, the result is likely to be a reduced amount of Kv11.1 protein and therefore reduced repolarisation capacity.

KCNH2:p.R100W was identified in two of 2 500 patients reported by Kapplinger et al. in 2009, however, no specific clinical information is provided.5 A mutation at residue 100 (p.R100G) has been reported in a 41-year-old French woman who had suffered an aborted cardiac arrest,38 which may indicate that the R100 residue has a particular functional relevance.

The p.G572S mutation has been reported in LQTS cohorts around the world4,5,23,25,39-44 but has not been identified in an exome sequencing project to date. Zhao et al. in 2009 determined that p.G572S causes a dominant negative trafficking defect.44 KCNH2:p.F627L was first identified by Splawski et al. in 2000 as part of his LQTS screen of 262 probands45 and later was reported to be the cause of LQTS with foetal onset of atrio-ventricular block and ventricular tachycardia.46

Double heterozygotesIn addition to the KCNQ1:p.A341V mutation, we have confirmed the presence of the KCNE1:p.D91E variant in a single proband. The clinical significance of this variant is unclear. It is a very rare variant, identified in a single African-American individual in an exome analysis of 4 406 African-American individuals (http://evs.gs.washington.edu/EVS/) (date accessed July 2012).

A more extensive analysis of the phenotypes in the family, where the clinical effect of individual mutations can be assessed as the KCNQ1 mutation is located on chromosome 11 and the KCNE1-encoded MinK variant is located on chromosome 2,14 is necessary to establish the clinical significance of the compound heterozygozity. Due to the rarity of the MinK variant and the known association between mutations in the N-terminus of MinK and adverse drug effects, we consider it a significant finding.

In a second proband, we identified both the KCNQ1:p.A341V mutation and KCNH2:p.R328C. The p.R328C variant was first reported by Chevalier et al. (2001) in an acquired LQTS cohort.47 Grunnet et al. (2005) described a cLQTS patient harbouring double mutations (KCNQ1:pR591H; KCNH2:p.R328C). They determined that p.R328C did not produce a functional phenotype and that KCNQ1:p.R591H was sufficient to explain disease.48

Further functional assessment of KCNH2:p.R328C by Anderson et al. (2006) determined the Kv11.1 channels carrying p.R328C were normally trafficked to the membrane and conferred

no functional phenotype.39 However, a subsequent report by Chevalier et al. (2007) suggested that p.R328C had a dominant negative effect on IKr. Finally, Kapa et al. (2009) identified KCNH2:p.R328C in a control individual.40 The p.R328C variant is, in all likelihood, a rare polymorphism; however, we cannot exclude that it has a functional effect in the presence of certain drugs or conditions, e.g. hypokalaemia.49

Apart from the variants described above and reported in Table 2, a number of synonymous (i.e. not having any effect on the amino acid sequence) variants as well as variants that have been found with a relatively high frequency (i.e. > 1%) in other populations were found during the screening of the 44 probands (data not shown). Such polymorphisms are not disease causing, but they may modify the phenotype.4 These potential forme fruste mutations, i.e. mutations that do not appear to cause disease in isolation, should be noted.

Numerous non-synonymous polymorphisms have been reported to be associated with an effect in cardiac repolarisation currents.50 KCNE1:p.D85N has been implicated in drug-induced LQTS30 and KCNH2:p.R1047L has been reported to reduce IKr in a mammalian cell-based system.51

Occasionally, the presence of very rare variants in the normal population (e.g. the KCNE1: p.D91E mentioned above) that have not previously been associated with disease and have a population frequency less than 1:4 000 may raise questions about their possible role in disease causation. In such a case, family studies, which may not be possible in small families, and electrophysiological analysis, which is costly and time consuming, may be necessary to ascribe disease causation with certainty. Consequently, novel mutations where the disease association has not been established should be evaluated carefully and the uncertainty should be considered when deciding the appropriate management of the family, particularly as prophylactic treatment with beta-blockers or implantation of an ICD unit can have adverse effects.

To establish a genetic diagnosis in a cLQTS family is in most cases complicated, as described above, and is best done as a collaborative effort involving cardiologists, clinical geneticists and molecular geneticists. The findings reported here suggest that most South African cLQTS cases will be caused by mutations already described in other populations, as we only found two novel mutations. However, this probably reflects the fact that most of the patients included have a European ancestry and that to date no black South African LQTS patients have been encountered for enrolment in the study.

Furthermore, no other African-based research groups have reported the occurrence of LQTS patients within their black African populations.52 It must be expected, due to the large genetic diversity of African populations, as is evident from the Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), that comprehensive genetic screening of at least five genes will be necessary to provide an adequate genetic diagnosis in these populations.

A limitation of this study was a failure to detect potential gene rearrangements, such as large duplications or deletions. Multi-CE-SSCP can only identify point mutations or small insertions and deletions in coding regions or at splice junctions. Koopman et al. detected a large duplication in the KCNH2 gene, which they determined to be responsible for cLQTS in a Dutch family.53 No mutation has so far been identified in approximately 10–20%


of cLQTS cases globally; gene rearrangements could account for a portion of these.

Furthermore, we only screened five of the 13 known LQTS-causing genes. However, the small sample size limits the possibility of identifying variants in genes that are rarely associated with cLQTS. These genes typically exhibit a prevalence of <1% of the LQTS population.4

ConclusionGenetic screening of five frequently implicated cLQTS causative genes in a predominantly white South African cLQTS cohort led to the identification of a disease-causing mutation in 77% of examined cases. The previously described founder mutation, p.A341V, is responsible for cLQTS in 52% of these probands, meaning that the extended screening increases the detection by 29% points. Furthermore, the frequency of double heterozygozity in South Africa is similar to the frequency seen in other populations.54 Therefore, 8.5% of the founder mutation-carrying families had members that were double heterozygotes.

These findings emphasise the importance of performing a comprehensive genetic screening when doing genetic work up, even in a population with a large founder effect. Despite the impressive diagnostic rate found here, it should be remembered that, using current techniques, it is not yet possible to establish a genetic diagnosis in many (23%) cLQTS families. In these cases, and wherever the clinical picture is complex, it is of paramount importance to realise that LQTS is a clinical condition requiring clinical management, irrespective of the genetic aetiology.

We thank Ina le Roux, Christine Bugay Valdez, Dennis Dion Petersen and Karina Liebmann Madsen for their excellent technical assistance. We acknowledge the financial support of the South African National Research Foundation, the Harry and Doris Crossley Foundation and the Danish Strategic Research Foundation.

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67. Jongbloed R, Marcelis C, Velter C, Doevendans P, Geraedts J, Smeets H. DHPLC analysis of potassium ion channel genes in congenital long QT syndrome. Hum Mutation 2002; 20(5): 382–391.

68. Li H, Chen Q, Moss AJ, Robinson J, Goytia V, Perry JC, et al. New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation 1998; 97(13): 1264–1269.

69. Crotti L, Spazzolini C, Schwartz PJ, Shimizu W, Denjoy I, Schulze-Bahr E, et al. The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratifica-tion. Circulation 2007; 116(21): 2366–2375.

70. Heradien MJ, Goosen A, Crotti L, Durrheim G, Corfield V, Brink PA, et al. Does pregnancy increase cardiac risk for LQT1 patients with the KCNQ1-A341V mutation? J Am Coll Cardiol 2006; 48(7): 1410–1415.

71. Schwartz PJ, Vanoli E, Crotti L, Spazzolini C, Ferrandi C, Goosen A, et al. Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome. J Am Coll Cardiol 2008; 51(9): 920–929.

72. Heijman J, Spatjens RL, Seyen SR, Lentink V, Kuijpers HJ, Boulet IR, et al. Dominant-negative control of cAMP-dependent IKs upregulation in human long-QT syndrome type 1. Circ Res 2012; 110(2): 211–219.

73. Crotti L, Monti MC, Insolia R, Peljto A, Goosen A, Brink PA, et al. NOS1AP is a genetic modifier of the long-QT syndrome. Circulation 2009; 120(17): 1657–1663.

74. Brink PA, Schwartz PJ. Of founder populations, long QT syndrome, and

destiny. Heart Rhythm 2009; 6(11 Suppl): S25–33.75. Mikuni I, Torres CG, Bienengraeber MW, Kwok WM. Partial restor-

ation of the long QT syndrome associated KCNQ1 A341V mutant by the KCNE1 beta-subunit. Biochim Biophys Acta 2011; 1810(12): 1285–1293.

76. Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J. Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J 1997; 16(17): 5472–5479.

77. Chouabe C, Neyroud N, Richard P, Denjoy I, Hainque B, Romey G, et al. Novel mutations in KvLQT1 that affect Iks activation through inter-actions with Isk. Cardiovasc Res 2000; 45(4): 971–980.

78. Itoh T, Tanaka T, Nagai R, Kikuchi K, Ogawa S, Okada S, et al. Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome. Hum Genet 1998; 103(3): 290–294.

79. Neyroud N, Richard P, Vignier N, Donger C, Denjoy I, Demay L, et al. Genomic organization of the KCNQ1 K+ channel gene and identifica-tion of C-terminal mutations in the long-QT syndrome. Circulation Res 1999; 84(3): 290–297.

80. Hayashi K, Shuai W, Sakamoto Y, Higashida H, Yamagishi M, Kupershmidt S. Trafficking-competent KCNQ1 variably influences the function of HERG long QT alleles. Heart Rhythm 2010; 7(7): 973–980.

81. Hinterseer M, Irlbeck M, Ney L, Beckmann BM, Pfeufer A, Steinbeck G, et al. Acute respiratory distress syndrome with transiently impaired left ventricular function and torsades de pointes arrhythmia unmask-ing congenital long QT syndrome in a 25-yr-old woman. Br J Anaesth 2006; 97(2): 150–153.

82. Millat G, Chevalier P, Restier-Miron L, Da Costa A, Bouvagnet P, Kugener B, et al. Spectrum of pathogenic mutations and associ-ated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet 2006; 70(3): 214–227.

83. Chevalier P, Bellocq C, Millat G, Piqueras E, Potet F, Schott JJ, et al. Torsades de pointes complicating atrioventricular block: evidence for a genetic predisposition. Heart Rhythm 2007; 4(2): 170–174.

CardioVasCular ConGrEss diary 2013/2014DATE CONFERENCE PLACE CONTACT DETAILS TO REGISTER

AUGUST 2013

25–29 August 2012 ESC, European Society of Cardiology congress Munich, Germany www.escardio.org

SEPTEMBER 2013

11–13 September 6th international symposium on hybrid approach to congenital heart disease 2012

Columbus, US www.nationwidechildrens.org/ishac-home

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Gender and ethnic differences in the control of hyperlipidaemia and other vascular risk factors: insights from the CEntralised pan-south african survey on tHE under-treatment of hypercholesterolaemia (CEpHEus sa) studyNAOMI RAPEPORT, COLIN LESLIE SCHAMROTH, DIRK JACOBUS BLOM

abstractAim: The aim of the CEntralised Pan-South African survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS SA) was to evaluate the current use and efficacy of lipid-lowering drugs (LLDs) in urban patients of differ-ent ethnicity with hyperlipidaemia, and to identify possible patient characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets. There is little published data on LDL-C attainment from develop-ing countries. Methods: The survey was conducted in 69 study centres in South Africa and recruited consecutive patients who had been prescribed LLDs for at least three months with no dose adjustment for six weeks. All patients provided written consent. One visit was scheduled for data collection, includ-ing fasting lipid and glucose, and HbA1c levels. Results: Of the 3 001 patients recruited, 2 996 were included in the final analyses; 1 385 subjects were of Caucasian origin (818 male), 510 of African ancestry (168 male), 481 of mixed ancestry (222 male) and 620 of Asian origin (364 male). Only 60.5% of patients on LLDs for at least three months achieved the LDL-C targets recommended by the NCEP ATP III/2004 updated NCEP ATP III guidelines and 52.3% the fourth JETF/South African guidelines. African females were on average younger than females of other ethnic origins, and had the lowest smoking rates but the highest prevalence of obesity, hypertension, the metabolic syndrome and diabetes mellitus (DM), with the worst glycaemic control. Although women were less likely than men to reach goal [OR 0.65 (CI 0.54–0.77), p < 0.001 for NCEP ATP III guidelines and OR 0.76 (CI 0.64–0.91), p < 0.003 for fourth JETF guidelines], women of African ancestry were just as likely not to reach goal as their Caucasian counterparts. Conclusion: The results of this survey highlight the sub-opti-mal lipid control achieved in many South African patients, and profile important gender and ethnic differences. Control of cardiovascular disease risk factors across gender and ethnic groups remains poor.



DOI: 10.5830/CVJA-2013-043

Elevated serum lipid levels have been identified as one of the modifiable risk factors in the aetiology of cardiovascular disease (CVD). The INTERHEART study established that elevated lipid levels was the greatest contributor to the development of myocardial infarction worldwide.1 Multiple studies have evaluated the control of serum lipid levels in clinical practice but these studies originate almost exclusively from the developed nations of North America and Europe.2-8 Cardiovascular risk-factor control is poorly studied in developing nations, and in particular, knowledge of the control of lipid levels is largely unknown. In the limited published data, there is no specific information on gender and/or ethnic differences.9

Different authorities, such as the Joint European Task Force (JETF) and the United States National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III) have developed clinical guidelines for the management of CVD risk, and there are extensive data showing that modification of risk factors can delay the development of CVD or prevent recurrent events in those with CVD at baseline.10-13 Over time, these guidelines have proposed progressively lower targets for CVD risk factors on the basis of evidence from clinical studies demonstrating that cardiovascular risk is further reduced by more rigorous risk-factor control. Aggressive low-density lipoprotein cholesterol (LDL-C) lowering remains the cornerstone of lipid management.

The CEntralised Pan-South African survey on tHE Undertreatment of hypercholeSterolaemia (CEPHEUS SA) was initiated to detect and quantify the degree of under-treatment of hypercholesterolaemia in South Africa, and the full overall results have been published.14 This study afforded us an opportunity to study both gender and ethnic differences in the prevalence of these CVD risk factors in a developing world population on drug treatment for elevated serum lipid levels, and forms the basis of this article.

MethodsCEPHEUS was a non-interventional study conducted in South Africa between November 2009 and April 2010. To be representative of the varied population demographics in the country, 101 investigators in 69 urban study centres were involved in recruiting patients; 67 were general/primary healthcare

Milpark Hospital, Johannesburg, south africaNAOMI RAPEPORT, MB BCh, FCP, FACP, [email protected] LESLIE SCHAMROTH, MB BCh, FCP, MMed

division of lipidology, department of Medicine, university of Cape town, south africa DIRK JACOBUS BLOM, MB ChB, MMed, FCP (SA), PhD


practitioners, 13 were cardiologists, seven endocrinologists, and 14 internists/specialist physicians. Investigators were drawn from both the public and private sectors. Public sector sites were located in tertiary level referral hospitals.

Subjects 18 years or older who had been receiving lipid-lowering drugs (LLDs) for at least three months (without dose adjustments for at least six weeks) were eligible. Consecutive patients who came for their regular scheduled visit to the doctor/clinic were invited to participate in the survey. Patients who agreed to participate provided informed written consent.

CEPHEUS was a single-visit non-interventional study. Each patient’s record form documented patient demographics, current LLD treatment, smoking status, known diabetes mellitus (DM), family history of premature vascular disease, known arterial hypertension (HT) and cardiovascular medical history. Physical examination by the investigator was limited to measurement of height, weight, waist circumference and blood pressure. A fasting blood sample was drawn to evaluate the serum lipid profile [total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides and apolipoprotein (apo) AI and apo B], fasting blood glucose (FG) and glycosylated haemoglobin (HbA1c) levels.

The primary endpoint was the percentage of patients who achieved the LDL-C goals according to either the NCEP ATP III/2004 updated NCEP ATP III guidelines or the fourth JETF/South African guidelines, which were current in South Africa at the time the CEPHEUS SA study was conducted. Secondary endpoints included achievement of LDL-C goals in patients with and without features of the metabolic syndrome, and primary versus secondary prevention.

The parent study (CEPHEUS-Europe) has been registered with the US National Institutes of Health (ClinicalTrials.gov), number NCT00542867. The CEPHEUS study was sponsored by AstraZeneca. The sponsor oversaw data collection and monitored study sites. The authors had full access to the study database and all analyses reported here were performed independently of the sponsor.

Statistical analysisWe subdivided the cohort by gender and ethnicity for the purposes of this analysis. The four major ethnic groups in South Africa were black Africans, Caucasians, Asians (including patients of Indian descent) and patients with mixed ancestry. The

risk category was determined for each patient and we calculated a dichotomous variable for each patient indicating whether their LDL-C had reached the guideline mandated target level.

We generated descriptive statistics for all clinical and laboratory parameters, following subdivision by gender only, and then following subdivision by both ethnicity and gender. We analysed the effect of ethnicity and gender on goal attainment using logistic regression with the logit function in a model that incorporated ethnicity and gender simultaneously.

We calculated odds ratios and 95% confidence intervals for the probability of not attaining LDL-C goal. The probability of not attaining LDL-C goal was referenced against Caucasian ethnicity and male gender, for which the odds ratio was set as 1. All p-values are two-sided and we regarded p < 0.05 as statistically significant. All analyses were performed with Statistica [StatSoft Inc (2011), STATISTICA (data analysis software system) version 10, www.statsoft.com].

resultsA total of 3 001 patients consented to participate in the survey. Full data sets were available from 2 996 patients and form the basis of this report. About two-thirds of patients were recruited from the private healthcare sector, with the remaining one-third coming from public sector institutions.

Demographic, anthropometric and clinical data are shown in Table 1. Of the total group, 47.1% had known DM but 2.4% of patients who did not give a history of DM had FG levels that would qualify for the diagnosis of DM. Glycaemic control in patients who gave a history of DM was generally poor, with a mean HbA1c level of 8.33%.

The prevalence of a history of HT in this study was 71.6%. The mean systolic blood pressure in the entire study cohort was 133.2 mmHg, with a diastolic pressure of 80.2 mmHg. In those subjects with a history of HT (Table 2), the mean systolic blood pressure was 136.1 mmHg, with a diastolic pressure of 81.3 mmHg. African-ancestry males had the highest systolic blood pressure and females of mixed ancestry the highest diastolic blood pressure but the inter-ethnic differences were small.

More Caucasian patients were receiving LLDs for primary prevention compared to those of African ancestry, few of whom were on treatment for primary prevention. The majority were receiving treatment for the CVD risk equivalent of DM.

The percentage of African patients who were on LLDs for

TABLE 1. BASELINE CHARACTERISTICS

Characteristics

Entire study Caucasian African Mixed ancestry Asian

Male Female Male Female Male Female Male Female Male Female

Number 1572 1424 818 567 168 342 222 259 364 256

Mean age (years) 59.2 59.6 60.9 62.0 57.4 57.4 58.1 59.0 56.8 58.0

Current smoker (%) 18.6 10.8 15.9 14.3 15.6 2.6 25.1 19.7 21.4 5.1

Family history of vascular disease (%) 27.0 29.5 29.0 36.3 4.1 11.1 25.2 30.9 39.2 37.5

Mean body mass index (kg/m2) 29.2 30.8 30.0 29.4 29.3 34.2 29.0 31.2 27.6 29.4

Mean waist circumference (cm) 101.0 101.0 105.7 95.6 101.5 102.2 101.7 100.4 99.4 97.6

Known diabetes mellitus (%) 45.8 48.5 34.4 26.8 70.6 74.9 54.1 54.5 38.7 55.1

Known systemic hypertension (%) 68.8 74.6 64.7 64.7 84.6 88.9 76.6 84.2 65.8 67.9

History of coronary heart disease (%) 45.8 23.9 46.3 19.6 19.0 14.3 58.1 38.2 49.4 31.6

History of cerebrovascular disease (%) 5.8 4.8 5.3 4.4 5.9 6.1 6.3 4.2 6.3 4.2

History of peripheral arterial disease (%) 6.2 3.5 7.8 3.2 3.0 2.6 6.8 6.2 3.3 2.7


coronary artery disease (CAD) was lower than that seen in the other ethnic groups. The prevalence of CAD was higher in males than in females in all ethnic groups. Among male participants, CAD rates were highest in men of Caucasian, Asian and mixed ancestry. Among the women, the highest prevalence of CAD was in women of mixed and Asian ancestry. Few African patients gave a family history of CAD and the percentage of smokers was also lowest among the African patients. Most patients (95.9%) were on LLD monotherapy, with this being almost exclusively (98.9%) statin based.

The on-treatment lipid and FG values are listed in Table 3. Overall, patients of African ancestry had lower TC, LDL-C, and non-HDL-C levels and higher FG levels than subjects of other ethnic groups. In the cohort with DM (Table 2), the African-ancestry patients had the highest levels of HbA1c, both for males and females.

The primary outcome or percentage of patients reaching LDL-C targets is given in Table 4. Overall 60.5% of patients reached goal as per the NCEP ATP II guidelines and 52.3% according to the JETF guidelines. Differences in attainment of goal were noted. Patients of mixed ancestry were less likely

to get to either of the two goals, with the exception of mixed-ancestry males, who had similar not-at-goal percentages as the male patients of Asian ancestry. Females subjects were less likely to get to goal, both for the NCEP ATP III [OR 0.65 (CI 0.54–0.77), p < 0.001] and JETF [OR 0.76 (CI 0.64–0.91), p < 0.003] guidelines. This difference was maintained across the various ethnic groups.

The secondary outcomes or percentages of patients receiving LLDs with the metabolic syndrome, and the breakdown of those receiving LLDs for primary versus secondary prevention is given in Table 5.

discussionThe World Health Organisation has indicated that cardiovascular disease will be the number one cause of mortality in the developing world by 2020.15 Subjects with cardiovascular disease in underdeveloped countries tend to exhibit mortality 10 or more years before their counterparts from the developed nations.16 These factors indicate that it is imperative to address all cardiovascular risk factors aggressively if there is to be any

TABLE 2. CONTROL OF DIABETES AND HYPERTENSION

Condition



Diabetic patients

Number 718 690 279 152 118 256 120 139 200 141

Glucose (mmol/l) 7.93 8.44 7.46 8.08 8.12 9.12 8.17 7.86 8.24 8.19

HbA1c (%) 7.94 8.73 7.33 7.64 8.66 9.60 8.19 8.52 8.26 8.57

Hypertensive patients

Number 1081 1063 529 367 142 304 170 218 240 174

Systolic blood pressure (mmHg) 134.9 137.3 135.6 135.6 137.3 137.1 136.6 141.9 130.6 135.3

Diastolic blood pressure (mmHg) 81.7 80.8 82.2 79.3 83.8 81.5 81.3 81.2 79.8 80.0

TABLE 3. LABORATORY RESULTS

Laboratory parameters



Total cholesterol (mmol/l) 4.72 5.06 4.75 5.26 4.44 4.57 4.78 5.20 4.75 5.13

LDL cholesterol (mmol/l) 2.63 2.85 2.62 2.93 2.44 2.55 2.65 3.01 2.72 2.91

HDL cholesterol (mmol/l) 1.21 1.41 1.25 1.53 1.19 1.31 1.15 1.36 1.19 1.33

Triglycerides (mmol/l) 2.01 1.79 2.03 1.80 1.83 1.55 2.31 1.83 1.88 1.99

Non-HDL cholesterol (mmol/l) 3.51 3.65 3.51 3.73 3.25 3.26 3.63 3.84 3.56 3.80

Glucose (mmol/l) 6.52 6.76 6.0 5.8 7.2 8.1 6.8 6.7 7.1 7.0

Glycosylated haemoglobin (%) 7.34 638 6.31 8.74 7.48 7.91

TABLE 4. ATTAINMENT OF PRIMARY GOAL (%)

Guidelines



NCEP ATP III 63.4 56.8 67.3 61.5 68.4 60.8 61.0 41.7 58.7 52.7

EAS/ESC 55.0 49.3 57.5 50.1 62.3 55.8 44.3 42.0 51.6 48.0

TABLE 5. SECONDARY OUTCOME VARIABLES

Variables



Metabolic syndrome (%) 65.2 71.5 62.8 55.7 72.6 88.0 71.2 77.6 63.7 78.1

Primary prevention (%) 40.3 48.7 47.4 66.7 32.7 24.9 32.4 44.0 34.1 45.7

Secondary prevention (including DM) (%) 59.7 51.3 52.6 33.3 67.3 75.1 67.6 56.0 65.9 54.3


curtailment of the looming epidemic. This survey, representing patients in a developing country,

indicates that a large proportion of patients on LLDs are not reaching the accepted LDL-C goals. While these percentages are not dissimilar to those from other studies in Europe, they are below what is currently achieved in North America. The percent of patients at goal in North America has risen over the course of six years, from the NHANES survey of 1999/2000 and the follow up conducted in 2005/2006, indicating that increased awareness and education can result in a greater percentage of patients reaching LDL-C goals, despite the targets becoming more stringent.

The current study indicates both ethnic and gender variances in cardiovascular risk-factor distribution and control in South Africa. Smoking was less prevalent in those of African ancestry and very few black females were smokers. In general black subjects used fewer cigarettes than their Caucasian counterparts (possibly due to economic constraints). The South African Heart of Soweto study confirms that African patients have the lowest smoking prevalence, with patients of mixed ancestry twice as likely, and Caucasian patients three-fold more likely to be current smokers.17 In the current study of patient on LLDs, patients of mixed ancestry had the highest prevalence of smoking among both males and females, followed by Asian males.

The majority of black subjects did not have a family history of premature heart disease, which probably reflects the evolution of the epidemiological transition in an urbanising population, compared to Caucasians, Asians and patients of mixed ethnicity. The Heart of Soweto study also noted that African patients were least likely to be diagnosed with CAD, and showed similar data to CEPHEUS SA for the Asian patients, who had the highest prevalence of a family history of vascular disease.

Control of DM was particularly poor in both male and female African subjects compared with their ethnic counterparts. This may have been due to differences in access to guideline-based management protocols. Despite a high prevalence of the metabolic syndrome in African females, with poor control of DM, their TG levels were the lowest of all subjects – male and female.

The Heart of Soweto study noted that patients of African descent had significantly lower total cholesterol (TC), LDL-C and triglyceride (TG) levels compared to other ethnicities.17 These patients were not receiving LLDs. In CEPHEUS SA, in the African-ancestry group, the TGs were not elevated despite a high prevalence of DM with poor control. This would lend credence to the finding that this population group may inherently have low TG levels, and the influence of DM on TGs may be muted.

The Heart of Soweto study confirmed a high prevalence of obesity in patients of African ancestry (43% of the patients having a body mass index greater than 30 kg/m2). This substantial burden of obesity among African subjects points to an elevated risk for the future development of DM. Given that DM in this group is poorly controlled, the ameliorating influence of lipid-lowering therapy on future cardiovascular risk could potentially be undermined, or at the very least minimised.

The number of African-ancestry patients who had CAD was low in proportion to the other ethnic groups; however these percentages reflect a change in the prevalence of a disease that was previously considered to be rare in this population. Other studies from South Africa have indicated a prevalence of CAD

of less than 10% in the African population.18 The prevalence of CAD in African subjects receiving LLDs in the current study was 15.9%.

The INTERHEART Africa study noted that patients of African ancestry presented with myocardial infarction a mean of 3.8 years earlier than patients from the overall INTERHEART study, and also found no inter-ethnic or gender differences.1,19 Although data for the INTERHEART Africa study were drawn from patients from sub-Saharan countries, more than 80% of subjects were from South Africa, indicating that the data may be comparable to the current CEPHEUS SA study.

LimitationsThis study had the same limitations that apply to many surveys that differ fundamentally from formal prospective studies. The study population was drawn from those already on LLDs and cannot be extrapolated to the general population. Although attempts were made to sample patients from as wide a spectrum as possible, potential selection bias may still have occurred. All centres were located in urban areas, and the applicability to patients of rural origin cannot be assumed.

The public sector provides healthcare to about 80% of the South African population but it made up only about one-third of the sample. Similarly, the study population does not strictly reflect the ratios of the different ethnic groups residing in South Africa. However all previous studies on lipid-lowering therapy in South Africa were predominantly Caucasian based. Private-sector patients were recruited from a wide variety of both specialist and non-specialist practices. The public-sector patients were predominantly recruited from tertiary-care lipid and diabetes clinics. The majority of African patients came from the public sector.

Several private-sector centres had practitioners who dealt predominantly with patients with DM, and this could have further swayed the emphasis of the results on the diabetic cohort. DM is often associated with an increase in body mass index and other anthropometric measures of obesity, and data from a cohort with a high prevalence of DM may therefore not be reflective of the general population.

As the veracity of the patient questionnaires was not tested, the validity of the CVD history may have been inaccurate. Measured clinical parameters (such as blood pressure) were from a single visit and methods of measurement were not standardised or checked, and therefore inaccuracies could have arisen. Causal correlations were not established, and relationships should therefore be interpreted with caution.

ConclusionManagement of lipid-lowering treatment in South Africa is sub-optimal, and in general lags behind control achieved in the more developed nations. Furthermore, other cardiovascular risk factors are not receiving due attention and their prevalence in this population remains high. For any serious impact to be made on the looming epidemic of cardiovascular disease in the underdeveloped world, more attention needs to be focused on more aggressive treatment of dyslipidaemia as well as the other cardiovascular risk factors and, in particular, diabetes mellitus and obesity.


The authors acknowledge the participation of all the investigators who partic-ipated in the study. Ms Michelle Nortje of AstraZeneca Pharmaceuticals was most helpful in the acquisition of data.

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Drug Trends in Cardiology

anticoagulation: ‘putting new evidence into clinical practice’

A CPD evening recently hosted in Cape Town examined the clinical implementa-tion and implications of recent evidence on the novel oral anticoagulants (NOACs). Dr Hans-Christian Mochmann (cardio-logist) and Dr Jan Beyer-Westendorf (vascular physician) discussed NOAC therapeutic outcomes in both clinical trials and daily practice, sharing their experience in the use of these agents.

The demographic transition to increased life expectancy is a global phenomenon, accompanied by increased incidence of stroke in the ageing population. Virchow’s triad describes the elements essential to thrombosis as blood stasis (secondary to immobility, congestive heart failure and vein compression), alteration in the vein wall (secondary to prior thrombosis, inflammation or infection, direct wall trauma and varicose veins), and blood hypercoagulability (a result of, among others, antiphospholipid syndrome, lower-limb surgery or trauma and hyperhomocysteinaemia).

Of the two main types of stroke, ischaemic stroke is the most common,

caused by a blood clot formed in a blood vessel or elsewhere, which is then transported in the blood (embolism). Haemorrhagic stroke arises from rupture of a blood vessel, which leads to bleeding in the brain or on the brain surface. Haemorrhagic stroke represents 15–20% of all strokes.

Atrial fibrillationAtrial fibrillation (AF) is the most common form of sustained abnormality of heart rhythm and represents a major risk factor for stroke due to thrombus formation in the left atrial appendage. The risk of AF increases with age. The risks of diabetes and hypertension also increase with age and are independent predictors of AF. Patients with stroke due to AF have a greater mortality risk and a higher severity of stroke compared to non-AF stroke patients.

Dr Mochmann addressed the question of how to prevent stroke in AF patients today. In 2012, the European Society of Cardiology adopted the CHA2DS2-VASc score assessment (Table 1), developed particularly to improve stroke predictive value in low-risk patients. A maximum score of 9 indicates a 15.2% stroke risk per year. Oral anticoagulation is recommended in individuals with two or more risk factors.

Warfarin has been successfully used over many decades, demonstrating a 62% risk reduction in stroke across trials.

However, INR therapeutic range is hard to control on a daily basis. Only 50% of all measurements are found to be within the target INR range of 2.0–3.0, which represents a fine balance between the risk of stroke and risk of bleeds. Other obstacles presenting with warfarin use are the high incidence of side effects, low patient adherence (approximately 50% loss of compliance at three years) and multiple drug interactions.

Novel antithrombotic therapies include the NOAC, dabigatran, a direct thrombin inhibitor, and the factor Xa inhibitors, rivaroxaban and apixaban. Dr Mochmann paid particular attention to the use of rivaroxaban in non-valvular AF, presenting the ROCKET-AF trial outcomes on the use of rivaroxaban compared to warfarin in elderly patients with high CHADS2 scores, many with previous stroke. These patients presented with both high risk of another stroke and a high risk for bleeds.

Results indicated that rivaroxaban was at least as effective as warfarin in reduction of stroke/systemic embolus in these fragile patients. Rivaroxaban and

dr Hans-Christian MochmannDr Mochmann is consultant of cardiology at Charite Campus Benjamin Franklin, Berlin, Germany. He focuses on coronary interventions and is responsible for pre-hospital emergency medicine involving mobile ICUs and Berlin’s rescue helicopter Christoph 31.

dr Jan Beyer-WestendorfDr Beyer-Westendorf is head of the Thrombosis Research Unit at the Centre for Vascular Medicine and Department of Medicine at the University Hospital Carl Gustav Carus in Dresden, Germany. He also serves as deputy head of the Angiology Division at the same hospital.

TABLE 1. STROKE RISK ASSESSMENT: CHA2DS2-VASc SCORE

Risk factor Points

C Congestive heart failure/left = ventricular dysfunction

1

H Hypertension 1

A2 Age ≥ 75 years 2

D Diabetes mellitus 1

S2 Stroke/transient ischaemic attack/thromboembolism

2

V Vascular disease (prior myocardial infarction, peripheral artery disease, aortic plaque)

1

A Age 65–74 years 1

Sc Gender category (i.e. female) 1


warfarin performed similarly in terms of bleed rates; however, the rivaroxaban arm displayed a lower incidence of intracranial bleeds. ‘Oral anticoagulation is the basis for almost all AF patients and NOACs should be the first choice in newly treated patients’, concluded Dr Mochmann.

Dr Beyer-Westendorf’s musings were directed to the efficacy and safety of NOACs in daily care, with the opening statement ‘… choose one NOAC with the broadest range indicated. Get experience …, if you are unhappy, change to another NOAC’. Dr Beyer-Westendorf also considered differences in clinical trial results compared to the use of these agents in daily practice.

Venous thromboembolismGlobally, venous thromboembolism (VTE) is estimated to cause at least three million deaths a year. Known conse-quences of VTE include fatal pulmonary embolism (PE), risk of recurrent VTE, post-thrombotic syndrome (PTS), chronic thromboembolic pulmonary hypertension (CTPH) and a reduced quality of life. Within a five-year period after idiopathic deep-vein thrombosis (DVT), approxi-mately one-third of patients will develop PTS. This is characterised by pain, oede-ma, hyperpigmentation, eczema, varicose collateral veins and venous ulceration.

Drawbacks of current VTE treatment options (vitamin K antagonists and heparin) are initial parenteral treatment, and its poor acceptance by patients. Barriers presented by the use of vitamin K antagonists in the treatment and prevention of VTE include the narrow therapeutic range, inter-patient variability in dose response, multiple food and drug interactions, and the requirement for regular coagulation monitoring and

dose adjustment. Major bleeds with poor outcome are common.

An FDA analysis performed in 2011 found the anticoagulants to have the most serious adverse events. Warfarin is at the top of this list, despite having been used for 50 years. The complicated dosing regimen of warfarin is not ideal, with long hospital stays associated with overdose.

Major orthopaedic surgery represents an increased risk of DVT and anticoagu-lants are routinely used to prevent these potentially life-threatening complications. Dr Beyer-Westendorf considered the net clinical benefit of the use of NOACs in VTE prevention after orthopaedic surgery, particularly rivaroxaban, apixa-ban and dabigatran. All of the NOACs were as good as, or better than, heparin in terms of prevention of symptomatic VTE and risk of bleeding.

Data from his retrospective ORTHO-TEP registry consisting of three cohorts, including 5 000 patients undergoing hip- or knee-replacement surgery, indicate that replacing heparin with rivaroxaban results in a symptomatic DVT relative risk reduction of up to 60%. In terms of proximal DVT, PE and death from VTE, rivaroxaban provides a relative risk reduction of up to 30% compared to heparin of fondaparinux, with equivalent safety.

For VTE therapy, rivaroxaban is rapidly becoming the standard in many countries, with the benefits of a simpler dosing regimen (15 mg bd for three weeks, 20 mg od thereafter) than warfarin, and with no adaptations required for gender and old age. Patients are unable to overdose on rivaroxaban due to a ‘ceiling effect’, a point where no further rivaroxaban can be absorbed. Combined data on rivaroxaban from the EINSTEIN DVT and EINSTEIN PE trials present a relative risk reduction

of 46% for major bleeds and 11% for recurrent VTE.

Furthermore, data from a large prospective daily-care registry of NOACs (run by Dr Beyer-Westendorf in Germany) seem to indicate a rather benign pattern of bleeding complications: of all NOAC bleeds seen in this registry, 62% were minor and did not require any treatment, and 33% were non-major but clinically relevant bleeds, most of which could be treated without surgery or interventions. Only 5% were major bleeds, most of which were treated by red blood cell transfusions, PCC or interventions. There was an 8% mortality rate within the major-bleed group, which is much lower than the mortality rate with major warfarin bleeds seen in daily care.

In his concluding statements, Dr Beyer-Westendorf intimated that the half-life and elimination rates of NOACs are very similar to low-molecular weight heparin (LMWH) and are therefore convenient for use in planned surgery, with good data for the safety profile. Treatment is interrupted at least 24 hours prior to surgery, depending on the thromboembolic and bleeding risk of the procedure. There is no need for and no use in giving LMWH in the interim. He further stated that switching from warfarin to rivaroxaban is safe and effective.

There are low discontinuation rates with rivaroxaban, with reports of high patient and doctor satisfaction. The use of rivaroxaban is effective and safe for acute and long-term VTE treatment as well as stroke prevention in AF. Bayer HealthCare Pharmaceuticals is anticipating the imminent registration of rivaroxaban for AF in South Africa.

G Hardy

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 6, July 2013AFRICA e1

Case report

new vascular ring connectors in surgery for intramural haematoma of the abdominal aorta progressing to ruptureCHIH-HSIEN LEE, LI-WEI KO, YI-CHANG LIN, CHIH-CHIEN YEN, HSIANG-YU YANG, CHIH-HONG KAO, CHIEN-SUNG TSAI, YI-TING TSAI

abstractAortic intramural haematoma is similar to classic aortic dissection, which causes a life-threatening medical condi-tion, and immediate diagnosis and treatment are crucial. The optimal therapy for intramural haematoma of the abdominal aorta remains controversial. Conservative medi-cal management is usually the first choice of treatment for uncomplicated cases. Surgical intervention is usually required for complicated intramural haematomas of the abdominal aorta, including conventional open repair and endovascular treatment with stent-grafts. A new vascular ring connector that achieves a quick, blood-sealed and sutureless anastomosis has been designed for aortic dissec-tion. We herein report a case of intramural haematoma of the abdominal aorta, progressing to rupture on day 14 after onset, which had successful aortic repair with the new vascu-lar ring connector. The new vascular ring connector could be an alternative method for the treatment of complicated intramural haematomas of the abdominal aorta.

Keywords: aortic dissection, intramural haematoma, vascular ring connector


Cardiovasc J Afr 2013; 24: e1–e3 www.cvja.co.za

DOI: 10.5830/CVJA-2013-049

Aortic intramural haematoma (IMH) develops as a result of spontaneous rupture of the vasa vasorum of the aorta or rupture of an atherosclerotic plaque.1 Conservative medical management is usually the first choice of treatment for Stanford type B acute aortic dissection without complications.

IMH has been recommended to be managed according to the same guidelines as classic dissection.2 However, IMH evolves very dynamically in the short term to regression, classic dissection, or aortic rupture.1 Surgical intervention is usually required for complicated intramural haematomas of the abdominal aorta, including conventional open repair and endovascular treatment with stent-grafts.

A new vascular ring connector (Vasoring, Sunwei Technology Co, Taipei, Taiwan) has been designed for aortic dissection.3 It is a titanium ring that is used as a stent in the vascular graft to achieve a quick, blood-sealed and sutureless anastomosis. We herein report a case of intramural haematoma of the abdominal aorta, progressing to rupture on day 14 after onset, which was successfully surgically repaired with the new vascular ring connector.

Case reportA 49-year-old man with a past history of hypertension without regular medical control presented to our hospital with acute, intense epigastric and back pain for six hours. On admission, his blood pressure was 180/110 mmHg and pulse rate was 78 beats per minute. Physical examination of the chest and abdomen showed no signs of visceral ischaemia. Peripheral arterial pulses were easily palpable in the upper and lower extremities.

Laboratory data were unremarkable. Initial contrast-enhanced computed tomography (CT) showed a focal wall thickening from the descending aorta to the left common iliac artery without a demonstrable intimal flap or false lumen. On suspicion of an intramural haematoma of the abdominal aorta, the patient was admitted to the medical intensive care unit for blood pressure control and further evaluation.

On day 14 after onset, the patient complained of recurrent refractory abdominal pain. Physical examination of the abdomen revealed intractable tenderness and normal bowel sounds. Arterial pulsations in both lower limbs were palpable. A follow-up contrast-enhanced CT (Fig. 1) showed aortic dissection with a large primary entry tear in the infra-renal section of the abdominal aorta, extending to the bifurcation of the distal abdominal aorta.

The patient received emergency open surgery with the traditional open procedure before anastomosis. We used a

department of Cardiac surgery, tungs’ taichung Metro-Harbor Hospital, taipei, taiwanCHIH-HSIEN LEE, MD

department of Biological science and technology, national Chiaotung university, taipei, taiwanCHIH-HSIEN LEE, MDLI-WEI KO, PhD

division of Cardiovascular surgery, department of surgery, tri-service General Hospital, national defense Medical Centre, taipei, taiwanCHIH-HSIEN LEE, MDYI-CHANG LIN, MDCHIH-CHIEN YEN, MDHSIANG-YU YANG, MDCHIH-HONG KAO, MDCHIEN-SUNG TSAI, MDYI-TING TSAI, MD, [email protected]

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 6, July 2013e2 AFRICA

vascular graft (Hemashield, Boston Scientific, Boston, MA, USA) with new vascular ring connectors (VRC). The VRC was attached to the vascular prosthesis by securing the edge of the graft against the narrow groove of the VRC with non-absorbable sutures. The ringed prosthesis was then inserted into the abdominal aorta, positioned at the planed proximal anastomotic site, and fixed to the abdominal aorta by tying the tapes against the wider groove. A similar manoeuvre was used for the distal anastomosis. The patient was well without deficit at the one-year follow up (Fig. 2).

discussionIMH results either from spontaneous rupture of the vasa vasorum of the aorta, causing haemorrhage within the aortic wall in the absence of initial intimal disruption, or from a penetrating atherosclerotic ulcer that penetrates into the internal elastic lamina and allows haematoma formation within the media of the aortic wall.4-7 IMH is a variant form of aortic dissection, and although less common, accounts for 10–30% of cases. It has been accepted as an increasingly recognised and potentially fatal entity of all acute aortic syndromes.4,7 Penetrating atherosclerotic ulcer of the IMH was reported to have a significantly progressive course.5,6 In our experience, IMH due to a penetrating atherosclerotic ulcer commonly had a progressively downhill clinical course.

IMH has a variable clinical course. It commonly affects elderly patients (mean age 66 years) with a history of hypertension.5,6,8 The most common presenting symptom is sudden onset of abdominal pain radiating to the back or the buttock.5 In our experience, onset of recurrent/refractory pain may be a sign of impending rupture and should therefore be considered for more aggressive intervention.

With recent advances in imaging techniques, IMH is now increasingly recognised. CT scans diagnose aortic dissection

reasonably well but may not be completely reliable in distinguishing IMH from classic aortic dissection.8 Aortography was performed, which showed no evidence of dissection but did reveal an ectatic descending aorta. With MRI, IMH is characteristically seen as a focal thickening of the aortic wall in the absence of dissection.8 It should be considered in the differential diagnosis of any patient with an acute onset of abdominal pain, radiation to the back or buttocks, with the presence or absence of a pulsatile abdominal mass or signs of limb ischaemia.

Most authorities currently recommend treatment of IMH similar to that of classic aortic dissection, with early surgery for patients with proximal IMH and medical management for patients with distal IMH.8 Initially stable patients with IMH of the abdominal aorta can be treated medically with frequent clinical and radiological re-assessment and they may have complete resolution.

A certain volume of haematoma in the aortic wall may cause the intima of the penetrating atherosclerotic ulcer to become fragile and lead to intimal disruption.1 Consequently IMH weakens the aorta and may progress to aortic dissection. This may explain why wall thickness is related to progression to overt dissection or aortic rupture. IMH may progress to classic dissection (i.e. with intimal disruption) in up to 33% of cases.5,8 In our case, intramural haematoma of the abdominal aorta progressed to rupture with medical failure.

Conservative medical management is usually the first choice of treatment for Stanford type B acute aortic dissection without complications, but surgical intervention is required in patients with complications, such as leakage or threatened rupture, malperfusion, persistent pain or intractable and progressive enlargement of the ulcer-like projection to more than 20 mm in diameter or depth during the follow-up period.1,2,8

Operative intervention includes open or endovascular repair of the abdominal aorta. The open technique usually involves

Fig. 1. a follow-up contrast-enhanced Ct showing aortic dissection with a large primary entry tear in the infra-renal site of the abdominal aorta, extending to the bifur-cation of the distal abdominal aorta on day 14 after onset.

Fig. 2. the ringed graft is inserted into the aorta and the braided nylon tapes are tied against the wider groove of the vascular ring connectors to achieve a sutureless anastomosis.


placement of a Dacron graft, although resection of the affected aorta with end-to-end anastomosis without graft insertion has been described.9 This decision is greatly influenced by anatomical conditions together with the surgeon’s experience. It is unclear what benefit endovascular stenting would have in the treatment of IMH.8 The fragile tissue makes suturing of the vascular prosthesis to the vascular wall difficult. Bleeding from the aortic anastomosis may lead to uncontrollable bleeding and even death.

A new vascular ring connector (Vasoring, Sunwei Technology Co, Taipei, Taiwan) has been designed for aortic dissections.3 In the series of Wei and co-workers,10 the VRC may improve mid-term results of aortic dissection by reducing both the anastomosis time and the risk of bleeding.

The VRC is composed of a biocompatible titanium alloy

that has two grooves on the outside of the VRC.3 The device is inserted into a vascular prosthesis to form an intraluminal graft and is fixed against the narrow groove with a non-absorbable suture. The narrow groove is designed for better external fixation. Then braided tape, tied around the overlapping region of the abdominal aorta and the VRC at the wider groove, provides a sutureless anastomosis and homogenous contact surface. The time of anastomosis is shorter than with conventional surgery.

We used the VRC for the first time in this case of the IMH that progressed to dissected abdominal aorta. The results provide evidence that the VRC is a promising method of treatment for IMH of the abdominal aorta progressing to rupture.

ConclusionAortic IMH is a difficult diagnosis that requires a high index of suspicion. The vascular ring connector may improve the results of aortic dissection by reducing both the anastomosis time and

the risk of bleeding. It is an alternative method for the treatment of dissected abdominal aorta.

References1. Moizumi Y, Komatsu T, Motoyoshi N, Tabayashi K. Clinical features

and long-term outcome of type A and type B intramural hematoma of the aorta. J Thorac Cardiovasc Surg 2004; 127: 421–427.

2. O’Gara PT, DeSanctis RW. Acute aortic dissection and its variants. Toward a common diagnostic and therapeutic approach. Circulation 1995; 92: 1376–1378.

3. Wei J, Chang CY, Chuang YC, Sue SH, Lee KC, Tung D. A new vascular ring connector in surgery for aortic dissection. J Thorac Cardiovasc Surg 2009; 138: 674–677.

4. Evangelista A, Dominguez R, Sebastia C, Salas A, Permanyer-Miralda G, Avegliano G, et al. Long-term follow-up of aortic intramural hema-toma: predictors of outcome. Circulation 2003; 108: 583–589.

5. Baikoussis NG, Apostolakis EE, Siminelakis SN, Papadopoulos GS, Goudevenos J. Intramural haematoma of the thoracic aorta: who’s to be alerted the cardiologist or the cardiac surgeon? J Cardiothorac Surg 2009; 4: 54–61.

6. Ganaha F, Miller DC, Sugimoto K, Do YS, Minamiguchi H, Saito H, et al. Prognosis of aortic intramural hematoma with and without penetrating atherosclerotic ulcer: a clinical and radiological analysis. Circulation 2002; 106: 342–348.

7. Song JK. Diagnosis of aortic intramural haematoma. Heart 2004; 90: 368–371.

8. Sawhney NS, DeMaria AN, Blanchard DG. Aortic intramural hema-toma: an increasingly recognized and potentially fatal entity. Chest 2001; 1204: 1340–1346.

9. Trimarchi S, Eagle KA, Nienaber CA, Pyeritz RE, Jonker FH, Suzuki T, et al. Importance of refractory pain and hypertension in acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD). Circulation 2010; 122: 1283–1289.

10. Wei J, Chang CY, Chuang YC, Sue SH, Lee KC, Wu CW, et al. Midterm results of vascular ring connector in open surgery for aortic dissection. J Thorac Cardiovasc Surg 2012; 143: 72–77.


Case report

Endovascular stent-graft repair for abdominal aortic aneurysm in a patient with a short and severely angulated proximal aortic neckAE-YOUNG HER, YONG HOON KIM

abstractSerious anatomical limitations to endovascular aortic aneu-rysm repair (EVAR) are mostly related to the anatomical characteristics of the proximal neck of the aneurysm. A 75-year-old male was referred for management of an inci-dentally found large asymptomatic infra-renal saccular abdominal aortic aneurysm. Its proximal aortic neck was short and severely angulated. We performed successful EVAR in this patient without surgical intervention.

Keywords: aortic aneurysm, stent-graft, aneurysm morphology


Cardiovasc J Afr 2013; 24: e4–e7 www.cvja.co.za

DOI: 10.5830/CVJA-2013-048

In 1991 Parodi first reported the technique of trans-femoral catheter-based repair of an infra-renal abdominal aortic aneurysm (AAA) as an alternative to the management of patients whose medical co-morbidities made them poor candidates for conventional surgical treatment.1 Currently, endovascular repair of AAA is known to be less invasive, reduce the need for hospitalisation, and decrease morbidity and mortality rates than standard open repair.2

However, serious anatomical limitations to endovascular aortic aneurysm repair (EVAR) remain, mostly related to anatomical characteristics of the proximal neck of the aneurysm.3 We report on a successful EVAR without surgical intervention in a patient with a large, asymptomatic infra-renal saccular AAA. Its proximal aortic neck was short and severely angulated.

Case reportA 75-year-old male was referred for the management of an incidentally found large asymptomatic infra-renal saccular AAA. His risk factors for coronary artery disease were age and hypertension. Approximately eight years previously, the patient had had a lumbar spine operation due to intervertebral disc herniation. Two weeks previously, he had visited the orthopaedic

clinic for more surgery. During the pre-operative MRI work up of the lumbar spine, they had incidentally found a large abdominal aortic aneurysm. He was referred to our hospital.

The patient underwent a contrast-enhanced CT angiogram of the abdominal aorta. Three-dimensional reconstruction was performed (Fig. 1). The image studies revealed that the aneurysm was large, saccular (6.0 × 7.8 cm) and there were mural thrombi within the abdominal aorta but not in the aneurismal neck. It was

division of Cardiology, department of internal Medicine, Kangwon national university school of Medicine, Chuncheon, KoreaAE-YOUNG HER, MD, PhD YONG HOON KIM, MD, PhD, [email protected]

Fig. 1. three-dimensional reconstructed Ct angiogram showing a large infra-renal saccular abdominal aortic aneurysm and aneurysm dilatation of both iliac arteries and the ascending aorta.


isolated to the infra-renal aorta with no involvement of the renal artery. Both iliac arteries and the ascending aorta were dilated (5.5 cm) (Fig. 2) and it involved the aortic arch.

We discussed with the cardiac surgeon the possibility of open surgery. He said it did not need elective or emergency surgery and recommended serial follow up of the change in the ascending aorta and aortic root diameter. We exclude the ascending aortic dilation in this report.

After detailed measurements of the length and angle of the infra-renal neck of the AAA we considered it a debatable candidate for EVAR due to the short (1.7 cm) and severely angulated proximal aortic neck (Fig. 3). We had suggested open surgical repair may be a safer option but the patient had rejected it. We carefully re-evaluated and measured all aspects of the aneurysm and the patient’s iliac arteries, as we considered the patient to be a challenge for stent-graft repair.

He was admitted the afternoon of his procedure. After lidocaine local anaesthesia, the right common femoral artery was exposed using a small incision, and the patient underwent pre-operative, percutaneous plug emobolisation of the outflow branch of the right internal iliac artery to prevent an endoleak.

Thereafter we deployed a bifurcated stent-graft measuring 28 mm (main body diameter) by 18 mm (iliac limb diameter) by 11.1 cm (total length) (Zenith®, Cook, Inc, Bloomington, Ind). Through the left femoral artery, a contralateral iliac device measuring 12 mm (iliac limb diameter) by 7.3 cm (length) was used. Thereafter an extender cuff was deployed to extend coverage to the right iliac artery.

The postoperative angiogram showed a proximal type 1 endoleak at the attachment site owing to the severely angulated proximal neck. We therefore performed several Coda® balloon (Cook, Inc, Bloomington, Ind) dilatations to attach the stent-graft to its aortic wall. However, the leak remained and we were undecided between EVAR and open surgical repair.

Fig. 2. the maximum diameter of the aneurismal dilated ascending aorta was 5.5 cm on Ct scan.

Fig. 3. the proximal aortic aneurysmal neck was short and severely angulated.

Fig. 4. one week later, a follow-up abdominal aorta Ct angiogram showed no visible endoleak and the proximal aortic neck angle had become more straightened.


Unfortunately we were forced to stop the procedure due to the prolonged procedure time and we did not have a suitable device at the institution. It was also the start of the Korean New Year and due to a traffic jam, the delivery of another device would have been impossible.

The procedure was scheduled for two days ahead. During those two days we had to find another device, such as an aortic extender cuff and a Palmaz-Schatz stent® (PS 204, Johnson and Johnson Interventional Systems) to close the endoleak. Palmaz-Schatz® stents were in limited supply in Korea at that time.

We planned two options. First, the use of an aortic extender cuff was considered. If we failed, a Palmaz-Schatz® stent would be used. Fortunately an aortic extender cuff sized 28 mm (main body diameter) by 5.8 cm (length) was deployed with success at the angulated neck. Post-deployment of a Coda® balloon dilatation was also done.

The angle of the proximal aortic neck had also become more straightened and more closely attached to the aortic wall. We redid the angiogram and the result was gratifying. The proximal type 1 endoleak had disappeared so there was no need to use the Palmaz-Schatz stent®.

The patient was discharged on postoperative day 3 with a normal serum creatinine value. One week later, a follow-up abdominal aortic CT angiogram was obtained. No visible endoleak flow was found (Fig. 4). Six months later a follow-up CT angiogram was done and we could not find any leakage at the previous graft site. There was however no change in the fusiform aortic aneurysm in the ascending aorta (Fig. 5).

discussionAbdominal aortic aneurysm is a common condition, especially among older men, and endovascular repair has become a common treatment option. Numerous reports describe difficulties in applying EVAR to an aneurysm with ‘hostile neck’ anatomy, including neck angulation, neck length, associated thrombus and complex morphology.4

Sternbergh reported that a patient with severe aortic neck angulation had a 54 to 70% risk of one or more adverse events. These outcomes occurred despite adequate length (> 2 cm) of the proximal aortic neck. He recommended great caution should be exercised in recommending EVAR for patients with aortic neck angulation ≥ 40 degrees.5 In our case the angle of aortic aneurismal neck was acute (75 degrees) and short (1.7 cm).

ACC/AHA guidelines6 recommend open or endovascular repair of infra-renal abdominal aortic anuerysms and/or common iliac aneurysms is indicated in patients who are good surgical candidates (Class I, level of evidence A). We agreed that open surgical repair may have been the more reasonable choice of treatment. However the patient refused open surgical repair. After we had obtained informed consent for endovascular repair, we decided on EVAR.

ConclusionWe obtained a good end result in this case, but we learned much from it. The surgeon must always ensure there is sufficient instrumentation to cope with unexpected situations.

References1. Parodi JC, Palmaz JC, Barone HD. Transfemoral intraluminal graft

implantation for abdominal aortic aneurysms. Ann Vasc Surg 1991; 5: 491–499.

2. Greenhalgh R, Brown L, Kwong G, Powell J, Thompson S, EVAR trial participants. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR 1), 30-day operative mortality results: randomized controlled trial, Lancet 2004; 364: 843–848.

3. Mohan IV, Laheij RJ, Harris PL, EUROSTAR collaborators. Risk factors for endoleak and the evidence for stent-graft oversizing in patients undergoing endovascular aneurysm repair. Eur J Vasc Endovasc Surgery 2001; 21: 344–349.

4. Dillavou ED, Muluk SC, Rhee RY, Tzeng E, Woody JD, et al. Dose hostile neck anatomy preclude successfulendovascular aortic aneurysm repair? J Vasc Surg 2003; 38: 657–663.

5. Sternbergh WC III, Carter G, York JW, Yoselevitz M, Money SR. Aortic neck angulation predicts adverse outcome with cardiovascular abdominal aortic aneurysm repair. J Vasc Surg 2002; 35: 482–486.

6. Rooke T, Hirsch A, Misra S, Sidawy A, Beckman J, Findeiss L, et al. American College of Cardiology Foundation; American Heart Association Task Force; Society for Cardiovascular Angiography and interventions; Society of Interventional Radiology; Society for Vascular Medicine; Society for Vascular Surgery. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline). Vasc Med 2011; 16(6): 452–476.

Fig. 5. six months later, a follow-up abdominal aorta Ct angiogram was done and we could not find any leakage at the previous graft site. there was also no change in the fusiform aortic aneurysm size in the ascending aorta.

Atorvastatin10 mg, 20 mg, 40 mg, 80 mg

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Cipla Medpro (Pty) Ltd. Reg. No. 1995/004182/07 Rosen Heights, Pasita Street, Rosen Park, Bellville, 7530. Tel (021) 943 4200, Fax (021) 914 4699 Email: [email protected], Website: www.cipla.co.za

REFERENCES:1. South African Dyslipidaemia Guideline Consensus Statement. March 2012, Vol. 102, No. 3 SAMJ2. Department of Health website http://www.doh.gov.za – accessed 06/20133. IMS data March 20134. Data on file

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