Interact CardioVasc Thorac Surg 2009;8:687-688. doi:10.1510/icvts.2009.203273
© 2009 European Association of Cardio-Thoracic Surgery
Apolipoprotein E alleles and bicuspid aortic valve stenosis in monozygotic twins
Palaniappan Saravanan* and
Isaac Kadir
Department of Cardiology, University Hospital of South Manchester, Southmoor Road, Wythenshawe, Manchester M23 9LT, UK
Received 21 January 2009;
received in revised form 2 March 2009;
accepted 3 March 2009
*Corresponding author. Tel.: +44 161 2751208, +44 7886 348056; fax: +44 161 2751183.
E-mail address: palaniappan.saravanan{at}manchester.ac.uk (P. Saravanan).
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Abstract
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Aortic valve disease is a common valvular heart disease but the underlying pathology that leads to the severe dysfunction of the aortic valve is unclear. There is increasing interest in the role of hypercholesterolaemia in the causation and progression of aortic valve disease. Apolipoprotein E is an essential component of cholesterol and previous studies have reported conflicting results on the association between various apolipoprotein E alleles and aortic valve disease. We report two interesting cases of severe dysfunction of bicuspid aortic valves in twin brothers who presented to us at the same time.
Key Words: Bicuspid aortic valve; Aortic stenosis; Apolipoprotein E alleles
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1. Introduction
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Aortic valve disease is a common valvular heart disease of the elderly with an overall incidence of 1–4% of the population. However, despite a high prevalence of this condition, the underlying pathology that leads to such severe dysfunction of the aortic valve is far from clear. There is increasing interest on the role of hyperlipidaemia in promoting calcific aortic valve changes as early valvular lesions show significant deposits of cholesterol [1]. While much of the existing evidence focuses on conventional tricuspid aortic valves, there are some studies which show a causative association between hypercholesterolaemia and aortic valve disease in a congenitally bicuspid aortic valve [2]. Apolipoprotein E is an essential component of cholesterol and previous studies have reported conflicting results on the association between various apolipoprotein E alleles and aortic valve disease. We report two interesting cases of severe dysfunction of bicuspid aortic valves in twin brothers who presented to us at the same time.
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2. Clinical summary
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W.H. and J.H., 73-year-old twin brothers, were referred at the same time for surgical opinion on their symptomatic aortic valve disease. They were both identified to have asymptomatic, mild to moderate aortic stenosis (with a mean gradient of 27 mmHg in W.H. and 20 mmHg in J.H.) approximately 3 years prior to referral and were being followed-up with serial echocardiography at their respective district general hospitals. W.H. presented with pre-syncopal symptoms while J.H. had angina and shortness of breath at presentation. Both the patients had a history of hypercholesterolaemia (diagnosed 6 and 8 years prior to surgery, respectively, with a total cholesterol value of 6.7 mmol/l and 7.1 mmol/l, respectively) and hypertension, for which they had been treated with anti-hypertensive medications and a high dose statin by their respective general practitioners (treated total cholesterol values were 5.2 mmol/l and 4.8 mmol/l, respectively). Neither of them smoked and there were no other relevant co-morbidities or risk factors. Echocardiography showed a stenosed bicuspid aortic valve in both patients, with a mean aortic valve gradient of 63 mmHg and 59 mmHg, respectively. Coronary angiography revealed non-obstructive coronary artery disease in W.H. while it showed a significant lesion in mid left anterior descending coronary artery (LAD) in J.H. Both patients were listed for surgery around the same time. W.H. underwent tissue aortic valve replacement (AVR) while J.H. had tissue AVR and coronary artery bypass graft surgery (CABG) with left internal mammary artery graft (LIMA) to LAD. Preoperatively, the valves looked very similar. They were congenitally bicuspid with fusion of the right and left coronary cusps. There was extensive calcification and deformation. Both patients had no major complications preoperatively and made an uneventful recovery following surgery. Having been aware of the controversies surrounding the genetic pre-disposition to develop aortic valve disease, we felt these patients offered an excellent opportunity to test the hypothesis that certain apoE alleles which predispose to hypercholesterolaemia may have a contributory role in the development of degenerative aortic valve disease. Hence, after obtaining verbal consent from the patients, we performed ApoE genotyping using allele specific oligo-nucleotide probes.
2.1. ApoE genotyping methods
Patients’ DNA (obtained from peripheral venous blood) was assayed for point mutations in codons 112 and 158 of the apolipoprotein E gene by polymerase chain reaction (PCR), and fluorescence monitoring using hybridization probes. This showed that both the patients had e3/e4 heterozygous ApoE genotype.
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3. Discussion
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There is some evidence to support the theory that hyper-cholesterolaemia may have a causative role in the development of calcific aortic stenosis as evidenced by significant cholesterol deposits in early valvular lesions [1]. Much of the evidence and a large volume of literature focus on the degenerative changes that lead to stenosis in conventional tricuspid aortic valves, however, small studies indicate that the mechanisms of development of stenosis i.e. degenerative and calcific changes may be similar in bicuspid valves [2]. Recently, mutations in the signalling and transcriptional regulator NOTCH1 has been shown to cause a spectrum of developmental aortic valve anomalies including bicuspid aortic valves and severe valve calcification in humans [3]. These associations, if proved, could lead to innovative therapeutic and important preventive strategies to be developed. In cholesterol metabolism, ApoE is an important candidate gene as it has been shown to accumulate in diseased valves. Clinical trials looking at the association between ApoE alleles and calcific aortic valve disease have shown conflicting results with one study [4] showing that the presence of any ApoE4 allele is an independent predictor of calcific aortic stenosis while another [5] clearly refuting this view. Our cases suggest a possibility of a link between ApoE genotype and calcific aortic stenosis. Both patients had ApoE4 heterozygous allele which would predispose them for hypercholesterolaemia (which they both suffered to a similar extent thereby confirming a genotype–phenotype relationship). While the severity of their CAD was not comparable, they both had similar degenerative changes in their aortic valves thereby lending support to the theory that ApoE alleles, particularly presence of ApoE4, may have a significant association with calcific aortic valve disease.
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References
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Abstract
1. Introduction