Apolipoprotein [epsilon]4 homozygosity and essential hypertension.

To the Editor: A 67-year-old Greek woman with a body mass index of 25 kg/[m.sup.2] was referred to the Lipid Clinic for dyslipidemia. She had stopped smoking 20 years previously, had been treated for hypertension for the past 10 years, and suffered a myocardial infarction 3 years prior. Her family history included stroke in her father at the age of 65, and hypertension in her son at age 47.

Coronary arteriography, performed 3 years before presentation, revealed 2-vessel disease. Percutaneous angioplasty and stent implantation of the right coronary artery followed. In addition, stenosis in peripheral arteries (60% of the right common carotid, 80% of the right renal [percutaneous implantation of stent was performed at age 65]), and diffuse stenosis of both femoral arteries were diagnosed by computed tomographic angiography. The patient's lipid profile without hypolipidemic treatment revealed a total cholesterol of 302 mg/dL, low-density lipoprotein cholesterol of 191 mg/dL, triglycerides 230 mg/dL, high-density lipoprotein cholesterol of 65 mg/dL, and lipoprotein (a) 40 mg/dL. The patient was treated with antihypertensive, hypolipidemic, and conventional antiischemic drugs, and was followed up every 6 months on an outpatient basis for 4 years. She was very cooperative, walking every day for 20 minutes, had good control of blood pressure (120/80 mm Hg) and dyslipidemia (low-density lipoprotein cholesterol <100 mg/dL). Her body mass index remained stable. The patient was asymptomatic until January 2003, when she complained of angina on effort. A new coronary arteriography was performed and revealed 3-vessel disease. The patient underwent coronary artery bypass grafting. Definite and probable familial hypercholesterolemia was excluded based on criteria published by Hopkins. (1) Glucose loading test was negative and serum homocysteine level was normal. For this reason, and in light of our previous study, (2) the genotype that could influence coronary heart disease (CHD)--such as apolipoprotein E--was evaluated, and the patient was found to be homozygous for the [epsilon]4 allele.

Several studies have linked the [epsilon]4 allele with a greater risk of coronary heart disease. In a case-controlled study, among men aged less than 40 years who were referred for coronary angioplasty, the frequency of homozygotes for the [epsilon]4 allele was 16-fold higher than in healthy subjects. (3) It was also reported that the [epsilon]4 allele could be an independent risk factor for death from coronary heart disease, and for nonfatal myocardial infarction. (4) In addition, a trend for the [epsilon]4 allele to be associated with a higher prevalence of target organ damage in patients with mild to moderate hypertension has been proposed. (5) Previously, we reported that the [epsilon]4 allele frequency among CHD patients was similar compared with healthy patients. (2) Greece belongs to those countries with a low [epsilon]4 allele frequency compared with other populations (10% versus 20-24%), (2) and this may explain the lack of association with CHD risk that we found. However, the presence of the [epsilon]4 allele, and particularly two of them in combination with hypertension and dyslipidemia, may become more deleterious. Patients with two [epsilon]4 alleles may be candidates for even more aggressive treatment.

References

1. Hopkins PN. Familial hypercholesterolemia-Improving treatment and meeting guidelines. Int J Cardiol 2003;89:13-23.

2. Kolovou G, Yiannakouris N, Hatzivassiliou M, et al. Association of apolipoprotein E polymorphism with myocardial infarction in Greek patients with coronary artery disease. Curr Med Res Opin 2002;18:118-124.

3. van Bockxmeer FM, Mamotte CD. Apolipoprotein epsilon 4 homozygosity in young men with coronary heart disease. Lancet 1992;340:879-880.

4. Tiret L, de Knijff P, Menzel HJ, et al. Apo E polymorphism and predisposition to coronary heart disease in youths of different European populations. The EARS study. European Atherosclerosis Research Study. Arterioscler Thromb 1994;14:1617-1624.

5. Yilmaz H, Isbir T, Agachan B, et al. Is epsilon4 allele of apolipoprotein E associated with more severe end-organ damage in essential hypertension? Cell Biochem Funct 2001;19:191-195.

Genovefa D. Kolovou, MD, PHD

Katherine K. Anagnostopoulou, MSC 

Dennis V. Cokkinos, MD

Cardiology Department and Molecular Immunology Laboratory, Onassis Cardiac Surgery Center, Athens, Greece

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