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CLINICAL STUDIES

Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin

The lipoprotein and coronary atherosclerosis study

Ali J. Marian, MD, FACC^*, Faye Safavi, BS^*, Laura Ferlic, MS^*, J. Kay Dunn, PhD^*, Antonio M. Gotto, MD, DPhil, FACC and Christie M. Ballantyne, MD, FACC^*

^* Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Cornell University Medical College, New York, New York, USA

Manuscript received February 28, 1999; revised manuscript received June 24, 1999, accepted October 5, 1999.

Reprint requests and correspondence: Dr. A. J. Marian, Section of Cardiology, One Baylor Plaza, 543E, Houston, Texas 77030
amarian{at}bcm.tmc.edu

OBJECTIVES

Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population.

BACKGROUND

Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI).

METHODS

Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo.

RESULTS

Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend.

CONCLUSIONS

Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.

Abbreviations and Acronyms   ACE = angiotensin-1 converting enzyme   ANOVA = analysis of variance   apo = apolipoprotein   CAD = coronary artery disease   DMSO = dimethyl sulfoxide   HDL-C = high density lipoprotein-cholesterol   HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A   I/D = insertion/deletion   LCAS = Lipoprotein and Coronary Atherosclerosis Study   LDL-C = low density lipoprotein-cholesterol   MI = myocardial infarction

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