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CLINICAL STUDIES

Endothelial cell damage and angiotensin-converting enzyme insertion/deletion genotype in elderly hypertensive patients

Kazuomi Kario, MD, PhD^*, Takefumi Matsuo, MD, PhD, Hiroko Kobayashi, PhD, Nobuyuki Kanai, MD, PhD, Satoshi Hoshide, MD^*, Takeshi Mitsuhashi, MD, PhD^*, Uichi Ikeda, MD, PhD^*, Shinichi Nishiuma, MD^||, Masafumi Matsuo, MD, PhD^|| and Kazuyuki Shimada, MD, PhD^*

^* Department of Cardiology, Jichi Medical School, Tochigi, Japan
Department of Pathology, Jichi Medical School, Tochigi, Japan
Department of Internal Medicine, Hyogo Prefectural Awaji Hospital, Hyogo, Japan
Central Laboratory, Hyogo Prefectural Awaji Hospital, Hyogo, Japan
^|| Division of Genetics, International Center for Medical Research, Kobe University School of Medicine, Kobe, Japan

Manuscript received August 22, 1997; revised manuscript received April 8, 1998, accepted April 23, 1998.

Address for correspondence: Dr. Kazuomi Kario, MD, PhD, Department of Cardiology, Jichi Medical School, 3311-1, Yakushiji, Minamikawachi, Kawachi, Tochigi, 329-0498, Japan

Objectives. The purpose of this study was to investigate the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotype and endothelial cell dysfunction or hypercoagulable state in elderly hypertensive patients.

Background. Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was recently reported to be associated with various cardiovascular diseases. However, the precise mechanism of this association remains unknown, and some confounding factors might also affect the association. Endothelial cell dysfunction and coagulation activation play important roles in both the atherosclerotic process and the onset of cardiovascular events.

Methods. We identified the ACE I/D genotype and measured the plasma levels of markers of endothelial cell damage (von Willebrand factor [vWF] and thrombomodulin) and of coagulation activation (prothrombin fragment F1 + 2 [F1 + 2]) in 318 asymptomatic elderly patients with hypertension, aged 59–93 years.

Results. The vWF level was significantly higher in those with the DD genotype (n = 54) than in those with the II genotype (n = 131, p < 0.0001) or with the ID genotype (n = 133, p < 0.0001). The TM levels were also higher in patients with the ID genotype (p < 0.005) and the DD genotype (p < 0.01) than in those with the II genotype. There were no differences in F1 + 2 level among the groups. Positive correlations of systolic blood pressure with levels of both vWF and thrombomodulin were found predominantly in patients with the II genotype (both p < 0.001), but no correlation was noted in those with the DD genotype.

Conclusions. Considering the increased plasma levels of both endothelial cell-derived markers in the hypertensive patients with ACE DD genotype, we speculate that the ACE D allele is a risk factor for the development of hypertensive cardiovascular disease associated with endothelial cell damage.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ANOVA = analysis of variance   BP = blood pressure   DNA = deoxyribonucleic acid   ECG = electrocardiography   ECG-LVH = left ventricular hypertrophy diagnosed by ECG   ELISA = enzyme-linked immunosorbent assay   F1+2 = prothrombin fragment 1+2   HDL = high density lipoprotein   I/D = insertion/deletion   PCR = polymerase chain reaction   vWF = von Willebrand factor

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