Elsevier

Atherosclerosis

Volume 157, Issue 2, August 2001, Pages 423-429
Atherosclerosis

Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin

https://doi.org/10.1016/S0021-9150(00)00733-4Get rights and content

Abstract

Patients with heterozygous familial hypercholesterolemia (hFH) are at very high risk for premature coronary heart disease. In the last decade, treatment with statins has reduced cardiovascular mortality in these patients. The aim of this study was to analyze arterial endothelial function assessed as flow-mediated dilatation (FMD) and soluble E-selectin (sE-selectin) levels in patients with hFH under a long-term lipid-lowering treatment. Twenty-five patients who completed the study received a dose of simvastatin to achieve a treatment goal of at least 30% reduction in serum low-density lipoprotein (LDL)-cholesterol (LDL-C) for 52 weeks. Functional and biochemical measurements were taken at entry, and at week 12 and 52 of treatment. FMD was measured by vascular ultrasound of the brachial artery. sE-selectin, tumor necrosis factor-α (TNF-α) and interleukin-6 were determined by enzyme linked immunosorbent assay (ELISA). LDL-C levels were significantly reduced by treatment at week 12 and maintained at week 52 (reduction vs. baseline, 44±12 and 43±11%, respectively, P<0.0001). A significant improvement in endothelial function, measured as FMD (baseline, 4.7±6.2%; 12 weeks, 12.3±5.9%; 52 weeks, 9.7±4.7%; P<0.005) and a reduction in sE-selectin levels (baseline, 16.2±3.4 ng/ml; 12 weeks, 11.0±3.2 ng/ml; 52 weeks, 12.3±4.2 ng/ml; P<0.01) were observed. Endothelial-independent relaxation induced by nitroglycerin was not modified during the study. Our results indicate that a long-term treatment with simvastatin produced a sustained beneficial effect in endothelial function in hFH patients.

Introduction

Heterozygous familial hypercholesterolemia (hFH), a frequent autosomal dominant disorder, causes very high plasma cholesterol levels and high risk for premature development of coronary artery disease (CAD) [1]. The relative risk of fatal CAD is increased by nearly 100-fold in young adults with hFH compared with the normal population [2]. Clinical management of these patients has been based on evidences from clinical trials of lipid-lowering therapy conducted in patients with non-hFH hypercholesterolemia [3], [4], [5], [6], [7].

It has been demonstrated that hypercholesterolemia is associated with an impaired endothelial function in human coronary and systemic arteries with or without atherosclerotic disease [8], [9], [10], possibly related to a reduced nitric oxide (NO) vasodilator effect [11]. Additionally, cholesterol reduction improves both coronary and systemic endothelial functions [12], [13], [14]. This effect can occur rapidly after 4 weeks of pharmacological therapy [15] and immediately after single low-density lipoprotein (LDL)-apheresis that dramatically reduces LDL-cholesterol (LDL-C) levels [16].

Lipid-lowering therapy may also influence endothelial function by normalizing its interaction with leukocytes through regulation of adhesion molecules. Plasma levels of the soluble fraction of some cell adhesion molecules (sCAM) have been reported either increased or unmodified by hypercholesterolemia and CAD [17], [18], [19], [20], [21], while an aggressive lipid-lowering treatment has shown a reduction of sCAM levels, suggesting a direct role for cholesterol in its regulation [17], [22]. Among them, E-selectin, that is involved in the rolling and adhesion on leukocytes, is expressed only by activated endothelial cells [23], and it is considered that the increase of a soluble form of E-selectin (sE-selectin) reflects endothelial expression of this CAM [24], [25].

To our knowledge, no study has measured the long-term impact of lipid-lowering treatment on both flow-mediated dilatation (FMD) and sE-selectin levels in hFH patients, that usually require high doses of medication to reach the LDL-C reduction goal. Our hypothesis is that the reduction in LDL-C levels may produce a sustained benefit in arterial endothelial function in patients with hFH. The objective of our study was to analyze whether in hFH patients, without clinical manifestations of atherosclerosis as yet, long-term treatment with high doses of simvastatin would lead to an improvement in FMD and a reduction of sE-selectin levels.

Section snippets

Patients and study design

Thirty patients with hFH were recruited for the study, 19 women (mean age 50±11-years old), and 11 males (mean age 45±8-years old). Diagnosis of hFH was based on the criteria previously reported by Williams et al. [26]. Ten patients were current smokers (five women and five males) during the study. Eight patients consumed alcohol (less than 30 g daily). None of the patients had a history of cardiovascular disease, diabetes mellitus or hypertension. All had normal electrocardiograms at the

Clinical evaluation

Simvastatin was well tolerated and drug compliance was over 90%. None of the patients required drug withdrawal. Twelve patients received a daily dosage of 40 mg of simvastatin, and the other 13 patients received 80 mg of simvastatin to produce a reduction in LDL-C of at least 30%. Only one patient receiving 80 mg of simvastatin presented a mild and transitory increase in ALT levels (1.5× upper limit of normal) and did not require suspension of medication. The BMI was unmodified during the study.

Discussion

The present study showed that the endothelial function in hFH patients, without clinical manifestation of atherosclerotic disease, improves with long-term treatment with simvastatin. hFH is a frequent inherited disease, characterized by very high LDL-C plasma levels and an increased risk for premature CAD. It is well known that hFH patients require early and aggressive treatment to control their cholesterol levels. In this study, we show that a sustained beneficial effect on endothelial

Acknowledgements

This work has been supported by funds provided in part by FEDER 2FD1997-2142-CO3, by MSD-Spain, by Lacer SA, Barcelona, Spain, by Fundación Española de Hipercolesterolemia Familiar, and by the Fundación de Investigación Cardiovascular-Catalana Occidente. We thank S. Morató for her secretarial help. We are indebted to the participants in the study for their cooperation and enthusiasm.

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