Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin
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.
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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.
References (39)
- et al.
Non invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis
Lancet
(1992) - et al.
Vascular function in the forearm of hypercholesterolemic patients off and on lipid-lowering medication
Lancet
(1995) - et al.
Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men
Lancet
(1998) - et al.
New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart disease
Atherosclerosis
(1997) - et al.
Circulating adhesion molecules in disease
Immunol. Today
(1993) - et al.
Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics
Am. J. Cardiol.
(1993) - et al.
Statins do more than just lower cholesterol
Lancet
(1996) - et al.
The role of endothelial cell adhesion molecules in the development of atherosclerosis
Cardiovasc. Pathol.
(1992) - et al.
Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?
Atherosclerosis
(2000) - et al.
Development of coronary heart disease in familial hypercholesterolemia
Circulation
(1989)