Heart rate as a risk factor for atherosclerosis and cardiovascular mortality: the effect of antihypertensive drugs.

The aim of this review is to highlight the importance of heart rate (HR) as a risk factor for cardiovascular disease, and to discuss the classes of drugs which can be potentially useful in clinical conditions in which an elevated HR may be present. Numerous studies have shown that high resting HR is prospectively related to the development of atherosclerosis and of cardiovascular events. This relationship was independent of other major risk factors for atherosclerosis and was observed in the general population, in elderly people, in hypertensive cohorts and in patients with myocardial infarction or heart failure. The clustering of several risk factors in individuals with fast heart rate may explain why cardiovascular morbidity is higher in individuals with tachycardia. Sympathetic overactivity seems to be responsible for both the increase in HR, blood pressure and the metabolic abnormalities. Experimental studies in monkeys have shown that HR can also exert a direct atherogenetic action on the arteries through increased wall stress. Moreover, tachycardia can favour the occurrence of ventricular arrhythmias and sudden death. Reduction of HR appears as an additional goal of antihypertensive therapy. If fast HR in hypertension is a marker of increased sympathetic tone, agents which decrease HR through a decline of sympathetic outflow should be particularly efficacious. Beta-blockers retard the development of coronary atherosclerosis in cholesterol-fed monkeys and have proven to be beneficial in patients with myocardial infarction or with heart failure, but their efficacy appear limited in hypertension, probably on account of their unfavourable metabolic profile. Phenylalkylamines are devoid of this untoward effect, and seem to act also through inhibition of sympathetic discharge from the CNS. Mibefradil, a more recent calcium antagonist that selectively blocks voltage-dependent T-type calcium channels decreases HR without affecting left ventricular contractility. New drugs with agonistic properties at the I1-imidazoline receptors of the rostral ventrolateral medulla are effective in reducing blood pressure and HR by inhibiting the sympathetic outflow and improved metabolic parameters in obese or fructose-fed rats. The goal of antihypertensive therapy in the future will be to prevent or reverse those functional abnormalities which accompany the hypertensive condition. In patients with tachycardia the reduction of HR appears a desirable additional goal of therapy.