Heart rate: A global target for cardiovascular disease and therapy along the cardiovascular disease continuum.

Custodis F, Reil JC, Laufs U, Böhm M
J Cardiol. 2013 Jun 24. doi: 10.1016/j.jjcc.2013.02.018. [Epub ahead of print]

Background

Heart rate has developed from an ordinary clinical variable into a relevant cardiovascular (CV) risk marker. Heart rate affects basically all stages of the CV continuum and is therefore a goal of therapy in CV prevention and disease. This article aims to shed light on the impact of heart rate on the different entities of the CV continuum and how a targeted reduction of heart rate may prevent CV events.

Resting heart rate and outcome in patients with risk factors

The Framingham study showed that CV mortality increased progressively with resting heart rate in a population without prior CV disease. Also in patients with hypertension, an association between higher heart rates and increases in blood pressure was seen. Analysis of the Framingham cohort showed that the rate of CV complications and total mortality doubled when heart rate increased by 40 beats/minute.
Increased heart rate appears to predict microalbuminuria in hypertensive patients, which appears to be a marker of vascular injury and increases cardiovascular risk.

Heart rate promotes atherosclerosis

Several lines of evidence suggest that sustained elevation of heart rate, irrespective of the underlying trigger, contributes to the pathogenesis of vascular disease. Animal studies showed that an accelerated heart rate was associated with vascular oxidative stress, endothelial dysfunction, acceleration of atherogenesis and vascular stiffness. In animals, heart rate reduction could reduce atherosclerosis. In humans, however, it is less clear whether heart rate reduction improves endothelial function, despite established links between accelerated resting heart rate and systemic inflammation and markers of endothelial dysfunction.
Vascular integrity may also be affected by local hemodynamic characteristics defined by heart rate such as endothelial shear stress or cyclic tensile stress. Disturbances therein may synergistically promote atherogenesis and vascular stiffness. However, experimental evidence for the effects of rate-dependent changes of the local hemodynamic environment remains sparse.

Heart rate in coronary heart disease and myocardial infarctions

Since resting heart rate is of prognostic value for morbidity and mortality in people without CV disease, it is also of importance for people with established CAD. Indeed, patients with CAD and left ventricular systolic dysfunction and a resting heart rate of >70 bpm had increased CV mortality and coronary vascular events. Since heart rate is a predictor for instability of coronary plaque, disruption of the coronary plaque may be the underlying cause of these effects.
Heart rate is a major determinant of myocardial oxygen demand and coronary blood flow. Heart rate affects both sides of the oxygen balance, and in CAD supply is decreased and demand in increased, thus leading to myocardial ischemia and subsequent angina. Heart rate reduction by beta-blockers as become the cornerstone of symptomatic (anti-anginal) treatment of CAD patients. However, beta-blocker use does not always give satisfying results. The new inhibitor of I(f) currents in the sinoatrial node ivabradine may be an alternative approach to reduce heart rate.

Resting heart rate and outcome in heart failure

Heart rate may directly affect myocardial performance through its effects on oxygen consumption, diastolic filling and coronary perfusion, impairment of relaxation and pro-arrhythmic effects. Several trials in heart failure patients showed that high heart rate at rest contributes to poor survival and represents a negative prognostic factor. Meta-analyses on the effects of beta-blockers suggest that the survival benefits are mostly due to the magnitude of heart rate reduction, rather than with the dose of beta-blocker given. This inspired other researchers to study the effects of selective heart rate reduction. Although treatment with ivabradine to obtain selective heart rate reduction had some beneficial effects in patients with stable angina en left ventricular dysfunction, a clear prognostic benefit could not be established. Heart rate is a modifiable risk factor in patients with heart failure, although the primary cardiovascular outcomes were not improved.
Current ESC guidelines acknowledge the prognostic relevance of heart rate and consider ivabradine as add-on therapy in patients with severe left ventricular dysfunction and a heart rate >70 bpm despite treatment with a beta-blocker.

Resting heart rate and neurological outcomes

It is unclear whether the intrinsic resting heart rate is also predictive for neurological disease and ischemic stroke. Since heart rate affects vascular function and phenotype, it is reasonable to consider the effect of heart rate on the cerebral vasculature and circulation. Studies in mice showed that selective heart rate reduction restored endothelial function and protected against ischemic brain injury via reduction of stroke size. Preliminary findings in humans suggest that heart rate might be a mediator of cerebrovascular effects. Heart rate may thus be a novel intervention target for improvement in cerebrovascular function, specifically after ischemic events.

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