LAUSR

Elevated resting heart rate (HR) is an established marker of adverse cardiovascular (CV) outcomes in a wide variety of patient populations. Several epidemiological, observational and interventional studies have demonstrated that not only elevated resting HR is associated with increased risk of mortality 1–6 but also that reducing it through different approaches results in improved clinical outcomes. Among various cardiac conditions, chronic heart failure (HF) [for the purpose of this discussion, term HF is used to imply HF with reduced left ventricular (LV) ejection fraction] best exemplifies the association between elevated resting HR and increased mortality. HF is a complex clinical syndrome characterized by a diverse array of cardiac structural and functional abnormalities. Neuro-endocrine system, comprising the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system, plays a crucial role in the pathophysiology of HF. Activation of SNS clinically manifests as increased resting HR, which, at least during the initial period, serves as an important compensatory mechanism to maintain cardiac output in the presence of compromised cardiac pump function. However, when sustained, the persistent activation of SNS with persistently elevated HR results in several deleterious effects on cardiac homeostasis which eventually culminate into increased risk for HF hospitalization and mortality. Elevated HR is not merely a manifestation of SNS activation, it also contributes to myocardial injury, thus initiating a vicious cycle. The mechanisms underlying this deleterious impact includeincreased myocardial oxygen demand, reduced diastolic duration with impaired coronary perfusion, downregulation of b-adrenergic receptors with suppressed signal transductions, impaired intracellular calcium handling and excitation–contraction coupling mechanisms, accumulation of oxygen free radicals, etc. Given the role of SNS activation in the pathogenesis of HF, its suppression with beta-blockers has been one of the most important therapeutic strategies in the management of HF. Several large-scale trials have demonstrated that in patients with HF, addition of a beta-blocker to background therapy significantly reduces all-cause and CV mortality. Unfortunately, despite the strong evidence supporting their efficacy, beta-blockers are often underused in HF as has been reported not only in observational studies in routine clinical practice but also in large clinical trials. A substantial proportion of patients are unable to tolerate target dosages of beta-blockers due to their undesirable hemodynamic effects. Moreover, optimal up-titration of beta-