Genetic Silencing of Pacemaker Cells: Local Intervention With Global Implications

H eart failure is a major public health epidemic that claims hundreds of thousands of lives annually in the United States alone. Despite important advances in the management and prevention of many cardiovascular disorders, the incidence and prevalence of heart failure are increasing with the aging of the population. Existing treatments for patients with heart failure are far from being optimal and are often associated with proarrhythmic activity and risk of sudden cardiac death. Therefore, the search for novel, effective, and safe therapeutic options for these patients represents a critical area of unmet need for this country and the rest of the world. In an elegant proof of concept study published in this issue of the Journal of the American Heart Association (JAHA), Lugenbiel et al1 describe a novel gene-based approach for potentially treating heart failure by targeting discrete cell populations within the sino-atrial node. Several lines of evidence derived from experimental and clinical studies indicate that a controlled heart rate is an important target for heart failure therapy.2 In fact, a strong link between average heart rate and cardiovascular morbidity in patients with heart failure has been documented. In clinical trials the ability of a given heart failure treatment to reduce overall mortality is, in some cases, predicted by its heart rate lowering efficacy. Moreover, a causative relation between elevated heart rate and heart failure is epitomized by the fact that sustained tachycardia, in the absence of other risk factors or insults, is a well-established mechanism of ventricular remodeling that culminates in the onset of heart failure.3 In the experimental laboratory, numerous groups have exploited the relation between elevated heart rate and left ventricular