Original Abstract

Obesity and heart failure with reduced ejection fraction (HFrEF) frequently coexist. In fact, most patients with HFrEF are overweight or have concomitant obesity. However, despite this high prevalence, obesity in HFrEF has received limited attention as most recent reviews have concentrated on heart failure broadly or on the heart failure with preserved ejection fraction (HFpEF) phenotype. This limited attention may, in part, be attributed to the stronger and more consistent pathophysiological and epidemiologic associations observed between obesity and HFpEF, whereas the relationship between obesity and HFrEF remains less well characterized. Much of this uncertainty reflects inconsistent findings across studies regarding whether body mass index independently predicts incident HFrEF, given its well-recognized limitations as a surrogate marker of adiposity. These challenges are further compounded by the phenomenon known as the obesity paradox in patients with HFrEF, in which higher body mass index is often associated with better outcomes. Nonetheless, in HFrEF, obesity may be better conceptualized as a modifiable disease amplifier that influences disease progression and clinical trajectory, rather than a primary etiologic driver. Weight loss interventions such as obesity pharmacotherapy have demonstrated safety and efficacy in patients with obesity and HFpEF, where obesity-related pathophysiologic processes including systemic inflammation, neurohormonal activation, local paracrine signaling, and mechanical loading are well-described contributors to disease development. Although the relative contribution of these processes may differ in HFrEF, excess adiposity may still exacerbate disease progression through these pathways, suggesting potential applicability of weight loss interventions in this population. To date, evidence in HFrEF remains limited and is derived largely from non-obesity-focused trials with methodological constraints. Despite the development of several novel weight loss agents, none are being specifically evaluated in patients with HFrEF, limiting understanding of their potential clinical impact in these patients.