Mechanistic Relevance of Ventricular Arrhythmias in Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is increasing at an alarming rate worldwide, with limited effective therapeutic interventions in patients. Sudden cardiac death (SCD) and ventricular arrhythmias present substantial risks for the prognosis of these patients. Obesity is a risk factor for HFpEF and life-threatening arrhythmias. Obesity and its associated metabolic dysregulation, leading to metabolic syndrome, are an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese, leading to an enhanced risk of incidence and mortality due to cardiovascular disease (CVD). Obesity predisposes patients to atrial fibrillation and ventricular and supraventricular arrhythmias-conditions that are caused by dysfunction in the electrical activity of the heart. To date, current therapeutic options for the cardiomyopathy of obesity are limited, suggesting that there is considerable room for the development of therapeutic interventions with novel mechanisms of action that will help normalize sinus rhythms in obese patients. Emerging candidates for modulation by obesity are cardiac ion channels and Ca-handling proteins. However, the underlying molecular mechanisms of the impact of obesity on these channels and Ca-handling proteins remain incompletely understood. Obesity is marked by the accumulation of adipose tissue, which is associated with a variety of adverse adaptations, including dyslipidemia (or abnormal systemic levels of free fatty acids), increased secretion of proinflammatory cytokines, fibrosis, hyperglycemia, and insulin resistance, which cause electrical remodeling and, thus, predispose patients to arrhythmias. Furthermore, adipose tissue is also associated with the accumulation of subcutaneous and visceral fat, which is marked by distinct signaling mechanisms. Thus, there may also be functional differences in the effects of the regional distribution of fat deposits on ion channel/Ca-handling protein expression. Evaluating alterations in their functional expression in obesity will lead to progress in the knowledge of the mechanisms responsible for obesity-related arrhythmias. These advances are likely to reveal new targets for pharmacological modulation. Understanding how obesity and related mechanisms lead to cardiac electrical remodeling is likely to have a significant medical and economic impact. Nevertheless, substantial knowledge gaps remain regarding HFpEF treatment, requiring further investigations to identify potential therapeutic targets. The objective of this study is to review cardiac ion channel/Ca-handling protein remodeling in the predisposition to metabolic HFpEF and arrhythmias. This review further highlights interleukin-6 (IL-6) as a potential target, cardiac bridging integrator 1 (cBIN1) as a promising gene therapy agent, and leukotriene B4 (LTB4) as an underappreciated pathway in future HFpEF management.

Keywords: arrhythmias; diabetes; heart failure; ion channel remodeling; obesity; sudden cardiac death; ventricular.

Figure 1

Cartoon illustration showing hypothesized obesity-linked channelopathies leading to pathological APD prolongation, LQT prolongation, ventricular arrhythmias, and ultimately, increased risk of sudden cardiac death in obese patients with HFpEF. We speculate that overactivated obesity-linked heightened proinflammation—possibly through individual or multiple combinations of IL-6 trans-signaling or LTB4 pathways—contributes prominently to the pathogenesis of HFpEF. The exact cellular proarrhythmic effects of IL-6 and LTB4 involved are poorly understood. We suspect that overactivated IL-6- and LTB4-signaling-linked remodeling processes may occur through altered gene and protein expressions of ion channel subunits and biophysical defects (subunit trafficking and/or gating defects). Whether and how I_Na and I_K1 are modulated in obesity-linked IL-6 and LTB4 signaling or HFpEF is unknown. We further speculate that understanding the contributions of distinct cellular arrhythmia triggers that are sensitive to obesity/lipotoxic mechanisms is important for interpreting the mechanistic bases of how obesity channelopathies promote life-threatening VA/SCD risk and inform targeted anti-arrhythmia therapy in patients. HFpEF may promote structural changes in the organizational integrity of Ca-handling proteins (including cBin-1, SERCA, and PLB) and contribute to VA/SCD risk. Interestingly, there is a growing interest in the potential beneficial cardiovascular impact of cBIN1 gene therapy in preserving the functional and structural integrity of Ca-handling mechanisms in HF, with significant implications for HFpEF. The modulation of ventricular ion channels by cBIN-1 is currently unknown, suggesting that there is significant room for improving the current therapeutic interventions in obese HF/HFpEF patients.