Distinct features of calcium handling and ß-adrenergic sensitivity in heart failure with preserved versus reduced ejection fraction.

KEY POINTS: Heart failure (HF), the leading cause of death in developed countries, occurs in the setting of reduced (HFrEF) or preserved (HFpEF) ejection fraction. Unlike HFrEF, there are no effective treatments for HFpEF, which accounts for ∼50% of heart failure. Abnormal intracellular calcium dynamics in cardiomyocytes have major implications for contractility and rhythm, but compared to HFrEF, very little is known about calcium cycling in HFpEF. We used rat models of HFpEF and HFrEF to reveal distinct differences in intracellular calcium regulation and excitation-contraction (EC) coupling. While HFrEF is characterized by defective EC coupling at baseline, HFpEF exhibits enhanced coupling fidelity, further aggravated by a reduction in ß-adrenergic sensitivity. These differences in EC coupling and ß-adrenergic sensitivity may help explain why therapies that work in HFrEF are ineffective in HFpEF. ABSTRACT: Heart failure with reduced or preserved ejection fraction (respectively, HFrEF and HFpEF) is the leading cause of death in developed countries. Although numerous therapies improve outcomes in HFrEF, there are no effective treatments for HFpEF. We studied phenotypically verified rat models of HFrEF and HFpEF to compare excitation-contraction (EC) coupling and protein expression in these two forms of heart failure. Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF. Impaired diastolic relaxation and preserved ejection fraction were confirmed in each animal echocardiographically, and clinical signs of heart failure were documented. To generate HFrEF, Sprague-Dawley (SD) rats underwent permanent left anterior descending coronary artery ligation which, 8-10 weeks later, led to systolic dysfunction (verified echocardiographically) and clinical signs of heart failure. Calcium (Ca2+ ) transients were measured in isolated cardiomyocytes under field stimulation or patch clamp. Ultra-high-speed laser scanning confocal imaging captured Ca2+ sparks evoked by voltage steps. Western blotting and PCR were used to assay changes in EC coupling protein and RNA expression. Cardiomyocytes from rats with HFrEF exhibited impaired EC coupling, including decreased Ca2+ transient (CaT) amplitude and defective couplon recruitment, associated with transverse (t)-tubule disruption. In stark contrast, HFpEF cardiomyocytes showed saturated EC coupling (increased ICa , high probability of couplon recruitment with greater Ca2+ release synchrony, increased CaT) and preserved t-tubule integrity. ß-Adrenergic stimulation of HFpEF myocytes with isoprenaline (isoproterenol) failed to elicit robust increases in ICa or CaT and relaxation kinetics. Fundamental differences in EC coupling distinguish HFrEF from HFpEF.

Reverse electrical remodeling in rats with heart failure and preserved ejection fraction.

Sudden death is the most common mode of exodus in patients with heart failure and preserved ejection fraction (HFpEF). Cardiosphere-derived cells (CDCs) reduce inflammation and fibrosis in a rat model of HFpEF, improving diastolic function and prolonging survival. We tested the hypothesis that CDCs decrease ventricular arrhythmias (VAs) and thereby possibly contribute to prolonged survival. Dahl salt-sensitive rats were fed a high-salt diet to induce HFpEF. Allogeneic rat CDCs (or phosphate-buffered saline as placebo) were injected in rats with echo-verified HFpEF. CDC-injected HFpEF rats were less prone to VA induction by programmed electrical stimulation. Action potential duration (APD) was shortened, and APD homogeneity was increased by CDC injection. Transient outward potassium current density was upregulated in cardiomyocytes from CDC rats relative to placebo, as were the underlying transcript (Kcnd3) and protein (Kv4.3) levels. Fibrosis was attenuated in CDC-treated hearts, and survival was increased. Sudden death risk also trended down, albeit nonsignificantly. CDC therapy decreased VA in HFpEF rats by shortening APD, improving APD homogeneity, and decreasing fibrosis. Unlike other stem/progenitor cells, which often exacerbate arrhythmias, CDCs reverse electrical remodeling and suppress arrhythmogenesis in HFpEF.