Arrhythmogenic Ca²⁺Signaling in a Metabolic Model of HFpEF

Heart failure with preserved ejection fraction (HFpEF) already represents approximately 50% of all cases of heart failure and its incidence continues to rise. Initially regarded as a disorder of hypertensive left ventricular dysfunction in older adults, HFpEF has emerged as a complex cardiometabolic syndrome in younger adults associated with other co-morbidities such as obesity, decreased insulin sensitivity, dyslipidemia and others. An important part of the high morbidity and mortality associated with HFpEF is a high rate of sudden cardiac death (∼ 25%) and malignant arrhythmias whose underlying mechanisms remain poorly understood. Here we have developed a three 'hit' model of metabolic-stress induced HFpEF in C57BL6/J mice (HFpEF mice) by adding high dietary fructose to the well-established two 'hit' HFpEF model that is based on a high fat diet plus nitric oxide synthase inhibition with L-NAME. Importantly, after 5 months, all HFpEF animals developed premature ventricular contractions (PVCs) and 50% showed episodes of sustained ventricular tachycardia (VT) after low-dose systemic isoproterenol treatment, while none of the control animals developed either PVCs or VT. We report that in isolated cardiac myocytes from HFpEF mice the incidence of spontaneous Ca 2+ release events or Ca 2+ sparks, is increased 9-fold compared to age-matched controls. This massive increase in spontaneous Ca 2+ release from the sarcoplasmic reticulum is reflected in a 7-fold increase in spontaneous Ca 2+ waves in cardiac myocytes from HFpEF mice when compared to controls. Surprisingly, in contrast to the changes documented in intracellular Ca 2+ homeostasis in heart failure with reduced ejection fraction (HFrEF), the diastolic intracellular Ca 2+ concentration ([Ca 2+ ] i ) in cells from HFpEF mice was not increased and stimulated Ca 2+ transients (CaT) had a higher amplitude than control myocytes. Taken together, here we demonstrate for the first time that arrhythmogenic intracellular Ca 2+ signaling likely underlies the malignant ventricular arrhythmias seen in metabolic HFpEF. Our findings also provide direct evidence that the cellular and molecular mechanisms of Ca 2+ based arrhythmogenesis in HFpEF are distinct from the processes known to occur in HFrEF.