Novel Pathomechanisms of Cardiomyocyte Dysfunction in a Model of Heart Failure with Preserved Ejection Fraction

Abstract

AIMS: Heart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na(+) /Ca(2+) exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) with HFpEF. METHODS AND RESULTS: Male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). After 8 and 24 weeks, in vivo (haemodynamics, echocardiography) and in vitro function (LV cardiomyocyte cell shortening (CS), and Ca(2+) transients (CaT)) were determined without and with SEA0400. In a subgroup of rats, SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. NXT resulted in stable compensated CKD and HFpEF [hypertrophied left ventricle, prolonged LV isovolumetric relaxation constant TAU (IVRc TAU), elevated end diastolic pressure (EDP), increased lung weight (pulmonary congestion), and preserved LV systolic function (EF, dP/dt)]. In NXT cardiomyocytes, the amplitude of CS and CaT were unchanged but relaxation and CaT decay were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. NCX forward mode activity (caffeine response) was progressively reduced, while NCX protein expression was up-regulated, suggesting increased NCX reverse mode activity in NXT. SEA0400 acutely improved relaxation in NXT in vivo and in cardiomyocytes and improved cardiac remodelling and diastolic function when given chronically. CONCLUSIONS: This model of renal HFpEF is associated with slowed relaxation of LV cardiomyocytes. Treatment with SEA0400 improved cardiomyocyte function, remodelling, and HFpEF.