Inhibition Of Ca2+Entry Mode Of Na+/Ca2+Exchanger Improves Survival Rate Of Rat Model For Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFPEF) has a poor prognosis as well as heart failure with reduced ejection fraction and its therapeutic strategy has not been established. Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of HFPEF. Plasma level of digitalis-like factors (DLFs) is increased in about a half of patients with hypertension, a principal underlying cardiovascular disease of HFPEF. DLFs inhibit ion-pumping function of Na+/K+-ATPase and activate the Ca2+ entry mode of Na+/Ca2+ exchanger (NCX). It is also known that DLFs promote collagen production in fibroblasts. Objective: The objective of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in preventing LV fibrosis and the development of HFPEF. Methods and Results: (1) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24-hour urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (2) Continuous administration of ouabain for 14 weeks developed LV fibrosis without the changes in blood pressure in Sprague-Dawley rats irrespective of NaCl loading. (3) Ouabain elevated intracellular Ca2+ concentration through the entry of extracellular Ca2+, increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced 3H-proline incorporation in cardiac fibroblast, and SEA0400, the inhibitor of the NCX entry mode, suppressed these in vitro effects of ouabain. (4) In the HFPEF model, chronic administration of SEA0400 at subdepressor dose prevented the elevation of LV filling pressure and improved the survival rate in association with the attenuation of LV fibrosis and stiffening. Conclusion: DLFs and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.