Compensated Cardiomyocyte Ca2+ Homeostasis in a Rat Model of Diastolic Heart Failure

Abstract

In approximately half of heart failure patients, systolic function is near normal while diastolic function is impaired. This condition, called diastolic heart failure (DHF), or heart failure with preserved ejection fraction (HFPEF), has been reported to result from reduced passive distensibility of the ventricle, which impairs filling. However, the contribution of altered Ca2+ handling to impaired cardiomyocyte relaxation in this condition remains largely uninvestigated. We examined this issue in a rat model of DHF following aortic stenosis. 6 weeks after aortic banding, cardiac function was characterized by echocardiography, and rats exhibiting systolic heart failure (left atrial diameter >5mm, left ventricular dilation and reduced fractional shortening) were excluded. Echo Doppler measurements revealed decreased peak early diastolic tissue velocity in DHF rats compared to sham-operated controls (64±5 vs 85±5 mm/s, P<0.05). Both heart and lung weights were increased in DHF animals, indicating hypertrophy and congestion. In isolated cardiomyocytes, Ca2+ transients recorded by whole-cell fluorescence (fluo 4-AM) during field stimulation were of larger magnitude in DHF than control cells, across a range of frequencies (0.5-6 Hz). Ca2+ transients also decayed more rapidly in DHF, and at high frequencies exhibited elevated SR content and a smaller increase in diastolic [Ca2+]. Such augmentation of Ca2+ homeostasis was consistent with an increase in both sarcoplasmic reticulum Ca2+ reuptake and Ca2+ extrusion in DHF cells. Confocal imaging of cells stained with di-8-ANEPPs indicated maintained t-tubule organization, consistent with an unaltered time to peak of the Ca2+ transients. Thus, contrary to impaired Ca2+ homeostasis widely reported in systolic heart failure, our results suggest that DHF develops despite improved Ca2+ handling. We postulate that other alterations such as increased passive ventricular stiffness or increased myofilament Ca2+ sensitivity must impair diastolic function in this condition.