Abstract
Introduction: Heart failure with preserved ejection fraction (HFpEF) is characterized in part by increased left ventricular (LV) stiffness and left atrial (LA) remodeling. LA myopathy in HFpEF is associated with poor clinical outcomes. In the LV, the magnitude of post-translational detyrosination of α-tubulin, regulated by vasohibins (VASH1/2), contributes to LV stiffness. However, the role of tubulin detyrosination in the LA is currently unknown. To this end, we assessed the extent of LA myopathy in the ZSF rat model of HFpEF, and assessed the effect of acute VASH inhibition on LA remodeling. Methods: ZSF obese rats with diastolic dysfunction were compared alongside ZSF lean hypertensive-only rats and Wistar Kyoto rats (WKY). Rats were aged to 30 weeks, then received a tail vein injection of VASH inhibitor or vehicle, followed by echocardiography. Following a second injection, hearts were excised, and LA and LV were separated for downstream protein analysis. Results : ZSF obese rats develop hallmark features of HFpEF including preserved systolic function, left ventricular hypertrophy, and slowed relaxation compared to lean and WKY. ZSF obese animals demonstrated significant LA myopathy, including increased LA area, reduced LA emptying fraction, and reduced LA strain. Acute VASH inhibition led to trends towards normalization of LA kinetics. There were no significant differences in levels of detyrosinated tubulin between vehicle and VASH inhibition groups in the LA, though there was a significant reduction of detyrosinated tubulin in the LV by Western Blot (detyrosinated tubulin / GAPDH relative quantity Vehicle: 1.5±0.2 vs. VASH inhibitor 0.5±0.1; p<0.05). Conclusions: Acute VASH inhibition improves LA kinetics in ZSF obese rats secondary to reductions in detyrosinated tubulin in the LV. Future studies employing sustained reductions of detyrosinated tubulin may lead to better understanding of LA-LV interactions in the pathogenesis of LA myopathy in HFpEF.
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