Colchicine improves the diastolic performance in HFpEF myocardium

Heart failure with preserved ejection fraction (HFpEF) arises from increased ventricular stiffening and impaired relaxation with cardiac microtubules recently identified as a source of both. This has motivated the development of cardiac-specific microtubule modifying treatments for heart failure as more common microtubule-depolymerizing agents such as colchicine have limited clinical tolerance from systemic effects. Nevertheless, low-dose colchicine is a commonly prescribed anti-inflammatory compound and has recently shown positive indication for the treatment of atherosclerotic cardiovascular disease and HFpEF. This raises the question whether colchicine directly improves myocardial performance. Herein we leverage recent advancements in living myocardial slices via a preparation that recapitulates physiological loading and the complexity of diastole to determine if colchicine can directly improve diastolic performance in a rat model of cardiometabolic diastolic heart disease. We found that working slices from obese rats maintained the hallmark mechanical features of HFpEF: namely, preserved force generation and work output, diastolic dysfunction by reduced E/A ratio and an inability to maintain work output at elevated contractile frequencies. Treatment with colchicine had insignificant effects on isometric twitch force but significantly enhanced ejection and filling efficiencies by restoring early filling performance. These data are therefore consistent with colchicine improving the mechanical properties of the myocardium through microtubule destabilization thereby enhancing the efficiency of myocardial movement without significantly altering force generation.