Abstract 15182: Recruiting Super-Relaxed Myosin to Restore Contractility in Human Right Heart Failure

Abstract

Intro: Right ventricular (RV) dysfunction worsens outcomes in pulmonary hypertension (PH) due to heart failure with reduced ejection fraction (HF), yet underlying mechanisms are unknown. We previously reported RV myofilament max calcium-activated tension (T max ) is reduced in human PH-HF. Here, we reveal that this decline is due to more myosin heads in the super-relaxed (SRX) state which lack force-production due to low ATP turnover. Methods: Frozen RV myocardium from 25 PH-HF and 9 control patients were permeabilized and myocyte mechanics and small angle X-ray diffraction measured. Results: RV T max (16±4 vs. 23±3 mN/mm 2 , p<1x10 -15 ) and peak power (0.06±0.01 vs. 0.11±0.03, p=7.9x10 -5 ) were 50% lower in HF. Unsupervised machine learning (infinite mixture Dirichlet process) using mechanics identified two HF subgroups distinguished by RV T max : Group 1 with slightly reduced T max (19±1 mN/mm 2 , p=3.8x10 -6 ) and Group 2 with 40% reduced T max (14±3 mN/mm 2 , p<1x10 -15 ), with Group 2 exhibiting clinically overt RV failure vs. Group 1 (right atrial pressure, RAP 14±6 vs. 9±4, p=0.01; RAP/pulmonary capillary wedge ratio 0.7±0.3 vs. 0.4±0.2, p=0.047). To test if low RV T max was associated with more SRX myosin, X-ray diffraction patterns from RV myofibers were used to determine the equatorial intensity ratio (I 1,1 /I 1,0 ), an indicator of myosin proximity to the thick filament backbone. The ratio was lower (more SRX), which was associated with reduced myosin ATP turnover in Group 2 vs. both 1 (p=9.0x10 -7 ) and controls (p=1.8x10 -9 ). We then tested the effect of SRX on T max by perturbing the proportion of SRX myosin using mavacamten (M), a myosin inhibitor that stabilizes the SRX state, and deoxy-ATP (dATP), a nucleotide that destabilizes SRX. In group 2, dATP augmented T max by 30% (p=0.0002) while M had no effect (p=0.1); meanwhile in group 1, M suppressed T max by 30% (p=0.0002) while dATP had no effect (p=0.9). Finally, a myosin activator EMD-57033, which increases probability of actin-myosin binding, augmented T max (correlation between ΔSRX-ΔT max r=-0.55, p=0.01). Conclusion: We find increased SRX myosin contributes to RV myofilament and chamber-level failure in PH-HF. Small molecules that recruit SRX myosin may have therapeutic benefit in patients with RV dysfunction.