Abstract P505: Rv Sarcomeres From Lv-hfref Patients With Low Papi Have Abnormal Rv Thick Filament Structure

Abstract

Patients with left heart failure and reduced ejection fraction (HFrEF) have variable RV failure that, if present, drastically worsens outcomes. In a cohort of 21 HFrEF patients from two hospital sites, we have previously shown (Aslam et al, Eur J HF; 2020: volume 23, pages 339-341) that like global function, RV myocyte maximum calcium-activated myocyte tension (T max ) is quite variable (COV 27%). To determine if a relationship between RV myocyte function and indices of RV chamber function exists, we trained a random forest classifier based on 41 clinical variables, including hemodynamic, laboratory, and echocardiographic data, and queried the importance of each. This revealed that the most predictive model for reduced T max was based on the pulmonary artery pulsatility index (PAPi), an established clinical index of RV failure. To gain insight into potential mechanisms for depressed T max in HFrEF patients with a low PAPi, we obtained small angle x-ray diffraction patterns in 5 HFrEF patients with depressed PAPi and T max and compared this to 5 non-failing (NF) controls. The equatorial intensity ratio I(1,1)/I(1,0) was reduced in low T max RV muscle fibers vs. controls (0.250.06 vs. 0.180.02, P<0.0001), suggesting myosin heads are more associated with the thick filament backbone. In meridional reflections, we find a significant decrease in M3 band spacing (14.340.03 nm in NF vs. 14.300.01 nm in HFrEF; P=0.0013) suggesting more myosin heads are in the “OFF” configuration. The latter may underly tension reduction in RV myocytes from failing RV HFrEF patients. Ongoing studies will examine these structural changes in HFrEF patients with a broader range of PAPi and T max to test if this association applies. These findings focus attention on thick filament structural and configuration abnormalities as potential culprits underlying RV disease in HFrEF. Further studies using novel sarcomere enhancers will test if these changes can be remedied, and if so, in which patients.