Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in patients with heart failure with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. To address the need for better diagnostics, the authors sought to characterize RV myocyte contractile depression in HFrEF-PH, identify those components reflected by clinical RV indices, and uncover underlying biophysical mechanisms.
X-ray diffraction and myosin ATP turnover quantification assays show that patients with HFrEF-PH RV dysfunction with depressed isometric tension have reduced on state and disordered-relaxed (DRX) myosin; moreover, increasing the proportion of DRX myosin rescues the RV failure myocyte phenotype, whereas depressing DRX induces it. These results show, for the first time, that reduced basal DRX (on state) myosin contributes to a heart failure phenotype. HFrEF-PH RV myocytes exhibit blunted stretch-mediated recruitment of myosin from its super-relaxed to its DRX state, in association with depressed length-dependent active stiffness, a key contributor to Frank-Starling reserve. Although there are many RV myocyte contractile deficits in HFrEF-PH, commonly used clinical indices only detect reduced isometric calcium-stimulated force, which is related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients. Direct sarcomere-acting drugs that augment the basal proportion of DRX myosin or improve the recruitment of DRX myosin under loaded stressed states should help restore RV contractile reserve in these patients.
See: Vivek Jani, M. Imran Aslam, Axel J. Fenwick, Weikang Ma, Henry Gong, Gregory Milburn, Devin Nissen, Ilton M. Cubero Salazar, Olivia Hanselman, Monica Mukherjee, Marc K. Halushka, Kenneth B. Margulies, Kenneth S. Campbell, Thomas C. Irving, David A. Kass, and Steven Hsu,. Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure With Pulmonary Hypertension. Circulation. 2023 147(25):1919-1932. DOI: 10.1161/CIRCULATIONAHA.123.064717. PMCID: PMC10270283