Clinical Parameters of Right Ventricular Dysfunction Predict Depressed RV Myofilament Function

Abstract

Purpose Right ventricular dysfunction (RVD) in heart failure with reduced ejection fraction (HFrEF) drives morbidity and mortality. Clinical hemodynamic parameters such as elevated right atrial pressure to pulmonary capillary wedge pressure ratio (RAP/PCWP) and low pulmonary artery pulsatility index (PAPi) are widely used to identify patients with significant RVD. However, their correspondence to intrinsic RVD is unknown. We therefore tested whether RAP/PCWP or PAPi are associated with sarcomere and molecular dysfunction. Methods Human RV tissue was obtained from explanted hearts of HFrEF patients and controls, along with corresponding demographic/hemodynamic data. Skinned myocytes were isolated and affixed to a force-length transducer to assess RV myofilament force-calcium curves. Protein was extracted from tissue and immunoblotting performed. Results Myofilament maximal calcium-activated force (Fmax) generation was significantly diminished in HFrEF patients with RVD (HFrEF-RVD, defined as RA:PCWP > 0.54 and PAPi Conclusion RAP/PCWP and PAPi, used to identify clinical RVD, predict true intrinsic RV sarcomeric dysfunction in human HFrEF, and are associated with a distinct molecular signature. Further work will uncover the RV sarcomeric defects underlying diminished RV hemodynamic performance.