Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions.

Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy. A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (↑PVR + ↓CPA + fibrosis) and decreasing Fmax (↑PVR + ↓CPA + fibrosis + ↓Fmax). A61603 (A6), a selective α-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH. Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (↑PVR + ↓CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (↑PVR + ↓PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (↑PVR + ↓PAC + fibrosis + ↓Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload. Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure.