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

Abstract

Introduction: 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.Methods: 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 α1A-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH.Results: 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.Conclusion: 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.

Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload

“…The recapitulation of the PAB phenotype in CTL myocytes with ML‐7 treatment, along with a lack of effect of ML‐7 on PAB myocytes, implicates the loss of cMLCK as a factor in the impaired contractility of PAB myocytes. A recent multiscale computation study has shown that impaired myocyte myofilament contractility is the major determinant of RV function in the pressure‐overloaded RV (Philip et al, 2018 ). Our data presented here, together with previous studies showing the importance of myocyte contractility to overall RV function in pressure‐overload and the increased expression level of cMLCK in the right ventricle, make this pathway a very promising target for the treatment of pressure‐overload induced RV hypertrophy and failure.…”

The role of regenerative therapy in the treatment of right ventricular failure: a literature review

“…The relative impact of these individual components and their interdependence on RV ventricular function is not fully understood. Computational modeling identified reduced myocyte contractility as an important cause of ventricular dysfunction in RV pressure overload but attributed little dysfunction to myocardial fibrosis [64]. Currently applied cell-based strategies to restore RV function are largely focused on exploiting paracrine effects with little evidence of direct or indirect cardiomyocyte regeneration.…”

“…Clearly, more study is warranted, as experiments in models of ischemic injury in the LV suggest that cell secretome can actually outperform cell-based strategies in terms of contractile recovery in some circumstances [43]. On the other hand, it remains unknown whether the indirect actions of a cell-free therapy, perhaps in combination with myocardial hypertrophy, will suffice to sustain the RV in the face of elevated afterload longer-term or whether the addition of force-generating units will prove essential to overcome heart failure in RV pressure overload [64].…”

Reversal of right ventricular failure by chronic α1A-subtype adrenergic agonist therapy

“…Our recent study using a multiscale computational model of the cardiovascular system suggested that decreased myofilament function plays a key role in the development of RVF (19). Furthermore, model simulations predicted that increased myofilament force after A61603 treatment would preserve RV function despite continued pressure overload (20).…”