Mechanisms of Right Ventricular Dysfunction in Scleroderma-associated PAH

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Project Summary Systemic sclerosis (SSc), is a heterogeneous disorder characterized by dysfunction of the endothelium, and dysregulation of fibroblasts and the immune system. SSc-associated pulmonary arterial hypertension (SSc-PAH), a common and often underdiagnosed complication of SSc, is a devastating syndrome leading uniformly to death through right ventricular (RV) failure. In the previous funding period, we demonstrated depressed intrinsic RV myocardial function in SSc-PAH compared to idiopathic PAH using gold standard RV pressure-volume (PV) analysis, and further revealed that in vivo dysfunction significantly correlates with profound sarcomeric dysfunction in SSc-PAH skinned cardiomyocytes (obtained from RV biopsies) as reflected by a marked decline in peak calcium-activated tension and enhanced calcium sensitivity. These novel findings, combined with preliminary analyses showing decreased troponin-I (TnI) phosphorylation and myosin binding protein-C (MyBP-C) degradation in RV myocardium, support the hypothesis that sarcomere dysfunction is a primary mechanism for RV failure, and likely early demise, in SSc-PAH. We also applied non-invasive RV imaging, including speckle-tracking echocardiography to assess RV regional function, and cardiac magnetic resonance (CMR) to assess RV remodeling, fibrosis, and myocardial perfusion to show that some of these parameters may predict survival. Our overall hypothesis is that impaired regional microperfusion and fibrosis, resulting in altered contractile function, are 1) pathobiologic processes at the core of RV maladaptation and decreased SSc-PAH survival; 2) can be detected non-invasively; and 3) can only respond to RV-targeted therapy. In Aim 1 we will assess treatment responsiveness of the RV rest function, physiologic reserve, and RV- Pulmonary arterial interaction in SSc-PAH patients by means of PV analysis and right heart catheterization. In Aim 2 we will derive optimal non-invasive measures of RV performance that respond to therapy and predict time to clinical worsening and survival. And in Aim 3 we will test whether best practice combination PAH therapy, or RV sarcomere sensitizers, improve pre- treatment sarcomere dysfunction in RV myofilaments isolated from SSc-PAH patients.