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.

Public Health Relevance

We have recently identified specific RV dysfunction in SSc-PAH with sarcomeric abnormalities, which are thought not to respond to best practice PAH therapy. Using state of the art imaging and hemodynamic assessment, this project will identify clinically reliable non-invasive markers and specific molecular pathways underlying RV dysfunction, to hopefully pave the way for future studies aimed at improving RV-targeted treatment strategies for precision medicine in SSc-PAH.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Xiao, Lei
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Hsu, Steven; Kokkonen-Simon, Kristen M; Kirk, Jonathan A et al. (2018) Right Ventricular Myofilament Functional Differences in Humans With Systemic Sclerosis-Associated Versus Idiopathic Pulmonary Arterial Hypertension. Circulation 137:2360-2370
Mercurio, Valentina; Mukherjee, Monica; Tedford, Ryan J et al. (2018) Improvement in Right Ventricular Strain with Ambrisentan and Tadalafil Upfront Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 197:388-391
Mukherjee, Monica; Mercurio, Valentina; Tedford, Ryan J et al. (2017) Right ventricular longitudinal strain is diminished in systemic sclerosis compared with idiopathic pulmonary arterial hypertension. Eur Respir J 50:
Mullin, Christopher J; Hsu, Steven; Amancherla, Kaushik et al. (2017) Evaluation of criteria for exercise-induced pulmonary hypertension in patients with resting pulmonary hypertension. Eur Respir J 50:
Metkus, Thomas S; Tampakakis, Emmanouil; Mullin, Christopher J et al. (2017) Pulmonary Arterial Compliance in Acute Respiratory Distress Syndrome: Clinical Determinants and Association With Outcome From the Fluid and Catheter Treatment Trial Cohort. Crit Care Med 45:422-429
Khair, Rubina M; Nwaneri, Chisom; Damico, Rachel L et al. (2016) The Minimal Important Difference in Borg Dyspnea Score in Pulmonary Arterial Hypertension. Ann Am Thorac Soc 13:842-9
Houston, Brian A; Kalathiya, Rohan J; Hsu, Steven et al. (2016) Right ventricular afterload sensitivity dramatically increases after left ventricular assist device implantation: A multi-center hemodynamic analysis. J Heart Lung Transplant 35:868-76
Hsu, Steven; Kass, David A (2016) Can Nitrite AMPk Up Sirt-ainty to Treat Heart Failure With Preserved Ejection Fraction? Circulation 133:692-4
Hassoun, Paul M; Nathan, Steven D (2016) Sildenafil for pulmonary hypertension complicating idiopathic pulmonary fibrosis: a rationale grounded in basic science. Eur Respir J 47:1615-7
Hsu, Steven; Houston, Brian A; Tampakakis, Emmanouil et al. (2016) Right Ventricular Functional Reserve in Pulmonary Arterial Hypertension. Circulation 133:2413-22

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