Pulmonary arterial hypertension (PAH) results from severe remodeling of the distal lung vessels, and can develop from unknown (idiopathic, IPAH) causes as well as diseases such as systemic sclerosis (SSc), a disorder characterized by endothelial and fibroblast dysregulation, and altered immunity. Right ventricular (RV) failure, the major cause of death with PAH, is particularly prominent in SSc-associated PAH (SSc-PAH) while important in all PAH. Despite modern therapy, SSc-PAH has a median survival of only 3 years, far worse than IPAH. We recently identified novel hemodynamic and non-invasive image-based risk factors predictive of survival and, in new preliminary data, reveal abnormal RV myocardial contractility in SSc-PAH. We propose that worse survival in SSc-PAH versus IPAH results from intrinsic RV dysfunction independent of pulmonary arterial (PA) loading, which is due in part to sarcomeric dysfunction and micro-vascular disease. We will fill major knowledge gaps regarding RV-PA disease in SSc-PAH and IPAH, and test new invasive and non- invasive clinical measures of RV function in PAH to reveal novel mechanisms and markers of disease evolution and risk. The three Specific Aims will 1) derive optimal non-invasive measures of RV performance based on cardiac magnetic resonance imaging to predict survival in both IPAH and SSc-PAH;2) determine RV function and PA interaction by invasive pressure-volume and right heart catheterization, using rate pacing and leg-exercise to assess reserve RV function;and 3) obtain RV biopsies to test the role of primary sarcomere dysfunction to reduced RV contractility in PAH (either form), identify cytokine activation pathways linked to transforming growth factor-beta cascades and angiogenesis modulators, and assess the potential for associated serum biomarkers to reflect RV disease. This will provide critically needed insights into RV function and novel biomarkers (functional and signaling) to assess RV dysfunction, which can be used clinically. We will also provide the first myofilament analysis and assessment of molecular pathways in human myocardial tissue in PAH, coupling this to intact organ physiology, and yielding critical new insights that can pave the way to future therapies aimed at improving RV function in PAH.

Public Health Relevance

This application will: 1) establish standard clinical imaging and hemodynamic biomarkers of RV function in PAH;2) identify the cause of RV dysfunction and role in SSc-PAH survival;and 3) unravel pathogenic mechanisms underlying altered myocardial contractile function in PAH that can serve as future therapeutic targets for RV dysfunction in PAH.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-H (M1))
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Moore, Timothy M
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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
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