The vast majority of patients with pulmonary hypertension, regardless of the etiology, ultimately succumb to the disease by two main causes: sudden death or intractable right heart failure. While there has been great focus paid to the vascular abnormalities associated with pulmonary hypertension, there has been a relative paucity of attention given to the role of the right ventricle in this disease. An under-recognized potential factor that may play an important role in patients with pulmonary hypertension is ventricular- vascular uncoupling secondary to pulmonary vascular stiffening especially in patients with scleroderma- associated pulmonary hypertension. Preliminary data suggest that, while there is some degree of large artery vascular stiffening in idiopathic pulmonary arterial hypertension, this pathology is markedly worsened in patients with pulmonary hypertension related to scleroderma. Since stiffening means that even modest increases in cardiac ejection are associated with greater arterial after-load pressures, it can limit mechanisms of cardiovascular reserve. The guiding hypothesis of this proposal is that ventricular- vascular stiffening is enhanced in patients with pulmonary arterial hypertension, limiting cardiac reserve and contributing to exertional dyspnea, fatigue, and is directly related to mortality. This proposal employs many novel techniques to study RV-pulmonary vascular interactions in a way that may prove to be easily translated to clinical practice, as well to study molecular mechanisms that reinforce this hypothesis, and the effect on intervention on these pathways on symptoms, outcomes, and mortality in this patient population. Moreover, this proposal will attempt to tie molecular changes to RV failure and remodeling to the degree of RV-PA uncoupling and we will test the hypothesis that measurement of this uncoupling will be prognostic with regard to treatment success.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZHL1)
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Johns Hopkins University
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