The vast majority of patients with pulmonary hypertension, regardless of the etiology, ultimately succumb tothe disease by two main causes: sudden death or intractable right heart failure. While there has beengreat focus paid to the vascular abnormalities associated with pulmonary hypertension, there has been arelative paucity of attention given to the role of the right ventricle in this disease. An under-recognizedpotential 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 largeartery vascular stiffening in idiopathic pulmonary arterial hypertension, this pathology is markedly worsenedin patients with pulmonary hypertension related to scleroderma. Since stiffening means that even modestincreases in cardiac ejection are associated with greater arterial after-load pressures, it can limitmechanisms of cardiovascular reserve. The guiding hypothesis of this proposal is that ventricular-vascular stiffening is enhanced in patients with pulmonary arterial hypertension, limiting cardiacreserve and contributing to exertional dyspnea, fatigue, and is directly related to mortality. Thisproposal employs many novel techniques to study RV-pulmonary vascular interactions in a way that mayprove to be easily translated to clinical practice, as well to study molecular mechanisms that reinforce thishypothesis, and the effect on intervention on these pathways on symptoms, outcomes, and mortality in thispatient population. Moreover, this proposal will attempt to tie molecular changes to RV failure andremodeling to the degree of RV-PA uncoupling and we will test the hypothesis that measurement of thisuncoupling will be prognostic with regard to treatment success.
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