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Vascular Stiffness and Pulmonary Congestion

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Sudden onset flash pulmonary edema (PE) is a significant co-morbidity of patients with underlying hypertension, diabetes, and coronary artery disease. More than 10 billion dollars annually are spent in the United States providing healthcare for those suffering this condition. Recent data suggests that heightened aortic stiffness (particularly after stress) may be involved in the development of flash PE by raising LV afterload and stimulating left ventricular (LV) hypertrophy and impeding forward LV ejection. Importantly however, it is unknown whether abnormalities of aortic stiffness (at rest or with stress) predict future PE, nor is it known how aortic stiffness may interact with other conditions (such as age;LV contraction or hypertrophy;or aortic wall thickness) that previously have been associated with the onset of flash PE. In this resubmission of a prior application, we hypothesize that increased aortic stiffness during dobutamine stress is predictive of future flash PE warranting hospitalization independent of other causes of PE. We also hypothesize that the mechanism by which aortic stiffness heightens the risk of future PE is by limiting the ability of LV stroke volume to increase during stress. To gather evidence in support of our hypotheses, we will implement in 608 subjects at risk for the development of flash PE a novel form of cardiovascular magnetic resonance (CMR) that will allow the simultaneous rest and stress assessments of aortic and LV structure and function. We will study those at high risk for PE which an identifiable cause has not been established. After testing, we will follow our participants over time to ascertain the post-testing outcome of the occurrence of flash PE warranting hospitalization. Our design will allow us to determine if change in aortic stiffness during dobutamine independently predicts flash PE after controlling for other factors that promote PE (e.g., age, LV hypertrophy, or increased aortic wall thickening). In addition, our study design will allow us to determine if change in aortic stiffness during intravenous dobutamine is an independent predictor of flash PE after controlling for its effect on LV stroke volume reserve (stress/rest ratio of LV stroke volume). Our results will be significant in that we will define the relationship between factors affecting aortic stiffness and LV performance, and the future occurrence of flash PE warranting hospitalization. With this understanding, we will gain mechanistic insight into the pathophysiology of flash PE that will be useful for developing interventions to prevent the morbidity and mortality associated with this disorder.

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