Endothelial Dysfunction and the RV in the Multi-Ethnic Study of Atherosclerosis

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Pulmonary hypertension is an elevation in pulmonary artery pressure which may result from a variety of heart and lung diseases. Chronically increased right ventricular (RV) afterload from pulmonary hypertension eads to RV hypertrophy and eventual RV failure. While the importance of systemic hypertension and subsequent left ventricular hypertrophy is quite well-defined, our understanding of the effects of pulmonary hypertension on the RV is infinitesimal by comparison. This gap in knowledge is firstly attributable to the greater difficulty in performing accurate and non-invasive assessments of the RV and the pulmonary vasculature. Also, patients with pulmonary hypertension usually present to medical attention with advanced RV structural changes and severe RV failure due to under-recognition of the problem and difficulty in diagnosis. This knowledge gap is most concerning since the morbidity and mortality attributable to pulmonary hypertension and RV failure are increasing, especially among minority and older Americans. Endothelial dysfunction incorporates the primary components of hypercoagulability and inflammation seen in pulmonary hypertension and RV failure. Medical therapies targeted at the endothelium have actually been found to restore anti-thrombotic properties, decrease inflammation, reduce symptoms, and prolong survival in certain forms of pulmonary hypertension. However, the relationship of endothelial dysfunction to subclinical pulmonary vascular disease and RV failure is not well-studied. The Multi-Ethnic Study of Atherosclerosis (MESA) is an NHLBI-sponsored, ten-year, prospective cohort study of 6814 patients with strong minority representation without clinical cardiovascular disease at baseline. In 2000-2001, 5099 MESA participants underwent baseline cardiac MRI in addition to multiple other measures and phlebotomy. In 2006-2007, a random sample of 1720 patients are slated to undergo repeat cardiac MRI. We propose to study the relationship between pulmonary vascular endothelial function and RV function by reading the RV measures for 4200 interpretable baseline and 1000 follow-up cardiac MRIs and assessing biomarkers of endothelial function. We aim to 1) establish normative values and indices of RV mass, RV volumes, and RV ejection fraction in MESA by gender, race, and ethnicity, 2) to determine whether plasma measures, such as von Willebrand factor, soluble thrombomodulin, C-reactive protein, interleukin-6, and fibrinogen, are associated with RV mass and RV ejection fraction, and 3) to determine whether plasma measures of endothelial dysfunction at baseline predict change in RV mass and RV ejection fraction at follow-up. This study will focus on subclinical markers of pulmonary vascular disease and RV failure, which are increasingly important diseases impacting on older and minority Americans.