Project Summary Insulin resistance is the decreased response to insulin signaling and is a major public health concern. In addition to being a risk factor for heart failure with preserved ejection fraction, insulin resistance also plays a role in right ventricular (RV) remodeling and dysfunction. RV function is an important determinant of cardiovascular health which is much less well-characterized compared to the left ventricular (LV) function – RV dysfunction is associated with worse outcomes in both the general population and in those with underlying cardiac disease. However, prior studies have used load-dependent measures of RV function, which is notoriously difficult to assess using traditional transthoracic echocardiography. Further, it is unknown whether therapies targeting insulin sensitivity (such as metformin and thiazolidinedione medications) could improve RV function. Disentangling the impact of insulin resistance selectively for the RV as opposed to interventricular interaction from concomitant left ventricular dysfunction has posed additional challenges. The goal of this study is to examine the longitudinal impact of insulin resistance across the spectrum of RV function using speckle-tracking echocardiography, a novel method which is more sensitive than traditional indices of RV function. First, we will determine the effect of insulin-sensitizing medications on right ventricular function in the Multi-Ethnic Study of Atherosclerosis (MESA), representing a community-based population. Second, we will examine the longitudinal effect of insulin resistance on RV and LV function in patients with pulmonary arterial hypertension (PAH), representing a cohort with underlying RV dysfunction. This proposal will improve understanding of the association between changes in insulin resistance on RV function. The research utilizes a novel echocardiography technique to study an emerging pathway that may be used in the future to identify individuals at increased risk for RV dysfunction and studying interventions aimed at improving insulin sensitivity on this population. Finally, this project will provide key preliminary data for a Career Development Award focused on studying interventions aimed at improving metabolic function among individuals at risk for RV dysfunction.