Clinical benefits and mechanism of action of angiotensin-II receptor blocker on Cardiovascular remodeling in patients with repaired coarctation of aorta

PROJECT SUMMARY/ABSTRACT The median survival in adults with repaired coarctation of aorta (COA) is ~55 years, and more that 50% of deaths are due to end-stage heart failure and sudden cardiac death from left ventricular (LV) systolic/diastolic dysfunction. LV dysfunction results from chronic pressure overload from hypertension, which in turn leads to LV remodeling (increased fibrosis and stiffness, and impaired relaxation). LV dysfunction has been observed in COA patients with borderline hypertension or stage 1 hypertension (B/S1) (blood pressure 120-139/80-89 mmHg), even though the severity of hypertension in these patients is considered significant enough to warrant antihypertensive therapy based on the current guidelines. Additionally, COA patients with B/S1 hypertension have impaired aerobic capacity and exhibit hypertensive response to exercise, both of which are associated with cardiovascular adverse events The pathophysiologic mechanisms responsible for LV remodeling and abnormal hemodynamic response to exercise in this subset of COA patients are not well understood but are postulated to be due to increased aortic stiffness. We recently demonstrated that a 2-week course of angiotensin-II receptor blocker (ARB) improved aortic stiffness, coronary flow reserve (CFR), cardiac output reserve and vasodilatory reserve (VDR) during exercise. However, it is unknown whether these hemodynamic changes will lead to LV reserve remodeling (decreased fibrosis and stiffness, and improved relaxation) and improved aerobic capacity during long-term therapy. Our long-term goal is to prevent early cardiovascular death in COA patients, by identifying and modifying the pathophysiologic mechanisms leading to LV dysfunction and vascular complications in this population. Our overall objective for this application is to determine whether ARB might promote LV reserve remodeling and improve aerobic capacity, and to delineate the mechanisms of response to ARB. Our central hypothesis is that ARB will promote LV reserve remodeling and improve aerobic capacity by improving CFR and VDR. This hypothesis will be tested by pursuing two specific aims: (1) Determine whether ARB promotes LV reverse remodeling in patients with repaired COA and B/S1 hypertension and delineate the mechanisms of response to ARB; (2) Determine whether ARB improves aerobic capacity and delineate the mechanisms of response to ARB. We will randomize 80 subjects 1:1 to ARB (losartan 50 mg) or placebo for 52 weeks. These subjects will undergo multi-domain assessment of cardiovascular structure and function at baseline and after 52 weeks of therapy. This proposal is innovative because it will novel magnetic resonance imaging techniques to assess cardiovascular response to ARB in patients with repaired COA. The results will be significant because it will enable the development of novel management paradigms for prevention of LV dysfunction and cardiovascular death in this population.