A Randomized Study of the Beneficial Effects of Aldosterone Antagonism on LV Function, Structure, and Fibrosis Markers in Metabolic Syndrome

Abstract

The purpose of this study was to identify the effects of spironolactone on left ventricular (LV) structure and function, and serological fibrosis markers in patients with metabolic syndrome (MS) taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Myocardial fibrosis may be an important contributor to myocardial impairment in MS, and aldosterone antagonism may reduce fibrosis. Eighty patients (age 59 ± 11 years) with MS, already being treated with angiotensin II inhibition, were randomized to spironolactone 25 mg/day or placebo for 6 months. Each patient underwent baseline and follow-up conventional echocardiography and color tissue Doppler imaging. Raw data files were used to measure calibrated integrated backscatter and to calculate radial and longitudinal strain. Blood was obtained at baseline and follow-up to measure fibrosis markers (procollagen type III amino-terminal propeptide and procollagen type I carboxy-terminal propeptide [PICP]). The spironolactone group showed significant improvement of LV function, myocardial reflectivity, and LV hypertrophy, with a parallel decrease in levels of PICP and procollagen type III amino-terminal propeptide. No analogous changes were seen in the placebo group. Baseline strain (β = 0.47, p < 0.0001), spironolactone therapy (β = -0.38, p < 0.0001), and change in PICP level (β = -0.19, p < 0.03) were independently associated with LV systolic function improvement (increase in strain). Correlates of LV diastolic function improvement (increase in early diastolic mitral annular velocity) were baseline early diastolic mitral annular velocity (β = 0.47, p < 0.0001), spironolactone therapy (β = -0.21, p < 0.03), change in PICP level (β = -0.23, p < 0.02), and age (β = 0.22, p < 0.04). Favorable effects of spironolactone on cardiac function were not demonstrated in patients with less fibrosis (the lower baseline PICP tertile) or preserved function (the upper baseline strain tertile). Addition of spironolactone to standard angiotensin II inhibition improved myocardial abnormalities and decreased fibrotic markers in MS. The magnitude of benefit on cardiac performance is determined mainly by baseline LV dysfunction and collagen turnover as well its response to intervention.