Mineralocorticoid Receptor Antagonism Ameliorates Left Ventricular Diastolic Dysfunction and Myocardial Fibrosis in Mildly Symptomatic Patients With Idiopathic Dilated Cardiomyopathy

Abstract

Background— Mineralocorticoid receptor antagonism reduces mortality associated with heart failure by mechanisms that remain unclear. The effects of the mineralocorticoid receptor antagonist spironolactone on left ventricular (LV) function and chamber stiffness associated with myocardial fibrosis were investigated in mildly symptomatic patients with idiopathic dilated cardiomyopathy (DCM). Methods and Results— Twenty-five DCM patients with a New York Heart Association functional class of I or II were examined before and after treatment with spironolactone for 12 months. LV pressures and volumes were measured simultaneously, and LV endomyocardial biopsy specimens were obtained. Serum concentrations of the carboxyl-terminal propeptide (PIP) and carboxyl-terminal telopeptide (CITP) of collagen type I were measured. The patients were divided into 2 groups on the basis of the serum PIP/CITP ratio (≤35, group A, n=12; >35, group B, n=13), an index of myocardial collagen accumulation. LV diastolic chamber stiffness, the collagen volume fraction, and abundance of collagen type I and III mRNAs in biopsy tissue were greater and the LV early diastolic strain rate (tissue Doppler echocardiography) was smaller in group B than in group A at baseline. These differences and the difference in PIP/CITP were greatly reduced after treatment of patients in group B with spironolactone, with treatment having no effect on these parameters in group A. The collagen volume fraction was significantly correlated with PIP/CITP, LV early diastolic strain rate, and LV diastolic chamber stiffness for all patients before and after treatment with spironolactone. Conclusions— Spironolactone ameliorated LV diastolic dysfunction and reduced chamber stiffness in association with regression of myocardial fibrosis in mildly symptomatic patients with DCM. These effects appeared limited, however, to patients with increased myocardial collagen accumulation.

Changes in collagen metabolism account for ventricular functional recovery following beta-blocker therapy in patients with chronic heart failure

“…This HR reduction enhances coronary perfusion and lowers O 2 demand and LV filling pressure. The above-mentioned changes induce LV reverse remodeling in patients with CHF some medications for CHF treatment might alter turnover of extracellular matrix [11,[35][36][37], they might have some influence on collagen metabolism. We think that this factor would have a minimal effect, because almost all of the patients were treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and a multivariate analysis showed that administration of aldosterone antagonist was not selected as a significant factor to explain LV functional recovery in this study.…”

Extracellular matrix fibrotic markers in heart failure

“…More recently, Izawa et al [13] investigated the effects of spironolactone in patients with dilated cardiomyopathy. The patients were divided into two groups on the basis of the serum PIP/CITP ratio (B35, group A, n = 12; [35, group B, n = 13), an index of myocardial collagen accumulation.…”

“…Thus, the PICP/CITP serum levels ratio serves as a serum marker of myocardial collagen accumulation. In patients with dilated cardiomyopathy, Izawa et al [13] demonstrated that both collagen volume fraction and the abundance of collagen types I and III mRNAs in the LV myocardium were higher in the patients with an increased PICP/CITP serum level ratio than in those with a lower PIP/CITP ratio. This is a direct evidence linking serum ECM markers to the heart ECM content, thus providing rationale for their use as potentially useful biomarkers of ECM remodelling in cardiac disease.…”

The paradox of left ventricular assist device unloading and myocardial recovery in end-stage dilated cardiomyopathy: implications for heart failure in the elderly

“…AngII has a direct effect on fibroblasts and increases transforming growth factor (TGF)-b which in turn increases collagen production [26][27][28]. ACE inhibition, ARBs, and aldosterone antagonists reduce collagen production and fibrosis [15,29]. Novel renin inhibitors such as aliskiren show promise in reducing cardiac fibrosis in animal models [30].…”