Abstract
Background: Abnormal aldosterone signaling is a recognized source of cardiovascular damage. Its influence on cardiomyocyte structure, function, and hormonal receptors when associated with heart failure is still unreported. Methods: Twenty-six consecutive patients with heart failure (LVEF < 40%) and normal coronaries and valves underwent left ventricular endomyocardial biopsy (EMB) for evaluation of myocardial substrate. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western blot analysis of myocardial aldosterone receptor and aquaporin-1 correlated with plasma aldosterone (AD) and renin activity (PRA). Eight patients with virus-negative inflammatory cardiomyopathy (ICM) had a control EMB after 6 months of immunosuppressive therapy and recovery of cardiac function with re-evaluation of cardiomyocyte structure and receptor expression. Results: EMB in addition to the diagnosis of myocarditis (15 cases), dilated cardiomyopathy CM (6), alcohol CM (2), and diabetic CM (3) showed vacuolar degeneration and cloudy swelling of cardiomyocytes corresponding at electron microscopy to ions and water accumulation into cytosol, membrane-bound vesicles, nucleus, and other organelles, and was associated with an increased AD, PRA, and myocardial expression of aldosterone receptor (2.6 fold) and aquaporin 1 (2.7 fold). In the 8 patients recovered from ICM, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles and normalization of cytosol, nucleus, and cell organelles’ electron-density, along with down-regulation of aldosterone receptor and aquaporin-1. Conclusion: Human heart failure is associated with overexpression of myocardial aldosterone receptor and aquaporin-1. These molecular changes are paralleled by intracellular water overloading and cardiomyocyte swelling and dysfunction. Cardiac recovery is accompanied by down-regulation of hormonal receptors and normalization of cell structure and composition.
Highlights
The role of excessive aldosterone signaling in mediating cardiovascular damage is increasingly recognized by clinical and experimental evidence.Convincing data come from Rales [1], Emphasis-HF [2,3], and Ephesus trials [4], where inhibition of myocardial aldosterone receptor (AR) has been followed by reduction in left ventricular hypertrophy and decrease in mortality and cardiovascular-related hospitalizations compared with placebo
15 patients received a diagnosis of virus-negative inflammatory cardiomyopathy, 6 had a non-familiar idiopathic dilated cardiomyopathy, 2 had alcoholic cardiomyopathy, and the remaining 3 had a diabetic cardiomyopathy correlated with a long history of diabetes
Twenty-six patients were included in the study; 20 were males (77%), median age was 58.4 ± 11.4 years
Summary
The role of excessive aldosterone signaling in mediating cardiovascular damage is increasingly recognized by clinical and experimental evidence.Convincing data come from Rales [1], Emphasis-HF [2,3], and Ephesus trials [4], where inhibition of myocardial aldosterone receptor (AR) has been followed by reduction in left ventricular hypertrophy and decrease in mortality and cardiovascular-related hospitalizations compared with placebo. Smooth muscle cells with water accumulation in the cytosol and organelles causing cell swelling and dysfunction These structural changes reverse with removal of hypersecreting adrenal adenoma and normalization of plasma aldosterone levels. Eight patients with virus-negative inflammatory cardiomyopathy (ICM) had a control EMB after 6 months of immunosuppressive therapy and recovery of cardiac function with re-evaluation of cardiomyocyte structure and receptor expression. Results: EMB in addition to the diagnosis of myocarditis (15 cases), dilated cardiomyopathy CM (6), alcohol CM (2), and diabetic CM (3) showed vacuolar degeneration and cloudy swelling of cardiomyocytes corresponding at electron microscopy to ions and water accumulation into cytosol, membrane-bound vesicles, nucleus, and other organelles, and was associated with an increased AD, PRA, and myocardial expression of aldosterone receptor (2.6 fold) and aquaporin 1 (2.7 fold). In the 8 patients recovered from ICM, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles and normalization of cytosol, nucleus, and cell organelles’
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