Dottorato in ARTERIAL HYPERTENSION AND VASCULAR BIOLOGY

Titolo della tesi: MYOCARDIAL ALDOSTERONE RECEPTORS AND AQUAPORIN 1 UP-REGULATION CAUSING CARDIOMYOCYTE REMODELING IN HUMAN HEART FAILURE

Background: Abnormal aldosterone signaling is a recognized source of cardio-vascular 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%), normal coronaries and valves, underwent a 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 receptors 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), 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, associated to an increased AD, PRA and myocardial expression of aldosterone receptors (2.3 fold) and aquaporin 1 (2.6 fold). In the 8 pts recovered from ICM, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles, normalization of cytosol, nucleus and cell organelles’ electron-density, along with down-regulation of aldosterone receptors and aquaporin-1. Conclusion: Human heart failure is associated with over-expression of myocyte aldosterone receptors and aquaporin-1 causing intracellular water overloading, swelling and functional compromise of cardiomyocytes. Cardiac recovery is accompanied by down-regulation of hormonal receptors and normalization of cell structure and composition. Key words: hyperaldosteronism, myocardial damage, heart failure, aldosterone receptors, aquaporin-1, vacuolar degeneration, cloudy swelling, cell volume control, cellular and molecular rehabilitation.