Background and Methods Aldosterone is important in the pathophysiology of heart failure. In a double-blind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting–enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. Results The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from prog...

https://www.nejm.org/doi/pdf/10.1056/NEJM199909023411001

The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.

Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling

The effect of spironolactone on morbidity and mortality in patients with severe heart failure

Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death. Decreased compliance of the central vasculature alters arterial pressure and flow dynamics and impacts cardiac performance and coronary perfusion. This article reviews the structural, cellular, and genetic contributors to arterial stiffness, including the roles of the scaffolding proteins, extracellular matrix, inflammatory molecules, endothelial cell function, and reactive oxidant species. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt, and changes in neurohormonal regulation are discussed. A review of the hemodynamic impact of arterial stiffness follows. A number of lifestyle changes and therapies that reduce arterial stiffness are presented, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, natriuretic peptides, insulin modulators, as well as novel therapies that target advanced glycation end products.

Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness

Swynghedauw, Bernard. Molecular Mechanisms of Myocardial Remodeling. Physiol. Rev. 79: 215–262, 1999. — “Remodeling” implies changes that result in rearrangement of normally existing structures. Th...

Molecular Mechanisms of Myocardial Remodeling

Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone.

Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism.

Activation of the renin-angiotensin-aldosterone system in arterial hypertension can lead to remodeling of the myocardial collagen network, with progressive collagen accumulation in the cardiac interstitium. This reactive myocardial fibrosis, which is not secondary to myocyte necrosis, appears to be an important determinant of diastolic dysfunction and thus of pathologic hypertrophy. To examine the effects of the aldosterone antagonist spironolactone on myocardial fibrosis, we analyzed interstitial fibrosis in 7 different models of arterial hypertension in rats: 2 kidney, 1 clip model of renovascular hypertension (RHT); continuous subcutaneous aldosterone (0.75 micrograms/hr) infusion; RHT and aldosterone models treated with 20 mg/kg per day of subcutaneous spironolactone; uninephrectomized rats on a high sodium diet; and age- and sex-matched controls with or without spironolactone treatment. Systolic arterial pressure was comparably elevated in RHT and aldosterone models; it was modestly lowered but not normalized by 8 weeks of spironolactone treatment at the low doses used. Such treatment also failed to prevent left ventricular hypertrophy (LVH) in all experimental groups with hypertension. Spironolactone, however, was able to prevent myocardial fibrosis in RHT and aldosterone models of acquired arterial hypertension irrespective of the development of LVH and the presence of hypertension. These findings provide further evidence that elevated aldosterone levels play an important role in the adverse remodeling of the myocardium in arterial hypertension. The antifibrotic effects of spironolactone, if confirmed in human studies, may be a valuable strategy in treating hypertensive heart disease.

Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension.

Left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR) is accompanied by a structural remodeling of the myocardium that includes myocyte hypertrophy and interstitial and perivascular fibrosis of intramyocardial coronary arteries. The structural abnormalities related to fibrous tissue accumulation lead to increased myocardial diastolic stiffness and ultimately impaired systolic function of the left ventricle. It has been shown in 14-week-old SHR with early hypertensive heart disease that myocardial fibrosis could be reversed and myocardial diastolic stiffness normalized by 12-week treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether such functional defects of the myocardium, based on adverse structural changes, are also reversible in advanced hypertensive heart disease has been questioned. Therefore, we treated 78-week-old male SHR that had chronic hypertension and advanced LVH with severe myocardial fibrosis and age- and sex-matched normotensive Wistar-Kyoto rats (WKY) with 20 mg/kg per day oral lisinopril for 8 months. Compared with untreated SHR or WKY, we found the following: (1) Systolic arterial pressure was normalized ( P P P P P 14 C]collagen with myocardial tissue extracts after trypsin activation of myocardial promatrix metalloproteinase 1; matrix metalloproteinase 1 activity remained unchanged in WKY treated with lisinopril; and (4) systolic dysfunction, measured by a significantly ( P

Luiz Matsubara

Papers

Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone.

Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism.

Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension.

Advanced Hypertensive Heart Disease in Spontaneously Hypertensive Rats Lisinopril-Mediated Regression of Myocardial Fibrosis

Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus