Aldosterone synthase (CYP11B2) expression and myocardial fibrosis in the failing human heart

Abstract

The pathway of tissue aldosterone production may exist in the heart, and may be an important contributory factor to myocardial fibrosis and cardiac remodelling in the failing heart. CYP11B2 (aldosterone synthase) catalyses the final step of aldosterone production. The aim of the present study was to determine whether CYP11B2 and CYP11B1 (11beta-hydroxylase) are expressed in myocardial tissues, and whether these enzymes contribute to collagen accumulation and myocardial dysfunction in the failing human heart. Endomyocardial tissues were obtained from 23 patients with chronic heart failure (CHF) and 10 controls. CYP11B2 and CYP11B1 mRNA levels were measured by real-time quantitative reverse transcriptase-PCR. The myocardial collagen volume fraction (CVF) was determined by digital planimetry. CYP11B2 mRNA expression was greater in the CHF group than in the controls (P<0.05), while CYP11B1 mRNA was barely expressed in either group. There was a positive correlation between CYP11B2 mRNA levels and CVF (r=0.64, P=0.001). CYP11B2 mRNA was particularly highly expressed in subgroups of CHF patients with a large left ventricular end-systolic diameter (>55 mm) or a low left ventricular ejection fraction (<30%). CYP11B2 mRNA expression and CVF were lower in a CHF subgroup treated with a combination of spironolactone and angiotensin-converting enzyme inhibitors (ACEIs) than in a subgroup not treated with these drugs. In conclusion, this study has shown that increased myocardial expression of CYP11B2 mRNA is associated with increased myocardial fibrosis and with the severity of left ventricular dysfunction in human CHF. In addition, CYP11B2 expression and cardiac fibrosis are found to be decreased in CHF patients on drug therapy comprising spironolactone combined with ACEIs.

Association between aldosterone synthase (CYP11B2) polymorphism and left ventricular mass in human essential hypertension

“…Moreover, it has been previously demonstrated that some vasoactive substances, such as angiotensin II and aldosterone, acting as growth factors, may be associated with the development of LVH (5). In the past few years, particular attention has been focused on aldosterone, for the following reasons: 1) myocardial and vascular fibrosis were shown to be induced by this hormone (6 -8); 2) the Randomized ALdactone Evaluation Study (RALES) has demonstrated that the combination of aldosterone antagonists and angiotensin-converting enzyme inhibitors can reduce the mortality and morbidity from cardiac heart failure; this effect does not appear to be due to the action of spironolactone on sodium and potassium renal handling, but implies a direct cardioprotective action of this drug (9); 3) intracardiac synthesis of aldosterone was found in isolated rat hearts (10); 4) increased aldosterone synthase (CYP11B2) expression was recently detected in biopsies from failing human hearts, along with a direct relationship between myocardial fibrosis and 11CYPB2 messenger ribonucleic acid expression (11); and 5) increased aldosterone production in the left ventricle (LV) of hypertensive patients, compared with those with normotension, has recently been demonstrated (12).…”

Imaging the renin-angiotensin-aldosterone system in the heart

“…Increased myocardial expression of aldosterone synthase, the enzyme that catalyzes the final step of aldosterone production, has been found in the myocardium of patients with CHF [29]. A positive correlation between level of aldosterone synthase and degree of myocardial fibrosis has been shown [30]. Further clinical evidence for locally active hormone comes from studies showing that baseline plasma aldosterone only poorly predicts the efficacy of aldosterone blockade.…”

Aldosterone action in the heart

“…They demonstrated that (1) aldosterone synthase is expressed in rat cardiac tissue, albeit at levels that are~500-fold lower than that of the adrenal glands; (2) rat cardiac tissue produces aldosterone, corticosterone and DOC with tissue aldosterone concentration as high as~16 nM (plasma aldosterone levels vary in the range 0.1-1 nM); (3) the myocardial aldosterone production is regulated by the same stimuli as in the adrenal glands (potassium, Ang II); (4) cardiac and plasma aldosterone concentration are regulated independently. Mizuno et al [23], Satoh et al [29] and Yoshimura et al [25] have shown that aldosterone synthase expression [25,29] or aldosterone production [23] are increased in failing human hearts. These observations led to a highly attractive "intracrine" hypothesis of aldosterone action in the heart.…”