Plasma aldosterone levels in patients with coronary artery disease without heart failure or myocardial infarction: implications for pathophsiology, prognosis, and therapy.

Increased plasma levels of aldosterone and cortisol have been associated with an increased risk of mortality and hospitalization for heart failure (HF) in patients with a reduced left ventricular ejection fraction (REF). Mineralocorticoid receptor antagonists (MRAs), which block the effects of both cortisol and aldosterone on the MR, are effective in reducing total mortality as well as hospitalizations for HF in patients with chronic HFREF and in patients with HFREF early post-myocardial infarction (MI). Increased levels of aldosterone in patients with HF and a preserved left ventricular ejection fraction (PEF) as well as in patients early post-MI without clinical evidence of HF have also been associated with an increase in cardiovascular risk. MRAs are therefore currently being investigated in patients with HFPEF and in patients with both ST-elevation and non-ST-elevation MI without clinical evidence of HF. Ivanes et al. have reported on the measurement of plasma aldosterone in 799 consecutive patients with coronary artery disease (CAD) referred for elective coronary angioplasty. Patients with an acute MI or an acute coronary syndrome requiring urgent revascularization and those with clinical evidence of HF were not included. Over a mean follow-up of 14.9 months, multivariant Cox model analysis showed that plasma aldosterone levels were independently associated with an increase in cardiovascular events. They also found that plasma aldosterone levels provided complementary and incremental prognostic information above and beyond that provided by measurement of brain natriuretic peptide (BNP) and high sensitivity C-reactive protein, and positively correlated with the presence of obesity and hypertension, suggesting a potentially important role for aldosterone in patients with the metabolic syndrome. Also of interest is their finding that the use of angiotensin-converting enzyme (ACE) inhibitors was not associated with a reduction in plasma aldosterone levels, suggesting ‘aldosterone escape’ and therefore an increased risk of cardiovascular events related to aldosterone despite the use of an ACE inhibitor. They also noted an increase in plasma aldosterone levels in patients with hypertension and those treated with diuretics, which in part might explain the increased risk of atherosclerosis and its cardiovascular consequences: MI, stroke, and sudden cardiac death in patients with hypertension. While activation of the angiotensin type 1 receptor (AT1-R) is an important stimulus for the production of aldosterone from the adrenal gland, neither ACE inhibitors nor angiotensin receptorblocking agents (ARBs) are sufficient to block the production of aldosterone, due to the presence of other stimuli such as potassium. Furthermore, an increase in aldosterone and or activation of the MR results in an upregulation of ACE activity and AT1-R expression, i.e. a vicious cycle with increasing activation of the renin–angiotensin–aldosterone system (RAAS). To block this vicious cycle and to obtain maximal benefits it is necessary to block both the MR and the AT1-R. The observations by Ivanes et al. as well as the association of an increase in plasma aldosterone levels with an increase in cardiovascular events in patients with CAD in the LOURIC study have important mechanistic, prognostic, and therapeutic implications for patients with CAD. While lipid-lowering therapy has been associated with a significant reduction in cardiovascular risk in patients with CAD, there remains a relatively high risk of cardiovascular events despite their use. Aldosterone increases the expression of the lecithin-like, oxidized, LDL receptor (Lox-1), predisposing to the oxidation of LDL-cholesterol (LDL-C), thus possibly negating some of the potential benefits of lipid-lowering therapy. Similarly, while ACE inhibitors are associated with a reduction in