1022 Circulation August 27, 2013 dehydrogenase activity. 14 Increases in cardiac aldosterone have been reported in experimental models of myocardial infarction, 15 correlating with LV remodeling. 16 The effects of aldosterone are similar to those observed with Ang II, including inhibition of nitric oxide synthase and promotion of inflammation, fibrosis, and cardiac myocyte apoptosis. 17 However, the use of spironolactone is limited because of the metabolic and endocrine side effects and variations in patient response, 18 which are largely absent with eplerenone. 13 In addition, patients with chronic HF have increased aldosterone synthase activity, leading to non–mineralocorticoid receptor–mediated responses. 19 Blockade of mineralocorticoid receptors increases aldosterone synthase activity. Consequently, MRA therapy results in high levels of aldosterone. Aldosterone may also have non–mineralocorticoid receptor–mediated deleterious effects on cardiomyocytes. 20 The aldosterone synthase inhibitor FAD28621 reduced LV remodeling in a rat model of HF, and another, LCI699, demonstrated safety and tolerability in 14 patients with primary aldosteronism. 22 Future studies will determine whether aldosterone synthase inhibitors are more effective than MRAs in treating HF.

A new class of therapeutics that target the renin-angiotensin-aldosterone axis comprises dual-acting agents for angiotensin receptor–neprilysin inhibition. Neprilysin activates the kinin and natriuretic peptide systems. One such inhibitor, LCZ696, combines a moiety of valsartan with an endopeptidase inhibitor. 23 An initial safety study of this inhibitor has led to the ongoing Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial (NCT01035255) to compare LCZ696 with enalapril. 23 Selective ARBs are also currently in development. Ang II can act through 2 different receptors: Ang II receptor type 1 and type 2. Whereas the Ang II receptor type 1 is ubiquitously