ReviewThe Role of Aldosterone Blockers in the Management of Chronic Heart Failure
Section snippets
Pathophysiology of Congestive Heart Failure
The traditional paradigm of CHF utilized the hemodynamic model to explain cardiac disease. Therapy based on reductions in preload and afterload were thought beneficial because they could “unload” the left ventricle and improve myocardial performance. However, over the last 20 years, this model was gradually replaced by the neurohormonal model, in which myocardial dysfunction is noted to activate both the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). Activation
Pathophysiology of Aldosterone in Congestive Heart Failure
Aldosterone escape occurs in approximately 33% of patients with CHF treated with ACE inhibitors.17., 18., 19., 20. This rebound in aldosterone concentration is not without clinical significance. Aldosterone escape reverses the beneficial effects of ACE inhibition on cardiac remodeling,22 induces cardiac fibrosis,23 and promotes endothelial and baroreceptor dysfunction,24., 25. all of which may contribute to progressive cardiac pump failure and sudden cardiac death.
In experimental animals,
Clinical Trials of Aldosterone Antagonists in Congestive Heart Failure with Systolic Dysfunction
The RALES trial randomized 1663 patients with NYHA class III or IV heart failure, recent class IV symptoms in the preceding 6 months, and ejection fraction less than 35% to therapy with 25 to 50 mg (mean dose 26 mg) of spironolactone or placebo.4 The mean age of patients was 65 years, mean left ventricular ejection fraction (LVEF) was 25%, and roughly 55% of patients in each group suffered from ischemic cardiomyopathy. Virtually all patients were treated with loop diuretics, ACE inhibitors, and
Clinical Trials of Aldosterone Antagonists in Left Ventricular Hypertrophy/Diastolic Dysfunction
Long-standing hypertension leads to pressure overload of the left ventricle, with resultant concentric LVH. Increased myocardial collagen content contributes to the myocardial stiffness in LVH26 27 and clinically causes an elevated pulmonary capillary wedge pressure and the clinical syndrome of CHF from diastolic dysfunction.
Studies in patients with LVH or diastolic dysfunction demonstrate that aldosterone antagonists reduce blood pressure and LVH to the same degree as ACE inhibitor therapy.20.
Role of Nephroprotective Effects of Aldosterone Antagonists in Cardiac Disease
Congestive heart failure is often accompanied by chronic kidney disease. Worsening degrees of kidney function portend a worse cardiovascular prognosis.50 In addition, micro- and macro-albuminuria are cardiovascular risk factors.51 Although these relationships between renal and cardiac disease are associative at this point, it is plausible from a pathophysiologic standpoint to presume that amelioration of both proteinuria and progressive chronic kidney disease may impact favorably on
Safety of Aldosterone Antagonists in Treatment of Cardiac Disease
Aldosterone antagonists have three major adverse effects. First, spironolactone, through alterations in sex hormone metabolism, can cause gynecomastia, impotence, and menstrual abnormality.57 Second, drug-induced inhibition of renal potassium secretion by the principal cells in the cortical collecting duct increases serum potassium concentration and may cause frank hyperkalemia. Third, the natriuretic effect of these drugs can reduce glomerular filtration rate (through intravascular volume
Other Issues
The populations in RALES and EPHESUS consisted entirely of patients with LVEF less than 40%. However, in RALES, the patients had chronic CHF, whereas in EPHESUS, the patients had recently suffered an acute myocardial infarction and had presumed new-onset left ventricular dysfunction. Whether spironolactone and eplerenone will be interchangeable in these populations and provide the same benefit is, from an evidence-based perspective, unknown. However, although the drugs possess different
Conclusions
Aldosterone antagonists have revolutionized the treatment of congestive heart failure. Given the conclusive evidence from several clinical trials, all patients with an LVEF less than 40% should be initiated first on ACE inhibitors1., 2., 3. and beta-blockers5., 6. to reduce morbidity and mortality. If ACE inhibitors cannot be tolerated, ARBs may be substituted, since these agents similarly reduce morbidity and mortality in CHF patients.14., 72. If the serum K+ concentration remains less than
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