Blocking aldosterone in heart failure.

Fifty years after its discovery, aldosterone continues to stimulate interest as a therapeutic target. Early studies focused on aldosterone's actions on hypertension, the kidney, and electrolyte handling. More recently, its actions on the heart and cardiovascular system have become more apparent. Aldosterone causes cardiac fibrosis and remodeling, and stimulates neurohormonal systems that adversely affect the cardiovascular system. Aldosterone antagonism attenuates these negative effects. Clinical studies have applied this science and demonstrated improved morbidity and mortality with aldosterone blockade, specifically in patients with chronic heart failure and patients who are postmyocardial infarction and with depressed left ventricular function. This article will address the pathophysiology of aldosterone in cardiac fibrosis and remodeling, review the current clinical trial data, and explore the application of aldosterone blockade in an expanded heart failure population. The Randomized Aldactone Evaluation Study showed that the aldosterone antagonist spironolactone reduced mortality when compared to placebo in patients with chronic advanced heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. A more provocative question is whether aldosterone antagonism will afford the same protection in patient populations with heart failure and preserved left ventricular function. Clinical trials are underway, and results are eagerly awaited.

Sympathetic neural mechanisms in human hypertension.

Compared with substantial clinical research on the renin-angiotensin-aldosterone system (RAAS), much less is known about the importance of the sympathetic nervous system as a therapeutic target to slow the initiation and progression of human hypertension. Using microelectrode recordings of sympathetic activity and radiotracer measurements of regional norepinephrine spillover in hypertensive patients, recent research has advanced several provocative findings with novel--but still largely potential--therapeutic implications for clinical hypertension. These include a stronger scientific rationale for using 1) combined alpha/beta-blockers in the early phases of primary hypertension and obesity-related hypertension; 2) RAAS blockers as central sympatholytics in hypertension associated with chronic kidney disease; and 3) a higher dialysis dose--either nocturnal or short daily hemodialysis--to reduce uremic stimulation of a blood pressure--raising reflex arising in the failing kidneys. New outcomes trials are needed if we are to translate this largely theoretical body of research into clinical practice.

Oral direct renin inhibition: premise, promise, and potential limitations of a new antihypertensive drug.

The first oral direct renin inhibitor, aliskiren, recently received approval for the treatment of hypertension. This article addresses the premise, promise, and potential limitations of this new class of renin-angiotensin system inhibitor. Although aliskiren adds to a list of more than 100 drugs approved for the treatment of hypertension, its introduction into clinical medicine is of particular interest because of the novel mechanism of action: inhibition of renin's catalytic activity, the most proximal and rate-limiting step in renin-angiotensin system activation. By producing more complete renin-angiotensin system inhibition than with existing agents, direct renin inhibitors may afford greater protection from hypertensive complications. Other potential advantages include additional blood pressure reduction when used in combination therapy, a placebo-like side-effect profile, avid renal concentration, and long duration of action. Potential limitations include modest levels of blood pressure reduction that are equivalent to but not greater than angiotensin receptor blockers, reduced gastrointestinal absorption with a high-fat meal, and large reactive increases in renin secretion--the functional importance of which is under intense investigation. The results of outcomes trials are eagerly awaited.