Congestive Heart Failure: A Salt-Avid Syndrome

In patients with congestive heart failure, persistent activation of the renin–angiotensin–aldosterone system is inappropriate, given the absence of salt deprivation or intravascular volume contraction, and it has pathologic effects. It induces inappropriate expansion of the intravascular and extravascular volumes and fibrosis of the heart, kidneys, and other organs. These adverse outcomes contribute to the progressive nature of congestive heart failure, with its inexorable downhill clinical course that includes recurrent episodes of symptomatic failure and sudden death from cardiac causes.

Congestive heart failure is a clinical syndrome involving a constellation of symptoms and signs that arise from congested organs and hypoperfused tissues. It begins with impaired ventricular function, but much of what follows is caused by the retention of salt and water.72,73 Because of the role of sodium retention, the severity of congestive heart failure cannot be gauged by indexes of systolic or diastolic pump function, as it can be in patients with acute heart failure (e.g., after myocardial infarction). Not all patients with heart failure, defined as chronic ventricular systolic dysfunction, have congestive heart failure. The left ventricular ejection fraction does not predict systemic blood flow or its distribution and therefore cannot predict renal perfusion that results in the activation of the renin–angiotensin–aldosterone system. Patients with a reduced ejection fraction can have compensated heart failure, with exertional dyspnea and fatigue that occur only with heavy muscular work, and no signs of expanded intravascular or extravascular volume. When patients with systolic dysfunction have these symptoms at rest and during mild exertion, they have decompensated heart failure. In patients whose heart failure is compensated, the ratio of sodium to potassium in urine is greater than 1.0, because of the release of natriuretic peptides from the distended atria and ventricles (Figure 4). Decompensation occurs when there are moderate-to-marked reductions in renal perfusion. Plasma renin activity increases, and the resulting increases in angiotensin II and aldosterone production override the action of the natriuretic peptides. Urinary sodium retention becomes nearly complete (i.e., the sodium:potassium ratio is less than 1.0), and intravascular and extravascular volumes increase.

Figure 4. Compensated and Decompensated Heart Failure, as Indicated by the Presence or Absence of Urinary Sodium Retention, Together with Symptoms and Signs of Expanded Intravascular and Extravascular Volume. In compensated heart failure with mild-to-moderate reductions in renal perfusion, natriuretic peptides, such as atrial natriuretic peptide (ANP) released by distended atria, stimulate sodium excretion (decreasing reabsorption, minus sign) so that the urinary sodium:potassium ratio is greater than 1.0. In decompensated heart failure, moderate-to-severe reductions in renal perfusion activate the renin–angiotensin–aldosterone system (RAAS), overriding the action of natriuretic peptides to stimulate nearly complete urinary sodium reabsorption (plus sign), resulting in a urinary sodium:potassium ratio of less than 1.0. Reproduced from Weber and Villarreal74 with the permission of the publisher.

In an international study (the Randomized Aldactone Evaluation Study [RALES]), conducted in 19 countries on 5 continents and involving more than 1660 patients with moderately severe or severe congestive heart failure, there was a 30 percent reduction in the rate of death from any cause among patients treated with spironolactone (25 mg daily) in combination with an ACE inhibitor and a loop diuretic, as compared with patients who received placebo (Table 1).6 In addition, there were similar reductions in sudden death from cardiac causes, death from progressive cardiac failure, and hospitalizations related to symptomatic heart failure. The patients enrolled in this trial had base-line serum creatinine concentrations of less than 2.5 mg per deciliter (221 nmol per liter); severe hyperkalemia occurred in less than 2 percent of the patients receiving spironolactone.