Metabolic alkalosis and cystic fibrosis.

Important and otherwise excellent articles by Weber1,2 and Schrier and Abraham3 strongly characterize persistent reninangiotensin-aldosterone system (RAAS) activation in congestive heart failure, a hypervolemic state, as “inappropriate” based on their view that the primary role of the RAAS is to prevent salt deprivation or intravascular volume contraction (hypovolemia). Actually, as the authors state but apparently dismiss, it is renal hypoperfusion not hypovolemia per se that activates the RAAS. Since hypoperfusion is hypoperfusion whether a result of heart failure (HF) or hypovolemia, RAAS activation is in fact no more inappropriate in HF than, say, a high thyrotropin in an athyreotic. RAAS activation is exquisitely sensitive to low cardiac output (CO)/low renal perfusion, responding to mere postural changes.1 Reduced CO in early HF prompts RAAS-activated fluid retention, which increases ventricular preload and CO until CO again meets the RAAS activation threshold. RAAS activation is maintained at this higher set-point to preserve the compensated CO. With sufficient further ventricular dysfunction, CO can no longer reach the RAAS activation threshold.4 Thus unable to achieve a new higher set point, the RAAS is persistently activated in proportion to the CO shortfall in a futile attempt to raise the intractably low CO.4 Since low CO stimulates the RAAS feedback control loop, RAAS activation is never inappropriate when CO is low or compensated, but when it raises venous pressure above the onset of the Starling plateau it is many things, including “ineffective” and “excessive” (because it no longer significantly increases CO), “congestive,” and even “toxic” (due to its cardiovasculopathic effects as well described by Weber1). Weber1 appropriately contrasts HF patients, whose hyperaldosteronism results in near-complete sodium reabsorption and edema, with: “Normal subjects given aldosterone and patients with primary (renin-independent) hyperaldosteronism (Conn’s syndrome) [who] escape the salt-retaining effects of aldosterone and do not have edema.” He points out that these subjects lack the elevated angiotensin II levels typical of HF, and because angiotensin II contributes to renal tubular sodium reabsorption, renal sodium conservation is incomplete. As he alludes, this could at least partly account for the escape phenomenon.1 But these subjects also lack the CO ceiling characteristic of HF. Thus, their aldosterone-enhanced preload increases CO above normal resting levels and this in turn increases BP and renal perfusion. Combined with the lesser angiotensin II levels, the increased renal perfusion reestablishes salt and water balance and thus curtails volume accumulation before its overt expression as edema. The characterization of persistent RAAS activation in congestive HF as “inappropriate” unfortunately fuels the popularity of the “neurohormonal”/“salt-avid kidney”2 HF model, which among other currently fashionable models including the cellular, molecular, genetic, inflammatory5 and even the (understood to be facetious) febrile6 model, regrettably obscures the reality that low CO remains, as always, the true pathophysiologic basis of HF.