Neurohormonal activation and the management of heart failure

Heart failure is a complex and usually progressive disease process in which structural and functional disturbances in the left ventricle are accompanied by activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) (Thomas and Marks, Am J Cardiol, 41:233-43, 1978; Levine et al., Am J Cardiol, 49:1659-66, 1982; Cohn et al., N Engl J Med, 311:819-23, 1984). Before the 1970s, managing heart failure aimed at improving the functional deficit of the left ventricular pump and relieving the resultant fluid accumulation with diuretic therapy (Weber, J Am Coll Cardiol, 44(6):1308-10, 2004). Although diuretic therapy has remained a mainstay of treatment, inotropic drug therapy was associated with adverse effects and no improvement in survival (Lee et al., N Engl J Med, 306(12):699-705, 1982; Guyatt et al., Am J Cardiol, 61(4):371-5, 1988). Consequently, since the 1970s, pharmacologic management has shifted more toward reducing the vascular bed's opposition to left ventricular emptying and inhibiting the vasoconstrictor and growth-promoting influences of neurohormonal stimulation that leads to left ventricular structural changes or remodeling (Cohn, Circulation, 48(1):5-8, 1973; Guiha et al., N Engl J Med, 291(12):587-92, 1974; Mikulic et al., Circulation, 56(4 Pt 1):528-33, 1977; Cohn and Franciosa, Am J Med, 65(1):181-8, 1978). This shift in emphasis has resulted in reduced dependence on digitalis and other positive inotropic interventions and greater reliance on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic receptor blockers, aldosterone inhibitors, and newer agents that appear to inhibit vasoconstrictor and growth-promoting forces that contribute to the progression of the disorder (CONSENSUS Trial Study Group, N Engl J Med, 316(23):1429-35, 1987; The SOLVD Investigators, N Engl J Med, 325(5):293-302, 1991; Cohn et al., N Engl J Med, 345(23):1667-75, 2001; Packer et al., N Engl J Med, 334(21):1349-55, 1996; McMurray et al., N Engl J Med, 371(11):993-1004, 2014). This chapter addresses the evidence for neurohormonal activation in heart failure, data demonstrating a favorable effect of these neurohormonal modulators on the course of heart failure, and future therapeutic strategies that may be effective in slowing the growing burden of heart failure in the developed world.