Pathogenesis of heart failure with a depressed ejection fraction 2
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LV remodeling devel- ops in response to a series of complex events that occur at the cellular and molecular levels (Table 252-3). These changes include (1) myocyte hypertrophy; (2) alterations in the contractile properties of the myo- cyte; (3) progressive loss of myocytes through necrosis, apoptosis, and autophagic cell death; (4) β-adrenergic desensitization; (5) abnormal myocardial energetics and metabolism; and (6) reorganization of the extracellular matrix with dissolution of the organized structural col- lagen weave surrounding myocytes and subsequent replacement by an interstitial collagen matrix that does not provide structural support to the myocytes. The biologic stimuli for these profound changes include mechanical stretch of the myocyte, circulating neurohormones (e.g., norepinephrine, angiotensin II), inflammatory cytokines (e.g., tumor necrosis factor [TNF]), other peptides and growth factors (e.g., endo- thelin), and reactive oxygen species (e.g., superoxide). The sustained overexpression of these biologically active molecules contributes to the progression of HF by virtue of the deleterious effects they exert on the heart and the circulation. Indeed, this insight forms the clinical rationale for using pharmacologic agents that antagonize these systems (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor-neprilysin inhibitors [ARNIs] and beta blockers) in treating patients with HF