Pathophysiology

The hemodynamic model of CHF has been largely abandoned and replaced by the concept of left ventricular remodeling (Francis, 2001). Remodeling of the left ventricle indicates stretching and dilation with subsequent reduction in left ventricular function. The remodeling process can be triggered by a multitude of potential injuries (Levy et al., 1996; Kannel et al., 1994), including CAD, MI, hypertension, valvular heart disease, diabetes, congenital heart defects, anemia, and alcoholism. Regardless of the precipitating injury, neurohormonal mechanisms are activated and promote the remodeling process. These include the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). A rise in endothelin-1 production, a product of dysfunctional endothelium, also occurs and contributes to vasoconstriction. In addition, inflammatory markers and cytokines are increased, further exacerbating endothelial dysfunction (Blum and Miller, 2001; Francis, 1998).

Pharmacologic interventions that block neurohormonal activation can reduce mortality and morbidity in patients with CHF (Fig. 27-12). A rise in angiotensin II (AII) promotes programmed cell death (apoptosis), hypertrophy, and fibrosis. AII also causes an increase in aldosterone secretion (Fig. 27-13), which in return augments the harmful effects of AII on myocardium and promotes adverse remodeling. Aldoste-rone, however, "escapes" angiotensin suppression (McKelvie et al., 1999) and, therefore, selective aldosterone blockade is needed in addition to therapy with ACEIs or ARBs (Pitt et al., 1999, 2001). A rise in circulating levels of catecholamines in response to SNS activation can lead to suppression of adren-ergic receptors and has direct toxic effects on myocardium (Bristow et al., 1993). Catecholamines mediate toxicity as a result of beta-adrenoceptor-mediated cyclic adenosine monophosphate (cAMP)-dependent calcium overload of cardiac myocytes (Mann, 1998; Mann et al., 1992). Also, cat-echolamines increase myocardial oxygen consumption and coronary blood flow requirements and decrease myocardial

Figure 27-12 The renin-angiotensin-aldosterone system and the sympathetic nervous system are currently the target for treating patients with congestive heart failure. ACE, Angiotensin-Converting enzyme; ARB, angiotensin receptor blocker.
Figure 27-13 Various pharmacologic interventions to block the renin-angiotension-aldosterone system; ACE, angiotensin-converting enzyme; AT, angiotensin.

mechanical efficiency (Nikolaidis et al., 2004). Catecholamines also induce left ventricular hypertrophy (LVH) and can precipitate potentially debilitating and fatal arrhythmias.

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