Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat

Abstract

Moreover, ␤-myosin heavy chain (␤-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased ␤-MHC and ANF expression. Although several studies report agerelated declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life. cardiac hypertrophy; isoproterenol IT IS WELL ESTABLISHED THAT older patients, when subjected to increases in sympathetic drive and/or afterload, develop heart failure (HF) more frequently compared with younger populations (21,23,33,36). Additionally, incidences of cardiovascular disease, cardiac hypertrophy, and HF are more prevalent with advancing age (7,8). The aging heart, in both humans and rats, becomes functionally impaired at the level of the organ and the cardiomyocyte (7,21,33). Age-related decreases in the contractile reserve of the heart are associated with left ventricular (LV) hypertrophy, activation of proapoptotic enzymes, and calcium cycling defects within the myocyte (2,9,19,22). The underlying cause of age-related declines in systolic performance are not completely understood but may include the following: a decrease in crucial Ca 2ϩ handling proteins such as sarco(endo)plasmic reticulum Ca 2ϩ -ATPase-2a (SERCA2a), a shift in myosin gene expression that results in higher levels of low-velocity ␤-myosin heavy chain (␤-MHC), or an increase in caspase activity. (1, 7-10, 21, 22, 33). Chronic administration of the nonselective ␤-receptor agonist isoproterenol (ISO) is an experimental model of cardiac hypertrophy that is characterized by decreases in cardiac contractility, disruptions in intracellular Ca 2ϩ handling, and increases in cardiomyocyte apoptosis and necrosis (6, 32, 51). Chronic increases sympathetic activity and the sustained elevation of circulating catecholamines are known to worsen systolic function and to decrease contractile reserve, whereas ␤-receptor antagonism mitigates the progression of clinical HF (31,36).A blunted contractile reserve is indicative of decreased myocardial viability and characteristic of human HF (5, 44). Inotrope-induced increases in [maximum of LV pressure development (ϩdP/dt max )] reflects contractile reserve, and this index is measured to clinically assess a patient's cardiac performance (26,44). Cardiac function can often appear normal until subjected to stresses, such as excessive adrenergic stimulation, which reveal underlying impairments (23, 36). In fact, an ample contractile reserve is predictive of a better prognosis in patients with LV dysfunction at rest (18).Because mature adults may have a diminished capacity to respond to cardiac stress compared with those in the growing phase, and because agi...

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