β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy

Abstract

Abstract-It is uncertain whether chronic ␤-adrenoreceptor (␤-AR)-activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure-volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic ␤-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

“…Prior studies have demonstrated the relatively more important role of LV dilatation in animal models of myocardial infarction (2), pressure-overload hypertrophy (23), and pressure-overload hypertrophy together with chronic adrenergic overstimulation (3,35). However, this is the first study to show that pump dysfunction induced by persistent adrenergic activation in otherwise normal hearts may occur primarily as a consequence of LV dilatation.…”

“…In contrast, in our present study, the Iso dose employed has previously been shown by us to produce minimal cardiac myocyte necrosis (35,38), data supported by findings in the present study. The dose employed by us is nevertheless sufficient to promote deleterious interstitial changes (qualitative rather than quantitative changes) upon chronic administration (3,35,38) and hence to induce LV dilatation.…”

“…However, as cardiac chamber dilatation usually coexists with myocardial damage and dysfunction, the extent to which pump dysfunction in a dilated chamber reflects the impact of chamber dilatation or the degree of underlying myocardial systolic failure is uncertain. Recent evidence obtained by our group suggests that the presence of cardiac dilatation and pump dysfunction may be independent of the degree of underlying intrinsic myocardial systolic dysfunction (3,23,35). Nevertheless, these studies were conducted in pressure-overload states where, even without pump failure, intrinsic myocardial systolic dysfunction may still occur (23).…”

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation

“…In these situations, it is believed that elevated levels of circulating and tissue catecholamines produce chronic stimulation of cardiac b-adrenoceptors that might result in desensitisation, downregulation and signalling abnormalities in cardiac myocytes (Castellano & Bohm, 1997;Badenhorst et al, 2003). However, little is known about the effects of chronic stimulation of b-adrenoceptors on vascular function and its endothelial modulation.…”

Down-Regulation of Na+Pump α2Isoform in Isoprenaline-Induced Cardiac Hypertrophy in Rat: Evidence for Increased Receptor Binding Affinity but Reduced Inotropic Potency of Digoxin

“…The reduced baseline LVDP 0 in the ISO-pretreated group (Table 1) points to a decompensated LV hypertrophy (Badenhorst et al, 2003). Although recent results in pressure-overload hypertrophied hearts (Minakawa et al, 2003) suggest that this contractile failure could be also explained by the decrease in the relative level of sarcoplasmic reticu- (Boluyt et al, 1995), this question is still under dispute (Badenhorst et al, 2003;Houser and Margulies, 2003;Ward et al, 2003) (vide infra). The lack of right ventricular hypertrophy (Fig.…”