Beta-adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(salpha) mouse

Abstract

Transgenic (TG) mice with cardiac G(salpha) overexpression exhibit enhanced inotropic and chronotropic responses to sympathetic stimulation, but develop cardiomyopathy with age. We tested the hypothesis that cardiomyopathy in TG mice with G(salpha) overexpression could be averted with chronic beta-adrenergic receptor (beta-AR) blockade. TG mice and age-matched wild-type littermates were treated with the beta-AR blocker propranolol for 6-7 months, starting at a time when the cardiomyopathy was developing but was not yet severe enough to induce significant cardiac depression (9.5 months of age), and ending at a time when cardiac depression and cardiomyopathy would have been clearly manifest (16 months of age). Propranolol treatment, which can induce cardiac depression in the normal heart, actually prevented cardiac dilation and the depressed left ventricular function characteristic of older TG mice, and abolished premature mortality. Propranolol also prevented the increase in myocyte cross-sectional area and myocardial fibrosis. Myocyte apoptosis, already apparent in 9-month-old TG mice, was actually eliminated by chronic propranolol. This study indicates that chronic sympathetic stimulation over an extended period is deleterious and results in cardiomyopathy. Conversely, beta-AR blockade is salutary in this situation and can prevent the development of cardiomyopathy.

Figure 1

Kaplan-Meier analysis of survival curves of propranolol-treated and untreated TG mice. Propranolol treatment significantly (P < 0.05 by log-rank test) reduced mortality in TG mice.

Figure 2

The effects of chronic propranolol treatment on heart rate in conscious mice (a) and on arterial blood pressure in anesthetized mice (b). Conscious heart rate, derived using a telemetry system, was elevated (P < 0.05) in untreated 16-month-old TG mice compared with untreated 16-month-old WT mice. Chronic propranolol treatment reduced conscious heart rate significantly (P < 0.05) in both 16-month-old TG and 16-month-old WT mice. Mean arterial pressure also tended to decrease in the propranolol-treated groups, but did not reach significance. *P < 0.05, untreated vs. propranolol-treated mice. ^†P < 0.05, TG mice vs. corresponding WT mice.

Figure 3

LV function assessed by echocardiography. Shown are representative LV M-mode echocardiographic recordings (a and b) and average data for LV function (c and d) in both untreated and propranolol-treated older TG mice at 15 months. Propranolol prevented LV dilation in older TG mice. LVEF and mean Vcfc are compared in untreated older (14- to 15-month-old) WT (light gray bars; n = 10), propranolol-treated WT (open bars; n = 14), untreated younger (9-month-old) TG (dark gray bars; n = 10), untreated older TG (black bars; n = 10), and propranolol-treated older TG mice (dotted bars; n = 9). LV function was significantly (P < 0.05) depressed in untreated older TG mice compared with age-matched untreated older WT mice, and depressed LV function was already observed in younger TG mice, whose ages are matched to the age of animals when the β-AR blockade therapy was begun. LV contractile function in propranolol-treated older TG mice was improved compared with that in both untreated younger and older TG mice. Error bars are ± SEM. *P < 0.05, ^†P < 0.05 vs. untreated WT mice.

Figure 4

Morphological analysis in the myocardium of 16-month-old G_sα TG mice treated with (b and d) and without (a and c) propranolol. (a and b) Silver staining showing myocyte sizes. (c and d) Picric acid/sirius red staining showing collagen content.

Figure 5

Myocyte cross-sectional area, collagen content, and number of TUNEL-positive myocytes were compared in untreated older (16-month-old) WT mice (light gray bars), propranolol-treated older (16-month-old) WT mice (open bars), untreated younger (9-month-old) TG mice (dark gray bars), and propranolol-treated (dotted bars) or untreated (black bars) older (16-month-old) TG mice. (a) Myocyte cross-sectional area measured 100–200 myocytes in each section. (b) Collagen. (c) TUNEL staining. Propranolol prevented the increase in myocyte cross-sectional area and myocyte fibrosis. Furthermore, myocyte apoptosis was eliminated by chronic propranolol. Error bars are ± SEM. *P < 0.05, ^†P < 0.05 vs. untreated WT mice.