Gender significantly influences the evolution of the early response to pressure overload, including the transition to heart failure in rats with aortic stenosis.

Abstract-To determine the effects of aging on vasoactivity in a primate model (Macaca fascicularis), 13 young male monkeys (aged 7.1Ϯ0.4 years) and 9 old male monkeys (aged 19.8Ϯ0.6 years) were chronically instrumented for measurement of left ventricular and aortic pressures and cardiac output. Total cholesterol, triglyceride, and fasting blood sugar levels were not different between the 2 groups. There were no significant differences in baseline mean aortic pressure and total peripheral resistance (TPR) in the young monkeys versus the old monkeys. TPR fell less (PϽ0.05) with acetylcholine (1 g/kg) in old monkeys (Ϫ25Ϯ1%) than in young monkeys (Ϫ34Ϯ2%), whereas decreases in TPR with sodium nitroprusside were similar in old and young monkeys. There was no evidence of atherosclerosis, but apoptosis of endothelial cells was enhanced (PϽ0.05) in the aortas and femoral arteries, but not in the media, of the old monkeys. There was a relationship (rϭ0.62, Pϭ0.013) between the incidence of terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling (TUNEL)-positive endothelial cells and endothelial cell density in the femoral artery. The reduced endothelial cell density was also correlated (rϭ0.82, PϽ0.01) with depressed TPR responses to acetylcholine. Thus, vascular endothelial dysfunction was present in old monkeys without evidence of atherosclerosis, which may be due to endothelial apoptosis and reduced endothelial cell density. (Arterioscler Thromb Vasc Biol.

To study the physiological effect of the overexpression of myocardial Gsalpha (protein levels increased by approximately threefold in transgenic mice), we examined the responsiveness to sympathomimetic amines by echocardiography (9 MHz) in five transgenic mice and five control mice (both 10.3 +/- 0.2 months old). Myocardial contractility in transgenic mice, as assessed by left ventricular (LV) fractional shortening (LVFS) and LV ejection fraction (LVEF) was not different from that of control mice at baseline (LVFS, 40 +/- 3% versus 36 +/- 2%; LVEF, 78 +/- 3% versus 74 +/- 3%). LVFS and LVEF values in transgenic mice during isoproterenol (ISO, 0.02 micrograms/kg per minute) infusion were higher than the values in control mice (LVFS, 68 +/- 4% versus 48 +/- 3%; LVEF, 96 +/- 1% versus 86 +/- 3%; P < .05). Norepinephrine (NE, 0.2 micrograms/kg per minute) infusion also increased LVFS and LVEF in transgenic mice more than in control mice (LVFS, 59 +/- 4% versus 47 +/- 3%; LVEF, 93 +/- 2% versus 85 +/- 3%; P < .05). Heart rates of transgenic mice were higher than those of control mice during ISO and NE infusion. In three transgenic mice with heart rates held constant, LV dP/dt rose by 33 +/- 2% with ISO (0.02 micrograms/kg per minute) and by only 13 +/- 2% in three wild-type control mice (P < .01). NE (0.1 micrograms/kg per minute) also induced a greater effect on LV dP/dt in the three transgenic mice with heart rates held constant compared with three wild-type control mice (65 +/ 8% versus 28 +/- 4%, P < .05). Pathological and histological analyses of older transgenic mouse hearts (16.0 +/- 0.8 months old) revealed hypertrophy, degeneration, atrophy of cells, and replacement fibrosis reflected by significant increases in collagen volume in the subendocardium (5.2 +/- 1.4% versus 1.2 +/- 0.3%, P < .05) and in the cross-sectional area of myocytes (298 +/- 29 versus 187 +/- 12 micron2, P < .05) compared with control mouse hearts. These results suggest that Gsalpha overexpression enhances the efficacy of the beta-adrenergic receptor-Gs-adenylyl cyclase signaling pathway. This in turn leads to augmented inotropic and chronotropic responses to endogenous sympathetic stimulation. This action over the life of the animal results in myocardial damage characterized by cellular degeneration, necrosis, and replacement fibrosis, with the remaining cells undergoing compensatory hypertrophy. As a model, this transgenic mouse offers new insights into the mechanisms of cardiomyopathy and heart failure and provides a new tool for their study.

Three independent methods were evaluated in an effort to obtain reliable values for myocyte size in adult Sprague-Dawley rats. Cell volume was determined from isolated myocytes by a Coulter Channelyzer system. Cell volume was also determined from the product of length and cross-sectional area of isolated myocytes. Additionally, myocyte cross-sectional area was measured morphometrically from electron micrographs of whole perfusion-fixed tissue. A major goal was to determine if anatomical methods used to measure cell volume produce values comparable to the more expeditious and objective Coulter Channelyzer method. The results of these experiments showed that myocyte dimensions obtained from all three techniques were similar. The second major objective was to use the above-mentioned techniques to evaluate regional differences in myocyte size. Myocyte cross-sectional area and volume were significantly larger in the endomyocardium than in the epimyocardium of the left ventricle. Right ventricle myocytes had significantly smaller volumes and cross-sectional areas than did left ventricle myocytes. There were no regional differences in cell lengths. We conclude that the Coulter Channelyzer system gives values for isolated myocyte volume that are similar to values obtained with histometric techniques; values for isolated myocyte cross-sectional area were representative of values obtained from myocytes in whole-sectioned tissue; significant regional differences in myocyte size are present in adult rat hearts; and regional variations in myocyte size are due to differences in myocyte cross-sectional area rather than cell length.

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of a-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.Development of the tissue-specific cells of the heart, the cardiac myocytes, has been extensively studied in vivo. Myocytes proliferate throughout fetal and early postnatal development, followed by a transition whereby proliferation ceases and further cardiac growth occurs through an increase in myocyte size rather than number (5, 9). The factors that control myocyte proliferation and the transition from hyperplastic to hypertrophic growth are unknown.Recent interest has centered on the role of proto-oncogenes in cellular development. In particular, c-myc has been implicated in controlling both proliferation and differentiation in various cell types (29). Increased expression of c-myc in chicken embryo fibroblasts results in an increase in the rate of proliferation of these cells (34). In hematopoietic cells, the expression of c-myc decreases concomitant with differentiation, and if these cells are made to constitutively express c-myc, differentiation is prevented (10,13,25,33 genes) encode proteins that induce myogenic determination in skeletal muscle. These genes all share regions of similarity with c-myc, suggesting a potential interaction of these gene products with c-myc, or with a common intracellular target, in regulating skeletal muscle differentiation. Although expression of these particular myogenic determination genes has not been observed in heart (4, 11, 43...