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To determine the effects of age on the myocardium, the functional and structural characteristics of the heart were studied in rats at 4, 12, 20, and 29 months of age. Mean arterial pressure, left ventricular pressure and its first derivative (dP/dt), and heart rate were comparable in rat groups up to 20 months. During the interval from 20 to 29 months, elevated left ventricular end-diastolic pressure and decreased dP/dt indicated that a significant impairment of ventricular function occurred with senescence. In the period between 4 and 12 months, a reduction of nearly 19% in the total number of myocytes was measured in both ventricles. In the subsequent ages, similar decreases in myocyte cell number were found in the left ventricle, whereas in the right ventricle, the initial loss was fully reversed by 20 months. Moreover, from 20 to 29 months, a 59% increase in the aggregate number of myocytes occurred in the right ventricular myocardium. In the left ventricle, a 3% increment was also seen, but this small change was not statistically significant. These estimations of myocyte cellular hyperplasia, however, were complicated by the fact that cell loss continued to take place with age. The volume fraction of collagen in the tissue, in fact, progressively increased from 8% and 7% at 4 months to 16% and 22% at 29 months in the left and right ventricles, respectively. In conclusion, myocyte cellular hyperplasia tends to regenerate the ventricular mass being lost with age in the adult mammalian rat heart.

To determine whether the hypertrophic response of the surviving myocardium after infarction leads to normalization of ventricular hemodynamics and wall stress, the left coronary artery was ligated in rats. One month later, the rats were killed. In infarcts affecting an average 38% of the free wall of the left ventricle (small infarcts), reactive hypertrophy in the spared myocardium bordering and remote from the scar was documented by increases in myocyte cell volume per nucleus of 43% and 25%, respectively. These cellular enlargements resulted in a complete reconstitution of functioning tissue. However, left ventricular end-diastolic pressure was increased, left ventricular dP/dt was decreased, and diastolic wall stress was increased 2.4-fold. After infarctions resulting in a 60%o loss of mass (large infarcts), myocyte hypertrophy was 81% and 32% in the regions adjacent to and distant from the scar, respectively. A 10% deficit was present in the recovery of viable myocardium. Functionally, ventricular performance was markedly depressed, and diastolic wall stress was increased ninefold. The alterations in loading of the spared myocardium were due to an increase in chamber volume and a decrease in the myocardial mass/chamber volume ratio that affected both infarct groups. Chamber dilation was the consequence of the combination of gross anatomic and cellular changes consisting, in the presence of small infarcts, of a 6% and a 19% increase in transverse midchamber diameter and in average myocyte length per nucleus, respectively. In the presence of large infarcts, transverse and longitudinal chamber diameters expanded by 27% and 11%, respectively, myocyte length per nucleus expanded by 26%, and the mural number of myocytes decreased by 10o. In conclusion, decompensated eccentric ventricular hypertrophy develops chronically after infarction, and growth processes in myocytes are inadequate for normalization of wall stress when myocyte loss involves nearly 40%1 or more of the cells of the left ventricular free wall. The persistance of elevated myocardial and cellular loads may sustain the progression of the disease state toward end-stage congestive heart failure. (Circulation Research 1991;68:856-869) After acute myocardial infarction, pump function is reduced in direct proportion to the extent of myocardium that is lost on an obligatory basis; that is, ejection fraction falls as a

Reactive oxygen species are recognized as important mediators of biological responses. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide. In several cell lines, oxidant stress has been linked to the activation of death programs. Here, we report for the first time that high ambient glucose concentration induces apoptosis in murine and human mesangial cells by an oxidant-dependent mechanism. The signaling cascade activated by glucose-induced oxidant stress included the heterodimeric redox-sensitive transcription factor NF-kappaB, which exhibited an upregulation in p65/c-Rel binding activity and suppressed binding activity of the p50 dimer. Recruitment of NF-kappaB and mesangial cell apoptosis were both inhibited by antioxidants, implicating oxidant-induced activation of NF-kappaB in the transmission of the death signal. The genetic program for glucose-induced mesangial cell apoptosis was characterized by an upregulation of the Bax/Bcl-2 ratio. In addition, phosphorylation of the proapoptotic protein Bad was attenuated in mesangial cells maintained at high-glucose concentration, favoring progression of the apoptotic process. These perturbations in the expression and phosphorylation of the Bcl-2 family were coupled with the release of cytochrome c from mitochondria and caspase activation. Our findings indicate that in mesangial cells exposed to high ambient glucose concentration, oxidant stress is a proximate event in the activation of the death program, which culminates in mitochondrial dysfunction and caspase-3 activation, as the terminal event.

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