To determine the effects of aging on the human myocardium, 67 O ne of the major difficulties encountered in the study of the effects of age on the cardiovascular system is the differentiation of the aging process itself from the presence of specific disease states. Atherosclerosis, diabetes, and ischemic heart disease are common events in humans, and the severity of these pathological conditions increases with age. Because the contribution of these variables to the alterations of the aged myocardium cannot easily be separated from the aging phenomenon alone, the changes of the heart throughout life are therefore the result of multifactorial events in which aging plays an important but indistinguishable role.1 There is no temporal reference point that can be used to distinguish between maturational changes beyond sexual maturity and the aging changes per se, since they are both controlled by time as a critical factor.'-3 Thus, the issue of whether aging of the heart has to be regarded as a successful adaptation or as a progressive disease state remains a matter of controversy, with data being accumulated in support of the former1-4 and the latter.5-9 However, it is well established that in both humans and animals myocyte proliferation occurs shortly after birth'0-13 and that the growth of the heart, during the relatively early phases of postnatal life and long before sexual maturity is reached, is controlled by hypertrophy of myocytesl213 and hyperplasia of capillary endothelial cells and interstitial fibroblasts.13 Although DNA synthesis with ploidy formation in adult human cardiac myocytes has been described,14-17 this phenomenon does not alter the number of muscle cells and/or muscle cell nuclei in the tissue, so that the total number of myocytes or myocyte nuclei in the ventricle can be used as an absolute reference parameter for the evaluation of the effects of aging on the myocardium. This approach was used in the present investigation to determine whether myocyte cell loss accompanies the life span of humans and may constitute the underlying cause for the occurrence of congestive heart failure in the elderly. Materials and Methods Study Design and Selection CriteriaSixty-seven human hearts were collected from a total number of 1,176 autopsies performed at the University Hospital of Parma Medical School during 1988 and 1989. All 67 hearts were collected within 24 hours after death. These cases were assumed to represent normal aging according to preautopsy criteria, autopsy criteria, and histological criteria, which are listed below.Preautopsy criteria for inclusion in the study. These criteria were as follows: 1) sudden death associated
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.
Diabetes mellitus is associated frequently with congestive heart failure in humans, even in the absence of associated coronary disease or hypertension. Nevertheless, the effects of the diabetic state on myocardial mechanics have not been studied. Accordingly, diabetes was induced in female Wistar rats by injection of streptozotocin (60 mg/kg). Left ventricular papillary muscles were studied 5, 10, and 30 weeks later and compared with controls. Relaxation was delayed significantly and velocity of shortening was depressed at all loads. However, the passive and active force-length curves, as well as the series elastic properties, were not altered. The changes in cardiac performance were found over a range of muscle lengths, stimulus frequencies, and bath concentrations of calcium, glucose, and norepinephrine. The duration of diabetes had no major effect on the mechanical changes observed. The possible influences of drug-induced cardiac toxicity, malnutrition, and altered thyroid hormone levels have been considered; the latter two factors could not be excluded completely from having some influence on the mechanical properties of diabetic cardiac muscle. Evidence is cited showing abnormalities in calcium uptake by sarcoplasmic reticulum and depressed actomyosin ATPase activity. Thus a cardiomyopathic state has been produced in the rat consequent to the induction of experimental diabetes mellitus. Various mechanisms for this entity have been suggested.
To determine whether acute left ventricular failure associated with myocardial infarction leads to architectural changes in the spared nonischemic portion of the ventricular wall, large infarcts were produced in rats, and the animals were killed 2 days after surgery. Left ventricular end-diastolic pressure was increased, whereas left ventricular dP/dt and systolic pressure were decreased, indicating the presence of severe ventricular dysfunction. Absolute infarct size, determined by measuring the fraction of myocyte nuclei lost from the left ventricular free wall, averaged 63%. Transverse midchamber diameter increased by 20%, and wall thickness diminished by 33%. The mural number of myocytes in this spared region of the left ventricular free wall decreased by 36% and the capillary profiles by 40%o. The combination of these functional abnormalities and structural rearrangement of the wall resulted in a 7.8-fold increase in diastolic wall stress. A comparable analysis of the interventricular septum demonstrated a 24% reduction in the number of cells across the septal thickness, whereas capillaries were diminished by 26%. Moreover, a 7.2-fold elevation in diastolic stress was computed in this region of the ventricle. The augmentation in diastolic stress was associated with a 22% and a 16% myocyte cellular hypertrophy in the wall and septum, respectively. In conclusion, side-to-side slippage of myocytes in the myocardium occurs in association with ventricular dilatation after a large myocardial infarction and contributes to ventricular remodeling and the occurrence of decompensated eccentric hypertrophy. (Circulation Research 1990;67:23-34) H uman1-4 and animal4-7 studies of the effects of myocardial infarction on ventricular architecture have demonstrated that the injured ventricle progressively enlarges with time and that this alteration is paralleled by a corresponding decline in cardiac performance.2'8'9 Moreover, chamber dilatation is not accompanied by a proportional increase in wall thicknessl-9 so that the ratio of wall thickness to chamber radius is not maintained, and decompensated ventricular hypertrophy occurs.10 Thinning of the ventricular wall occurs not only in the necrotic region but also in the zone of surviving myocardium where a number of tissue and cellular
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
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