Cardiac hypertrophy and ventricular remodeling.
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Animals↗
Biomedical subjects
J M Capasso
Publications and source records attributed to J M Capasso.
Mechanisms of myocyte and capillary growth in the infarcted heart.
To identify the structural mechanisms of cardiac hypertrophy following myocardial infarction, the changes in the dimensional characteristics of the spared myocytes were measured 40 days after coronary occlusion. Further, to determine whether tissue oxygenation in the hypertrophied ventricle was supported by a proportional growth of the capillary network, morphometric analysis was used to measure capillary luminal volume and surface densities, and the diffusion distance for oxygen. Large infarcts of the ventricle (50%) produced a 10% increase in myocyte diameter and a 38% increase in myocyte length. Small infarcts (23%) induced 6% and 15% expansions of cellular diameter and length. After large infarcts, there was a 22% decrease in capillary numerical density that resulted in an 18% reduction in capillary surface and a 16% increase in the diffusion distance for oxygen. The 15% reduction in capillary numerical density seen with small infarcts was associated with a 10% decrease in surface and a 9% increase in diffusion distance. In conclusion, cardiac hypertrophy following myocardial infarction is consistent with cellular shape changes characteristic of a combination of concentric and eccentric hypertrophic growth. The relatively inadequate adaptation of the capillary vasculature suggests that the injured ventricle is more vulnerable to additional ischaemic episodes.
Animals↗
Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts.
To determine if aging engenders alterations in the functional properties of the myocardium and ventricular remodeling, the hemodynamic performance and structural characteristics of the left ventricle of male Fischer 344 rats at 4, 12, 20, and 29 mo of age were studied by quantitative physiology and morphology. In vivo assessment of cardiac pump function showed no change up to 20 mo, whereas left ventricular end-diastolic pressure was increased at 29 mo. Moreover, peak rates of pressure rise and decay, stroke volume, ejection fraction, and cardiac output were depressed at the later age interval, demonstrating the presence of ventricular failure at this time. The measurements of chamber size and wall thickness showed that ventricular end-diastolic and end-systolic volumes progressively increased with age with the greatest change occurring at 20-29 mo. Aging was also accompanied by a marked augmentation in the volume fraction of fibrotic areas in the ventricular myocardium that was due to an increase in their number and cross-sectional area with time. These architectural rearrangements, in combination with the abnormalities in ventricular function, resulted in an elevation in the volume of wall stress throughout the cardiac cycle. Wall stress increased by 64, 44, and 50% from 4 to 12, 12 to 20, and 20 to 29 mo of age. In conclusion, aging leads to a continuous rise in wall stress that is not normalized by ventricular remodeling. These two independent processes appear to be responsible for the onset of heart failure in the senescent rat.
Aging↗
Left ventricular failure induced by long-term hypertension in rats.
To determine whether the duration of hypertension is an essential component in the evolution of myocardial dysfunction, renal artery constriction was performed in male Fischer 344 rats at 4 months of age, and in vivo global cardiac performance of sham-operated and experimental animals was evaluated 8 months later. Systemic arterial blood pressure increased to 173 +/- 5 mm Hg 2 weeks after the arteries were clipped and remained elevated for the following 5 months. Blood pressure decreased over the remaining 3 months to a value not significantly different from control rats that were killed, 132 +/- 4 mm Hg. After 8 months of renovascular hypertension, we observed that the elevated level of systolic arterial pressure was accompanied by a distinct absence of left ventricular hypertrophy when measured at the ventricular weight level. Moreover, left ventricular end-diastolic pressure increased in hypertensive animals from 6.0 to 24.0 mm Hg while peak left ventricular pressure was identical to controls. In addition, peak +dP/dt and -dP/dt were depressed in hypertensive animals. Although stroke volume was unaltered, cardiac output in renal artery clipped animals was depressed by 34% while total peripheral resistance was elevated by 50%. Ventricular chamber remodeling in the hearts of hypertensive animals was evidenced as a 19% increase in the transverse and a 16% increase in the longitudinal axes of the left ventricle with a 27% diminution of wall thickness. Myocardial damage, in the form of myocyte loss and replacement fibrosis, increased in the hearts of hypertensive animals resulting in a ninefold augmentation in the volume fraction of collagen within the ventricular wall. These alterations in the architectural properties of chamber geometry coupled with the abnormalities in contractile performance resulted in a severe reduction in ejection fraction from 82% to 47% and a marked elevation in transmural diastolic and systolic stress in hypertensive animals. The gradient in stress across the ventricular wall, from epicardium to endocardium, revealed a direct correlation with the regional distribution of myocardial damage. In conclusion, the loading state of the myocardium, tissue injury, and myocardial fibrosis all appear to be critical determinants in the genesis of left ventricular failure in long-term pressure overload.
Animals↗
Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats.
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%. 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.
Animals↗
Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart.
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.
Aging↗
Chronic calcium channel blockade prevents the progression of myocardial contractile and electrical dysfunction in the cardiomyopathic Syrian hamster.
The programmed onset of myocardial dysfunction and its progression to congestive heart failure in the cardiomyopathic Syrian hamster is hallmarked by alterations in myocellular calcium regulation. To determine whether calcium channel blockade is effective in halting the progressive depression of myocardial contractile performance in this animal model of congestive heart failure, oral verapamil therapy was instituted at 50 days of age, and treatment continued for various durations until the time of study at either 150 or 250 days of age. Left ventricular papillary muscle isometric and isotonic performance, as well as transmembrane electrical characteristics, was depressed in diseased hamsters at 150 days of age and deteriorated further by 250 days of age. These changes were evidenced by prolongation of contraction duration, a marked depression in the load-velocity relation, and a significant prolongation in the repolarization phase of the transmembrane action potential. Myocardial functional and electrical alterations associated with the progression of life in myopathic hamsters were completely halted by verapamil therapy that was continuous from 50 days after birth until death by diastolic arrest, at 150 or 250 days of age. However, premature termination of verapamil treatment before death resulted in a progressive renewal of the functional and electrical alterations for the duration of drug termination. It is concluded that the pathological changes seen during the lifetime of the cardiomyopathic hamster can be prevented by continuous calcium channel blockade and that intermediate prevention can be attained by protracted verapamil therapy. Thus, chronic verapamil therapy may be a useful adjunct in the prevention of human congestive heart failure of similar etiology.
Animals↗
Hypertensive cardiomyopathy. Myocyte nuclei hyperplasia in the mammalian rat heart.
To determine whether long-term hypertension leads to hyperplasia of myocyte nuclei in the heart, a phenomenon suspected to occur in humans, renal hypertension was produced in rats and the animals were killed 8 mo later. Arterial blood pressure remained elevated for approximately 5 mo, but decreased progressively in the last 3 mo so that at 8 mo this parameter was practically identical to that found in controls. Moreover, left ventricular end diastolic pressure was markedly increased in experimental animals in association with a substantial decrease in left ventricular dP/dt. The alteration of these physiological measurements was indicative of severe ventricular dysfunction. Quantitative analysis of the transmural distribution of myocyte nuclei in the left ventricle showed 36 and 23% increases in myocyte nuclei concentration in the epimyocardium and endomyocardium, respectively. These changes in nuclei were accompanied by 25 and 16% reductions in myocyte cell volume per nucleus in the outer and inner layers of the wall. In conclusion, long-term hypertension leads to impairment of ventricular function and proliferation of nuclei in myocytes.
Animals↗
Noncoordinate regulation of alpha-1 adrenoreceptor coupling and reexpression of alpha skeletal actin in myocardial infarction-induced left ventricular failure in rats.
To determine the effects of myocardial infarction-induced left ventricular failure on the regulation of surface alpha-1 adrenoreceptors and signal transduction, large infarcts were produced in rats and the animals killed seven days later. After the documentation of impaired left ventricular pump performance, radioligand binding studies of the alpha-1 adrenoreceptor, norepinephrine-stimulated phosphoinositol turnover, and ADP ribosylation of 41 kD substrate by pertussis toxin were examined in the hypertrophying unaffected myocardium. Moreover, the expression of sarcomeric actin isoforms was analyzed by Northern blots and hybridization with specific oligonucleotide probes. Alpha-1 adrenoreceptor density was found not to be altered in membranes obtained from the spared left ventricular tissue, whereas phosphoinositol turnover was increased 3.1-fold in the viable myocytes of infarcted hearts. Furthermore, pertussis toxin substrate was augmented 2.5-fold in membranes prepared from the surviving left ventricular myocardium. Finally, an upregulation of the skeletal actin isoform was detected in the tissue of the failing left ventricle. In conclusion, the possibility is raised that in the presence of severe myocardial dysfunction and ongoing reactive hypertrophy, effector pathways linked to the alpha-1 adrenoreceptor may stimulate the myocyte hypertrophic response which would tend to normalize cardiac hemodynamics. The reexpression of alpha skeletal actin may be a molecular indicator of the persistance of an overload on the myocardium.
Actins↗
Mechanism of phosphorylation in the lumen of the Golgi apparatus. Translocation of adenosine 5'-triphosphate into Golgi vesicles from rat liver and mammary gland.
The occurrence of phosphorylated secretory proteins such as caseins and vitellogenin and the recent characterization of phosphorylated proteoglycans, in the xylose and protein core, has raised the question of where in the cell and how this phosphorylation occurs. Previous studies have described a casein kinase activity in the lumen of the Golgi apparatus and this organelle as the site of xylose addition to the protein core of proteoglycans. We now report the translocation in vitro of ATP into the lumen of rat liver and mammary gland Golgi vesicles which are sealed and have the same membrane topographical orientation as in vivo. The entire ATP molecule was translocated into the lumen of the Golgi vesicles; this was established by using ATP radiolabeled with tritium in the adenine and gamma-32P. Translocation was temperature dependent and saturable, with an apparent Km of 0.9 microM and Vmax of 58 pmol/mg protein/min. Preliminary evidence suggests that translocation of ATP into the vesicles' lumen is coupled to exit of AMP from the lumen. Following translocation of ATP into the lumen of the vesicles, proteins were phosphorylated.
Adenosine Triphosphate↗
Morphometric analysis of the infarcted heart.
To determine whether left ventricular hypertrophy following myocardial infarction leads to a complete or incomplete reconstitution of myocardial mass, the left coronary artery in rats was ligated and the animals sacrificed 30 days later. Infarcts affecting an average 43% of the ventricle were characterized by a 90% hypertrophic growth of the remaining myocardium that was inadequate for a full restoration of ventricular tissue. Myocyte hypertrophy, evaluated by changes in mean cell volume per nucleus, was again insufficient for a total recovery of the myocyte compartment of the ventricle. These observations suggest that infarcts comprising nearly 50% of the ventricle produce a sufficiently large stress on the spared myocytes to stimulate their maximal hypertrophic reserve capacity. Cardiac muscle cells, however, appear to be unable to offset by cellular hypertrophy alone the loss of mass induced by infarcts of this size. The inadequate compensatory response of the myocytes could be the underlying structural mechanism responsible for impaired ventricular function in large infarcts.
Animals↗
Alterations of coronary blood flow and reserve with aging in Fischer 344 rats.
To determine whether aging affects the coronary circulation, left and right ventricular coronary blood flow and vascular resistance at rest and after maximal vasodilation were measured by left atrial injection of radioactive microspheres in conscious, unrestrained male Fischer 344 rats at 4, 12, and 20 mo of age. As a function of age, maximal coronary blood flow per 100 g of tissue decreased by 43% in the left ventricle at both 12 and 20 mo, whereas a 44 and a 47% reduction was found in the right side of the heart at the same time intervals. Minimal coronary vascular resistance per 100 g of myocardium increased by 56 and 36% in the left ventricle and by 48 and 44% in the right at 12 and 20 mo, respectively. No change was found in total minimal coronary resistance for either ventricle despite an increase in myocardial mass. Maximal coronary blood flow per 100 g to the endocardium was depressed more than epicardial flow, leading to a 24% reduction in the endocardial-to-epicardial flow ratio at 20 mo. Coronary vascular reserve per 100 g, expressed as the increase in coronary blood flow during maximal coronary vasodilation, was greater in the right than in the left ventricle at all ages. It is concluded that the changes in coronary hemodynamics associated with maturation and aging are comparable with those seen in pressure overload hypertrophy with an increased vulnerability potential of the myocardium to ischemic episodes, particularly of the subendocardial region of the left ventricle.
Aging↗
Effects of age on mechanical and structural properties of myocardium of Fischer 344 rats.
To determine whether the mechanical and structural characteristics of the myocardium from the left and right ventricles are comparable in the adult rat and whether aging affects the two ventricles in a similar manner, the left and right posterior papillary muscles of rats at 10-11 and 19-20 mo of age were studied in terms of function and quantitative morphology. At 10-11 mo of age, the duration of isometric contraction was shorter and resting tension higher in the right muscle than in the left muscle. Isotonic velocity of shortening and relengthening were quicker in the left, but time-to-peak shortening was faster in the right. With aging (19-20 mo), velocity of shortening fell in the left ventricle while duration of contraction became prolonged. No such age-related effects were found in the right papillary muscle. On a structural basis, myocardial damage in the form of replacement scarring was present in the left and right muscles at 10-11 mo of age. However, the left muscle was more severely injured, and this difference persisted with age because a comparable increase in replacement fibrosis occurred in both muscles. It was concluded that cardiac performance is distinctly different in the left and right papillary muscles and aging exerts its detrimental impact on the left more than in the right myocardium, an observation that is further supported by the magnitude of tissue injury.
Aging↗
Long-term pressure-induced cardiac hypertrophy: capillary and mast cell proliferation.
To determine whether a prolonged duration of mechanical load on the ventricular myocardium leads to capillary proliferation, constriction of the pulmonary artery was produced in rats at 3 mo of age, and the hearts were examined 200 days later. Functionally, elevations of right ventricular systolic pressure, from 30 +/- 12 to 67 +/- 11 mmHg, and right ventricular end-diastolic pressure, from 2.4 +/- 1.4 to 8.6 +/- 2.4 mmHg, were found. Anatomically, a 69% enlargement in right ventricular mass was observed, and this hypertrophic growth was characterized by a 78% thickening of the wall with no change in ventricular wall area, the latter calculated from the quotient of ventricular volume and wall thickness. Morphometric data showed a 44% increase in the capillary-to-myocyte ratio, a 66% augmentation of the total length of capillaries in the whole ventricle, and a 77% greater number of capillaries across the ventricular wall. Furthermore, these indexes of neogenesis of capillary units were associated with a more than three fold increase in the numerical density of mast cell profiles in the myocardium. In conclusion, capillary proliferation occurs in the adult rat heart, and this process appears to be coupled with mast cell hyperplasia.
Animals↗
Mechanical and electrical properties of cardiomyopathic hearts of Syrian hamsters.
To determine whether the cardiomyopathy that develops in the Syrian hamster before the occurrence of congestive heart failure is associated with mechanical and electrical alterations consistent with myocardial dysfunction, left ventricular posterior papillary muscles of control and cardiomyopathic animals at 120 days of age were studied in vitro. Moreover, the electrocardiographic response to ouabain was investigated in vivo to analyze the arrhythmogenic potential of the cardiomyopathic heart to glycoside exposure. Results showed a decreased tension-generating ability of the myocardium in the diseased animals, which was accompanied by a prolongation of the timing parameters of contraction and an increase in the duration of the repolarization phase of the transmembrane action potential. Furthermore, the velocity of isotonic muscle shortening and relengthening was depressed at all physiological loads. Glycoside infusion elicited premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation in diseased hamsters much earlier in time than in healthy controls. The impairment in mechanical performance in association with the abnormality in membrane electrical activity may be responsible for the progression of the disease process and the occurrence of lethal arrhythmias in this animal model.
Action Potentials↗
Ventricular remodeling induced by acute nonocclusive constriction of coronary artery in rats.
To determine the consequence of acute nonocclusive constriction of the epicardial coronary artery on the adaptation of the left ventricle and its impact as a function of age, the left main coronary artery was narrowed in rats 4 and 12 mo of age, and the animals were killed 45 min later. Similar reductions in the luminal diameter, averaging 4%, were obtained in both groups of animals, and this change resulted in an increase in left ventricular end-diastolic pressure and a decrease in positive and negative change in pressure overtime (dP/dt) and in peak-developed ventricular pressure. Left ventricular volume increased by 66% and 56% at 4 and 12 mo because of increases in both the longitudinal and transverse chamber diameters. In contrast, wall thickness decreased by 27% and 35%, whereas sarcomere length increased only by 8.0% and 6.0%, respectively. These changes implied the occurrence of side-to-side slippage of myocytes within the wall to accommodate the larger chamber volume. The alterations in myocardial performance combined with the variations in ventricular size and wall thickness produced a marked elevation in diastolic and systolic wall stress. Moreover, myocyte cell damage in the form of contraction bands and disorganization of the intercalated disc region was seen. No consistent difference was found in any of the parameters measured as a function of age. Measurements of resting coronary blood flow across the left ventricular wall before coronary artery narrowing were comparable with those obtained 45 min after constriction. In conclusion, acute nonocclusive coronary artery stenosis has profound detrimental effects on the function and structure of the myocardium in the absence of an impairment of resting coronary blood flow.
Aging↗
Capillary growth in anemia-induced ventricular wall remodeling in the rat heart.
To determine whether anemia-induced cardiac hypertrophy affects ventricular size and shape and the component structures of the capillary network of the left and right ventricles, young male rats were fed an iron- and copper-deficient diet for 7 weeks. By that time, blood hemoglobin content fell to 5 +/- 1 g/dl, and packed cell volume fell to 18 +/- 3%. To further characterize the implications of anemia, red blood cell number, hemoglobin corpuscular content, systemic arterial pressure, heart rate, and blood viscosity were measured. Moreover, the changes in ventricular weights were analyzed in terms of the alterations in ventricular wall area and ventricular wall thickness to establish the impact of the elevation in load associated with a high cardiac output state on ventricular remodeling. The quantitative properties of the capillary circulation were also examined biventricularly by low power electron microscopic morphometry to evaluate the adaptive growth potential of the coronary microcirculation in this form of cardiac hypertrophy. Anemia was found to interfere with the production of red blood cells and their mean corpuscular hemoglobin content and resulted in a 40% reduction in blood viscosity and a 12% and 27% decrease in systolic and diastolic blood pressure, respectively. The changes in heart rate were not statistically significant. In comparison with control animals, heart weight increased by 50%, but the enlargement in right ventricular mass (65%) was greater than that of the left ventricle (47%). Ventricular hypertrophy occurred with increases in wall area and wall thickness although the former increased consistently more than the latter in either ventricle. Tissue growth was accompanied by a 60% lengthening of the capillary network, which in combination with an increase in capillary diameter resulted in a 65% and 34% expansion in capillary luminal volume and 56% and 20% larger luminal surface density in the left and right sides of the heart, respectively. In conclusion, hypochromic microcytic anemia leads to eccentric ventricular hypertrophy with a significant amount of capillary proliferation that may tend to protect the myocardium from the increased potential for ischemic injury.
Adaptation, Physiological↗
Differences in load dependence of relaxation between the left and right ventricular myocardium as a function of age in rats.
To determine whether the variation in the magnitude of work load sustained by the left and right ventricles during adulthood and senescence affects the load-dependent aspect of relaxation, posterior papillary muscles from the left and right ventricles of rats at 4, 10, and 20 months of age were studied under variably loaded conditions in vitro. Because of differences between the life spans of Fischer and Sprague-Dawley rats, the functional characteristics of relaxation were investigated to evaluate the possibility of a differential age-associated response in these two strains of animals. The kinetic performance of the diastolic phase of myocardial contraction was measured by assessing the relative time during which load bearing occurred in a series of afterloaded isotonic twitches. This measurement was expressed as the ratio of the duration of afterloaded isotonic shortening and relengthening to the time required for isometric force to decline to the same level during isometric relaxation. A ratio of less than unity identified a load-dependent state whereas a value greater than one reflected a load-independent condition. Results showed that the right myocardium was completely load independent whereas the left myocardium was fully load dependent at all physiological afterloads. Aging reduced the load independence of the right ventricle and the load dependence of the left ventricle in Fischer rats. In contrast, no aging effect on the properties of afterloaded isotonic relaxation was seen in Sprague-Dawley rats. In conclusion, distinct differences exist in the mechanical dynamics of inactivation between the left and right ventricular myocardium. Aging reduced these variations in Fischer rats but had no apparent influence in Sprague-Dawley animals up to 20 months after birth.
Aging↗