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Objective: Catecholamines induce myocyte necrosis and myocardial fibrosis. These effects are probably related to beta adrenergic receptor stimulation and to thyroid hormonal status. The aim of the study was to test the hypothesis that amiodarone prevents myocardial damage induced by isoprenaline and that these effects are not observed when thyroid hormone is administered., Methods: Myocardial injury was assessed in the first experiment. Isoprenaline (1 mg.kg-1 subcutaneously once) was given to two groups of rats which received monoclonal antimyosin. Group 1 (n = 5) was pretreated with amiodarone and group 2 (n = 6) received only isoprenaline. In the second experiment, the effects of amiodarone on isoprenaline induced myocardial fibrosis and of supplementary triiodothyronine (T3) were examined. Group 3 (n = 10) received only isoprenaline for 4 d. Group 4 (n = 10) received amiodarone for 14 d and isoprenaline during 4 d. Group 5 (n = 8) received amiodarone and isoprenaline like group 4, plus T3. Untreated rats served as controls (group 6; n = 10). Collagen volume fraction (CVF) was measured in each heart., Results: No rats pretreated with amiodarone showed antimyosin labelling, while the mean score of rats receiving only isoprenaline was 2.8 (p < 0.05), indicating the presence of significant myocyte injury. In group 3, CVF was significantly higher than in controls, at 7.63(SEM 0.89)% v 1.74(0.07)%, p < 0.001, whereas rats pretreated with amiodarone (group 4) showed significantly less fibrosis [CVF 2.96(0.19)%]. This protective effect was lost when amiodarone and T3 were given together [CVF 7.92(1.8)%, p < 0.005 between groups 4 and 6]., Conclusions: By preventing isoprenaline induced myocardial injury and fibrosis, amiodarone may have a cardioprotective role. This effect is completely abolished by thyroid hormone.

Objective: The aim was to clarify the role of cyclic AMP dependent protein kinase (PKA) and changes in mechanical heart function during development of cardiac hypertrophy induced by volume overload., Methods: Protein and DNA contents, PKA activity, and peak systolic stress-strain relationships in hearts from animals submitted to aortocaval shunt were assessed as a function of time. Sham operated (control) rats were used as controls., Results: Heart weight to body weight ratio and cardiac protein content per heart increased from d 7 (p < 0.005 and p < 0.01, respectively) reaching their highest values by d 56; the same occurred with cardiac DNA content. PKA activity.g-1 tissue in soluble extracts of hearts from rats with aortocaval shunt increased by 2.7-fold on d 2 (p < 0.005), reached a ninefold peak increase by d 7 (p < 0.0001) and declined to fourfold by d 56 with respect to control values. The end peak systolic stress-strain relation slopes were: control, 368(SEM 14) g.cm-2 (n = 16); aortocaval shunt values: 2 d, 514(28) g.cm-2 (n = 6); 7 d, 579(10) g.cm-2 (n = 7); and 56 d, 554(28) g.cm-2 (n = 7). The force generating capacity at 0% strain was also significantly higher in the shunt groups as compared to sham operated controls (p < 0.01). Early activation of PKA was also confirmed through endogenous cardiac protein phosphorylation. SDS-PAGE gel electrophoretogram and autoradiography showed more heavily phosphorylated bands in aortocaval shunt hearts than in the control group., Conclusions: PKA activity and the slope of systolic stress-strain regression line followed a similar trend throughout the study, with an early increase in both variables by d 2 in the shunt group, reaching a peak at d 7, and decreasing thereafter but remaining higher than in controls. PKA activity appears to be related to increased force generating capacity rather than to hypertrophy or increased cardiac protein content. Thus PKA activation is an early biochemical event after aortocaval shunt, followed later by cardiac hypertrophy. Changes in PKA activity showed a similar trend to mechanical heart function over time. These findings help to explain the changes in the mechanical properties of the heart preceding the development of cardiac hypertrophy in the rat model of volume overload.

Study Objective: The aim was to compare the temporal sequence and structural relationship between perivascular and interstitial fibrosis and microscopic scarring seen in the left ventricle in response to either a transient or sustained stimulus to fibrosis., Design: In 72 male Wistar rats (250-350 g) the transient stimulus model was based on the administration of isoprenaline (500 micrograms.kg-1) while the sustained stimulus model was produced by abdominal aortic banding with right renal artery constriction. Serial sections of myocardium were examined and compared at 4 and 12 weeks in each model and to corresponding controls., Experimental Material: The collagen specific stain, Sirius Red F3BA, was used to determine collagen volume fraction and the fibrillar nature of the fibrous tissue response seen by light microscopy., Measurements and Main Results: Following isoprenaline a stable reparative fibrosis of the endomyocardium and increase in collagen volume fraction was seen without an interstitial or perivascular fibrosis of the non-involved myocardium. In unilateral renal ischemia, on the other hand, a progressive perivascular fibrosis was evident throughout the myocardium and from which fibrillar collagen extended into the extracellular space between muscle bundles creating an interstitial fibrosis; microscopic scarring of the endomyocardium became evident at 12 weeks., Conclusions: The reactive perivascular fibrosis of intramyocardial coronary arteries seen in renovascular hypertension is a progressive process that leads to an interstitial fibrosis and eventual microscopic scarring. In contrast, the endomyocardial scarring that follows isoprenaline induced myocyte necrosis is stable and intramural vessels in remote regions are not involved.

This study had two objectives: (a) to determine the accumulation of collagen and its structural remodelling in the hypertrophied rat left ventricle after 4 and 8 weeks of abdominal aorta banding; and (b) to correlate these findings with the diastolic stress-strain relation of the intact myocardium. In comparison to age and sex matched controls, the collagen volume fraction of the hypertrophied myocardium after 4 and 8 weeks of aortic banding increased significantly from 3.5(SD1.0)% to 7.8(4.2)% and 6.2(2.0)% respectively. This accumulation of collagen, or fibrosis, occurred in the absence of myocyte necrosis. Scanning electron microscopy showed increased density and thickness of the collagen weave and tendons. At 4 weeks, light microscopy showed interstitial oedema and disrupted collagen fibrils. Left ventricular diastolic stress-strain relations of both pressure overload groups were significantly steeper than that of the control group. Thus the response of the interstitium to the hypertrophic process that accompanies abdominal aorta banding is a complex process that includes a structural remodelling of the fibrillar collagen matrix and the early appearance of interstitial oedema, each of which may contribute to a rise in the passive stiffness of the intact myocardium.