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Contractile protein transitions during hypertrophy and development of the heart: Limitations on the relevance of small animal models to studies in man
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MORPHOMETRICAL ANALYSIS OF MYOCARDIAL FIBROSIS IN VALVULAR DISEASES. T. Romppanen, Jantunen, A. Seppl. Department of Pathology, University of Kuopio, Kuopio, Finland. The relative amount of connective tissue ("grade of fibrosis") in the left ventricular myocardium was measured morphometrically in 50 autopsy hearts including IO aortic stenoses, 9 mitral stenoses, 8 mitral insufficiencies, 8 combined aortic and mitral valvular diseases and 15 control hearts completely devoid of valvular diseases. Three tissue samples of each heart (anterior, posterior and septal left ventricular wall) were analyzed by the point counting method. The tissue sections of 6 ;Im thickness were stained with van Gieson and hematoxylin method. A squaregrid of 36 points in a projection microscope (magnification X200) was used in analyzing a total of 2700 points per section. The results showed an increase of the total amount of collagen (red stained connective tissue) in aortic stenosis (collagen amount 5.6SD 1.3tc), mitral insufficiency (6.4tSD1.7.) and ln combined aortic and mitral valvular disease (5.4iSD1.4,!) as compared with the control hearts (3.3+SD1.22). The correspondgrade of fibrosis in valvular ing value in mitral stenosis was 4.OkSD1.6 . The higher diseases was due to increase of the diffusely arranged connective tissue, whereas the amount of the perivascular connective tissue showed no increase. No significant differences were found in the amount of connective tissue when hearts with valvular diseases associated with cardiac insufficiency were compared to those without any heart failure. E.
164RE-EVALUATION OF THE VENTRICULAR MYOCYTE PROLIFERATIVE CAPACSTIES IN MAMMALS AND POIKILOTHERMS USING LONG-TERM ADMINISTRATION OF H-THYMIDINE. P.P.Rumyan$sev. Institute of Cytology, Leningrad, USSR. Multiple H-thymidine injections have enabled us to reveal by means of autoradiography an unexpectedly high proliferative capacity of cardiomyocytes (CM) in rat overloaded atria (Rumyantsev, Adv.Myocard., 4,147, 1892). This method was emploved in experiments with: 1) rats and mice receiving two isoproterenol injections (85 mg/kg body weight); 2) amphibians (Rana temporaria) and reptilians (Agama caucasica) after local ventricular crushing. Contrary to Adler's and Sandritter's (Bas.Res. Card., 5, 126,198O) data, we did not find appreciable DNA synthesis in ventricular CM of isoproterenol-treated animals irrespective of the presence of necro?es and of the degree of myocardial hypertrophy. Practically all the H-thymidine labeling was confined to non-muscle cells. However, juxtanecrotic myocardia of frogs and agamae have cumulated 94.120.8 and 73.2+2.3% of labeled CM respectively. Our data demonstrate that there is a si?arp difference in the proliferative behaviour not only between atria1 and ventricular CM of rats but also between ventricular CM of mammals and those of poikilotherms including such higher vertebrates as agamae. 166CONTRACTILE PROTEIN TRANSITIONS DURING HYPERTROPHY AND DEVELOPMENT OF THE HEART: LIMITATIONS ON THE RELEVANCE OF SMALL ANIMAL MODELS TO STUDIES IN MAN. P. Cumins, J.E. Humphreys, R.A. Janes, S.J. Lambert. Molecular Cardiology Unit, Department of Cardiovascular Medicine, University of Birmingham, Birmingham, 815 ZTH,U.K. Attention has focused on possible defects at the molecular level of the contractile proteins in myocardial hypertrophy and failure. In animals such as the rat and rabbit, myofibrillar and myosin ATPases are depressed in situations of decreased contractility. Converse increases in enzymic activity together with enhanced contractility are seen in the hyperthyroid state. The molecular basis for these changes in enzymic activity is now known to result from transitions in three heavy chain isoenzymes of myosin, V , V and V which possess different ATPase activities. Transitions in isoenzyme compAsit?on occ& during hypertrophy, thyrotoxicosis and development in the myocardium of small mammals. In larger animals such as the rhesus monkey, baboon, cow. and in particular, man, only V the lowest ATPase isoenzyme can be detected in the normal ventricle and this is the'only form present throughout development. Changes in myosin isoenzyme composition in large mammals as an explanation of depressed contractile function would therefore seem unlikely on the basis of these findings. Evidence for lowered ATPase activities in the failing human myocardium is moreover scarce. Major differences in the compositions of small and large mammalian hearts are also seen for other contractile proteins. Caution should be exercised in using small animals as models of myocardial hypertrophy and failure in man.
MORPHOMETRICAL ANALYSIS OF MYOCARDIAL FIBROSIS IN VALVULAR DISEASES. T. Romppanen, Jantunen, A. Seppl. Department of Pathology, University of Kuopio, Kuopio, Finland. The relative amount of connective tissue ("grade of fibrosis") in the left ventricular myocardium was measured morphometrically in 50 autopsy hearts including IO aortic stenoses, 9 mitral stenoses, 8 mitral insufficiencies, 8 combined aortic and mitral valvular diseases and 15 control hearts completely devoid of valvular diseases. Three tissue samples of each heart (anterior, posterior and septal left ventricular wall) were analyzed by the point counting method. The tissue sections of 6 ;Im thickness were stained with van Gieson and hematoxylin method. A squaregrid of 36 points in a projection microscope (magnification X200) was used in analyzing a total of 2700 points per section. The results showed an increase of the total amount of collagen (red stained connective tissue) in aortic stenosis (collagen amount 5.6SD 1.3tc), mitral insufficiency (6.4tSD1.7.) and ln combined aortic and mitral valvular disease (5.4iSD1.4,!) as compared with the control hearts (3.3+SD1.22). The correspondgrade of fibrosis in valvular ing value in mitral stenosis was 4.OkSD1.6 . The higher diseases was due to increase of the diffusely arranged connective tissue, whereas the amount of the perivascular connective tissue showed no increase. No significant differences were found in the amount of connective tissue when hearts with valvular diseases associated with cardiac insufficiency were compared to those without any heart failure. E.
164RE-EVALUATION OF THE VENTRICULAR MYOCYTE PROLIFERATIVE CAPACSTIES IN MAMMALS AND POIKILOTHERMS USING LONG-TERM ADMINISTRATION OF H-THYMIDINE. P.P.Rumyan$sev. Institute of Cytology, Leningrad, USSR. Multiple H-thymidine injections have enabled us to reveal by means of autoradiography an unexpectedly high proliferative capacity of cardiomyocytes (CM) in rat overloaded atria (Rumyantsev, Adv.Myocard., 4,147, 1892). This method was emploved in experiments with: 1) rats and mice receiving two isoproterenol injections (85 mg/kg body weight); 2) amphibians (Rana temporaria) and reptilians (Agama caucasica) after local ventricular crushing. Contrary to Adler's and Sandritter's (Bas.Res. Card., 5, 126,198O) data, we did not find appreciable DNA synthesis in ventricular CM of isoproterenol-treated animals irrespective of the presence of necro?es and of the degree of myocardial hypertrophy. Practically all the H-thymidine labeling was confined to non-muscle cells. However, juxtanecrotic myocardia of frogs and agamae have cumulated 94.120.8 and 73.2+2.3% of labeled CM respectively. Our data demonstrate that there is a si?arp difference in the proliferative behaviour not only between atria1 and ventricular CM of rats but also between ventricular CM of mammals and those of poikilotherms including such higher vertebrates as agamae. 166CONTRACTILE PROTEIN TRANSITIONS DURING HYPERTROPHY AND DEVELOPMENT OF THE HEART: LIMITATIONS ON THE RELEVANCE OF SMALL ANIMAL MODELS TO STUDIES IN MAN. P. Cumins, J.E. Humphreys, R.A. Janes, S.J. Lambert. Molecular Cardiology Unit, Department of Cardiovascular Medicine, University of Birmingham, Birmingham, 815 ZTH,U.K. Attention has focused on possible defects at the molecular level of the contractile proteins in myocardial hypertrophy and failure. In animals such as the rat and rabbit, myofibrillar and myosin ATPases are depressed in situations of decreased contractility. Converse increases in enzymic activity together with enhanced contractility are seen in the hyperthyroid state. The molecular basis for these changes in enzymic activity is now known to result from transitions in three heavy chain isoenzymes of myosin, V , V and V which possess different ATPase activities. Transitions in isoenzyme compAsit?on occ& during hypertrophy, thyrotoxicosis and development in the myocardium of small mammals. In larger animals such as the rhesus monkey, baboon, cow. and in particular, man, only V the lowest ATPase isoenzyme can be detected in the normal ventricle and this is the'only form present throughout development. Changes in myosin isoenzyme composition in large mammals as an explanation of depressed contractile function would therefore seem unlikely on the basis of these findings. Evidence for lowered ATPase activities in the failing human myocardium is moreover scarce. Major differences in the compositions of small and large mammalian hearts are also seen for other contractile proteins. Caution should be exercised in using small animals as models of myocardial hypertrophy and failure in man.