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Effect of cardiac hypertrophy on tolerance to ischemia
J Mol Cell Cardiol 21 (Supplement
IV) (1989)
L 1 GROWTH SIGNALS AND MEMBRANE PROTEINS OF THE HYPERTROPHIED B. Swynghedauw. INSERM U 127 - Hopital Lariboisi&e, Paris.
MYOCYTE.
It is the goal of this work tosummarize the studies which have been carried out on the membrane proteins in compensatory cardiac hypemophy, at least in rat. Calculations have been based upon our data, mmphological findings and electrophysiological measurements of membrane capacity. One can schematicahy distinguish three groups of membrane proteins with respect of the process of mechanical overlaod. (i) The synthesis of the beta 1 adrenergic and muscarinic receptors, of the low affinity iso(Na+, K+)-ATPase, possibly of the Na+/Caz+ exchanger, and of the Ca2+-ATPase of sarcoplasmic reticulum is not activated by overload since their density drops and their number per cell (or per ventricle) does not change. (ii) The Ca2+-channels of the sarcolemma whose synthesis is proportionahy activated with the degree of hypertrophy. Their number is enhanced and their density is unmodified. (iii) The synthesis of the high affinity iso(Na+, K+)-ATPase is activated such that the number density increase. Research in the field of inotropes and vasodilatators has to take in account these modifications. Indeed the keys that these drugs represent must be modeled as a function of the lock they have to fit in. Growth signals able to take in account the process hypemophy include oncogenes and heat shock proteins, an isolated heart preparation is the best model appropriate to this study.
L2 BIOCHEMICAL
CHANGES ASSOCIATED WITH HYPERTROPHY: IMPLICATIONS FOR MYOCARDIAL FUNCTION. P. Cummins. British Heart Fcundation Molecular Cardiology Unit, Department of Cardiovascular Medicine, Clinical Research Block, University of Birmingham, Bitmingham, B15 2TH., UK. The msponse of the myocardium to overload and subaequent hypettrophy is particularly evident at the level of protein phenotypic expression. Ttansitions in myofibtillar protein isoforms directly involved in the contractile response have been the subject of considerable study. However, attempts to relate differences in the biochemical structure of different protein isofomrs to functional parameters have been limited. In part this is due to ditlkulties in working with small, but functionally intact catdiac gbrea in which protein composition can be both determined and manipulated, and also to the lack of basic knowledge on the relationship between structure and function of many conttactile and regulatory proteins and their isofomrs. Limited but direct information is available from skeletal muscle indicating a direct link between physiological function and type of contractile isoform present. Indirect evidence is also available in hypertrophied cardiac muscle, both in animals and man, suggesting compensatory cbauges in physiological function related to &urges in isofomr, particulary myosin, expression. A feature of these studies is that observed transitions tend to follow defined and predictable patterns and that these can be related to other conditions in which haemodynamic performance is subject to change. However, the level of response may be limited which in turn poses important questions on the significance of these changes and the progression to cardiac failure.
L3 EFFECT OF CARDIAC HYPERTROPHY
ON TOLERANCE TO ISCHEMIA. G.J. van der Vusse and L.H.E.H. Snoeckx. Department of Phvsiologv. Universitv of Limbura, Maastricht. The Netherlands. Diminished tole&nce to &he&a of h&ertrophied~hearts has a&eady been recognized in the clinical setting in the early seventies. Recent studies on laboratory animals have revealed that the degree of vulnerability to the ischemic insult is greatly influenced by the developmental stage of the hypertrophied heart. Hearts in the compensation phase of hypertrophy seem to be mom resistant to ischemia than endstage hypertrophied hearts. Lower tissue levels of high-energy phosphates might be a cellular factor rendering end-stage hypertrophied hearts more vulnerable to ischemia. Other cellular factors may imply changes in Ca2+ homeostasis of the hypertrophied myocyte, alterations in the lipid content of the cardiac membranes and reduced contents of endogenous anti-oxidants. The latter factor might be of relevance since oxygen free radical production is increased during the acute phase of reperfusion after ischemia. The finding that the release. of end-stage nrcducts of adenine nucleotides. such as xanthine and uric acid. is hieher in reperfused hypertrophied he& than in control hearts might’indicate a higher production of’oxyg& free radicals. In addition to cellular factors, alterations in the structure and perfusion of the hvnertronhied heart have to be considered. The observation that hypertrophied hearts are more prone to @St-ischemic “noreflow” (especially in the subendocardial layers) suggests local circulatory disorders. Increased sensitivity of the coronary vasculatum to the ischemia and/or reperfusion-elicited insult might be responsible for this phenomenon. Impaired reperfusion can (partialiy) be circumvented by higher post-ischemic perfusion pressures. The latter finding has most likely important clinical implications. s.1
IV) (1989)
L 1 GROWTH SIGNALS AND MEMBRANE PROTEINS OF THE HYPERTROPHIED B. Swynghedauw. INSERM U 127 - Hopital Lariboisi&e, Paris.
MYOCYTE.
It is the goal of this work tosummarize the studies which have been carried out on the membrane proteins in compensatory cardiac hypemophy, at least in rat. Calculations have been based upon our data, mmphological findings and electrophysiological measurements of membrane capacity. One can schematicahy distinguish three groups of membrane proteins with respect of the process of mechanical overlaod. (i) The synthesis of the beta 1 adrenergic and muscarinic receptors, of the low affinity iso(Na+, K+)-ATPase, possibly of the Na+/Caz+ exchanger, and of the Ca2+-ATPase of sarcoplasmic reticulum is not activated by overload since their density drops and their number per cell (or per ventricle) does not change. (ii) The Ca2+-channels of the sarcolemma whose synthesis is proportionahy activated with the degree of hypertrophy. Their number is enhanced and their density is unmodified. (iii) The synthesis of the high affinity iso(Na+, K+)-ATPase is activated such that the number density increase. Research in the field of inotropes and vasodilatators has to take in account these modifications. Indeed the keys that these drugs represent must be modeled as a function of the lock they have to fit in. Growth signals able to take in account the process hypemophy include oncogenes and heat shock proteins, an isolated heart preparation is the best model appropriate to this study.
L2 BIOCHEMICAL
CHANGES ASSOCIATED WITH HYPERTROPHY: IMPLICATIONS FOR MYOCARDIAL FUNCTION. P. Cummins. British Heart Fcundation Molecular Cardiology Unit, Department of Cardiovascular Medicine, Clinical Research Block, University of Birmingham, Bitmingham, B15 2TH., UK. The msponse of the myocardium to overload and subaequent hypettrophy is particularly evident at the level of protein phenotypic expression. Ttansitions in myofibtillar protein isoforms directly involved in the contractile response have been the subject of considerable study. However, attempts to relate differences in the biochemical structure of different protein isofomrs to functional parameters have been limited. In part this is due to ditlkulties in working with small, but functionally intact catdiac gbrea in which protein composition can be both determined and manipulated, and also to the lack of basic knowledge on the relationship between structure and function of many conttactile and regulatory proteins and their isofomrs. Limited but direct information is available from skeletal muscle indicating a direct link between physiological function and type of contractile isoform present. Indirect evidence is also available in hypertrophied cardiac muscle, both in animals and man, suggesting compensatory cbauges in physiological function related to &urges in isofomr, particulary myosin, expression. A feature of these studies is that observed transitions tend to follow defined and predictable patterns and that these can be related to other conditions in which haemodynamic performance is subject to change. However, the level of response may be limited which in turn poses important questions on the significance of these changes and the progression to cardiac failure.
L3 EFFECT OF CARDIAC HYPERTROPHY
ON TOLERANCE TO ISCHEMIA. G.J. van der Vusse and L.H.E.H. Snoeckx. Department of Phvsiologv. Universitv of Limbura, Maastricht. The Netherlands. Diminished tole&nce to &he&a of h&ertrophied~hearts has a&eady been recognized in the clinical setting in the early seventies. Recent studies on laboratory animals have revealed that the degree of vulnerability to the ischemic insult is greatly influenced by the developmental stage of the hypertrophied heart. Hearts in the compensation phase of hypertrophy seem to be mom resistant to ischemia than endstage hypertrophied hearts. Lower tissue levels of high-energy phosphates might be a cellular factor rendering end-stage hypertrophied hearts more vulnerable to ischemia. Other cellular factors may imply changes in Ca2+ homeostasis of the hypertrophied myocyte, alterations in the lipid content of the cardiac membranes and reduced contents of endogenous anti-oxidants. The latter factor might be of relevance since oxygen free radical production is increased during the acute phase of reperfusion after ischemia. The finding that the release. of end-stage nrcducts of adenine nucleotides. such as xanthine and uric acid. is hieher in reperfused hypertrophied he& than in control hearts might’indicate a higher production of’oxyg& free radicals. In addition to cellular factors, alterations in the structure and perfusion of the hvnertronhied heart have to be considered. The observation that hypertrophied hearts are more prone to @St-ischemic “noreflow” (especially in the subendocardial layers) suggests local circulatory disorders. Increased sensitivity of the coronary vasculatum to the ischemia and/or reperfusion-elicited insult might be responsible for this phenomenon. Impaired reperfusion can (partialiy) be circumvented by higher post-ischemic perfusion pressures. The latter finding has most likely important clinical implications. s.1