Altered calcium handling at normal contractility in hypertrophied rat heart

Left or right ventricular hypertrophy was induced by banding of the aorta or pulmonary artery in different groups of rats. After 5 to 10 weeks the degree of hypertrophy was about 15% in left and 80-160% in right ventricles, as determined by weight of the ventricle or by myocyte size. Action potentials and force-interval relationships were measured in papillary muscles isolated from either ventricle. As compared to muscles from control and SHAM-operated rats, hypertrophied papillary muscles showed: (1) Marked prolongation of the action potential and greater degree of post-extrasystolic potentiation. This indicates enhanced influx of Ca2+ probably via Ica; (2) Delayed relaxation of isometric force and faster decay of potentiation, which indicates reduced sequestration of Ca2+ by the sarcoplasmic reticulum; (3) Minor changes in steady-state peak force under standard conditions, which is explained from the opposite inotropic effects of enhanced Ca2+ influx and impaired function of the reticulum. Myocyte volume in the normal left ventricle was almost two times larger than in the normal right ventricle, and this was associated with a longer action potential and greater degree of post-extrasystolic potentiation in left as compared with right ventricular muscles. The rate of decay of potentiation, however, was not different. This might indicate that depressed function of the sarcoplasmic reticulum occurs with pressure-overload hypertrophy and not with normal age-dependent growth.     

Na,K-pump concentration in hypertrophied human hearts

Several studies have associated myocardial dysfunction withreduced myocardial Na, K-pump concentration, but whether impairedNa, K-pump capacity is a pathogenetic factor or an epiphenomenonrelated to accompanying cardiac hypertrophy is not established.We measured Na, K-pump concentrations in 10 hypertrophied and11 normal weighted hearts obtained at autopsy using [³H]ouabainas ligand. Specific [³H] ouabain binding site concentration(OBC) in the left ventricle (L V) averaged 449 ± 40 (pmol.g ^–1 wet weight; mean ± SEM) in hypertrophied and598 ± 36 in normal weighted ventricles (P=0.02). A trendtowards lower LV OBC ( –19% P=0.25) was found in hypertrophiedhearts from patients with congestive heart failure as comparedwith non-failing hypertrophied hearts. In multivariate analysiswith 18 variables including age and heart failure, only LV weightcorrelated independently with LV OBC (r= –0.61; P=0.003).When OBC was related to either dry weight or to protein content,a 25–35% reduction was consistently found in hypertrophiedLV, whereas RV OBC was similar in both groups. In conclusion,myocardial Na, K-pump concentration and thus the capacity tomaintain homeostasis is reduced in LV, but not in RV, of hypertrophiedhearts. Whether the moderately reduced myocardial Na, K-pumpconcentration is a pathogenetic factor in LV dysfunction remainsto be determined.     

Maximum contractility of the experimentally hypertrophied heart in situ and survival of the acute coronary occlusion

Summary Studies were carried out in dogs with significant moderate left ventricular hypertrophy (LVH) induced by artifical coarctatio aortae to reveal the reserve of performance and the behavior in response to acute ligation of the LCA (left circumflex artery). The hemodynamic data at rest and during catecholamine stimulation were not essentially different, whereas the maximal inotropic state was a little enhanced in LVH dogs (LVH₁=12; CG₁=6). The acute maximal pressure rise of the left ventricle — obtained by acute clamping of the aorta ascendens — was nearly the same in both groups (LVH₂=6; CG₂=6) when related to 100 g left ventricular wet weight. The LVH hearts react to a rapid volume overload with a slightly higher increase of HR and LVEP indicating a minor adaption to an acute volume overload explained by diminished compliance. In consequence to acute ligation of the LCA (LVH₃=13; CG₃=11) LVH hearts showed a higher (p<0.05) survival rate (69%) than controls with comparable collateral status of the coronary collateral vessels because 91% of these developed ventricular fibrillation. To explai this phenomenon we determined the catecholamine-concentration in each part of the heart in a further group (LVH₄=5; CG₄=6). Unexpectedly a significant diminution was seen in the non-hypertrophied right ventricle, but the other compartments also showed a decrease of the catecholamine concentration. Subsequent studies have to be done to explore the better electrophysiologic protection of the LVH heart in consequence to acute ligation of the LCA.

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Maximales Kontraktilitätsverhalten experimentell hypertrophierter Herzen in situ und die Überlebensrate nach akuter Koronarokklusion

Zusammenfassung Die Untersuchungen wurden an Hunden mit einer signifikanten, mäßiggradigen, linksventrikulären Hypertrophie unter der Fragestellung der maximalen Leistungsbreite dieser Herzen und des Verhaltens nach akuter Ligatur der linken Koronararterie durchgeführt. Die linksventrikuläre Hypertrophie wurde durch eine Coarctatio aortae erzeugt.Die hämodynamischen Parameter wurden während der Ausgangsphase und einer stufenweise erhöhten Katecholamin-Infusion gemessen und zu Kontrolltieren (CG=6) verglichen. Dabei stellte sich heraus, daß die maximale Kontraktilität bei den LVH-Tieren (LVH=12) gegenüber den Kontrollen gering erhöht war. Bezogen auf 100 g linksventrikuläres Feuchtgewicht ergab sich für beide Gruppen nach akuter Abklemmung der Aorta ascendens ein nahezu identischer maximaler Druckanstieg im linken Ventrikel. Gegenüber einer schnellen Volumeninfusion reagierten die hypertrophierten Herzen mit einem geringgradig höheren Anstieg der Herzfrequenz und des enddiastolischen Druckes, was als Ausdruck einer verminderten Compliance angesehen werden kann.Nach akuter Ligatur des Ramus circumflexus der linken Kranzarterie (LVH₃=13, CG₃=11) zeigte sich eine signifikant (p<0,05) höhere Überlebensrate bei den Tieren mit linksventrikulärer Hypertrophie und vergleichbarem Kollateralstatus. In einer vierten Gruppe (LVH₄=5, CG₄=6) wurde die Katecholaminkonzentration in den verschiedenen Kompartimenten des Herzens als mögliche Erklärungsursache für die unterschiedliche Häufigkeit des Kammerflimmerns nach akuter Koronarligatur bestimmt. Unerwarteterweise sahen wir eine signifikant geringere Katecholaminkonzentration im nicht hypertrophierten rechten Ventrikel der Hypertrophietiere, jedoch waren die Konzentrationen in allen Kompartimenten des hypertrophierten Herzens gering vermindert. Weitere Untersuchungen sind erforderlich, um den besseren elektrophysiologischen Schutz des hypertrophierten Herzens gegenüber einer akuten Koronarligatur zu erklären.

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Paper, presented at the Erwin Riesch Symposium, Tübingen, April 3–7, 1979

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With 3 figures and 3 tables     

Cellular mechanisms in congestive heart failure

There is substantial, although not yet conclusive, evidence that the failing heart is in an energy-depleted state. Such an imbalance between energy production and energy utilization would have important implications for the management of patients with congestive heart failure (CHF), most important of which is that therapeutic measures that increase myocardial energy demand could have long-term detrimental effects on the heart. By increasing energy expenditure, vasoconstrictors and positive inotropic agents could worsen cell damage, exacerbate relaxation abnormalities and promote arrhythmias. Conversely, therapy that improved the balance between energy delivery and energy expenditure might be expected to improve prognosis in CHF. For this reason, vasodilators and reduced inotropic drive to the failing heart could prolong survival in these patients. Further understanding of the energetics of the failing heart will be of considerable importance in the formulation of hypotheses regarding long-term therapy that could be evaluated in controlled clinical trials.     

Quantitative electron microscopic description of heart muscle cells. Application to normal, hypertrophied and thyroxin-stimulated hearts

Mathematical techniques can be used to extract quantitative information from tissue electron micrographs of heart muscle. With these methods it has been possible to measure the fractions of myocardial cell volume made up of myofibrils, mitochondria, sarcotubules, T system and sarcoplasm, as well as the membrane areas per unit of cell volume of plasma membrane, sarcotubular membrane and mitochondrial cristae. The techniques have been used to quantitate the changes in the ultrastructure of myocardial cells in experimental left ventricular hypertrophy and in experimentally induced hypothyroidism before and after treatment with thyroxin. These measurements have demonstrated striking and physiologically significant changes in the ultrastructural composition of the cells. The pattern of ultrastructural change in ventricular hypertrophy differs in characteristic ways from the pattern during thyroxin-stimulated cardiac cellular growth. These observations have suggested certain generalizations about the constraints to which growing myocardial cells are subject.New and simple microchemical methods have been developed to determine the cardiac contents of myofibrils and mitochondrial cristae. The methods are applicable to samples of heart muscle obtained at autopsy, surgery or biopsy, as well as to experimental material. Application of these techniques to the study of experimental left ventricular hypertrophy and thyroxin-stimulated growth of myocardial cells has confirmed and extended the results of quantitative measurements on electron micrographs. It is suggested that the approaches described can form the basis of a quantitative electron microscopic and microchemical pathology of heart muscle.     

Intracellular calcium and myocardial contractility. V. Calcium uptake of sarcoplasmic reticulum fractions in hypertrophied and failing rabbit hearts

To evaluate calcium uptake in the sarcoplasmic reticulum (SRF) in the hypertrophied and failing myocardium, SRF was prepared from hearts of rabbits with experimentally produced aortic insufficiency (AI). In SRF preparations from the hypertrophied hearts of animals killed shortly (2 weeks) after AI production calcium uptake was normal, 0.146 ± 0.001 compared to control values of 0.137 ± 0.010 μmol×mg^?1×min^?1. However, calcium uptake was reduced in SRF preparations from hypertrophied hearts removed from animals later (4 to 7 weeks) after AI production. In this latter group, some of the animals had no pathologic evidence of left ventricular failure but a significant reduction of calcium uptake was observed, 0.086 ± 0.002 μmol×mg^?1×min^?1 (P < 0.01). In other animals, with clear pathologic findings of failure, further reduction of calcium uptake was observed, 0.058 ± 0.006 μmol×mg^?1×min^?1. Ouabain was not effective in reversing these depressed activities, either when given in vivo or in vitro. These findings indicate that the decrease in SRF function is not a necessary accompaniment of ventricular hypertrophy, but may develop later as hypertrophy becomes more extensive and/or heart failure occurs. It remains to be demonstrated whether or not the abnormality of SRF uptake of calcium initiates the onset of heart failure or is in fact the result of the development of such depressed cardiac function.     

Repetitive acidosis protects the ischemic heart: implications for mechanisms in preconditioned hearts.

Repetitive brief ischemic episodes (ischemic preconditioning, PC) result in transient intracellular acidosis and protect the heart from subsequent ischemic injury, potentially through a protein kinase C (PKC)-dependent mechanism. We hypothesized that repetitive brief acidification of the heart without concomitant ischemia would also protect the heart from ischemic injury via a PKC-dependent mechanism. Isolated rat hearts underwent 30 min of global ischemia following control perfusion (CTL), or after PC or repetitive acidosis (RA), in the presence of absence of chelerythrine, a specific PKC inhibitor. Intracellular pH, PCr and ATP were measured using 31P NMR spectroscopy, while intracellular sodium [Na]i was measured using 23Na spectroscopy. Na,K-ATPase activity was measured prior to ischemia and on reperfusion. Both PC and RA resulted in transient acidification prior to ischemia. Ischemic injury, as assessed by creatinine kinase (CK) release on reperfusion, was reduced in both the PC and RA hearts [63+/-14 and 16+/-4 IU/g dry weight (dw) respectively, v 705+/-72 IU/gdw for control P<0.001], and was associated with improved functional recovery on reperfusion. PC and RA each significantly reduced Na,K-ATPase activity prior to ischemia (8.18+/-0.47 and 7.76+/-0.54 micromol ADP/h/mg protein) when compared to control (11.05+/-0.54 micromol ADP/h/mg protein P<0.05), limited the rate of ATP depletion during ischemia, and resulted in more rapid normalization of [Na]i on reperfusion. Chelerythrine resulted in intermediate CK release in PC and RA hearts (443+/-48 and 375+/-72 IU/gdw, P<0.001 v PC, P<0.01 v control), but did not alter the rate of ATP depletion or [Na]i kinetics in either PC or RA hearts. PC and RA each protect the ischemic heart, having in common ATP preservation during ischemia and more rapid normalization of [Na]i on reperfusion. These effects, not modulated by protein kinase C, are consistent with the hypothesis that ATP preservation during ischemia provides enhanced substrate for sodium efflux via the Na,K-ATPase on reperfusion.     

Normalization of impaired coronary circulation in hypertrophied rat hearts

We tested the hypothesis that impaired coronary autoregulation, decreased flow reserve, and diminished reactive hyperemic response in hypertrophied hearts with coronary arterial hypertension may be reversible after relief of pressure overload. In 4-week ascending aortic banded rats, in vivo peak systolic left ventricular pressure increased to 178 +/- 8 mm Hg (103 +/- 6 mm Hg in sham-operated control group). This increased pressure produced myocardial hypertrophy, and the left ventricular weight/body weight ratio was 46% above that of the control group. After the rats were killed, the coronary perfusion pressure-flow relations were obtained during resting conditions and maximal vasodilation after a 40-second period of ischemia in beating but nonworking isolated hearts perfused with Tyrode's solution with bovine red blood cells and albumin. In hearts from control rats, coronary autoregulation (i.e., a slight decrease in flow with reduction of pressure) was observed in the range of 50-100 mm Hg of perfusion pressure. A pronounced reactive hyperemic response was observed: a peak flow/resting flow ratio of 2.9 +/- 0.1 and a repayment ratio of 1.7 +/- 0.2 at 100 mm Hg of perfusion pressure. In hearts of banded rats the resting pressure-flow relation was rectilinear in the range of 25-175 mm Hg of perfusion pressure. Flow reserve and the time of reactive hyperemia to one half peak flow decreased at 50, 100, and 150 mm Hg of perfusion pressure compared with values in control rat hearts. Four weeks after debanding, peak systolic left ventricular pressure and cardiac hypertrophy had normalized. The impaired autoregulation, decreased flow reserve, and diminished reactive hyperemic response had completely reversed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial energy metabolism in the hypertrophied hearts of spontaneously hypertensive rats

Summary Age-related changes in the myocardial energy metabolism were studied in spontaneously hypertensive (SHR) rats of 5–25 weeks of age. Systolic blood pressure increased rapidly during 5 to 10 weeks of age (developing phase) and attained a plateau level at 10 to 15 weeks (sustained phase). Even during the developing phase, the heart was hypertrophic, as assessed by an increase in the ratio of the ventricular weight to body weight. However, myocardial contents of glycolytic intermediates and high energy phosphate compounds and thus, the myocardial energy state (phosphorylation potential) in SHR rats did not differ from those in age-matched normotensive Wistar-Kyoto (WKY) rats. The lactate/pyruvate ratio was significantly lower in SHR rats. On the other hand, during the sustained phase, cardiac hypertrophy progressed only gradually, and myocardial contents of creatine phosphate and ATP were lower, while the lactate content was higher than in WKY rats. The lactate/pyruvate ratio was elevated, while phosphorylation potential was lowered. These findings suggest that the energy state is normal during the developing phase of hypertension despite the presence of cardiac hypertrophy and the increased pressure load, whereas the energy state is at a lower level during the sustained phase of hypertension.

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Zusammenfassung Die altersabhängigen Änderungen des myokardialen Energieumsatzes wurden bei spontanhypertensiven, 5 bis 25 Wochen alten Ratten (SHR) untersucht. Der systolische Blutdruck stieg zwischen der 5. und 10. Lebenswoche rasch an (Entwicklungsphase) und erreichte nach 10 bis 15 Wochen ein Plateau (Dauerphase). Auch während der Entwicklungsphase war das Herz hypertrophiert, gemessen an einem Anstieg des Verhältnisses Ventrikelgewicht: Körpergewicht. Jedoch unterschied sich der Gehalt des Myokards an Intermediärprodukten der Glykolyse und energiereichen Phosphaten und damit bezüglich des energetischen Status (Phosphorylierungspotential) bei SHR-Ratten nicht von gleichaltrigen normotensiven Wistar-Kyoto-Ratten (WKY). Das Lactat-Pyruvat-Verhältnis war bei SHR-Ratten signifikant vermindert. Andererseits nahm die Herzhypertrophie während der Dauerphase nur allmählich zu; der Gehalt an Kreatinphosphat und ATP war geringer, während der Lactatgehalt höher war als bei WKY-Ratten. Das Lactat-Pyruvat-Verhältnis war gesteigert, während das Phosphorylierungspotential vermindert war. Diese Befunde lassen vermuten, daß der energetische Status während der Entwicklungsphase der Hypertension normal ist trotz des Vorliegens einer Herzhypertrophie und gesteigerter Druckbelastung, während der energetische Status während der Dauerphase herabgesetzt ist.

     

Insufficiency of the hypertrophied heart]

The mechanism limiting the function of a normal heart is considered and the key part played in it by the system of an active ionic transport of the myocardial cell is pointed out. With an excessive load on the heart and also in cases of hypoxic and other lesions of the heart muscle--the mechanism limiting the cardiac function becomes the main causative factor of cardiac insufficiency.     

Altered gene expression in the hypertrophied heart

Abstracts

Altered gene expression in the hypertrophied heart     

Histopathological study on the effects of aging in myocardium of hypertrophied hearts

To clarify the effects of aging in myocardium of hypertrophied hearts, 555 autopsied hearts were studied histopathologically. Degrees of myocyte hypertrophy, disarrangement and fibrosis and lipofuscin deposits were estimated light-microscopically in tissue specimens taken from the anterior wall of the left ventricle. Myocyte hypertrophy was assigned to one of four classes from 0 to 3+ according to size. Other findings were estimated using the conventional three classes. All cases were divided according to heart weight, into the following groups: severe hypertrophy (Group I; more than 450 g for males and 400 g for females), mild hypertrophy (Group II; 450 greater than HW greater than 350 g for males and 400 greater than HW greater than 300 g for females) and no hypertrophy (Group III: less than 350 g for males and 300 g for females). Lipofuscin deposits increased with aging, but in Group I the increase was delayed in comparison to that in other groups. As a rule, myocyte size in the outer layer was equal to or smaller than that in the inner layer (outer-layer-selective atrophy). This was particularly true in pressure-overloaded hypertrophy and less so in volume-overloaded hypertrophy. Myocyte disarrangement was observed in the inner and median layers in the oldest group. Peri-vascular fibrosis became thick with aging, and perimysial fibrosis increased with age. The fibrotic process was accelerated in hypertrophied myocardium. As to the mode of hypertrophy, aging appears to result in a kind of myocardial asymmetry of layer-selective atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pyruvate dehydrogenase and the regulation of glucose oxidation in hypertrophied rat hearts

OBJECTIVE: Coupling of glucose oxidation to glycolysis is lower in hypertrophied than in non-hypertrophied hearts, contributing to the compromised mechanical performance of hypertrophied hearts. Here, we describe studies to test the hypothesis that low coupling of glucose oxidation to glycolysis in hypertrophied hearts is due to reduced activity and/or expression of the pyruvate dehydrogenase complex (PDC). METHODS: We examined the effects of dichloroacetate (DCA), an inhibitor of PDC kinase, and of alterations in exogenous palmitate supply on coupling of glucose oxidation to glycolysis in isolated working hypertrophied and control hearts from aortic-constricted and sham-operated male Sprague-Dawley rats. It was anticipated that the addition of DCA or the absence of palmitate would promote PDC activation and consequently normalize coupling between glycolysis and glucose oxidation in hypertrophied hearts if our hypothesis was correct. RESULTS: Addition of DCA or removal of palmitate improved coupling of glucose oxidation to glycolysis in control and hypertrophied hearts. However, coupling remained substantially lower in hypertrophied hearts. PDC activity in extracts of hypertrophied hearts was similar to or higher than in extracts of control hearts under all perfusion conditions. No differences were observed between hypertrophied and control hearts with respect to expression of PDC, PDC kinase, or PDC phosphatase. CONCLUSIONS: Low coupling of glucose oxidation to glycolysis in hypertrophied hearts is not due to a reduction in PDC activity or subunit expression indicating that other mechanism(s) are responsible.