Cellular mechanisms of myocardial stunning.
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Actin Cytoskeleton↗
Biomedical subjects
H Kusuoka
Publications and source records attributed to H Kusuoka.
Myocardial energetics during ventricular fibrillation investigated by magnetization transfer nuclear magnetic resonance spectroscopy.
Ventricular fibrillation (VF) is known to produce alterations in myocardial energetics, but the mechanism of these changes remains unclear. To investigate energy metabolism during VF, phosphorus nuclear magnetic resonance spectroscopy and magnetization transfer were applied to isolated perfused ferret hearts. VF was induced either by perfusion with digitalis (strophanthidin, 30 microM) or by high-frequency electrical stimulation. We measured the flux in two critical reactions: from inorganic phosphate (Pi) to ATP (ATP synthesis rate) and from phosphocreatine (PCr) to ATP (energy transfer capacity). During digitalis-induced VF, energy-related phosphates showed changes similar to those during hypoxia: myocardial [Pi] increased and [PCr] decreased. Concomitantly, the ATP synthesis rate increased to levels about threefold higher than control, whereas oxygen consumption increased by only 16%. The ATP synthesis rate exhibited a strong negative correlation with left ventricular pressure during VF (r = -0.95, n = 5, p < 0.02), whereas oxygen consumption did not (r = 0.19, p > 0.05). On the other hand, energy transfer capacity catalyzed by creatine kinase was significantly smaller during VF than in the control condition but still higher than the simultaneous ATP synthesis rate. In contrast to the marked energetic deterioration during VF induced by digitalis, electrically induced VF led to only a small increase in [Pi] and a small decrease in [PCr], and there were no significant changes in the ATP synthesis rate, energy transfer capacity, or O2 consumption. These results indicate that the rundown in energy metabolism during VF induced by digitalis was mainly attributable to a limitation of energy production through oxidative phosphorylation as well as to a marked increase in energy consumption. In contrast, myocardial energy generation remained unimpaired during VF induced by electrical stimulation. Intracellular calcium overload is more severe during VF induced by digitalis than during electrically induced VF (Circ Res 1991;68:1378-1389); severe calcium overload would be expected to compromise the capacity for energy generation by mitochondria. Thus, we propose that known differences in cellular calcium loading underlie the discrepant energetic patterns of the two types of VF.
Animals↗
Assessment of valvular regurgitation using cine magnetic resonance imaging coupled with phase compensation technique: comparison with Doppler color flow mapping.
To elucidate whether or not a newly developed technique in cinematic-displayed (cine) magnetic resonance imaging (MRI) can improve the semiquantitative evaluation of valvular regurgitant flow, 20 patients with valvular lesions were studied. Three pulse sequences of cine MRI, ie, standard, short echo time (TE), and rephasing scans, were compared with reference obtained by Doppler color flow mapping. Short TE technique and rephasing scan technique improved image quality remarkably as compared with standard technique. Each of the three cine MRI techniques showed good correlation with the Doppler method (p < 0.001). However, short TE and rephasing scan techniques gave a faithful estimation of the extent as compared with the Doppler method, whereas standard technique overestimated the regurgitation. Thus, cine magnetic resonance imaging with phase compensation technique can be utilized for the semiquantitative assessment of valvular regurgitation in a manner similar to that of Doppler color flow mapping.
Aged↗
Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure.
To elucidate the mechanism of acute contractile failure induced by adriamycin, the intracellular concentrations of free calcium ([Ca2+]i) and energy-related phosphate compounds were determined in isolated ferret hearts. The time-averaged [Ca2+]i was measured at 10 min resolution using fluorine nuclear magnetic resonance (NMR) spectroscopy and the NMR-sensitive Ca2+ indicator 5F-BAPTA. [Ca2+]i significantly increased from a control of 381 +/- 66 nM (mean +/- SEM, N = 5) to 789 +/- 171 nM during 30 min of perfusion with adriamycin (30 mg/L), and remained elevated for at least 30 min after washout. The isovolumic LV pressure decreased to 80.7 +/- 8.9% of control (N = 12, p less than 0.05) and did not recover after washout. Intramyocardial contents of energy-related phosphates were determined by phosphorus NMR spectroscopy in seven other hearts. No significant change in myocardial energy metabolism was observed during adriamycin exposure and after washout; inorganic phosphate did not increase, and phosphocreatine and ATP did not decrease. These results indicate that Ca overload induced by adriamycin is associated with acute contractile failure. Adriamycin has been reported to inhibit Na-Ca exchange and to affect the gating of Ca2+ release channels in sarcoplasmic reticulum. Whatever the cause of the calcium overload, the fact that dysfunction persists as an aftereffect of adriamycin is consistent with the hypothesis that calcium overload, in the absence of ischemia, can leave behind long-lasting contractile dysfunction.
Adenosine Triphosphate↗
Positive inotropism in hypothermia partially depends on an increase in maximal Ca(2+)-activated force.
We investigated the contribution of maximal Ca(2+)-activated force to the positive inotropism induced by mild hypothermia. Phosphorus-31 nuclear magnetic resonance spectroscopy revealed that neither energy-related phosphorus compounds in myocardium nor intracellular pH was responsible for the change in contractility. Maximal Ca(2+)-activated pressure (MCAP), the intact-heart correlate of maximal Ca(2+)-activated force, was determined in isolated perfused rabbit hearts by measuring isovolumic left ventricular pressure during tetani at extracellular Ca2+ concentrations greater than or equal to 10 mM. Tetani were elicited by rapid pacing after exposure to ryanodine. MCAP increased by 2.17 +/- 0.28% (mean +/- SE, P less than 0.001, n = 19) for each degree of myocardial cooling between 30 and 38 degrees C. Our results indicate that a primary change in myofilament Ca2+ responsiveness underlies the positive inotropism in hypothermia. The increase in maximal Ca(2+)-activated force may explain the observation of positive inotropism without an upward shift in the relation between oxygen consumption and pressure-volume area, as previously reported for cooled whole hearts.
Animals↗
Mechanism of early ischemic contractile failure. Inexcitability, metabolite accumulation, or vascular collapse?
The basis of early ischemic contractile failure was investigated in perfused ferret hearts at 27 degrees C. Isovolumic left ventricular developed pressure fell by more than 50% within 30 seconds of the onset of total global ischemia and reached zero by 5 minutes. Monophasic action potential recordings revealed no decrease in excitability during this period. Phosphorus nuclear magnetic resonance spectra obtained at 30-second resolution showed no significant changes in inorganic phosphate or phosphocreatine during the first 30 seconds of ischemia. Intracellular pH (pHi) and ATP changed even more slowly; therefore, none of these metabolites could account for the rapid fall in force. To gauge the contribution of intravascular pressure, we compared ordinary aortic flow occlusion with tissue-level ischemia induced by massive coronary microembolization at the level of the precapillary arterioles. Functional depression developed significantly more slowly in the microembolized hearts, despite accumulation of inorganic phosphate and protons comparable with that in ordinary ischemia. After microembolization, the time course of functional depression reflected much more closely the concomitant inorganic phosphate and pHi changes. Thus, our results provide novel evidence supporting the importance of vascular collapse in the mechanism of early ischemic contractile failure.
Animals↗
Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts.
Free radicals have been implicated in the pathogenesis of reperfusion injury, but it is unclear how they exert their deleterious effects on cellular metabolism. Several lines of indirect evidence suggest that free radicals elevate intracellular Ca2+ concentration ([Ca2+]i) and inhibit glycolysis as part of their mechanism of injury. We tested these ideas directly in hearts subjected to hydroxyl radicals produced by the Fenton and Haber-Weiss reactions. Nuclear magnetic resonance spectra were obtained from Langendorff-perfused rabbit hearts before, during, and after 4 min of perfusion with H2O2 (0.75 mM) and Fe(3+)-chelate (0.1 mM). Isovolumic left ventricular pressure exhibited progressive functional deterioration and contracture after exposure to H2O2 + Fe3+. Phosphorus nuclear magnetic resonance (NMR) spectra revealed partial ATP depletion and sugar phosphate accumulation indicative of glycolytic inhibition. To measure [Ca2+]i, fluorine NMR spectra were acquired in a separate group of hearts loaded with the Ca2+ indicator 5F-BAPTA [5,5'-difluoro derivative of 1,2-bis-(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid]. Mean time-averaged [Ca2+]i increased from 347 +/- 14 nM in control to 1,026 +/- 295 nM 4 min after free radical generation (means +/- SEM, n = 7), and remained elevated thereafter. We conclude that free radicals induce clear-cut, specific derangements of cellular metabolism in the form of glycolytic inhibition and calcium overload. The observed increase in [Ca2+]i suggests that the deleterious effects of free radicals are at least partially mediated by secondary changes in cellular calcium homeostasis.
Adenosine Triphosphate↗
Pathophysiology and pathogenesis of contractile failure in stunned myocardium.
To investigate excitation-contraction coupling in stunned myocardium, intracellular free calcium concentration [( Ca2+]i) was measured before and after ischemia in perfused hearts using gated 19F NMR and the Ca2+ indicator 5F-BAPTA. Maximal Ca(2+)-activated force was also measured in parallel experiments. Stunned myocardium was created by reperfusion after 15 min global ischemia at 37 degrees C in isolated ferret hearts. In stunned myocardium, peak [Ca2+]i was paradoxically higher than that in control, but maximal Ca(2+)-activated pressure was lower in stunned hearts. These results indicate that contractile failure in stunned myocardium is due to a decrease in the myofilament sensitivity to Ca2+ as well as to a decrease in maximal Ca(2+)-activated force; failure of activator Ca2+ delivery cannot be implicated. The role of intracellular calcium overload in the pathogenesis of stunned myocardium was also investigated. Time-averaged 19F NMR measurements directly revealed the increase in [Ca2+]i during ischemia and in the early phase of reperfusion. The strategies to prevent Ca overload during reperfusion with modified reperfusate succeeded in preserving contractile function. Transient Ca overload without ischemia induced by different causes, i.e., high [Ca]0 perfusion, ventricular fibrillation or treatment with adriamycin, also produced contractile dysfunction that outlasted the interventions themselves. Thus, we propose that transient Ca overload during ischemia and early reperfusion initiates long-lasting contractile dysfunction in stunned myocardium.
Animals↗
[Cellular basis of pathophysiology in stunned myocardium].
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Animals↗
[Physiological function tests and the progress in medical electronics].
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Diagnosis↗
Theoretical analysis of T-wave polarity based on a model of cardiac electrical activity.
The effect of the gradient of transmembrane action potential duration through the ventricular wall on T-wave polarity and QRS-T angle was investigated using a mathematical model of the electrical activity of the heart which incorporates the characteristic electrophysiological properties of the left ventricular wall. Two models, a rectangular solid model and a concave model, were constructed to simulate a part of the left ventricular wall. The ventricular gradient was defined as a linear decrease (beta msec/cm) of the action potential duration from the endocardium to epicardium. The theoretically-obtained relationship between the QRS-T angle and the ventricular gradient revealed that the transmural gradient (beta) was 10--40 msec/cm when the QRS-T angle was within the normal range. The positive T wave was obtained at the observation point which would correspond to the precordial lead when the transmural gradient was more than 30 msec/cm. The amplitude of the simulated T-wave increased with the ventricular gradient. Thus, our mathematical models can provide the quantitative relationship between the transmural ventricular gradient and T-wave polarity and are compatible with further simulation study for various pathological conditions.
Action Potentials↗