Mechanism Of Myocardial Stunning Research Articles

Diastolic Ca2+ overload caused by Na+/Ca2+ exchanger during the first minutes of reperfusion results in continued myocardial stunning

The pathogenesis of myocardial stunning caused by brief ischemia and reperfusion remains unclear. The aim of the present study was to investigate the underlying mechanism of myocardial stunning. An isolated cell model of myocardial stunning was firstly established in isolated rat ventricular myocytes exposed to 8 min of simulated ischemia and 30 min of reperfusion, the cardiomyocyte contractile function was used to evaluate myocardial stunning. A diastolic Ca(2+) overload without significant changes in systolic Ca(2+) and the amplitude of Ca(2+) transient during the first 10 min of reperfusion played an important role in the occurrence of myocardial stunning. Decreasing Ca(2+) entry into myocardial cells with low Ca(2+) reperfusion was a very efficient way to prevent myocardial stunning. Diastolic Ca(2+) overload was closely related to the reverse mode of Na(+)/Ca(2+) exchanger (NCX) rather than L-type Ca(2+) channel. The activity of the reverse mode of NCX was found significantly higher at the initial time of reperfusion, and KB-R7943, a selective inhibitor of the reverse mode of NCX, administered at first 10 min of reperfusion rather than at the time of ischemia significantly attenuated myocardial stunning. In addition, NCX inhibition also attenuated the Ca(2+) oscillation and cardiac dysfunction when field stimulus was stopped at first 10 min of reperfusion. These data suggest that one of the important mechanisms of triggering myocardial stunning is diastolic Ca(2+) overload caused by activation of the reverse mode of NCX of cardiomyocytes during the initial period of reperfusion following brief ischemia.

Hyperkalemic Cardioplegia-Induced Myocyte Swelling and Contractile Dysfunction: Prevention by Diazoxide

Hyperkalemic cardioplegia (9 degrees C) results in significant myocyte swelling and reduced contractility, representing a possible mechanism of myocardial stunning. Adenosine triphosphate-sensitive potassium channel (KATP) openers have been shown to ameliorate stunning. This study evaluated the hypothesis that a KATP opener would prevent hyperkalemic cardioplegia-induced myocyte swelling and reduced contractility. Isolated rabbit myocytes were perfused with 37 degrees C Tyrode's solution for 20 minutes, followed by test solution (9 degrees C or 37 degrees C) including control Tyrode's, Tyrode's + 100 micromol/L diazoxide (KATP opener), St. Thomas's solution; or 9 degrees C St. Thomas's + 100 micromol/L diazoxide or St. Thomas's + 100 micromol/L diazoxide + 20 micromol/L HMR1098 or 50 micromol/L 5-hydroxydeconoate (KATP blockers) for 20 minutes (n = 8 per group). Myocytes were then reexposed to 37 degrees C Tyrode's solution for 20 minutes. Volume and contractility were measured by videomicroscopy and video-based edge detection, respectively. St. Thomas's solution (9 degrees C) caused significant myocyte swelling and associated reduced contractility (p < 0.05). The addition of diazoxide abolished myocyte swelling (p < 0.0001), and eliminated the associated reduced contractility (p < 0.05). Findings were unchanged by the addition of HMR 1098 and 5-hydroxydeconoate. Diazoxide prevented myocyte swelling and reduced contractility secondary to hyperkalemic cardioplegia, and this was unchanged by the addition of either KATP channel blocker. Prevention of myocyte swelling was associated with improved contractility, consistent with the hypothesis that myocyte swelling may be a mechanism of myocardial stunning. Diazoxide may play a role in myocyte volume homeostasis by means of a mechanism separate from opening the KATP channel.

Effect of free radical scavengers on myocardial function and Na+, K+-ATPase activity in stunned rabbit myocardium

Objectives. The role of reactive oxygen species (ROS) in the mechanism of myocardial stunning was investigated. Material and methods. Isolated Langendorff-perfused rabbit hearts were subjected to 15 min normothermic ischemia followed by 10 min reperfusion with Krebs-Henseleit solution±mannitol or histidine. Results. In hearts reperfused without free radical scavenger the left ventricular developed pressure as well as its maximal positive and negative first derivatives (+dP/dt, −dP/dt) was significantly depressed, whereas end diastolic pressure (LVEDP) increased when compared to preischemic values. Treatment with mannitol had little protective effects, whereas singlet oxygen scavenger histidine significantly improved the recovery of LVEDP and −dP/dt. Sarcolemmal Na+, K+-ATPase activity (control, 400±41 nmol Pi.min−1.mg−1) was depressed in untreated stunned hearts (260±27 nmol Pi.min−1.mg−1), but was almost completely recovered in hearts pretreated with histidine (364±27 nmol Pi.min−1.mg−1). The inhibition of Na+, K+-ATPase was only slightly prevented by mannitol (302±29 nmol Pi.min−1.mg−1l). Conclusions. The results suggest that ROS-induced inhibition of Na+, K+-ATPase activity is involved in the mechanism of postischemic contractile dysfunction and support the view that singlet oxygen may be one of the major causes of oxidative injury during ischemia and reperfusion.

Postischemic Ventricular Function of Stunned Myocardium: A Modeling Perspective

Myocardial stunning is a prolonged postischemic dysfunction that compromises ventricular performance. Several contributing factors have been identified, but the exact mechanism of myocardial stunning remains unclear. A computer model of the ventricle can be effective in modeling the dominant observable features of myocardial stunning. A regional ventricular model is first introduced here, followed by a single cardiac muscle fiber model. The regional model is based on a previously developed multicompartment model with normal and ischemic zones incorporating time-varying elastance and viscoelastic properties. The mathematical model of the single cardiac muscle fiber consisted of three elements: a contractile element, a series elastic element, and a parallel elastic element. On the basis of the classic force-velocity-length relations, the single muscle model could generate muscle length waveforms based on time-dependent force and contractile stiffness functions. By entering the same parameter values used in the regional ventricular model, and by reducing contractile stiffness function or the rates of activation and deactivation, the three-element model could mimic similar results observed in canine experiments.

A novel mechanism for myocardial stunning involving impaired Ca(2+) handling.

The mechanism of myocardial stunning has been studied extensively in rodents and is thought to involve a decrease in Ca(2+) responsiveness of the myofilaments, degradation of Troponin I (TnI), and no change in Ca(2+) handling. We studied the mechanism of stunning in isolated myocytes from chronically instrumented pigs. Myocytes were isolated from the ischemic (stunned) and nonischemic (normal) regions after 90-minute coronary stenosis followed by 60-minute reperfusion. Baseline myocyte contraction was reduced, P<0.01, in stunned myocytes (6.3+/-0.4%) compared with normal myocytes (8.8+/-0.4%). The time for 70% relaxation was prolonged, P<0.01, in stunned myocytes (131+/-8 ms) compared with normal myocytes (105+/-5 ms). The impaired contractile function was associated with decreased Ca(2+) transients (stunned, 0.33+/-0.04 versus normal, 0.49+/-0.05, P<0.01). Action potential measurements in stunned myocytes demonstrated a decrease in plateau potential without a change in resting membrane potential. These changes were associated with decreased L-type Ca(2+)-current density (stunned, -4.8+/-0.4 versus normal, -6.6+/-0.4 pA/pF, P<0.01). There were no differences in TnI, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a), and phospholamban protein quantities. However, the fraction of phosphorylated phospholamban monomer was reduced in stunned myocardium. In rats, stunned myocytes demonstrated reduced systolic contraction but actually accelerated relaxation and no change in Ca(2+) transients. Thus, mechanisms of stunning in the pig are radically different from the widely held concepts derived from studies in rodents and involve impaired Ca(2+) handling and dephosphorylation of phospholamban, but not TnI degradation.

Subarachnoid Haemorrhage with Transient Myocardial Injury and Normal Coronary Arteries

We present a case of cerebral subarachnoid haemorrhage, with T-wave inversions and myocardial akinesia on echo-cardiography and ventriculography. Acute coronary angiography showed normal arteries. An aneurysm of the right middle cerebral artery was clamped. Echocardiogram was normalized. We discuss coronary spasm as the possible mechanism of myocardial stunning in subarachnoid haemorrhage.

The Role of Adenosine and ATP-sensitive Potassium Channels in the Protection Afforded by Ischemic Preconditioning Against the Post-ischemic Endothelial Dysfunction in Guinea-pig Hearts

The role of adenosine and ATP-sensitive potassium channels (KATP) in the mechanism of ischemic preconditioning (IPC)-induced protection against the post-ischemic endothelial dysfunction was studied. Langendorff-perfused guinea-pig hearts were subjected either to 40 min of global ischemia and 40 min reperfusion or were preconditioned prior to the ischemia/reperfusion with three cycles of either 5 min ischemia/5 min reperfusion (IPC) or 5 min infusion/5 min wash-out of adenosine, adenosine A1receptor agonist, N6-cyclohexyladenosine (CHA) or KATPopener, pinacidil. The magnitude of coronary flow reduction caused by NO-synthase inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME), served as an index of a basal endothelium-dependent vasodilator tone. Coronary overflows produced by a bolus of acetylcholine (ACh) and sodium nitroprusside (SNP) were used as measures of agonist-induced endothelium-dependent and endothelium-independent vascular function, respectively. The coronary flow, LVDP, ACh response andl-NAME response were reduced by 8, 32, 41 and 54%, respectively, while SNP response was not changed in the hearts subjected to ischemia/reperfusion. ACh response was fully restored,l-NAME response was partially restored, and SNP response was not affected in the hearts subjected to IPC. The post-ischemic recoveries of coronary flow and LVDP were not improved by IPC. The protective effect of IPC on the ACh response was mimicked by adenosine, CHA, and pinacidil. The protective effect of IPC, CHA and pinacidil was abolished by KATPantagonist, glibenclamide. The IPC protection was affected neither by a non-specific adenosine antagonist, 8-p-sulfophenyltheophylline, nor by a specific adenosine A1receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Our data indicate that: (1) IPC affords endothelial protection in the mechanism that involves activation of KATP, but not adenosine A1receptors; (2) exogenous adenosine and A1receptor agonist afford the protection, which might be of a potential clinical significance; (3) the endothelial dysfunction is not involved in the mechanism of myocardial stunning in guinea-pig hearts.

Do we know the mechanism of myocardial stunning?

Do we know the mechanism of myocardial stunning?

Role of sodium/calcium exchange in the mechanism of myocardial stunning: Protective effect of reperfusion with high sodium solution

Objectives. This study was conducted to elucidate the role of sodium/calcium (Na+/Ca2+) exchange in the mechanism of myocardial stunning.Background. Cellular Ca2+overload mediated by Na+/Ca2+exchange during reperfusion has been proposed as a mechanism for myocardial stunning. Because no specific pharmacologic inhibitors of the exchanger are available, we increased extracellular sodium concentration ([Na]0) during the early phase of reperfusion to decrease the driving force for Ca2+influx through the pathway.Methods. Isovolumetric left ventricular pressure and phosphorus-31 nuclear magnetic resonance spectra were measured in isolated perfused ferret hearts. Hearts were reperfused with different solutions after 15 min of total global ischemia at 37 °C.Results. Hearts reperfused with standard solution ([Na]0= 140 mmol/liter; the stunned hearts, n = 8) showed only 69 ± 3% (mean ± SEM) recovery of developed pressure relative to preischemic control developed pressure, In contrast, hearts reperfused with a high [Na]0solution ([Na]0= 268 mmol/liter) during the initial 5 min, followed by a gradual decrease of [Na]0to the standard level over 25 min (the high [Na]0group, n = 8) showed significantly better recovery of developed pressure (85 ± 2%, p < 0.05 vs. the stunned hearts). in contrast, reperfusion with solutions in which the additional Na was substituted either by 256 mmol/liter sucrose or 128 mmol/liter chollne chloride did not improve functional recovery, indicating that the beneficial effects of high [Na]0reperfusion are not due to either high ionic strength or high osmolarity. Phosphorus-31 nuclear magnetic resonance spectra showed no correlation between functional recovery and intramyocardial contents of phosphorus compounds or pH.Conclusions. High [Na]0reperfusion protects against stunning, supporting the concept that Na+/Ca2+exchange plays an important role in the mechanism of stunned myocardium.

Contractile proteins in globally “stunned” rabbit myocardium

The isolated working rabbit heart preparation was used to study whether the "contractile machinery" remains unchanged in globally stunned myocardium. The function of the heart has been measured in nonischemic and postischemic conditions. The effect of isoprenaline or calcium chloride administration in both conditions was also studied. Myocardial contractile function was significantly depressed after 20-min global ischemia and returned to normal after CaCl2 and supranormal values after isoprenaline administration. From hearts used in experiments myofibrils were prepared and their ATPase activity was determined. It was observed that myofibrils prepared from "stunned" myocardium showed about 50% increase in ATPase activity in the presence of CaCl2. Subjection of the heart to ischemia caused a decrease in calcium sensitivity of the myofibrillar ATPase. Myofibrils obtained from ischemic hearts but subjected to isoprenaline or CaCl2 administration exhibited increased calcium sensitivity over that of control heart. These effects were accompanied by changes in the extent of phosphorylation of troponin I (TNI) and myosin light chains. The modification of contractile apparatus in the postischemic period described in this paper may contribute to the overall mechanism of myocardial stunning.

Degradation and altered function of the calcium-release channel during acute ischaemia: A possible mechanism of myocardial stunning

Degradation and altered function of the calcium-release channel during acute ischaemia: A possible mechanism of myocardial stunning