Early Phase Of Myocardial Ischemia Research Articles

Chemical ablation of the left ventricular endocardium reduces ventricular fibrillation inducibility in acute ischemic canine heart.

Ventricular fibrillation remains as the major cause of death in patients with acute myocardial infarction. Effects of trans-atrial chemical ablation of the left ventricular (LV) endocardium with Lugol's solution on ventricular fibrillation inducibility and ventricular conduction were examined in canines with acute myocardial ischemia. Chemical ablation of the LV endocardium with Lugol's solution or normal saline was preformed through a left atrial appendage in 14 canines 30 min after occlusion of the left anterior coronary artery. Ventricular fibrillation threshold decreased after the coronary artery occlusion and increased after endocardial chemical ablation. There was a significant difference in the ventricular fibrillation threshold after chemical ablation between with Lugol's solution and with normal saline (25.9 ± 9.2 mA vs. 11.3 ± 2.7 mA, p < .01). QRS width significantly increased from 88 ± to 116 ± (p < .01) after the chemical ablation with Lugol's solution, and the activation map of the ventricles demonstrated a left bundle branch block ventricular conduction pattern. Histological examination of the LV endocardium showed lymphocyte infiltration for a depth of 1 mm. Chemical ablation of the LV endocardium with Lugol's solution injures endocardial conduction system and increases ventricular fibrillation threshold in the early phase of myocardial ischemia in canines. The procedure may be useful in suppressing intractable ventricular tachyarrhythmias in patients with acute myocardial ischemia.

Evaluating Subtle Pathological Changes in Early Myocardial Ischemia Using Spectral Histopathology.

Early myocardial ischemia (EMI) is morphologically challenging, and the results from conventional histological staining may be subjective, imprecise, or even silent. The size of myocardial necrosis determines the acute and long-term mortality of EMI. The precise diagnosis of myocardial ischemia is critical for both clinical management and forensic investigation. Fourier transform infrared (FTIR) spectroscopic imaging is a highly sensitive tool for detecting protein conformations and imaging protein profiles. The aim of this study was to evaluate the application of FTIR imaging with multivariate analysis to detect biochemical changes in the protein conformation in the early phase of myocardial ischemia and to visually classify different disease states. The spectra and curve fitting results revealed that the total protein content decreased significantly in the EMI group and that the α-helix content of the secondary protein structure continuously decreased as ischemia progressed, while the β-sheet content increased. Differences in the control and EMI groups and perfused and ischemic myocardium were confirmed using principal component analysis and partial least squares discriminant analysis. Next, two support vector machine classifiers were effectively created. The accuracy, recall, and precision were 99.98, 99.96, and 100.00%, respectively, to differentiate the EMI group from the control group and 99.25, 98.95, and 99.54%, respectively, to differentiate perfused and ischemic myocardium. Ultimately, high EMI diagnostic accuracy was achieved with 100.00% recall and 100.00% precision, and ischemic myocardium diagnostic accuracy was achieved with 99.30% recall and 99.53% precision for the test set. This pilot study demonstrated that FTIR imaging is a powerful automated quantitative analysis tool to detect EMI without morphological changes and will improve diagnostic accuracy and patient prognosis.

Class I and III antiarrhythmic drugs for prevention of sudden cardiac death and management of postmyocardial infarction arrhythmias. A review

The aim of the present paper is to review the evolution of concepts regarding the use of Class I and III antiarrhythmic drugs (AADs) in myocardial infarction over the past four decades. Results of animal experiments carried out by the authors and papers published between 1970 and 2012 in journals and the PubMed search system were used. Animal experiments carried out as early as the 1970s showed that Class IB and IC AADs lose their antiarrhythmic effect and electrically destabilize ventricles in the very early phase of myocardial ischemic focus formation. The cause of this is interaction between Class IB and IC AADs as well as Class III AADs with sympathetic neural activation (SNA) of the heart in the early phase of myocardial ischemia. Given the extremely high and uneven distribution of noradrenaline in tissue, SNA results in dispersion of the depolarization and repolarization processes in the ventricles. The clinical sequels of the interaction between the effects of AADs and SNA are as follows: the antiarrhythmic effect of AADs is restored in AMI once SNA has resolved; membrane-destabilization of the ventricles can be restored any time in the presence of randomly occurring SNA not only due to increasing myocardial ischemia but, also, as a result of psychological stress (emotions), and any pre-existing structural heart disease will enhance the pro-fibrillatory effect of a randomly occurring SNA. Despite the above risks, AADs continue to play an irreplaceable role in suppressing post-myocardial arrhythmias and in preventing sudden cardiac death following ICD placement. The risk of AADs' proarrhythmic effect in SNA can be reduced by combining them with beta-blockers. The last recourse when attempting to suppress malignant ventricular tachyarrhythmias is left sympathetic denervation of the heart.

Opioid receptor agonist reduces myocardial ischemic injury when administered during early phase of myocardial ischemia

Aim of the study Postresuscitation myocardial dysfunction is one of the leading causes of early death after initial success of resuscitation, the mechanisms of postresuscitation myocardial dysfunction remain controversial. We hypothesize that ischemia injury, rather than reperfusion injury is the major cause of postresuscitation myocardial dysfunction. We proposed to investigate the separate effects of ischemia and reperfusion injury on postresuscitation myocardial dysfunction. Methods Thirty-three Langendorff-perfused isolated rat hearts were subjected to 15 min of global ischemia followed by 120 min of reperfusion. Pentazocine was utilized as a myocardial protective agent, either before ischemia or during reperfusion. All hearts were randomized into 3 groups: (1) “ischemia protection”, in which pentazocine was infused 10 min prior to global ischemia, (2) “reperfusion protection”, in which pentazocine was infused during 2 h of reperfusion and (3) “control”, with no pentazocine infusion. Left ventricular (LV) functions were measured by the maximal rate of LV pressure rise (d P/d t max) and decline (−d P/d t max), the maximal LV diastolic pressure (LVDP). The incidences of postischemic arrhythmias were measured. Results When pentazocine was administered before onset of ischemia, the LV systolic and diastolic functions were significantly greater, and the postischemic arrhythmias were significantly less in comparison to those with reperfusion protection ( p < 0.05) and the control group ( p < 0.05). Conclusions In this model, the severity of postischemic myocardial dysfunction was less when the heart was protected during ischemia. Ischemia injury may therefore be the major cause of postresuscitation myocardial dysfunction.

Abstract 271: Ca 2+ /Calmodulin-Dependent Kinase Kinase β (CaMKKβ) Contributes to AMPK Activation in the Heart during Hypoxia

AMP-activated protein kinase (AMPK) is a stress signaling enzyme that regulates important cellular responses to ischemic stress in the heart. AMPK stimulates glucose uptake and utilization during myocardial ischemia and limits cardiac apoptosis and contractile dysfunction associated with ischemia/reperfusion injury. Activation of AMPK involves allosteric regulation by AMP/ATP ratio as well as phosphorylation by upstream AMPK kinases (AMPKKs) including LKB1 and CaMKKβ. The identity of the AMPKKs involved in the activation of AMPK during myocardial ischemia is not fully defined. The aims of this study were to determine whether CaMKKβ is expressed in the heart and in cardiomyocytes CaMKKβ is activated during ischemia and CaMKKβ contributes to AMPK activation during ischemia. CaMKKβ mRNA and protein were found to be expressed in mouse and rat hearts and isolated rat cardiomyocytes. To determine whether myocardial ischemia stimulates CaMKKβ activity in vivo , mouse hearts were subjected to regional ischemia by LAD occlusion, and assessed for phosphorylation of CaMKI (Thr 177 ), a direct downstream substrate of CaMKKβ. There was a 4-fold increase in CaMKI phosphorylation on its activating Thr 177 site within 2–5 min of ischemia (p&lt;0.05 vs. control). CaMKKβ signaling was transiently activated and correlated with the initial rise in AMPK phosphorylation during the early phase of myocardial ischemia. To further determine whether CaMKKβ participates in ischemia-induced heart AMPK activation and glucose uptake, isolated rat left ventricular papillary muscles were subjected to hypoxia in the presence of a specific CaMKKβ inhibitor, STO-609 (2 μM). CaMKKβ inhibition resulted in a 60% reduction in hypoxia-induced AMPK activation (p&lt;0.01 vs. hypoxia). In addition, inhibition of CaMKKβ yielded an 85% and 30% reduction in hypoxia-induced ACC phosphorylation and glucose uptake, respectively (p&lt;0.05 vs. hypoxia), two well-known downstream consequences of AMPK activation. CONCLUSION: Myocardial ischemia leads to an early, transient stimulation of the CaMKKβ pathway which correlates with the initial activation of AMPK during ischemic stress. CaMKKβ partially mediates hypoxia-induced activation of AMPK pathway in the heart.

The chicken or the egg? Voltage and calcium dynamics in the heart

t-wave alternans, corresponding to repolarization alternans in the ventricles, has been shown to predict the risk of cardiac arrhythmias and sudden cardiac death ([13][1], [25][2]). Theoretical studies have shown that arrhythmogenic repolarization alternans can originate from either the dynamics of

Platelets activated by collagen through the immunoreceptor tyrosine-based activation motif in the Fc receptor γ-chain play a pivotal role in the development of myocardial ischemia-reperfusion injury

Platelet activation and the formation of platelet microaggregates in coronary vessels play pivotal roles in myocardial ischemia and reperfusion injury. The Fc receptor γ-chain (FcR γ) is coexpressed with glycoprotein (GP) VI, forming a platelet collagen receptor, and the activation of platelets by collagen is closely coupled with tyrosine phosphorylation of the FcRγ. To examine the functional significance of platelet FcR γ/GPVI complex in the early phase of myocardial ischemia and reperfusion injury in mice, we performed coronary occlusion and reperfusion experiments using wild type mice and FcRγ-deficient (FcRγ –/–) mice that lack GPVI. The infarct size was significantly smaller in FcRγ –/– mice subjected to occlusion and reperfusion of the coronary artery than in control FcR γ +/+ mice. Twenty-four hours after the reperfusion, electron microscopy of the injured tissue showed substantially more platelet aggregation and occlusive platelet microthrombi in the capillaries of the damaged areas of the wild type mice than in those of the FcR γ –/– mice. Platelet Syk was scarcely activated in the FcR γ –/– mice after myocardial ischemia and reperfusion, but significantly activated in the FcR γ +/+ mice. CD11b expression on neutrophils was elevated after myocardial ischemia and reperfusion in both mouse groups, whereas myeloperoxidase activity in the injured areas was significantly lower in the FcRγ –/– mice than in the FcRγ +/+ mice. These results suggest that the collagen-induced activation of platelets through the FcR γ plays a pivotal role in the extension of myocardial ischemia-reperfusion injury. FcRγ and GPVI may be important therapeutic targets for myocardial ischemia-reperfusion injury.

Interaction between opioid receptor and adrenoceptor signaling in ischemia reperfusion of the isolated rat heart

To investigate the interaction between opioid receptor (OR) stimulation and adrenergic receptor (AR) stimulation in the isolated ischaemia/reperfusion (I-R) rat heart. Male Sprague-Dawley rats were used for Langendoff isolated heart perfusion. Myocardial ischemia for 20 min was followed by 30 min of reperfusion, during which the kappa-OR agonist U50488h and beta(1)-AR agonist norepinephrine (NE) were administered. (1) 50488h antagonized the effect of NE in rising left ventricular systolic pressure (LVSP) in the early phase of myocardial ischemia at 10, 20, 30 min of reperfusion. (2) Arrhythmia scores in the I-R+NE+U50488h group were markedly lower than those in the I-R group during the 10 - 20 min reperfusion period. No significant differences in arrhythmia scores were found in either I-R+U50488h or I-R+NE group when compared with I-R group. (3) Compared with the I-R group, U50488h alone or plus NE decreased reperfusion heart rates after myocardial ischemia while NE alone showed no effect. It is suggested that the interaction in the signaling pathway between kappa-OR and beta(1)-AR occurred during myocardial I-R of rat heart.

Spatial heterogeneity of calcium transient alternans during the early phase of myocardial ischemia in the blood-perfused rabbit heart.

Optical mapping of cytosolic calcium transients in intact mammalian hearts is now possible using long-wavelength [Ca(2+)](i) indicators. We propose that beat-to-beat [Ca(2+)](i) transient alternans during ischemia may lead to spatial and temporal heterogeneity of calcium-activated membrane currents. To test this hypothesis, isolated rabbit hearts were loaded with the fluorescent [Ca(2+)](i) indicator, rhod-2 AM, and imaged at 300 frames/sec during blood-perfused ischemic trials. High-quality [Ca(2+)](i) transients were recorded in each of 8 hearts.[Ca(2+)](i) transient alternans was never present in control records but occurred in each of the hearts during ischemia, with onset after 2 to 4 minutes. Alternans was confined to circumscribed regions of the heart surface 5 to 15 mm across. Multiple regions of alternans were found in most hearts, and regions that were out of phase with one another were found in 6 hearts. Quantitative maps of alternans were constructed by calculating an alternans ratio. This ratio behaved as a continuous variable that reached a maximum value in the center of the regions with alternans. These results demonstrate marked spatial heterogeneity of the [Ca(2+)](i) transient during the early phase of ischemia, which could produce electrical instability and arrhythmias in large mammalian hearts.

Modulation of L-type calcium current by internal potassium in guinea pig ventricular myocytes.

The early phase of myocardial ischemia is characterized by a considerable K+ efflux from cardiac myocytes, causing decreasing internal ([K+]i) and increasing external ([K+]o) K+ concentrations. The change in [K+]i and [K+]o is one of the factors thought to initiate the ischemia-induced changes in electrical activity. Nevertheless, little is known about the influence of [K+]i and [K+]o on the L-type calcium current. The whole-cell patch-clamp technique combined with an internal perfusion system was used to test possible actions of altered [K+]i and [K+]o on L-type current carried by Ca2+ and Ba2+ in isolated guinea pig ventricular myocytes. Changing the [K+]i in the range of 110-170 mM revealed a sigmoidal concentration-response relationship between the L-type current and [K+]i. The maximum change in current amplitude was more than 40% with a half-saturation concentration of 136 mM which is near the physiological [K+]i. Ca2+ influx during action potential clamp increased by approximately 42% after raising [K+]i from 130 to 170 mM. Internal perfusion with Cs+ demonstrated that Cs+ is less effective than K+ in regulating the L-type current. By using ATP-analogues, [K+]i was shown to affect the L-type channel in a phosphorylation-independent way. Changes in [K+]o only modulated the L-type current via alterations in [K+]i. The decrease in [K+]i during early ischemia is, per se, sufficient to reduce the L-type current by up to 15%, thereby decreasing the action potential duration, and Ca2+ influx into the cells. This may act in addition to well-known mechanisms such as changes in internal pH and falling ATP levels, which influence the L-type current. Moreover, the phenomenon may complicate the interpretation of electrophysiological measurements of L-type current under conditions where [K+]i is not precisely controlled.

Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia.

ECG peaked T wave appears during the early phase of myocardial ischemia, but the underlying mechanisms remain unknown. The purpose of this study was to elucidate the role of ATP-sensitive K+ channel (KATP) in this ECG change. In 12 anesthetized, open-chest dogs, the sinus node was crushed and the right atrium was paced at a cycle length of 400 ms. The left anterior descending coronary artery was abruptly occluded for 60 s before (control) and 15 min after an intravenous infusion of vehicle (n = 6) or glibenclamide (1 mg/kg, n = 6), a blocker of KATP. Forty-eight epicardial electrograms were simultaneously recorded from the anterior surface of the left ventricle. The potentials at 40, 80 and 120 ms from the J point were measured, and these points corresponded to the early, middle and late phases of the T wave, respectively. During the control occlusion, T wave increased time-dependently and the maximal T-wave change was noted at the end of 60 s of coronary occlusion. The extents of T-wave elevation at the early, mid and late T phases were 5.5 +/- 0.5, 7.3 +/- 0.8 and 11.7 +/- 1.8 mV, respectively, and these T-wave elevations were significantly reduced by 33 +/- 21%, 59 +/- 12% and 63 +/- 13%, respectively, after the pretreatment with glibenclamide but not with its vehicle. The % reductions of mid and late T by glibenclamide were significantly larger than that of early T wave (P < 0.05). An abrupt coronary occlusion accompanied peaked T wave as an early ECG wave change. As the extent of this T-wave elevation was attenuated by glibenclamide, the ischemia-induced alteration of ventricular repolarization can partly (60%) be explained by the modification of KATP activation.

Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia

Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia

Effects of glyburide on ischemia-induced changes in extracellular potassium and local myocardial activation: A potential new approach to the management of ischemia-induced malignant ventricular arrhythmias

The increase in extracellular potassium [K+]o levels during the early phase of myocardial ischemia may result in part from activation of adenosine triphosphate-sensitive K+ channels. Glyburide, a second-generation hypoglycemic sulfonylurea, is a potent blocker of these channels. We studied the effects of glyburide on [K+]o and on intramyocardial conduction delay during a 10-minute occlusion of the left anterior descending artery in the dog. K(+)-sensitive electrodes and bipolar plunge electrodes were introduced to record, respectively, [K+]o and local electrograms from close sites in midmyocardial regions in normal, border, and ischemic zones. Recordings were obtained before (control ischemia [CI]) and 20 minutes after intravenous administration of 0.15 mg/kg of glyburide (glyburide plus ischemia [G + I]). During G + I the extent of the increase in [K+]o was less compared to that during CI, and the difference was statistically significant during the first 7 minutes of ischemia in the ischemic zone and during the first 4 minutes of ischemia in the border zone. On the other hand, the degree of local intramyocardial conduction delay was significantly reduced during G + I compared to CI during the entire 10 minutes of ischemia in both the ischemic and border zones. In summary, our results have shown that glyburide significantly reduced the rise of [K+]o and intramyocardial delay during the early phase of acute ischemia and could thus attenuate the electrophysiologic consequences of ischemia that underlie the initial phase of malignant tachyarrhythmias. Although the effects of glyburide may result in part from a direct action of the drug on cardiac adenosine triphosphate-sensitive K+ channels, other metabolic antiischemic effects cannot be ruled out.

Cellular electrical uncoupling, contracture and conduction during the early phase of myocardial ischemia: Discordant effects of verapamil or hypocalcemia

Cellular electrical uncoupling, contracture and conduction during the early phase of myocardial ischemia: Discordant effects of verapamil or hypocalcemia

Lysosomal hypothesis in evolution of myocardial infarction. Subcellular fractionation and electron microscopic cytochemical study.

Twenty-two cat hearts were perfused according to Langendorff technique and myocardial regional ischemia was induced by occlusion of left anterior coronary artery. Separation of particulate (bound) from soluble (free) fraction, and subsequent fractionation into plasma membranes, lysosomes, sarcoplasmic reticulum, and mitochondria were performed by sucrose density gradient ultracentrifugation. By ischemia for 60 min, particle-bound activity of cathepsin D decreased from 4.2 +/- 0.24 U/mg protein to 3.2 +/- 0.31 U/mg protein (p less than 0.01). Likewise, the particle-bound activity of beta-glucuronidase decreased from 11.9 +/- 0.92 U/mg protein to 6.2 +/- 1.28 U/mg protein (p less than 0.01). Accordingly, free/bound activity ratios of cathepsin D increased from 0.8 to 1.9 and beta-glucuronidase from 0.9 to 2.8, respectively. Conspicuous fall from 12.8 +/- 0.6 U/mg protein to 8.0 +/- 0.97 U/mg protein (p less than 0.01) in absolute specific activity of cathepsin D bound to the lysosomal fraction, presents definitive evidence of lysosomal release of the acid hydrolases during the early phase of myocardial ischemia. Electron microscopic observation of the ischemic myocytes revealed ultrastructural alterations of the lysosomes suggestive of autophagic degradation of various subcellular organelles.

Effect of hyaluronidase during the early phase of acute myocardial ischemia: An ultrastructural and morphometric analysis

Hyaluronidase has been shown to reduce the size of experimental myocardial infarcts and to prevent the reduction in collateral coronary blood flow that normally occurs 15 minutes to 6 hours after coronary occlusion. To study the mechanism of action of this agent further, its effects on cardiac ultrastructure during the early phases of myocardial ischemia in the rat were examined. The left coronary artery was ligated for 1 or 3 hours in untreated and hyaluronidase-treated rats and tissue was sampled for electron microscopy. Morphometric analysis, using light microscopy on 1 μ thick specimens of tissue taken from comparable anatomic sites of the ischemic anterior left ventricular wall 3 hours after occlusion, showed that in the untreated rats 80 ± 7 percent (mean ± standard error) of myocardial cells and 48 ± 8 percent of vessels had morphologic evidence of ischemic damage, whereas in treated rats 50 ± 10 percent of myocardial cells ( P < 0.05) and 24 ± 6 percent ( P < 0.05) of vessels had ischemic changes. Ultrastructural studies of untreated ischemic tissue at 1 hour showed absence of glycogen, nuclear chromatin clumping, intermyofibrillar edema, I bands, intramitochondrial dense bodies and edema, endothelial blebs, gaps and swelling and decreased pinocytotic vesicles, red cell sludging and microscopic foci of hemorrhage. At 3 hours myocardial cell and vascular damage were more severe. In treated animals, more myocardial and endothelial cells from the ischemic anterior ventricular wall appeared normal on electron microscopy at both times. In these animals, myocardial cells that showed ischemic damage had nuclear, mitochondrial and myofibrillar morphologic features similar to those of untreated rats, but more glycogen granules were present than in the untreated group. Hyaluronidase may protect ischemic myocardium by preserving glycogen, and its preservation of collateral flow may be related to its reduction of ischemic damage in the microvasculature.

Lack of a significant protective effect of augmented circulating glucose on the ischemic myocardium

Infusion of glucose alone or glucose with insulin in cats subjected to acute myocardial ischemia did not alter the hemodynamic response of the cats to coronary artery ligation. Furthermore, determination of myocardial creatine phosphokinase (CPK) (ATP:creatine N-phosphotransferase, EC 2.7.3.2) activities failed to reveal a protective effect of glucose and insulin upon the status of the developing infarct in the ischemic myocardium. However, glucose and insulin apparently promote clearance of CPK from the plasma and inhibit proteolysis during the early phase of myocardial ischemia. These actions may be of value in generalized adaptive response of the animal to the stress of ischemia, but does not per se appear to diminish the spread of the ischemic damage within the heart not to limit the extension of the evolving infarct.