Periods Of Coronary Artery Occlusion Research Articles

The Role of Pyroptosis in Ischemic and Reperfusion Injury of the Heart.

While ischemia itself can kill heart muscle, much of the infarction after a transient period of coronary artery occlusion has been found to result from injury during reperfusion. Here we review the role of inflammation and possible pyroptosis in myocardial reperfusion injury. Current evidence suggests pyroptosis's contribution to infarction may be considerable. Pyroptosis occurs when inflammasomes activate caspases that in turn cleave off an N-terminal fragment of gasdermin D. This active fragment makes large pores in the cell membrane thus killing the cell. Inhibition of inflammation enhances cardiac tolerance to ischemia and reperfusion injury. Stimulation of the purinergic P2X7 receptor and the β-adrenergic receptor and activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) by toll-like receptor (TLR) agonists are all known to contribute to ischemia/reperfusion (I/R) cardiac injury through inflammation, potentially by pyroptosis. In contrast, stimulation of the cannabinoid CB2 receptor reduces I/R cardiac injury and inhibits this pathway. MicroRNAs, Akt, the phosphate and tension homology deleted on chromosome 10 protein (PTEN), pyruvate dehydrogenase and sirtuin-1 reportedly modulate inflammation in cardiomyocytes during I/R. Cryopyrin and caspase-1/4 inhibitors are reported to increase cardiac tolerance to ischemic and reperfusion cardiac injury, presumably by suppressing inflammasome-dependent inflammation. The ambiguity surrounding the role of pyroptosis in reperfusion injury arises because caspase-1 also activates cytotoxic interleukins and proteolytically degrades a surprisingly large number of cytosolic enzymes in addition to activating gasdermin D.

Hyperpolarized metabolic imaging of myocardial ischemia-reperfusion in a small-animal model at 9.4T

Background Dynamic hyperpolarization (DNP) of Carbon-13 (13C) allows in-vivo assessment of metabolic processes. The aims of the present study were to establish a living rat model of ischemia-reperfusion and to study the metabolic changes in the myocardium following short periods of coronary artery occlusion using intravenous injection of hyperpolarized 1-13C pyruvate. Methods An inflatable balloon was secured around the left coronary artery of Sprague Dawley rats. 5-7 days after surgery rats were placed in a Bruker Biospec 9.4T small animal MR system. To enhance bicarbonate signal, animals received an iv glucose/potassium infusion. The tubing of the occluder was connected to extension tubing to allow occlusion while the animal remained in the bore of the MR system. A custom-built multi-sample DNP polarizer (1) was used to polarize samples (25.4 μ L[ 1- 13 C]-pyruvic acid and 13.5 mM trityl radical doped with 1.5 mM Dotarem). The rats were injected with 1.4 ml DNP solution at 4 time points: baseline, reperfusion directly after 15 minutes of coronary occlusion, after 30 minutes of reperfusion, after 60 minutes of reperfusion. A subgroup of rats underwent repeat imaging 1 week after ischemia. Metabolic data were acquired with a multiband pulse in combination with a multi-echo single-shot EPI readout (2). Hearts were removed and stained to delineate the area at risk (AAR), and for myocardial infarction. Results

Delayed Cardioprotection by Inhaled Anesthetics

SCHEMIC PRECONDITIONING (IPC) is a process by which a brief ischemic insult confers protection against a subsequent ischemic episode of similar or greater magnitude. Murry et al 1 first described IPC in the canine myocardium. The investigators showed that 4 transient (5 minutes) periods of coronary artery occlusion interspersed with 5 minutes of reperfusion did not enlarge as anticipated but rather paradoxically reduced the size of a myocardial infarction resulting from a subsequent more prolonged (40 minutes) episode of ischemia and reperfusion. This seminal article showed, for the first time, that the heart was capable of recognizing and rapidly adapting to stress, thereby becoming more resistant to subsequent injury. 1 Bolli et al 2-4 described this IPC phenomenon as a form of “vaccination” that stimulated the “innate plasticity” of myocardium by altering its phenotype and promoting its “self-preservation” as a primary defense mechanism. In the 25 years since IPC was first described, basic science and clinical research examining the mechanisms, limitations, and potential applicability of this process have expanded exponentially. Indeed, a recent PubMed search of the key words “myocardial ischemic preconditioning” indicated that more than 900 articles addressing this subject were published in the peer-reviewed literature in 2009 alone. 5 A large portion of this extraordinary body of work showed that a remarkable plethora of other stimuli, including a diverse variety of drugs, nitric oxide (NO), reactive oxygen species (ROS), endotoxins, inflammatory cytokines, heat stress, rapid pacing, and strenuous exercise, are capable of inducing this prosurvival phenotype, thereby protecting against irreversible ischemic injury independent of an antecedent period of brief myocardial ischemia. 6 Of most immediate relevance to this review, modern volatile anesthetics and the anesthetic noble gas xenon are among the drugs that have been shown to mimic IPC through nearly identical intracellular mechanisms. 7,8

Mechanism of Cardioprotection by Early Ischemic Preconditioning

A series of brief ischemia/reperfusion cycles (termed ischemic preconditioning, IPC) limits myocardial injury produced by a subsequent prolonged period of coronary artery occlusion and reperfusion. Over the last 2 decades our understanding of IPC's mechanism has increased exponentially. Hearts exposed to IPC have a better metabolic and ionic status during prolonged ischemia compared to naïve hearts. However, this difference is not thought to be the main mechanism by which IPC protects against infarction. Signaling pathways that are activated by IPC distinguish IPC hearts from naïve hearts. During the trigger phase of IPC, adenosine, bradykinin and opioid receptors are occupied. Although these three receptors trigger signaling through divergent pathways, the signaling converges on protein kinase C. We have proposed that at the end of the index ischemia the activated PKC sensitizes the low-affinity A(2b) adenosine receptor (A(2b)AR) through phosphorylation of either the receptor or its coupling proteins so that A(2b)AR can be activated by endogenous adenosine released by the previously ischemic cardiomyocytes. The sensitized A(2b)AR would then be responsible for activation of the survival kinases including PI3 kinase, Akt and ERK which then act to inhibit lethal mitochondrial permeability transition pore formation which normally uncouples mitochondria and destroys many myocytes in the first minutes of reperfusion. Herein we review the evidence for the above mechanisms and their functional details.

Man Overboard!

Man Overboard!

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-alpha would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and age-matched Wistar rats (n >or= 7) were given either 1) the PPAR-alpha agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor N(G)-nitro-l-arginine (l-NNA), 4) l-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/nitrate were determined. The IS was 75 +/- 3% and 72 +/- 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 +/- 3% in Wistar (P < 0.05) and to 46 +/- 5% in GK rats (P < 0.001). The addition of either l-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 +/- 5% and 65 +/- 5%, respectively) and GK (IS, 66 +/- 4% and 64 +/- 4%, P < 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats (P < 0.05). The results suggest that PPAR-alpha activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.

The value of both ST-segment and QRS complex changes during acute coronary occlusion for prediction of reperfusion-induced myocardial salvage in a canine model

Background Analysis of ST-segment elevation for assessment of patients with suspected acute coronary occlusion is in widespread use for diagnostic and prognostic purposes. In this study, changes in the QRS complex also were analyzed to determine if these changes that are seldom used clinically can provide additional prognostic information. An acute coronary occlusion canine model, in which direct measurements of myocardial salvage were made, was used to assess whether ST-segment and QRS complex changes during coronary occlusion yielded independent estimates of the amount of salvage provided by reperfusion with arterial blood. Methods and Results Continuous electrocardiographic recordings were obtained from 14 study dogs undergoing a 90-minute period of coronary artery occlusion in which the severity of the ischemia during the occlusion was estimated at 10 and 45 minutes by microsphere injections. After 3 hours of reperfusion, the myocardium at risk and postmortem infarct size was measured. Myocardial salvage correlated inversely with both ST-segment elevation ( r = −0.85; P < .0001), and QRS complex prolongation ( r = −0.72; P = .003). When dogs were paired so that they had equal amounts of ST elevation but differed with respect to the presence of QRS prolongation, less myocardial salvage was found in those with QRS prolongation. The independent value of QRS prolongation was supported further by the observation that presence of QRS prolongation resulted in a loss of the highly significant correlation between ST elevation and salvage ( r = −0.60; P = .2). Conclusions High magnitudes of ST elevation are correlated significantly with less myocardial salvage. Moreover, for a given magnitude of ST elevation, the presence of concurrent QRS prolongation is associated with even less myocardial salvage.

Protection against myocardial ischaemia/reperfusion injury by PPAR–α activation is related to production of nitric oxide and endothelin–1

Ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-alpha exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin-1 (ET-1). Five groups of anaesthetized open-chest Sprague-Dawley rats were given the PPAR-alpha agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA, 2 mg/kg) (n = 7), L-NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L-NNA; n = 8) i.v. before a 30 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), eNOS and iNOS protein and ET-1 mRNA expression were determined. There were no haemodynamic differences between the groups during the experiment. The IS was 78 +/- 3% of the area at risk in the DMSO group and 77 +/- 2% in the NaCl group (P = NS). WY reduced IS to 56 +/- 3% (P < 0.001 vs. DMSO group). When WY was administered in combination with L-NNA the cardioprotective effect was abolished (IS 73 +/- 3%, P < 0.01 vs. WY 14643). L-NNA did not affect IS per se (78 +/- 2%, P = NS). The expression of eNOS but not iNOS protein in ischaemic myocardium from rats was increased in the group given WY (P < 0.05). ET-1 mRNA levels were lower in the ischaemic myocardium following WY administration. The results suggest that the PPAR-alpha activation protects the rat myocardium against ischaemia/ reperfusion injury via a mechanism related to production of NO, and possibly ET-1.

Myocardial preconditioning and remote renal preconditioning

It is still unknown whether remote ischemic preconditioning is mediated by a humoral or a neurogenic mechanism from the preconditioning to the preconditioned tissue. The purpose of the following study was to identify a possible humoral trigger of ischemic myocardial preconditioning and remote renal preconditioning. Open chest rats were subjected to a coronary artery occlusion period of 45 min followed by 2 h of reperfusion (Control animals; n = 6). The coronary preconditioned group (IPC, n = 6) was subjected to a preceding preconditioning period of 5 min coronary artery occlusion followed by 5 min of reperfusion, repeated three times. The renal preconditioned group (IPR, n = 6) was subjected to a preceding renal artery occlusion period of 10 min followed by 20 min of reperfusion. Area at risk (AAR) and infarcted area (IA) were determined at the end of each protocol. Blood samples were taken at the end of the preconditioning protocols from parallel experiments for proteomic analysis using two-dimensional gel electrophoresis (2-DE), matrix assisted laser desorption and ionization-time of flight-mass spectrometry (MALDI-TOF-MS), and liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoLC-ESI-MS/MS). IA/AAR was 87.8 +/- 10.7% in the control group. IPC and IPR significantly reduced IA/AAR (58.2 +/- 9.3% and 56.9 +/- 9.0%, p < 0.001). Proteomic analyses detected four protein spots which were either up- (n = 3) or down-regulated in the preconditioned groups vs. the control group. The three up-regulated protein spots were identified as albumin fragments, whereas the down-regulated spot was identified as liver regeneration-related protein (LRRG03). Interestingly, albumin modification by brief ischemia has been recently shown and evaluated for the clinical diagnosis of sublethal myocardial ischemia. However, no differentially abundant proteins which possess a known signaling function could be found. Hence, though there is a differential protein expression in blood following IPC and IPR, our data are not in favor of a humoral mediator of remote preconditioning with a molecular weight of more than 8 kDa. Our results rather suggest either a neurogenic pathway or a mediator smaller than 8 kDa.

Sevoflurane confers additional cardioprotection after ischemic late preconditioning in rabbits.

Sevoflurane exerts cardioprotective effects that mimic the early ischemic preconditioning phenomenon (EPC) by activating adenosine triphosphate-sensitive potassium (KATP) channels. Ischemic late preconditioning (LPC) is an important cardioprotective mechanism in patients with coronary artery disease. The authors investigated whether the combination of LPC and sevoflurane-induced preconditioning results in enhanced cardioprotection and whether opening of KATP channels plays a role in this new setting. Seventy-three rabbits were instrumented with a coronary artery occluder. After recovery for 10 days, they were subjected to 30 min of coronary artery occlusion and 120 min of reperfusion (I/R). Controls (n = 14) were not preconditioned. LPC was induced in conscious animals by a 5-min period of coronary artery occlusion 24 h before I/R (LPC, n = 15). Additional EPC was induced by a 5-min period of myocardial ischemia 10 min before I/R (LPC+EPC, n = 9). Animals of the sevoflurane (SEVO) groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min at 10 min before I/R with (LPC+SEVO, n = 10) or without (SEVO, n = 15) additional LPC. The KATP channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg) was given intravenously 10 min before sevoflurane administration (LPC+SEVO+5-HD, n = 10). Infarct size of the area at risk (triphenyltetrazolium staining) was reduced from 45 +/- 16% (mean+/-SD, control) to 27 +/- 11% by LPC (P < 0.001) and to 27 +/- 17% by sevoflurane (P = 0.001). Additional sevoflurane administration after LPC led to a further infarct size reduction to 14 +/- 8% (LPC+SEVO, P = 0.003 vs. LPC; P = 0.032 vs. SEVO), similar to the combination of LPC and EPC (12 +/- 8%; P = 0.55 vs. LPC+SEVO). Cardioprotection induced by LPC+SEVO was abolished by 5-HD (LPC+SEVO+5-HD, 41 +/- 19%, P = 0.001 vs. LPC+SEVO). Sevoflurane administration confers additional cardioprotection after LPC by opening of KATP channels.

Prologue: nonclassical modalities of myocardial preconditioning.

classical ischemic preconditioning (IPC) occurs when single or multiple brief periods of coronary artery occlusion interspersed with brief periods of reperfusion precede a prolonged ischemic insult ([3][1]). IPC has been shown to result in a marked reduction of myocardial infarct size in all species

Mitochondrial KATP channels and cardioprotection

AbstractSince its identification in 1983, the myocardial ATP‐sensitive potassium channel (KATP channel) has been recognized as an important ion channel that couples the cellular energy status to electrical activity in ischemic or hypoxic myocytes, and early studies with selective potassium channel openers suggested that opening this channel may result in cellular protection. This concept was strengthened in 1992, when it was shown that this channel was an integral part of ischemic preconditioning (IPC), a phenomenon in which one or several short periods of coronary artery occlusion were shown to protect the heart from a more prolonged coronary artery occlusion. Endpoints of injury, which have been used as indices to demonstrate the efficacy of IPC, include a reduction in myocardial infarct size, a reduction in contractile dysfunction after brief periods of ischemia (myocardial stunning), and a decrease in the incidence of cardiac arrhythmias during coronary artery occlusion and/or reperfusion. Since the seminal observation of a myocrdial KATP channel, two KATP channels have been identified: one in the sarcolemmal membrane (sarc KATP) and one in the inner mitochondrial membrane (mito KATP). There is evidence to support a role for both channels in mediating cardioprotection; however, the majority of recent evidence suggests that the mito KATP channel is the major channel responsible for cardioprotection after IPC or the administration of KATP opener drugs. This review will summarize the evidence supporting a role for the mito KATP channel in both acute and delayed preconditioning produced by ischemia. The review will also summarize, from a pharmacological viewpoint, the potential mechanisms responsible for the cardioprotection observed and the potential clinical implications of developing drugs that are selective mito KATP channel openers. Drug Dev. Res. 55:17–21, 2002. © 2002 Wiley‐Liss, Inc.

Cyclooxygenase-2 in Myocardium Stimulation by Angiotensin-II in Cultured Cardiac Fibroblasts and Role at Acute Myocardial Infarction

Myocardial infarction is followed by a complex repair process that includes a significant role for inflammatory cells. Cyclooxygenase-2 (COX-2) plays a key role in mediating inflammation. Contribution of COX-2 to inflammatory response following myocardial infarction is less certain. In an effort to evaluate the function of COX-2 and prostaglandin E2(PGE2) in myocardial infarction, we examined the role of COX-2 after angiotensin II (Ang II) stimulation in cardiac fibroblasts and in rats with experimental myocardial infarction (MI). We combined Western blot analysis and enzyme immunoassay to demonstrate COX-2 expression and PGE2release in cardiac fibroblasts. Isolated cardiac fibroblasts were stimulated with Ang II. Unstimulated fibroblasts showed no COX-2 protein expression. Fibroblasts stimulated with Ang II showed a strong time-dependent expression of COX-2 protein. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 but not the p42/44 MAPK-inhibitor PD98059 suppressed Ang II-induced COX-2 protein expression. COX-2 expression correlated with a significantly increased PGE2release from cardiac fibroblasts. The COX-2 specific inhibitor NS-398 suppressed the Ang II-stimulated PGE2production. We then investigated COX-2 expression and inflammatory cell infiltration in our rat model of myocardial infarction. MI was produced by coronary artery ligation in adult female Wistar rats. The period of coronary artery occlusion was 96 h. The selective COX-2 inhibitor rofecoxib (3 mg/kg/d), administered orally, was given one day before MI and continued for four days. Western blotting showed expression of COX-2 protein in the area of necrosis and the infarct border zone. Immunofluorescence analysis showed macrophage infiltration as well as fibroblast proliferation in the infarct border zone of 4-d infarcted tissue and a significantly reduced cell invasion and fibroblast proliferation in infarcted tissue of rats treated with rofecoxib. MI size at day 4 was comparable in untreated and treated rats. In conclusion, we demonstrate that pharmacological interference with prostaglandin synthesis in myocardial infarction is associated with reduced myocardial invasion of inflammatory cells.

Reperfusion Arrhythmias and Sudden Cardiac Death

The observation that ventricular fibrillation may occur within seconds after restoration of blood flow to myocardium turned ischemic by a period of coronary occlusion (reperfusion) was originally made in the experimental laboratory in the 19th century by Cohnheim and Von Schulthess-Rechberg1 and later confirmed in the early 20th century by Tennant and Wiggers.2 In fact, it was found in subsequent laboratory experiments that ventricular fibrillation may occur more frequently after reperfusion than after coronary artery occlusion.3 It took until the latter part of the 20th century for these early laboratory studies to be translated to clinical medicine. It was noticed that only a minority of those individuals who have been successfully resuscitated from sudden ventricular fibrillation associated with coronary artery disease subsequently developed a myocardial infarction,4,5 suggesting that, if indeed myocardial ischemia caused by coronary occlusion was involved, it was transient. Reperfusion must have occurred. This proposed relationship between transient ischemia, reperfusion, and arrhythmias was corroborated by studies in patients with transient coronary artery spasm in whom ventricular arrhythmias, including ventricular fibrillation, occurred within minutes after the beginning of electrocardiographic signs of myocardial ischemia caused by the spasm6 but also after ST segment changes had returned to normal, when reperfusion had occurred.6–9 What is the mechanism responsible for this occurrence of fibrillation? This is a subject that has been pursued in more than a century of experimentation with slow but continued progress. The most recent advance, now in the 21st century, is the article by Cascio et al10 in this issue of Circulation Research . The initial information on mechanisms of reperfusion arrhythmias came from experiments on in situ hearts of large animals subjected to periods of coronary artery occlusion followed by release of the occlusion that allowed reperfusion. In these experiments, the …

Angerlike behavioral state potentiates myocardial ischemia-induced T-wave alternans in canines

OBJECTIVESThe main goal of this study was to determine whether induction of an angerlike state can result in significant levels of T-wave alternans, a marker of electrical instability, in the normal and ischemic heart.BACKGROUNDOutbursts of anger have been implicated in the occurrence of myocardial infarction and sudden cardiac death, but the pathophysiologic mechanisms remain unknown.METHODSA standardized behavioral challenge of eliciting an angerlike state was conducted before and during a 3-min period of coronary artery occlusion in six canines.RESULTSPrecordial T-wave alternans increased from 0.04 ± 0.02 at baseline to 1.40 ± 0.32 mV × ms (p < 0.05) during the angerlike response. When the angerlike state and myocardial ischemia were superimposed, the augmentation in T-wave alternans magnitude (to 3.27 ± 0.61 mV × ms, p < 0.05) exceeded their additive effects, increasing by 130% over the angerlike state alone (p < 0.05) and by 390% over occlusion alone (p < 0.05). Adrenergic influences were reduced by the beta1-adrenergic receptor blocking agent metoprolol (1.5 mg/kg, intravenous), which diminished T-wave alternans magnitude (p < 0.0004 for all) during the angerlike response (from 1.40 ± 0.32 to 0.80 ± 0.17 mV × ms) and during the combined intervention (from 3.27 ± 0.61 to 1.23 ± 0.13 mV × ms). In five additional normal anesthetized canines, atrial pacing at 180 beats/min did not increase T-wave alternans magnitude monitored from lead II electrocardiogram.CONCLUSIONSProvocation of an angerlike state results in T-wave alternans in the normal heart and potentiates the magnitude of ischemia-induced T-wave alternans. Elevation in heart rate during arousal does not appear to be the main factor in the development of alternans in the normal heart but may be an important component during myocardial ischemia. Enhanced adrenergic activity appears to mediate the effects in both the normal and ischemic hearts. T-wave alternans may constitute a useful electrophysiologic measure for clinical use in conjunction with behavioral stress testing or ambulatory monitoring.

Diabetes and hyperglycemia impair activation of mitochondrial K(ATP) channels.

Hyperglycemia is an important predictor of cardiovascular mortality in patients with diabetes. We investigated the hypothesis that diabetes or acute hyperglycemia attenuates the reduction of myocardial infarct size produced by activation of mitochondrial ATP-regulated potassium (K(ATP)) channels. Acutely instrumented barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3 h of reperfusion. Myocardial infarct size (triphenyltetrazolium chloride staining) was 25 +/- 1, 28 +/- 3, and 25 +/- 1% of the area at risk (AAR) for infarction in control, diabetic (3 wk after streptozotocin-alloxan), and hyperglycemic (15% intravenous dextrose) dogs, respectively. Diazoxide (2.5 mg/kg iv) significantly decreased infarct size (10 +/- 1% of AAR, P < 0.05) but did not produce protection in the presence of diabetes (28 +/- 5%) or moderate hyperglycemia (blood glucose 310 +/- 10 mg/dl; 23 +/- 2%). The dose of diazoxide and the degree of hyperglycemia were interactive. Profound (blood glucose 574 +/- 23 mg/dl) but not moderate hyperglycemia blocked the effects of high-dose (5.0 mg/kg) diazoxide [26 +/- 3, 15 +/- 3 (P < 0.05), and 11 +/- 2% (P < 0.05), respectively]. There were no differences in systemic hemodynamics, AAR, or coronary collateral blood flow (by radioactive microspheres) between groups. The results indicate that diabetes or hyperglycemia impairs activation of mitochondrial K(ATP) channels.

Ethanol enhances the functional recovery of stunned myocardium independent of K(ATP) channels in dogs.

Chronic, intermittent exposure to small amounts of ethanol reduces myocardial infarct size in vivo. We tested the hypothesis that acute administration of ethanol enhances the functional recovery of stunned myocardium and that adenosine triphosphate-dependent potassium (K(ATP)) channels mediate this beneficial effect. Barbiturate-anesthetized dogs were instrumented for measurement of aortic and left ventricular pressure, +dP/dt(max), and subendocardial segment shortening (%SS) and were subjected to five 5-min periods of coronary artery occlusion, each separated by 5 min of reperfusion followed by a 3-h final reperfusion. In four groups (n = 7 each), dogs received 0.9% saline or ethanol (0.25, 0.5, or 1.0 g/kg over 30 min) in a random manner before occlusions and reperfusions. In other groups (n = 7 each), dogs received the K(ATP) channel antagonist glyburide (0.3 mg/kg, IV) 30 min before saline or ethanol (0.25 g/kg) was administered. Dogs receiving saline or glyburide alone demonstrated poor recovery of contractile function during reperfusion (%SS = 0.9% +/- 2.0% and 1.6% +/- 1.2% at 3 h, respectively). Recovery of %SS was enhanced in dogs receiving the 0.25- and 0.5-g/kg doses of ethanol (10.0% +/- 1.8% and 8.6% +/- 2.2% at 3 h, respectively) independent of alterations in hemodynamics or coronary collateral blood flow (radioactive microspheres). Glyburide did not affect improvement of recovery of stunned myocardium produced by ethanol (11.8% +/- 2.2% at 3 h). The results indicate that ethanol enhances the functional recovery of stunned myocardium independent of K(ATP) channels in vivo.

Minor cardiac troponin t release in patients undergoing coronary artery bypass graft surgery on a beating heart

Objectives: To determine whether and to what extent coronary artery bypass graft (CABG) surgery without extracorporeal circulation is associated with cardiac troponin T (TnT) release. Design: Prospective study. Setting: A single university hospital. Participants: Twenty-three patients scheduled for minimally invasive CABG surgery. Sixteen patients received one coronary anastomosis, and seven received two. Interventions: TnT and creatine kinase-MB (CK-MB) levels were determined immediately before induction of anesthesia (baseline) and at 0, 12, and 24 hours after surgery. Hemodynamic measurements were made, and 5-lead electrocardiograms with continuous automated ST-segment trends were analyzed. Measurements and Main Results: All patients had a good cardiac outcome. Median cumulative coronary artery occlusion time was 27 minutes (range, 10 to 49 minutes). TnT levels were undetectable in 91.3% of patients at baseline when a detection limit of 0.01 ng/mL was employed. TnT and CK-MB showed significant elevations at 12 and 24 hours versus baseline. Postoperatively, TnT was detectable in 91.3% of patients, and 17.4% suffered minor myocardial damage, as evidenced by an abnormal increase in TnT greater than 0.2 ng/mL, excluding those exhibiting myocardial infarction. ST segment changes developed in seven patients, persisting for 13.0 minutes (range, 9.5 to 15.8 minutes) and disappearing immediately after coronary artery clamp release. There were no significant correlations between cumulative coronary occlusion time and peak TnT or CK-MB levels. Conclusions: TnT was detected after surgery in most patients, and significant TnT levels indicative of myocardial injury (>0.2 ng/mL) were detected in only 17% of patients, probably as a result of brief periods of coronary artery occlusion.

Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality.

Recent evidence indicates that hyperglycemia is an important risk factor for the development of cardiovascular disease. We tested the hypothesis that myocardial infarct size is related to blood glucose concentration in the presence or absence of ischemic preconditioning (PC) stimuli in canine models of diabetes mellitus and acute hyperglycemia. Barbiturate-anesthetized dogs were subjected to a 60-min period of coronary artery occlusion and 3-h reperfusion. Infarct size was 24 +/- 2% of the area at risk (AAR) for infarction in control dogs. PC significantly (P < 0.05) decreased the extent of infarction in normal (8 +/- 2% of AAR), but not diabetic (22 +/- 4% of AAR), dogs. Infarct size was linearly related to blood glucose concentration during acute hyperglycemia (r = 0.96; P < 0.001) and during diabetes (r = 0.74; P < 0.002) in the presence or absence of PC stimuli. Increases in serum osmolality caused by administration of raffinose (300 g) did not increase infarct size (11 +/- 3% of AAR) or interfere with the ability of PC to protect against infarction (2 +/- 1% of AAR). The results indicate that hyperglycemia is a major determinant of the extent of myocardial infarction in the dog.

Brief myocardial ischemia attenuates platelet thrombosis in remote, damaged, and stenotic carotid arteries.

Brief antecedent periods of coronary artery occlusion improve subsequent vessel patency in damaged and stenotic coronary arteries via release of adenosine from ischemic/reperfused myocardium and resultant adenosine receptor stimulation. However, the site of receptor stimulation-circulating blood-borne elements (ie, platelets) versus vessel-wall components of the culprit artery-remains unclear. If platelet adenosine receptors are involved, then the benefits of brief coronary occlusion (1) should be manifested systemically and improve patency at a remote site and (2) should be inhibited by an antagonist of adenosine A(2) receptors, whereas, in contrast, (3) brief vascular occlusion not associated with appreciable adenosine release should be ineffective in improving vessel patency. In Protocol 1, anesthetized rabbits received 5 minutes of transient coronary occlusion, 5 minutes of transient bilateral carotid occlusion (purported to cause negligible adenosine release from the brain), or no intervention. All rabbits then underwent injury plus stenosis of the left carotid artery, resulting in repeated cyclic variations in carotid blood flow (CFVs). Carotid patency during the initial 2 hours after stenosis (assessed by quantifying the nadir of the CFVs and area of the flow-time profile) was significantly enhanced with antecedent coronary-but not carotid-occlusion versus controls. In Protocol 2, improvement in carotid patency after brief coronary occlusion was corroborated in anesthetized dogs. However, the benefits of brief coronary occlusion were abrogated by the A(2)/A(1) antagonist CGS 15943. Brief antecedent coronary artery occlusion enhanced vessel patency in remote, damaged, and stenotic carotid arteries, largely due to adenosine receptor stimulation on circulating elements.