Central Ischemic Zone Research Articles

The mechanisms of potassium loss in acute myocardial ischemia: New insights from computational simulations.

Acute myocardial ischemia induces hyperkalemia (accumulation of extracellular potassium), a major perpetrator of lethal reentrant ventricular arrhythmias. Despite considerable experimental efforts to explain this pathology in the last decades, the intimate mechanisms behind hyperkalemia remain partially unknown. In order to investigate these mechanisms, we developed a novel computational model of acute myocardial ischemia which couples a) an electrophysiologically detailed human cardiomyocyte model that incorporates modifications to account for ischemia-induced changes in transmembrane currents, with b) a model of cardiac tissue and extracellular K + transport. The resulting model is able to reproduce and explain the triphasic time course of extracellular K + concentration within the ischemic zone, with values of close to 14mmol/L in the central ischemic zone after 30min. In addition, the formation of a border zone of approximately 1.2cm 15minafter the onset of ischemia is predicted by the model. Our results indicate that the primary rising phase of is mainly due to the imbalance between K + efflux, that increases slightly, and K + influx, that follows a reduction of the NaK pump activity by more than 50%. The onset of the plateau phase is caused by the appearance of electrical alternans (a novel mechanism identified by the model), which cause an abrupt reduction in the K + efflux. After the plateau, the secondary rising phase of is caused by a subsequent imbalance between the K + influx, which continues to decrease slowly, and the K + efflux, which remains almost constant. Further, the study shows that the modulation of these mechanisms by the electrotonic coupling is the main responsible for the formation of the ischemic border zone in tissue, with K + transport playing only a minor role. Finally, the results of the model indicate that the injury current established between the healthy and the altered tissue is not sufficient to depolarize non-ischemic cells within the healthy tissue.

Effects of electrophysiological heterogeneity on vulnerability to re-entry in human ventricular tissue: A simulation study.

In this study, we constructed a two-dimensional ventricular tissue sheet with cellular electrophysiology modified from the Ten Tusscher 2006 Model. Heterogeneity was created by dividing the tissue into endocardium, midmyocardium and epicardium, further enhanced by a central ischemic zone. Subsequently, we investigated how electrophysiological heterogeneity affects re-entry initiation and maintenance in this tissue. Furthermore, we analyzed the vulnerable window (VW) under several conditions and concluded that heterogeneity across various myocardia expands the VW further than the monolayer myocardium model does.

Visualizing the cortical microcirculation in patients with stroke*

Visualizing the cortical microcirculation in patients with stroke*

D Modulation of gap junctional coupling as an anti-arrhythmic strategy to prevent reperfusion ventricular arrhythmias

<h3>Background</h3> Reperfusion arrhythmias can occur within seconds of restoration of blood flow to previously ischaemic myocardium. Heterogeneities and abrupt changes in both gap junctional coupling and action potentials during early reperfusion are thought to contribute to their pathophysiology. We tested the hypothesis that modulating gap junctional coupling can reduce the incidence of reperfusion arrhythmias, and used optical mapping to assess the mechanisms of any anti-arrhythmic effect. <h3>Methods</h3> Using a Langendorff apparatus, rat hearts were perfused with either 50 nM AAP10 to increase gap junctional coupling (n=10), 30 μM carbenoxolone (CBX) to reduce coupling (n=13) or control Krebs-Henseleit solution (n=10). Hearts were then subjected to regional ischaemia by occlusion of the left anterior descending artery for 8 min and then reperfused. Ventricular arrhythmia incidence was documented. For optical mapping experiments, a further eighteen hearts were loaded with a voltage-sensitive dye (RH237), perfused with an excitation-contraction uncoupler (10μM blebbistatin) and either AAP10 (n=6), carbenoxolone (n=6) or control (n=6), and then subjected to ischaemia and reperfusion as above whilst transmembrane voltage (V_m) transients were recorded. <h3>Results</h3> Both AAP10 and CBX reduced the incidence of reperfusion VF (AAP10 50%, CBX 77%, Control 90%) and delayed time to onset of reperfusion VF (AAP10 29.0±9.9 s; CBX 52.2±13.2 s; Control 21.8 s±6.4 s) (LogRank p&lt;0.05). AAP10 reduced the dispersion of action potential duration (APD) in ischaemic myocardium (AAP10 2.3±0.8 ms; CBX 5.1±1.2 ms; Control 4.9±2.0 ms, p&lt;0.05). AAP10 also improved conduction across a 0.6 cm² central ischaemic zone in the anterior left ventricle (LV) (Activation time: AAP10 15.3 ± 1.3ms; CBX 25.7 ±2.2 ms; Control 23.2±2.0 ms, p&lt;0.05) immediately prior to reperfusion. CBX slowed conduction and prolonged this activation time post-reperfusion (AAP10 10.3±0.8 ms; CBX 15.8±2.8 ms; Control 9.5±1.2 ms), thus resulting in smaller changes in conduction velocities pre- and post-reperfusion compared with control. <h3>Conclusions</h3> Both increasing and reducing gap junctional coupling, with AAP10 and CBX respectively, reduced the rate and delayed the onset of reperfusion VF. This suggests that the partial uncoupling that occurs during early reperfusion is a determinant of reperfusion arrhythmias, and that both normalising the degree of coupling or further exacerbating uncoupling may be anti-arrhythmic. The anti-arrhythmic effect of increasing gap junctional coupling may be mediated by its dual effect of reducing action potential heterogeneity and improving conduction during reperfusion. Further uncoupling may be protective via attenuation of the abrupt changes in coupling and conduction that occur at reperfusion following ischaemia.

Mechanisms for initiation of reentry in acute regional ischemia phase 1B

During phase 1B of acute regional ischemia, the subepicardial and subendocardial layers coupled to the inexcitable midmyocardium remain viable. The purpose of this study was to examine how the degree of hyperkalemia in the surviving layers, the lateral width of border zone between the normal tissue and the central ischemic zone, and the degree of cellular uncoupling between the surviving layers and the midmyocardium contribute to initiation of reentry. Simulations were conducted on the state-of-the-art model of rabbit ventricles with realistic representation of the spatial distribution of the ischemic insult. Hyperkalemia in the surviving layers led to induction of reentry by increasing refractoriness and slowing conduction in the layers. Such reentries were formed solely in the subepicardium. A minimal level of hyperkalemia was required for induction of reentry. Progress increase in hyperkalemia led to a biphasic change in vulnerability to reentry. For each level of hyperkalemia, increased cellular uncoupling between subepicardium and midmyocardium increased inducibility of reentry by restoring subepicardial tissue excitability via blocking midmyocardial electrotonic effect. In addition, increased lateral width of the border zone prevented inducibility of reentry as conduction block occurred in the central ischemic zone when the wave propagated across the border zone from the normal zone. The degree of hyperkalemia in the surviving subepicardium, the lateral width of border zone, and cellular uncoupling between the subepicardium and midmyocardium determine dispersion of refractoriness, conduction velocity, excitability, and, therefore, inducibility of reentry during phase 1B.

Mechanisms of Mechanically Induced Spontaneous Arrhythmias in Acute Regional Ischemia

Although ventricular premature beats (VPBs) during acute regional ischemia have been linked to mechanical stretch of ischemic tissue, whether and how ischemia-induced mechanical dysfunction can induce VPBs and facilitate their degradation into reentrant arrhythmias has not been yet addressed. This study used a novel multiscale electromechanical model of the rabbit ventricles to investigate the origin of and the substrate for spontaneous arrhythmias arising from ischemia-induced electrophysiological and mechanical changes. Two stages of ischemia were simulated. Dynamic mechanoelectrical feedback was modeled as spatially and temporally nonuniform membrane currents through mechanosensitive channels, the conductances of which depended on local strain rate. Our results reveal that both strains and strain rates were significantly larger in the central ischemic zone than in the border zone. However, in both ischemia stages, a VPB originated from the ischemic border in the left ventricular apical endocardium because of mechanically induced suprathreshold depolarizations. It then traveled fully intramurally until emerging from the ischemic border on the anterior epicardium. Reentry was formed only in the advanced ischemia stage as the result of a widened temporal excitable gap. Mechanically induced delayed afterdepolarization-like events contributed to the formation of reentry by further decreasing the already reduced-by-hyperkalemia local excitability, causing extended conduction block lines and slowed conduction in the ischemic region. Mechanically induced membrane depolarizations in the ischemic region are the mechanism by which mechanical activity contributes to both the origin of and substrate for spontaneous arrhythmias under the conditions of acute regional ischemia.

Modeling of cardiac ischemia in human myocytes and tissue including spatiotemporal electrophysiological variations / Modellierung kardialer Ischämie in menschlichen Myozyten und Gewebe

Cardiac tissue exhibits spatially heterogeneous electrophysiological properties. In cardiac diseases, these properties also change in time. This study introduces a framework to investigate their role in cardiac ischemia using mathematical modeling and computational simulations at cellular and tissue level. Ischemia was incorporated by reproducing effects of hyperkalemia, acidosis, and hypoxia with a human electrophysiological model. In tissue, spatial heterogeneous ischemia was described by central ischemic (CIZ) and border zone. Anisotropic conduction was simulated with a bidomain approach in an anatomical ventricle model including realistic fiber orientation and transmural, apico-basal, and interventricular electrophysiological heterogeneities. A model of electrical conductivity in a human torso served for ECG calculations. Ischemia increased resting but reduced peak voltage, action potential duration, and upstroke velocity. These effects were strongest in subepicardial cells. In tissue, conduction velocity decreased towards CIZ but effective refractory period increased. At 10 min of ischemia 19% of subepi- and 100% of subendocardial CIZ cells activated with a delay of 34.6±7.8 ms and 55.9±18.8 ms, respectively, compared to normal. Significant ST elevation and premature T wave end appeared only with the subepicardial CIZ. The model reproduced effects of ischemia at cellular and tissue level. The results suggest that the presented in silico approach can complement experimental studies, e.g., in understanding the role of ischemia or the onset of arrhythmia.

Mechanistic investigation into the arrhythmogenic role of transmural heterogeneities in regional ischaemia phase 1A

Studies of arrhythmogenesis during ischemia have focused primarily on reentrant mechanisms manifested on the epicardial surface. The goal of this study was to use a physiologically-accurate model of acute regional ischemia phase 1A to determine the contribution of ischaemia-induced transmural electrophysiological heterogeneities to arrhythmogenesis following left anterior descending artery occlusion. A slice through a geometrical model of the rabbit ventricles was extracted and a model of regional ischaemia developed. The model included a central ischaemic zone incorporating transmural gradients of I(K(ATP)) activation and [K+]o, surrounded by ischaemic border zones (BZs), with the degree of ischaemic effects varied to represent progression of ischaemia 2-10 min post-occlusion. Premature stimulation was applied over a range of coupling intervals to induce re-entry. The presence of ischaemic BZs and a transmural gradient in I(K(ATP)) activation provided the substrate for re-entrant arrhythmias. Increased dispersion of refractoriness and conduction velocity in the BZs with time post-occlusion led to a progressive increase in arrhythmogenesis. In the absence of a transmural gradient of I(K(ATP)) activation, re-entry was rarely sustained. Knowledge of the mechanism by which specific electrophysiological heterogeneities underlie arrhythmogenesis during acute ischaemia could be useful in developing preventative treatments for patients at risk of coronary vascular disease.

Mechanical left ventricular unloading prior to reperfusion reduces infarct size in a canine infarction model

We tested the hypothesis that unloading the left ventricle just prior to reperfusion provides infarct size reduction compared with left ventricular (LV) unloading postreperfusion and reperfusion alone. Twenty-four mongrel dogs were subjected to 2 hr of left anterior descending artery occlusion and 4 hr of reperfusion. A transvalvular (TV) left ventricular assist device (LVAD) was inserted just prior to reperfusion and maintained during the rest of the experiment (LV Assist Pre group). In the LV Assist Post group, the TV LVAD was inserted and activated just after reperfusion. A control group was subjected to reperfusion alone with a sham-TV LVAD. At baseline, the hemodynamic data were similar in the three groups. Myocardial infarct size expressed as percentage of area at risk was significantly reduced in the LV Assist Pre group compared to the control group (P = 0.011) and to the LV Assist Post group (P < 0.05). At 4 hr of reperfusion, transmural myocardial blood flow in the ischemic zone was slightly higher in the animals unloaded prior to reperfusion compared to controls and significantly higher than in the LV Assist Post group (P = 0.04). Postreperfusion end-diastolic wall thickness returned to baseline level in the TV LV Assist Pre group compared to both controls and TV LV Assist Post group. In these latter two groups, a significant increase in postreperfusion end-diastolic wall thickness and contraction band necrosis in the central ischemic zone correlated well with the degree of reperfusion injury. LV unloading prior to, but not after, reperfusion reduces the extent of myocardial necrosis in canine hearts subjected to 2 hr of left anterior descending artery occlusion and 4 hr of reperfusion compared to either reperfusion alone or LV unloading after reperfusion.

Triggered alternans in an ionic model of ischemic cardiac ventricular muscle.

It has been known for several decades that electrical alternans occurs during myocardial ischemia in both clinical and experimental work. There are a few reports showing that this alternans can be triggered into existence by a premature ventricular contraction. Detriggering of alternans by a premature ventricular contraction, as well as pause-induced triggering and detriggering, have also been reported. We conduct a search for triggered alternans in an ionic model of ischemic ventricular muscle in which alternans has been described recently: a one-dimensional cable of length 3 cm, containing a central ischemic zone 1 cm long, with 1 cm segments of normal (i.e., nonischemic) tissue at each end. We use a modified form of the Luo-Rudy [Circ. Res. 68, 1501-1526 (1991)] ionic model to represent the ventricular tissue, modeling the effect of ischemia by raising the external potassium ion concentration ([K(+)](o)) in the central ischemic zone. As [K(+)](o) is increased at a fixed pacing cycle length of 400 ms, there is first a transition from 1:1 rhythm to alternans or 2:2 rhythm, and then a transition from 2:2 rhythm to 2:1 block. There is a range of [K(+)](o) over which there is coexistence of 1:1 and 2:2 rhythms, so that dropping a stimulus from the periodic drive train during 1:1 rhythm can result in the conversion of 1:1 to 2:2 rhythm. Within the bistable range, the reverse transition from 2:2 to 1:1 rhythm can be produced by injection of a well-timed extrastimulus. Using a stimulation protocol involving delivery of pre- and post-mature stimuli, we derive a one-dimensional map that captures the salient features of the results of the cable simulations, i.e., the {1:1-->2:2-->2:1} transitions with {1:1<-->2:2} bistability. This map uses a new index of the global activity in the cable, the normalized voltage integral. Finally, we put forth a simple piecewise linear map that replicates the {1:1<-->2:2} bistability observed in the cable simulations and in the normalized voltage integral map. (c) 2002 American Institute of Physics.

Exercise training reduces ischemic myocardial dysfunction.

This study tested the hypothesis that exercise training improves myocardial blood flow and regional myocardial contractile function in a lateral border zone located adjacent to the ischemic zone during coronary artery occlusion. Fourteen dogs were subjected to either 12 wk of dynamic exercise training or cage rest. Dogs were anesthetized and instrumented to assess regional myocardial contractile function (percent segment length shortening and rate of shortening) and regional myocardial blood flow (tracer microspheres) in the central ischemic, lateral border, and nonischemic zones. Measurements were made preocclusion and at 2 min and 3 h after occlusion of the left anterior descending coronary artery (CAO). Contractile function and regional myocardial blood flow were not affected by CAO in the nonischemic zone in both cage-rested and exercise trained dogs. Regional myocardial contractile function and blood flow in the lateral border zone were significantly higher in exercise trained dogs compared with cage-rested dogs, both at 2 min and 3 h after CAO. Ischemic dysfunction was similar in the central ischemic zone in both cage-rested and exercise trained dogs both at 2 min and 3 h after CAO. Regional myocardial blood flow was similarly reduced in the ischemic zone in both groups after 2 min of CAO, but was significantly higher in the inner (subendocardial) region of the exercised trained hearts after 3 h (P < 0.05). These data suggest that there was greater border zone perfusion in exercise trained animals during prolonged CAO, which was associated with significantly improved myocardial contractile function.

Characterization of contraction and perfusion in the lateral border zone between normal and ischemic myocardium following coronary occlusion by myocardial contrast echocardiography

We performed myocardial contrast echocardography with power Doppler imaging during left anterior descending occlusion in 10 dogs, and found that video intensity and dyssynergy in lateral border zones of ischemic myocardium were present, but the video intensity was significantly lower than adjacent nonischemic zones. The results of this study demonstrate that levels of perfusion and contraction, which are intermediate between normal and central ischemic zones, are observed in the border zone with coronary occlusion by myocardial contrast echocardography, and may have implications in identifying myocardium that will be spared necrosis and in measuring ultimate infarct size.

Attenuated Neurotransmitter Release and Spreading Depression-Like Depolarizations after Focal Ischemia in Mutant Mice with Disrupted Type I Nitric Oxide Synthase Gene

Nitric oxide (NO) plays a complex role in the pathophysiology of cerebral ischemia. In this study, mutant mice with disrupted type I (neuronal) NO synthase (nNOS) were compared with wild-type littermates after permanent focal ischemia. Cerebral blood flow in the central and peripheral zones of the ischemic distribution were measured with laser doppler flowmetry. Simultaneously, microdialysis electrodes were used to measure extracellular amino acid concentrations and DC potential in these same locations. Blood flow was reduced to <25 and 60% of baseline levels in the central and peripheral zones, respectively; there were no differences in nNOS mutants versus wild-type mice. Within the central ischemic zone, DC potentials rapidly shifted to -20 mV in all mice. In the ischemic periphery, spreading depression (SD)-like waves of depolarization were observed. SD-like events were significantly fewer in the nNOS mutant mice. Concurrent with these hemodynamic and electrophysiological perturbations, extracellular elevations in amino acids occurred after ischemia. There were no detectable differences between wild-type and mutant mice in the ischemic periphery. However, in the central zone of ischemia, elevations in glutamate and GABA were significantly lower in the nNOS mutants. Twenty-four hour infarct volumes in the nNOS mutant mice were significantly smaller than in their wild-type littermates. Overall, the number of SD-like depolarizations and the integrated efflux of glutamate were significantly correlated with infarct size. These results suggest that NO derived from the nNOS isoform contributes to tissue damage after focal ischemia by amplifying excitotoxic amino acid release in the core and deleterious waves of SD-like depolarizations in the periphery.

Regional myocardial perfusion and mechanics: a model-based method of analysis.

A new parametric model-based method has been developed that allows epicardial strain distributions to be computed on the left ventricular free wall in normal and ischemic myocardium and integrated with the regional distributions of anatomic and physiological measurements so that underlying relationships can be explored. An array of radiopaque markers was sewn on the anterior wall of the left ventricle (LV) in three anesthetized open-chest canines, and their positions were recorded using biplane video fluoroscopy before and 2 min after occlusion of the left anterior descending coronary artery. The three-dimensional (3D) anatomy of the LV and epicardial fiber angles were measured post-mortem using a 3D probe. A prolate spheroidal finite element model was fitted to the epicardial surface points (with <0.2 mm accuracy) and fiber angles (<5 degrees error). Regional myocardial blood flows (MBFs) were measured using fluorescent microspheres and fitted into the model (<0.3 ml min(-1) g(-1) error). Epicardial fiber and cross-fiber strain distributions were computed by allowing the model to deform from end-diastole to end-systole according to the recorded motion of the surface markers. Systolic fiber strain varied from -0.05 to 0.01 within the region of the markers during baseline, and regional MBF varied from 1.5 to 2.0 ml min(-1) g(-1). During 2 min ischemia, regional MBF was less than 0.3 ml min(-1) g(-1) in the ischemic region and 1.0 ml min(-1) g(-1) in the nonischemic region, and fiber strain ranged from 0.05 in the central ischemic zone to -0.025 in the remote nonischemic tissue. This analysis revealed a zone of impaired fiber shortening extending into the normally perfused myocardium that was significantly wider at the base than the apex. A validation analysis showed that a regularizing function can be optimized to minimize both fitting errors and numerical oscillations in the computed strain fields.

Adverse influence of systemic vascular stiffening on cardiac dysfunction and adaptation to acute coronary occlusion.

[corrected] Age is an independent risk factor for increased mortality from ischemic heart disease. Arterial stiffening with widening of the pulse pressure may contribute to this risk by exacerbating cardiac dysfunction after total coronary artery occlusion. To test the above hypothesis, 14 open-chest dogs underwent surgery in which the intrathoracic aorta was bypassed with a stiff plastic tube. Directing ventricular outflow through the bypass widened the arterial pulse pressure from 41 to 115 mm Hg at similar mean pressure and flow. Hearts ejecting into the native aorta (NA) exhibited only modest dysfunction after two minutes of mid-left anterior descending coronary artery occlusion. However, the same occlusion applied during ejection into the bypass tube (BT) induced far more severe cardiodepression (ie, systolic pressure fell by -41+/-10 mm Hg for BT versus -15+/-3 mm Hg for NA, and end-systolic volume rose by 15+/-3 versus 6+/-2 mL), with a threefold greater decline in ejection fraction. This disparity was not due to higher baseline work loads because total pressure-volume area was similar in both cases. Furthermore, marked increases in basal work load and wall stress induced by angiotensin II infusion (in four additional studies) did not reproduce this behavior. Although peak systolic chamber stress was greater with the BT, this did not increase systolic dyskinesis as measured in the central ischemic zone. However, the total mass of myocardium that was rendered severely ischemic (ie, flow reduced by > or = 80%) was twice as large with BT ejection, likely expanding the region of dyskinesis. This disparity may relate to altered phasic coronary flow during BT ejection, which displays marked enhancement of systolic flow and renders the heart more vulnerable to diminished mean and systolic perfusion pressures. Cardiac ejection into a stiff systemic vasculature augments cardiac dysfunction and ischemia due to coronary occlusion by tightening the link between cardiac systolic performance and myocardial perfusion. This may contribute to the higher mortality risk from ischemic heart disease due to age.

Desflurane and isoflurane exert modest beneficial actions on left ventricular diastolic function during myocardial ischemia in dogs.

Volatile anesthetics exert cardioprotective effects during myocardial ischemia. This investigation examined the regional systolic and diastolic mechanical responses to brief left anterior descending coronary artery (LAD) occlusion in the central ischemic zone and in remote normal myocardium in the conscious state and during desflurane and isoflurane anesthesia. Eighteen experiments were performed in nine dogs chronically instrumented for measurement of aortic and left ventricular pressure, cardiac output, LAD coronary blood flow velocity, and LAD and left circumflex coronary artery subendocardial segment length. Regional myocardial contractility was evaluated with the slope of the preload recruitable stroke work relationship determined from a series of left ventricular pressure-segment length diagrams in the LAD and left circumflex coronary artery zones. Diastolic function was assessed with a time constant of isovolumic relaxation (tau), maximum segment lengthening velocity in LAD and left circumflex coronary artery regions, and regional chamber stiffness constants derived using monoexponential and three-element exponential curve fitting in each zone. On separate experimental days, hemodynamics and indices of regional functional were obtained in the conscious state and during 1.1 and 1.6 minimum alveolar concentration end-tidal desflurane or isoflurane before and during LAD occlusion. In conscious dogs, LAD occlusion abolished regional stroke work, increased chamber stiffness (monoexponential: 0.39 +/- 0.04 during control to 1.34 +/- 0.39 mm-1 during LAD occlusion), and decreased the rate of early ventricular filling in the ischemic zone. These changes were accompanied by increased contractility (slope: 103 +/- 8 during control to 112 +/- 7 mmHg during LAD occlusion), rapid filling rate (maximum segment lengthening velocity: 46 +/- 5 during control to 55 +/- 7 mm.s-1 during LAD occlusion), and chamber stiffness (monoexponential: 0.43 +/- 0.05 during control to 1.14 +/- 0.25 mm-1 during LAD occlusion) in the normal region. Increases in tau were also observed in the conscious state during the period of myocardial ischemia. Desflurane and isoflurane increased tau and decreased the slope and maximum segment lengthening velocity in a dose-related manner. Monoexponential and three-element element exponential curve fitting were unchanged by the volatile anesthetics in the absence of ischemia. Myocardial contractility and rapid filling rate were enhanced in the nonischemic region during LAD occlusion in the presence of desflurane and isoflurane. In contrast to the findings in the conscious state, ischemia-induced increases in tau and chamber stiffness in the ischemic and normal zones were attenuated during anesthesia induced by desflurane and isoflurane. The results indicate that increases in contractility of remote myocardium during brief regional ischemia were preserved in the presence of desflurane and isoflurane anesthesia. In addition, desflurane and isoflurane blunted ischemia-induced increases in tau and regional chamber stiffness in both the ischemic and nonischemic zones. These results demonstrate that the volatile anesthetics may exert important beneficial actions on left ventricular mechanics in the presence of severe abnormalities in systolic and diastolic function during ischemia.

Noninvasive assessment of no-reflow phenomenon in a canine model of reperfused infarction by contrast-enhanced magnetic resonance imaging

The aim of this study was to test whether contrast-enhanced magnetic resonance (MR) imaging may assess in vivo the severity of the no-reflow phenomenon in a dog model of infarction with 2-hour coronary occlusion followed by reperfusion (6 hours). Subsecond MR imaging combined with intravenous bolus administration of superparamagnetic iron oxide particles (SPIO) was performed at the fifth hour of reperfusion. An MR index was calculated using the difference of signal-intensity enhancement between ischemic and nonischemic zones during the SPIO first pass. Dogs were separated into two groups according to the severity of ischemia: collateral blood flow in the central ischemic zone at 120 minutes of occlusion (radioactive microsphere technique) <22.5% of the flow in the nonischemic zone (group I) or >22.5% (group II). Mean collateral blood flow during occlusion was lower in group I (11.3% ± 2.9%, n = 7) than in group II (66.8% ± 19.8%, n = 6, p < 0.05). Mean infarct size was significantly larger in group I (58.6% ± 4.9% of the area-at-risk, n = 7) than in group II (16.5% ± 6.5%, n = 6, p < 0.05). For the entire population ( n = 13), the infarct size was inversely correlated to the collateral blood flow ( r = −0.64, p = 0.02, standard error of estimate = 0.24). The relative rate of enhancement in ischemic myocardium (MR index) was significantly lower in group I (38.1% ± 10.9%) than in group II (142.8% ± 32%; p < 0.05). In addition, there was an inverse relation between the MR index and the infarct size ( n = 13, r = −0.69, standard error of estimate = 0.07, p = 0.009). In conclusion, these data suggest that ultrafast MR images with intravenous bolus administration of SPIO during reperfusion is a valuable new method to assess the no-reflow phenomenon in a dog model of myocardial infarction.

The relation between extracellular potassium concentration and pH in the border zone during regional ischemia in isolated porcine hearts

During regional ischemia gradients of extracellular potassium concentration ([K +] 0) and extracellular pH (pH 0) exist. In globally ischemic papillary muscles increased Pco 2 causes a rise in [K +],. We studied whether pH 0 and [K +] 0 are causally related during acute regional ischemia in the isolated blood-perfused pig heart. Multiple pH − or K +-sensitive electrodes were inserted in the left ventricular midmyocardium. Local electrograms and ionic data were simultaneously acquired. Regional ischemia was produced by interrupting left anterior descending (LAD) artery flow (10 min). Up to 5 mm from the electrophysiological border the pH-K relation deviated from that in the central ischemic zone. Respiratory acidosis (pH about 7.10) of the perfusate in the presence of LAD-ischemia caused acidification of the ischemic border zone without a local change in [K +] 0. We conclude that pH o changes are not related to changes of intramural [K +] o in the lateral border zone during regional ischemia.

988-7 Endothelin ETA/B Receptor Antagonist Reduces Infarct Size: A Novel Therapy for Acute Myocardial Infarction

We have previously shown that regional myocardial ischemia foliDwed by reperfusion (rep) significantly enhances cardiac release of the potent vasoconstrictor endothelin (ET). We now examine the association of ET production and myocardial blood flow IMBF) in rabbits (n = 14) undergoing 30 min Df circumflex occlusion and 3 hrs of rep. MBF was measured with radioactive microspheres at baseline, 15 min into occlusion, 1 min, 1 and 3 hrs into rep. Utilizing molecular biology techniques, ET 1 mRNA was measured at 3 hrs and found to be elevated in the central ischemic zone (CIZ) compared to the non ischemic zone INIZ). In a second study we investigated the effects of exogenous ET l and PD145065 (an ET A/B receptor antagonist) on infarct size of rabbits undergoing 30 min of circumflex occlusion and 48 hrs of rep. Drug infusion started with an initial bolus (PD145065 3 mg/kg; n = 10 or ET l 10 -10 m/kg; n = 9) 10 min before occlusion followed by 10 -11 m/kg/min of ET 1 or 0.6 mg/kg/min of PD145065 for 2 hrs and 40 minutes. Control animals (n = 10) received the same volumes in saline. Infarct size (AN) was measured histologically and expressed as percentage of area at risk (AR).Results as Mean ± SEM. 1. Myocardial rep after ischemia is associated with marked reactive hyperemia. This flow decreases significantly in the CIZ at 3 hrs into rep demonstrating for the first time that the “no-reflow phenomenon” exists in the rabbit model. 2. ET 1 mRNA was elevated in the CIZ at 3 hrs, suggesting a cause-effect relationship between ET 1 production and the “no-reflow phenomenon”. 3. Exogenous infusion of ET 1 fails to alter infarct size but antagonism of the ET A/B receptors significantly reduces infarct size in rabbits and this might represent a novel therapy for acute myocardial infarction in man.

Reperfusion enhances the local release of endothelin after regional myocardial ischemia

The role of endothelin, a potent long-acting vasoconstrictor peptide, in the pathogenesis of the “no-reflow” phenomenon was investigated in nine closed-chest mongrel dogs undergoing 90 minutes of proximal left anterior descending artery occlusion and 3.5 hours of reperfusion. Endothelin levels were measured serially from the coronary sinus (CS) and aorta (Ao) by radioimmunoassay and correlated with regional myocardial blood perfusion. Prolonged anesthesia, surgery, and vascular instrumentation did not change endothelin levels in four sham animals. A progressive and parallel increase in CS and Ao endothelin levels occurred during coronary occlusion. A further increase in CS levels was observed during the reperfusion period, resulting in significantly higher values of the peptide at 30 and 60 minutes (30 minutes: CS 22.1 ± 3.5 vs Ao 15.1 ± 5.1 pg/ml; 60 minutes: CS 21.1 ± 4.5 vs Ao 15.0 ± 3.6 pg/ml; p < 0.05 by analysis of variance). Microvascular perfusion determined semiquantatively with fluorescent beads was significantly reduced in the central ischemic zone (CIZ) compared with that in the nonischemic zone (NIZ) (CIZ endocardium 1.14 ± 0.4 beads/m 2, CIZ midmyocardium 1.19 ± 0.3 beads/m 2, NIZ 3.8 ± 0.6 beads/m 2; p < 0.05). A significant correlation was noted between mean reperfusion levels of endothelin in the CS and endocardial flow in the CIZ ( r = −0.88; p = 0.009). This study demonstrates that reperfusion per se enhanced the spillover of endothelin from the cardiac interstitium. Local release of endothelin may contribute to the progressive decrease in microvascular flow in the reperfused bed.