Coronary Occlusion In Pigs Research Articles

Reflection of Cardioprotection by Remote Ischemic Perconditioning in Attenuated ST-Segment Elevation During Ongoing Coronary Occlusion in Pigs: Evidence for Cardioprotection From Ischemic Injury.

Reduction of infarct size by remote ischemic perconditioning (perRIC) is evident only after several hours reperfusion. To develop a potential real-time estimate of cardioprotection by perRIC, we have analyzed the time course of ST-segment elevation. Anesthetized open-chest pigs were subjected to 60-minute coronary occlusion and 180-minute reperfusion (placebo; n=19). PerRIC (n=18; 4×5 min/5 min hindlimb occlusion/reperfusion) was induced 20 minutes after coronary occlusion. Regional myocardial blood flow was measured with microspheres, areas of no-reflow with thioflavin-S, area at risk with blue dye, and infarct size with triphenyl tetrazolium chloride staining. Phosphorylation of protein kinase B α/β/γ, extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 3 was determined by Western blot. ST-segment elevation was analyzed in a V2-like ECG-lead at baseline, 5- and 55-minute coronary occlusion, and 10-, 30-, 60-, and 120-minute reperfusion. Transmural blood flow at 5-minute coronary occlusion was not different between perRIC (0.029±0.015 mL/min per gram; mean±SD) and placebo (0.024±0.018 mL/min per gram) as was area at risk (perRIC: 24±6% of the left ventricle; placebo: 21±4%). Areas of no-reflow tended to be smaller with perRIC (9±12% of area at risk versus 15±14% with placebo; P=0.13). Infarct size with perRIC was 23±12% of area at risk versus 40±11% with placebo (P<0.001). PerRIC increased phosphorylation of signal transducer and activator of transcription 3 at 120-minute reperfusion by 196±142% versus 109±120% with placebo (P=0.047). The time courses of ST-segment elevation in perRIC and placebo protocols, respectively, were different (P=0.017). With similar ST-segment elevation at 5-minute coronary occlusion (perRIC 282±34 µV; placebo 259±28 µV), partial recovery of ST-segment elevation between 5- and 55-minute coronary occlusion was more pronounced with perRIC than placebo (by 111±84 versus 15±94 µV; P=0.028). Infarct size reduction by perRIC is reflected in the ST-segment elevation during coronary occlusion in pigs, supporting the notion of protection from ischemic injury.

Treating Ischemic Left Ventricular Dysfunction With Hypertonic Saline Administered After Coronary Occlusion in Pigs

The effects of hypertonic saline on ventricular function are controversial, whether it is increasing contractility or preload. There are no data, however, on the influence of hypertonic saline in a stunned myocardium. This study was prospective and randomized in order to analyze the effects of hypertonic saline solution (7.5%) on myocardial function and systemic hemodynamics in a porcine model of ischemia and reperfusion. A university teaching hospital, animal research laboratory. Twelve adult domestic swine. Myocardial stunning was produced by the complete occlusion of the proximal left anterior descending artery for 15 minutes followed by reperfusion. Five minutes after reperfusion, the animals were assigned to receive 4 mL/kg of hypertonic saline (n = 7) or normal saline (n = 5) over 10 minutes. Pressure-tipped catheters were placed in the left ventricular cavity and aorta. The dimensions of the left ventricle were measured with ultrasonic microcrystals. Cardiac output was measured with transit time ultrasound. Data were recorded continuously and compared before the occlusion, 5 minutes after reperfusion, and at the end of the infusion. Compared with baseline, ventricular function was significantly depressed after left anterior descending artery occlusion. Left ventricular dP/dT and its end-systolic pressure-volume slope decreased (38% and 52%, respectively; p < 0.05), with a concomitant increase in systemic vascular resistance. The administration of hypertonic saline significantly improved left ventricular function (Emax 1,422 +/- 198 mmHg/mL, and dP/dT 3.2 +/- 0.4 mmHg/s v normal saline group values of 1,156 +/- 172 and 2.5 +/- 0.5, respectively; p < 0.05), cardiac output (2.5 +/- 0.5 v 1.84 +/- 0.4 L/min, p < 0.05), and lowered systemic vascular resistance (from 28.8 +/- 2.3 to 23.5 +/- 1.4, p < 0.05), with no significant changes with normal saline administration. After transient myocardial ischemia, hypertonic saline administered over a short period of time acts as an inodilator by increasing contractility while simultaneously lowering systemic vascular resistance.

Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability

Background A mechanism for myocardial dysfunction after ischemia and reperfusion is Na +/H + exchanger activation. Although past in vivo models of limited ischemia and reperfusion intervals demonstrate that Na +/H + exchanger inhibition confers myocardial protection when administered at the onset of ischemia, the effect of Na +/H + exchanger inhibition on myocardial function after prolonged ischemia and reperfusion remains unknown. This investigation tested the hypothesis that Na +/H + exchanger inhibition instituted at reperfusion and after prolonged coronary occlusion in pigs would influence myocardial contractility independent of myocardial viability. Methods A coronary snare and sonomicrometry crystals were placed in pigs (n = 21, 32 kg). Coronary occlusion was instituted for 120 minutes followed by reperfusion for 180 minutes. At 105 minutes of ischemia, pigs were randomized to ischemia and reperfusion only (saline solution, n = 11) or Na +/H + exchanger inhibition (HOE-642, 3 mg/kg intravenously, n = 10). Myocardial injury was determined by tissue staining and measurement of plasma myocyte–specific enzymes. Myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (millimeters of mercury per centimeter) and by assessment of interregional shortening. Results Infarct size was not different between groups (39% ± 6%, P = .26). Moreover, at 180 minutes of reperfusion, plasma troponin-I and creatine kinase MB values had increased to identical levels in the ischemia and reperfusion–only and Na +/H + exchanger inhibition groups (300 ± 35 and 50 ± 6 ng/mL, respectively). At 90 minutes of ischemia, regional end-systolic pressure-dimension relation decreased from baseline (5.7 ± 0.5 versus 2.7 ± 0.3, P < .05) in the area at risk. By 30 minutes of reperfusion, regional end-systolic pressure-dimension relation decreased further in the ischemia and reperfusion–only group (1.6 ± 0.2, P < .05), but improved with Na +/H + exchanger inhibition (4.4 ± 0.7, P < .05). Conclusions Na +/H + exchanger inhibition instituted at reperfusion improved contractility independent of myocardial viability as assessed by absolute infarct size and myocyte-specific enzyme release. Thus, modulation of Na +/H + exchanger activity in the setting of prolonged ischemia and reperfusion may hold therapeutic potential.

Lack of effect of glycoprotein IIb/IIIa blockade on myocardial platelet or polymorphonuclear leukocyte accumulation and on infarct size after transient coronary occlusion in pigs

ObjectivesWe sought to assess the effect of glycoprotein (GP) IIb/IIIa blockade on myocardial platelet and polymorphonuclear leukocyte accumulation and on infarct size after coronary injury and transient coronary occlusion (CO) in pigs. BackgroundIt has been suggested that platelet GP IIb/IIIa blockade might reduce the severity of microvascular damage after reperfusion. MethodsSixteen thiopental-anesthetized, open-chest pigs, in whom platelets had been labeled with technetium-99m (99mTc) on the previous day, were submitted to catheter-induced left anterior descending coronary artery (LAD) injury followed by 55 min of CO and 5 h of reperfusion. Five minutes before reflow, the animals were blindly allocated to receive lamifiban (intravenous bolus of 250 μg/kg body weight and continuous infusion of 3 μg/kg per min) or saline. ResultsLamifiban had a rapid and potent platelet anti-aggregatory effect, as demonstrated by significant prolongation of the bleeding time and profound (∼90%) inhibition of ex vivo platelet aggregation, and completely prevented the development of cyclic flow reductions of the LAD (0 vs. 5 ± 1, one of them followed by re-occlusion, in control animals, p = 0.005). However, compared with animals receiving placebo, those treated with lamifiban had a similar (p = NS) content of 99mTc platelets in the reperfused myocardium (288 ± 40% vs. 205 ± 27% of the value in the control region, respectively) and similar myeloperoxidase activity (0.50 ± 0.17 U/g vs. 0.47 ± 0.17 U/g, respectively) and infarct size (46.8 ± 12.0% vs. 49.8 ± 10.5% of the area at risk, respectively). Arteriolar platelet thromboemboli were very rarely seen on histologic analysis. Lamifiban did not modify platelet P-selectin expression in additional studies. ConclusionsPlatelet GP IIb/IIIa blockade has a potent antithrombotic effect at the culprit lesion, but does not significantly reduce the magnitude of microvascular platelet accumulation or myocardial damage after transient CO.

Preconditioning of swine heart with monophosphoryl lipid A improves myocardial preservation

Background. Ischemic preconditioning has been proven to be a powerful tool for myocardial protection in the setting of ischemia and reperfusion. A new drug to provide pharmacologic preconditioning, monophosphoryl lipid A (MLA), was administered 24 hours before an acute coronary occlusion in pigs to determine the effect on pharmacologic preconditioning. Methods. Two studies were completed. In the first, swine were distributed into five groups: group I, control; group II,. aminoguanidine (AMG) (30 mg/kg), a selective inducible nitric oxide synthase (iNOS) blocker; group III, MLA (10 μg/kg); group IV, MLA (35 μg/kg); and group V, MLA and AMG (35 μg/kg and 30 mg/kg, respectively). Twenty-four hours after administration of the MLA, AMG, or both, regional left anterior descending coronary artery ischemia was induced for 15 minutes followed by one hour of global normothermic cardioplegic arrest and three hour reperfusion. Left ventricular function, tissue injury, and percentage of myocardial infarction were measured. Left ventricular myocardium in the left anterior descending coronary artery region was sampled for iNOS messenger RNA (mRNA) during ischemia and reperfusion. In the second study, pigs were sacrificed 0, 4, 6, 8, and 24 hrs after MLA/AMG administration for iNOS mRNA determination in nonischemic myocardium. Results. Use of MLA significantly improved postischemic ventricular function, and reduced creatinine kinase release and percentage of infarction. Monophosphoryl lipid A induced expression of iNOS mRNA in nonischemic myocardium within four hours of administration which returned to base line by 24 hours. Normothermic regional ischemia then induced expression of iNOS mRNA, which returned to base line during reperfusion. Aminoguanidine completely abolished both MLA-induced and ischemia-induced iNOS mRNA and blocked the beneficial effects of MLA. Conclusions. Use of MLA can provide myocardial preservation through enhanced expression of iNOS mRNA.

Stunning enhances regional metabolic recovery following 60′ of coronary occlusion in pigs: R. Schott, E. Braun, S. Rohmann, W. Schaper. Max-Planck-Institute, Bad Nauheim, F. R. Germany

Stunning enhances regional metabolic recovery following 60′ of coronary occlusion in pigs: R. Schott, E. Braun, S. Rohmann, W. Schaper. Max-Planck-Institute, Bad Nauheim, F. R. Germany

Effects of regional denervation on epicardial DC electrograms during coronary occlusion in pigs.

Sympathetic innervation of the normal and acutely ischemic myocardium and the effects of regional myocardial sympathetic denervation of the ischemic area on the evolving electrical changes during coronary occlusion were assessed in pigs anesthetized with pentobarbital sodium. The histofluorescence of the adrenergic nerve fibers (glyoxylic acid reaction), which in the normal myocardium were distributed in a diffuse network, decreased slightly after 45 min of occlusion of the left anterior descending (LAD) coronary artery and nearly disappeared after 2 h of ischemia. Topical application of phenol (carbolic acid, 88%) to the coronary arterial wall produced a transmural loss of catecholamine histofluorescence in the distal myocardium supplied by the phenol-treated arterial segment. Mapping of the epicardial direct current (DC) electrograms in sympathetically denervated and in nondenervated sections of the same ischemic area, using three rows of seven cotton-wick electrodes, was performed in eight pigs and validated in eight other nondenervated pigs. During 45 min of LAD occlusion, the denervated area, with respect to the nondenervated region, showed a greater decline in T-Q segment depression after 20 min of ischemia (P less than 0.0001), a lesser degree of S-T segment elevation throughout the study (P less than 0.0001), a delayed development of monophasic potentials (P less than 0.05), a minor degree of S-T segment alternans (P less than 0.0001), and a less marked, but still present, period of transient electrical recovery. Thus acute regional myocardial sympathectomy reduces the magnitude of the local electrical manifestations of acute myocardial ischemia in the in situ pig heart. Also in this model, sympathetic fibers appeared to lose the catecholamine histofluorescence after 2 h of acute ischemia.

Inotropic changes in ischaemic and non-ischaemic myocardium and arrhythmias within the first 120 minutes of coronary occlusion in pigs.

In 16 anaesthetized open-chest pigs occlusion of the distal third of the LAD was performed. Local myocardial contractility within and outside the ischaemic area, measured using electromagnetic and ultrasonic probes, arrhythmias and plasma catecholamine concentrations were monitored during 180 min before and 120 min after occlusion of the distal LAD. 5 pigs developed ventricular fibrillation (VF) during phase 1 a of arrhythmias (1-6 min post occlusion) and a further 5 pigs during phase 1 b (10-30 min post occlusion). Segment lengthening within the ischaemic area, measured at the beginning of ventricular ejection, started within a few seconds of ischaemia and reached 11-13.5% of end-diastolic length prior to occlusion after 2 min of ischaemia. Between 2 min and 120 min after the onset of occlusion, no further segment lengthening was observed. There were no significant differences in segment lengthening between VF and non-VF pigs. However, within the VF group, mechanical alterations 2 min after the onset of ischaemia were more marked in pigs developing VF within phase 1 a than those with VF in phase 1 b. VES increased markedly after 50 min of occlusion and seemed to occur independently of further mechanical alterations, VF within the first 30 min of ischaemia often occurred without preceding VES.

The single precordial lead for ST segment monitoring: Comparison with the multiple lead map

ST segment elevation, used as an index of the relative extent of myocardial ischemic injury, was measured using a single precordial lead located at the point of maximum ST elevation. ST changes were followed for two hours after acute coronary occlusion in pigs, and were compared to the sum of ST elevation recorded with an 18 lead precordial map. Some animals were subjected to Reperfusion (n = 12), others to infarct extension (n = 10), while a control group (n = 9) was followed without an ST-modifying intervention. Correlation between ΣST and ST in the single lead was good, with a correlation coefficient of 0.844 at 360 points of comparison. Time to peak ST elevation using the single lead technique was comparable to that using the 18 lead map. Changes in the ST elevation using both techniques were similarly reduced following reperfusion, increased following extension, and followed a similar downslope pattern in the unmodified infarct group. This single lead technique offers the advantage of simplicity of use without sacrifice of accuracy. Its use can facilitate clinical studies of myocardial ischemic injury and its modification.

Consequences of myocardial reperfusion following temporary coronary occlusion in pigs: effects on morphologic, biochemical and haemodynamic findings

The effects of myocardial reperfusion have been examined following a 1 h coronary occlusion and compared to a permanent coronary ligation in pigs. Haemodynamic investigations were carried out throughout the surgical intervention and repeated after 7 days. Cellular injury was estimated by serial serum enzyme determinations (creatin phosphokinase, alpha-hydroxybutyric dehydrogenase, aspartate aminotransferase, lactic dehydrogenase) during the first 5 postoperative days; infarct size was assessed morphometrically by a histochemical staining procedure 1 week after the temporary or permanent coronary occlusion. A linear correlation was found between the logarithmically plotted peak serum activity of AST, HBDH, CPK and the morphometrically determined infarct size. Based upon enzyme and morphometrical studies no significant difference could be detected between the two experimental groups. In the animals subjected to transient coronary occlusion, however, the development of a ventricular aneurysm had been prevented to early and sustained reperfusion. Early re-establishment of coronary circulation appears to accelerate the proliferation of a more resistant granulation tissue into the infarcted area. Cardiac performance was not improved by myocardial reperfusion.

DELAYED DEVELOPMENT OF VENTRICULAR ARRHYTHMIAS FOLLOWING EXPERIMENTAL CORONARY OCCLUSION IN PIGS

DELAYED DEVELOPMENT OF VENTRICULAR ARRHYTHMIAS FOLLOWING EXPERIMENTAL CORONARY OCCLUSION IN PIGS

Collateral vessel development after right ventricular infarction in the pig

Although the right coronary artery supplies both ventricles in the pig, a gradual proximal right coronary occlusion produces infarction in the left ventricle, whereas the right ventricle is usually spared. This study evaluates the influence of right ventricular hypertension and hypertrophy (RVHH) on the occurrence of right ventricular infarction and the difference in the rate and extent of collateral vessel development after gradual right coronary occlusion in pigs with (RVHH group) and without (control group) increased right ventricular pressure and mass. Right ventricular hypertension and hypertrophy were induced by pulmonary arterial banding which raised right ventricular systolic pressure from 24 to 74 mm Hg and doubled right ventricular mass in 4 weeks. Right coronary occlusion was produced with an ameroid constrictor in 24 control group pigs and 15 RVHH pigs. Serial selective coronary cineangiograms on days 4, 8, 14, 21 and 28 after ameroid constrictor placement showed no difference in first appearance of collateralization to the occluded right coronary artery. Total collateralization, which was present in all pigs studied in the control group by days 21 and 28, was present in only 57 percent of the RVHH group at the same time. Although left ventricular infarction occurred in all animals in both groups, right ventricular infarction was not found in the control group but was seen in 80 percent of the RVHH group. There was no correlation between the degree of collateralization seen and the size of the right ventricular infarction found. Experimentally induced right ventricular hypertrophy and hypertension make the right ventricle susceptible to infarction and impeded total collateral filling of the occluded right coronary artery in some of the animals studied.

Acute coronary occlusion in pigs: effects of acetyl strophanthidin.

Transient occlusion of the left anterior descending coronary artery in pigs produced haemodynamic changes of left ventricular failure. Administration of acetyl strophanthidin before a second occlusion led to less marked haemodynamic changes.

Natural history of experimental coronary occlusion in pigs: A serial cineangiographic study

In order to evaluate, in vivo, the serial changes of the coronary arteries and the development of collateral circulation during the course of a gradual coronary occlusion, 32 farm pigs were studied with serial selective coronary cineangiograms following placement of an Ameroid constrictor on the left anterior descending coronary artery. Delaved clearance of contrast medium and poststenotic dilatation of the constricted artery appeared by the second to third day; complete occlusion on the sixth to seventh day. Demonstrable collateral vessels developed in most of the surviving animals by the sixth to seventh day. These channels increased in size and number in the subsequent 4 to 5 weeks so that the left anterior descending artery distal to the constrictor again became completely opacified through the collateral channels. In 16 animals that survived longer than 6 days, major collateral channels perfusing the distal portion of the obstructed artery arose proximal to the constrictor in 8, from the left circumflex artery in 11, and from the right coronary artery in 13. Despite the development of such collateral circulation, massive myocardial infarction developed indicating that the rapidity and/or extent of the collateralization was inadequate to prevent myocardial death. These findings also provide the basic information needed for using this preparation as the model for studies of myocardial infarction.