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Background: Ectonucleotidase dependent adenosine generation has been implicated in preconditioning related cardioprotection against ischemia-reperfusion injury, and treatment with a soluble ectonucleotidase has been shown to reduce myocardial infarct size (IS) when applied prior to induction of ischemia. However, ectonucleotidase treatment according to a clinically applicable protocol, with administration only after induction of ischemia, has not previously been evaluated. We therefore investigated if treatment with the ectonucleotidase apyrase, according to a clinically applicable protocol, would reduce IS and microvascular obstruction (MO) in a large animal model., Methods: A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min, in 16 anesthetized pigs (40-50 kg). The pigs were randomized to 40 min of 1 ml/min intracoronary infusion of apyrase (10 U/ml, n = 8) or saline (0.9 mg/ml, n = 8), twenty minutes after balloon inflation. Area at risk (AAR) was evaluated by ex vivo SPECT. IS and MO were evaluated by ex vivo MRI., Results: No differences were observed between the apyrase group and saline group with respect to IS/AAR (75.7 +/- 4.2% vs 69.4 +/- 5.0%, p = NS) or MO (10.7 +/- 4.8% vs 11.4 +/- 4.8%, p = NS), but apyrase prolonged the post-ischemic reactive hyperemia., Conclusion: Apyrase treatment according to a clinically applicable protocol, with administration of apyrase after induction of ischemia, does not reduce myocardial infarct size or microvascular obstruction.

Purpose: The aim of this study was to examine whether the retinal circulation in the pig can be accessed using interventional neuroradiology and to explore the possibility of creating occlusions that result in experimental retinal ischemia., Methods: Six experiments were performed using 100-kg pigs. The external carotid system was catheterized using a fluoroscopy-monitored, transfemoral, endovascular approach. Transient and permanent vascular occlusions were performed using an angioplasty balloon catheter or a liquid embolic agent that was administered via an injection-catheter., Results: A technique for transfemoral catheterization of arteries supplying the retina was established. The ophthalmic artery was demonstrated to give rise to the main ciliary artery from which the retinal artery branched as a single artery or as several arteries. A balloon-catheter could be introduced into the ophthalmic artery but not into the main ciliary artery. An injection-catheter could, in all experiments, be introduced into the main ciliary artery and, in some experiments, into the retinal artery. Occlusion of the ophthalmic artery, over the branching of the main ciliary artery, caused incomplete ischemia, presumably because of collaterals feeding the distal parts of the vasculature. Multifocal ERG (mfERG) recordings showed decreased amplitudes and increased implicit times, indicating retinal ischemia. Occlusion of the ciliary and retinal arteries caused complete ischemia, as shown by complete flattening of the mfERG recordings and, by indirect ophthalmoscopy, blanching of the retinal arteries and a pale retina,, Conclusions: The authors show for the first time that the ophthalmic and retinal artery can be catheterized using a transfemoral endovascular approach. This technique may be useful to produce clear-cut experimental retinal ischemia.

Ethics committees approved human and animal study components; informed written consent was provided (prospective human study [20 men; mean age, 62 years]) or waived (retrospective human study [16 men, four women; mean age, 59 years]). The purpose of this study was to prospectively evaluate a clinically applicable method, accounting for the partial volume effect, to automatically quantify myocardial infarction from delayed contrast material-enhanced magnetic resonance images. Pixels were weighted according to signal intensity to calculate infarct fraction for each pixel. Mean bias +/- variability (or standard deviation), expressed as percentage left ventricular myocardium (%LVM), were -0.3 +/- 1.3 (animals), -1.2 +/- 1.7 (phantoms), and 0.3 +/- 2.7 (patients), respectively. Algorithm had lower variability than dichotomous approach (2.7 vs 7.7 %LVM, P < .01) and did not differ from interobserver variability for bias (P = .31) or variability (P = .38). The weighted approach provides automatic quantification of myocardial infarction with higher accuracy and lower variability than a dichotomous algorithm., ((c) RSNA, 2007.)

Background: The endothelial ADP receptor P2Y(1) is responsible for a large part of the reactive hyperemia following cardiac ischemia. Tissue plasminogen activator (t-PA) increases during reactive hyperemia. We postulated that the release of t-PA during reactive hyperemia could be mitigated through blocking the coronary endothelial P2Y(1) receptor., Methods: t-PA was measured in peripheral arterial blood and locally in the venous blood from the coronary sinus in a porcine model. The stable ADP analogue 2-MeSADP (10(-5) M), alone or as co-infusion with a selective P2Y(1) receptor blocker, MRS2179 (10(-3) M) was locally delivered in the left anterior descending artery through the tip of a coronary angioplasty balloon. In separate pigs the coronary artery was occluded with the balloon for 10 min. During the first and tenth minute of coronary ischemia, 2.5 ml of MRS2179 (10(-3) M) was delivered distal to the occlusion in 8 pigs, 10 pigs were used as controls., Results: 2-MeSADP increased levels of t-PA in the coronary sinus, which could be significantly inhibited by co-infusion with MRS2179. During cardiac ischemia and reperfusion, t-PA increased significantly, an effect that could be significantly inhibited by MRS2179., Conclusions: Intra coronary administered MRS2179, a selective P2Y(1) receptor blocker, significantly reduces the increased levels of t-PA caused by both 2-MeSADP and cardiac ischemia in coronary arteries. Thus, ADP acting on the endothelial P2Y(1) receptor may mediate release of t-PA during ischemia and post-ischemic hyperemia, an effect that may counteract some of the platelet activating effects of ADP. Abbreviated Abstract We postulated that the release of t-PA during post ischemic reactive hyperemia could be mitigated through blocking the coronary endothelial P2Y(1) receptor in a porcine model. The ADP analogue 2-MeSADP (10(-5) M), alone or as co-infusion with a the P2Y(1) receptor blocker, MRS2179 (10(-3) M) was locally delivered in the left anterior descending artery. In separate pigs the coronary artery was occluded for ten min. During the first and tenth min of coronary ischemia, 2.5 ml of MRS2179 (10(-3) M) was delivered distal to the occlusion. t-PA was measured in peripheral arterial blood and also from the Coronary Sinus. We found that levels of t-PA in the blood from the coronary Sinus increased during infusion with 2-MeSADP as well as during ischemia and reperfusion. In pigs treated with MRS2179 levels of t-PA in the Coronary Sinus were significantly reduced during both coinfusion with 2-MeSADP and during ischemia/reperfusion. Thus, ADP acting on the endothelial P2Y(1) M receptor may mediate release of t-PA during ischemia and post-ischemic hyperemia, an effect that may counteract some of the platelet activating effects of ADP.

Background: In experimentally induced myocardial infarction, mild hypothermia (33-35 degrees C) is beneficial if applied prior to ischemia or reperfusion. Hypothermia, when applied after reperfusion seems to confer little or no benefit. The mechanism by which hypothermia exerts its cell-protective effect during cardiac ischemia remains unclear. It has been hypothesized that hypothermia reduces the reperfusion damage; the additional damage incurred upon the myocardium during reperfusion. Reperfusion results in a massive increase in blood flow, reactive hyperemia, which may contribute to reperfusion damage. We postulated that hypothermia could attenuate the post-ischemic reactive hyperemia., Methods: Sixteen 25-30 kg pigs, in a closed chest model, were anesthetized and temperature was established in all pigs at 37 degrees C using an intravascular cooling catheter. The 16 pigs were then randomized to hypothermia (34 degrees C) or control (37 degrees C). The left main coronary artery was then catheterized with a PCI guiding catheter. A Doppler flow wire was placed in the mid part of the LAD and a PCI balloon was then positioned proximal to the Doppler wire but distal to the first diagonal branch. The LAD was then occluded for ten minutes in all pigs. Coronary blood flow was measured before, during and after ischemia/reperfusion., Results: The peak flow seen during post-ischemic reactive hyperemia (during the first minutes of reperfusion) was significantly reduced by 43 % (p < 0.01) in hypothermic pigs compared to controls., Conclusion: Mild hypothermia significantly reduces post-ischemic hyperemia in a closed chest pig model. The reduction of reactive hyperemia during reperfusion may have an impact on cardiac reperfusion injury.

Background: The same mechanisms by which ultrasound enhances thrombolysis are described in connection with non-beneficial effects of ultrasound. The present safety study was therefore designed to explore effects of beneficial ultrasound characteristics on the infarcted and non-infarcted myocardium., Methods: In an open chest porcine model (n = 17), myocardial infarction was induced by ligating a coronary diagonal branch. Pulsed ultrasound of frequency 1 MHz and intensity 0.1 W/cm2 (ISATA) was applied during one hour to both infarcted and non-infarcted myocardial tissue. These ultrasound characteristics are similar to those used in studies of ultrasound enhanced thrombolysis. Using blinded assessment technique, myocardial damage was rated according to histopathological criteria., Results: Infarcted myocardium exhibited a significant increase in damage score compared to non-infarcted myocardium: 6.2 +/- 2.0 vs. 4.3 +/- 1.5 (mean +/- standard deviation), (p = 0.004). In the infarcted myocardium, ultrasound exposure yielded a further significant increase of damage scores: 8.1 +/- 1.7 vs. 6.2 +/- 2.0 (p = 0.027)., Conclusion: Our results suggest an instantaneous additive effect on the ischemic damage in myocardial tissue when exposed to ultrasound of stated characteristics. The ultimate damage degree remains to be clarified.

The physiological mechanisms that regulate reactive hyperemia are not fully understood. We postulated that the endothelial P2Y(1) receptor that release vasodilatory factors in response to ADP might play a vital role in the regulation of coronary flow. Intracoronary flow was measured with a Doppler flow-wire in a porcine model. 2-MeSADP (10(-5) M), ATP (10(-4) M) or UTP (10(-4) M) alone or as co-infusion with a selective P2Y(1) receptor blocker, MRS 2179 (10(-3) M) was locally delivered through the tip of a coronary angioplasty balloon. In separate pigs the coronary artery was occluded with the balloon for 10 min. During the first and tenth minutes of coronary ischemia, 2.5 ml of MRS 2179 (10(-3) M) was delivered distal to the occlusion in 8 pigs, 10 pigs were used as controls. MRS 2179 fully inhibited the 2-MeSADP-mediated coronary flow increase (P < 0.05) with no effect on UTP, indicating selective P2Y(1) inhibition. ATP-mediated flow increase was significantly inhibited by MRS 2179. During reactive hyperemia following coronary occlusion, flow increased by nearly sevenfold. MRS 2179, however, reduced the post-ischemic hyperemia by a mean of 46% during the period 1-2.5 min following balloon deflation (P < 0.05), which corresponds to peak velocity flow during reperfusion. In conclusion, MRS 2179, a selective P2Y(1) receptor blocker, significantly reduces the increased coronary flow caused both by 2-MeSADP and reactive hyperemia in coronary arteries. Thus, ADP acting on the endothelial P2Y(1) receptor may play a major role in coronary flow during post-ischemic hyperemia.