Reperfusion Injury in Patients With Acute Myocardial Infarction: JACC Scientific Statement.

Despite impressive improvements in the care of patients with ST-segment elevation myocardial infarction, mortality remains high. Reperfusion is necessary for myocardial salvage, but the abrupt return of flow sets off a cascade of injurious processes that can lead to further necrosis. This has been termed myocardial ischemia-reperfusion injury and is the subject of this review. The pathologic and molecular bases for myocardial ischemia-reperfusion injury are increasingly understood and include injury from reactive oxygen species, inflammation, calcium overload, endothelial dysfunction, and impaired microvascular flow. A variety of pharmacologic strategies have been developed that have worked well in preclinical models and some have shown promise in the clinical setting. In addition, there are newer mechanical approaches including mechanical unloading of the heart prior to reperfusion that are in current clinical trials.

Update on Cardioprotective Strategies for STEMI: Focus on Supersaturated Oxygen Delivery.

Despite the fact that door-to-balloon times have been greatly reduced, the rates of death and the incidence of heart failure in patients with ST-segment elevation myocardial infarction (MI) have plateaued. There is still an unmet need to further reduce MI size in the reperfusion era. Most adjunctive therapies to enhance myocardial salvage have failed, but some have shown promise. Currently, the only adjunctive therapy in a pivotal trial that has demonstrated reductions in infarct size is localized delivery of supersaturated oxygen (SSO2) therapy. This review provides background on prior infarct size reduction efforts. The authors describe the preclinical data that shows the effectiveness of SSO2 in reducing MI size, improving regional myocardial blood flow and cardiac function, and reducing adverse left ventricular remodeling-presumably by reducing patchy areas of residual ischemia within the reperfused risk zone. Potential mechanisms by which SSO2 is beneficial are described, including the delivery of high levels of dissolved oxygen through plasma to ischemic, but viable, vascular and myocardial cells, thus allowing their survival and function. The authors then describe the SSO2 clinical trials, demonstrating that in patients with anterior ST-segment elevation MI, SSO2 therapy safely and effectively reduces infarct size, improves cardiac function, and reduces adverse left ventricular remodeling.

Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT): a prospective, randomized trial of intracoronary hyperoxemic reperfusion after percutaneous coronary intervention.

OBJECTIVES: This study sought to determine whether hyperoxemic reperfusion with aqueous oxygen (AO) improves recovery of ventricular function after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: Hyperbaric oxygen reduces myocardial injury and improves ventricular function when administered during ischemia-reperfusion. METHODS: In a prospective, multicenter study, 269 patients with acute anterior or large inferior AMI undergoing primary or rescue PCI (<24 h from symptom onset) were randomly assigned after successful PCI to receive hyperoxemic reperfusion (treatment group) or normoxemic blood autoreperfusion (control group). Hyperoxemic reperfusion was performed for 90 min using intracoronary AO. The primary end points were final infarct size at 14 days, ST-segment resolution, and delta regional wall motion score index of the infarct zone at 3 months. RESULTS: At 30 days, the incidence of major adverse cardiac events was similar between the control and AO groups (5.2% vs. 6.7%, p = 0.62). There was no significant difference in the incidence of the primary end points between the study groups. In post-hoc analysis, anterior AMI patients reperfused <6 h who were treated with AO had a greater improvement in regional wall motion (delta wall motion score index = 0.54 in control group vs. 0.75 in AO group, p = 0.03), smaller infarct size (23% of left ventricle in control group vs. 9% of left ventricle in AO group, p = 0.04), and improved ST-segment resolution compared with normoxemic controls. CONCLUSIONS: Intracoronary hyperoxemic reperfusion was safe and well tolerated after PCI for AMI, but did not improve regional wall motion, ST-segment resolution, or final infarct size. A possible treatment effect was observed in anterior AMI patients reperfused <6 h of symptom onset.

Intracoronary aqueous oxygen perfusion, performed 24 h after the onset of postinfarction reperfusion, experimentally reduces infarct size and improves left ventricular function.

BACKGROUND: Intracoronary aqueous oxygen (AO) hyperoxemic perfusion, initiated shortly (15-30 min) after the onset of postinfarction reperfusion, reduces infarct size and improves left ventricular function. Whether such therapy provides similar benefits when administered many hours after the onset of reperfusion is unknown. Accordingly, the hypothesis was tested that AO hyperbaric perfusion, performed 24 h after the onset of postinfarction reperfusion, reduces infarct size and improves left ventricular ejection fraction (LVEF) in swine. METHODS: Following a 1-h balloon occlusion of the left anterior descending coronary artery in air-ventilated juvenile domestic swine, reperfusion was allowed to proceed without adjunctive therapy overnight in all animals. The following day, half of the reanesthetized, air-ventilated swine were randomized to treatment with intracoronary AO hyperbaric perfusion for 90 min (n=6, mean arterial perfusate PO(2)=899+/-78 mm Hg), while the remainder served as controls (n=6). RESULTS: Infarct size by triphenyl tetrazolium chloride was reduced by 48% and the [area of necrosis]/[area at risk] ratio was reduced by 44% in the AO group compared to the control group (p<0.05). By serial ventriculography, mean LVEF improved by 21% during AO perfusion, relative to baseline and control group values (p<0.05), with no significant change 1 h after completion of treatment (p>0.05). CONCLUSION: AO hyperbaric perfusion, delayed 24 h after the onset of postinfarction reperfusion, reduces infarct size and improves LVEF in an experimental animal model.

Aqueous oxygen near the homogeneous nucleation limit of water: stabilization with submicron capillaries.

Previous studies have demonstrated that the metastability threshold of aqueous oxygen (AO) is inversely dependent on the internal diameter of capillary tubes used to deliver it into blood. The hypothesis was tested herein that significantly higher thresholds are attainable with capillaries having markedly smaller dimensions (submicron) than those previously studied. Water was equilibrated with oxygen over a 0.3- to 0.7-k bar range. Inert gases (argon, helium) facilitated studies at pressures to 2.5 k bar. An argon-ion laser was used to visualize fluorescein in the liquid effluent from silica capillaries that were tapered at the distal end to a submicron internal diameter (0.5 +/- 0.3 microns). During infusion of the fluorescent effluent into host water at 21 degrees C and atmospheric pressure, integrity of the effluent and lack of microbubbles were monitored by videomicroscopy. No microbubbles were noted at AO concentrations ranging from 7.5 to 12.8 ml O2/g (0.34 to 0.68 k bar, respectively) or in the aqueous argon effluent at concentrations to 14 ml Ar/g (0.75 k bar). For aqueous helium, effluent nucleation was not observed at a mean concentration of 13 +/- 3 ml He/g (2.0 +/- 0.5 k bar), with an upper value of 15.2 ml He/g (2.4 k bar). The data represent the highest values of the tensile strength of water ever observed and approximate its theoretical homogeneous nucleation limit. Thus, remarkably high metastable concentrations of AO and other gases are attainable with the use of submicron capillaries.

Interventional approach to recurrent myocardial infarction in HIV-1 infection.

We report a case of recurrent myocardial infarction occurring in two different coronary territories in a man with HIV-1 infection. On each occasion, clinical and angiographic success was obtained by intracoronary stent placement.

Angiographic observations 10 years following coronary laser balloon angioplasty.

A patient underwent laser balloon angioplasty (LBA) combined with local intracoronary heparin therapy for treatment of a high grade stenosis of the mid-portion of the left anterior descending (LAD) coronary artery. Sustained patency of the LBA-treated lesion and no new coronary stenoses were found in a 10-year angiographic follow-up study.

Aqueous oxygen attenuation of reperfusion microvascular ischemia in a canine model of myocardial infarction.

Uncorrected microvascular ischemia may contribute to left ventricular impairment during reperfusion after prolonged coronary artery occlusion. Attenuation of such ischemia in microvessels with impaired erythrocyte flow may require delivery of oxygen at high levels in plasma. Intraarterial infusion of aqueous oxygen (AO) can be used in a site specific manner to achieve hyperoxemic levels of oxygenation in the perfusate. With this new approach, the hypothesis was tested that reperfusion microvascular ischemia can be attenuated. After a 90 min coronary balloon occlusion in a canine model, AO hyperoxemic intracoronary perfusion was performed for 90 min after a 30 min period of autoreperfusion. Control groups consisted of normoxemic reperfusion, both passive (autoreperfusion) and active (roller pump). A significant improvement in left ventricular ejection fraction (p < 0.05) at 2 hr of reperfusion was noted only in the AO hyperoxemia group (17 +/- 6% by two dimensional echo), without a significant reduction in the improvement 1 hr after termination of treatment. During AO hyperoxemic perfusion, ECG ST segment isoelectric deviation normalized, and frequency of ventricular premature contractions was significantly reduced, in contrast to the autoreperfusion control group (p < 0.05). Microvascular blood flow, measured as the ischemic/normal left ventricular segment ratio by radiolabeled microspheres immediately after AO hyperoxemic perfusion, was double the value of the autoreperfusion control group at 2 hr of reperfusion (p < 0.05). We conclude that reperfusion microvascular ischemia is attenuated by intracoronary AO hyperoxemic perfusion and acutely improves left ventricular function in this model.

Hyperbaric oxygen as a chemotherapy adjuvant in the treatment of metastatic lung tumors in a rat model.

OBJECTIVES: The objectives of the study were to test the hypothesis that hyperbaric levels of oxygen enhance the sensitivity of a sarcoma cell line to doxorubicin (Adriamycin) both in vitro and in vivo in a rat model of pulmonary metastases and to test the feasibility of arterialization of mixed venous blood by direct injection of aqueous oxygen into the pulmonary artery in a rat model. METHODS: Rat sarcoma (MCA-2) cells were incubated in the presence of increasing concentrations of doxorubicin (0.1-2.0 micromol/L). A dose-dependent toxicity relationship at 12 hours of treatment was examined with and without pretreatment with hyperbaric oxygen (3.7 atm absolute for 1.5-3.5 hours). In vivo, Sprague-Dawley rats (n = 24) were injected intravenously with 10(6) MCA-2 cells, and the lung tumors were allowed to mature for 14 days. At that time the animals were divided into four groups: control (no treatment), doxorubicin at 2 mg/kg, hyperbaric oxygen (oxygen at 2 atm absolute for 30 minutes), and hyperbaric oxygen plus doxorubicin. Seven days after treatment, the numbers of lung nodules were counted and the lung weights were determined. In additional rats (n = 7), aqueous oxygen (1 mL oxygen/g saline solution) was infused into the pulmonary artery to determine whether arterialization of mixed venous blood was comparable to pulmonary artery oxygenation with a hyperbaric chamber (n = 7). RESULTS: Hyperbaric oxygen plus doxorubicin produced significantly greater cytolysis of MCA-2 cells (P <.01) than did doxorubicin alone. Hyperbaric oxygen plus doxorubicin also significantly decreased the number of lung metastases and the lung weight relative to doxorubicin alone (P <.01 and P <.01, respectively). The feasibility of arterialization of mixed venous blood (>100 mm Hg) with aqueous oxygen infusion was demonstrated. CONCLUSIONS: Hyperbaric oxygen enhanced the chemotherapeutic effect of doxorubicin both in cell culture and in the rat model. Aqueous oxygen infusion can be used to oxygenate mixed venous blood at levels similar to those obtained with the use of a hyperbaric chamber.

Aqueous oxygen hyperbaric reperfusion in a porcine model of myocardial infarction.

OBJECTIVES: The purpose of the study was to test the hypothesis that intracoronary aqueous oxygen (AO) hyperbaric reperfusion reduces myocardial injury after prolonged coronary occlusion. Background. Attenuation of ischemia/reperfusion injury by the use of hyperbaric oxygen (HBO) administered during reperfusion has been demonstrated for a wide variety of tissues, including myocardium. We have recently developed a more practical, catheter-based, site-specific method for delivery of oxygen at hyperbaric levels with aqueous oxygen infusion. METHODS: Following a 60-minute balloon occlusion of the left anterior descending coronary artery in swine, intracoronary AO hyperoxemic perfusion (50 mL blood/minute; 1.5 mL AO/minute; mean pO2 = 834 104 mmHg) was performed for 90 minutes after a 15-minute period of normoxemic autoreperfusion (physiologic reperfusion). Control groups consisted of autoreperfusion alone; active normoxemic perfusion (50 mL/minute) for 90 minutes; and hyperoxemic perfusion with a hollow fiber oxygenator (HFO) for 90 minutes. Results. A significant improvement in left ventricular ejection fraction was noted by ventriculography at 105 minutes of reperfusion (ANOVA, p < 0.05), compared to the 15-minute autoreperfusion period, only in the AO and HFO groups. Mean percent infarct size (area of necrosis)/(area at risk), quantitative post-mortem hemorrhage score, and myocardial myeloperoxidase levels at 3 hours of reperfusion were significantly less in the AO group (ANOVA, p < 0.05), but not in the HFO group, compared to normoxemic groups. Conclusions. The results demonstrate that intracoronary hyperbaric reperfusion with AO, but not with a membrane oxygenator, attenuates myocardial ischemia/reperfusion injury.