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Intracoronary adenosine administered after reperfusion limits vascular injury after prolonged ischemia in the canine
D G Babbitt1, R Virmani, M B Forman
1Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Insights
Intracoronary adenosine administration after reperfusion significantly improves myocardial blood flow and ventricular function in a canine model by preventing microvascular damage and the no-reflow phenomenon.
Area of Science:
- Cardiovascular Research
- Myocardial Ischemia and Reperfusion Injury
- Vascular Pharmacology
Background:
- Myocardial salvage after reperfusion can be limited by microvascular dysfunction, leading to the no-reflow phenomenon.
- Deleterious vascular changes in the ischemic microcirculation can progressively decrease blood flow to viable myocytes.
Purpose of the Study:
- To assess the effect of intracoronary adenosine on microvascular changes and myocardial salvage after prolonged ischemia and reperfusion in a canine model.
- To evaluate adenosine's impact on endothelial-dependent and independent coronary vasodilator reserve, regional myocardial blood flow, and ventricular function.
Main Methods:
- 15 closed-chest dogs underwent 2 hours of left anterior descending artery (LAD) occlusion followed by 3 hours of reperfusion.
- Animals received either intracoronary adenosine (n=8) or saline (control, n=7) for 1 hour post-reperfusion.
- Coronary vasodilator reserve, myocardial blood flow (microspheres), and regional contractile function (ventriculography) were assessed.
Main Results:
- Adenosine treatment significantly improved endothelial-dependent and independent coronary vasodilator reserve compared to controls.
- Adenosine administration attenuated the progressive decrease in mid-LAD flow and increase in coronary vascular resistance observed in controls.
- Improved regional myocardial blood flow, reduced neutrophil infiltration, preserved endothelial ultrastructure, and enhanced ventricular function were noted in the adenosine group.
Conclusions:
- Selective intracoronary adenosine administration post-reperfusion significantly mitigates microvascular dysfunction and the no-reflow phenomenon in a canine model of prolonged ischemia.
- Adenosine preserves reversibly injured myocytes by preventing microvascular injury, thereby enhancing myocardial salvage.
- Adenosine represents a potential therapeutic strategy to improve outcomes after myocardial infarction.
Abstract:
Myocardial salvage after reperfusion may be limited by deleterious vascular changes in the previously ischemic microcirculatory bed. This could result in a progressive decrease in blood flow in the capillary bed to potentially viable myocytes (no-reflow phenomenon). The effect of intracoronary adenosine on these changes was assessed in 15 closed-chest dogs subjected to 2 hours of proximal left anterior descending artery (LAD) occlusion followed by 3 hours of reperfusion. Animals randomly received adenosine (n = 8) 3.75 mg/min into the proximal LAD or an equivalent volume of saline (control) (n = 7) for 1 hour after reperfusion. Endothelial-dependent and independent coronary vasodilator reserve was determined using a chronically implanted volume-flowmeter on the mid-LAD at baseline and 1 and 3 hours after reperfusion with acetylcholine and papaverine infusions, respectively, into the proximal vessel. Regional myocardial blood flow was measured serially with radioactive microspheres and regional contractile function with contrast ventriculography. Both agonists produced a significant increase in LAD flow before occlusion. Endothelial-dependent and independent vasodilatory reserve was significantly reduced (p less than 0.05) at 1 and 3 hours after reperfusion in control animals compared with adenosine treatment. A progressive decrease in mid-LAD flow and increase in coronary vascular resistance after reperfusion was observed in control animals (p less than 0.05). The treated group manifested improved regional myocardial blood flow in endocardial regions from the central (0.73 +/- 0.15 versus 0.24 +/- 0.11 ml/g/min; p less than 0.02) and lateral ischemic zones (0.80 +/- 0.15 versus 0.34 +/- 0.12 ml/g/min; p less than 0.05) 3 hours after reperfusion. A significant reduction (p less than 0.05) in endocardial and midmyocardial flow compared with baseline was seen in control animals at 3 hours. Intravascular and interstitial neutrophil infiltration was reduced in adenosine animals and this was associated with relative ultrastructural preservation of endothelial cells. Regional ventricular function in the ischemic zone was improved in the adenosine group 3 hours after reperfusion (13.4 +/- 3.9% versus -5.3 +/- 1.6%; p less than 0.001). This study demonstrates that selective administration of adenosine after reperfusion significantly attenuates functional and structural abnormalities in the microvasculature after prolonged (2 hours) regional ischemia in the canine model. Prevention of microvascular injury and the non-reflow phenomenon by adenosine may preserve reversibly injured myocytes following restoration of blood flow to previously ischemic myocardium.