Comparison of combination therapy of adenosine and nitroprusside with adensosine alone in the treatment of angiographic no‐reflow phenomenon: Does 1 plus 1 equal 11?

Microembolization probably occurs during every intervention [1] and is more common in complex lesions such as those associated with acute myocardial infarctions, atherectomy devices, and especially stent placement [2]. Atherectomy and stents are both more likely to disrupt the plaque and result in liberation of microparticulate matter, thrombus, and inflammatory components. Angiographic sequelae of embolization of these microparticulates are seen in a significant percentage of patients undergoing PCI for acute myocardial infarction and saphenous vein graft lesions. Even in the absence of angiographically visualized embolization, CPK-MB or troponin elevations can be detected as markers of microembolization. These chemical infarcts have identified a group of patients at significantly increased risk of late cardiovascular events. The use of glycoprotein IIb/IIIa inhibitors has decreased the incidence of microembolization as defined by enzyme elevation but not eliminated this clinically significant event. The most severe form of this event, lack of myocardial perfusion, as evidenced by delayed or absent arteriolar or capillary filling in the catheterization suite, is termed no-reflow. Barcin et al. in this issue present an interesting retrospective analysis that suggests that direct arteriolar dilation that utilizes two different pharmacologic mechanisms may have additive benefit in treating no-reflow. Adenosine is an interesting agent with direct effects on the microvasculature. Adenosine directly increases blood velocity by decreasing arteriolar resistance while avoiding increases in capillary blood volume [3]. The exact mechanism is debated but the current hypothesis is that K release occurs via ATP channels mediated by specific adenosine (A2a and A2B) receptors. Adenosine has also been identified as having specific effects on superoxide generation and neutrophil accumulation as well as blocking coronary endothelin release. There is clearly a dose-response to adenosine administration that was previously reported by the same group, indicating that the left anterior descending artery may require up to 54 g for maximal CVR and 42 g for the right coronary artery [4]. This investigation used 18–36 g of adenosine infusion, suggesting suboptimal dosing for complete arteriolar dilatation may not have been achieved. Whether there is a dose-response to the antiinflammatory/antineutrophil effect of adenosine is unknown. It is possible that the dose-response effect may play a role in the findings from this study that adenosine, as a single agent given at less than maximal doses, was less effective than combination therapy. Alternatively, adenosine may be less effective in this situation due to the redistribution of endo and epicardial flow as well as alterations in local microcirculatory flow [5,6]. Sodium nitroprusside is a direct source of nitric oxide without need for conversion and provides a potent stimulus to the microcirculation. It is the most potent stimulus currently available for direct dilation but its effect is attenuated with chronic nitroglycerin administration and in the setting of prolonged myocardial ischemia. By acting directly on the NO pathway, it provides a second stimulus to promote vascular dilation and improved tissue perfusion. The combination of increased velocity of flow provided by adenosine and maximal vessel dilation provided by increases in endothelial and smooth muscle nitric oxide seems compelling. The current study suggests that this approach should be evaluated in a prospective manner. Of greater interest is whether all patients should routinely receive this therapy prior to interventions as to avoid the no-reflow phenomenon or even to decrease the enzyme elevation that occurs during routine PCI. This is an intriguing hypotheis that should generate future studies.