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Ann Thorac Surg 2003;75:S691-S699
© 2003 The Society of Thoracic Surgeons
a The Cardiothoracic Research Laboratory, Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
* Address reprint requests to Dr Vinten-Johansen, The Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, 550 Peachtree St NE, Atlanta, GA 30308-2225, USA
e-mail: jvinten{at}emory.edu
Presented at the 3rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.
Abstract
Adenosine is most well known for its potent vasodilation of the vasculature. However, it also promotes glycolysis, and activates potassium-sensitive adenosine triphosphate (KATP) channels. Adenosine also strongly inhibits neutrophil function such as superoxide anion production, protease release, and adherence to coronary endothelial cells. Hence adenosine attenuates ischemic injury as well as neutrophil-mediated reperfusion injury. Adenosine has also been implicated in the cardioprotective phenomenon of ischemic preconditioning. Accordingly experimental evidence shows that adenosine reduces postischemic injury when administered before ischemia and at the onset of reperfusion. Clinical studies in cardiology and cardiac surgery show cardioprotective trends with adenosine treatment but the effects are not as dramatic as those reported by experimental studies.
Considerable interest has been shown in adenosine for its cardiovascular effects. Certainly its cardiovascular actions have long been recognized [1,2] and its ability to vasodilate has been proposed as a central mechanism of autoregulation of coronary blood flow [3]. In addition, its negative inotropic and chronotropic effects have been understood for many years [4, 5]. However, it has not been until the last 15 years that adenosine has been appreciated for its cardioprotective potential against ischemic-reperfusion injury on two fronts: (1) coronary occlusion-reperfusion and its clinical corollary of percutaneous transluminal angioplasty, and (2) global ischemia-reperfusion with the clinical counterpart of cardiac surgery. Recently, adenosine has also become recognized for its inhibitory actions on the inflammatory response [6]. Since the seminal observations of Olafsson and associates [7] there has been a virtual explosion of research focused on unraveling the mechanisms by which this endogenous purine nucleoside protects the heart from reversible as well as nonreversible injury after ischemia and reperfusion. As research into the cardiovascular and cardioprotective effects of adenosine has progressed, the temporal dynamics and mechanisms by which adenosine exerts cardioprotection have become more intriguing and more complex. Adenosine has the potential to exert cardioprotection during all three windows of cardioprotection (pretreatment or preconditioning, ischemia and reperfusion). Knowing when during these windows adenosine exerts its effects on the participants in the pathophysiology of ischemia-reperfusion injury will determine its optimal therapeutic use [8]. This manuscript will review the mechanisms of myocardial protection by adenosine in the nonsurgical (ie, catheterization-laboratory) and surgical contexts. A full discussion of adenosine analogs and regulating agents is beyond its scope.
Pharmacology
The cardiovascular effects of adenosine are mediated primarily by activating membrane receptors coupled to G-proteins that differentially couple to adenylate cyclase (Table 1). There are at least four receptor subtypes: A1, A2A, A2B, and A3 receptors. The A1 and A3 subtypes are coupled to inhibitory G-proteins (Go, Gi) that inhibit adenylate cyclase. The affinity of adenosine for the A3 receptor subtype is lower than that for the A1 receptor subtype. The A1 receptor is purportedly the trigger or mediator, or both, of ischemic preconditioning, whereby short periods of ischemia preceding a longer lethal period of ischemia (index ischemia) engages an adaptive response making the myocardium more resistant to ischemia (and by extension to hypoxia and anoxia). Activation of the A1 receptor subtype activates (opens) ATP-sensitive potassium (KATP) channels, touted as a primary effector, thereby causing membrane hyperpolarization particularly in the sinoatrial node, with resultant bradycardia. But activation of the KATP channels may also be a primary mechanism of the adaptation to ischemia. This hyperpolarizing property is used clinically to attenuate sinus arrhythmias and to reduce heart rate for various different procedures. The A1 and A3 receptor subtypes are coupled to kinases including protein kinase C (PKC). Activation of PKC is linked to the opening of sarcolemmal KATP channels, resulting in transmembrane hyperpolarization. Adenosine also suppresses the L-type calcium channels through A1 receptor-mediated effects, an action which has implications regarding calcium accumulation during ischemia-reperfusion. The A1 and A3 receptor subtypes are also coupled to other kinases, notably receptor tyrosine kinases that are responsible for phosphorylation and desensitization of the A1 and A3 receptors after prolonged exposure to agonists.
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Myocardial protection
Experimental evidence
Pretreatment before ischemia
The administration of adenosine before ischemia is often referred to as chemical preconditioning, as adenosine has been implicated in the trigger of ischemic preconditioning. However, this is a slight misnomer because to be truly a "preconditioning" treatment there has to be an intervening period of reperfusion (viz-a-viz washout) before the index ischemia and "pretreatment" requires no such washout period. Pretreatment of the heart before ischemia has been shown to reduce infarct size [9, 10] and attenuate contractile dysfunction [11, 12]. Although many of the studies investigating restoration of contractile function with pretreatment adenosine were conducted in isolated perfused heart preparations, Randhawa and associates [13] reported recovery of regional function with intracoronary adenosine (5 µg · kg-1 · min-1 which did not increase interstitial levels of adenosine, or 50 µg · kg-1 · min-1 that did increase interstitial adenosine concentration) after 15 minutes of coronary artery occlusion in an in vivo canine preparation. Interestingly, administration of adenosine at reperfusion, as opposed to before ischemia, only transiently improved functional recovery, which disappeared after discontinuation of the drug. Salutary effects of adenosine were independent of increases in regional blood flow (ie, by the garden hose effect). Therefore it may be that intravascular adenosine exerts the cardioprotective effects observed in the group treated with the lower concentration of adenosine, although this study by Randhawa and associates [13] could not rule out an undetectable increase in interstitial adenosine concentration.
Overall the evidence available suggests that the cardioprotective actions of pretreatment adenosine are mediated largely by activation of A1 receptor subtypes [11, 12], because (a) selective A1 receptor agonists confer cardioprotection; (b) cardioprotection by adenosine administered before ischemia is blocked by A1 receptor antagonists; and (c) cardioprotection can be blocked by inhibitors of Gi signal transduction proteins such as pertussis toxin. A1-mediated cardioprotection may involve activation and translocation of protein kinase C (PKC) from the cytosol to the sarcolemmal and mitochondrial membranes, as briefly discussed above. PKC activation in turn activates (opens) the KATP channels in these membranes; the mitochondrial KATP channels have been implicated as being more important in the protection conferred by preconditioning. However, involvement of mitochondrial KATP channels in adenosine-mediated cardioprotection is somewhat controversial. Activation of adenosine A1 receptors may also reduce the generation of reactive oxygen species during ischemia-reperfusion [14] by mechanisms involving opening of KATP channels [14, 15].
Inhibition of inflammatory-related processes in ischemia-reperfusion
Neutrophils play an important role in the pathogenesis of myocardial ischemic-reperfusion injury (infarction and contractile dysfunction) by inducing a localized inflammatory-like response [16–20]. In this response, neutrophils generate oxygen free radicals, release of proteases, arachidonic metabolites and hypochlorous acid, and release of proinflammatory cytokines. Neutrophil-mediated reperfusion injury involves specific interactions between neutrophils and coronary artery and venous endothelial cells in the early moments of reperfusion. Neutrophils are recruited to the reperfused myocardium during the early minutes of reperfusion by proinflammatory cytokines (TNF-
, IL-6, platelet activating factor, complement) and chemotactic factors (IL-8) released by the myocardium during ischemia [38, 39]. The first interaction is a tethering or "rolling" of neutrophils along the endothelial surface, which is mediated by P-selectin on the endothelium and a sialylated glycoprotein on the neutrophil, most likely sialyl Lewisx or the sialomucin P-selectin glycoprotein ligand-1 (PSGL-1) [29, 40]. Two to 4 hours later, platelet activating factor [44, 45] and LTB4 [45] in the micro-environment can increase the surface expression of CD11/CD18 on neutrophils, while IL-1 [46] and TNF- [46] increase ICAM-1 expression on the endothelium. Firmer adherence of neutrophils to the endothelium then ensues. The initial loose adherence step is obligatory for later firm adherence mediated by the CD11/CD18 complex on neutrophils and ICAM-1 on endothelial cells, and is critical in the pathogenesis of myocardial infarction (MI), microvascular injury, and apoptosis [28, 41–43]. A link has been established between the accumulation of neutrophils and the development of reperfusion injury during the early reperfusion period. This link has been substantiated by several studies investigating the time course of neutrophil accumulation and progression of injury.
Adenosine has been shown to inhibit neutrophil-endothelial cell interactions during ischemia-reperfusion [6]. Studies from our laboratory [21] using canine coronary artery segments have shown that adenosine directly inhibits superoxide generation by canine neutrophils stimulated by platelet activating factor (PAF). This inhibitory effect was reversed by 8-SPT, suggesting a receptor-mediated effect. Adenosine in the presence of an A1-selective antagonist retained this inhibitory effect, implying an A2-mediated mechanism. Accordingly, this notion of A2-mediated inhibition of neutrophil function was confirmed in studies using the specific A2 agonist CGS-21680, which inhibited superoxide anion production, adherence to coronary artery endothelium, and endothelial dysfunction caused by PAF activated neutrophils in vitro. Adenosine-induced inhibition of PMN adherence is not attenuated by A1 antagonism, again implying an A2-mediated effect of adenosine. Finally, adenosine partially inhibited neutrophil-induced injury to coronary artery endothelium primarily by A2-receptor mechanisms [22, 23].
Adenosine treatment at reperfusion
In a landmark in vivo study Olafsson and associates [7] reported that intracoronary adenosine infused during the early phase of reperfusion after left anterior descending (LAD) occlusion reduced infarct size by 75% and improved regional contractile function 24 hours after the start of reflow. Histology demonstrated preservation of endothelial morphology with decreased neutrophil infiltration and intravascular plugging in the central necrotic zone. These data strongly suggested an inhibitory effect on neutrophil-mediated reperfusion injury by adenosine and implied a relationship between neutrophil accumulation and infarct size. Other studies reported similar results with intravenous adenosine [24] or adenosine receptor-specific analogues [25] administered at reperfusion. The attenuation of endothelial injury with intracoronary adenosine was demonstrated by a subsequent study from the same group [26] in which intracoronary adenosine attenuated the loss of vasodilator reserve and reduced neutrophil infiltration and morphologic injury to the endothelium. This study [26] therefore further confirmed the hypothesis raised by Olafsson and associates [7] that adenosine reduced necrosis, possibly by preventing neutrophil accumulation and microvascular injury. However, in vitro and further in vivo demonstration of mechanisms of this suspected action of adenosine was lacking.
Since adenosine has potent antineutrophil properties, Jordan and associates [27] hypothesized that adenosine would reduce in vivo reperfusion injury in part by inhibiting neutrophil events through A2-receptor–mediated mechanisms. A canine model of 60 minutes of collateral-deficient (LAD arteriotomy) LAD occlusion was used in which reperfusion was initiated with an intracoronary infusion of either saline (control) or the A2-receptor–specific analogue CGS-23680 for the first hour of reperfusion. Jordan and associates [27] found that the adenosine A2-receptor analogue CGS-21680 significantly reduced infarct size from 29.8% ± 2.3% of the area at risk in a saline vehicle group to 15.4% ± 2.9% of the area at risk. However, there was no improvement in wall motion. An analogue to adenosine, AMP579 administered intraatrially at reperfusion similarly reduced infarct size but additionally attenuated endothelial dysfunction and reduced accumulation of neutrophils in the area at risk after 24 hours of reperfusion [28]. This study is important because it demonstrated that the cardioprotection conferred by adenosine-like activity was permanent rather than simply representing a delay in the inevitable extent of injury.
Adenosine-enhanced preconditioning
Although ischemic preconditioning, defined above, has been universally demonstrated to reduce infarct size, its effects on attenuating contractile dysfunction (stunning) have been inconsistent and controversial. Even in cardiac surgery the benefits of ischemic preconditioning have been equivocal [29]. McCully and associates [30] combined the concepts of ischemic preconditioning with pharmacologic preconditioning with adenosine in what was termed adenosine-enhanced ischemic preconditioning, in which adenosine is administered coincident with ischemic preconditioning. In a series of studies in isolated perfused heart preparations, the infusion of adenosine and a coincident transient period of ischemia preceded a longer period of global ischemia sufficient to create infarction and contractile dysfunction. This combined treatment had greater benefit in both physiologic outcomes (reduced infarct size and greater functional recovery) as opposed to ischemic preconditioning alone, which reduced only infarct size. The reduction in infarct size was achieved by adenosine receptor activation primarily during ischemia for the infarct size reduction component, while functional recovery was achieved by adenosine receptor activation during both ischemia and reperfusion [31]. The benefits of adenosine-enhanced preconditioning extended to aged hearts in which adenosine receptors have been reported to be down-regulated and the pharmacologic benefits of adenosine treatment were blunted [32]. The salutary effects of adenosine-enhanced preconditioning have been confirmed in an in vivo model as well [33, 34]. However, the concept of adenosine-enhanced preconditioning has not been tested in the clinical setting at the time of this writing. In addition, the application of preconditioning in other clinical settings, ie, angioplasty, remains unclear because a pretreatment presumes knowledge of the offending ischemic event to come.
Clinical use of adenosine
Percutaneous coronary interventions
Based on the conclusions drawn from recent studies in the catheterization-laboratory setting that ischemic preconditioning (ie, the initial balloon inflation) during percutaneous interventions in humans decreases the severity of ischemia during subsequent balloon inflations [35, 36], studies have tested the safety and benefits of adenosine administered either intravenously or intracoronary during percutaneous interventions. The use of adenosine or adenosine-related therapy has targeted two categories of injury: (1) injury occurring during the balloon inflation itself, and (2) ischemia-reperfusion injury after the balloon procedure, ie, reduction of postischemic injury from the coronary disease as well as the balloon inflation intervals. In the first category, Strauer and associates [37] reported that intracoronary infusion of dipyridamole before balloon inflation reduced ventricular systolic and diastolic dysfunction during the inflation procedure, ostensibly by increasing endogenous adenosine levels in the myocardium. Others have reported that intracoronary dipyridamole administered before angioplasty decreased anginal pain and ST-segment elevation observed during sequential balloon inflation to a greater extent than did ischemic preconditioning [38]. A similar attenuation of ST-segment elevation and angina was reported for intracoronary adenosine administered before repetitive balloon inflations, ie, delivered as a pretreatment [35]. This study also reported that intracoronary adenosine had no adverse effect on hemodynamics or cardiodynamics as determined by echocardiography [35]. The only adverse effects of intracoronary adenosine were mild chest pain during infusion, and atrioventricular block during adenosine infusion into the right coronary artery that resolved after discontinuation of the drug.
To determine if adenosine could reduce postischemic injury after percutaneous intervention, Garratt and associates [39] reported that intravenous adenosine (70 µg · kg-1 · min-1) tended to reduce perfusion defects (indicative of infarction) measured by technetium 99m sestamibi after angioplasty. However, there was a relatively high incidence of hypotension warranting reduction or discontinuation of drug. The AMISTAD (Acute Myocardial Infarction Study of Adenosine) trial investigated the cardioprotective effects of intravenous adenosine (also 70 µg · kg-1 · min-1) before thrombolytic therapy was initiated in 236 patients; balloon angioplasty was not a treatment option [40]. There was a 33% reduction in relative infarct size with adenosine treatment compared with control patients treated with thrombolytic agents alone; the infarct reduction was most pronounced in patients with anterior infarcts (67% relative reduction). However, there was a nonsignificant but worrisome trend toward increased number of deaths (10 versus 6), reinfarction (7 versus 3) and heart failure (13 versus 8) in adenosine-treated patients. Compelling data on the efficacy of intracoronary adenosine treatment in MI at the time of angioplasty were reported by Marzilli and associates [41]. In 54 randomized patients undergoing primary angioplasty, either saline or 4 mg adenosine in 2 mL saline was hand-injected through the central lumen of the angioplasty catheter over a 1-minute period while the balloon was inflated. The dilatation of the target vessel then proceeded according to standard angioplasty protocol. Thrombolysis in myocardial infarction trial 3 flow was achieved in all adenosine-treated patients; the no-reflow phenomenon occurred in only 1 patient in the adenosine group whereas it occurred in 7 saline-treated patients. Increased creatine kinase activity and incidence of Q-wave MI occurred less frequently in adenosine-treated patients compared with saline-treated patients. Despite this reported success in adjunctive intracoronary adenosine in patients undergoing primary angioplasty for acute MI, laboratory-based data using a model similar to the patient undergoing angioplasty is not abundant. The authors’ laboratory is currently investigating adjunctive intracoronary adenosine during angioplasty balloon-induced infarction in a closed-chest porcine model. Initial evidence is promising for an antiinfarct effect of adenosine consistent with experimental reports described above.
Use in cardiac surgery
Pretreatment adenosine
Lee and associates [42] first reported favorable results with pretreatment adenosine administered preoperatively to patients with poor left ventricular performance (ejection fraction approximately 30%) and at least three-vessel disease undergoing coronary artery bypass graft surgery. Adenosine was infused at a hemodynamically benign dose of 250 to 350 µg/kg for 10 minutes before cardiopulmonary bypass. Cardiac index was improved over that observed in nontreated patients immediately after discontinuation of bypass and 40 hours postoperatively and creatine kinase levels 24 hours postoperatively were significantly lower in adenosine treated patients. More recently Wei and associates [43] reported that pretreatment with 650 µg/kg adenosine before the initiation of cardiopulmonary bypass resulted in lower creatine–kinase–MB fraction release and improved cardiac index postoperatively. However, there was no significant reduction in neutrophil counts or cytokine release with pretreatment adenosine, as one might have expected from the experimental literature. These data are extremely promising since the question of unwanted complications such as hypotension and bradycardia have dampened the enthusiasm for adenosine therapy. However, the use of adenosine as a pharmacologic preconditioning agent administered before delivery of cardioplegia (5-minute delivery of 140 µg · kg-1 · min-1 followed by 10-minute washout) demonstrated no decrease in troponin release compared with a control cardioplegia group [44]. Therefore the pretreatment modality of adenosine seems to be more effective than administration separated by a washout period.
Adenosine-enhanced cardioplegia
In 1976 Hearse and associates [45] reported that adenosine, either administered alone during ischemia or as an adjunct to hyperkalemic crystalloid cardioplegia, was cardioprotective. However, few studies have tested adenosine as a sole adjunct to blood cardioplegia, perhaps because there is concern that the nucleoside would be too rapidly degraded by plasma adenosine deaminase to achieve therapeutic levels in the heart. Catabolism of adenosine in blood cardioplegia can be attenuated by hypothermia, using a double lumen tube delivery system to deliver adenosine as close as possible to the aortic root [46], or by coinfusing a short acting deaminase inhibitor. In addition the concentration of adenosine delivered at the aortic root judiciously increased to compensate for degradation along the delivery line.
Hudspeth and associates [47] investigated adenosine as an adjunct to a standard hypothermic, hyperkalemic blood cardioplegic solution in hearts with 30 minutes of antecedent normothermic global ischemia. Blood cardioplegia supplemented with 400 µmol/L adenosine (final concentration) reversed the postcardioplegic systolic dysfunction (left ventricular pressure-volume loop analysis) observed with unsupplemented blood cardioplegia. This protection was reversed with the adenosine receptor antagonist 8-SPT, suggesting a receptor-mediated mechanism rather than a purely biochemical mechanism such as increased ATP levels. Interestingly, adenosine did not increase the total volume of blood cardioplegia delivered, probably because the myocardium was maximally dilated by the antecedent ischemia or during the intermittent ischemia between deliveries of cardioplegia. However, the study by Hudspeth and associates [47] did not determine the mechanisms by which adenosine reduced postcardioplegia dysfunction in these injured hearts, a topic which would provide some interesting science. Based on the known mechanisms summarized above it can be speculated that these mechanisms include (1) increasing the tolerance to ischemia between infusions of cardioplegia related to improved glycolysis and phosphorylation potential, KATP channel activation, calcium accumulation, antiadrenergic effect (all possibly A1-receptor–mediated events during ischemia) and (2) attenuating neutrophil events and endothelial injury by direct inhibition of PMNs and endothelium or their interactions (purportedly A2-mediated events occurring during infusion of blood cardioplegia and during reperfusion).
Based on the potent antineutrophil effects of adenosine at reperfusion, Thourani and associates [48] investigated whether use of adenosine in cardioplegia (during cardioplegia ischemia) or administration of adenosine during the period of reperfusion after aortic declamping would provide similar benefits. The model used was 75 minutes of LAD occlusion (off cardiopulmonary bypass) to cause potential myocardial injury, and subsequent surgical reperfusion using hypothermic blood cardioplegia delivered intermittently by antegrade infusion. The LAD ligature was released just before the second infusion of blood cardioplegia, thereby simulating a surgical revascularization. In the groups that received adenosine either as an adjunct to blood cardioplegia (100 µmoles/L) alone or only during reperfusion (140 µg · kg-1 · min-1), infarct size was smaller than in unenhanced blood cardioplegia. However, the infarct size was smallest in the group receiving adenosine only upon reperfusion (Fig 1). In both adenosine groups, postischemic contractile function was improved, myocardial edema was reduced, and neutrophil accumulation in the ischemic-reperfused area was attenuated compared with the unsupplemented blood cardioplegia group. Surprisingly the hearts treated with adenosine only during reperfusion demonstrated improved postischemic coronary artery endothelial function, which was not observed with either unsupplemented blood cardioplegia or adenosine-enhanced blood cardioplegia. This observation is consistent with adenosine’s potent antineutrophil effects.
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In a recently completed clinical trial performed at Emory University/Crawford Long Hospital in Atlanta (the Emory Adenosine in Coronary Artery Revascularization trial), 44 low-risk patients (ejection fraction > 35%) undergoing primary elective coronary artery bypass grafting were randomized to groups receiving unsupplemented blood cardioplegia or adenosine supplemented (100 µmol/L) cardioplegia, followed by 140 µg · kg-1 · min-1 for 15 minutes immediately after cross-clamp removal (unpublished data). There were no major adverse events in the adenosine cardioplegia group. The number of diseased vessels and grafts performed were similar between groups. The major findings in this study were that the time to arrest was lower in the adenosine cardioplegia group (84 ± 20 versus 141 ± 34 seconds, p = 0.17), and plasma levels of IL-6 were significantly (p = 0.04) lower at 24 hours in the adenosine group. In addition, there was a strong tendency (p = 0.09) for less frequent use of cardioversion in the adenosine patients (17.6% versus 41.2% of patients). However, there were no significant differences in plasma IL-8 or TNF levels. There were no untoward hemodynamic effects either during or after delivery of adenosine cardioplegia; there were no differences in postcardioplegia hemodynamics or cardiodynamic measures (peak or end-diastolic left ventricular pressure, heart rate, mean arterial pressure). Future studies should focus on more challenging patients, for example those with ejection fractions less than 35% or those undergoing concomitant valve and coronary artery bypass surgery.
Adenosine in off-pump coronary artery revascularization: adenosine as an adjunct to perfusion-assisted strategies
Off-pump coronary artery bypass (OPCAB) graft surgery has been shown to be feasible and effective with nearly comparable postoperative morbidity and mortality rates compared with on-pump cardiac surgery. One potential source of iatrogenic injury to myocardium in off-pump surgery is the ligation of the target vessel for 10 to 12 minutes. In normal myocardium this brief period of ischemia causes only reversible injury and modest contractile dysfunction. In myocardium with preexisting ischemia, however, this period of ligation may cause acutely irreversible changes (Vinten-Johansen, unpublished data). In this case, damage may occur during the ligation period or during the postligation period when blood flow through the lesion (ie, stenosis) is restored. Perfusion of the target vessel immediately after construction of the distal anastomosis would avoid this period of ischemia when blood flow is otherwise insufficient through the native vessel before the proximal anastomoses is completed. In addition, exogenous perfusion of the target vessel through the distal graft would allow the selective delivery of drugs designed to avoid reperfusion injury. Recently, Guyton and associates [53] described a method for perfusing the target vessel after the distal anastomosis was complete but before the proximal anastomosis was constructed (ie, a "distals first" approach) during OPCAB surgery. After completion of the distal anastomosis, the vascular graft was connected to a microprocessor-controlled, servo-regulated, constant flow pump system (Myocardial Protection System; Quest Medical, Inc, Allen, TX) that allowed control of blood flow rate and graft perfusion pressure. With this technique, coined perfusion-assisted direct coronary artery bypass (PADCAB), ischemia could be avoided, blood flow could be controlled independent of systemic perfusion pressure, and drugs could be added to the blood perfusate for a specific purpose. These drugs would include vasodilators to increase collateral blood flow to collateral-dependent areas adjacent to the target myocardium, adenosine, positive inotropic agents, or antiarrhythmic agents. In the study by Guyton and associates [53], electrocardiographic evidence of ischemia was reversed and hemodynamic stability was improved by avoiding ischemia-related dysfunction during the period of perfusion, especially when hypotension caused by positional manipulation of the heart reduced perfusion pressure to the target vessel.
In a laboratory study by Muraki and associates [54] the PADCAB technique was used to introduce intracoronary (LAD) adenosine to the revascularized segment ostensibly to avoid reperfusion injury after severe regional ischemia. Using a model of 75 minutes of severe coronary occlusion that causes contractile dysfunction, infarction, and edema in the area at risk and severe LAD endothelial dysfunction, adenosine (10 µmol/L/L) was added to the blood perfusing the LAD for the initial 30 minutes of reperfusion, after which the adenosine was discontinued and the segment was perfused with normal blood at systemic pressures. After 2 hours of reperfusion, this very brief treatment with intracoronary adenosine reduced infarct size (Fig 2), attenuated neutrophil accumulation and edema in the area at risk, and avoided endothelial dysfunction in the ischemic-reperfused LAD compared with a group reperfused in similar manner but without adjunctive adenosine. Because of the selective nature of delivery of this otherwise potent vasodilator there was no hypotension associated with intracoronary delivery of adenosine. Further studies need to be performed with this PADCAB technique to determine whether adjunct adenosine delivery can overcome regional dysfunction in other forms of coronary artery disease such as severe stenosis.
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Adenosine is a purine nucleoside that has a broad spectrum of physiologic effects, which makes it suitable as a cardioprotective agent with effectiveness in all three windows of opportunity (pretreatment, ischemia, and reperfusion). Adenosine has the potential to reduce ischemic injury with pretreatment administration largely by A1-receptor–mediated mechanisms involving effectors or targets in the myocyte or interstitial compartment, including KATP channel activation, improved anaerobic metabolism, improved energy status and attenuated PMN-myocyte interactions. The duration of the physiologic actions of adenosine seem to extend well beyond its plasma half-life and therefore adenosine may act as a trigger of effects that are then perpetuated. In addition to pretreatment applications, adenosine reduces reperfusion injury by inhibiting neutrophil-endothelial cell interactions directly, largely by A2-receptor mechanisms. The adenosine used as an adjunct to cardioplegia may have significant effects in attenuating reperfusion injury. Adenosine administered just before removal of the aortic cross-clamp (ie, reperfusion) has benefit beyond that exerted as an adjunct to cardioplegia, including protecting the coronary vascular endothelium. Clinical studies in which adenosine is incorporated as an adjunct to cardioplegia are encouraging, but suffer the limitations of many such clinical studies in that the data are "soft" and do not necessarily reflect the outcomes and mechanisms demonstrated in laboratory studies. Because adenosine’s cardioprotection is dose dependent, the optimal dose still needs to be identified, taking full advantage of the beneficial effects while avoiding unwanted side effects such as hypotension and bradycardia. In this regard the localized infusion of adenosine to the target vessel during off-pump cardiac surgery using PADCAB technology may achieve sufficiently high concentrations that optimally inhibit neutrophils, endothelium and other mechanisms of ischemia-reperfusion injury while having little systemic effects by virtue of dilution when washed into the systemic circulation [54]. Further research is required to elucidate the role of adenosine in potentially modulating "late" reperfusion injury, and its role in modulating signals involved in the neutrophil-mediated response to ischemia-reperfusion, and its potential role in modulating the apoptotic component of postischemic cell death. Other effects of adenosine, which may attract the surgeon’s interest, are termination of supraventricular tachyarrhythmias, and negative chronotropy and inotropy, both of which may also reduce myocardial oxygen demands during the critical immediate postoperative period. The latter is effective only against adrenergically augmented inotropic state and may have mixed blessings in the postbypass patient.
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