Ischemic preconditioning refers to the ability of short periods of ischemia to make the myocardium more resistant to a subsequent ischemic insult. This term was introduced for the first time by Murry and coworkers, who found in a canine model that four consecutive periods of coronary occlusion of 5 minutes were able to reduce the infarct size caused by a subsequent period of occlusion of 40 minutes by as much as 75%. This classic form of ischemic preconditioning has now been observed in several animal species.
Although ischemic preconditioning initially referred to the ability of short periods of ischemia to limit infarct size, some investigators extended this definition to include a beneficial effect on ischemia- and reperfusion-induced arrhythmias and on myocardial stunning. It is controversial, however, whether the reduction in the incidence of arrhythmias by ischemic preconditioning is due to a direct antiarrhythmic effect or whether it is a mere consequence of the delay of ischemic cell death. , Regarding the beneficial effects of ischemic preconditioning on postischemic contractile dysfunction, Cohen and colleagues showed that in rabbits preconditioning can lead to enhanced recovery of contractile function of the myocardial region at risk. In this case also, the beneficial effects of preconditioning on acute recovery of contractile function might be a consequence of the delay of ischemic cell death; indeed, parameters of necrosis extent, i.e., infarct size and enzyme leakage, correlate with the enhancement of functional recovery.
The chain of events that confers resistance to ischemia is only partially understood. Downey and coworkers have developed the hypothesis that binding of surface receptors by agonists (including adenosine, bradykinin, opioids, acetylcholine, catecholamines, and oxygen radicals) results in the activation of protein kinase C (PKC). This appears to be the first element of a complex kinase cascade that ultimately causes opening of mitochondrial adenosine triphosphate (ATP)-sensitive potassium (K ATP ) channel, which may be a trigger and mediator, end-effector, or both, for ischemic preconditioning. , How the opening of mitochondrial K ATP channel may be protective, however, is still uncertain. The following three hypotheses have been proposed: (1) mitochondrial swelling and optimization of respiration; (2) a decrease in the extent of mitochondrial calcium overload; and (3) stimulation of mitochondrial reactive oxygen species production. Figure 24-1 is a diagram showing the proposed mechanism of preconditioning at the cellular level.
It is now well established that the protective effects of preconditioning are transient and last for less than 2 hours. , However, a so-called second window of protection or delayed ischemic preconditioning has been shown in different species, occurring 24 hours after the preconditioning stimulus and lasting for about 48 hours. , This time course is consistent with the concept that the second window of protection is mediated by the activation of genes encoding for cytoprotective proteins. , Similarly to the early phase of preconditioning, aside from a delayed anti-infarct effect, a delayed anti-arrhythmic effect following preconditioning has been reported. Furthermore, Bolli’s group has described a delayed preconditioning against myocardial stunning, independent of ischemic necrosis since the ischemic challenge utilized was insufficient to induce infarction.
Evidence for Preconditioning in Human Myocardium
Ischemic preconditioning represents the most powerful form of protection against experimental myocardial infarction (MI) described to date. , Indeed, this endogenous form of myocardial protection has been shown in all animal species investigated. , It seems, therefore, reasonable to assume that such a form of endogenous cardioprotection might also occur in the clinical setting. If this were the case, the possibility of exploiting this endogenous form of protection by pharmacologic means would be of great importance in the attempt to reduce myocardial infarct size. However, experimental findings on ischemic preconditioning cannot be directly extrapolated to humans. In fact, for both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning in which infarct size is the end point. Thus, surrogate end points have been used, including contractile function, electrocardiographic ischemic changes, or biochemical evidence of cell damage. This has to be taken into account in the evaluation of clinical studies on preconditioning, as the mechanisms of such nonclassic forms of ischemic preconditioning may differ from those involved in the reduction of infarct size in the experimental models. Another important limitation of several published clinical studies is represented by the extent of coronary collateral flow, which, in humans, is a major determinant of the severity of myocardial ischemia during coronary occlusion; it cannot always be accurately quantified. However, in vitro human studies, in which confounding effects due to coronary collateral flow can be overcome, have shown that human cardiomyocytes can be preconditioned. Carr and his co-workers showed that isolated superfused isometrically contracting human atrial trabeculae can be preconditioned against a combined hypoxic and substrate depletion challenge by simulated ischemia and by A 1 and A 3 adenosine receptor activation. The same group has also demonstrated that protection against contractile dysfunction caused by a combined hypoxic and substrate depletion challenge can be induced by activation of PKC and by the opening of K ATP channels and that the protection induced by PKC activation and preconditioning can be blocked by blockade of K ATP channels. Indeed, Cleveland and coworkers have shown that in this model there is not evidence of any protection when the myocardium is obtained from diabetic patients exposed to long-term oral hypoglycemic agents, thus suggesting important clinical implications. Finally, Morris and Yellon have shown in human atrial trabeculae that angiotensin-converting enzyme inhibitors can potentiate the protective effects of a subthreshold preconditioning stimulus, possibly due to bradykinin degradation inhibition resulting in enhanced B 2 bradykinin receptor activation. Such a demonstration may help to explain the mechanisms involved in the reduction of fatal ischemic events in patients treated with angiotensin-converting enzyme inhibitors.
The limitations of the model of isolated superfused isometrically contracting human atrial trabeculae are the use of hypoxia rather than ischemia to initiate protection, of recovery of contractile function as surrogate end point, and of atrial rather than ventricular tissue. Finally, in vitro human studies do not provide answers about the clinical situations in which preconditioning does indeed occur nor clarify which mechanisms are involved in mediating ischemic preconditioning in different clinical settings. Thus, ischemic preconditioning in humans has been studied in the following clinical settings: (1) preinfarction angina; (2) exercise-induced ischemia (warm-up phenomenon); (3) coronary angioplasty; and (4) cardiac surgery.
Preinfarction Angina
Some studies have shown that patients with MI preceded by angina have smaller infarcts and a better in-hospital outcome after thrombolytic therapy than patients without preinfarction angina. At least three of the following mechanisms may explain this difference between infarctions that are preceded by angina and those that are not: (1) coronary collaterals; (2) reperfusion rate; and (3) ischemic preconditioning. Kloner and associates found that patients with angina within 48 hours of MI had a lower in-hospital death rate and a smaller infarct size than patients without angina, despite a similar development of coronary collateral vessels assessed at angiography 90 minutes after MI, suggesting that preconditioning by pre-infarction angina might render the myocardium more resistant to infarction from the subsequent prolonged ischemic episode. Another attractive hypothesis about the protective role of preinfarction angina has been suggested by Andreotti and colleagues. They compared the infarct size of patients with or without unstable angina during the week before MI, taking into account also the speed of recanalization. Interestingly, in patients with preinfarction angina, as compared with those without, thrombolytic therapy resulted in more rapid reperfusion and smaller infarcts, suggesting that the benefit of preinfarction angina on infarct size might depend on a speedier coronary thrombolysis in addition to, or perhaps, instead of preconditioning. Also in this study there was no significant difference in collateral development between patients with and without preinfarction angina, implying that it is unlikely collaterals play a major role in explaining the beneficial effects of preinfarction angina. Ishihara and coworkersl confirmed that reperfusion was more frequently achieved in patients with prodromal angina in the 24 hours before infarction, rather than in those without, suggesting a more efficient response of the infarct-related artery to thrombolytic therapy in the former. However, they also demonstrated that prodromal angina in the 24 hours before infarction, but not angina occurring at an earlier time, was independently associated to a better 5-year outcome, suggesting a role for ischemic preconditioning.
The Warm-up Phenomenon
The warm-up phenomenon, that is, the improved performance exhibited by more than half of patients with coronary artery disease following a first exercise test, , may be another clinical correlate of ischemic preconditioning. Okazaki and colleagues demonstrated that in patients with a single lesion of the left anterior descending coronary artery, great cardiac vein flow is similar during the first and second exercise stress test, thus suggesting that the warm-up phenomenon is not accompanied by an increase in total myocardial blood flow. Interestingly, myocardial oxygen consumption was reduced during the second test, suggesting increased metabolic efficiency, a feature of preconditioning. A role for preconditioning is also supported by the demonstration that the time course of the warm-up phenomenon is consistent with that of classic ischemic preconditioning (lasting no longer than 60 and 90 minutes). Indeed, we found that in patients with stable angina undergoing three consecutive exercise tests, the warm-up phenomenon observed within minutes of a first exercise test is a result of adaptation to ischemia, whereas warm-up phenomenon observed 2 hours after the second exercise test is a result of a training effect caused by peripheral mechanisms. However, studies that have examined the cellular mechanisms of the warm-up phenomenon do not fully support this hypothesis. For example, the involvement of K ATP channels in the warm-up phenomenon is uncertain. In fact, K ATP channel blockade by glibenclamide, given in the attempt to prevent the warm-up phenomenon at a dose previously shown to block adaptation to ischemia during coronary angioplasty, have yielded conflicting results. Furthermore, adenosine receptors, which have been identified as key mediators in experimental ischemic preconditioning, do not seem to play a major role in the setting of the warm-up phenomenon. Indeed, both aminophylline, a nonselective antagonist of adenosine receptors, and bamiphylline, a selective antagonist of A 1 adenosine receptors, fail to prevent the warm-up phenomenon. , Thus, future work is necessary in order to better understand the mechanisms of the warm-up phenomenon, including studies on transmural distribution of myocardial perfusion and on triggers of ischemic preconditioning different from adenosine.
Coronary Angioplasty
Since its introduction in 1976, coronary angioplasty has provided a useful model for studying the effects of transmural myocardial ischemia due to controlled coronary occlusions in patients with coronary artery disease. Studies during coronary angioplasty have greatly contributed to the understanding of several pathophysiologic aspects of myocardial ischemia in humans, including the role of collateral circulation, stenosis severity, and small vessel function. More recently, the experimental demonstration of preconditioning, together with the common clinical observation of fewer electrocardiographic ischemic changes and less anginal pain during sequential coronary balloon occlusion, led to the utilization of coronary angioplasty as a model for the study of ischemic preconditioning in humans. The procedure usually involves repeated intracoronary balloon inflations with intervening periods of reperfusion; the first period of ischemia may enhance the myocardial tolerance to subsequent balloon inflations via classic ischemic preconditioning. The first formal study aimed at assessing adaptation to ischemia during coronary angioplasty was published by Deutsch and coworkers and involved 12 patients with an isolated obstructive stenosis in the left anterior descending coronary artery undergoing two sequential 90-second balloon inflations. In comparison with the initial balloon occlusion, the second occlusion was characterized by less subjective anginal pain, less ST-segment shift and lower mean pulmonary artery pressure, despite a reduction in cardiac vein flow and unchanged coronary wedge pressure. These findings have been observed in several other angioplasty studies, confirming an adaptive response of the myocardium to repeated ischemic episodes, akin to ischemic preconditioning. Of note, some angioplasty studies failed to show adaptation to ischemia during repeated coronary occlusions, probably because they neglected some crucial methodologic aspects, such as short balloon inflations of less than 90 seconds, preinflation ischemia, or inadequate end points. ,
A limitation of the angioplasty model of ischemic preconditioning is that the myocardial adaptation to ischemia observed following repeated coronary balloon occlusions is at least partially related to collateral recruitment. However, although collateral recruitment during a first coronary balloon inflation does occur, further recruitment during following inflations is infrequent (in about 30% of the patients) and occurs only after multiple inflations. , Furthermore, it is still controversial whether ST-segment changes are a reliable indicator of a protected state ; yet, several studies in patients undergoing coronary angioplasty have shown that the ST-segment shift correlates with metabolic (i.e., lactate production), mechanical (i.e., regional wall motion abnormalities), and clinical (i.e., anginal pain) parameters of myocardial ischemia. ,
The most convincing evidence that the adaptation to ischemia during repeated balloon inflations is mediated by ischemic preconditioning, however, comes from the observation that in this setting the adaptation to ischemia can be prevented or mimicked by agents that specifically prevent or mimic preconditioning in experimental models. Indeed, adaptation to ischemia during repeated coronary occlusions is prevented by glibenclamide, adenosine antagonists, , phentolamine, naloxone, and caffeine, whereas it is mimicked by adenosine, enalaprilat, morphine sulfate bradykinin, and nitroglycerin. ,
Cardiac Surgery
Intermittent ischemia achieved by aortic cross-clamping in a fibrillating heart during coronary artery bypass grafting has been utilized as a clinical model of ischemic preconditioning. In this model the confounding effects due to collateral flow are overcome by utilizing global rather than regional ischemia. Yellon and coworkers examined the effect of two ischemic episodes of 3 minutes, each followed by 2-minute reperfusion, on high energy phosphate metabolism during 10-minute cross-clamping, while the first distal coronary anastomosis was performed. Myocardial biopsies taken after the 10-minute ischemic insult exhibited a significantly higher ATP content than that found in controls not previously exposed to brief ischemic episodes, thus proving that the human myocardium shows the typical biochemical features of preconditioning observed by Murry and colleagues in their classic canine model of ischemic preconditioning. Yet, Perrault and colleagues have also reported that 3-minute aortic cross-clamping followed by 2-minute reperfusion before warm-blood cardioplegic arrest during coronary artery bypass surgery fails to provide any beneficial effect. Nevertheless, evidence that preconditioning may offer patients protection against irreversible myocyte injury comes from another study by Yellon and coworkers, who showed a reduction of troponin T release in patients exposed to two periods of myocardial ischemia of 3 minutes each at the beginning of the revascularization operation. Furthermore, it has been shown that, in the setting of coronary artery bypass surgery, adenosine, acadesine, and bradykinin are effective in improving postoperative left ventricular function. Finally, other studies have shown that volatile anesthetics, including enflurane and isoflurane, are able to optimize myocardial protection during cardiac surgery, probably through activation of K ATP channels.
Adenosine Triphosphate–Sensitive Potassium Channel Openers and Adenosine in Acute Coronary Syndromes
A tantalizing clinical application of pharmacologic preconditioning is in patients with acute coronary syndromes, in the attempt to slow down the progression of myocardial necrosis, thus increasing the time available for effective reperfusion. The exploitation of preconditioning, however, depends on the possibility of administering preconditioning drugs before ischemia, making this approach difficult in patients at low risk of MI, such as those with chronic stable angina. Conversely, it is well known that patients with unstable angina or with a recent MI have a higher risk of MI in the few months following the initial ischemic episode. In this group of patients, the administration of drugs mimicking ischemic preconditioning in the time period at increased risk might slow necrosis rate in those patients who would eventually develop an acute myocardial infarction (AMI), thus increasing the time available for reperfusion therapy. The myocardium of patients with unstable angina, however, might already be preconditioned by prior ischemic episodes, limiting the potential advantages of preconditioning drugs. Another theoretical problem may be the development of tachyphylaxis to preconditioning agents. Indeed, Tsuchida and coworkers have shown in a rabbit model that continuous infusion of a selective A 1 adenosine receptor agonist led to downregulation of the signaling mechanism and loss of protection. However, more encouraging data have been obtained recently using a different dosing schedule, in which the same drug was administered to rabbits by intermittent dosing over a 10-day period with persistence of myocardial protection assessed 48 hours after the last dose.
Very few studies have evaluated the protective role of pharmacologic preconditioning strategies in patients with acute coronary syndromes ( Tables 24-1 and 24-2 ). In particular, the preconditioning-mimetic drugs investigated so far are adenosine, acadesine (an adenosine-regulatory agent), and the only clinically available K ATP channel opener licensed for cardiovascular use, nicorandil. Of note, adenosine was the first endogenous ligand to be identified as a trigger of the cardioprotective action of experimental ischemic preconditioning and the mitochondrial K ATP channel is thought to be the distal target or effector of protection.
| Clinical Setting | Reperfusion Treatment | Agent | Potential Mechanism | Results | Reference |
|---|---|---|---|---|---|
| Unstable angina | — | IV Nicorandil | Preconditioning | ↓ Ischemic episodes and arrhythmias | Patel et al. |
| Unstable angina | PTCA | IV Nicorandil | Preconditioning | ↓ Levels of cardiac troponin T and I | Kim et al. |
| AMI | Thrombolysis or PTCA | IC Nicorandil | ↓ Reperfusion injury | ↑ LV function | Sakata et al. |
| AMI | Thrombolysis | Oral Nicorandil | ↓ Reperfusion injury | ↓ Arrhythmias | Sen et al. |
| AMI | PTCA | IV Nicorandil | ↓ Reperfusion injury | ↑ LV function and in-hospital outcome | Ito et al. |
| AMI | PTCA | IV Nicorandil | ↓ Reperfusion injury | ↓ Incidence of cardiovascular death or re-H for CHF | Ishii et al. |
| AMI | PTCA | IV Nicorandil | ↓ Reperfusion injury | No difference in LV size and LV ejection fraction compared to placebo | Kitakaze et al. |
| Clinical Setting | Reperfusion Treatment | Agent | Potential Mechanism | Results | Reference |
|---|---|---|---|---|---|
| AMI | PTCA | IV Adenosine | ↓ Reperfusion injury | ↓ Infarct size | Garratt et al. |
| AMI | Thrombolysis | IV Adenosine | ↓ Reperfusion injury | ↓ Infarct size (anterior infarction) | Mahaffey et al. |
| AMI | PTCA | IC Adenosine | ↓ Reperfusion injury | ↑ LV function and in-hospital outcome | Marzilli et al. |
| AMI | Thrombolysis or PTCA | IV Adenosine | ↓ Reperfusion injury | No difference compared with placebo in the primary endpoint (new HF, re-H for HF, or death) | Ross et al. |
| AMI | PTCA | AMP579 | ↓ Reperfusion injury | ↓ Infarct size (anterior infarction) | Kopecky et al. |
Nicorandil
The first clinical trial aimed at assessing the cardioprotective role of nicorandil in patients with unstable angina was published by Patel and coworkers (CESAR 2 investigation). This study suggests that opening of K ATP channel with nicorandil, in addition to standard maximal anti-anginal therapy, results in a significant reduction in the incidence of myocardial ischemic episodes and tachyarrhythmias. Of note, because the majority of patients were already on treatment with either oral or intravenous nitrates, it is unlikely that the beneficial effects of oral nicorandil were due to its vasodilatory properties. It is therefore possible that the protection observed in the nicorandil group was due to pharmacologic preconditioning resulting in a significant reduction in the number of ischemic events. Recently, Kim and colleagues randomized 200 patients with unstable angina to intravenous isosorbide dinitrate or intravenous nicorandil. A coronary angioplasty was performed 12 to 48 hours after infusion of each agent in 96 patients. Nicorandil was associated with a significant decrease in levels of cardiac troponin T and I at 6, 12, and 24 hours after angioplasty compared with isosorbide dinitrate.
Further large scale randomized trials are warranted to assess the effects of nicorandil on prognosis and adverse outcome in this setting.
As pointed out earlier, the exploitation of ischemic preconditioning depends on the possibility of administering preconditioning drugs before the prolonged, potentially lethal ischemic insult (e.g., patients with unstable angina). However, some authors have proposed that the cardioprotective effects of preconditioning might also be operative during the reperfusion phase of ischemia-reperfusion injury resulting in a reduction in cytosolic calcium oscillations and free radical formation. These observations prompted investigation into the potential cardioprotective properties of nicorandil following AMI. Sakata and coworkers investigated the effects of an intracoronary bolus of nicorandil following successful coronary thrombolysis or primary angioplasty. They found that, compared with controls, nicorandil-treated patients exhibited improved restoration of myocardial blood flow to the infarcted myocardium as assessed by contrast echocardiography and improved regional wall motion at 1 month. Similar findings have been obtained by Sen and coworkers, who evaluated the safety and efficacy of oral nicorandil as an adjunct to routine therapeutic management in patients with AMI. They showed that nicorandil was safe and well tolerated in the setting of AMI with no increase in adverse events compared with controls. They also showed a trend toward a reduction in development of Q-waves in patients presenting with subendocardial infarction and a reduced incidence of arrhythmias in the nicorandil-treated group. Ito and colleagues investigated the effects of intravenous infusion of nicorandil in patients with AMI undergoing primary coronary angioplasty. They found that intravenous nicorandil in conjunction with coronary angioplasty is associated with better functional and in-hospital clinical outcomes compared with angioplasty alone. It is worth noting, however, that in the setting of AMI, the cardioprotective effects of nicorandil are probably related to an improvement in microvascular perfusion rather than to myocardial preconditioning, as suggested by the lesser frequency of no-reflow phenomenon in nicorandil-treated patients than in controls. ,
Recently, Ishii and colleagues demonstrated that nicorandil before coronary angioplasty exerts pharmacologic cardioprotective effects similar to ischemic preconditioning seen in patients with prodromal angina pectoris. The authors compared cardioprotective effects of intravenous nicorandil with preconditioning effects by prodromal angina in patients with AMI. In total, 368 patients with first AMI who underwent coronary angioplasty were randomly assigned to receive nicorandil 12 mg or a placebo intravenously just before coronary angioplasty. Subjects were assigned to 1 of 4 groups: 52 patients with prodromal angina were given placebo, 129 patients without prodromal angina were given nicorandil, 56 patients with prodromal angina were given nicorandil, and 131 patients without prodromal angina were given placebo. Coronary microvascular impairment after coronary angioplasty was prevented at similar frequencies in groups with prodromal angina and groups on nicorandil. Five-year rates for freedom from major cardiac events were significantly lower in the group without prodromal angina given placebo compared with the other three groups. At 5 years, the addition of intravenous nicorandil to primary coronary angioplasty led to less incidence of cardiovascular death or rehospitalization for congestive heart failure, as well as various aspects of epicardial flow and microvascular function compared with placebo.
The recently published single-blind, prospective, J-WIND trial randomized 276 AMI patients to receive intravenous nicorandil (0.067 mg/kg as a bolus, followed by 1.67 µg/kg per min as a 24-hour continuous infusion), and 269 the same dose of placebo. At a median follow-up of 2.7 years, intravenous nicorandil did not affect the size of the left ventricular ejection fraction, although oral administration of nicorandil during follow-up increased the left ventricular ejection fraction between the chronic and acute phases.
Thus, all these studies provide evidence for safety and tolerability of nicorandil in the setting of AMI; furthermore, they suggest that either intravenous or oral administration of this drug as an adjunct to standard reperfusion strategies improves microvascular perfusion of the ischemic myocardium and, therefore, possibly improves left ventricular function.
Adenosine
Adenosine or acadesine, an adenosine-regulating agent, have been shown to confer cardioprotection in the settings of coronary angioplasty and cardiac surgery, but no clinical trial in patients with unstable angina has yet been reported. Thus, a potential therapeutic exploitation of preconditioning with adenosine or its analogues in the setting of unstable angina remains to be investigated.
Of note, adenosine, in addition to its role in myocardial ischemic preconditioning, has been shown to attenuate ischemia-reperfusion injury in animals, through inhibition of neutrophil activation, inhibition of oxygen free radical formation, and improvement of microvascular function, resulting in a reduction of infarct size and an improvement of left ventricular function and coronary blood flow. This has prompted investigation into the potential cardioprotective properties of adenosine in patients with AMI. Garratt and coworkers investigated the effects of intravenous adenosine and lidocaine in patients with AMI undergoing primary angioplasty. They found that moderate doses of adenosine may be given intravenously in this setting without unacceptable risk of complication and that, compared with historical controls, adenosine-treated patients had smaller infarcts at 6-week follow-up. These findings have been confirmed by a relatively larger multicenter, randomized trial (AMISTAD) designed to test the hypothesis that intravenous adenosine as an adjunct to thrombolysis would reduce myocardial infarct size. Patients with anterior AMI assigned to adenosine had a 67% relative reduction in final infarct size as assessed by single photon emission computed tomography (SPECT) imaging 6 days after the infarct; however, there was no reduction in the final infarct size observed in patients with non-anterior infarction, nor evidence of morbidity/mortality in-hospital benefit. Experimental studies, however, have shown that the beneficial effect of adenosine on infarct size is remarkable and consistent when this agent is given before coronary occlusion, and that it is still present, but weaker, when adenosine is given before reperfusion, and negligible and inconsistent when adenosine is given during reperfusion. , Thus, the lack of an obvious beneficial impact of adenosine on clinical outcome observed in the AMISTAD trial may be at least partially due to delayed adenosine administration (after thrombolytic administration) in about 50% of the patients. This drawback has been overcome in a recent small randomized trial in patients with AMI undergoing primary angioplasty, in which intracoronary adenosine was given right before balloon dilation. In this study, in fact, intracoronary adenosine administration prevented the no-reflow phenomenon, improved ventricular function, and was associated with a more favorable clinical course.
The AMISTAD-II trial evaluated the effect of 3-hour intravenous infusion of either adenosine 50 or 70 µg/kg/minute or placebo on clinical outcomes in 2118 patients with evolving anterior AMI receiving thrombolysis or primary angioplasty. The primary end point was new congestive heart failure beginning more than 24 hours after randomization, or the first re-hospitalization for heart failure, or death from any cause within 6 months. Infarct size was measured in a subset of 243 patients by technetium-99m sestamibi tomography. There was no difference in the primary end point between placebo and either the pooled adenosine dose groups or, separately, the 50-µg/kg/min and 70-µg/kg/min dose groups. Notably, the pooled adenosine group trended toward a smaller median infarct size compared with the placebo group. A dose-response relationship with final median infarct size was seen: 11% at the high dose and 23% at the low dose, a finding that correlated with fewer adverse clinical events. Notably, in a post hoc analysis, adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 hours onset of evolving anterior AMI enhanced early and late survival, and reduced the composite clinical end point of death or heart failure at 6 months. Since the major limitation of this study was that the sample size was too small to confirm that the observed adenosine-related reduction in the combined clinical end point was statistically significant, a more robustly powered investigation of this relatively safe and inexpensive drug as adjunctive therapy to reperfusion is warranted to demonstrate whether the reduced infarct size achieved with the higher infusion dose translates into enhanced event-free survival.
In the randomized, placebo-controlled ADMIRE trial, the administration of an adenosine agonist with high affinity for A 1 and A 2 receptors, that is, AMP579, given intravenously before primary angioplasty was associated with a trend toward smaller infarct size and greater myocardial salvage in patients with anterior MI.
Recently, data from the Multicenter Study of Perioperative Ischemia (McSPI) Research Group from the IREF trial have been reported. This study randomized 2698 patients undergoing coronary artery bypass grafting (CABG) surgery to receive placebo or acadesine by intravenous infusion (0.1 mg/kg/min; 7 hours) and in cardioplegia solution (placebo or acadesine; 5 µg/mL) in order to assess the safety and efficacy of acadesine for reducing long-term mortality among patients with postreperfusion MI. Acadesine treatment reduced mortality by 4.3-fold, from 27.8% to 6.5% ( P = .006), with the principal benefit occurring over the first 30 days after MI. The acadesine benefit was similar among diverse subsets, and multivariable analysis confirmed these findings. This study successfully moves forward the concept of preconditioning as a therapy from bench to bedside. Nevertheless, large clinical trials are needed to confirm the cardioprotective effects of adenosine (or its agonists) in the setting of acute coronary syndromes.
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