Review |
From The Hatter Institute, Department of Academic and Clinical Cardiology, University College London Hospitals and Medical School, London, UK.
Correspondence to D.M. Yellon, The Hatter Institute, Department of Academic and Clinical Cardiology, University College Hospital, Grafton Way, London WC1E 6DB, UK. E-mail s.bush-cavell{at}ucl.ac.uk
| Abstract |
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Key Words: preconditioning unstable angina myocardial infarction coronary angioplasty coronary bypass surgery
| Introduction |
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30 to 90 minutes, but is ineffective when
this period is extended to 3 hours.3 This temporal
limitation of ischemic preconditioning implies that the
protection is only observed when prolonged ischemia is followed
by timely reperfusion. The potential for clinical application of such a powerful protective phenomenon has generated enormous interest in identification of the underlying intracellular signaling pathways, with the ultimate aim of pharmacologically exploiting these mechanisms to develop therapeutic strategies that can enhance myocardial tolerance to ischemia-reperfusion injury in patients with coronary artery disease. Extensive research over the past 15 years has gone a long way in elucidating a number of membrane receptorlinked cellular triggers, intracellular signaling cascades, and potential cytoprotective end-effector proteins that may be involved in mediating the protective effects of ischemic preconditioning.3 However, the application of these findings to the clinical setting depends primarily on proof of safety and efficacy when compared with other strategies of myocardial protection and secondarily on identification of well-defined cohorts of patients who stand to benefit from pretreatment with such cardioprotective agents. Several important issues need to be addressed and are discussed below.
| Does Preconditioning Occur in the Human Heart? |
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In the clinical setting, there is some evidence to suggest that preconditioning may occur naturally in patients with coronary artery disease. Patients suffering angina before a myocardial infarction (MI) have a better in-hospital prognosis; a reduced incidence of cardiogenic shock, congestive cardiac failure, and life-threatening ventricular arrhythmias associated with reperfusion; and smaller infarcts as assessed by release of cardiac enzymes.16 17 18 19 Follow-up studies have suggested that in patients with preinfarction angina, long-term survival is also improved as compared with patients who are asymptomatic before infarction.20 21 Whether the protection conferred to these patients as a result of their preceding ischemic symptoms represents a form of myocardial adaptation similar to ischemic preconditioning remains a subject of debate.22 On the one hand, the issue of enhanced collateral development in patients with preceding anginal symptoms remains unresolved. Another equally attractive hypothesis, although not mutually exclusive from the mechanisms underlying ischemic preconditioning, is facilitation of more rapid reperfusion of the infarct-related artery after thrombolysis in patients with preinfarction angina.20 23 This hypothesis is based on the known inhibitory effects of adenosine, released during the brief periods of preinfarction ischemia, on platelet aggregation after activation of A2 receptors on platelet membranes, which has been suggested to modify thrombus formation and thereby promote earlier reperfusion after thrombolysis.24 Indeed, in anesthetized open-chest dogs, brief periods of ischemia before a long ischemic insult attenuates platelet-mediated thrombosis and improves vessel patency, and this effect is abolished by inhibition of adenosine receptors.25
The phenomenon of "warm-up angina," in which patients complain that their anginal symptoms are worse in the morning but improve during the course of the day, has been the subject of research over the past few years.26 27 This work has provided evidence for increased efficiency of myocardial metabolism, in terms of reduced oxygen consumption at a given workload and a reduction in anginal symptoms and ST-segment changes, during a second period of either exercise or angina resulting from pacing-induced tachycardia. These favorable changes were not accompanied by recruitment of collateral vessels, as evidenced by similar coronary and great cardiac vein blood flow measurements. Similarly, a reduction in electrocardiographic evidence of silent ischemia during successive periods of exercise has been demonstrated.28 A recent study suggests that the degree of myocardial stunning after exercise-induced myocardial ischemia may also be attenuated if the patient had performed a preceding period of exercise 30 minutes earlier.29 Studies investigating the temporal profile of warm-up angina have demonstrated that the duration of this phenomenon is 1 to 2 hours after the first period of exercise, a time course that closely parallels that of classic ischemic preconditioning.30 31 Moreover, we have recently shown that in addition to immediate protection, patients with stable angina have improved exercise tolerance 24 hours after a period of exercise-induced myocardial ischemia, a finding that may represent delayed preconditioning.32 However, a recent study using a similar study protocol failed to show enhanced exercise tolerance 24 hours after a period of exercise, thereby arguing against delayed protection in this model.33 The reasons for the differences between these studies is not immediately obvious and requires further investigation.
These findings suggest that the warm-up phenomenon is at least partly due to metabolic adaptation of myocardium, which induces tolerance to subsequent ischemia, a process that closely resembles ischemic preconditioning. However, studies that have examined the cellular mechanisms mediating warm-up angina do not fully support this hypothesis. For instance, inhibition of adenosine receptors before exercise fails to abolish the warm-up phenomenon.34 35 Furthermore, investigation into the role of KATP channels in mediating this form of myocardial adaptation has provided conflicting results.36 37 It is therefore not clear at this point whether the adaptation observed during repeated exercise is a representation of the preconditioning phenomenon or whether other mechanisms are involved. Furthermore, despite attempts by some investigators, a major role for recruitment of collateral vessels contributing to this phenomenon has not been ruled out.
Myocardial Adaptation During Revascularization Procedures
Percutaneous transluminal coronary
angioplasty (PTCA) provides a unique opportunity to study the response
of the human myocardium to brief periods of controlled
ischemia and reperfusion. The procedure usually involves
repeated intracoronary balloon inflations with intervening
periods of perfusion, and in theory the first period of
ischemia may enhance the myocardial tolerance to subsequent
balloon inflations via classic ischemic preconditioning.
Several recent studies have addressed this issue using various indices
of myocardial ischemia including clinical,
electrocardiographic, metabolic, and
hemodynamic measurements. Most of these studies have
shown that if the duration of the first balloon inflation is longer
than a "threshold" of
60 to 90 seconds, all indicators of
myocardial ischemia, including chest pain severity,
abnormalities of left ventricular regional wall motion,
ST-segment elevation, QT dispersion, ventricular ectopic
activity, lactate production, and release of myocardial markers
such as CKMB, are attenuated during subsequent balloon
inflations, which provides evidence for myocardial adaptation induced
by the first period of ischemia.38 39 40 41 42 43 As with
many studies of ischemic preconditioning in humans, a major
confounding factor during successive balloon inflations in PTCA studies
is the acute recruitment of collateral vessels. However, studies that
have controlled for this effect by angiographic grading of the
collateral vessels39 ; measurement of cardiac vein
flow38 ; changes in blood flow velocity in the
contralateral coronary artery44 ; and, more
accurately, by assessment of intracoronary pressure-derived
collateral flow index during successive balloon
inflations45 have shown that although collateral
recruitment occurs in some patients, it cannot fully explain the
myocardial adaptation observed during repeated balloon inflations.
Investigation into the mechanisms underlying this rapid protection of the myocardium during PTCA has provided further support for a preconditioning-like effect. Blockade of KATP channels with oral glibenclamide before angioplasty abolishes the reduction in ischemic indices observed during subsequent balloon inflations, which implies a role for these channels in mediating this form of adaptation.46 This finding is supported by the observation that opening of these channels with nicorandil reduces the electrocardiographic indices of ischemia during coronary angioplasty.47 Furthermore, an important role has been demonstrated for adenosine in mediating myocardial adaptation during coronary angioplasty. Inhibition of adenosine receptors by bamiphylline48 or aminophylline49 abolishes myocardial adaptation during the second balloon inflation. Conversely, intracoronary infusion of adenosine before PTCA, independent of its vasodilatory effect, attenuates ischemic indices during the first balloon inflation.50 Two other recent reports have suggested a role for both opioid51 and bradykinin52 receptors in mediating myocardial adaptation during PTCA. These studies provide further evidence that myocardial tolerance to further ischemic episodes can be induced by preceding brief periods of ischemia and that this tolerance may be mediated by the same mechanisms as those involved in ischemic preconditioning in animal models.
However, recent experimental evidence has provided grounds for caution when interpreting the results of these PTCA studies, which have mostly used ST-segment elevation on the surface or intracoronary ECG as an end point reflecting the degree of myocardial ischemia, and its attenuation during successive balloon inflations as an indicator of enhanced myocardial resistance to ischemia. Although this assumption was supported by earlier experimental studies of repeated coronary artery occlusion in collateral-deficient pig and rabbit hearts,53 54 a recent study clearly indicates a dissociation between ST-segment changes on the ECG and myocardial protection in terms of infarct limitation.55 The finding of these authors, that the changes in ST-segment voltage during coronary artery occlusion may merely represent an epiphenomenon distinct from the cardioprotective effect of ischemic preconditioning, is particularly pertinent when evaluating or designing mechanistic studies using pharmacological agents to mimic or abolish the cellular signaling mechanisms of ischemic preconditioning. It is imperative that the influence of these pharmacological tools on the sarcolemmal KATP channels, which are thought to modulate ECG voltages, is clearly distinguished from their effect on the mitochondrial KATP channels, which have been proposed as a mediator of cardioprotection.56
Possibly the most direct evidence for preconditioning in humans comes from studies that have examined the effect of preconditioning protocols in patients undergoing cardiac surgery in which resistance to global ischemia is assessed, a setting that is not confounded by changes in collateral recruitment. In this respect, we reported a prospective study examining the effects of a preconditioning protocol of 2 cycles of 3 minutes of global ischemia (induced by intermittently cross-clamping the aorta and pacing the heart at 90 bpm) followed by 2 minutes of reperfusion before a 10-minute period of global ischemia and ventricular fibrillation.57 Patients subjected to this protocol had better preservation of ATP levels in myocardial biopsies during a subsequent 10-minute global ischemic period. These metabolic changes were almost identical to those seen in dogs by Reimer et al.1 However, total myocardial ATP content may not reflect local turnover within subcellular compartments and certainly does not provide information about the efficiency of cellular metabolism in terms of ATP requirements. In a more recent study involving a larger group of patients, serum levels of troponin T were used as an indicator of myocardial cell necrosis. Using this end point, patients subjected to the same preconditioning protocol suffered less necrosis as determined by release of troponin T.58 Of considerable interest, however, was the finding that the ATP levels did not differ between preconditioned and control groups. This emphasizes the need for multiple end points to be used, especially in studies in which small differences in myocardial viability without overt clinical effects are expected.
On the other hand, studies that have used other cardioprotective strategies during the prolonged period of ischemia, such as hypothermia or cardioplegia, have not consistently demonstrated additional protection by ischemic preconditioning. For instance, the use of similar preconditioning protocols of one 3-minute episode of aortic cross-clamping before the onset of cardioplegic arrest failed to show any beneficial effects compared with the control group; in fact, the preconditioned group of patients had more creatine kinase release compared with case-matched controls.59 Similarly negative results have been reported by another group.60 These divergent results have led to the hypothesis that in the setting of coronary artery bypass surgery, the additional protection conferred by ischemic preconditioning may only be demonstrable in cases in which a potential for suboptimal myocardial protection increases the risk of perioperative infarction.61 However, this hypothesis is not supported by recent studies that indicate improved myocardial preservation by ischemic preconditioning during coronary bypass or valve surgery despite optimal protection with hypothermia and cardioplegia.62 63 Resolution of these discrepancies is obviously required before brief antecedent ischemia can be advocated as a means of prophylactic therapy.
| Which Patients May Benefit? |
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First, deployment of pharmacological preconditioning strategies necessitates pretreatment; the pathophysiology of the preconditioning phenomenon dictates that the myocardium must be preconditioned before the onset of a potentially lethal ischemic insult. This depends on identification of a relatively well-defined cohort of patients who are at high risk of acute coronary occlusion and stand to benefit from preconditioning or from pretreatment with agents that trigger or augment myocardial preconditioning.
The acute coronary syndromes (ACSs) comprise a spectrum of pathophysiological conditions spanning unstable angina, nonST-elevation MI, and acute ST-elevation MI. In patients with acute MI with persistent ST elevation, early reperfusion to re-establish epicardial blood flow is well established as the standard of care, be it with early fibrinolytic therapy or, where the facilities and expertise are available, with primary angioplasty.64 As far as pharmacological preconditioning strategies are concerned, these patients are unlikely to benefit from such treatment, and their management should focus on early restoration of coronary artery patency and potential strategies to minimize reperfusion injury. On the other hand, nonST-elevation ACSs, including unstable angina and nonQ-wave MI, mark the transition from stable coronary artery disease to an unstable state and constitute the leading cause of hospital admission in patients with coronary artery disease. This group of patients is at a high risk of progression to acute coronary occlusion, and >10% die or suffer a MI (or reinfarction) within 6 months, with about one half of these events occurring during the acute early phase.65
This cohort of patients with nonST-elevation ACS forms a reasonably well-defined high-risk group that might benefit from pretreatment with agents that trigger or augment myocardial preconditioning over a period of several days or weeks and could therefore effectively maintain the myocardium in a protected or "preconditioned" state. A number of these patients who suffer a MI after unstable symptoms may be "naturally" preconditioned by their preceding ischemic episodes. Recent evidence, however, suggests that this natural protection is limited to those patients in whom the episodes of preinfarction angina occur during a narrow time window in relation to the infarct.20 21
Second, even when prior treatment with the pharmacological preconditioning agent is feasible, the duration of the protection afforded is limited. The temporal profile of the protective effects of preconditioning in humans is unknown but, according to experimental evidence in laboratory animals, it is unlikely to exceed 48 to 72 hours.66 67 Therefore, unless the onset of an ischemic event can be predicted with accuracy, repeated dosing with the potential preconditioning drug will be necessary in these high-risk patients to maintain the preconditioned state. Early experimental evidence suggested that the protective effects of classic ischemic preconditioning are lost after prolonged periods of repetitive ischemia68 or chronic pharmacological preconditioning with selective adenosine A1 agonists.69 However, recent encouraging evidence indicates that tachyphylaxis could be overcome by exploiting the prolonged time course of the second window of protection. Intermittent treatment of conscious rabbits with an optimal dosing regimen of pharmacological preconditioning with selective adenosine A1 receptor agonists maintains the animals in a preconditioned state over a period of several days and results in a significant reduction in infarct size.70 71
Very few studies have evaluated a protective role for pharmacological preconditioning strategies in patients with nonST-elevation ACS. In this regard, a recent report suggests that opening of KATP channels with nicorandil, in addition to standard aggressive medical therapy for unstable angina, results in a significant reduction in the incidence of myocardial ischemic episodes and tachyarrhythmias.72 This may purely represent an anti-ischemic effect due to the vasodilatory properties of nicorandil. However, because the patients in this study were already on maximal antianginal therapy, and in particular a significant proportion were treated with intravenous or oral nitrates, it is possible that the protection observed in the nicorandil group, be it only using soft end points of myocardial injury, may at least partially be due to a preconditioning-like effect.73 These encouraging findings, coupled with very recent experimental evidence indicating that nicorandil specifically activates the mitochondrial rather than the sarcolemmal KATP channels in rabbit ventricular myocytes,74 provide a promising new approach to myocardial protection in patients with unstable angina.
Although the conditions of the majority of patients with
nonST-elevation ACS will stabilize with effective
anti-ischemic medications,
50% of such patients will
require coronary angiography and
revascularization because of failure of medical
therapy assessed by recurrence of ischemic symptoms at
rest or demonstration of provokable ischemia during stress
testing.65 The optimal timing of
revascularization procedures in patients with ACS
is under debate, although recent evidence points to the benefit of
early intervention.75 However, the complication rate
associated with revascularization procedures in
unstable patients is appreciably higher than that in patients with
stable coronary artery disease. For example, emergency PTCA in
patients with refractory unstable angina is associated with a
periprocedural mortality rate of 1% to 3% and nonfatal infarction
occurs in a further 6% to 10%, with a need for emergency surgery in
up to 12%.65 76 The potential for and the time course of
any protection conferred by preceding anginal episodes in this
situation is not known, although some evidence suggests that unstable
symptoms occurring in the 6 to 12 hours before PTCA may have a
preconditioning-like effect.77 Conversely, the
Thrombolysis in Myocardial Ischemia (TIMI) IIIB
study suggested that emergency PTCA performed within 24 hours of
enrollment was the most powerful predictor of periprocedural death and
MI.76 Although the risk associated with the procedure
diminishes if a patient is allowed to "cool off" and the plaque is
at least partly healed, this longer waiting period carries the risk of
progression to MI and death. These patients may therefore have the most
to benefit from pretreatment with agents that mimic preconditioning or
augment the protection afforded by naturally occurring ischemic
preconditioning, thereby reducing the degree of myocardial injury in
the event of periprocedural complications associated with PTCA. At the
other end of the spectrum are patients with stable angina undergoing
elective PTCA, who have a relatively low risk of complete
coronary artery occlusion and MI (<5%). However, as more
high-risk procedures are performed, and considering the potential
benefits associated with this potent mode of cardioprotection, it is
possible that application of pharmacological preconditioning agents may
find a place routinely before elective angioplasty.
Similar complications may arise during cardiac surgery. In patients with unstable angina undergoing coronary artery bypass grafting (CABG), perioperative mortality rates of 3.7% and infarction rates of 9.9% have been reported,78 which are considerably higher than those associated with elective surgery. Even in patients with stable coronary artery disease, despite carefully controlled intraoperative ischemic periods and hypothermia, sensitive markers of tissue injury such as troponin T indicate that discrete necrosis occurs.79 80 Moreover, as surgeons undertake more complex and higher-risk operations, the need for better preservation methods increases. In a situation such as CABG, the administration of an agent before surgery that could enhance myocardial defenses would reduce susceptibility to focal necrosis during surgery and permit the extension of the intraoperative ischemic period. High-risk patients with poor preoperative left ventricular function, extensive coronary artery disease, or severe left ventricular hypertrophy could certainly benefit if the degree of protection were improved by invoking endogenous cellular adaptive mechanisms. The possibility that organ preservation before transplantation might be amenable to the same improved protection, as suggested by some experimental evidence,81 82 is also of significant interest. This might allow an extension of the "cold ischemic time" between harvesting and implantation, facilitating optimal matching of recipient to donor, as well as affording a potential improvement in early myocardial function.
| What Are We Trying to Improve Upon? |
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Similarly, in the surgical setting, effective strategies of myocardial preservation have already been developed, including the use of various cardioplegic solutions. In general, the rationale behind the use of cardioplegic techniques includes rapid diastolic arrest, membrane stabilization, hyperosmolarity (to prevent intracellular edema), acid buffering, and hypothermia. Additional strategies such as continuous coronary perfusion, warm instead of cold cardioplegia (to avoid cold injury), and the use of blood instead of crystalloid solutions (to improve oxygen delivery) have all added to the choices available to the cardiac surgeon. The potential use of endogenous myocardial protection must be seen in the context of these pre-existing efficacious techniques.
| How Can We Measure Our Success? |
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| Conclusions and the Future |
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Received May 24, 2000; revision received August 14, 2000; accepted August 16, 2000.
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