Number 46, 2010
The cardiac cell: its survival and performance

The winding road to cardioprotection

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Rupert Williams, Michael Marber
Department of Cardiology, Guy's & St Thomas’ Hospitals, The Rayne Institute, St Thomas’ Hospital, London, UK
Correspondence: Professor Michael Marber, Department of Cardiology, Guy's & St Thomas’ Hospitals, The Rayne Institute, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK.
E-mail: mike.marber@kcl.ac.uk

Introduction
After an acute myocardial infarction (AMI), reperfusion is paramount, and is the most powerful intervention for limiting infarct size. Minimizing infarct size is essential to preserve left ventricular systolic function, which is the critical determinant of clinical outcome. With the widespread use of reperfusion strategies alongside ancillary anti-ischemic, antithrombotic, and antiplatelet therapies, the overall 1-month mortality from AMI has been reduced from 18% in the mid-1980 s [1] to 6–7% [2] currently. However, despite such advances from these established therapies, the morbidity and mortality from AMI remains significant, with 5–6% of patients having a subsequent cardiovascular event by 30 days [3]. It is therefore necessary to develop novel cardioprotective strategies that can further reduce infarct size, preserve left ventricular function, and improve clinical outcome.
Over the past two decades, the focus on primary percutaneous coronary intervention (PCI) as the gold-standard reperfusion therapy in acute ST-segment elevation myocardial infarction (STEMI) provides a unique opportunity for adjunctive pharmacological agents, given just before or simultaneously with reperfusion, to attenuate reperfusion injury. This concept defines the pathophysiological process via which myocardium that is viable at the onset of reperfusion subsequently dies – not as an indirect result of predetermined events that occurred during ischemia, but as a direct result of the reperfusion process itself. Such pharmacological manipulation also has great potential for improving clinical outcome in other forms of ischemia-reperfusion injury outside acute STEMI; for example, during coronary artery bypass graft surgery, or in PCI for unstable angina or non ST-segment elevation myocardial infarction (NSTEMI). It seems appropriate, therefore, to dedicate this Special Anniversary Issue of Heart and Metabolism to summarizing established therapies in the treatment of AMI, and to focus on novel treatments that specifically target reperfusion injury.

Established therapies

Reperfusion therapies
The landmark studies Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-1 [4] and International Study of Infarct Survival (ISIS)-2 [5] demonstrated a 23% reduction in 30-day mortality with fibrinolytic treatment compared with placebo after STEMI. Nine subsequent phase III trials confirmed a similar benefit, and reinforced the time-dependent loss of benefit. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO)-1 [6] trial subsequently demonstrated a further 15% mortality reduction with “accelerated” alteplase compared with streptokinase, albeit associated with a greater risk of intracranial hemorrhage. The role of primary PCI as compared with thrombolysis in STEMI was debated for a considerable period; however, 22 randomized trials (involving 7437 patients) undertaken between 1990 and 2003 demonstrated a 19% mortality benefit with PCI when compared with accelerated alteplase, alongside a reduced incidence of myocardial re-infarction, stroke, and intracranial hemorrhage [7].

Antiplatelet and antithrombotic therapies
The role of antiplatelet therapy in AMI is also very well established: four clinical trials encompassing 3096 patients with NSTEMI were the first to demonstrate a 53% reduction in relative risk with aspirin against the incidence of death or myocardial infarction, albeit with dosing varying between 324 and 1300 mg [8–11]. The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial [12] highlighted a further 20% reduction in cardiovascular death, myocardial infarction, or stroke with the use of clopidogrel, a prodrug causing irreversible inhibition of the ADP receptor P2Y₁₂, in dual antiplatelet therapy. Prasugrel and ticagrelor are more novel ADP inhibitors, ticagrelor having the advantage of reversible inhibition without any need for metabolic activation [13]. With regard to efficacy, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38 trial [14], involving 13 608 high-risk patients with acute coronary syndrome undergoing PCI, demonstrated a 19% reduction in relative risk of cardiovascular death with prasugrel compared with clopidogrel, but with an adverse significant increase in major and life-threatening bleeds. Wallentin et al [15] have recently published impressive data from the Platelet Inhibition and Patient Outcomes (PLATO) trial (involving 18 624 patients with AMI), demonstrating a 17% reduction in relative risk of composite vascular deaths achieved with ticagrelor as compared with clopidogrel, and without an increase in the rate of overall major bleeding.
Glycoprotein IIb/IIIa inhibitors are potent antiplatelet agents, blocking the final common pathway in platelet aggregation. A meta-analysis [16] of the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) [17], Chimeric 7E3 Antiplatelet in Unstable Angina Refractory to Standard Treatment (CAPTURE) [18], and Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM PLUS) [19] trials demonstrated a 41% reduction in relative risk in periprocedural complications with glycoprotein IIb/IIIa inhibitors in patients with NSTEMI undergoing early PCI. However, prolonged treatment after PCI actually showed a significant adverse effect on mortality [20].
With regard to antithrombotic therapy, six randomized trials involving 1353 patients with NSTEMI demonstrated a 34% reduction in relative risk in the composite endpoint of death and myocardial infarction with unfractionated heparin [10,11,21–24]. Subsequently, the low-molecular-weight heparin enoxaparin was show to afford a marginally significant advantage over unfractionated heparin in the same composite endpoint [25]. More recent research has been targeted towards the use of direct thrombin inhibitors, which may be administered orally, although they are not currently licensed for use in AMI.

Anti-ischemic therapies
Anti-ischemic treatments in AMI include β-blockers, nitrates, and calcium-channel antagonists. However despite symptomatic benefit observed with all three agents, β-blockers have been the only treatment to demonstrate a reduction in mortality: the ISIS-1 trial, albeit before the use of fibrinolysis, revealed a 20% reduction in relative risk of overall mortality at 1 year [26]. The reflex tachycardia associated with some calcium-channel antagonists led to a non significant adverse effect in STEMI [27] and limited their use to third-line agents for symptomatic relief in NSTEMI. After an AMI, evidenced-based therapies include early treatment with angiotensin-converting enzyme (ACE) inhibitors (following the large GISSI-3 [28] and ISIS-4 [29] trials), alongside statins, antiplatelet, and anti-ischemic therapies.

Pathogenesis of reperfusion injury
In order to discuss targets for pharmacological manipulation of reperfusion injury, it is first necessary to understand the proposed mechanisms via which such injury occurs. The term “reperfusion injury” encompasses stunning, the no-reflow phenomenon, and reperfusion arrhythmias (which all occur in the absence of irreversible damage), and irreversible or lethal reperfusion injury. This distinction is very important, as the latter implies reperfusion as an independent mediator of cell death, as opposed to an exacerbator of cellular stress initiated during ischemia. Some controversy remains as to whether reperfusion injury provokes such independent pathology, although consistent basic laboratory data demonstrating reduction in infarct size with pharmacological agents added to the reperfusate have provided striking evidence, which has been taken very seriously.
During ischemia of cardiomyocytes, mitochondrial production of ATP is compromised as a result of inadequate supply of substrates and oxygen. This results in derangement of the mitochondrial electron transport chain, causing further incapacitation of aerobic glycolysis and adverse generation of reactive oxygen species (ROS). Reduced ATP results in the failure of the sarcolemmal Na⁺/K⁺-ATPase and the sarcoplasmic reticulum Ca²⁺-ATPase pumps. Anaerobic glycolysis compensates in an attempt to meet energy demands, and results in increased accumulation of H⁺ ions, leading in turn to intracellular acidosis. Overactivity of the Na⁺–H⁺ exchanger occurs to attempt to correct this acidosis. However this, in combination with ATPase pump failure, results in intracellular Na⁺ overload, which can reverse the Na⁺–Ca²⁺ exchanger, leading to intracellular Ca²⁺ overload. The degree of Ca²⁺ overload is also influenced by the extent of generation of ROS, and both are dependent upon the duration of ischemia (Figure 1).

Can ischemia be protective?
The term “ischemic preconditioning” describes the phenomenon whereby brief periods of sublethal ischemia and reperfusion protect against a subsequent lethal “index” ischemia; this was first demonstrated by Murry et al [38]. Unfortunately, clinical application of ischemic preconditioning is limited because the cardioprotective stimulus must be applied before the index ischemic event. As AMI is often unheralded, the use of ischemic preconditioning is therefore restricted to elective procedures inducing ischemia-reperfusion injury, such as coronary artery bypass grafting or heart transplant surgery. Before the concept of ischemic preconditioning, Jaffe and Quinn [39] illustrated a form of innate cardioprotection in patients with coronary artery disease whereby exertional angina induced by initial exercise was greatly attenuated on second exercise if interrupted by a brief rest period; this was termed the “warm-up phenomenon”. However, to this day, the mechanisms involved in this cardioprotective mechanism remain uncharacterized.
It has subsequently been found that brief periods of ischemia and reperfusion also protect against infarct size when applied simultaneously with the onset of reperfusion – so-called “postconditioning” [40]. This is an area of intensive research at present; current clinical trials [41–48] are summarized in Table I. Basic research data suggest that the protective mechanisms initiated by both ischemic preconditioning and postconditioning converge to target inhibition of opening of the mPTP [49]. However, postconditioning is also limited by its invasive nature, and therefore is restricted to patients with AMI undergoing PCI. Interestingly, more recent data have demonstrated cardioprotection with brief remote ischemic stimuli, which can be applied before, during, or immediately after the index ischemia; these are termed “remote ischemic preconditioning”, “remote preconditioning”, and “remote postconditioning”, respectively, and they offer the opportunity for protection in all patients with AMI. Some animal studies have failed to demonstrate cardioprotection with these remote phenomena, but this may reflect an insufficient remote ischemic stimulus.

Table I. Cardioprotection induced by ischemia [41–48].

Pharmacological manipulation of reperfusion injury
Improvement in clinical outcome with pharmacological intervention at the onset of reperfusion defines the very concept of reperfusion injury. Several mechanisms highlighted in the section above on ischemia-reperfusion have been specifically targeted, with several more potential targets yet to be tested. Space constraints prevent us, in this review, from expanding on each treatment tried to date, therefore we have produced a Table (Table II), which summarizes the most important clinical studies [52–75], grouped into categories based on the pharmacological intervention used. In particular, note that, despite a substantial number of adjuncts to reperfusion initially showing great promise, subsequent larger multicenter studies were unable to confirm efficacy (for examples, see [29,50,51]).

Table II. Pharmacological manipulation of reperfusion injury [29,50–75].

Conclusions
To determine the efficacy of adjunctive treatments given at the onset of reperfusion, meticulous attention to study design and careful selection of end points are paramount. From the two Tables in this article alone, one can see the great variety in both of these parameters, which makes interpretation of a small but potentially invaluable effect on clinical outcome very difficult. Furthermore, established treatments have greatly reduced the morbidity and mortality from AMI, reducing the potential absolute benefit from novel therapies. A notable strength of more recent studies is the use of magnetic resonance imaging to assess infarct size with late gadolinium enhancement. This technique is particularly accurate at quantifying the region of ischemia-reperfusion injury and therefore identifying a potential therapeutic benefit. Furthermore, MRI-LGE has been shown to have a significantly higher correlation with prognosis, compared with SPECT. Hence, with an increased awareness of the importance of scrupulous study design that incorporates the use of novel techniques such as MRI–LGE as well as relevant clinical end points, we will be better able to assess the effects of new therapies, thus enabling progression along the winding road to cardioprotection.

REFERENCES