Abstract
ST-segment elevation myocardial infarction (STEMI) remains a leading cause of death and morbidity, despite declining incidence and improved short-term outcome in many countries. Although mortality declines in developed countries with easy and fast access to optimized treatment, development of heart failure often remains a challenge in survivors and still approaches 10% at 1 year. Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy frequently establish complete reperfusion and acutely stabilize the patient, but the reperfusion itself adds further to the damage in the myocardium compromising the long-term outcome. Reperfusion injury is believed to be a significant—if not the dominant—contributor to the net injury resulting from STEMI and has become a major focus of research in recent years. Despite a plethora of pharmacological and mechanical interventions showing consistent reduction of reperfusion injury in experimental models, translation into a clinical setting has been challenging. In patients, attempts to modify reperfusion injury by pharmacological strategies have largely been unsuccessful, and focus is increasingly directed toward mechanical modalities. Remote ischemic conditioning of the heart is achieved by repeated brief interruption of the blood supply to a distant part of the body, most frequently the arm. At present, remote ischemic conditioning is the most promising adjuvant therapy to reduce reperfusion injury in patients with STEMI. In this review, we discuss the results of clinical trials investigating the effect of remote ischemic conditioning in patients admitted with STEMI and potential reasons for its apparent superiority to current pharmacologic adjuvant therapies.
Introduction
The injury caused by ischemia and reperfusion is the primary reason that cardiovascular disease remains a leading cause of death and disability. 1,2 For the last 2 decades, more people have died of coronary heart disease than any other cause of death and conditions involving ischemia–reperfusion syndromes. Hence, diseases such as myocardial infarction and stroke remain a dominant burden on public health worldwide. 3,4 Despite important advances in the handling and treatment of patients with acute ischemic conditions, including rapid referral, primary interventional therapy, and optimized medical treatment, substantial organ injury often occurs resulting in early and late morbidity and mortality. 5
For patients admitted with ST-segment elevation myocardial infarction (STEMI), early and successful restoration of myocardial reperfusion is the most effective strategy to reduce final infarct size and improve clinical outcome. 6 However, reperfusion itself induces further myocardial damage, but the development of pharmacological therapies, so-called pharmacological conditioning, to counter the detrimental effects of reperfusion injury has so far been unsuccessful. Although investigation of infarct size modification in acute myocardial infarction (AMI) by adenosine (AMISTAD I and II trials) showed reduction in infarct size and improved outcome in a subgroup of patients, 7 in most other pharmacological conditioning studies, from the first-generation large clinical trials such as testing the metabolic impact by glucose–insulin–potassium infusion (the CREATE-ECLA trial) 8 and anti-inflammatory effects by pexelizumab (APEX-MI trial) 9 to recent clinical trials investigating the effect of cyclosporine A 10 and exenatide, 11,12 no convincing clinical effect has been demonstrated.
Another and arguably more effective means to protect the heart against reperfusion injury is by exposing it to brief episodes of nonlethal ischemia prior to the long-lasting ischemic event, so-called local ischemic preconditioning. 13 For obvious reasons, local ischemic preconditioning is not directly relevant to patients with STEMI. Since the discovery that brief episodes of ischemia in a distant tissue induce a similar protection of the heart (remote ischemic conditioning [RIC]) 14,15 and that this effect also occurs even when the stimulus is conducted during evolving myocardial infarction, 16 clinical applicability has been achieved by inducing brief episodes of limb ischemia to patients admitted with STEMI, either during transfer (Figure 1) or immediately after arrival to the hospital.
After telemedical diagnosis of STEMI and triage to the catheterization unit, remote ischemic conditioning is optimally performed during transport to the cardiac center. PCI indicates primary coronary intervention; STEMI, ST-elevation myocardial infarction.
Several clinical trials have studied the effect of RIC in patients admitted with STEMI for primary percutaneous intervention (pPCI) 17 ∓19 or thrombolysis, 20 and most have shown beneficial effects of RIC, either demonstrating reduced myocardial injury 17 or improved clinical outcome. 21 Small clinical studies indicate that other mechanical interventions such as cooling 22 and local ischemic postconditioning may also reduce myocardial injury in patients with STEMI, 23 but presently RIC appears to be the most attractive adjuvant therapy due to its low cost and easy applicability. In this review, we will discuss the results of trials investigating the effects of RIC in patients with STEMI.
The Development of RIC
In their seminal paper from 1986, Murry and colleagues demonstrated that myocardial infarct size in dogs after 40-minute occlusion of the circumflex artery and 4 days of reperfusion was reduced from 29% to 7% of the area at risk by local ischemic preconditioning through 4 times of 5-minute occlusion of the same coronary artery prior to the ischemic insult. 13 Being cited more than 100 000 times, this discovery has defined research in cardioprotection for the last 30 years.
An important step toward clinical applicability was achieved when Przyklenk et al demonstrated that preconditioning 1 coronary territory in the heart protects the rest of the heart against a subsequent ischemic injury. 14 Next, studies demonstrated that protection of the heart also occurs after exposing the gastrocnemius muscle, kidney, or limb to brief episodes of nonlethal ischemia, 15,24,25 remote ischemic preconditioning. Importantly, the remote ischemic stimulus protects also the heart when conducted during or immediately after cardiac ischemia (remote ischemic preconditioning and postconditioning), 16 and the general term remote ischemic conditioning or RIC (with no indication of timing) is now predominantly used. Due to the easy application, conditioning through brief episodes of limb ischemia won most widespread use and today is almost synonymous with RIC.
In experimental studies, RIC has been shown to afford protection against ischemia–reperfusion in the liver, 26,27 lung, 28,29 kidney, 30 brain, 31 and heart 15 and against cardiopulmonary bypass–induced neural, pulmonary, and myocardial injury. 32 From the site of the remote stimulus, through humoral 33 and neuronal 34,35 pathways, RIC activates several protective mechanisms in the target organ similar to those activated by local ischemic preconditioning. Furthermore, RIC modifies the systemic inflammatory response 36,37 and prevents endothelial dysfunction 15 and platelet activation, 38 following ischemia–reperfusion injury.
Translation of RIC Into Clinical Use
The first clinical study investigating the effect of RIC in a clinical setting was conducted by Cheung et al who showed that RIC conducted prior to cardiac surgery for congenital structural heart disease reduced myocardial injury in children. 39
The observation in a porcine study that RIC also affords cardioprotection when conducted during ongoing myocardial ischemia 16 prompted potential relevance for patients with STEMI.
Therefore, we conducted a randomized clinical trial (the CONDI-trial) to investigate the effect of RIC in patients with STEMI admitted for pPCI. A total of 333 patients were enrolled and randomized to either standard therapy or RIC + standard therapy. Remote ischemic conditioning intervention was initiated in the ambulance during transport to the interventional center using intermittent arm ischemia achieved by 4 cycles of alternating 5-minute inflation (200 mm Hg) followed by 5-minute deflation of a blood pressure cuff placed on the upper arm. We showed that RIC improves myocardial salvage index (0.75 in the RIC group vs 0.55 in the control group, P = .033) as measured by single-photon emission computed tomography. 17 In a substudy, Munk et al showed that in patients with anterior infarcts, RIC improved ejection fraction. 40 Later, Sloth et al published 4-year follow-up data on our original study, showing that the improved myocardial salvage translates into clinical prognostic benefit, as the major adverse cardiac and cerebral event occurred for 17 (13.5%) patients in the RIC-treated group compared to 32 (25.6%) patients in the control group, yielding a hazard ratio of 0.49 (95% confidence interval: 0.27-0.89, P = .018). Furthermore, only 5 deaths (4%) occurred in the intervention group compared with 15 (12%) in the control group, yielding a hazard ratio 0.32 (95% confidence interval: 0.12-0.88, P = 0.027). 21
Other Studies of RIC in Patients With STEMI
In a small but important study, Rentoukas et al showed that RIC increases the proportion of patients with STEMI achieving full ST-segment resolution after pPCI, indicating that RIC also improves microvascular perfusion after STEMI. 18
Three independent studies subsequently showed that RIC reduced markers of myocardial injury (troponin T or creatine kinase–myocardial band) after STEMI, 20,41,42 and Eitel et al confirmed our finding of improved salvage afforded by RIC, in their study measured with cardiac magnetic resonance imaging (MRI). 43
Notably, RIC also reduced myocardial injury in patients treated with thrombolysis for STEMI in a study conducted on Mauritius, 20 suggesting RIC may be beneficial even when reperfusion is not established by PCI, which extends its potential relevance to the large parts of the world with no access to pPCI.
However, a recent study by Verouhis et al found no effect of RIC on myocardial salvage as assessed by MRI and troponin release. 44 The authors used intermittent lower limb ischemia initiated after arrival to the catheterization laboratory. In most studies investigating the effect of RIC in patients with STEMI, RIC was performed on the upper limb. Although Crimi et al also used lower limb ischemia and did find protective effect of RIC (see Table 1), in our experience, it is difficult to induce consistent ischemia in the adult human leg through inflation of a blood pressure cuff around the thigh. Furthermore, Verouhis and colleagues also used a protocol of combined preconditioning and postconditioning adding up to a higher number of conditioning cycles, even ≥7 in a subgroup of patients, which could potentially lead to “hyperconditioning” as suggested by Whittaker and Przyklenk. 48 Together with a later timing, potentially not achieving the full effect of RIC if 3 to 4 cycles were not completed prior to establishment of reperfusion, these deviations may explain the absence of effect of RIC in the study by Verouhis.
Overview of Clinical Studies of Remote Ischemic Conditioning in Patients With STEMI Undergoing Reperfusion.
Abbreviations: AUC, area under the curve; CK-MB, creatine kinase–myocardial band; CON, conditioning; I/R, ischemia reperfusion; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiac and cerebral event; MRI, magnetic resonance imaging; PCI, percutaneous intervention; RIC, remote ischemic conditioning; SPECT, single-photon emission computed tomography; TnT, troponin T.
A potentially important effect of RIC is its protective effect on other organs during evolving myocardial infarction and the subsequent revascularization therapy. Of particular interest is acute kidney injury, which may occur from both hemodynamic instability and contrast use during pPCI. Yamanaka et al showed 72% reduction in the occurrence of acute kidney injury in RIC-treated patients with STEMI compared to controls. 47 This finding was confirmed in a recent retrospective study showing renal protection in patients with STEMI when RIC was conducted during interfacility helicopter transport in the United States. 45
Finally, Lotfollahi et al have showed that RIC also reduces markers of oxidative stress and increases total oxidative capacity in patients with STEMI. 46 Overall, 12 studies have provided evidence of a beneficial effect of RIC in patients with STEMI with a variety of end points and only 1 study showed no beneficial effect of RIC (see Table 1).
Meta-analyses of the above-mentioned and other studies seem to support that RIC reduces myocardial injury and improves clinical outcome in clinical situations at risk of myocardial ischemia/reperfusion damage, although these papers include both emergent and nonemergent settings. 49,50
Factors Influencing the Effect of RIC
Animal studies have suggested that a number of conditions such as high age, diabetes, and left ventricular hypertrophy attenuate or abolishe the effect of ischemic conditioning. We performed a post hoc analysis of risk factors and medication use in patients enrolled in the CONDI trial. 51 We found no effect modification by diabetes, hypertension, gender, or age. Similarly, the use of β-blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium channels blockers did not affect the efficacy of RIC. However, smoking seemed to attenuate the effect of RIC, whereas statin use may increase the effect. Propofol also seems to abolish the cardioprotection afforded by RIC but is rarely used in the setting of STEMI.
Present reperfusion therapy by pPCI is effective in the majority of patients with STEMI. However, some patients, predominantly those with large anterior infarcts, may develop heart failure due to myocardial injury and subsequent left ventricular remodeling months or even years after the infarct, despite optimal medical treatment. In addition to mortality reduction, RIC seems to improve clinical outcome by reduced postinfarction left ventricular dysfunction and heart failure. 21 No serious adverse effects have been observed by RIC until now, and initiation of RIC should seem to be effective when applied in the ambulance before assessment of outcome is possible. Patients at risk of extensive myocardial injury and global tissue damage seem to be those who may benefit the most. 17
Timing of the RIC procedure may influence its efficacy. The first window of protection by RIC lasts for 2 to 3 hours and onset appears to be instant, as RIC initiated immediately prior to revascularization reduces infarct size in patients with STEMI. 41 Patients presenting with an AMI are recommended interventional or thrombolytic reperfusion within 12 hours of the onset of chest pain. Although infarct size is larger in patients presenting with symptoms >12 hours of duration than in early presenters after primary angioplasty for STEMI, substantial myocardial salvage can be obtained beyond the 12-hour limit, even when the infarct-related artery is totally occluded. 52,53 Interestingly, RIC also seems to attenuate the detrimental effect of system delay before pPCI in patients with STEMI with symptom onset of >12 hours, suggesting an extended window of opportunity for pPCI. 54 Please see a recent comprehensive review by Heusch and Rassaf for a more detailed discussion of the influence of timing in cardioprotective strategies. 55
Some patients presenting with an STEMI have already undergone spontaneous reperfusion prior to interventional reperfusion. Because RIC is designed to protect mainly against reperfusion injury, its efficacy is most pronounced in patients with totally occluded vessels prior to interventional reperfusion. 17 However, patency status of the coronary arteries will remain unknown for the majority of patients with STEMI at the decision time of RIC institution. If future studies motivate implementation of RIC as an additional treatment modality beyond reperfusion therapy in patients with STEMI, this limitation should not detract any patient from RIC due to its safe and cheap nature.
In patients with STEMI, substantial collateralization is associated with improved clinical outcome. 56 Intuitively, this has been connected to reduced area-at-risk size and the evolving infarct. Hence, the extent of collateralization has also been thought to negatively influence the ability to demonstrate an effect of any novel cardioprotective strategy. However, consistent with previous findings, 57,58 Pryds et al demonstrated that area at risk did not differ between patients with and without coronary collateral blood flow to the infarct-related artery and that collateral blood flow rather increased myocardial salvage index in patients with STEMI undergoing pPCI. 59 Thus, the coronary collateral circulation may facilitate the delivery of circulating humoral cardioprotective factors generated during the RIC stimulus 60 and transported to the myocardium threatened by ischemia-reperfusion injury.
Preinfarction angina per se may be cardioprotective and improve outcome following AMI, predominantly when closely preceding the infarct. 61,62 The development of coronary collaterals 63 and activation of an inherent ischemic preconditioning-like effect 64 are potential underlying mechanisms. Although the development of functional collateral vessels presumably requires time, 65 a preconditioning effect would be almost immediate 60 and might interfere with RIC. Although results are not consistent, 57 we have not found an overall effect of preinfarction angina on myocardial salvage. 59 More importantly, however, preinfarction angina prior to the STEMI did not compromise the efficacy of RIC.
Purinergic P2Y inhibitors have infarct size–reducing effect in animal models. Their mechanisms of action seem not only dependent on the presence of platelets in the blood 66,67 but may also be mediated by activating the recognized conditioning pathway and depend on similar signaling components as conditioning. Adding ischemic postconditioning to the platelet inhibitor offered no additional protection to a rabbit heart. 68 Moreover, ticagrelor specifically increases adenosine availability by inhibiting adenosine reuptake via the equilibrative nucleoside transporter potentially triggering conditioning by this mechanism. 69,70 Because most clinical studies until now have been conducted with concurrent clopidogrel treatment, the clinical impact of any interaction with ticagrelor remains unknown.
Should RIC Be Continued/Repeated After pPCI?
Myocardial remodeling continues for several weeks after a myocardial infarction and involves inflammation, fibrosis, and rebuilding of vital myocardium. In a meticulous study of several different “chronical” conditioning protocols, Wei et al demonstrated that RIC repeated daily for 4 weeks after myocardial infarction protected against adverse left ventricular remodeling and increased survival in a rat model. 71 Although a similar study has not been conducted in a clinical setting, a benefit of RIC may be amplified by repeated daily treatment after the index event. A clinical study clarifying potential additional protection of chronic RIC is clinically relevant and highly warranted.
Remote Ischemic Conditioning in Stroke and Other Acute Ischemia–Reperfusion Syndromes
As a clinical condition involving acute ischemia–reperfusion injury, stroke is the obvious parallel of myocardial infarction. It is appealing to think RIC may afford protection in patients with stroke similar to what has been shown in patients with STEMI. However, several factors challenge the use of RIC in stroke. Firstly, in the treatment of ischemic stroke, reperfusion is most frequently achieved through thrombolysis. Although thrombolytic therapy of stroke is frequently successful, the onset of reperfusion is unpredictable, making timing of the RIC procedure challenging even with proven efficacy in patients with STEMI. 20 Secondly, assessing the cerebroprotective effect of RIC (or any other adjuvant therapy) is far more challenging than measuring markers of myocardial infarction. Nevertheless, Hougaard et al demonstrated that RIC increased tissue survival and tended to improve some clinical outcome variables in patients admitted with ischemic stroke for thrombolytic therapy. 72 Animal studies suggest that RIC may also afford organ protection in the setting of multi-trauma and hemorrhagic shock, 73 but this remains to be confirmed in clinical studies.
Can RIC Be Mimicked by a Drug?
The systemic effects of RIC have turned out to be much more complex than initially believed. Remote ischemic conditioning protects the target organ through a plethora of parallel intracellular and extracellular pathways, modifies inflammatory processes, reduces platelet activation, and affects endothelial function, all of which may indicate that this inherent protection system in mammalian species is a fundamental and complex part of the biological response to stress. 60,74 Recent studies suggest that microvesicles and microRNA play a controlling role in the “upstream” events following RIC, 75,76 but the identification of which microRNAs are involved and their individual importance remain to be determined. 77 Although biological insight into the mechanisms underlying the effects of RIC is increasing rapidly, a pharmacological replication of remote or local ischemic conditioning has not yet been developed. Future work should consider combination therapies or “upstream” intervention, which may mimic the signaling systems sufficiently to achieve clinically relevant organ protection comparable to the effects of remote and local ischemic conditioning. It is not unlikely, though, that RIC may prove too complex to be fully recapitulated by a single pharmacological intervention.
Conclusion and Potential of RIC in Patients With STEMI Undergoing Reperfusion
Although reperfusion therapy by pPCI is effective in the majority of patients with STEMI, some patients may develop heart failure due to extensive myocardial injury. Remote ischemic conditioning reduces cardiac injury after myocardial infarction in many experimental studies, and translation into clinical use has been mostly successful until now. ST-segment elevation myocardial infarction seems the ideal candidate to exploit the potential clinical profit of RIC. Still, it remains to be shown that the repeatedly observed effect on surrogate markers translates into improved clinical outcome. The result of the ongoing CONDI2-ERIC-PPCI study 78 investigating the effect of RIC in 5200 patients will hopefully provide an answer to whether it is time to introduce RIC as a standard adjuvant therapy to patients with STEMI in clinical practice and in the guidelines.
Footnotes
Acknowledgements
The authors thank the Danish Council for Independent Research (11-108354), Novo Nordisk Foundation, and Trygfonden.
Author Contributions
Hans Erik Bøtker and Michael Rahbek Schmidt contributed to conception or design, contributed to acquisition, analysis, or interpretation, drafted the manuscript, and critically revised the manuscript. Mathis Ersted Rasmussen contributed to conception or design and critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Michael Rahbek Schmidt and Hans Erik Bøtker are shareholders in CellAegis Inc.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.