Remote Ischemic Conditioning and the Long Road to Clinical Translation
2016; Lippincott Williams & Wilkins; Volume: 118; Issue: 7 Linguagem: Inglês
10.1161/circresaha.115.308102
ISSN1524-4571
AutoresKirk N. Garratt, Peter Whittaker, Karin Przyklenk,
Tópico(s)Anesthesia and Neurotoxicity Research
ResumoHomeCirculation ResearchVol. 118, No. 7Remote Ischemic Conditioning and the Long Road to Clinical Translation Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRemote Ischemic Conditioning and the Long Road to Clinical TranslationLessons Learned From ERICCA and RIPHeart Kirk N. Garratt, Peter Whittaker and Karin Przyklenk Kirk N. GarrattKirk N. Garratt From the Center for Heart and Vascular Health, Christiana Care Health System, Wilmington, DE (K.N.G.); Cardiovascular Research Institute (P.W., K.P.) and Departments of Emergency Medicine (P.W., K.P.) and Physiology (K.P.), Wayne State University School of Medicine, Detroit, MI. , Peter WhittakerPeter Whittaker From the Center for Heart and Vascular Health, Christiana Care Health System, Wilmington, DE (K.N.G.); Cardiovascular Research Institute (P.W., K.P.) and Departments of Emergency Medicine (P.W., K.P.) and Physiology (K.P.), Wayne State University School of Medicine, Detroit, MI. and Karin PrzyklenkKarin Przyklenk From the Center for Heart and Vascular Health, Christiana Care Health System, Wilmington, DE (K.N.G.); Cardiovascular Research Institute (P.W., K.P.) and Departments of Emergency Medicine (P.W., K.P.) and Physiology (K.P.), Wayne State University School of Medicine, Detroit, MI. Originally published1 Apr 2016https://doi.org/10.1161/CIRCRESAHA.115.308102Circulation Research. 2016;118:1052–1054Remote ischemic preconditioning and outcomes of cardiac surgeryHausenloy et alN Engl J Med. 2015;373:1408–1417.A multicenter trial of remote ischemic preconditioning for heart surgeryMeybohm et alN Engl J Med. 2015;373:1397–1407.Remote ischemic conditioning (RIC) is the phenomenon whereby brief episodes of peripheral ischemia-reperfusion, typically applied to ≥1 limbs by inflation–deflation of a standard blood pressure cuff, increase the tolerance of the myocardium to a sustained ischemic episode. Compelling preclinical evidence of infarct size reduction with RIC, together with promising results from small, proof-of-concept phase II trials, has yielded cautious optimism that RIC may be the long sought-after cardioprotective strategy capable of attenuating morbidity and mortality in patients having a spontaneous or planned period of prolonged cardiac ischemia. Progress toward clinical translation may, however, be hindered by the recent release of 2 eagerly anticipated phase III trials. ERICCA (Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery) and RIPHeart (Remote Ischaemic Preconditioning for Heart Surgery), both published in the New England Journal of Medicine and both designed to assess major adverse cardiac and cerebrovascular events after cardiac surgery in RIC-treated cohorts versus sham controls, concluded that RIC had no benefit on clinical outcomes.Rationale: RIC in Cardiac SurgeryIn the 2 decades since the first report of the phenomenon of "preconditioning at a distance,"1 RIC has evolved from theoretical concept2 to preclinical investigation3 to multiple phase II clinical trials in patients undergoing cardiac surgery or percutaneous coronary intervention.4–6 RIC has largely been investigated as a pretreatment before planned ischemic events, including elective coronary artery bypass grafting (CABG), and is particularly well suited to the controlled surgical environment. Among the phase II trials that focused on CABG in adult patients and provided the foundation for ERICCA and RIPHeart, the primary end point was postoperative release of cardiac enzymes: ie, well-established surrogate markers of cardiomyocyte damage that have been associated with increased perioperative morbidity and mortality and attributed to ischemia-reperfusion injury.6,7 Most (but not all) of these proof-of-concept studies provided encouraging evidence of a significant attenuation in plasma concentrations of creatine kinase and/or cardiac troponins after surgery in patients randomized to receive RIC when compared with controls.4–6ERICCA is the largest clinical trial to date evaluating RIC in cardiac surgery. Higher-risk patients (those with a European System for Cardiac Operative Risk Evaluation ≥5) undergoing elective CABG with or without concomitant valve surgery were randomly assigned to receive either a standard RIC stimulus (four 5-minute manual inflations of a sphygmomanometer, positioned on the upper arm, to a pressure ≥200 mm Hg: n=801) or time-matched simulated sham inflations (n=811). Clinical outcome was assessed by quantifying the composite end point of cardiovascular death, nonfatal myocardial infarction, additional coronary revascularization, or stroke within 12 months of surgery. In addition, postoperative cardiac troponin release—the mainstay of the previous phase II trials—was among the secondary end points included in the protocol.8 RIPHeart also focused on patients undergoing elective cardiac surgery but, in contrast to ERICCA, enrolled lower-risk patients, was not limited to CABG, and compared the composite end point of all-cause death, nonfatal myocardial infarction, stroke, or acute renal failure at hospital discharge or 14 days post surgery. Cohorts were randomized to receive the same standard RIC stimulus utilized in ERICCA, applied to either the patient's upper arm (n=692) or, for the sham control group, to an artificial arm positioned under the surgical drape (n=693).9 As in ERICCA, measurement of plasma troponin concentrations during the initial days after surgery was included as a secondary end point.8,9Contrary to expectations, the favorable effects of RIC on cardiac enzyme release reported in the majority of phase II studies were not corroborated in ERICCA or RIPHeart. Moreover, in both trials, there was no evidence of a difference in composite clinical outcomes in RIC-treated groups versus controls (P=0.58 and P=0.89, respectively; Figure [A]).8,9 These data have, not surprisingly, stirred debate on the future of this cardioprotective phenomenon10,11: Do ERICCA and RIPHeart herald the end of the long road to clinical translation for RIC? Based on the unequivocally neutral findings of these landmark phase III trials, should RIC be abandoned as a cardioprotective strategy?Download figureDownload PowerPointFigure. A, Hazard ratios (ERICCA: Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery) and odds ratios (RIPHeart: Remote Ischaemic Preconditioning for Heart Surgery) with their 95% confidence intervals for the studies' primary end points. The odds ratios were adjusted for EuroSCORE, the presence of diabetes mellitus, treatment with statin-lowering drugs, and treatment center. In RIPHeart, the combined end point (defined as death, myocardial infarction [MI], stroke, or acute renal failure) was assessed at hospital discharge or 14 d post surgery. In ERICCA, the combined end point (defined as cardiovascular death or major adverse cardiac and cerebral events) was assessed at 12 mo. B, Proportion of patients who received propofol. In RIPHeart, 100% received propofol per protocol; in ERICCA, >90% of patients in each group received propofol.Disappointing but Predictable?The acknowledged weaknesses of previous phase II studies include (1) the fact that conclusions on the potential cardioprotective efficacy of RIC were based exclusively on attenuated release of creatine kinase and cardiac troponins, combined with (2) uncertainty regarding the relationship between the observed ≈10% to 40% reductions in cardiac enzyme release during the initial 2 to 3 days after surgery and longer-term morbidity and mortality.12 In this regard, ERICCA and RIPHeart, and their shift in focus from surrogate end points to quantitative assessment of clinical outcomes, represent an important advance in the field of RIC and cardioprotection. Nonetheless, despite their more robust study design, the aspect of ERICCA and RIPHeart that merits scrutiny is not the failure of RIC to attenuate the incidence of longer-term major adverse events; these results are predictable, given the lack of short-term benefit. Rather, the germane issue is why, in contrast to most previous smaller studies, RIC was not associated with a favorable reduction in cardiac enzyme release.Although it is possible that the discrepancy may be a consequence of statistical type 1 errors in earlier positive trials, we propose that the outcomes of ERICCA and RIPHeart are more likely explained by (1) our overall lack of understanding of the temporal and physiological requirements for RIC-induced cardioprotection; (2) our limited knowledge of the mechanisms of RIC; and (3) our failure to capitalize on the little mechanistic insight that is available. With regard to the first issue, recent dose–response studies conducted using young adult male mice demonstrated that the standard RIC stimulus (four 5-minute periods of limb ischemia, interspersed with 5 minutes of reperfusion) yielded a significant infarct-sparing effect, with no added benefit provided by increasing the number of ischemia-reperfusion cycles.13 However, there is no evidence to establish that this algorithm is effective (and optimal) for all patients and all applications. Is the standard stimulus equally appropriate for CABG (as implied by the outcome of the majority of phase II studies), the ≈50% of patients in ERICCA who underwent CABG combined with valve surgery, and the ≈50% of patients in RIPHeart who underwent valve repair/reconstruction or other surgical procedures?8,9 Is there leeway in the standard RIC stimulus, or do variations in timing (including prolongation of the intervening period between the RIC stimulus and the onset of sustained myocardial ischemia, typically on the order of minutes in preclinical studies, to a mean of 1.5–2 hours in ERICCA and RIPHeart8,9), and violations in the RIC algorithm (as occurred in ≈10% of patients in RIPHeart9) have a significant influence on outcome? Although these specific questions remain unresolved, emerging data argue against the concept that, for RIC, one-size-fits-all. In addition to the possible confounding effect of diabetes mellitus and other comorbidities,14 there is evidence that the magnitude of cardioprotection achieved with RIC is proportional to the ischemic burden.6,15,16 Specifically, in patients undergoing CABG, recent retrospective analysis revealed that RIC evoked significant reductions in troponin I release with cross-clamp times >57 minutes, but had no effect with ischemic durations ≤56 minutes.16 Accordingly, in cohorts undergoing elective cardiac surgeries, with cross-clamp times as short as 18 minutes in the ERICCA trial,8 and in which myocardial ischemia-reperfusion injury may have already been blunted by cardioplegia, hypothermia and, in subsets of patients, volatile anesthetics and opioids, the scope for improvement with RIC may have been modest at best.Although all of the aforementioned factors may have had mitigating effects, we posit that a common component in the design of both studies—specifically, the use of propofol in the anesthetic regimen—may have acted as a negative confounder, thereby diluting or obscuring the effect of RIC on study outcomes. That is, propofol may have (1) attenuated RIC-induced cardioprotection,17 possibly by precluding the activation/phosphorylation of signal transducer and activator of transcription 5 (STAT5: the sole kinase identified to date to be associated with RIC-induced cardioprotection in human myocardium18,19), and (2) conferred protection in control subjects, potentially via dual activation of the phosphoinositide 3-kinase/Akt and janus kinase 2/STAT3 pathways.20 Indeed, >90% of subjects in ERICCA and 100% of patients in RIPHeart received propofol8,9 (Figure [B]).Lessons Learned and Proposed Next StepsERICCA and RIPHeart have, without question, dealt a blow to both cardioprotection in general and RIC in particular. Some investigators and clinicians may, based on these neutral outcomes, conclude that RIC has no clinical utility. In contrast, we propose that ERICCA and RIPHeart have delivered 4 critical lessons: (1) the danger of working blind, moving forward in the design and execution of clinical protocols without a firm physiological and mechanistic understanding of RIC-induced cardioprotection; (2) acknowledgment that, for RIC, one size probably does not fit all; (3) the need for attention to detail in all aspects of study design and execution, including choice of appropriate patient cohorts and specific clinical applications, as well as identification and consistent delivery of the optimal RIC algorithm(s); and (4) the importance of heeding the still-limited insights that have been obtained from both positive and negative preclinical studies and phase II trials.These lessons underscore the need to address the gaps in knowledge, and pursue RIC in populations most likely to realize substantial benefit. In this regard, RIC may show greater promise in patients undergoing percutaneous coronary intervention for ST-segment–elevation myocardial infarction,15 particularly in cohorts with anterior wall infarctions and thus large volumes of at-risk myocardium: ie, a population in which treatment is logistically more challenging, but the outcomes are not confounded by the effects of propofol (or cardioprotection caused by cardioplegia, hypothermia, etc) and the scope for meaningful reward with RIC is high. Thus, rather than abandoning RIC, we advocate that the failed outcomes of ERICCA and RIPHeart ". . . should be our teacher, not our undertaker." Denis Waitley.DisclosuresDrs Garratt and Przyklenk serve as advisors to LifeCuff, Inc. Dr Whittaker reports no conflicts.FootnotesThe opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association.Commentaries serve as a forum in which experts highlight and discuss articles (published here and elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine.Commentaries are edited by Aruni Bhatnagar & Ali J. Marian.Correspondence to Karin Przyklenk, PhD, Cardiovascular Research Institute, Wayne State University School of Medicine, Elliman Bldg, Room 1107, 421 E Canfield, Detroit, MI 48201. E- mail [email protected]References1. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion.Circulation. 1993; 87:893–899.LinkGoogle Scholar2. Przyklenk K, Whittaker P. Genesis of remote conditioning: action at a distance–'hypotheses non fingo'?J Cardiovasc Med (Hagerstown). 2013; 14:180–186. doi: 10.2459/JCM.0b013e328358c8eb.CrossrefMedlineGoogle Scholar3. Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R. Transient limb ischemia induces remote ischemic preconditioning in vivo.Circulation. 2002; 106:2881–2883.LinkGoogle Scholar4. Sharma V, Marsh R, Cunniffe B, Cardinale M, Yellon DM, Davidson SM. From protecting the heart to improving athletic performance - the benefits of local and remote ischaemic preconditioning.Cardiovasc Drugs Ther. 2015;29:573–588.CrossrefMedlineGoogle Scholar5. Heusch G, Bøtker HE, Przyklenk K, Redington A, Yellon D. Remote ischemic conditioning.J Am Coll Cardiol. 2015; 65:177–195. doi: 10.1016/j.jacc.2014.10.031.CrossrefMedlineGoogle Scholar6. Ovize M, Thibault H, Przyklenk K. 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A multicenter trial of remote ischemic preconditioning for heart surgery.N Engl J Med. 2015; 373:1397–1407. doi: 10.1056/NEJMoa1413579.CrossrefMedlineGoogle Scholar10. Zaugg M, Lucchinetti E. Remote ischemic preconditioning in cardiac surgery–ineffective and risky?N Engl J Med. 2015; 373:1470–1472. doi: 10.1056/NEJMe1510338.CrossrefMedlineGoogle Scholar11. Heusch G, Gersh BJ. ERICCA and RIPHeart: two nails in the coffin for cardioprotection by remote ischemic conditioning? Probably not!Eur Heart J. 2016; 37:200–202. doi: 10.1093/eurheartj/ehv606CrossrefMedlineGoogle Scholar12. Iliodromitis EK, Andreadou I, Iliodromitis K, Dagres N. Ischemic and postischemic conditioning of the myocardium in clinical practice: challenges, expectations and obstacles.Cardiology. 2014; 129:117–125. doi: 10.1159/000362499.CrossrefMedlineGoogle Scholar13. Johnsen J, Pryds K, Salman R, Løfgren B, Kristiansen SB, Bøtker HE. The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection.Basic Res Cardiol. 2016; 111:10. doi: 10.1007/s00395-016-0529-6.CrossrefMedlineGoogle Scholar14. Przyklenk K. Ischaemic conditioning: pitfalls on the path to clinical translation.Br J Pharmacol. 2015; 172:1961–1973. doi: 10.1111/bph.13064.CrossrefMedlineGoogle Scholar15. Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sørensen HT, Bøtker HE; CONDI Investigators. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention.Eur Heart J. 2014; 35:168–175. doi: 10.1093/eurheartj/eht369.CrossrefMedlineGoogle Scholar16. Kleinbongard P, Neuhäuser M, Thielmann M, Kottenberg E, Peters J, Jakob H, Heusch G. Confounders of Cardioprotection by Remote Ischemic Preconditioning in Patients Undergoing Coronary Artery Bypass Grafting.Cardiology. 2016; 133:128–133. doi: 10.1159/000441216.CrossrefMedlineGoogle Scholar17. Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial.Acta Anaesthesiol Scand. 2012; 56:30–38. doi: 10.1111/j.1399-6576.2011.02585.x.CrossrefMedlineGoogle Scholar18. Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication.Circ Res. 2012; 110:111–115. doi: 10.1161/CIRCRESAHA.111.259556.LinkGoogle Scholar19. Kottenberg E, Musiolik J, Thielmann M, Jakob H, Peters J, Heusch G. 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Mieszkowski J, Kochanowicz M, Żychowska M, Kochanowicz A, Grzybkowska A, Anczykowska K, Sawicki P, Borkowska A, Niespodzinski B and Antosiewicz J (2019) Ferritin Genes Overexpression in PBMC and a Rise in Exercise Performance as an Adaptive Response to Ischaemic Preconditioning in Young Men, BioMed Research International, 10.1155/2019/9576876, 2019, (1-9), Online publication date: 11-Apr-2019. Le Bourg É (2019) Mild Stress-Induced Hormesis The Science of Hormesis in Health and Longevity, 10.1016/B978-0-12-814253-0.00002-4, (25-33), . Basalay M, Davidson S, Gourine A and Yellon D (2018) Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects, Basic Research in Cardiology, 10.1007/s00395-018-0684-z, 113:4, Online publication date: 1-Jul-2018. 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