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Abstract

Translation of the cardioprotective effect by pharmacological and mechanical conditioning therapies into improvement of clinical outcome for the patients has been disappointing. Confounding factors like comorbidity and comedications may explain some of the loss in translation. However, the substantial improvement of outcome in disease states involving ischemia–reperfusion injury, that is, planned cardiac surgery, elective percutaneous coronary intervention, and even primary percutaneous coronary intervention for ST-segment myocardial infarction (STEMI), is the most plausible explanation for the missed demonstration of a clinical benefit. Remote ischemic conditioning has demonstrated consistent cardioprotective effect in experimental and in clinical proof-of-concept studies. As an adjunctive cardioprotective treatment beyond reperfusion, remote ischemic conditioning should address target populations at risk of extensive tissue damage, including patients who experience complications, which may induce profound myocardial ischemia in relation to cardiac surgery or elective percutaneous coronary intervention. Moreover, patients with STEMI and predictable impaired clinical outcome due to delayed hospital admission, high Killip class, cardiogenic shock, and cardiac arrest remain target groups. For high-risk patients, daily remote ischemic conditioning or the corollary of blood flow-restricted exercise may be alternative cardioprotective options during postoperative and post-myocardial infarct rehabilitation.

Keywords

cardiac surgery acute myocardial infarction ischemia–reperfusion injury ischemic preconditioning remote ischemic conditioning

The injury caused by myocardial ischemia and reperfusion (IR) is the main reason for disability and death by coronary artery disease. Reduction of the ischemic injury can be obtained by hypothermic cardioplegia during cardiac surgery and by rapid admission to primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). Even though patients remain at higher risk than a general population comparison cohort, routine implementation of such modalities has translated into a consistent clinical benefit by reducing subsequent disability and death.^1
-3 Reduction of the inevitable reperfusion injury that occurs by restoration of blood flow is conceptually achievable. Decades of experimental and clinical proof-of-concept studies have consistently demonstrated that a variety of pharmacological therapies, such as cyclosporine⁴ and the GLP-1 receptor antagonist, exanatide,⁵ and mechanical conditioning strategies, that is, ischemic preconditioning (IPC), ischemic postconditioning (IPOST), and remote ischemic conditioning (RIC), provide reduction of myocardial injury beyond current cardioprotective strategies and rapid reperfusion (for overview, see studies by Heusch et al⁶ and Botker et al⁷). However, translation of the benefits into improvement of clinical outcomes for the patients has been disappointing,^8

-11 most recently amplified by the neutral results in clinical outcome by the CONDI-2/ERIC-PPCI study testing RIC in patients with STEMI undergoing primary PCI.¹² Naturally, the frustrating results raise doubt whether cardioprotection beyond revascularization as a concept is a way to pursue in order to improve clinical outcome in disease states involving IR injury.^13,14 In cardiological perspective, the question is of relevance in 3 scenarios that expose the heart to IR injury: (1) revascularization by coronary artery bypass graft (CABG) surgery, (2) elective PCI for chronic coronary artery disease, and (3) primary PCI for STEMI.

Cardioprotection in CABG Surgery

The need for surgical procedures is growing in an aging population with an increasing prevalence of comorbidities. Hence, an increasing number of patients with expanding risk profile undergo CABG surgery, which may result in an increased risk of perioperative myocardial injury (PMI) and type 5 myocardial infarction (MI).¹⁵ Both conditions are associated with impaired clinical outcomes.¹⁶ Even though isolated elevations in cardiac troponin T (cTnT) >7 times upper reference limit (URL) and/or cardiac troponin I (cTnI) >20 times URL in the 48-hour postoperative period may indicate the presence of prognostically significant PMI,^16,17 the prognostic cutoff limit is currently not validated.¹⁵ Outcome in relation to PMI is most frequently assessed by total mortality, cardiac mortality, and major adverse cardiovascular and cerebral events (MACCE), including cardiovascular death, MI, stroke, and repeat revascularization at 30 days or 12 months postoperatively.^9,18,19 Whereas cardiac death is clearly associated with PMI,¹⁷ the incidence of a subsequent MI, stroke, or need for repeated revascularization is not, so the incidence of these adverse outcomes may not be modified by any cardioprotective intervention. Perioperative myocardial injury may leave left ventricular function compromised. Hence, cardiac death and postoperative congestive heart failure are the most appropriate outcome measures for the effect of cardioprotective interventions during cardiac surgery. Because operative techniques have improved and selection of patients is careful, the risk of PMI necessitating immediate coronary angiography is currently as low as 2%.²⁰ Thirty-day as well as 12-month mortality is low, with a magnitude of 1% to 3%¹⁸ and 2% to 5%,⁹ respectively. Overall, outcome following CABG surgery is favorable. The potential for further improvement is challenging and a substantial number of patients required to demonstrate a beneficial clinical effect by any routinely applied cardioprotective intervention beyond current best practice.

Local IPC or IPOST by repeated clamping of the aorta has demonstrated protection of the heart by preserved energy levels²¹ and reduced perioperative MI.²² No studies have been undertaken to study whether the modalities translate into an improved clinical outcome in terms of mortality reduction.

Because of its easy application, safety, and inexpensive technique, focus has changed to RIC over the past 2 decades. A number of studies relying on surrogate end points, predominantly perioperative and postoperative release of biochemical myocardial ischemia marker, have demonstrated cardioprotective potential, but the findings are not consistent (for overview, see Botker et al⁷). More recent studies have not only relied on surrogate markers of cardioprotection but also included clinical outcomes and demonstrated a reduction of major cardiovascular events by RIC up to 4 years after CABG.¹⁸ Three large randomized trials have tested the translation into a beneficial clinical outcome.^9,19,23 All studies used broadly similar composite clinical end points including death, MI, and stroke and all failed to show a protective effect of RIC in patients undergoing cardiac surgery. Failure to translate the protective effects of RIC into cardiac surgery may be due to the multifactorial etiology of myocardial injury, potential confounding factors such as patient age, comorbidities including diabetes, concomitant medications, and coadministered cardioprotective general anesthetic agents, of which propofol is most frequently used and known to interfere with successful RIC signal transduction. Additionally, hypothermia and transient ischemia comprehended by instituting a patient on cardiac bypass may replicate cardioprotection in the control group. The disappointing results of well-conducted clinical trials using RIC as routine intervention against PMI indicate that interventions should address specific causes underlying cause of impaired outcome.

Perioperative myocardial injury is definitely associated with impaired outcome, when the release of biochemical myocardial markers is substantial and even more when assessment of PMI is supplemented with electrocardiography (ECG) or imaging modalities of myocardial dysfunction—in clinical practice transthoracic or transesophageal echocardiography. The most important approach to establish an adequate treatment strategy is to identify the underlying cause of PMI and discriminate between graft-related and graft-unrelated ischemia. Coronary angiography is the gold standard for distinguishing between graft-related and graft-unrelated causes in patients with ongoing perioperative myocardial ischemia. Suspicion of perioperative and postoperative myocardial ischemia must be raised by problems with weaning from cardiopulmonary bypass, postoperative ECG changes, wall motion disturbances, and significant biochemical myocardial marker release, and demands prompt transfer to the catheterization lab. Graft occlusion, stenosis, kinking, and spasm are examples of graft-related causes that require immediate operative or pharmacological intervention.¹⁵ Inappropriate myocardial protection, air embolization, thrombosis or spasm in native vessels, and incomplete revascularization may cause graft-unrelated ischemia.¹⁵

At present, additive cardioprotective interventions as a routine supplement to current best practice in anesthetics and surgical and perioperative and postoperative treatments do not seem to add beneficial outcome during CABG. If needed, RIC appears the most applicable and potentially promising modality. However, whether RIC provides benefits in patients exposed to PMI caused by graft-related or graft-unrelated perioperative or postoperative myocardial ischemia remains unclear. In a perspective, patients with graft-related and graft-unrelated myocardial ischemia may represent the most appropriate target cohort for additional cardioprotective intervention by RIC, because PMI is associated with compromised clinical outcome even when graft-related ischemia is adjusted by immediate albeit inherently delayed surgical or pharmacological corrective treatment.

Cardioprotection in Elective PCI

General anesthesia and hypothermia inherent to cardiac surgery are not confounders during cardiac interventions. Thus, PCI may be a cleaner model to translate benefits of RIC to clinical practice. The prognostic importance of post-PCI elevations in cardiac biomarkers in patients with chronic coronary syndrome undergoing planned PCI has been a matter of long dispute as the prognostic implications have been unclear. The Fourth Definition of Acute Myocardial Infarction used >1× 99th percentile URL to define myocardial injury and >5× 99th percentile URL to define type 4a MI²⁴ as recent studies have demonstrated that this cutoff limit is a strong predictor of all-cause death at 1 year.²⁵ Despite a lowering threshold definition of type 4a MI and use of high-sensitivity troponin assays, rates of postprocedural troponin elevation after elective PCI are decreasing reaching a level as low as 8%.²⁶ Appreciation of the low type 4a MI rate is crucial for the interpretation of studies of patients undergoing elective PCI as any cardioprotective modality will only work in patients with a need of cardioprotection. This group of patients is a minority, because evolving PCI techniques and improvements in stent technology appear to have made elective PCI a safe procedure unless mechanical complications occur.

The majority but not all of the studies in patients undergoing elective PCI have demonstrated that RIC reduces ischemic biomarker release in the post-PCI period up to 48 hours.^{27

-36} The Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study demonstrated no significant reduction in type 4a MI according to the existing universal definition (cTnI 0.12- <0.78 ng/mL) and only a nonsignificant reduction (P = .075) according to the World Health Organization criteria (cTnI < 0.78 ng/mL).²⁸ Nevertheless, the CRISP stent study and the late preconditioning trial (that did not report incidences of type 4a MI)³⁵ have demonstrated translation into a clinical benefit in terms of reduction in incidence of all-cause death, MI, or stroke²⁸ and adverse effects (all-cause death, admission for acute coronary syndrome, documented acute coronary syndrome, left ventricular failure, and transient cerebral ischemic attack)³⁵ for follow-up periods of 6 and 11 months, respectively. The CRISP stent long-term follow-up study established that the rate of all-cause death, MI, or stroke remained lower up to 6 years after PCI in the RIC group.³⁰ Of note, neither of the studies, including 224, 200, and 192 patients, respectively, were powered to detect differences in clinical outcome. A closer look at the components of the composite end points revealed that readmission for acute coronary syndrome was the principal adverse event and also the main contributing event that was reduced within 6 to 11 months, while heart failure and death were not.^28,35 In the analysis of the CRISP stent study after 6 years, left ventricular dysfunction requiring hospital admission was added to the composite end point. All of the components of the composite end point (death, MI, acute coronary syndrome including unstable angina pectoris, left ventricular dysfunction, stroke, and transitory cerebral ischemic attack) were lower in the RIC group, but not statistically significant, indicating a beneficial effect that was not gained by a specific component.

How can these findings be interpreted to provide a biologically meaningful explanation of the beneficial effect? Importantly, the studies included a relatively low number of patients and the favorable long-term outcome of the CRISP stent study may relate to selection of patients with favorable outcome predominantly due to the absence of recurrent acute coronary syndrome at the initial follow-up. Given the anticipated major effect of RIC on PMI, the absent effect on death and left ventricular dysfunction is intriguing. The etiology underlying procedural myocardial injury is multifactorial and may result from periprocedural events or complications, either alone or in combination. Side branch occlusion is the most common cause of procedural myocardial injury and type 4a MI in patients with chronic coronary syndrome undergoing PCI,^37,38 but the impact on outcome is only significant when large side branches are occluded.³⁹ Despite current anticoagulant and antiplatelet adjunctive therapies, and use of aspiration or protection devices, distal coronary embolization of intracoronary thrombus and atheromatous material may result in no-reflow/slow-flow during PCI in patients with chronic coronary syndrome. Thrombosis, neurohormonal activation, and release of potent vasoconstrictors, like serotonin and endothelin, from activated platelets may induce coronary epicardial and microvascular vasospasm during PCI, resulting in no-reflow/slow-flow and procedural myocardial injury.^40,41 Because conditioning strategies mainly address reperfusion injury,⁴² a prerequisite is that reperfusion is actually achieved. This is not always the case by minor side branch occlusion and even more infrequent by peripheral embolization.

The observation that recurrent acute coronary syndrome rather than death and left ventricular dysfunction, which is biologically more directly related to PMI, was the main component that was modified by RIC, raises the question whether the beneficial effect of conditioning strategies during elective PCI might be sought beyond the effect on IR injury. The CRISP stent study demonstrated that the initial 6-month reduction in cardiac events associated with reduced post-PCI troponin release was sustained up to 6 years. Hence, the beneficial long-term outcome may reflect an initially improved outcome, mainly in terms of reduced incidence of new acute coronary syndrome and MI that is inherently associated with a reduced incidence of death and heart failure because additional myocardial necrosis and deterioration of the left ventricular function were prevented. Remote ischemic conditioning also modifies the inflammatory response, arterial remodeling,⁴³ and thrombocyte reactivity.⁴⁴ Such modifications may be contributors to the favorable effect on recurrent acute coronary syndrome following elective PCI.

Despite some evidence of a clinical effect of RIC, routine use of cardioprotective intervention beyond current optimized PCI techniques and antiplatelet therapy must be justified by large studies powered for hard clinical end points. Elective PCI can be complicated by events that lead to extensive myocardial IR injury with serious clinical consequences. Remote ischemic conditioning is a safe and inexpensive treatment and may have the potential to modify impaired clinical outcome in patients exposed to complications during elective PCI.

Cardioprotection in Primary PCI

ST-segment myocardial infarction caused by unpredictable myocardial ischemia due to an occluded coronary artery is associated with worse outcome than elective procedures. Contemporary Scandinavian registries report a 1-year mortality of 11% to 15% for patients with acute MI.^1,45 Moreover, the decline in mortality during the past 25 years seems to level out, indicating a continued need for additional treatment beyond rapid revascularization. Hence, STEMI is the most proper target disease to translate the benefits of cardioprotective interventions to clinical practice, when primary PCI is used as the cleanest model to document achievement of rapid reperfusion.

Given this ideal clinical IR injury setting, the clear relationship between infarct size and mortality⁴⁶ and the reiterated demonstration of infarct size reduction by pharmacological, that is, cyclosporine⁴ and β-blockers,⁴⁷ and mechanical conditioning, that is, iPOST and RIC (for overview, see Botker et al⁷), therapies in preclinical, and clinical proof-of-concept studies, the lack of translation into a clinical benefit for patients with STEMI^10
-12 is unexpected. A post hoc analysis of our initial proof-of-concept RIC study in 333 patients with STEMI⁴⁸ revealed promising results on clinical outcome by demonstrating a reduction of MACCE and even all-cause death.⁴⁹ Also, a single-center prospective randomized trial with >500 patients with STEMI has demonstrated that RIC of the leg reduced the primary end point of cardiac mortality and hospitalization for heart failure.⁵⁰ The neutral results on clinical outcome of the CONDI-2/ERIC-PPCI study¹² including 5200 patients randomized to standard care or RIC during ambulance transfer or at hospital arrival added another disappointing experience to the field. Not only did RIC not reduce infarct size as measured by troponin release over 48 hours in 15% of the patients with a full troponin data set of 3 measurements, but the primary composite end point of cardiac mortality or hospitalization for heart failure after 1 year was also not modified.

Comedications and comorbidities may affect the cardioprotective efficacy of RIC. Experimental studies have provided evidence that P2Y12 receptor antagonists may confound the cardioprotective effects of ischemic conditioning.^51,52 A potentially important difference between our first proof-of-concept study⁴⁸ and our subsequent clinical outcome study was a change from clopidogrel to ticagrelor as antiplatelet therapy. In contrast to the first study, 69% of the patients received ticagrelor in the CONDI-2/ERIC-PPCI trial.¹² Even though we found no interaction in terms of clinical outcome between RIC and ticagrelor, the composite primary outcome, cardiac death, and hospitalization for heart failure were lower in the ticagrelor group than in those who received clopidogrel or no antiplatelet therapy, suggesting that ticagrelor may reduce event rate to an extend such that an effect of RIC may be more difficult to demonstrate.

Although confounding factors such as comorbidities, comedication, the temporal pattern of coronary occlusion and reperfusion, the presence of atherosclerosis and collaterals, and microvascular function are known dissimilarities between experimental models and patients, these confounders may not be the dominating reasons for the loss of translation.

The use of biochemical biomarkers of myocardial injury may compromise the possibility to reproduce minor changes in infarct size in large clinical trials than by imaging modalities for quantification of infarct size and myocardial salvage in smaller studies because infarct size with contemporary reperfusion therapy is small and in the order of magnitude of 15% to 17% of the left ventricle.⁴⁸ An infarct size within this scale rarely manifests with clinical symptoms within the usual 6- to 12-month follow-up period used in most clinical trials. Mortality has declined substantially by rapid and optimized reperfusion therapy and the use of potent platelet inhibitors and drugs that attenuate postinfarction remodeling.¹ Accordingly, in our CONDI2/ERIC-PPCI trial, >95% of the patients were classified as Killip class 1.¹² The first component of the primary end point, cardiac death at 1 year, was ≈2%, while the other, hospitalization for heart failure occurred in only 6% to 7% of patients. Given these very low event rates, it is challenging to translate a potential reduction in infarct size, which may have been missed from the biomarker data, into a clinical benefit.

The limitation of our accomplishments inherently includes selection bias because the most severely compromised patients could not be included for ethical reasons as these patients are often unable to give informed consent. Hence, our study cohort may not reflect the entire clinical reality.

Even though a routine application of cardioprotection beyond rapid reperfusion has not translated into clinical benefit in an optimized clinical setting, RIC remains a safe, simple, and inexpensive intervention that may have beneficial effect in settings with long transportation times and less optimized logistic organization. Available data indicate that the cardioprotective effect is preserved with extended duration of ischemia in a clinical STEMI setting⁵³ and that RIC has cardioprotective capacity in patients undergoing reperfusion by thrombolysis.⁵⁴ Thus, future studies should focus on patients with long symptom duration and patients with elevated Killip class, in whom cardiac death and risk of heart failure are high, leaving room for improved clinical outcome.

Other Directions for Research in Cardioprotection

In addition to cardioprotection in conditions inferring acute IR injury, RIC has been tested beyond the approach as a single-occasion treatment. Because of its simplicity, it can be applied as a repeated treatment. Evolving evidence suggests that repeated RIC treatment may provide beneficial effects. The remodeling process continues for several weeks after an MI and involves endothelial dysfunction, inflammation, fibrosis, and rebuilding of vital myocardium. Experimental data indicate that RIC repeated daily for 28 days after MI protects against adverse left ventricular remodeling and increased survival in rats even though infarct size was not reduced further compared to the single-occasion treatment.⁵⁵ A beneficial effect upon contrast-induced acute kidney injury has been demonstrated in patients with STEMI even when RIC treatment was not commenced before 4 weeks after MI.⁵⁶ In humans, repeated RIC modifies human inflammatory response and leukocyte adhesion⁵⁷ and improves coronary microcirculation in healthy volunteers and patients with heart failure.^58
-60 In patients with chronic heart failure, RIC does not seem to change left ventricular ejection fraction after 28 days of once-daily treatment.^61,62 However, RIC reduced systolic blood pressure, decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), and improved global longitudinal strain in the subgroup of heart failure patients with NT-proBNP plasma levels above the geometric mean of 372 ng/L. Interestingly, RIC increased skeletal muscle strength. This may be of clinical importance because patients with heart failure and reduced left ventricular ejection fraction manifest with increased fatigability, rapid exercise-induced declines in skeletal muscle high-energy phosphates, and reduced oxidative capacity.⁶³ In a subsequent study, we found that blood flow-restricted exercise had a beneficial effect on skeletal muscle function and mitochondrial function beyond the effect of RIC in patients with chronic heart failure.⁶⁴ Blood flow-restricted exercise, which is applied by a restrictive cuff placed around the thigh and only inflated to diminish the venous return during lower extremity exercise, does not induce intermittent remote tissue ischemia by cyclic occlusion and reperfusion but rather limits blood flow to working muscles.⁶⁵ The advantage of blood flow-restricted exercise is the need of much lighter workloads than typically prescribed to obtain a beneficial effect on muscle strength. Blood flow-restricted exercise seems capable of mobilizing endogenous protective mechanisms resembling RIC by yet unidentified similar mechanisms.⁶⁶ Blood flow-restricted exercise seems more potent than RIC and may represent a more multitargeted approach than RIC alone.⁶⁷ However, it is not known whether blood flow-restricted exercise or RIC has potential as an extended cardioprotective treatment as an adjunct to revascularized MI. Recruitment of patients in the clinical DREAM trial (https://clinicaltrials.gov: NCT01664611), which investigates the effect of repeated RIC on ventricular function in patients with reduced ventricular function after an acute coronary event, is completed and the results are eagerly awaited.

Conclusion

There is conceptual experimental and clinical evidence that a variety of pharmacological and mechanical conditioning treatments are effective cardioprotective strategies, but their translation into a clinical benefit for the patients remains to be a challenge. Although confounding factors like comorbidity and comedications may explain some of the lacking translation, the steadily improving outcome following disease states involving IR injury may be the most plausible explanation for the challenge. Rather than a routine approach, adjunctive cardioprotective treatment should address target populations at risk of extensive tissue damage, including patients who experience complications, which may induce profound myocardial ischemia in relation to cardiac surgery or elective PCI. Moreover, patients with STEMI and predictable impaired clinical outcome due to delayed hospital admission, high Killip class, cardiogenic shock, and cardiac arrest remain a target group. For high-risk patients, daily RIC or the corollary of blood flow-restricted exercise may be cardioprotective options during postoperative and post-MI rehabilitation.

Footnotes

Acknowledgments

The author thanks Department of Clinical Epidemiology, Aarhus University Hospital, for linguistic revision.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Hans Erik Bøtker is a shareholder of CellAegis Inc, Toronto, Canada.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: H.E.B. is supported by the Danish Council for Strategic Research (11-115818), Independent Research Fund Denmark (11-108354), the Novo Nordisk Foundation (NNF14OC0013337 and NNF 15OC0016674), TrygFonden (109624), and the European Union Cost Action (CA16225).

ORCID iD

Hans Erik Bøtker

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The Future of Cardioprotection—Pointing Toward Patients at Elevated Risk as the Target Populations

Abstract

Keywords

Cardioprotection in CABG Surgery

Cardioprotection in Elective PCI

Cardioprotection in Primary PCI

Other Directions for Research in Cardioprotection

Conclusion

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Funding

ORCID iD

References