Myocardial ischemic conditioning: Clinical implications

Authors:: Derek J Hausenloy, MD, PhD, FRCP, FACC, FESC; Derek M Yellon, PhD, DSc, Hon FRCP, FACC, FESC
Section Editor:: Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC
Deputy Editor:: Todd F Dardas, MD, MS

Literature review current through: Jan 2024.

This topic last updated: May 04, 2022.

INTRODUCTION — The myocardium possesses innate physiologic adaptive processes that render it more resistant to ischemic injury. Two important mechanisms are ischemic pre- and postconditioning. Other protective mechanisms include the long-term development of coronary collateral vessels and myocardial hibernation and stunning. (See "Coronary collateral circulation" and "Pathophysiology of stunned or hibernating myocardium".)

The potential clinical use of myocardial ischemic conditioning to improve outcomes in patients with coronary artery disease will be discussed here. The definition and pathogenesis of ischemic conditioning are discussed separately.

DEFINITIONS — Ischemic pre- and postconditioning are types of ischemic conditioning.

Ischemic preconditioning — Myocardial ischemic preconditioning refers to the protection conferred to ischemic myocardium by preceding brief periods of sublethal ischemia separated by periods of reperfusion. (See "Myocardial ischemic conditioning: Pathogenesis", section on 'Ischemic preconditioning'.)

Ischemic postconditioning — Ischemic postconditioning refers to the ability of a series of brief occlusions of the coronary artery, after a severe ischemic insult, to protect against ischemic reperfusion injury of the myocardium. (See "Myocardial ischemic conditioning: Pathogenesis", section on 'Remote ischemic conditioning'.)

Remote ischemic preconditioning — In addition to the effects of local ischemia, remote ischemia can protect distant organs or tissue during subsequent ischemia [1]. This has been termed remote ischemic preconditioning or cardioprotection at a distance [2]. In animal models, ischemia of the hind limb reduced subsequent myocardial infarction size after coronary artery occlusion. In humans, three five-minute cycles of ischemia to one upper extremity prevented endothelial dysfunction induced by subsequent ischemia to the contralateral upper extremity [3]. Studies have shown mixed effects on the human coronary circulation, with some studies showing improved coronary artery blood flow [4], but others failing to show any effect on myocardial perfusion [5]. (See "Myocardial ischemic conditioning: Pathogenesis", section on 'Remote ischemic conditioning'.)

OBSERVATIONS IN HUMANS — The following are observations of a potential benefit from ischemic conditioning.

Warm-up angina — "Warm-up angina" refers to the improvement in anginal symptoms reported by some patients during the course of the day or after a period of exertion. Exercise sufficient to induce ischemia will improve the anginal threshold during a subsequent period of exercise later in the same day. If the first period of exercise is not sufficient to induce ischemia, no such effect is seen [6-13].

Unstable angina — A number of studies have found that outcomes after an acute myocardial infarction are better in patients who have gone through a period of unstable angina (preinfarction angina) [14-34]. Reports in both the fibrinolytic and percutaneous coronary intervention (PCI) era have suggested that patients with a history of preinfarction angina have a more favorable outcome than those without prior angina [35,36]. The mechanism of protection conferred by preinfarction angina is not known but is speculated to be related to ischemic preconditioning.

Percutaneous coronary intervention — PCI provides a unique opportunity to study the response of the human myocardium to brief periods of controlled ischemia and reperfusion. Some studies have evaluated various indices of myocardial ischemia including clinical, electrocardiographic, metabolic, and hemodynamic measurements during consecutive balloon inflations in patients undergoing elective PCI [37-40]. These reports have consistently shown that, if the duration of the first balloon inflation is longer than a "threshold" of about 60 to 90 seconds, all indices of myocardial ischemia, including angina severity, left ventricular wall motion abnormalities, reduction in left ventricular ejection fraction, ST-segment elevation and QT dispersion on the electrocardiogram, ventricular ectopic activity, biomarker levels, and lactate production are attenuated during subsequent balloon inflations [39-43].

Coronary artery bypass graft surgery — Patients undergoing cardiac surgery are subject to myocardial ischemia that is planned and of moderate severity. The most direct evidence for preconditioning in humans has emerged from a study in patients undergoing cardiac surgery in which the resistance to global ischemia was assessed; changes in collateral flow do not play a role in this setting [44]. Intermittent application of the aortic cross clamp was used to deliver repeated episodes of global ischemia to provide the preconditioning stimulus. Patients subjected to this protocol had better preservation of adenosine triphosphate levels in myocardial biopsies during a subsequent 10-minute period of global ischemia.

A subsequent study, using the same preconditioning protocol, monitored serum troponin T as a marker of myocardial cell necrosis [45]. Prior to surgery, troponin T was not detectable in any patient. At 72 hours after surgery, patients in the preconditioned group had significantly lower serum troponin T concentrations than those who were not preconditioned (0.3 versus 1.4 mcg/L). This has been confirmed this finding in subsequent studies [46,47].

However, applying this preconditioning protocol when using hypothermia and/or cardioplegic arrest has produced mixed results [47,48]. In addition, preconditioning in cardiac surgery has met with resistance because intermittent cross-clamping can prolong surgery by 15 to 30 minutes, represents an embolic risk, and has not been examined in terms of mortality and morbidity. In addition, ischemic preconditioning in cardiac surgery may offer no more protection than the drugs used for premedication (opioids) [49], anesthesia (isoflurane) [50], and cardiopulmonary bypass itself [51].

THERAPEUTIC APPLICATIONS — Ischemic conditioning as a therapeutic intervention has been evaluated in patients undergoing coronary artery bypass surgery (CABG) or elective percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS).

While the intervention has shown some promise, we do not recommend its use to improve outcomes in patients at risk for myocardial infarction (MI).

Coronary artery bypass graft surgery — During CABG, the heart is exposed to prolonged ischemic insult during the period of aortic cross clamping and cardiopulmonary bypass. Reperfusion injury may occur when these interventions are stopped. Clinical outcomes after remote ischemic conditioning have been best studied in patients undergoing cardiac surgery and in particular coronary artery bypass graft surgery. Rates of death and myocardial infarction have not been shown to be improved despite studies showing lower rates of acute kidney injury, ventricular arrhythmias, and perioperative myocardial injury [52].

Most early studies of remote ischemic conditioning in patients undergoing CABG surgery demonstrated beneficial effects, including decreased release of perioperative myocardial biomarkers of injury [52-56]. Most studies have applied ischemic preconditioning. (See "Early noncardiac complications of coronary artery bypass graft surgery".)

However, two large randomized trials and a meta-analysis of prior trials did not find clinical benefit from remote ischemic preconditioning:

●The ERICCA trial investigated the effect of remote ischemic preconditioning (RIPC) on long-term clinical outcomes in patients undergoing elective on-pump CABG [57]. In ERICCA, 1612 patients at increased surgical risk undergoing CABG (with or without valve surgery) were randomly assigned to RIPC (four five-minute inflations/deflations of a standard blood pressure cuff on the upper arm) applied after anesthesia and prior to surgical incision or sham conditioning. The combined primary end point included cardiac death, non-fatal MI, coronary revascularization, and stroke at 12 months. Compared with control, RIPC had no effect on the combined primary end point (26.5 versus 27.7 percent; hazard ratio 0.95, 95% CI 0.79-1.15). It is not clear why the study was neutral but it may relate to concomitant medications such as propofol, the patient population, and the RIPC protocol itself.

●In the Remote Ischemic Preconditioning for Heart Surgery (RIPHeart) Study, 1385 patients at increased surgical risk undergoing on-pump CABG (with or without additional heart/aorta procedures) were randomly assigned to RIPC or sham conditioning (control group) [58]. There was no significant difference in the rate of the combined primary end point of death, MI, stroke, or acute renal failure up to the time of hospital discharge (14.3 versus 14.6, respectively; p = 0.89).

●In a 2014 meta-analysis of 23 trials with 2200 patients undergoing major adult cardiovascular surgery, remote ischemic preconditioning was not associated with an improvement in individual end points of perioperative death, perioperative MI, or stroke [59-61].

Acute coronary syndromes — At present, we do not recommend ischemic conditioning for patients with ACS. Some patients with ACS may be preconditioned by their preceding ischemic episodes (see 'Unstable angina' above). The best evidence for the role of ischemic conditioning in patients with ACS comes from studies of individuals with ST-segment elevation MI (STEMI).

In patients with STEMI undergoing reperfusion therapy with either primary PCI or fibrinolysis, outcomes are significantly improved compared to no reperfusion. However, the degree of benefit may be limited by reperfusion injury. Ischemic postconditioning and remote ischemic conditioning have been evaluated in this setting:

●Ischemic postconditioning uses repeated short balloon inflations at low pressure to temporarily occlude the infarct-related artery after blood flow has been restored with stenting. Several small studies of patients with STEMI have come to differing conclusions [62-66]. In a larger study, the DANAMI-3 trial of over 1230 patients with STEMI and TIMI grade 0 to 1 flow at arrival, ischemic postconditioning did not reduce the composite outcome of death from any cause and hospitalization for heart failure compared with conventional PCI [67].

●Remote (limb) ischemic conditioning has been found to reduce myocardial infarct size (quantified by cardiac biomarkers and cardiovascular magnetic resonance imaging), and improve myocardial salvage (assessed by myocardial nuclear and cardiovascular magnetic resonance imaging) in a few small studies of STEMI patients treated before primary PCI [68-74].

The large CONDI-2/ERIC-PPCI trial randomly assigned 5401 patients eligible for primary PCI to standard treatment (including a sham-simulated remote ischemic conditioning intervention) or remote (limb) ischemic conditioning (intermittent ischemia and reperfusion applied to the arm through four cycles of five-minute inflations and deflations of an automated cuff device) [75]. There was no significant difference in the rate of the primary composite outcome of cardiac death or hospitalization for heart failure at 12 months (8.6 in control versus 9.4 percent with remote ischemic conditioning; hazard ratio 1.10, 95% CI 0.91-1.32). However, the patient population in this study received rapid reperfusion therapy and were low risk in terms of mortality and risk of hospitalization for heart failure.

Thus, there may be a role for remote (limb) ischemic conditioning in higher-risk patients such as those with acute heart failure (Killip Class 3), cardiogenic shock, delayed reperfusion, or thrombolysis. In this regard, the RIC AFRICA study will investigate the effects of remote (limb) ischemic conditioning on clinical outcomes in patients with STEMI treated by thrombolysis [76]. This group of patients are at high risk of complications due to suboptimal reperfusion, high burden of cardiovascular risk factors, prolonged ischemic times, and poor compliance with secondary preventative therapies.

Percutaneous coronary intervention in patients with stable coronary artery disease — In patients with stable coronary artery disease undergoing PCI, we do not recommend ischemic conditioning.

An elevation of cardiac troponin above the upper limits of normal following PCI has been noted in as many as 50 percent of patients undergoing PCI [77-80]. It is seen more often following multivessel or complex procedure. The mechanism is often acute ischemic injury (embolization or distal branch occlusion).

The impact of remote limb ischemic preconditioning (given before PCI) on cardiac biomarkers has been evaluated; studies have led to conflicting results. A 2014 meta-analysis of five studies with 731 patients suggested that limb ischemic preconditioning may be of value in complicated cases [81].

The CRISP stent trial is one example. In CRISP, 242 patients with stable angina were randomly assigned to receive either three five-minute inflations of a blood pressure cuff to 200 mmHg around the upper arm, interspersed with five-minute intervals of reperfusion, or an uninflated cuff around the arm approximately one hour before PCI [82]. Median troponin release at 24 hours was significantly reduced by remote ischemic preconditioning (0.06 versus 0.16 mcg/L), as was the severity of chest pain and the extent of ST segment deviation during the procedure.

SUMMARY AND RECOMMENDATIONS

●Definitions – Ischemic preconditioning refers to the protection conferred to ischemic myocardium by preceding brief periods of sublethal myocardial ischemia. It has been reported to protect the heart against perioperative myocardial injury during cardiac bypass surgery, but its effect on clinical outcomes has not been tested. (See 'Ischemic preconditioning' above.)

●Remote ischemic preconditioning – This refers to the protection conferred to ischemic myocardium by applying brief periods of sublethal myocardial ischemia to an organ or tissue away from the heart. It has been reported to protect the heart against myocardial injury during cardiac bypass surgery, elective percutaneous coronary intervention (PCI), and primary PCI, but has not been shown to improve clinical outcomes. (See 'Remote ischemic preconditioning' above.)

●Ischemic postconditioning – This refers to the protection conferred to ischemic myocardium by interrupting reperfusion with intermittent short-lived episodes of sublethal myocardial ischemia. It has been reported to protect the heart against myocardial injury during cardiac bypass surgery and following primary PCI but has not been shown to improve clinical outcomes. (See 'Therapeutic applications' above.)

●No current clinical role – The evidence does not support the use of myocardial ischemic conditioning for any patient group.

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Topic 1489 Version 25.0

References

1 : Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion.

2 : Remote ischaemic preconditioning: underlying mechanisms and clinical application.

3 : Transient limb ischemia induces remote ischemic preconditioning in vivo.

4 : Remote ischemic conditioning improves coronary microcirculation in healthy subjects and patients with heart failure.

5 : Effect of remote ischemic conditioning on myocardial perfusion in patients with suspected ischemic coronary artery disease.

6 : What induces the warm-up ischemia/angina phenomenon: exercise or myocardial ischemia?

7 : Adaptation to the stress of tachycardia in patients with coronary artery disease: insight into the mechanism of the warm-up phenomenon.

8 : Attenuation of increased regional myocardial oxygen consumption during exercise as a major cause of warm-up phenomenon.

9 : Improvement in ischemic parameters during repeated exercise testing: a possible model for myocardial preconditioning.

10 : Blockade of K(ATP) channels with glibenclamide does not abolish preconditioning during demand ischemia.

11 : Attenuation of myocardial ischemia with repeated exercise in subjects with chronic stable angina: relation to myocardial contractility, intensity of exercise and the adenosine triphosphate-sensitive potassium channel.

12 : The warm-up effect protects against ischemic left ventricular dysfunction in patients with angina.

13 : Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment.

14 : Angina pectoris prior to myocardial infarction protects against subsequent left ventricular remodeling.

15 : Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction.

16 : Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart?

17 : Beneficial effect of prodromal angina pectoris is lost in elderly patients with acute myocardial infarction.

18 : High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients.

19 : Preinfarction angina as a major predictor of left ventricular function and long-term prognosis after a first Q wave myocardial infarction.

20 : Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning?

21 : Prodromal angina limits infarct size. A role for ischemic preconditioning.

22 : Pre-infarction angina elicits greater myocardial viability on reperfusion after myocardial infarction: a dobutamine stress echocardiographic study.

23 : Cardioprotective effect of unstable angina prior to acute anterior myocardial infarction.

24 : New-onset angina preceding acute myocardial infarction is associated with improved contractile recovery after thrombolysis.

25 : Evidence for the delayed effect in human ischemic preconditioning: prospective multicenter study for preconditioning in acute myocardial infarction.

26 : Association of preceding angina with in-hospital life-threatening ventricular tachyarrhythmias and late potentials in patients with a first acute myocardial infarction.

27 : Preinfarction angina protects against out-of-hospital ventricular fibrillation in patients with acute occlusion of the left coronary artery.

28 : Association between preinfarction angina and a lower risk of right ventricular infarction.

29 : Previous angina reduces in-hospital death in patients with acute myocardial infarction.

30 : Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B.

31 : Implications of prodromal angina pectoris in anterior wall acute myocardial infarction: acute angiographic findings and long-term prognosis.

32 : Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction.

33 : Brief antecedent ischemia enhances recombinant tissue plasminogen activator-induced coronary thrombolysis by adenosine-mediated mechanism.

34 : Brief antecedent ischemia attenuates platelet-mediated thrombosis in damaged and stenotic canine coronary arteries: role of adenosine.

35 : Preinfarction angina reduces infarct size in ST-elevation myocardial infarction treated with percutaneous coronary intervention.

36 : Effect of preinfarction angina pectoris on long-term survival in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention.

37 : Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features.

38 : Improved myocardial ischemic response and enhanced collateral circulation with long repetitive coronary occlusion during angioplasty: a prospective study.

39 : Adaptation to myocardial ischemia during coronary angioplasty demonstrated by clinical, electrocardiographic, echocardiographic, and metabolic parameters.

40 : Electrophysiologic effects of ischemic preconditioning on QT dispersion during coronary angioplasty.

41 : Antiarrhythmic effect of repeated coronary occlusion during balloon angioplasty.

42 : Continuous monitoring of global left ventricular ejection fraction during percutaneous transluminal coronary angioplasty.

43 : Beneficial impact of preconditioning during PTCA on creatine kinase release.

44 : Preconditioning the human myocardium.

45 : Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery.

46 : The effect of preconditioning (ischemic and pharmacological) on myocardial necrosis following coronary artery bypass graft surgery.

47 : A comparison between ischemic preconditioning, intermittent cross-clamp fibrillation and cold crystalloid cardioplegia for myocardial protection during coronary artery bypass graft surgery.

48 : Normothermic retrograde blood cardioplegia with or without preceding ischemic preconditioning.

49 : Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle.

50 : Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery.

51 : Does cardiopulmonary bypass alone elicit myoprotective preconditioning?

52 : Ischaemic preconditioning during cardiac surgery: systematic review and meta-analysis of perioperative outcomes in randomised clinical trials.

53 : Prospective, randomized clinical study of ischemic preconditioning as an adjunct to intermittent cold blood cardioplegia.

54 : Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial.

55 : Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial.

56 : Ischaemic conditioning: are we there yet?

57 : Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery.

58 : A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery.

59 : Does remote ischaemic preconditioning with postconditioning improve clinical outcomes of patients undergoing cardiac surgery? Remote Ischaemic Preconditioning with Postconditioning Outcome Trial.

60 : Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial.

61 : Remote preconditioning and major clinical complications following adult cardiovascular surgery: systematic review and meta-analysis.

62 : Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction: a pilot study.

63 : Postconditioning the human heart.

64 : Long-term benefit of postconditioning.

65 : Ischemic postconditioning during primary percutaneous coronary intervention: the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction (POST) randomized trial.

66 : Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial.

67 : Effect of Ischemic Postconditioning During Primary Percutaneous Coronary Intervention for Patients With ST-Segment Elevation Myocardial Infarction: A Randomized Clinical Trial.

68 : Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.

69 : Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial.

70 : Cardioprotective role of remote ischemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action.

71 : Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction.

72 : Remote Ischemic Conditioning in Patients With Myocardial Infarction Treated With Primary Angioplasty: Impact on Left Ventricular Function Assessed by Comprehensive Echocardiography and Gated Single-Photon Emission CT.

73 : Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI).

74 : Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial.

75 : Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

76 : Remote Ischaemic Conditioning in STEMI Patients in Sub-Saharan AFRICA: Rationale and Study Design for the RIC-AFRICA Trial.

77 : Myocardial infarction after percutaneous coronary intervention: a meta-analysis of troponin elevation applying the new universal definition.

78 : Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients.

79 : Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial.

80 : Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention: an analysis of preintervention and postintervention troponin T levels in 5487 patients.

81 : Cardiac remote ischaemic preconditioning reduces periprocedural myocardial infarction for patients undergoing percutaneous coronary interventions: a meta-analysis of randomised clinical trials.

82 : Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial.

خرید پکیج

Myocardial ischemic conditioning: Clinical implications

References