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Featured Articles: Systematic Review Article

Perioperative Cardioprotection: Clinical Implications

Roth, Sebastian MD*; Torregroza, Carolin MD*,†; Huhn, Ragnar MD, PhD*; Hollmann, Markus W. MD, PhD, DEAA; Preckel, Benedikt MD, MA, DEAA

Author Information
doi: 10.1213/ANE.0000000000005234

Abstract

See Article, p 1663

Cardiovascular disease is one of the most common causes of death worldwide and is associated with significant impairment in quality of life.1 An aging society and rising numbers of comorbidities lead to far more patients with cardiac risk factors undergoing surgery.2 Protecting the heart against the consequences of ischemia–reperfusion injury (IRI) will reduce cardiac complications, thereby potentially improving long-term outcome. Perioperatively, a relevant number of patients suffer from myocardial injury, for example, due to perioperative myocardial ischemia3 or after induced IRI, for example, when using cardiopulmonary bypass (CPB) in cardiac surgery.4,5 Cardioprotective strategies should therefore be beneficial, and several treatments have been identified to provide cardioprotection in experimental tissue and animal models.6–8 Potential underlying mechanisms have been studied, allowing for the development of new cardioprotective measures.9

Clinical proof-of-concept studies revealed a significant reduction of tissue injury in patients undergoing primary percutaneous coronary interventions (PCIs)10 or cardiac surgery.11,12 However, although promising, the final translation of the experimental evidence to beneficial clinical outcome has been disappointing: large randomized controlled clinical trials mostly revealed neutral or negative results for different cardioprotective strategies.13–17

Perioperative cardioprotection can be divided into nonpharmacological treatments, for example, ischemic preconditioning (IPC) and remote ischemic preconditioning (RIPC) and remote ischemic postconditioning (RIPostC), and pharmacological treatments mimicking the effects of IPC, RIPC, and IPostC using specific drugs, for example, inhalational anesthetics, noble gases, opioids. This review provides an overview of the current evidence regarding clinical implications of perioperative cardioprotective therapies from an anesthesiological perspective, discussing reasons why translation of promising experimental results into clinical practice and outcome improvement is hampered by potential confounders, and suggests future perspectives to overcome these limitations.

STRATEGIES OF CARDIOPROTECTION IN THE CLINICAL SETTING

Nonpharmacological Cardioprotection

In IPC—the “fundamental version” of nonpharmacological cardioprotection—short periods of nonlethal myocardial ischemia and reperfusion protect the heart against the detrimental consequences of a following ischemic event.18 Due to its invasiveness and potential harm from additional organ ischemia, establishing IPC in clinical routine is not suitable in the majority of clinical ischemia–reperfusion situations. However, ischemic conditioning does not necessarily have to be induced in the organ to be protected (eg, the heart) but could also be initiated in other tissues, for example, a limb (RIPC).19 This measure seems to mediate the same cardioprotective effect as IPC but is realized via short cycles of noninvasive ischemia–reperfusion interventions, for example, upper arm or limb ischemia induced by inflating a blood pressure cuff.19

To achieve organ protection by preconditioning, one has to know when organ ischemia will occur, which is reasonably the case in patients undergoing vascular or cardiac surgery (including organ transplantation), or elective PCI. However, in patients with acute myocardial infarction (AMI), either in nonsurgical conditions or perioperatively, myocardial ischemia occurs before a preconditioning intervention could be performed. In these circumstances, it is also possible to perform ischemic conditioning after the ischemic event, called IPostC: brief episodes of ischemia/reperfusion performed at the onset of reperfusion protect against further organ damage.15,20–24 This has also been shown for the remote stimulus, making remote ischemic postconditioning (RIPostC) a therapeutic option in humans.15

Pharmacological Cardioprotection

Another way to protect the heart against the consequences of IRI is pharmacological conditioning (PC), a concept that is based on the administration of specific drugs mimicking the effect of IPC, for example, volatile anesthetics25,26 and noble gases,27 opioids, dexmedetomidine, cyclosporine A, β-adrenoceptor blockers, or other medications.6,28 Comparable to ischemic protection, pharmacological postconditioning has been proposed.25,29 Data on the best start and/or length of application of the specific drugs, as well as on dosage regimes, are still scarce.

BASIC MECHANISMS OF CONDITIONING IN HUMANS

Although numerous promising experimental results regarding basic mechanisms of conditioning have been published over the years,9 the specific underlying mechanisms of conditioning in the human heart are still unknown.30 Detailed information concerning the molecular basis of cardioprotection can be found in previously published reviews31; we will here shortly focus on mechanisms described in human tissue.

A suggested mechanism of cardioprotection is the release of humoral factors after induction of an ischemic stimulus32; these circulating factors may directly protect the end organ, for example, the myocardium. Different signal transduction pathways have been described, namely a pathway including activation of stimulatory G proteins (protein kinase A, protein kinase C [PKC], protein kinase G),31 the “Reperfusion Injury Salvage Kinase (RISK) pathway,”33 and the “Survivor Activating Factor Enhancement (SAFE) pathway.”34

It has been shown that mitochondrial and contractile function of atrial myocardium taken from patients undergoing cardiovascular surgery reflects cardioprotection induced by RIPC.35 In human atrial trabeculae subjected to pre- and postconditioning in vitro, mediation of protection via the RISK pathway has been demonstrated in subjects without diabetes and with diabetes,36,37 with divergent roles of different PKC subunits.38 In left ventricular tissue of patients undergoing coronary artery bypass graft (CABG) surgery, RIPC preserves mitochondrial function and activates prosurvival serine/threonine protein kinase (AKT).39 In right atrial tissue, RIPC preserves mitochondrial respiration and prevents upregulation of myocardial expression of microRNAs.39

Referring to the SAFE pathway, the signal transducers and activators of transcription (STAT) factor 3 (STAT3) plays a key role in animals, while this seems to be STAT5 in human tissue.40 This has been confirmed later, while also demonstrating that autophagy, another mechanism of cell death, does not play a role in RIPC.41 Early data from Speechly-Dick et al42 suggested that preconditioning in isolated human atrial tissue subjected to simulated ischemia acts via PKC and relies on the action of the adenosine triphosphate (ATP)-dependent potassium (K+) channel (KATP) as a possible end effector.

In patients subjected to CABG surgery, no effect of helium preconditioning, postconditioning, or the combination thereof on activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2) or levels of heat shock protein 27 (HSP27), and protein kinase C ε (PKCε) in the human heart was observed,43 although in animal models, all enzymes have previously been shown to be involved in noble gas induced conditioning.44 Also RIPC did not affect known transduction cascades of conditioning in human tissue: ERK1/2, protein kinase B (PKB/AKT), glycogen synthase kinase 3 β (GSK-3β), and PKCε phosphorylation in right atrial samples of patients undergoing CABG surgery were not different compared to control patients; no differences were seen in interleukin (IL)-6, C-X-C motif chemokine ligand 8 (CXCL8), and IL-10 serum levels between groups.45

To summarize, although signal transduction of conditioning strategies is clearly described in animal tissues, data from human tissue are scarce and do not allow for definitive unraveling of protective mechanisms.

CURRENT CLINICAL EVIDENCE FOR MYOCARDIAL CONDITIONING

Nonpharmacological Cardioprotection

Based on promising experimental results and its feasibility and noninvasiveness, RIPC was the focus of recent clinical studies (Table 1). In 2007, Hausenloy et al46 reported a cardioprotective effect measured as reduced release of troponin by RIPC in a monocentric randomized controlled trial (RCT) including 57 consecutive patients undergoing elective CABG surgery. These results were confirmed by Thielmann et al47 who revealed in a single-center RCT including 329 patients undergoing CABG surgery that RIPC reduced postoperative release of troponin and improved the prognosis: all-cause mortality over 1.5 years seemed to be lower with RIPC than without. However, a weakness of this study is that it was only powered to detect differences in myocardial biomarker release but not to detect differences in other outcome parameters.

Table 1. - Important Clinical Trials of Remote Ischemic Preconditioning
Clinical Studies on Nonpharmacological Cardioprotection
Study Title Authors Journal/Year Design Sample Size Population Intervention End Points Results
Effect of remote ischemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery Hausenloy et al45 Lancet, 2007 Single-center RCT 57 CABG RIPC versus placebo Troponin T at 6, 12, 24, 48, and 72 h after CABG RIPC significantly reduced troponin T release at 6, 12, 24, and 48 h after surgery
Cardioprotective and prognostic effects of remote ischemic preconditioning in patients undergoing coronary artery bypass surgery Thielmann et al46 Lancet, 2013 Single-center RCT 329 CABG RIPC versus placebo Troponin I in the first 72 h after CABG + all-cause mortality RIPC significantly reduced troponin I release and significantly reduced all-cause mortality
Does remote ischemic preconditioning with postconditioning improve clinical outcomes of patients undergoing cardiac surgery? Hong et al14 Eur Heart J, 2014 Multicenter RCT 1280 Elective cardiac surgery RIPC + RIPostC versus placebo Composite of major adverse outcomes, including death, myocardial infarction, arrhythmia, and stroke RIPC + RIPostC did not improve clinical outcome
Remote ischemic preconditioning and outcomes of cardiac surgery Hausenloy et al13 N Engl J Med, 2015 Multicenter RCT 1612 Adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia RIPC versus placebo Combined primary end point of death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 mo after randomization RIPC did not improve clinical outcomes
A multicenter trial of remote ischemic preconditioning for heart surgery Meybohm et al12 N Engl J Med, 2015 Multicenter RCT 1403 Elective cardiac surgery requiring cardiopulmonary bypass RIPC versus placebo Composite of death, myocardial infarction, stroke, or acute renal failure up to hospital discharge RIPC did not show a relevant benefit (no significant differences)
Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery Zarbock et al47 JAMA, 2015 Multicenter RCT 240 Patients undergoing cardiac surgery with high risk for acute kidney injury RIPC versus placebo Rate of acute kidney injury within the first 72 h after cardiac surgery Significant reduction of the rate of acute kidney injury and use of renal replacement therapy
Effect of remote ischemic conditioning on clinical outcomes in patients with acute myocardial infarction Hausenloy et al48 Lancet, 2019 Multicenter RCT 5401 ST elevation myocardial infarction RIC before primary PCI versus placebo Combined end point of cardiac death or hospitalization for heart failure at 12 mo Remote ischemic conditioning did not improve clinical outcomes
Abbreviations: CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; RIC, remote ischemic conditioning; RIPC, remote ischemic preconditioning; RIPostC, remote ischemic postconditioning.

Those early trials raised the hope that the promising data on RIPC from animal studies could be translated into clinical practice. Unfortunately, following publication of some neutral studies on RIPC in humans,50,51 an RCT including >1200 patients revealed that RIPC by transient upper limb ischemia did not improve clinical outcome (defined as composite of major adverse outcomes, including death, myocardial infarction, arrhythmia, stroke, coma, renal failure or dysfunction, respiratory failure, cardiogenic shock, gastrointestinal complication, and multiorgan failure) in patients undergoing cardiac surgery.15 Two large international multicenter RCTs followed in the course of 2015, both showing no beneficial effects of RIPC on clinical outcome.13,14 Meybohm et al13 concluded from their study including 1403 patients that upper limb RIPC did not show a relevant benefit among patients undergoing elective cardiac surgery. Also after 12-month follow-up, RIPC had no effect on myocardial dysfunction, neurocognitive function, and long-term outcome.52 As the whole cohort received propofol-based anesthesia, the authors suggested that the use of propofol may have interfered with RIPC.45 Hausenloy et al14 included 1612 patients and came to a similar conclusion, for example, that RIPC did not improve clinical outcomes in patients undergoing elective on-pump CABG surgery with or without valve surgery. In the following years, no RCT could disprove the results of these 3 trials.

Zarbock et al48 investigated in patients undergoing CABG surgery the effect of RIPC on acute kidney injury (AKI) in 240 high-risk patients: RIPC significantly reduced the incidence of AKI and the need for renal replacement therapy. Although this study did not assess cardioprotective effects, it demonstrated that RIPC in cardiac surgery may be beneficial in specific patient populations.

With regard to IPostC, most studies included patients with AMI, as this is the typical clinical situation where myocardial ischemia occurs before a conditioning intervention can be achieved. Khan et al21 performed a meta-analysis of 19 studies analyzing the cardioprotective role of IPostC and revealed that IPostC during PCI in ST segment elevation myocardial infarction (STEMI) appeared to be superior to PCI alone in both reduction of myocardial injury and improvement of left ventricular function. According to the authors, this effect seemed to be more pronounced when a greater myocardial area was at ischemic risk.21 A meta-analysis by Lou et al23 reported that local and RIPostC improved myocardial salvage index and decreased myocardial edema in STEMI patients without affecting final infarct size, left ventricular infarct volume, or microvascular obstruction. However, Hausenloy et al49 recently presented data of RIPostC on the incidence of cardiac death and hospitalization for heart failure at 12 months in 5401 patients with AMI undergoing primary PCI. As with RIPC, also RIPostC did not produce a clinically meaningful beneficial effect as an adjunct to PCI on clinical outcomes (cardiac death or hospitalization for heart failure) at 12 months when compared with PCI alone. RIPostC also had no effect on major secondary end points including myocardial infarct size assessed by cardiac biomarker release.49

Pharmacological Cardioprotection

Inhalational Anesthetics and Gases.

Several pharmacological agents have been evaluated in the context of myocardial IRI in clinical trials (Table 2). Volatile anesthetics (eg, sevoflurane, isoflurane, or desflurane) have been proposed to provide cardioprotective effects as they activate or prime the same cellular pathways as IPC and RIPC.58 Well-designed animal studies have repeatedly demonstrated that exposure of the myocardium to a volatile anesthetic before a period of ischemia significantly protects the myocardium against subsequent IRI.59

Table 2. - Important Clinical Trials of Pharmacological Conditioning
Clinical Studies on Pharmacological Cardioprotection
Study Title Authors Journal/Year Design Sample Size Population Intervention End Points Results
Volatile anesthetics versus total intravenous anesthesia for cardiac surgery Landoni et al16 N Engl J Med, 2019 Multicenter RCT 5400 Elective CABG Volatile anesthetic versus total intravenous anesthesia Death from any cause at 1 y Anesthesia with a volatile agent did not result in significantly fewer deaths at 1 y than total intravenous anesthesia
Cyclosporine A in reperfused myocardial infarction Ottani et al15 J Am Coll Cardiol, 2016 Multicenter RCT 410 Patients with STEMI, TIMI flow grade 0 to 1, and committed to primary PCI Cyclosporine A versus placebo Incidence of ≥70% ST segment resolution 60 min after TIMI flow grade 3, troponin T, and clinical outcome parameters No effect on ST segment resolution or troponin T; no improvement of clinical outcomes up to 6 mo
NO for inhalation in ST elevation myocardial infarction Janssens et al52 Eur Heart J, 2018 Multicenter RCT 250 STEMI NO versus oxygen Infarct size assessed by delayed enhancement contrast magnetic resonance imaging Inhalation of NO in STEMI patients was safe but did not reduce infarct size at 48–72 h
Clonidine in patients undergoing noncardiac surgery Devereaux et al53 N Engl J Med, 2014 Multicenter RCT 10,010 Patients at risk for atherosclerotic disease undergoing noncardiac surgery Clonidine versus placebo Composite end point of death or nonfatal myocardial infarction at 30 d Clonidine did not reduce the rate of the composite outcome but increase risk of hypotension and cardiac arrest
Effect of xenon anesthesia compared to sevoflurane and total intravenous anesthesia for coronary artery bypass graft surgery on postoperative cardiac troponin release Hofland et al54 Anesthesiology, 2017 Multicenter RCT 492 Low-risk, on-pump CABG Xenon versus sevoflurane and TIVA Cardiac troponin I concentration in the blood 24 h postsurgery In postoperative troponin I release, xenon was noninferior to sevoflurane in CABG patients
Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery Mehta et al55 N Engl J Med, 2017 Multicenter RCT 882 Left ventricular ejection fraction of ≤35% and cardiac surgery with cardiopulmonary bypass Levosimendan versus placebo Composite of death, renal replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device Levosimendan did not result in a rate of the composite end point
Effect of early metoprolol on infarct size in ST segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention Ibanez et al56 Circulation, 2013 Multicenter RCT 270 Patients with STEMI undergoing PCI within 6 h of symptoms onset Metoprolol versus placebo Infarct size on magnetic resonance imaging performed 5–7 d after STEMI Early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events
Abbreviations: CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; STEMI, ST segment elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction; TIVA, total intravenous anesthesia.

In addition, postconditioning can be induced by volatile anesthetics thereby reducing myocardial injury after ischemia.25 First clinical trials followed, supporting a protective effect of volatile anesthetic induced conditioning,11,12,60 reflected in an improvement of secondary end points and surrogate parameters of organ injury, for example, reduction of troponin release. Additional studies in different surgical populations followed, and the beneficial effects of volatile anesthetics were promising.61 These results lead to recommendation in guidelines, for example, from the American College of Cardiology and the American Heart Association5 and from the European Association for Cardiothoracic Surgery,62 to prefer volatile agents for anesthesia in cardiothoracic surgery. However, there were also negative trials, showing no reduction of myocardial biomarkers after cardiac and noncardiac surgery by use of volatile agents.63–65 Most available data came from small studies and small early meta-analyses,26 primarily focusing on biomarker release. A more recent meta-analysis concluded that sevoflurane reduces postoperative 24-hour cardiac troponin I concentration compared with propofol-based anesthesia and is associated with lower incidence of late adverse cardiac events in patients undergoing cardiac surgery.66

The question whether volatile anesthetics protect the heart and thereby induce improvement of outcome remained open for a long time. A meta-analysis by Uhlig et al67 concluded that general anesthesia with volatile anesthetics in cardiac surgery may be associated with reduced mortality, while no benefits were seen in noncardiac surgical patients. In a moderate-sized RCT including 868 patients undergoing CABG surgery, a reduced length of hospital stay and a possible reduction in 1-year mortality was observed when using sevoflurane instead of total intravenous anesthesia using propofol.68 However, there was no beneficial effect on the composite end point of prolonged intensive care unit stay, mortality, or both in patients undergoing high-risk cardiac surgery (combined valvular and coronary surgery).69 In a recently published pragmatic, multicenter RCT including 5400 patients undergoing isolated CABG surgery, use of volatile anesthetics (desflurane, sevoflurane, isoflurane) at any given moment during anesthesia versus propofol-based total intravenous anesthesia did not significantly reduce mortality at 1 year after surgery.17 There were also no significant differences with regard to secondary outcomes such as myocardial infarction or other adverse events.17

Therefore, to date, there is no final answer regarding cardioprotective effects of volatile anesthetics. As mentioned, according to different guidelines,5,62 volatile anesthetics should be favored over propofol in cardiothoracic anesthesia, given the hypothesis that propofol counteracts cardioprotection.32

Next to volatile anesthetics, also inhalation of noble gases induced organ protection.70,71 In healthy volunteers, helium protected human endothelium against ischemia/reperfusion damage.72 However, investigating cardioprotection, application of a gas mixture containing helium (70%) for 3 × 5 minutes before (preconditioning) or at the end of aortic cross-clamping (postconditioning) during CABG surgery (or a combination of both) had no effect on postoperative troponin release.43 Xenon anesthesia was noninferior to sevoflurane anesthesia and superior (determined by perioperative troponin release) to total intravenous anesthesia with propofol in low-risk CABG surgery patients.55 In comatose survivors of out of hospital cardiac arrest, inhaled xenon combined with hypothermia (compared to hypothermia alone) was suggested to lead to less severe myocardial injury as demonstrated by a significantly reduced release of troponin-T.73 However, there are yet no outcome studies addressing noble gas induced cardiac protection in larger patient populations.

Opioids.

Solid evidence from in vitro and in vivo animal studies demonstrates that opioids protect the myocardium against IRI.74 Endogenous opioid receptors play a significant role in cardioprotection,75,76 and namely activation of κ and Δ opioid receptors is directly involved in protective strategies.77 However, clinical evidence is scarce. In cardiac surgery, commonly used opioids such as sufentanil or remifentanil have been shown to reduce infarct size defined as decreased release of cardiac biomarkers. Aortic root infusion of sufentanil in patients undergoing mitral valve repair attenuated IRI as measured by significantly lower plasma concentrations of creatinine kinase (CK)-muscle-brain type (MB) and troponin I.78 In a small RCT (40 patients undergoing elective on-pump CABG surgery), the addition of remifentanil to the anesthesia regimen consisting of fentanyl (25 μg/kg in total) and propofol reduced myocardial damage.79 A meta-analysis including 1473 patients from 16 randomized trials stated that remifentanil reduced cardiac troponin release, time of mechanical ventilation, and length of hospital stay in patients undergoing cardiac surgery.80

Because opioids are commonly used in cardiac surgery, the most interesting questions are (1) which opioid is most protective and (2) which dose is needed to achieve a cardioprotective effect? Both questions can currently not be answered, but available evidence suggests that cardioprotective doses are much higher than opioid doses routinely used for general anesthesia.74 More research is needed to finally define the role of cardioprotection by opioids in the clinical setting.

α-2 Receptor Agonists.

Application of the α-2 receptor agonist clonidine has long been suggested to improve outcome of high-risk cardiac patients undergoing surgery,81 most likely by blunting central sympathetic outflow. However, low-dose clonidine did not reduce the rate of a composite outcome of death or nonfatal myocardial infarction in patients undergoing noncardiac surgery.54 A direct conditioning effect of clonidine in human myocardial tissue has not been shown so far.

Dexmedetomidine, a more selective α-2 receptor agonist primarily used as a sedative and for prevention of postoperative delirium,82 confers cardioprotection in experimental models.83–85 Cardioprotective effects in humans might be a result of hemodynamic changes86; however, a small prospective trial including 38 patients undergoing CABG surgery indicated that myocardial damage was not reduced by dexmedetomidine, although a higher cardiac index and lower mean pulmonary arterial pressures were observed in the treatment group.87 In a retrospective analysis, Zhou et al88 indicated that in patients undergoing valve surgery postoperative release of myocardial biomarkers (cardiac troponin I) was lower in patients receiving dexmedetomidine during the procedure, an observation that was confirmed in a small prospective randomized study in 28 patients undergoing valve replacement89 and in patients undergoing CABG surgery.90 However, large outcome trials are pending and the available data on clinical relevant cardioprotection by dexmedetomidine are of low to moderate quality.

β-Blockers and Nitrates.

Perioperative use of β-blockers to prevent cardiovascular adverse events and to improve outcome has been discussed for a long time.91 β-blockers were indeed shown to be cardioprotective: postoperative release of myocardial biomarkers was reduced, however, at the expense of an increased risk of cerebral insult and higher mortality.92 Metoprolol given as a postconditioning stimulus before coronary artery reperfusion reduced infarct size in animals,93 an effect that was confirmed after intravenous metoprolol injection in patients with AMI undergoing emergency PCI.57 A follow-up study including 683 patients randomized to receive 2 times 5 mg metoprolol or placebo before primary PCI revealed a reduced incidence of malignant arrhythmias in the acute phase but did not show an infarct size reduction as measured by cardiac magnetic resonance imaging (CMRI).94 Today, no clinical studies assessing the conditioning effect of β-blockers in cardiac surgery patients are available.

NO plays a significant role in transduction pathways of conditioning, and single doses of nitroglycerin, an NO donator, protects endothelial function against IRI.95 In contrast, long-term treatment with nitrates leads to nitrate tolerance, which can aggravate ischemic injury. In nitroglycerin-naive patients, inhalation of NO reduced infarct size in patients after AMI undergoing primary PCI. However, this effect was not observed in patients on chronic treatment with nitrates.53 Protection by nitrates in patients undergoing cardiac surgery is hindered by their vasodilatory effects. However, local application of NO into the CPB system in patients undergoing CABG surgery reduced postoperative release of ischemic myocardial biomarkers.96 Analyzing data of control patients from an RCT addressing remote conditioning in cardiac surgery patients, Candilio et al97 showed intravenous glyceryl trinitrate (GTN) intraoperatively to cause 39% less perioperative myocardial infarction compared with those not receiving GTN. However, analyzing individual patient data from 3 randomized studies in patients undergoing cardiac surgery showed no evidence of myocardial protection by nitroglycerin per se, nor an interference of nitroglycerin with RIPC.98 The Effect of Remote Ischemic Conditioning and Glyceryl Trinitrate on Perioperative Myocardial Injury in Cardiac Bypass Surgery Patients (ERIC-GTN) trial (www.clinicaltrials.gov:NCT01864252) aims to determine the role of GTN administered during cardiac surgery for cardioprotection and whether GTN interferes with other cardioprotective strategies, for example, RIPC.99

Inotropic Agents: Phosphodiesterase Inhibitors (Milrinone) and Calcium Sensitizers (Levosimendan).

Inotropic agents improve cardiac function and have been shown to be beneficial in specific clinical situations, namely in cardiac surgery patients. Milrinone, a phosphodiesterase inhibitor improving cardiac contractility, given as a conditioning stimulus, reduced myocardial damage in experimental models,100,101 but clinical studies are not yet available.

Levosimendan is a calcium sensitizer enhancing cardiac contractility; in addition, it promotes vasodilation through opening of KATP channels on vascular smooth muscle cells102 and has pleiotropic effects on the heart and other organs.103 Intracoronary Levosimendan reduced cell death induced by ischemia/reperfusion (I/R) in pigs and activated survival signaling through KATP channel opening and NO.104 Levosimendan given before initiation of cardiac bypass reduced the release of myocardial biomarkers in patients undergoing CABG surgery,105 an effect that was confirmed in an early meta-analysis.106 Several clinical studies and numerous meta-analyses followed, but still the cardioprotective effect of Levosimendan is unclear.107 In patients with reduced left ventricular function undergoing cardiac surgery, Levosimendan did not improve postsurgical clinical outcome.56 However, a recent post hoc analysis of the latter study showed that Levosimendan was associated with a lower 90-day mortality and reduced incidence of low cardiac output syndrome in patients undergoing isolated CABG, while there was no beneficial effect in patients subjected to isolated valve or combined CABG/valve surgery.108 A retrospective analysis of Levosimendan preconditioning of the right heart in patients receiving a left ventricular assist device showed no adverse events and a lower mortality of Levosimendan treated patients compared to nontreated subjects.109

Cyclosporine A.

Opening of the mitochondrial permeability transition pore (MPTP) is a critical determinant of cell death in the setting of acute IRI, and cyclosporine A (CsA) inhibits opening of the MPTP. After promising experimental data showed cardioprotection by CsA, a small trial including 58 patients with AMI undergoing primary PCI (postconditioning) showed a reduction in infarct size by >20%, as measured by biomarker release and CMRI on day 5 after infarction.110 Application of CsA was without acute side effects, and for a subset of 28 patients, the infarct reducing effect was still present after 6 months, with no negative effects on long-term LV remodeling.111 However, in an adequately sized multicenter RCT, the protective effects of CsA as a postconditioning stimulus on a composite end point of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse LV remodeling at 1 year could not be confirmed.112 The same negative results were observed in patients treated with thrombolytic therapy for AMI.113 A recent meta-analysis summarizing the effects of CsA on myocardial IRI also concluded lack of a cardioprotective action.114 In 78 adult patients undergoing elective CABG surgery randomized to receive either an intravenous bolus of CsA (2.5 mg/kg) or placebo directly after induction of anesthesia and before sternotomy (preconditioning), no significant difference in mean peak troponin release was observed; however, in higher-risk patients with longer CPB times, a significant reduction in myocardial damage with CsA therapy when compared with controls was demonstrated.115 In 61 patients undergoing elective aortic valve surgery and randomly assigned to receive an intravenous bolus of 2.5 mg/kg CsA or placebo 10 minutes before aortic cross-unclamping (postconditioning), CsA reduced IRI as measured by the 72-hour area under the curve for cardiac troponin I. This beneficial effect remained significant after adjustment for the duration of aortic cross-clamping.116 An accompanying editorial stated that before giving CsA routinely to cardiac surgery patients, knowledge of effects in heterogeneous patient populations, effects on longer-term outcomes, effects of confounders (genetics, sex, age, and/or comorbidities), and a possible time window of protection is needed.117

LIMITED TRANSLATABILITY OF EXPERIMENTAL AND CLINICAL DATA TO PERIOPERATIVE CARDIOPROTECTION

The above-cited clinical data show a significant gap between experimental evidence and clinical effectiveness for perioperative cardioprotection. Various confounders and specific clinical circumstances have been suggested as underlying reasons.118 These include (but are not limited to) age, presence of comorbidities, duration of disease and comorbidity, comedication for treatment of disease or comorbidity, acute treatment related to the intervention, use of anesthesia and specifically use of anesthetic and analgesic drugs, and differences in measurement of end points in experimental and various clinical settings.28

Most clinical data are available from studies in patients with STEMI undergoing primary PCI. Thus, in these patients, an anti-ischemic or postconditioning cardioprotective effect is studied, as myocardial ischemia already occurred. In STEMI patients, cardioprotection depends on the extent of myocardial damage, location of myocardial infarction, coronary collateral flow, partial recanalization before PCI, timing, and result of PCI.119 In contrast, perioperative cardioprotection (namely preconditioning) is mostly studied in cardiac surgery patients, undergoing isolated CABG, isolated valve surgery, or a combination of CABG/valve surgery. Preinfarct angina and long-term use of GTN significantly influence clinical cardioprotection and are common in patients undergoing cardiac surgery. In these patients, mostly short global myocardial ischemia in combination with other proven cardioprotective strategies, for example, use of cardioplegic arrest, is applied.

Release of cardiac-specific biomarkers plays a central role in defining perioperative myocardial infarction or injury after CABG (type 5 myocardial infarction).120 Compared to isolated CK-MB measurements, cardiac troponin release has higher sensitivity and specificity for cardiomyocyte necrosis and has been shown to be associated with short- and long-term outcome after cardiac surgery.120 Thus, most clinical proof-of-principal studies on perioperative cardioprotective strategies focused on myocardial biomarker release, specifically on troponin release. However, direct myocardial damage by the surgical procedure, for example, excision of aortic valve, opening of the atrium or ventricle, contributes to cardiac biomarker release, thereby hampering determination of potentially preventable IRI damage.

Myocardial injury not only involves necrosis but also more regulated forms of cardiomyocyte death as apoptosis, necroptosis, pyroptosis, and autophagy-related cell death.121–123 In addition, noncardiomyocyte damage to fibroblasts, endothelial and smooth muscle cells, platelets, and immune cells contribute to myocardial damage.6,28 Factors released from these cells might disrupt endothelial barrier function, induce interaction of endothelial cells with blood cells, and activate platelets and leukocytes to generate clots—all mechanisms that finally contribute to microvascular obstruction.124 Cardioprotective interventions targeting these cells have also been shown to contribute to reduction of myocardial damage,125,126 but this aspect is mostly not measured in clinical studies.

FUTURE STRATEGIES

Multitarget Protection

Optimal clinical cardioprotection might need multiple interventions targeting different cells, different signaling pathways, and different time points during IRI. Recently, multitarget strategies to reduce myocardial IRI have been formulated, looking for additive or synergistic cardioprotection from combined agents or interventions.6 These could target, for example, activation of prosurvival pathways (RISK, SAFE, protein kinase G), plus inhibition of cell death pathways, plus protection against different forms of cardiomyocyte death (necrosis, apoptosis, autophagy, etc.),33 for example, protection by xenon (targeting signal transduction pathways) combined with hypothermia (targeting necrosis and apoptosis).127 Another strategy could be a combined cardiomyocyte and noncardiomyocyte protection, for example, improving coronary microcirculation by P2Y12 inhibitors. The latter drugs are widely taken by patients with coronary artery disease undergoing CABG surgery and resemble a significant confounder in clinical studies investigating cardioprotection.128 Comedication might also enhance or restitute cardioprotection: statins have been shown to restore cardioprotection in diabetic animals,129 and cardioprotective strategies seem to be less efficient in nonstatin users.130 Thus, optimal comedications need to be defined to optimize perioperative cardioprotection.

Combining pre-, per-, and postconditioning strategies improves organ protection in animals to some extent,131 whereby results from clinical studies are conflicting. A combination of RIPC and ischemic postconditioning in STEMI patients either improved myocardial salvage index (measured by CMRI) or had no effect on myocardial damage.132,133 Combining cardioprotective strategies might also help to overcome blockade of protection by known confounders, for example, comorbidities (hypertension, diabetes mellitus)134 or cotreatments (eg, use of glibenclamide, nitrates). Using long-term conditioning to improve functional outcomes in patients with chronic conditions (eg, heart failure) has also shown promising results.135

Developing New Experimental and Clinical Studies

Future studies evaluating novel targets for cardioprotection need to use more clinical relevant experimental models, including animals with chronic coronary artery atherosclerosis (resembling AMI patients) or animal models using extracorporeal circulation and I/R settings (resembling CABG surgery), taking into account comorbidities and comedications of respective patient populations.28 Additionally, clinical studies need to be designed properly, taking into account known confounders118 and defining relevant end points not only for proof-of-principle studies28 but also for long-term outcome in phase III studies.136,137

CONCLUSIONS

A number of nonpharmacological and pharmacological strategies have the potential to protect the heart against IRI in the perioperative setting. Results of experimental studies are convincing, but translation into clinical practice remains challenging. Several confounders have been identified contributing to the mainly negative results from clinical studies, and at least some of them might be modifiable in the perioperative setting. Carefully designed clinical trials in well-defined patient cohorts evaluating combination of protective strategies targeting different cellular pathways, different cell types, and different kinds of cell damage are warranted. At this moment, we should not give up as there is still high potential to improve patient outcome by perioperative cardioprotection.

DISCLOSURES

Name: Sebastian Roth, MD.

Contribution: This author helped initiate the concept and write the manuscript.

Name: Carolin Torregroza, MD.

Contribution: This author helped write and revise the manuscript.

Name: Ragnar Huhn, MD, PhD.

Contribution: This author helped revise the manuscript.

Name: Markus W. Hollmann, MD, PhD, DEAA.

Contribution: This author helped revise and finally edit the manuscript.

Name: Benedikt Preckel, MD, MA, DEAA.

Contribution: This author helped initiate the concept and revise the manuscript.

This manuscript was handled by: Alexander Zarbock, MD.

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