The Pathophysiology of Myocardial Ischemia and Perioperative Myocardial Infarction

ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 112

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Review Article

The Pathophysiology of Myocardial Ischemia and Perioperative Myocardial Infarction 1

Marli Smit, MB ChB, MMed (Anes), FCA (SA), PhD*, , A.R. Coetzee, MB ChB, MMed (Anes), FFA (SA), FFARCS, PhD, MD, PhD*, A. Lochner, DSc, PhDy *

Department of Anesthesiology and Critical Care, Stellenbosch University, Tygerberg Academic Hospital, Cape Town, South Africa y Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa

Ischemic heart disease, the leading cause of death worldwide, may result in devastating perioperative ischemia and infarction. The underlying pathophysiology, precipitating factors, and approach to prevention differ between patients presenting for noncardiac surgery, developing acute coronary syndrome versus stable angina. The first half of this article reviews the pathophysiology of acute coronary syndrome and stable angina. Acute coronary syndrome, otherwise known as Type 1 myocardial infarction, includes unstable angina, non-ST segment elevated myocardial infarction and ST segment elevated myocardial infarction. Acute coronary syndrome occurs as a result of vulnerable plaque rupture with subsequent varying degrees of thrombus formation, arterial spasm, and thus coronary occlusion. Stable angina, on the other hand, results from a myocardial oxygen delivery and demand mismatch in the setting of fixed coronary stenosis. After this discussion, the review article considers how both apply to perioperative myocardial infarctions and myocardial injury after noncardiac surgery. This article furthermore argues why myocardial oxygen delivery demand mismatch (Type 2) myocardial infarction is the most likely underlying pathophysiology responsible for perioperative myocardial infarctions. Being aware of this and knowledgeable about Type 2 infarctions may enable anesthetic providers to better predict the majority of triggers contributing to, and thus decreasing the incidence of, perioperative myocardial infarctions. Ó 2019 Elsevier Inc. All rights reserved. Key Words: pathophysiology; acute coronary syndrome; stable angina; peri-operative myocardial infarction; myocardial injury after non cardiac surgery

ISCHEMIC HEART disease (IHD) is the leading cause of morbidity and mortality in the world and a principal contributor to the burden of disease.1-3 In addition, patients with IHD undergoing noncardiac surgery are at an increased risk for perioperative myocardial complications including perioperative ischemia, infarction, cardiac failure, and dysrhythmias, all associated with increased morbidity and mortality.4,5 Furthermore, the number of patients with coronary Funding: A part of this work came from a doctoral study, supported by the Jan Pretorius Research Fund, South African Society of Anesthesiologists. 1 Address reprint requests to M. Smit, Department of Anesthesiology and Critical Care, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, Francie van Zijl Drive, Tygerberg, 7505, South Africa. E-mail address: [email protected] (M. Smit). https://doi.org/10.1053/j.jvca.2019.10.005 1053-0770/Ó 2019 Elsevier Inc. All rights reserved.

artery disease (CAD), who are on medical treatment or have already undergone stent placement or a coronary artery bypass graft and require surgery, is increasing as a result of the aging population.6 The degree of the coronary occlusion, the volume of the affected ischemic myocardium, extent of collateral circulation, pre-existing myocardial metabolic rate, genetic factors, and the intrinsic survival capacities of the myocytes will collectively determine the specific clinical presentation of myocardial ischemia.7 This review article initially discusses the underlying pathophysiology of IHD. This is followed by a review of the literature focusing on the pathophysiology responsible for the development of perioperative ischemia and infarction in patients with CAD, presenting for noncardiac surgery Table 1.

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Table 1 The Old, New and Future Questions Current knowledge  IHD is as a result of acute coronary syndrome or prolonged myocardial oxygen supplydemand imbalance in the presence of stable coronary artery disease. Recent advances  Inflammation is viewed as a more prominent risk factor than LDL in the development of atherosclerosis.  Nonfoamy macrophages, and not foamy macrophages as previously thought, play the dominant role in the immune response during atherosclerosis. What this article supports  Type 2 myocardial infarctions are the most likely underlying pathophysiology for the majority of PMIs.  The importance of postoperative ECG and troponin screening in high risk and/or symptomatic patients.  Preoperative coronary angiogram screening only for patients with acute coronary syndrome or high-grade stable angina, refractory to optimal medical therapy, and/or high-risk features on noninvasive testing.  Perioperative emphasis on maximizing myocardial DO2 and minimizing myocardial VO2, if excessive, aiming to optimize the oxygen supplydemand balance. Future research opportunities  The precise role of the foamy macrophages in atherosclerosis and plaque instability.  An effective treatment protocol after postoperative troponin elevation.  The tailored use of perioperative b-blocker protocols, in combination with a meticulous maintenance of perfusion pressure, in the prevention of MINS and mortality after surgery.

Part 1: Myocardial Ischemia Atherosclerosis Risk factors associated with IHD (Table 2) will contribute to coronary atherosclerosis with resulting damage and dysfunction of the vascular endothelium. Conventionally, the initiating factor for atherosclerosis is considered to be high levels of low-density lipoprotein (LDL).16 Half of atherosclerotic-related deaths, however,

Table 2 Risk Factors Associated With Ischemic Heart Disease8-15 Modifiable

Nonmodifiable

High total serum cholesterol High LDL-cholesterol Low (<60 mg/dL) and high (>80 mg/dL) HDL-cholesterol High triglycerides Hypertension and left ventricular hypertrophy Diabetes Obesity Physical inactivity Smoking Excessive alcohol Excessive stress Diet

Family history of ischemic heart disease

Age Gender (male) Post-menopausal

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein.

occur in patients without obvious hyperlipidemia. Nontraditional risk factors, with the emphasis on inflammation, are now considered to play an important role.17-19 Raised highly sensitive C-reactive protein (hs-CRP) levels have been shown to be predictive of an increased risk of coronary heart disease in healthy adults.20 Many of the beneficial effects of statins are attributed to their anti-inflammatory effects, regardless of the level of LDL decrease, as illustrated by a reduction in C-reactive protein.21 This was confirmed by the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial during which the effect of rosuvastatin on the rates of first major cardiovascular events in healthy adults, with normal LDL cholesterol and elevated hs-CRP levels, was evaluated. This trial recorded a 37% reduction in the hs-CRP levels, as well as a significant reduction in the incidence of major cardiovascular events.22 The initial step in the initiation of atherosclerosis is the accumulation of LDL particles in the arterial intima (Fig 1).23 The degree of LDL flux is determined by the plasma concentration and the size of the LDL molecule in combination with the arterial wall permeability (which will increase as a result of mechanical and immunologic injury).24 The accumulated lipoproteins then undergo oxidation and glycation,17,25 which promote the proinflammatory properties of LDL, contributing to atherosclerotic plaque development.26 Normal endothelium usually opposes, and has a low affinity for the adhesion of nearby leucocytes. Oxidized and glycated LDL, however, trigger the release of cell adhesion molecules facilitating the bond between monocytes and T lymphocytes to the endothelial cells, enabling their entry into the intima.17,23,25 Once inside the intima, monocytes change into macrophages. The macrophages increase the expression of surface scavenger receptors that facilitate further lipoprotein uptake.23,25 The lipoproteins are subsequently stored and oxidized by the macrophages, after which these lipid laden macrophages (“foam cells”) leave the arterial wall in an attempt to cleanse the blood vessels.25 A foam cell collection is known as a fatty streak, which is the foundation of an atherosclerotic plaque. The endothelium covering a fatty streak, although anatomically intact, is already dysfunctional.26 New research, however, contradicts the aforementioned role of foamy macrophages, with studies demonstrating that foam cells may play a smaller role in inflammation and atherosclerosis than previously thought.27,28 A recent study regarding the different roles of nonfoamy versus foamy macrophages demonstrated that nonfoamy macrophages play the dominant role in the immune response. In this study, the foamy macrophages were mainly involved in lipid processing (and not inflammation, as previously thought).28 The question is—are foamy macrophages less damaging than the current belief, or do they possess other (noninflammatory driven) properties that drive plaque instability and thus cardiovascular complications? The answer to this question will only be determined by extensive future research. Smooth muscle cells (which originate from the tunica media and migrate to the intima) generate extracellular matrix macromolecules (collagen, proteoglycans, and elastin) responsible for the upkeep and integrity of the arterial wall. Inflammation

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Fig 1. Initiation of an atherosclerotic plaque. LDL particles accumulate in the arterial intima after which it undergoes oxidation and glycation, triggering the release of CAM that facilitates the bond between monocytes and the endothelial cells.9,15,17 Once inside the intima, monocytes change into macrophages. Macrophages storing lipoproteins are referred to as “foam cells,” of which a collection is referred to as a fatty streak. Smooth muscle cells, originating from the tunica media, migrate to the intima where it is responsible for the formation of the fibrous cap surrounding the mature atherosclerotic plaque. CAM, cell adhesion molecules; LDL, low density lipoprotein.

causes an overexpression of extracellular matrix proteins, which is responsible for the fibrous cap (Fig 1) that covers the more mature atherosclerotic plaques.26 The thickness of the fibrous cap is determined by the balance between the synthesis of the extracellular matrix molecules versus their breakdown by proteolytic enzymes (matrix metalloproteinases). Matrix metalloproteinases (with collagenase activity) are produced by foam cells secondary to inflammatory stimuli.17,18 Inflammation also contributes to the death of smooth muscle and foam cells,23 which results in the initiation of a necrotic lipid core in the atherosclerotic plaque.25 A mature plaque therefore comprises a collagen rich fibrous capsule surrounding the lipid rich, necrotic core.26 Endothelial Function in Atherosclerosis Endothelium normally expresses nitric oxide synthase in response to stimuli such as shear stress.29 Oxidized LDL causes a reduction in the production of nitric oxide,30 which, in turn, contributes to platelet aggregation, impaired endothelium dependent vasodilatation, hypertension, and enhanced leukocyte aggregation.31 The atherosclerotic endothelium is thus dysfunctional and contributes to a prothrombotic, vasoconstrictive environment that increases the likelihood of developing occlusive thrombus formation during plaque rupture.26,30 Nitric oxide, however, also may have toxic and cytolytic effects. Inducible nitric oxide synthase (iNOS), present in human atherosclerotic plaques, may contribute to the inflammatory process of plaque development as a result of an increase in peroxynitrite and possible lipid hydroperoxide levels. Detmers et al.32 demonstrated, in an animal study, that iNOS contributes to the size of atherosclerotic lesions, whereafter Huang et al.33 highlighted the potential role of iNOS as target in the reduction of plaque formation during atherosclerosis.

Pathophysiology of Myocardial Ischemia Atherosclerosis, a chronic disease, may morphologically be present in coronary arteries as either eccentric or concentric lesions. These may result in myocardial ischemia or infarction via different pathophysiological mechanisms.23,25 Compensatory outward enlargement of atherosclerotic arteries, to “accommodate” the plaque while preventing lumen stenosis, is a common finding associated with coronary plaque growth.34 Extensive plaques therefore can exist in the walls of affected arteries without causing symptoms or being detected on arteriograms (eccentric lesion).18 Luminal stenosis will occur only when the plaque growth overtakes the compensating expanding ability of the artery (resulting in a concentric lesion).35,36 There are 2 distinct identities responsible for the development of myocardial ischemia (Fig 2): the first is acute coronary syndrome (ACS), also known as Type 1 myocardial infarction (MI), and the second is as a result of prolonged myocardial oxygen supply-demand imbalance in the presence of stable CAD (Type 2 MI).6

1. ACS ACS will occur as a result of vulnerable (unstable) plaque rupture or endothelial ulceration, and is essentially a plateletassociated disease process consisting of unstable angina, nonST segment elevated myocardial infarction, and ST segment elevated MI (Fig 2).6 The factors37 contributing to plaque instability include atherosclerotic risk factors (Table 2) of which inflammation is an important factor,38 the heterogeneity of plaque histology (ie, how vulnerable the plaque is),39 and the physical forces impacting upon the plaque.40

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Fig 2. Pathophysiological mechanisms responsible for cardiac ischemia. DO2, oxygen delivery; NSTEMI, non-ST segment elevation myocardial infarction; STEMI, ST segment elevation myocardial infarction; VO2, oxygen consumption.

A plaque with a fibrous cap of less than 65 to 150 microns and a necrotic lipid core that involves more than 40% of the lesion can be defined as a “vulnerable plaque.”40-43 This combination implies a high wall stress in the fibrous cap, which is conducive to plaque rupture.26,40 The thrombotic environment, plaque volume and composition, the degree of luminal narrowing, quality of the fibrous cap, and the extent of fibrous cap rupture will collectively determine ACS presentation (ie, unstable angina, non-ST segment elevated myocardial infarction, or ST segment elevated myocardial infarction).44 A study by Deanfield et al. raised awareness of the fact that myocardial ischemia is not always driven by hemodynamic factors.45 Turbulent flow, platelet aggregation, and coronary spasm, as part of the pathophysiology of ACS, were elucidated by Gallagher et al.46 These observations partially led to the successful implementation of aspirin therapy in patients with CAD.47

of the high oxygen extraction under normal resting conditions (coronary sinus oxygen saturation at rest is around 25%-30%), and the myocardium thus normally takes up a major portion of the oxygen present in the coronary blood.49,51 The coronary circulation can therefore be defined as a low flowhigh extraction regional circulation, which implies that an increase in myocardial oxygen consumption cannot be met with an increase in oxygen extraction.50 Determinants of Myocardial Oxygen Consumption and Oxygen Delivery. The major determinants for myocardial oxygen delivery (MDO2) and MVO2 are summarized in Figure 3. Coronary perfusion to the left ventricle occurs mainly in diastole and the diastolic time (ie, heart rate) is therefore of

2. Myocardial Oxygen SupplyDemand Imbalance (MDO2MVO2 Imbalance) Myocardial ischemia occurs when oxygen delivery is not sufficient to meet the current myocardial oxygen demands. The heart is an obligate aerobic organ, entirely dependent on coronary perfusion for an uninterrupted oxygen supply. During normal physiology, the myocardial oxygen demand also is met by myocardial oxygen delivery, and the normal myocardium does not become ischemic when oxygen consumption is increased (as occurs during maximal exercise testing).48 The ability of the supply chain to meet the increased demand is to a large extent dependent on the ability of the coronary circulation to dilate and increase the flow as required.49 The almost perfect linear relationship between coronary blood flow and myocardial oxygen consumption remains central to our understanding of myocardial ischemia.42,50,51 The obligatory increase in coronary blood flow (during high myocardial oxygen consumption [MVO2]) is required because

Fig 3. The determinants of MDO2 and MVO2. The major determinants of MVO2 are myocardial contractility and ventricular wall tension (and therefore left ventricular size).50,135 MDO2 equals the product of CaO2 and CBF. CaO2, CBF, CPP, and R depend on the variables as portrayed in the equations.50 CPP equals the difference between aortic diastolic pressure (AoDP, the driving pressure) and the downstream pressure tissue pressure, which is difficult to obtain, and hence the use of the LVEDP, which usually underestimates the downstream pressure. AoDP, aorta diastolic pressure; CaO2, arterial oxygen content; CBF, coronary blood flow; CPP, coronary perfusion pressure; Hb, hemoglobin; l, vessel length; LVEDP, left ventricular end diastolic pressure; MDO2, myocardial oxygen delivery; MVO2, myocardial oxygen consumption; h, viscosity; PaO2, partial pressure of oxygen; R, coronary vascular resistance; r, vessel radius; SaO2, arterial oxygen saturation; VO2, oxygen consumption.

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crucial importance for sufficient left ventricular coronary perfusion. The right ventricle perfusion pattern follows the aortic pressure (ie, it occurs mainly in systole).52 3. Pathophysiology of Stable Angina Fibrous cap fissures and rupture are not always accompanied by significant clot (thrombus) formation, as observed during ACS. It may (only) stimulate a fibrotic response with a subsequent slowly enlarging fibrous tissue cap, which may result in a decrease in the lumen of the vessel once the external dilation of the vessel, as compensation, is exhausted. This reduction in the coronary artery diameter is responsible for the increase in resistance in the coronary artery, with a resulting reduction in coronary blood flow.26 Coronary flow reserve refers to the potential increase in coronary perfusion (via coronary vasodilatation) to accommodate an increase in metabolic needs (because extraction is already near maximal). Coronary flow reserve is represented by the difference between the basal and maximal coronary blood flow.50 Atherosclerosis may have a 2-fold effect on coronary blood flow: in the first place, it may be responsible for coronary artery stenosis causing an increase in resistance and therefore a reduction in coronary flow, the simple and predictable hydrodynamic effect. The increase in alpha adrenergic receptors,53 in combination with a dysfunctional endothelium (with an inability to release sufficient vasodilating mediators)—both as a result of atherosclerotic arteries—may prevent the coronary flow reserve from achieving its normal and maximum capacity.42 In patients with atherosclerosis, an increase in myocardial oxygen consumption thus may not be matched by a sufficient increase in coronary flow, therefore creating the potential for myocardial ischemia.45 The resultant myocardial ischemia is therefore more likely to originate from the inconsistencies in coronary flow reserve rather than variability of myocardial oxygen consumption.50 The application of Ohms Law to the blood flow in the coronary artery assists in the understanding of the hydrodynamic effects of the progression of a coronary artery lesion: flow (Q) is the quotient of the pressure difference (upstream pressure [P1]  downstream pressure [P2]) and resistance to flow (R) [ie, Q = (P1P2)/R].44 Once R is significantly increased (arterial diameter decreases owing to the developing intracoronary lesion) and P1 decreases (hypotension), P2 will have to decrease (coronary vasodilatation must occur) in an attempt to maintain flow. Reductions of upstream perfusion pressure (P1) are normally countered by coronary vasodilation (P2) (during intact autoregulation) in an attempt to maintain sufficient blood flow (Q). A very prominent characteristic of a flow limiting coronary stenosis is the marked, already existing, reduction in coronary pressure distal to the stenosis (decrease in P2).54,55 Rouleau et al. demonstrated that progressive reductions of perfusion pressure resulted in maximal vasodilation of the subendocardial vessels,56 and a further decrease in coronary perfusion pressure (P1) will then be followed by a reduction of subendocardial flow (causing ischemia) as a direct function of pressure.

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Gallagher et al. confirmed that, “in the presence of a critical stenosis there is no coronary reactive hyperemic response because maximal vasodilation has already occurred.”57,58 In these circumstances, coronary blood flow becomes directly dependent on upstream coronary perfusion pressure (as opposed to a normal autoregulated coronary flow pattern).59 Maximum distal coronary vasodilation will be present when a coronary artery lesion occupies approximately 80% of the diameter of the vessel.55 4. Coronary Artery Spasm Except for ACS (thrombosis) and prolonged MVO2MDO2 mismatch in the presence of stable CAD, there is a further distinct cause for myocardial ischemia (ie, isolated coronary spasm), otherwise known as Prinzmetal angina.49 This is the result of coronary vasospasm and can be characterized as an exaggerated normal vasospastic response to a particular stimulus. For instance, normally hypocapnia results in coronary vasoconstriction but the local regulatory mechanisms will override its effect and prevent spasm resulting in myocardial ischemia.60 In the human Prinzmetal sufferer, hypocapnia results in angina, which is relieved when the carbon dioxide tension (PaCO2) is restored.61 This syndrome usually occurs at rest and is caused by vasospasm in (often normal) coronary arteries rather than atherosclerosis.62 The pathophysiology of coronary artery spasm is multifactorial, but it appears that the most important causative factor for this phenomenon is an increased intracellular calcium concentration in combination with elevated calcium sensitivity.63 Coronary artery spasm, although rare, is still an important cause of angina, as well as an important cause of perioperative myocardial ischemia, as illustrated by several case reports.64,65 MacAlpin, in a 2018 review, investigated how coronary artery spasm complicates noncardiac surgery. He reported the incidence of perioperative coronary artery spasm in patients without preoperative coronary vasospasm, undergoing noncardiac surgery, as between 0.2 and 0.02%. Perioperative coronary artery spasm is, however, a common occurrence in patients with pre-existing coronary vasospasm, and special preventative measures, to reduce the risk of coronary spasm in these patients, are justified.66 Part 2: Perioperative Myocardial Infarction and Ischemia Definitions of Myocardial Infarction, Myocardial Injury, and Clinical Classification According to the 2018 Joint Task Force of the European Society of Cardiology, American College of Cardiology Foundation, the American Heart Association, and the World Health Federation, the fourth universal definition of MI is as follows: a clinical (or pathologic) event in the setting of myocardial ischemia (ischemic symptoms, ischemic electrocardiographic changes, coronary artery intervention, new wall motion abnormalities, or fixed defect on radionuclide scanning) in which there is evidence of myocardial cell death.67 Myocardial injury

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is defined as evidence of elevated cardiac troponin with at least one value above the 99th percentile upper reference limit. Myocardial injury after noncardiac surgery (MINS) is defined as myocardial cell injury owing to an ischemic etiology during the first 30 days after noncardiac surgery. MINS includes patients with MI (both symptomatic and nonsymptomatic) and patients with postoperative elevations in troponin without symptoms, electrocardiographic abnormalities, or other criteria that meet the aforementioned universal definition. MINS does not include nonischemic etiology for troponin elevation (eg, pulmonary embolism, sepsis, cardioversion, or chronically elevated troponin).68 The expert consensus statement furthermore clinically classifies MIs as follows67: MI caused by ACS and thus usually precipitated by atherosclerotic plaque rupture complicated by intraluminal thrombosis and/or hemorrhage is referred to as a Type 1 MI. Ischemic myocardial injury and infarction precipitated by an oxygen supply and demand mismatch are classified as Type 2 MI. Acute atherothrombotic plaque disruption is thus not a feature of Type 2 MI, per definition. A Type 3 MI occurs when suspicion for an acute myocardial ischemic event is high (typical presentation of myocardial ischemia/infarction), even when cardiac biomarker evidence of MI is lacking (patient, for example, died before blood could be obtained for biomarker determination). MI associated with percutaneous coronary intervention is known as Type 4 MI, and infarctions as a result of coronary artery bypass grafting as Type 5 MIs. The term myocardial infarction with nonobstructive coronary arteries has been coined for MIs in patients with no angiographic obstructive CAD (
50% diameter stenosis in a major epicardial vessel). An ischemic mechanism responsible for the myocyte injury has to be confirmed before diagnosing myocardial infarction with nonobstructive coronary arteries, as with all other MIs. Worldwide, 200 million adults undergo major noncardiac surgery every year, and approximately 8 million of these patients will suffer a MINS.69 A recent observational cohort study reported that perioperative myocardial infarction (PMI) occurs in 0.9% of patients undergoing major noncardiac surgery and that there is a strong association between PMI and in-hospital mortality.70 Studies investigating perioperative cardiac troponin elevation report an 8% to 19% MINS incidence. In these studies, MI accounts for approximately 20% to 40% of MINS depending on whether a non-high sensitivity or a high sensitivity cardiac troponin is measured.71-73 PMI and MINS are viewed as prognostically relevant myocardial injury. Troponin elevation after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality.68,73 The patients with CAD who are likely to undergo noncardiac surgery are those on medical treatment, and who have undergone coronary artery bypass grafting or stenting. Amongst these, the patients on medical management and undergoing major noncardiac surgery are the most vulnerable to suffer from perioperative myocardial ischemia. The question is if the majority of PMIs are as a result of ACS (and thus thromboembolism, Type 1 MI) or an oxygen

supply demand mismatch in the presence of coronary stenosis (Type 2 MI). Understanding the pathophysiology of myocardial ischemia and how it applies to PMI is important in an attempt to reduce its incidence and increase early detection. This may ultimately result in a decrease in mortality, shorter hospitalization, a decrease in medical cost, and fewer longterm cardiac complications. Presentation of PMI Le Manach described 2 patterns for PMI according to the troponin rise, early PMI (troponin rise at 37 § 22 hours post surgery) and delayed PMI (troponin rise at 74 § 39 hours post surgery).74 Although 2 patterns exists, the vast majority (90%) of the initial troponin elevations occurred within less than 24 hours after surgery.74 The early presentation of myocardial damage (within 24 to 48 hours) after surgery is supported by several other studies.74-76 Le Manach et al. postulated that early PMI is a Type 1 MI as a result of postoperative inflammatory syndrome on the background of established CAD. They further suggested that PMI after prolonged ischemia (delayed PMI) most likely occurs in the presence of severe but stable CAD, and thus Type 2 MIs.74 Their study was however not designed to explore the specific pathophysiology responsible for PMIs. The majority of PMIs are asymptomatic; reports of chest pain or other symptoms are rare, and range between only 6% and 34.7%.73,76-79 In the Perioperative Ischemic Evaluation (POISE) trial, 34.7% of patients with PMI experienced ischemic symptoms79; this is in comparison to the fact that chest pain is the most common presenting complaint for MI outside the perioperative period. This is most likely as a result of postoperative analgesia, sedation (and therefore under reporting); or distracting pain.80 The lack of reported ischemic cardiac symptoms furthermore contributes to electrocardiography (ECG) not being routinely performed. This, in combination with the transient and infrequent postoperative ischemic ECG changes,79 collectively contributes to missed diagnosis, resulting in missed opportunities for the initiation of treatment.81 This typical asymptomatic presentation associated with PMI suggests an increase in a clinician’s reliance on postoperative screening tests to detect ischemic events and to allow for early intervention. Even though routine ECGs are a potentially low yield test (with only 22.8%78 to 24%73 of patients with PMI displaying ischemic ECG changes), the authors are of the opinion that it remains a potentially valuable, low risk and low-cost tool used in the diagnosis of PMIs. The authors thus recommend postoperative 12-lead ECG screening in high-risk and/or symptomatic patients. There are also concerns associated with routine troponin screening: troponin elevation in low-risk patients is associated with a low mortality rate (mortality rate was less than 1% in low to intermediate risk patients82); troponin elevation often occurs as a result of causes other than myocardial ischemia (it therefore has a stronger association with all-cause mortality than with MI72,83); and lastly, the fact that no effective protocol exists to respond to elevated troponin levels. Elevated

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postoperative troponin thus identifies patients at higher risk of any adverse event but not specifically of cardiac-specific events.84 This is why the authors do not recommend routine postoperative troponin screening for all patients, but only for those with a high clinical risk, which includes patients with confirmed CAD and those undergoing high-risk surgical procedures. The Pathophysiology of PMI The predominant pathophysiology of PMI is incompletely understood and still a matter of debate. A distinction between the 2 processes, an oxygen supply-demand imbalance (Type 2 MI) or ACS (Type 1 MI), is essential in terms of prevention and therapeutic considerations. The majority of patients presenting with an acute MI to the emergency department will do so as a result of the typical type 1 MI (atherosclerotic plaque rupture).67 The question is, what is the most common underlying mechanism for PMIs? 1. Post Mortem Studies Post mortem studies after PMI can be summarized as follows: the overall incidence of plaque rupture after fatal PMI was found to be 46% (n = 1,841)85 and 55% (n = 67).86 The patients with plaque rupture, however, died at random distribution within almost 3 weeks postoperatively, therefore lacking a clear relationship to the date of surgery. This is in contrast with the majority (71%) of patients without plaque rupture who died within the first 3 postoperative days.85 Cohen et al. found that the only statistically significant clinical difference between the patient groups, with and without plaque rupture, was a longer interval from surgery to death in patients with plaque rupture (7.8 § 4.4 days v 4.4 § 4.8 days, p = 0.047).85 Another important finding after fatal PMI was that the majority (93%) occurred in patients with established CAD.85,86 In summary, although biased toward fatal events, these post mortem studies thus support the predominance of Type 2 MIs in the first 3 postoperative days, and the random occurrence of Type 1 MIs throughout the postoperative period.85 2. Perioperative Coronary Angiography Perioperative coronary angiography was utilized to further investigate the pathophysiologic mechanism of PMIs after the aforementioned autopsy studies. Preoperative and postoperative coronary angiography also support the finding that established CAD is important in the pathophysiology of PMI, as aforementioned.87,88 A study on evaluating preoperative angiograms demonstrated important differences between groups with and without PMI after vascular surgery: the index group (n = 21) had a larger number of diseased coronary vessels (p < 0.001) and coronary lesions of more than 30% (p < 0.001) in comparison to the control group (n = 42).87 Another significant finding in this study by Ellis et al. was the 81% incidence of collateralized obstructions (and therefore a lack of collateral blood supply) in the index group.87 Sheth et al. confirmed the importance of established

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CAD in patients experiencing PMIs, in this study postoperative angiography demonstrated a culprit lesion in 100% of the patients (n = 30).88 Three angiographic studies suggest that Type I and Type 2 MIs contribute (more or less) equally to PMIs: a retrospective study done by Duvall et al. identified demand ischemia as the predominant (55% contribution) etiology of PMI.89 In 2013, Hanson et al. reported that 59% of the PMI patients studied had a Type 1 PMI.90 A larger prospective study, done by Gualandro et al. (consisting of 120 patients), found that 45% of patients with perioperative ACS had evidence of plaque rupture.91 The small sample size of the studies done by Duvall (n = 66) and Hanson (n = 54), in combination with the exclusion of patients with PMIs who were not referred for perioperative angiograms, or who died before the angiography,91 however, influences the reliability of these results. Coronary angiography is furthermore not the gold standard to diagnose the presence of plaque disruption.92 Experts6 were therefore of the opinion that the majority of PMIs may occur as a result of a supplydemand imbalance of oxygen without plaque rupture (Type 2 MI). Above expert opinion recently found support in 2 studies: the first, by Helwani et al., is a retrospective cohort study that spanned over 7 years. In this study, of the almost 150 patients identified who developed postoperative MI, 72.6% was attributed to Type 2 MI, 25.3% to Type 1 infarction, and 2.1% as a result of stent thrombosis. Demand ischemia thus was demonstrated convincingly as the principal mechanism of perioperative ACS in this cohort.93 The second study, also supporting Type 2 PMI as the dominant pathology, used angiography as well as optical coherence tomography to determine the presence of thrombus and to study plaque morphology. In this study, patients experiencing a PMI as well as matched patients experiencing an MI unrelated to surgery were studied. They found that thrombosis was less common in perioperative (13.3%) than nonoperative (66.7%) MIs, despite similar underlying plaque morphology. The differences in plaque morphology can therefore not be solely responsible for the difference in thrombus at the culprit lesion site.88 3. Postoperative ECG Findings The majority of MINS and PMIs are preceded by STsegment depression rather than ST-segment elevation type ischemia.43,94,95 ST-segment depressions associated with postoperative ischemia and infarction are characteristic of a long duration (cumulative duration >1-2 h) rather than a short (>2030 min) duration. Another consistent finding is that the majority of PMIs are of the non-Q-wave rather than the Q-wave type.76,77 Above ECG findings suggest that total coronary occlusion (ST-segment elevation as a result of potential transmural myocardial necrosis and Type 1 PMI) is less common than the Type 2, oxygen supply-demand mismatch, PMI.96 In summary, the time of presentation of PMIs in association with autopsy results, supporting angiographic studies, prolonged ST-segment depression, and non-Q-wave rather than Q-wave type MIs, all suggest prolonged stress-induced (Type

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2) MIs as the most likely underlying pathophysiology for the majority for PMIs.6,71,96 Perioperative Triggers for Perioperative Myocardial Ischemia and Infarction Perioperative triggers that may contribute to perioperative myocardial ischemia include tissue trauma, the way in which anesthesia is administered, airway manipulation, fluctuations in fluid status and body temperature, pain, bleeding, and preoperative fasting.97 The aforementioned triggers may result in perioperative inflammation, hypercoagulability, stress response, hemodynamic changes, hypothermia, hypoxia, and anemia, all playing potential prominent roles in the pathophysiology of PMI. 1. Pre-existing CAD Established CAD, although not viewed as a traditional trigger, is a very important predicting factor for PMI as demonstrated by pre- and postoperative angiography,87,88 as well as post mortem studies.85,86 With this in mind, the question is whether routine preoperative angiograms are indicated in patients at risk for IHD, presenting for noncardiac surgery? Before answering this question, the following need to be considered: the culprit lesion is unidentifiable in 30% of patients with PMIs, collateral blood supply is the most significant predictor of an infarct, and coronary angiography is only indicated for chronic total obstruction and crude risk stratification (thus not for coronary collateral assessment).98 Another important consideration is the lack of clear evidence in terms of indications for preoperative angiograms, as well as an outcome benefit after preoperative coronary artery revascularization.99,100 The potential delay in surgery after preoperative coronary revascularization and the risk associated with this procedure101 are other important factors that need to be taken into account before coronary angiography. There is currently no evidence to support the routine use of coronary angiography and revascularization in patients who have to undergo noncardiac surgery, even though the incidence of PMI is much higher in patients with pre-existing CAD. Preoperative coronary angiograms (and thus possible coronary intervention) should thus be reserved for patients with ACS or high-grade stable angina, refractory to optimal medical therapy, and/or high-risk features on noninvasive testing.102 2. Perioperative Inflammation Surgical trauma and invasive procedures associated with general anesthesia can both initiate inflammatory states as a result of an increase in plasma tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, and C-reactive protein levels.103-105 There is a correlation between the size of the surgical trauma and the proinflammatory response; an increase in surgical trauma is associated with a greater serum IL-6 response and therefore an increase in the inflammatory response.103 General anesthetic agents, however, are responsible for the impairment of various aspects of the immune system, either directly by

suppressing immunocompetent cells or indirectly by modulation of the stress response.106 Inflammation significantly contributes to plaque instability resulting in fissuring, rupture, and Type 1 PMI. This is supported by studies that demonstrated that serum C-reactive protein concentration serves as a better predictor of MI than total and LDL cholesterol concentrations.6,105 An increased perioperative inflammatory response also may contribute indirectly to a Type 2 PMI as a result of associated hemodynamic changes. A recent systematic review done to evaluate the impact of prophylactic steroids on clinical outcomes in patients undergoing on-pump cardiac surgery, found that myocardial injury was significantly more frequent in the steroid group than in the control group (p = 0.008).107 Decreasing the inflammatory response associated with surgery will theoretically lessen the incidence of Type 1 MIs, the results of this study may thus lend further support to Type 2 PMIs being the most common, keeping in mind that it cannot be extrapolated to noncardiac surgery. A meta-analysis done in 2018 reviewed the effects of perioperative statin therapy on clinical outcome after noncardiac (and cardiac) surgery. They concluded that a significant association exists between perioperative statin therapy and a lower incidence of PMI after noncardiac surgery (p < 0.0001).108 The beneficial effect as a result of statin therapy may be as a result of anti-inflammatory (plaque stabilization and less hemodynamic changes) and/or pleiotropic mechanisms. 3. Hypercoagulable State Postoperative hypercoagulability may occur as a consequence of the surgery performed and of the general anesthesia administered. This is as a result of an increase in procoagulants (fibrinogen, factor VIII, von Willebrand factor, alpha1-antitrypsin, and plasminogen activator inhibitor-1), a decrease in anticoagulants (protein C, antithrombin III), an increase in platelet reactivity, and decreased fibrinolysis.109-113 Although postoperative hypercoagulability is more notorious for contributing to venous, rather than arterial occlusion, it still may play a contributing role in the occurrence of Type 1 PMI.6 Antiplatelet therapy, given the central role of platelets in this disease process, as well as thrombolysis or other reperfusion techniques, in the correct circumstances, will form part of the management options after a Type 1 PMI. 4. Stress Response The aforementioned perioperative triggers will activate the sympathetic tone and increase the circulating levels of catecholamines (epinephrine and norepinephrine) and cortisol.43,114-116 Resulting hemodynamic changes will increase MVO2 (increase in myocardial contractility) and reduce MDO2 (increase in heart rate), both contributing to Type 2 PMI. Less invasive surgery in comparison to more invasive surgery will result in a smaller stress response; the question is whether the anesthetic technique (general anesthesia v neuraxial anesthesia) also has an influence on the magnitude of the stress response? A regional anesthetic technique (normally resulting in very effective analgesia, sympatholysis, and an attenuated

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surgical-stress response) theoretically may be superior to general anesthesia. When Hopkins et al. investigated the impact of regional anesthesia on clinical outcomes, they concluded that the effect on cardiovascular complications was variable.117 Another study, conducted on patients undergoing vascular surgery, also reported that no clinically relevant difference in terms of adverse cardiac outcomes exist between regional and general anesthesia.118 The capability of the anesthesiologist in managing different clinical scenarios and different types of anesthesia is probably more important than the type of anesthesia.

5. Hemodynamic Changes The increase in stress hormone levels results in hemodynamic changes, which include hypertension and tachycardia. The resulting coronary artery shear stress may trigger plaque fissuring, rupture, and acute coronary thrombosis.43,119 The tachycardia-associated decrease in diastolic time, and thus coronary filling time,120 plays an important role as illustrated by the fact that an increase in baseline heart rate (of only 10 beats) is a significant independent predictor of PMI.71 The contribution of tachycardia to the (Type 2) ischemic myocardium is mainly as a result of a decrease in DO2. An increase in heart rate will only result in an increase in VO2 if there is an associated increase in heart diameter (and thus wall tension) or if accompanied by an increase in catecholamine release (responsible for an increase in contractility).121,122 Clinically important hypotension (decreasing myocardial oxygen delivery), as a result of different triggers (fluid shifts, bleeding), was identified in the POISE-2 trial as another predictor for perioperative MI.123 The subsequent baroreceptormediated increase in heart rate will further contribute to a Type 2 PMI. Abbott et al. demonstrated that intraoperative tachycardia and hypotension are independently associated with MINS and mortality.124 Although individualization is important, this study found an association between MINS and an intraoperative heart rate of more than 100 beats per minute (for a duration of longer than 30 minutes), and systolic blood pressure of less than 100 mmHg (for less than 15, or more than 61-minute duration). A minimum intraoperative heart rate of less than 55 beats per minute was furthermore associated with reduced risk of MINS and mortality.124 An association was even demonstrated between preoperative heart rate elevation (heart rate more than 96 beats per min) and MINS, MI, and mortality after noncardiac surgery.125 A very recent review on perioperative b-adrenergic blockade in cardiac and noncardiac surgery, however, has reported that the evidence to support perioperative use of b-blockers, to decrease perioperative morbidity and mortality, remains inconclusive.126 The authors are of the opinion that the individualized and judicious use of perioperative b-adrenergic blockade may play a valuable role in the prevention of cardiac complications and mortality after surgery. Studies investigating the tailored use of perioperative b-blocker protocols, in combination with a meticulous maintenance of perfusion

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pressure, in the prevention of MINS and mortality after surgery, are still lacking. 6. Hypothermia Hypothermia is defined as a body core temperature below 35.0˚C (95.0˚F) in humans.127 Perioperative hypothermia has been shown to be associated with postoperative myocardial ischemia.128 After this it was demonstrated that the maintenance of perioperative normothermia, in patients with cardiac risk factors presenting for noncardiac surgery, is associated with a reduced incidence of morbid cardiac events.129 Hypothermia’s role in perioperative ischemia is as a consequence of stress hormone release with the associated hemodynamic changes, as well as shivering increasing oxygen consumption significantly (as a result of increased contractility and afterload through sympathetic nervous system activation).130,131 7. Hypoxia Perioperative triggers potentially contributing to tissue hypoxia (arterial partial pressure of oxygen of less than 8 kPA) include bleeding, temperature fluctuations, anesthesia (causing low ventilation perfusion units or potential low mixed venous oxygen saturation), and analgesia (as a result of hypoventilation). Perioperative hypoxia, decreasing myocardial DO2, also may result in myocardial ischemia (and Type 2 PMI) in the setting of significant coronary artery stenosis. Hypoxia can further contribute to a decrease in DO2 by means of hemodynamic changes. Hypoxia-induced tachycardia132 will decrease diastolic time and coronary perfusion, as discussed previously. 8. Anemia Major perioperative hemorrhage (resulting in a decrease in DO2) also appears to independently increase the risk of perioperative myocardial ischemia. 123,133,134 Kamel et al.134 demonstrated an independent association between major hemorrhage (more than 4 units of red blood cells) and Q-wave MI. Nelson et al. found a hematocrit of <28% to be significantly associated with myocardial ischemia (p = 0.001) and morbid cardiac events (p = 0.0058).133 These studies are supported by results from the POISE-2 trial, stating that life-threatening occurrences or major bleeding are independent predictors of MI (hazard ratio, 1.82; 95% confidence interval, 1.40 to 2.36; p < 0.001).123 Aspirin prevents MI in patients with, or at risk for, atherosclerotic disease in the nonoperative setting. The POISE-2 trial, however, found that the continuation of preoperative aspirin does not prevent PMI.123 This may be viewed as further support that coronary-artery thrombus (Type 1 MI) may not be the dominant mechanism of PMI. Not diminishing the potential beneficial, and very important role of aspirin, statins, thrombolytics, coronary stents, and coronary arterial bypass surgery—perioperative emphasis possibly needs to be on b-adrenergic blockade, adequate perfusion pressures, optimization of oxygen-carrying capacity, adequate

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anesthetic depth and pain management, and neutral fluid balance to avoid detrimental hemodynamic changes. Meticulous attention to and prevention of PMI triggers that may disrupt the DO2 and VO2 balance are likely more important than the (potential) beneficial effects associated with continuation of preoperative aspirin, regional anesthetic technique versus general anesthesia and inhalation agents versus total intravenous anesthesia. Conclusion Cardiac ischemia may present as a result of an unstable plaque, with varying degrees of occluding thrombus formation and coronary vasoconstriction. This can be referred to as ACS and is viewed as a platelet associated disease process, with acute thrombus formation or the dislodgement of an embolus associated with plaque rupture, which can result in myocardial ischemia-infarction irrespective of a normal MDO2MVO2 relationship. On the other hand, ischemia may follow a MDO2MVO2 mismatch. Stable angina may thus be the result of a reduction in oxygen delivery to the myocardium distal to a segment with a fixed stenosis. The typical underlying pathophysiology here is a stable plaque responsible for a potential critical stenosis, which limits the ability for an increase in coronary flow. Perioperative physicians need to increase their awareness of the typical presentation of MINS, the strong association between an elevated heart rate and ischemia, and that the majority of PMIs most likely occur as a result of VO2DO2 imbalance, rather than thrombotic occlusion. Anesthesiologists need to tailor perioperative care, maximizing DO2 and minimizing MVO2, if excessive, aiming to optimize the oxygen supplydemand balance. Conflict of Interest The authors declare no conflicts of interest. References 1 Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: Heart disease and stroke statistics—2015 update. Circulation 2015;131:434–41. 2 Neri M, Riezzo I, Pascale N, et al. Ischemia/reperfusion injury following acute myocardial infarction: A critical issue for clinicians and forensic pathologists. Mediators Inflamm 2017;2017:14 pages. 3 Anderson JL, Morrow DA. Acute myocardial infarction. N Engl J Med 2017;376:2053–64. 4 Kristensen SD, Knuuti J. New ESC/ESA guidelines on non-cardiac surgery: Cardiovascular assessment and management. Eur Heart J 2014;35: 2344–5. 5 Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: Executive summary a report of the american college of cardiology/american heart association task force on practice guidelines. Circulation 2014;130:2215–45. 6 Landesberg G, Beattie S, Mosseri M, et al. Perioperative myocardial infarction. Circulation 2009;119:2936–44. 7 Ferrari R, Balla C, Malag
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