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To understand the pathophysiology of myocardial infarction.
To review the imaging and biochemical biomarkers that measure infarct size.
To review the pharmacological and mechanical treatments available that impact infarct size.
Coronary artery disease is the leading cause of death worldwide, with ST segment elevation myocardial infarction (STEMI) an important contributor. Infarct size following STEMI is a determinant of heart failure and death. This article provides an update on key modalities used to determine infarct size, and recent advances in interventions used to reduce infarct size.
Determinants of infarct size and their pathophysiology
The area at risk (AAR) is the region of the myocardial bed supplied by the infarct related artery (IRA). In the era of reperfusion, not all the AAR will become infarcted. Depending on time to reperfusion and the exact location of occlusion, there will be a proportion of the AAR (jeopardised but not infarctedw1) that can be salvaged by reperfusion therapy. This can be calculated as AAR−infarct size (figure 1).
The cause of irreversible myocardial damage in STEMI can be divided into two categories: myocardial damage as a result of the myocardial ischaemic process itself; and myocardial damage as a result of reperfusion, termed reperfusion injury. It is difficult to separate out these two components (figure 2).
Following a coronary occlusion, the myocardial bed supplied by the IRA is rendered ischaemic. Ischaemic cells switch to anaerobic metabolism which is much less efficient at producing ATP and results in lactic acid accumulation. The fall in ATP, accompanied by intracellular acidosis, disrupts ionic homeostasis and triggers an uncontrolled rise in intracellular ions including calcium (Ca2+). Ischaemia also triggers the production of reactive oxygen species (ROS) which, in addition to loss of control over Ca2+, can disrupt the sarcolemmal and mitochondrial function leading to cell death. Oedema occurs due to leakage of large molecules from blood vessels causing water to follow by osmosis. This ischaemic damage progresses with time in a ‘wavefront’ from the subendocardium to the epicardial layer as described in the landmark paper by Reimer and Jennings.1 This wavefront combines acute inflammation and oedema (reversible damage) with necrosis (irreversible damage).1 The presence of collateral flow leads to a reduction in infarct sizew2 and improved prognosis.w3 The longer the duration of coronary occlusion the larger the infarct size.1 Time to reperfusion (opening of the IRA) significantly affects myocardial salvage,2 infarct size,2 and mortality,3 w4 and improves prognosis.w5 This is the basis for reperfusion strategies.
Restoring epicardial coronary blood flow in itself can cause myocardial damage (reperfusion injury). The cause of this is multifactorial and not entirely understood. Known components include oxidative stress, Ca2+ overload, the rapid restoration of physiological pH, and inflammation with neutrophil infiltration.w6 In response to this, the mitochondrial permeability transition pore (MPTP) (non-selective channels of the inner mitochondrial membranes) opens and induces cardiomyocyte death.w7 Therefore, agents that diminish this reperfusion injury are essential. It is known that preconditioning with prodromal angina decreases infarct sizew8 and increases myocardial salvage.4 w9 Angina before myocardial infarction also has a mortality benefit.w10 This has led to a better understanding of reperfusion injury, by identifying reperfusion signalling cascades that are the targets for therapy. Interventions can include the use of antioxidants, inhibitors of Ca2+ transporters, substrates for improved energy provisions and delivery, and directly inhibiting the MPTP. The latter is by far the most targeted mechanism. Several trials in the setting of cardiology and cardiac surgery that target MPTP are currently underway (NCT01502774, NCT01374321, NCT01572909). These included remote preconditioning (NCT01857414, NCT01665365) and ciclosporin A (NCT01502774).
Why infarct size is important
The mortality from STEMI varies according to patient factors (comorbidities: age, renal failure, diabetes, heart failure, bystander coronary disease) and treatment factors (time to presentation and reperfusion, treatment strategy). Those with a larger infarct are at an increased risk of symptomatic heart failure and death.w11 w12 Infarct size is directly associated with mortality; patients with an infarct >12% of the left ventricle (LV) have a 7% mortality at 2 years as compared to 0% with an infarct <12% of the LV.w11 Therefore, it is important to optimise the strategy to minimise infarct size.
How to assess infarct size, AAR, and myocardial salvage
Infarct size, AAR, and myocardial salvage can be assessed accurately histologically or in experimental models, neither of which is applicable in clinical practice. However, in clinical practice we can use blood biomarkers or imaging biomarkers to obviate this.w13 These biomarkers have been validated against histology and have demonstrated prognostic importance. These can be used in clinical practice but also as surrogate endpoints in clinical trials.
The development of creatinine kinase (CK-MB) assays has allowed earlier diagnosis of myocardial infarction. CK-MB values have been shown to predict prognosisw14 and have become a tool for estimating infarct size.w15 The ability of troponins to accurately predict infarct size for surrogate endpoints in clinical trials is more controversial.w16 The troponin concentration in the myocardium varies between patients, therefore measurements of plasma/serum troponin may not reach optimal precision to estimate infarct size.w17 In addition, reperfusion changes the kinetics of troponin release and degradation, inducing an early peak.w18 However, single point troponin measurement has been shown to be as effective in estimating infarct size as the derived measure of area under the curve.5
Transthoracic echocardiography (TTE) is an accessible and simple bedside measure of the consequences of STEMI in the myocardium. However, TTE measures indirect effects of infarct size by assessing regional wall motion abnormalities (RWMA), quantifying the ejection fraction, and LV end systolic and end diastolic volumes. A key obstacle in using TTE to estimate infarct size is the confounding factor of myocardial stunning of the salvaged myocardium contributing to the initial RWMA and overall systolic dysfunction. An increase in myocardial thickness (the result of oedema) is associated with infarct transmuralityw19; however, TTE cannot directly assess and measure infarct size.
Single photon emission CT
Single photon emission CT (SPECT) myocardial perfusion imaging, with the injection of a technetium compound before primary revascularisation, has the ability to detect both infarct size and myocardial salvage.w20
A radiotracer (technetium, 99Tc) needs to be injected at the time of the occlusion, but the imaging is performed subsequently, following revascularisation. 99Tc does not redistribute significantly after reperfusion. SPECT measurement of infarct size is histologically validated against microspheres,w21 and has been used extensively in clinical trials as a surrogate endpoint.w20 SPECT is a widely available technique for assessing myocardial salvagew21 w22 with prognostic implications.w23 Myocardial salvage index is usually defined by the initial perfusion defect (tracer injected before reperfusion and patient imaged 6–8 h after) minus the final infarct size (at follow-up SPECT scan, 7–14 days after) divided by the initial perfusion defect.
However, the requirement of radiotracer administration in the emergency room, the related radiation burden, and the relatively lower spatial resolution represent limitations of this technique.
Cardiovascular magnetic resonance
One of the main strengths of cardiovascular magnetic resonance (CMR) is its ability to characterise myocardial tissue non-invasively. Among imaging techniques, CMR is a newly established technique that has been well validated for the assessment of myocardial infarction,6 AAR,7 and myocardial salvage.w24
The increase in water content in the oedematous myocardium can be detected using the intrinsic T2 relaxation properties of tissues with different water content. This can be used to assess the AAR.
A gadolinium based contrast is administered for determination of infarct size. This is an extracellular contrast which accumulates in regions of increased interstitial space (ie, scar). Gadolinium reduces the T1 relaxation time and therefore provides a pronounced difference in contrast between normal and abnormal myocardium using an inversion recovery MR sequence. Using the high resolution of CMR imaging (∼2 mm spatial resolution), infarct size can be accurately identified and quantitated with high reproducibility.w25
CMR overcomes the limitations of SPECT and provides a retrospective evaluation of reversible and irreversible myocardial damage 2–3 days after primary percutaneous coronary intervention (PPCI)8—with no ionising radiation—and can determine all parameters on a single scan following STEMI with no need for up front tracer injection. Myocardial oedema, myocardial salvage, and myocardial infarct size can be calculated as a mass in grams or as a percentage of the LV.
There is increasing data that CMR measurements of infarct sizew26 and myocardial salvagew24 have prognostic importance. Given its high spatial resolution, high reproducibility, and lack of ionising radiation, CMR is an increasingly used surrogate endpointw27 in trials testing different reperfusion strategies aimed at infarct size reduction.
Methods to reduce infarct size
Primary percutaneous coronary intervention
Opening the IRA restores epicardial blood flow to the jeopardised myocardium. PPCI is the recommended reperfusion therapy for STEMI within 120 min of first medical contact.w28 Prognosis following PPCI has consistently been shown to be superior to fibrinolysis in patients with STEMI.w29 Infarct size is reduced in patients with PPCI versus fibrinolysis,w30 and myocardial salvage is increased by PPCI.w30 Delays in reperfusion result in reduced myocardial salvage2 and a larger infarct size.
During PPCI, thrombectomy devices have been assessed to determine their impact on infarct size. The rationale for these devices is to prevent the downstream embolisation of thrombotic material with balloon dilatation and stenting. Initial studies on infarct size reduction by CMR observed in the thrombectomy device groups appeared promising.9 Although there have been further contradictory studies,w31 a recent meta-analysis has shown a 29% reduction in all-cause mortality for aspiration thrombectomy, but with no significant difference in infarct size by CMR or SPECT between the thrombectomy and PPCI alone arms.10 The authors of the meta-analysis suggest the lack of reduction in infarct size is likely a result of bias, incomplete follow-up, and inconsistent methods for assessing the infarct size.10 The most recent and largest randomised study (TASTE trial), which enrolled >7000 patients, showed no significant difference in 30 day mortality for PCI plus thrombectomy versus PCI alone; infarct size was not reported.w32
Ischaemic post-conditioning refers to causing transient pulses of ischaemia and reperfusion directly within the IRA by repetitive inflations and deflations of an occluding balloon during reperfusion.w33 Alternatively, brief cycles of non-lethal ischaemia of a tissue remote from the heart before reperfusion11 (remote pre-conditioning) or following reperfusionw34 (remote post-conditioning) can be achieved by applying, most commonly, repetitive inflations and deflations of a blood pressure cuff. Both appear to trigger a common cardioprotective signalling pathway. Post-conditioning reduces infarct size up to 44% in a canine model.w35 In humans, post-conditioning has been shown to reduce infarct size by over 30% as measured by CK-MB,w36 SPECT,w37 and CMR.12 Indeed, remote conditioning has been shown to also reduce infarct size by troponinw38 and significantly increase myocardial salvage by SPECT.11 Further multicentre large population studies are investigating the prognostic benefits of this technique (NCT01857414, NCT01665365).
Intra-aortic balloon counterpulsation mechanically augments coronary blood flow and reduces afterload and myocardial oxygen demand. It is recommended for use in STEMI patients with cardiogenic shock.w28 However, a recent large randomised controlled multicentre study (IABP-SHOCK II) showed no reduction in 12 month all-cause mortality in this population.w39 It is perhaps not surprising therefore that routine intra-aortic balloon pump insertion in addition to PPCI in patients without cardiogenic shock (CRISP-MI) showed no reduction in infarct size by blood biomarkers.w40
Hyperoxaemia and hypothermia
Hyperoxaemia has been hypothesised to reduce infarct size by reducing lipid peroxidase radicals, altering nitric oxide synthase expression, and reducing microvascular obstruction by leucocytes.w6 Unfortunately, the evidence for hyperoxaemia to reduce infarct size on SPECT is limited and inconsistent.w41 w57
Myocardial hypothermia during ischaemia reduces metabolic demand and the inflammatory response.w6 In swine, therapeutic hypothermia can reduce infarct size as shown by histology.w42 The CHILL-MI study (NCT01379261) may provide further insight as to whether this can be translated into clinical practice and reduce infarct size on CMR.
Pharmacological: coagulation cascade
Intracoronary thrombus formation and activation of the coagulation cascade is central to STEMI. Agents to reduce clotting are therefore integral to reperfusion and effective PPCI.
Oral antiplatelet agents
Guidelines recommend aspirin as an adjunct to PPCI.w28 Aspirin reduces infarct sizew43 and reduces mortality.w44 Clopidogrel has been shown in a retrospective study to decrease enzymatic infarct size.w45 There is little evidence on infarct size reduction in humans for the novel P2Y12 inhibitors, although there is good prognostic and mortality data for their use. Prasugrel or ticagrelor have surpassed clopidogrel for treatment of STEMI.w28 It has been shown that prasugrel reduces infarct size in animal models,w46 improves prognosis in human clinical trials,w47 and reduces ischaemic events as compared to clopidogrel.w48 Ticagrelor also reduces infarct size in animal models compared with clopidogrelw49 and reduces mortality.w50 Cangrelor has been shown to reduce infarct size in a primate modelw51 and reduces ischaemic events during PCI as compared with clopidogrel.w52
Glycoprotein IIb/IIIa inhibitors
Glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors work via a receptor on the surface of platelets to prevent platelet aggregation and, therefore, thrombus formation. Gp IIb/IIIa inhibitors plus unfractionated heparin (UFH) have been shown to reduce infarct size following PPCI for STEMI.w53 The INFUSE AMI trial showed a modest reduction in infarct size (5.3 g) by CMR using a bolus of intracoronary abciximab in addition to bivalirudin, compared with bivalirudin alone.w56 There are ongoing questions as to whether intravenous or intracoronary administration is optimal. Gp IIb/IIIa inhibitors reduce infarct size if administered intracoronary as compared to intravenously, both enzymaticallyw54 and on CMR.w55
Bivalirudin is a specific direct thrombin inhibitor with a rapid onset of action and short half-life. In the HORIZONS-AMI trial, although bivalirudin has been shown to reduce mortality in PPCI as compared to UFH and abciximab,w56 there was no reduction in infarct size in the CMR sub-study.13 The possible explanation for this decrease in mortality in the absence of infarct size reduction is the decline in bleeding events with bivalirudin compared to UFH/abciximab.w58 More recently, a large scale European trial confirmed a reduction in bleeding complications,w59 but not a mortality benefit. A direct comparison of heparin versus bivalirudin in a single centre trial did not show a benefit in the major efficiency and safety endpoint.w60 Neither trial documented the infarct size.
Pharmacological: reperfusion injury
Stimulation of adenosine receptors by receptor agonists in an animal model mimics ischaemic pre-conditioning.w61 Adenosine also has an antiplatelet effect.w62 Intracoronary and intravenous infusion and boluses of adenosine have been proposed as potential adjuvant therapies to reduce infarct size. Studies so far have had contradictory results.w63 A double blind placebo controlled trial with a mixed adenosine agonist (ADMIRE) has shown no reduction in infarct size.w64 The larger AMISTAD-II, a randomised placebo controlled trial of adenosine, showed a notable reduction in infarct size by SPECT14 but no significant difference in clinical outcomes. A recent meta-analysis has shown no reduction in infarct size as measured by CK-MB with intracoronary adenosine.w63 Overall, adenosine administration is safew63 but its efficacy is controversial.
Ca2+ overload and generation of ROS are key triggers of reperfusion injury and it is now generally agreed that their effects are mediated through opening of the MPTP.15
Further evidence in support of a role for MPTP comes from work showing that inhibitors of pore opening are cardioprotective. This effect may be mediated either through direct inhibition of the pore with agents such as ciclosporin A (CsA) or through an indirect effect associated with a decrease in the factors responsible for MPTP opening such as oxidative stress or mitochondrial Ca2+ overload.15
There is conflicting evidence on the use of ciclosporin for infarct size reduction. A meta-analysis of 20 papers on animal models of myocardial infarction demonstrated that ciclosporin reduced infarct size in only two thirds of studies with a heterogeneous effect.16 In humans, a randomised trial of intravenous ciclosporin A showed a reduction in infarct size as measured by CK-MB and CMR, but no change on infarct size as measured by troponin I.w65 Further studies are investigating the clinical prognosis of MPTP inhibitor administration in STEMI: ciclosporin in the CIRCUS study (NCT01502774); and indirect MPTP inhibitors in MitoCare with TRO40303 (NCT01374321), and EMBRACE (NCT01572909).
Erythropoietin is a hormone secreted by the kidney in response to hypoxia and regulates plasma haemoglobin concentrations. Evidence suggests that erythropoietin has effects beyond that of haematopoiesis, including providing protection from apoptosis and inflammation due to hypoxia, toxicity or injury. In animal models of acute myocardial infarction, erythropoietin has been shown to reduce histological infarct sizew66; however, this has not been supported by human clinical trials.17 A meta-analysis of 1564 patients investigating erythropoietin has shown neither reduction of infarct size by CK-MB or CMR, nor any reduction in all-cause mortality.w67 There is an ongoing study (ICEBERG) with the endpoint of infarct size by CMR that may address this issue further.w68
Nitric oxide donors
Low levels of nitric oxide have been hypothesised as being beneficial in ischaemia/reperfusion injury.w69
Nicorandil is a combined ATP-sensitive potassium channel opener and nitrate preparation that has shown promise as an adjunctive treatment for STEMI. Nicorandil has proved beneficial in reducing infarct size in animal modelsw70 and reducing infarct size by SPECT in patients on nicorandil presenting with STEMI with previous angina.18 However, this has not translated into results in randomised clinical trials; nicorandil did not reduce infarct size according to CK-MB in a double blind randomised controlled trial.w71
Sodium nitrite is a selective nitric oxide donor that causes vasodilatation in ischaemic (acidotic) tissue.19 It has been proven to reduce infarct size in mice by up to 67%.w72 Multiple clinical studies are ongoing to assess the potential benefits of administering sodium nitrite for infarct size reduction in myocardial infarction. The NITRITE-MI study will assess infarct size by CK-MB and CMR (NCT01584453).20 The NIAMI study will assess infarct size on CMR adjusted for the AAR (NCT NCT01388504).w73
Atrial natriuretic peptide
Atrial natriuretic peptide (ANP) has been shown to reduce infarct size in animal models.w74 In a rabbit model, administering ANP before reperfusion reduced infarct size from 31% to 12% of the AAR by activation of protein kinase G and stimulation of downstream kinases.w74 This has been translated into a small clinical study that has shown a reduction in infarct size by CK-MB.w71
Blood and imaging biomarkers are tools used in clinical practice to assess infarct size and can be adopted in clinical trials. Among the imaging techniques, CMR represents the most promising technique due to its unique myocardial tissue characterisation, high resolution, and accurate quantitative assessment of myocardial damage. Many agents/interventions have been, and continue to be, investigated in trials to reduce infarct size following STEMI, with the aim of reducing mortality and morbidity. Some have been adopted into clinical care while others are more controversial, and ongoing studies will hopefully determine the best strategy to reduce infarct size in STEMI. Whatever the outcome, such a strategy is likely to involve a combination of pharmacotherapy and interventions.
Infarct size reduction in acute myocardial infarction: key points
Intervening early during acute myocardial infarction (STEMI) can increase myocardial salvage
Reperfusion can itself cause myocardial damage (reperfusion injury)
How to affect infarct size
Primary percutaneous coronary intervention
Pharmacological methods to reduce infarct size
Glycoprotein IIb/IIIa inhibitors*
Pharmacological methods that may have potential to reduce reperfusion injury
Nitric oxide donors
*Evidence not conclusive
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- ↵This article describes the pathophysiological process of the wavefront of ischaemia and why intervening early through the process allows myocardial salvage.
- ↵A clinical study delineating the damage as assessed by CMR of early versus delayed primary percutaneous intervention for STEMI.
- ↵This article depicts the histological validation of late gadolinium enhancement on CMR in myocardial infarction.
- ↵A large meta-analysis of thrombectomy during PPCI for STEMI.
- ↵This study provides an insight into the potential beneficial effects of pre-conditioning to increase myocardial salvage.
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Contributors EMcA: review of literature, writing of manuscript. CB-D: review of literature, editing of manuscript. MSS: writing of science paragraph, editing of the manuscript. AB: design of manuscript, review of literature, editing of manuscript.
Funding This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. This article presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests.
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