ST-segment elevation myocardial infarction · 2020. 3. 22. · Abstract | ST- segment elevation myocardial infarction (STEMI) is the most acute manifestation of coronary artery disease

Coronary artery disease (CAD) most of the time refers to coronary atherosclerotic disease that results in severe coro-nary artery narrowing, leading to inadequate blood supply to the heart muscle (myocardium). Acute coronary syn-dromes (ACSs) comprise the acute manifestations of CAD, including unstable angina (myocardial ischaemia without necrosis), non-ST-segment elevation myocardial infarc-tion (NSTEMI) and ST-segment elevation myo cardial infarction (STEMI). Myocardial infarction (MI) is com-monly defined as cardiomyocyte death caused by substan-tial and sustained ischaemia due to an imbalance of oxygen supply and demand. On the basis of the electro cardiogram (EKG or ECG) trace, MI is differentiated between STEMI and NSTEMI. STEMI is the result of transmural ischaemia (that is, ischaemia that involves the full thickness of the myocardium) (Fig. 1), whereas NSTEMI does not spread through all the myocardial wall. With the introduction of highly sensitive cardiac biomarkers, new definitions of MI that include biochemical and clinical aspects have been developed. The fourth universal definition of MI1 is based on a classification system with five subcategories. This Primer focuses mostly on type 1 MI, which is caused by atherothrombotic CAD and usually precipitated by rupture or erosion of the atherosclerotic plaque.

In most STEMI cases, the transmural myocardial ischaemia results from a total occlusion of an epicardial coronary artery caused by a thrombus (a blood clot) that developed on a coronary atherosclerotic plaque. STEMI is suspected when a patient presents with chest pain and persistent ST- segment elevation in two or more anatom-ically contiguous ECG leads (Fig. 1). In addition, STEMI should be suspected if the clinical presentation is com-patible and the ECG trace shows left bundle branch block (LBBB) and no ST- segment elevation, as in some cases total coronary occlusion manifests as LBBB2. By contrast, ECG findings of ST- segment depressions, T wave inver-sions or transient ST- segment elevations are suggestive of non- ST-segment elevation ACS and may reflect NSTEMI or unstable angina3.

STEMI is the most acute manifestation of CAD, with substantial morbidity and mortality. Early reperfusion (re-establishing the blood flow in the occluded artery) is the most effective way to preserve the viability of the ischaemic myocardium and limit infarct size. Early diag-nosis of STEMI is crucial to initiate appropriate treatment and should ideally be made within 10 minutes of first medical contact2. Initiatives have raised awareness on the importance of minimizing time to reperfusion with early

ST- segment elevation myocardial infarctionBirgit Vogel1, Bimmer E. Claessen1, Suzanne V. Arnold2,3, Danny Chan4, David J. Cohen2,3, Evangelos Giannitsis5, C. Michael Gibson6, Shinya Goto7, Hugo A. Katus5, Mathieu Kerneis6, Takeshi Kimura8, Vijay Kunadian4,9, Duane S. Pinto10, Hiroki Shiomi8, John A. Spertus2,3, P. Gabriel Steg11,12 and Roxana Mehran1*

Abstract | ST- segment elevation myocardial infarction (STEMI) is the most acute manifestation of coronary artery disease and is associated with great morbidity and mortality. A complete thrombotic occlusion developing from an atherosclerotic plaque in an epicardial coronary vessel is the cause of STEMI in the majority of cases. Early diagnosis and immediate reperfusion are the most effective ways to limit myocardial ischaemia and infarct size and thereby reduce the risk of post- STEMI complications and heart failure. Primary percutaneous coronary intervention (PCI) has become the preferred reperfusion strategy in patients with STEMI; if PCI cannot be performed within 120 minutes of STEMI diagnosis, fibrinolysis therapy should be administered to dissolve the occluding thrombus. The initiation of networks to provide around- the-clock cardiac catheterization availability and the generation of standard operating procedures within hospital systems have helped to reduce the time to reperfusion therapy. Together with new advances in antithrombotic therapy and preventive measures, these developments have resulted in a decrease in mortality from STEMI. However, a substantial amount of patients still experience recurrent cardiovascular events after STEMI. New insights have been gained regarding the pathophysiology of STEMI and feed into the development of new treatment strategies.

*e- mail: [email protected]

https://doi.org/10.1038/ s41572-019-0090-3

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diagnosis and immediate transfer to a facility with the option for cardiac catheterization and subsequent pri-mary percutaneous coronary intervention (PCI)4. Studies on the detection of atherosclerotic plaques at increased risk of being associated with a future cardiac event have resulted in a more- comprehensive view on the patho-physiology of acute MI and support the concept of the ‘vulnerable patient’ rather than the ‘vulnerable plaque’5–7. New treatment strategies including treatment that tar-gets inflammation are under investigation and may help to further reduce the risk of recurrent cardiovascular events. This Primer on STEMI summarizes these new developments and provides a general overview of epide-miology, alternative coronary causes, diagnosis and pre-vention of STEMI, as well as post-STEMI complications and quality of life.

EpidemiologyDisease burden and risk factorsThe epidemiology of patients with STEMI continues to evolve. The Global Registry of Acute Coronary Events (GRACE)8 documented that STEMI accounted for ~36% of ACS cases. Similar findings have been reported in a developing country, with STEMI accounting for ~37% of ACS cases enrolled in the Jakarta Acute Coronary Syndrome (JAC) Registry database9. According to an analysis of a large United States database, the age- adjusted and sex- adjusted incidence of hospitalizations for STEMI significantly decreased from 133 per 100,000 person-years in 1999 to 50 per 100,000 person-years in 2008 (reF.10). These results reflect the situation in the Western world, whereas the prevalence and incidence of cardiovascular disease (CVD) in developing countries are increasing11. Reasons for this increase include expand-ing life expectancy, changing lifestyles and the adoption of a Western diet (which is typically rich in saturated fats and refined sugars) in these regions. In addition, CVD occurs at a younger age in developing countries than in developed ones. For example, a case–control

study found that acute MI occurred at a signifi cantly younger age in individuals living in south Asian countries than in individuals from other countries12. These results were largely explained by higher prev-alence of risk factors at younger ages in south Asia. This higher prevalence of risk factors may also be the reason for the markedly high prevalence of ischaemic heart disease in central and eastern European coun-tries13. Although tobacco smoking (one of these risk factors) occurs worldwide and in many countries is declining, its prevalence seems to be high in eastern European and Asian countries and is increasing in the WHO Eastern Mediterranean Region and the African Region14. Overall, low socioeconomic status is associ-ated with higher risk of and an earlier occurrence of acute MI, and similar results were observed in black and Hispanic patients compared with white patients within the United States15.

Regardless of country or ethnicity, STEMI tends to occur at a younger age in men than in women owing to the protective effect of oestrogen before menopause16–19. Of note, women presenting with STEMI before the age of 60 have been shown to have worse outcome than their male counterparts16.

MortalityDevelopments in reperfusion therapies and preventive measures have contributed to a reduction in mortality from STEMI20. However, mortality seems to have pla-teaued, and a substantial amount of patients still expe-rience recurrent cardiovascular events after STEMI21. Post- STEMI complications (see below) are decreasing22, a reduction that is probably related to improved systems of care and use of guideline- directed therapy. In a nation-wide Swedish registry of almost 200,000 patients admit-ted with STEMI from 1996 to 2008, the incidence of heart failure decreased from 50% to 28%23. Several large- scale registries suggest an increase in unadjusted mor-tality after STEMI over time but a decrease in adjusted mortality. In one report using data from the United States Nationwide Inpatient Sample, between 2004 and 2012, in- hospital mortality increased from 3.9% in 2004 to 4.7% in 2012 (reF.24) (Fig. 2). Data from another analysis showed no changes over time in unadjusted in- hospital mortality after STEMI in patients treated with primary PCI (3.40% to 3.52%) or coronary artery bypass graft (CABG) surgery (5.79% to 5.70%)25. However, in- hospital mortality increased for patients who did not receive PCI or CABG surgery (12.43% to 14.91%)25. These findings are probably related to the increased age and prevalence of multiple comorbidities at presenta-tion, which is becoming more common in patients with STEMI. The proportion of patients with three or more comorbidities significantly increased (14.8% to 29.0%), as did the proportion of patients who were intubated or experienced cardiac arrest on presentation (3.2% to 7.8%)24. After multivariable adjustment for these factors, risk- adjusted in- hospital mortality decreased between 2004 and 2012 (reF.24). Other studies have simi-larly demonstrated that, after multivariable adjustment, in- hospital mortality decreased26. Furthermore, assum-ing similar comorbi dities, the odds of dying within

Author addresses

1The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.2Department of Cardiovascular Medicine, Saint Luke’s Mid America Heart Institute, Kansas City, MO, USA.3University of Missouri- Kansas City, Kansas City, MO, USA.4Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.5Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, Heidelberg, Germany.6Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.7Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Kanagawa, Japan.8Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.9Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK.10Division of Cardiology, Richard A. and Susan F. Smith Center for Cardiovascular Outcomes Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.11FACT, French Alliance for Cardiovascular Trials, Paris, France.12Université Paris- Diderot, Paris, France.

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1 year after discharge are estimated to be 50% lower among patients with STEMI in 2005 than they were in 1997 (reF.22).

Mechanisms/pathophysiologyThe predominant underlying mechanism of the total coronary occlusion in STEMI is thrombosis developing on a coronary atherosclerotic plaque27. A few exceptions exist and include spontaneous coronary artery dissec-tion (Box 1), coronary spasm (Box 2) and coronary embolism (Box 3).

Beyond the concept of the vulnerable plaqueA vulnerable plaque can be described as an atheroscle-rotic lesion that has a high risk of rupture and is charac-terized by a large lipid- rich or necrotic core that is separated from the vessel lumen by a thin fibrous cap (also called thin- capped fibroatheroma)28. Disruption of a so- called vulnerable plaque has been reported as

the most common cause of acute MI29,30. The underlying mechanism is based on the atherosclerotic progression through expansion of the lipid core and accumulation of macrophages at the edges of the plaque, leading to plaque rupture31.

It was hypothesized that by detecting these vul-nerable plaques, preventive measures (such as high- intensity statin therapy or PCI) could be implemented to potentially prevent future cardiovascular events32. This theory was partly supported by optical coherence tomography studies that revealed that patients with STEMI had atherosclerotic plaques with larger thin fibrous cap surface area, thinner minimum fibrous cap thickness and a larger macrophage area than plaques observed in patients with stable angina pectoris (chest pain due to inadequate blood supply to the heart that mostly presents during physical exertion and is relieved by rest or nitroglycerine administration)33. In addi-tion, thin- capped fibroatheromas were more frequent

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Fig. 1 | Healthy and STEMI ECG traces. a | Electrocardiography (ECG) uses sensors attached to the skin (electrodes) to record the electrical activity of the heart. A 12-lead ECG system includes 3 limb leads (bipolar), 3 augmented limb leads (unipolar) and 6 precordial leads (unipolar). With regard to the bipolar leads, two electrodes ( + and –) are placed equidistant from the heart, and electricity flow from the negative to the positive electrode is recorded. In the case of the unipolar leads, electricity flow from the centre of the heart towards the positive electrode is recorded. The different segments of an ECG trace indicate electrical events during the cardiac cycle. Each lead generates a certain pattern in the trace, corresponding to the electrical activity in the area of the myocardium that is captured by the lead. In ST- segment elevation myocardial infarction (STEMI), the presence of ST- segment elevation in certain leads may provide information on the localization of the myocardial infarction and the culprit vessel (for example, ST- segment elevation in leads II, III or aVF denotes inferior infarction, with the right coronary artery as a culprit vessel in ~80% of cases265). b | Specific changes in certain segments of the ECG trace (indicated by arrows), especially the ST segment, can be documented over time in patients with STEMI. AV, atrioventricular; aVF, augmented vector foot; aVL , augmented vector left; aVR , augmented vector right.

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in patients with STEMI than in patients with stable angina pectoris34,35. The large prospective PROSPECT study used virtual histology intravascular ultrasono-graphy (a type of intravascular ultrasonography that enables the identification of different plaque compo-nents, such as fibrous tissue and necrotic lipid core) to evaluate lesion- related risk factors associated with future adverse cardiovascular events5. Recurrent ischae-mic events were equally attributable to culprit lesions (that is, the lesions that caused the initial ACS) and to non- culprit lesions. Although non- culprit lesions responsible for a recurrent ischaemic event were fre-quently angiographically mild at baseline (mean ± s.d. diameter stenosis 32.3 ± 20.6%), most of them were thin- capped fibroatheromas characterized by a large plaque burden, a small luminal area or both. Although these findings are consistent with the concept of the vulnerable plaque, the overall risk of MI associated with thin- capped fibroatheroma was low (Kaplan–Meier event rate 4.9% over a median 3.4 years follow- up time). In addition, previous studies have suggested that many plaques rupture without any clinical symptoms36, and plaque morphology can change over time, which can result in gain or loss of high- risk features37. These find-ings suggest that the mechanisms leading to acute MI are more complex than previously assumed and are not only based on the presence or absence of plaques with high- risk characteristics.

Several investigations support the theory of sys-temic mechanisms that contribute to the occurrence of an ischaemic event, and the concept of the vulnerable patient rather than the vulnerable plaque seems appro-priate to evaluate for the risk of MI6,7. CAD might be considered a systemic and dynamic process with hardly any possibility to predict which plaque could be respon-sible for a future cardiovascular event. Consistent with this hypothesis, studies suggested that inflammation as a systemic process plays a major part in atherogenesis, plaque evolution and plaque rupture (Fig. 3).

Superficial plaque erosion is another pathological process that can lead to ACS that is receiving increasing

attention38. The pathological picture of superficial ero-sion differs substantially from the one of the thin- capped fibroatheroma. It seems that endothelial cells at the plaque–thrombus interface are generally absent, lead-ing to the term plaque erosion39. Although the plaque morphology is not consistent with the vulnerable plaque, simultaneous processes of endothelial cell loss, neutro-phil recruitment and thrombosis may have a central role39. Although data suggest that superficial plaque erosion accounts for approximately one- third of cases of ACS, this mechanism is probably most frequently associated with NSTEMI, whereas plaque rupture is most probably associated with STEMI38. The reason for a gain in incidence of superficial erosion and the shift in occurrence from STEMI to NSTEMI may be associated with the wide use of lipid- lowering and other preven-tive therapies. For example, in addition to low- density lipoprotein (LDL)-lowering properties, statins also have antiinflammatory effects that potentially contribute to plaque stabilization.

MI from total coronary occlusionAfter plaque rupture, thrombogenic material residing within the plaque is exposed to the blood and circula-ting coagulation factors, resulting in the formation of a thrombus on the ruptured plaque (Fig. 3). If the throm-bus completely occludes the coronary vessel, the aero-bic metabolism in the affected myocardium is halted, resulting in rapid ATP depletion as well as accumula-tion of metabolites such as lactate40. These metabolic effects in turn lead to electrolyte changes including a K+ shift to the extracellular space and a reduction in the action potential duration and amplitude41. Within seconds, these processes lead to a reduced contractil-ity of the myocardium42. Although these effects are completely reversible if blood flow is restored rapidly, animal models have shown that a 20–30-minute time interval of sustained ischaemia is sufficient to cause irreversible damage to cardiomyocytes42–44. Necrosis occurs first in the endocardium, which is most dis-tal to the blood supply, before it progresses into the subepicardial layers43.

Myocardial cell death leads to the release of creati-nine kinase (CK) into plasma. CK exists as different isoenzymes, of which CK- MB has its greatest activity in the heart muscle. Thus, elevation of CK can occur with damage of tissues other than myocardium, especially skeletal muscle, whereas CK- MB is more specific for myocardial necrosis; levels of both markers are assessed in patients with STEMI to confirm diagnosis. In addi-tion, the pathological degeneration of the actin and myosin filaments of the heart muscle results in troponin release. Both skeletal and cardiac muscle contract via a troponin- dependent mechanism, and different isoforms of the troponin subunits (troponin I, T and C) exist. In contrast to troponin C, troponin I and troponin T have distinct cardiac and skeletal isoforms45, and, there-fore, cardiac troponin I (cTnI; also known as TNNI3) and cardiac troponin T (cTnT; also known as TnTc) are specific for myocardial injury and can be used as bio-markers for early diagnosis of MI (see below) and for evaluation of prognosis.

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Fig. 2 | Trends in MI in- hospital mortality. The overall estimated risk of in- hospital mortality after myocardial infarction (MI) has increased between 2004 and 2012. However, after multivariable adjustment that accounted for the increasing trend in intubation or cardiac arrest at ≤24 hours, risk- adjusted in- hospital mortality decreased. Error bars show 95% confidence intervals. Adapted with permission from reF.24, Elsevier.


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Infarct size, reperfusion injury and remodellingThe infarct size depends on several factors, including the level of coronary occlusion, the presence or absence of collateral blood supply to the ischaemic area and the duration of total vessel occlusion. More proximal occlu-sion is associated with greater infarct size, as blood sup-ply to a greater area is interrupted. The most effective way to preserve the viability of ischaemic myocardium and limit infarct size is early reperfusion of the occluded vessel. However, even after successful revasculariza-tion with PCI, cardiac tissue may still fail to perfuse normally, a condition called ‘no- reflow phenomenon’. No-reflow seems to occur predominately when ischae-mia persists for ≥90 minutes, and underlying mecha-nisms include injury related to ischaemia, reperfusion or distal embolization of thrombus and atheroscle-rotic materials, with resultant coronary microvascular dysfunction and obstruction (MVO)46,47. Coronary microvascular dysfunction might also be a preexisting condition.

Reperfusion of the occluded vessel itself can para-doxically induce cardiomyocyte death and injury, a phenomenon called myocardial reperfusion injury, and can contribute to an increase in infarct size. With resto-ration of coronary blood flow, an intense inflammatory response occurs at the site of infarction. An influx of leukocytes and the activation of pro- inflammatory cas-cades have both beneficial and detrimental effects on the healing process and post- MI remodelling48,49. The initial pro- inflammatory response aims at removing necrotic cell debris and is followed by an antiinflammatory restorative phase, which enables wound healing and scar formation. In a mouse model, a pro- inflammatory subset of monocytes that express high levels of lympho-cyte antigen 6 C (LY6Chi) seems to predominate during the initial phase, whereas an antiinflammatory subset (LY6Clow) predominates during the restorative phase (4–7 days after the MI)50. Disturbances in the balance as well as the transition between the two phases can con-tribute to post- MI ischaemia, reperfusion injury and adverse remodelling50. Despite growing evidence from many studies, many aspects related to MVO, ischaemia

and reperfusion injury or the inflammatory response in STEMI are not completely understood yet, and this gap in our knowledge underlies the lack of co- adjuvant therapies for reperfusion.

Because the myocardium has negligible regener-ative potential, the dead cardiomyocytes are replaced by a non- contractile collagen- based scar tissue. If a large myocardial area is damaged and replaced by fibrous tissue, this change can lead to substantial alterations in the geometry of the ventricle. Whereas infarcted areas thin, the rest of the myocardium undergoes hypertro-phy. The failure to normalize increased wall stresses results in progressive ventricular dilatation51, and the shape becomes more spherical. This adverse remodel-ling has substantial consequences for the contractility of the ventricle and can eventually lead to heart failure. In the presence of myocardial wall stress, blood levels of natriuretic peptide B (BNP, which is synthesized and secreted mostly by myocardium), its biologically inac-tive amino- terminal fragment (NT- proBNP) and atrial natriuretic peptide (ANP) increase. As a consequence of the increased release of these two peptides, diuresis and vasodilatation also increase52,53. Finally, the struc-tural changes of the ventricle may also have electrical effects. Changes in patterns of excitation and conduc-tion due to altered activity of ion channels and decreased cellular connectivity have been documented54.

Diagnosis, screening and preventionECG and clinical presentationTime delay to treatment is a relevant factor that has a great effect on mortality in patients with STEMI2,20; thus, early diagnosis is crucial. The fourth definition of MI has updated the diagnostic criteria for type 1 MI (Box 4). The working diagnosis is usually based on symptoms consistent with myocardial ischaemia, that is, persistent chest pain and new ST- segment elevation. However, it is important to also recognize atypical symptoms, such as pain in neck, back or jaw as well as weakness, nausea or fatigue, which are more frequent in women than in men55. In the presence of persistent chest pain, a 12-lead ECG must be recorded and interpreted as soon as pos-sible at the point of first medical contact, with a maxi-mum target delay of 10 minutes56,57. Field transmission of the ECG is recommended if ECG interpretation is not possible on site2,20. The registration of a pre- hospital ECG improves clinical outcomes and time to reperfu-sion, particularly when coupled with communication of a STEMI diagnosis and preferential transport to a PCI- capable hospital57–59. ST- segment elevation is considered persistent when not resolving before revascularization therapy and transient in the case of resolution before intended revascularization therapy. Atypical electrocar-diographic presentation of STEMI in certain situations is possible, and criteria to support the diagnosis in such cases have been provided by guidelines2. The diagnosis of STEMI can be particularly difficult in the presence of left ventricular hypertrophy, LBBB, ventricular paced rhythm, Brugada syndrome and early repolarization patterns because these conditions interfere with the classic ST- segment elevation pattern in the ECG60. For LBBB, electrocardio graphic criteria were identified and

Box 1 | Alternative causes of STEMI: SCAD

Spontaneous coronary artery dissection (SCAD) is defined as a nontraumatic and noniatrogenic tear within the layers of the coronary vessel wall, with intramural haemorrhage that creates a false lumen248. This dissection can be caused by either an intimal tear, resulting in blood from the lumen of the vessel entering the intimal space, or a rupture of the vasa vasorum (small arterioles that provide blood supply to the vessel wall). Both mechanisms eventually lead to the formation of an intramural haematoma that compresses the lumen of the vessel. A multifactorial pathogenesis of SCAD has been suggested, with associated factors including underlying arteriopathies248 (for example, fibromuscular dysplasia), genetic factors, hormonal influences and systemic inflammatory diseases. Hormonal changes are thought to influence the architecture of the vessel wall by altering elastic fibres and impairing collagen synthesis and mucopolysaccharide content249. Although SCAD is rare, its prevalence in women of <50 years of age with an acute coronary syndrome was reported to be ~10%250. Furthermore, it is the most common cause of acute myocardial infarction in women who are pregnant or postpartum251. It has been reported that ~50% of patients with SCAD present with ST- segment elevation myocardial infarction (STEMI)251. However, the true prevalence of SCAD is still uncertain, and large prospective investigations are needed to better understand the natural history of this disease.


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validated61 to assist diagnosis in those presenting with suspected STEMI, but these criteria do not provide diagnostic certainty62. New LBBB does not predict an MI per se. Nevertheless, patients with a clinical suspi-cion of ongoing myo cardial ischaemia and LBBB should be managed in a way similar to patients with STEMI. In some conditions such as acute occlusion of a vein graft or the left main coronary artery, ST- segment elevations may be absent. In patients with right bundle branch block, ST- segment abnormalities are common and con-found the detection of ischaemia in the corresponding leads, unless ECG changes can be proven to be new.

STEMI may occur in the absence of obstructive CAD on angiography63–66 and is termed MI with non- obstructed coronary arteries (MINOCA). MINOCA that is associated with ST- segment elevations may be based on atherosclerotic plaque rupture, ulceration, fissuring, erosion or coronary dissection with nonobstructive or no CAD, but also myocardial disorders such as myo-carditis and Takotsubo stress cardiomyopathy2. The 2013 European Society of Cardiology (ESC) Task Force introduced criteria for clinically suspected myo-carditis67. Among patients with a clinical diagnosis of MINOCA, myocarditis had a prevalence of up to 33% in a meta- analysis68. The gold standard for confirma-tion of suspected myocarditis is endomyocardial biopsy, although its use is limited by its invasive nature67,69. Cardiac MRI may be an alternative test, as good diag-nostic performance has been shown at least for acute myocarditis70. Diagnostic criteria for Takotsubo cardio-myopathy have been published in an international expert consensus document71.

Role of cardiac biomarkersBlood tests for biomarkers of myocardial injury are indi-cated as soon as possible in the acute phase, but rep-erfusion treatment should not be delayed awaiting the

results. The preferred biomarker for diagnosis of MI is cTnI or cTnT owing to high myocardial tissue specific-ity and high clinical sensitivity. However, for qualifying patients with STEMI (with symptoms of ischaemia for ≤12 hours and persistent ST- segment elevation), guide-lines recommend immediate reper fusion therapy with-out waiting for cardiac marker results2,20. The release of cTn over time in STEMI is distinct from the heteroge-neous release pattern of cTn following an NSTEMI72,73. The release kinetics of cTn following a STEMI depend on the type (primary PCI or fibrinolytic therapy) and success of reper fusion therapy72,73 and several other factors, including the type and sensitivity of the cTn assay used and the presence of collateral flow to the infarct- related artery. Typically, a steep rise and subse-quent gradual fall with a monophasic (cTnI) or biphasic (high- sensitivity cTnT) curve is observed following successful primary PCI or fibrinolytic therapy72,73.

The presence and magnitude of cTn elevations after STEMI are useful for short- term and long- term prog-nosis of cardiovascular events such as recurrent MI and death. Elevated cTn at admission74,75, peak values76 and persistence of elevated cTn beyond the initial weeks after STEMI77–79 have been shown to confer impor-tant prognostic information for long- term outcomes. Elevated cTn concentrations return to normal levels within days to weeks, depending on the cTn assay (cTnT or cTnI, and conventional sensitivity or high- sensitivity cTn), but may also persist in 31–37% of patients for up to weeks or months after MI77–79. The reasons for persistent cTn elevation after an index ACS are rather multifacto-rial77–79. However, a significant correlation between ele-vated high- sensitivity-cTnT levels at 7 weeks after ACS and reduced systolic left ventricular ejection fraction (LVEF) as well as BNP has been demonstrated78 and suggests an association between persistently elevated troponins and impaired left ventricular function.

Role of imagingEmergency transthoracic echocardiography should be performed in patients with inconclusive STEMI diag-nosis and in patients presenting with cardiac arrest, cardiogenic shock (a life- threatening condition with inadequate tissue (end- organ) blood perfusion), haemo-dynamic instability or suspected mechanical complica-tions. However, it should not be routinely performed before revascularization in order to not delay reperfu-sion. Routine transthoracic echocardiography after PCI is indicated in all patients with STEMI to evalu ate left ventricular, right ventricular and valve function and to exclude early post- infarction mechanical compli-cations and left ventricular thrombus. In patients with pre- discharge LVEF <40%, echocardiography should be repeated 6–12 weeks after MI, after complete revas-cularization and optimal medical therapy have been achieved, to assess the potential need for implantation of an implantable cardioverter–defibrillator for primary prevention of life- threatening arrhythmias2,20. Although assessment of left ventricular function by transthoracic echocardiography has been considered as one of the most important prognostic factors in patients after STEMI, the prognostic value of left ventricular function

Box 2 | Alternative causes of STEMI: coronary spasm

Coronary spasm is a variant form of angina252 characterized by symptoms of chest pain at rest with ST- segment elevation. Coronary spasm typically occurs in the early hours of the morning during depressed vagal tone and is associated with transient vasoconstriction of the epicardial coronary arteries, resulting in total or subtotal vessel occlusion with consecutive myocardial ischaemia. Underlying mechanisms are a mostly localized abnormality of a coronary artery that results in hyper- reactivity to vasoconstrictor stimuli and a vasoconstrictor stimulus capable of inducing the spasm. Most common stimuli are illicit drugs, such as cocaine, but also include some weight- loss products, over- the-counter drugs, chemotherapies, antimigraine medications and antibiotics253. Mechanisms that mediate the vasoconstriction include stimulation of the α- adrenergic receptors in smooth muscle cells in the coronary arteries, increased levels of the powerful vasoconstrictor endothelin 1 and decreased production of the vasodilator nitric oxide. Endothelial dysfunction and primary hyper- reactivity of vascular smooth muscle cells (increased contractile response to stimuli) have been proposed as contributing factors254. Although coronary spasm may potentially result in total occlusion of an epicardial coronary artery, the size of the resultant myocardial infarction (MI) is usually small, suggesting rapid reperfusion in the early stages of MI owing to the transient nature of the spasm253. The true prevalence of coronary spasm is uncertain, as prevalence estimates depend very much on the population studied. The long- term prognosis of MI caused by coronary spasm is relatively benign when compared with that of ST- segment elevation MI (STEMI) caused by plaque rupture, according to several registry studies255,256.


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has been mainly derived from studies of the pre- PCI era. In patients who have undergone primary PCI, this parameter is heavily influenced by post- ischaemic stunning (a state of prolonged contractile dysfunc-tion of post- ischaemic myocardium in which normal myocardial function is gradually restored after a given recovery period)80.

Cardiac MRI is an excellent tool for tissue character-ization and enables the documentation of the different pathophysiological processes after STEMI, including myocardial oedema and intramyocardial haemorrhage, as well as MVO and changes in the remote myocardial interstitial space (in the zone opposite to the infarct zone) in patients developing adverse left ventricular remodelling81. Several studies evaluated these param-eters as prognostic factors. In 810 patients, MI size, MVO and left ventricular volumes and function were evaluated by early post- MI MRI (median of 4 days after STEMI). In contrast to left ventricular function, MVO (shown as a dark hypo- intense core within the areas of hyper- enhancement on early or late gadolinium enhancement MRI images) was shown to be a strong independent prognostic factor in patients after STEMI82. MVO was confirmed as a strong prognostic factor by another study of 1,688 patients83. In addition, cardiac MRI- derived MI size has been frequently used as a surrogate end point in randomized controlled trials for novel cardioprotec-tive therapies aiming to reduce MI size84. Cardiac MRI is well suited to have an important role in the evalua-tion of patients with STEMI owing to its capability to provide quantitative multiparametric characterization of the infarcted myocardium along with comprehensive assessment of left ventricular function and morphol-ogy82. However, efforts are needed to achieve standardi-zation of the technique (timing of MRI acquisition, dose of contrast and time elapsed between contrast admin-istration and acquisition of late gadolinium enhance-ment imaging) and to improve accessibility for patients (techniques that do not require breath hold and reducing scan time and costs) in order for it to become a tool rou-tinely used in clinical practice to evaluate prognosis and guide treatment.

Echocardiography and cardiac MRI but also single photon emission CT (SPECT) and PET are useful to detect residual ischaemia and evaluate myocardium via-bility in patients with multivessel disease (that is, with one or more additional coronary arteries with a substan-tial atherosclerotic burden, in addition to the culprit ves-sel) who received treatment only of the infarct- related artery or in patients who present days after the acute event with completed MI2.

ScreeningScreening in the context of STEMI is mostly focused on detecting cardiovascular risk factors and atherosclerosis. The descriptive INTERHEART study enrolled patients from 52 countries and identified nine potentially modi-fiable factors (abnormal blood levels of lipids, smoking, hypertension, diabetes mellitus, abdominal obesity, psycho-social factors, consumption of fruits and vegetables, con-sumption of alcohol and regular physical activity) that account for >90% of the population- attributable risk of a first MI85. An analysis of the National Health and Nutrition Examination Survey (NHANES) revealed that five modifiable risk factors for CVD (elevated choles terol, diabetes mellitus, hypertension, obesity and smoking) accounted for one- half of CVD deaths in US adults of 45–79 years of age from 2009 to 2010 (reF.86).

As atherosclerosis is usually the result of several risk factors, guidelines recommend comprehensive cardio-vascular risk assessment87. Risk assessment models based on pooled cohort equations such as Framingham88, the ASCVD89 or SCORE87 can help to evaluate the 10-year risk of atherosclerotic CVD and guide preventive meas-ures. However, data from cardiac imaging cohorts sug-gest that the value of these models to assess the risk of an individual might be limited. Studies that evaluated coronary artery calcium with CT have shown that many individuals who are deemed to be at high cardio-vascular risk on the basis of assessment with risk mod-els have in fact no atherosclerosis and are at very low risk of cardio vascular events90. Coronary artery calcium scoring seems to be an excellent tool for guiding pre-ventives therapies (especially statin and/or aspirin use) and can add valuable prognostic information beyond the traditional risk factors91.

PreventionAs the majority of STEMI cases result from thrombus formation on a ruptured coronary atherosclerotic plaque, prevention aims at reducing the burden of athero-sclerosis. Several strategies have been recommended in the primary prevention of CVD. All individuals should be offered lifestyle modification advice to reduce CVD risk regardless of risk score values.

Smoking is one of the major risk factors for the development of atherosclerotic conditions including MI92 and worsens outcomes after intervention. Patients who smoke are at a higher risk of mortality and mor-bidity following PCI93. Several mechanisms by which cigarette smoking leads to CAD have been proposed, including oxidative damage to the endothelium, lead-ing to endothelial damage and accelerating atheroscle-rosis, platelet activation and thrombosis, reduced oxygen availability and sympathetic nervous system activation, resulting in coronary vasoconstriction94–97.

Obesity prevalence has increased globally98. In the United Kingdom, the prevalence increased from 15% in 1993 to 27% in 2015 (reF.99), and more than half of the population could have obesity by 2050. Obesity and over-weight increase the risk of developing MI by adversely contributing to risk factors including hypertension, dys-lipidaemia, chronic inflammatory state, type 2 diabetes mellitus and metabolic syndrome. The mechanisms by

Box 3 | Alternative causes of STEMI: coronary embolism

The reported prevalence of coronary embolism as the cause of ST- segment elevation myocardial infarction (STEMI) ranges from 4% to 13% according to angiographic and autopsy studies257–260. However, evaluation of the true prevalence is difficult owing to the acute clinical setting of the disease. In a report on data derived from an observational cohort study257, the most frequent cardiac causes of coronary embolism were atrial fibrillation, followed by dilated cardiomyopathy, endocarditis and intracardiac tumour, whereas among systemic diseases, malignancy, systemic autoimmune disease and antiphospholipid syndrome were present.


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which excessive body weight worsens these risk factors have been reviewed elsewhere100,101.

An unhealthy diet (based on food high in sodium, refined sugar and fat) is associated with an increased risk of MI by inducing weight gain. It also has an adverse effect on other risk factors for MI including hyper-cholesterolaemia, hypertension and type 2 diabetes mellitus102–104. High sodium intake has been shown to increase blood pressure, whereas sodium reduction has

been shown to decrease CAD, and in particular, elderly patients or individuals with underlying elevated blood pressure may benefit the most from it105. One of the main forms of sugar in diet is sweetened beverages, and a sys-tematic review has demonstrated a positive association between sweetened beverages and CAD106. Excessive consumption of saturated and trans- fat is also considered to be a risk factor for coronary heart disease107,108. Not all types of fat have an adverse effect on cardiovascular

Endothelial cell

Collagen

Blood flow

LDLLum

enIn

tim

aM

edia

Adhesionmolecule

Macrophage Foam cell

T cell

OxidizedLDL

Activated platelet

Fibrin

Necrotic core

• Inflammation• Matrix degradation• Expansive remodelling

Microparticlerelease

Monocyte

Prothrombin

Thrombin

Endothelial cell

Apoptotic body

Apoptotic body

LDLR

Smooth muscle cell

Platelet tethering

vWF

GPIb–IX–V

PlateletPlatelet activation

P2Y12

ADP

Red blood cell

Inside-out signalling

GPIIb/IIIa (high affinity)

GPIIb/IIIa (low affinity)

Fibrinogen

Cholesterolcrystal

a

b

Fig. 3 | Atheromatous plaque development, plaque rupture and thrombus formation. a | Retention of low- density lipoprotein (LDL) particles within the subendothelial layer results in recruitment of monocytes to the growing athero sclerotic plaques, where they differentiate into macrophages48,266,267. Macrophages perpetuate inflammation and destabilize the extracellular matrix and the endothelial layer266. Inflammation results in stimulation of procoagulant factors that trigger thrombus formation, resulting in acute coronary syndrome38. Furthermore, it increases the production of fibrin, one of the main components of thrombus, and of plasminogen activator inhibitor 1 (PAI1), the major endogenous inhibitor of fibrinolysis38. Mechanisms such as recurrent intraplaque haemorrhage have been suggested to contribute to the accelerated plaque progression268,269. Intraplaque bleeding was reported to increase the deposition of free cholesterol and macrophage infiltration, resulting in rapid necrotic core expansion270. An ongoing vicious cycle of inflammation, extracellular matrix degradation and expansive remodelling may lead to accelerated growth and eventually to acute plaque disruption271. b | The rupture of the atherosclerotic plaque causes endothelial damage and triggers thrombus formation. Platelets start to adhere to the exposed subendothelial matrix; initial adhesion of platelets is mediated by the platelet membrane protein glycoprotein (GP) Ibα, a binding protein making up part of the GPIb–IX–V complex on the platelet cell, binding to von Willebrand factor (vWF)272,273. After activation, platelets change their shape and release various bioactive substances including ADP274,275. Locally released ADP further activates platelets through continuous stimulation of P2Y purinoceptor 12 (P2Y12) ADP receptors276. After platelet activation, inside- out signal transduction mechanisms trigger a conformational change in the fibrinogen receptor GPIIb/IIIa to a high- affinity ligand- binding state. The GPIIb/IIIa receptors mediate the final common pathway of platelet aggregation. Excessive platelet activation overcomes regulatory haemostatic mechanisms and leads to generation of unwarranted levels of thrombin277. Several thrombin receptors that are located on the surface of the platelet are efficiently activated by thrombin, which further activates the platelets277,278. In the presence of an increased thrombogenic and inflammatory milieu, the process of thrombus formation is also regulated by the fibrinolytic system, which may be inhibited by inflammation. LDLR , LDL receptor. Part a adapted from reF.279, Springer Nature Limited.


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health; mono- unsaturated or polyunsaturated fatty acids such as omega-3 have been demonstrated to be cardio-protective. For a healthy and balanced diet, eating at least five portions of fruit and vegetables a day is rec-ommended, along with at least two portions of fish weekly109. Adherence to dietary recommendations has been shown to lower the risk of fatal and nonfatal acute MI110. If LDL cholesterol is elevated, lifestyle modifica-tion plays a crucial part in lowering the cardiovascular risk. However, certain patient groups need additional pharmacological treatment with statins to lower LDL cholesterol. Statins reduce LDL cholesterol levels by inhibiting the activity of HMG- CoA reductase, a key enzyme in the synthesis of cholesterol. Patients who might need statins for primary prevention include indi-viduals with baseline LDL cholesterol levels of ≥190 mg per dl, patients with diabetes mellitus and patients with increased atherosclerotic CVD risk resulting from the presence of risk factors such as arterial hypertension, smoking and increased age111. As mentioned above, coro-nary artery calcium scoring may also provide valuable information on which patient may benefit from statin therapy. Different guidelines in the United Kingdom112, United States111 and Europe113 provide slightly different recommendations.

The beneficial effect of physical exercise on coronary heart disease has long been recognized114. Many studies have strongly supported the protective effect of physical activity on CAD, with the incidence of CAD halved in the most physically active individuals compared with the most sedentary115,116. The mechanisms by which exercise exerts its protective effect are probably by reducing the risk factors associated with the development of CAD, such as lowering blood pressure117 and triglycerides118, and improving endothelial function, enhancing nitric oxide bioavailability and promoting collateral vessel development119,120. The current recommendation is to do physical activity for 150 minutes per week and strength exercises on ≥2 days on a weekly basis121.

ManagementThe acute treatment of STEMI is centred around pro-viding emergency effective reperfusion of the myocar-dium via recanalization of the occluded coronary artery. Compared with fibrinolysis, primary PCI has shown beneficial outcomes in patients with STEMI if performed within 120 minutes of diagnosis and, therefore, became the preferred reperfusion strategy2,20. PCI is a catheter- based technique to dilate the narrowed vessel with an inflatable balloon (a procedure known as balloon angio-plasty) and keep it open by consecutive implantation of a stent (a small tube made of metal mesh). The initi-ation of STEMI networks to provide around- the-clock cardiac catheterization availability and the development of standard operating procedures within hospital sys-tems have helped to reduce the time to reperfusion and resulted in improved clinical outcomes122,123. Data from the National Cardiovascular Data Registry (NCDR) ACTION Registry–Get With the Guidelines (GWTG) showed that 60% of >37,000 patients with STEMI used emergency medical services (EMS) to reach the hospital. Elderly adults, women, adults with comorbidities and

individuals with cardiogenic shock and heart failure used EMS more frequently. Hospital arrival time was shorter for those who used EMS (89 minutes) than for those who did not (120 minutes)124.

If primary PCI is not available within 120 minutes of diagnosis, then fibrinolysis should be performed unless contraindicated. Fibrinolytic therapy aims to dissolve the thrombus by activating plasminogen, resulting in the formation of plasmin, which cleaves the fibrin crosslinks within the thrombus. Alteplase, tenecteplase and reteplase are fibrin- specific agents, which means that they preferentially bind to fibrin in a thrombus and cat-alyse cleavage of entrapped plasminogen to plasmin125, resulting in localized fibrinoly sis with limited systemic proteolysis. Conversely, streptokinase is a nonfibrin- specific agent and causes an indirect conformational change in the plasminogen molecule, which then acts as plasmin125. The role of CABG surgery is generally limited to indications such as complicating mechani-cal defects, coronary anatomy not suitable for PCI and failed PCI (Fig. 4). Additional pharmacological thera-pies are recommended, and treatment is well codified in practice guidelines2,20 and fairly standardized126.

Reperfusion therapyIn- hospital mortality after STEMI has dramatically decreased to <10% because of establishment of coronary care units, improvements in medical therapy and wide-spread use of early reperfusion therapy127,128. The current clinical guidelines for STEMI in the United States and Europe recommend primary PCI over fibrinolysis if pri-mary PCI can be initiated promptly2,20, and algorithms for the selection of reperfusion therapy are available in clinical guidelines (Fig. 4). The large- scale United States National Registry of Myocardial Infarction (NRMI) reported that the mortality advantage of primary PCI over onsite fibrinolysis disappeared when the delay from first medical contact to PCI exceeded 120 minutes129.

Thus, guidelines recommend the use of fibrinoly-sis for patients with STEMI who present within 12 hours of symptom onset in whom PCI cannot be performed within 120 minutes. Treatment should then be started within 30 minutes of first medical contact, after careful assess-ment for contraindications. Guidelines generally give pref-erence to fibrin- specific fibrinolytic agents (tenecteplase,

Box 4 | Criteria for type 1 MI1

Detection of a rise and/or fall in cardiac troponin values with at least one value above the ninety- ninth percentile upper reference limit and with at least one of the following:

• Symptoms of acute myocardial ischaemia

• New ischaemic electrocardiogram changes

• Development of pathological Q waves

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology

• Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy

MI, myocardial infarction.


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alteplase or reteplase), with specific dosing according to age and body weight2,20. It is important to note that even if fibrinolysis is performed as the primary therapy approach, it should always be followed by coronary angi-ography and potentially PCI. The timing of coronary angiography is dependent on the success of fibrinolysis on the basis of certain criteria (Fig. 4). In patients who pres-ent late (>12 hours from symptom onset), a PCI is indi-cated in the presence of ongoing symptoms suggestive of ischaemia, haemodynamic instability or life- threatening arrhythmias2,20.

Depending upon the population evaluated, the use of the different reperfusion strategies and the proportions of patients eligible to receive them vary. In general, the use of fibrinolysis is steadily declining, whereas primary PCI is increasingly performed23,127,130. For individuals directly admitted to centres with PCI facilities, ‘door to balloon time’ (time from presenting at the hospital to

inflation of the balloon during primary PCI to reperfuse the occluded artery) declined significantly. Of note, an analysis of data from a Swedish registry evaluated sex disparities and documented that women were less likely than men to receive reperfusion therapy131.

Despite differences in the studies, it is clear that patients with STEMI are more frequently being treated with primary PCI and that reperfusion times are shorter than in the past. Of note, the management of patients with multivessel disease by culprit- only or multivessel PCI is still a matter of debate (Box 5).

Trans- radial intervention. Compared with traditional trans- femoral intervention (TFI), trans- radial inter-vention (TRI) is less invasive and has proved to be a safer approach in emergency PCI for ACS132,133. With TRI, access to the occluded coronary artery is gained through the radial artery, which is a smaller artery than

Yes

No

Yes

No

Additional drugs for secondary prevention if indicated

Pharmacological therapy

Reperfusion therapy In the case of mechanical complication,CABG surgery is recommended

If coronary anatomy is not suitable for PCI, CABG surgery is recommended

CABG surgery

Emergency PCI• Emergency PCI performed as soon as possible in case of failed fibrinolysis

Routine PCI strategy• Coronary angiography, with PCI if indicated, performed between 2 and 24 hours after successful fibrinolysis

<50% ST-segment resolution at 60–90 min?and/or one or more of the following:• Heart failure and/or shock• Haemodynamic or electrical instability• Worsening ischaemia

Primary PCI Fibrinolysis

• Anticoagulation therapy needsto be discontinued for surgery

• Antiplatelet therapy:- Aspirin as soon as possible without cessation for surgery- P2Y12 antagonist as soon as possible; consider

discontinuation for surgery

• Anticoagulation therapy duringthe PCI procedure

• Antiplatelet therapy:- Aspirin as soon as possible- P2Y12 antagonist (prasugrel or ticagrelor) at the time of the PCI procedure at the latest

• Anticoagulation therapy untilrevascularization (if performed) orduring hospital stay for at least 48 hoursand up to 8 days

• Antiplatelet therapy:- Aspirin as soon as possible- P2Y12 antagonist (clopidogrel) as soon as possible

Time to PCI centre ≤120 min?

EMS Patient presentingto a non-PCI centre

STEMI diagnosis

STEMI diagnosis

Patient presenting to a PCI centre

Symptoms suggestive of STEMI

Fig. 4 | Management algorithm for STEMI. At first medical contact, the diagnosis of ST- segment elevation myocardial infarction (STEMI) should be made within 10 minutes. After the diagnosis is confirmed, the decision on the reperfusion strategy (percutaneous coronary intervention (PCI), fibrinolysis or coronary artery bypass graft (CABG) surgery) has to be made. Depending on the reperfusion strategy , the choice of antithrombotic and anticoagulant therapy may differ. Additional pharmacological therapies should be given as indicated. EMS, emergency medical services; P2Y12, P2Y purinoceptor 12.


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the femoral artery that is used with TFI. The smaller size of the radial artery compared with the femoral artery and the superficial location at the hand wrist with good pos-sibility of manual compression are associated with lower bleeding risk. TRI was demonstrated to be superior to TFI in terms of reducing not only bleeding complica-tions, particularly access site bleeding, but also mortality in the MATRIX trial and in a meta- analysis133,134. The current European clinical guidelines recommend trans- radial access for PCI in ACS as class Ia (as a general rule, the numeral in the class of recommendation indi-cates the strength of the recommendation (the lower the numeral the higher the strength), and the letter indicates the quality of the supporting evidence (from strongest to weakest))2.

Stent technology: new generation drug- eluting stents. Stent implantation for the culprit lesion in STEMI dur-ing primary PCI is the recommended treatment (class Ia recommendation)2,20. Compared with balloon angio-plasty alone, PCI with bare- metal stent implantation decreased the risk of reinfarction and subsequent target vessel revascularization (that is, the need for a recurrent revascularization with PCI or CABG surgery of the initially treated vessel), although there was no signifi-cant mortality benefit135. First- generation drug- eluting stents (DESs) are coated with an antiproliferative agent (such as everolimus) and reduced the risk of repeat coronary revascularization even further136. Newer- generation DESs have several improvements compared with first- generation DESs, such as thinner stent struts and biocompatible polymers, potentially reducing the risk of stent thrombosis. In the EXAMINATION trial, second- generation everolimus- eluting stents with

durable, biocompatible acrylic and fluorinated copol-ymer showed significantly lower rates of repeat target vessel revascularization and stent thrombosis than bare- metal stents137. Considering the reduced rate of thrombotic events with newer- generation DESs138, deter-mining the optimal duration of dual antiplatelet therapy after DES implantation in patients with STEMI would be an important clinical research question, particularly in patients with high bleeding risk.

Haemodynamic support. In primary PCI for STEMI, haemodynamic support is frequently needed for patients with high- risk PCI and/or cardiogenic shock. However, haemodynamic support using an intraaortic balloon pump (IABP) did not lead to a benefit in 30-day mor-tality compared with control in the IABP- SHOCK II trial139. Newer left ventricular assist devices such as Impella (Abiomed) and TandemHeart (LivaNova) have theoretical advantages over an IABP by unloading the left ventricle (blood from the left ventricle or atrium is pulled and expelled into the ascending aorta or femoral artery) and increasing cardiac output. Several previ-ous trials reported the benefits of these new devices on haemo dynamic parameters compared with an IABP140,141, but no trials have demonstrated the benefits in clinical outcomes. Large- scale randomized controlled trials are warranted to evaluate whether these new devices could have a mortality benefit in patients with STEMI and cardiogenic shock.

Aspiration thrombectomy and distal protection device. Aspiration thrombectomy is a procedure in which the thrombus in the culprit lesion is aspirated and removed through the guiding catheter. However, large- scale clini-cal trials evaluating the efficacy of PCI with aspiration thrombectomy reported no clinical benefits compared with primary PCI alone142,143. Furthermore, in the TOTAL trial, routine aspiration thrombectomy was associated with an increased rate of stroke within 30 days142. On the basis of these results, routine aspiration thrombec-tomy during primary PCI is not recommended in the clinical guidelines2,144.

Distal protection devices are used to capture debris from the atherosclerotic plaques and thrombi to pre-vent distal embolization and no- reflow phenomenon during PCI, but there is no strong evidence supporting their routine use during primary PCI. However, these devices might be beneficial in selective situations, such as large thrombus burden. Notably, in the VAMPIRE 3 trial, use of a distal protection device was associated with a significantly lower rate of no- reflow phenome-non in patients with STEMI with attenuated plaques >5 mm in length on the basis of pre- PCI intravascular ultrasonography145.

Concomitant pharmacological treatmentIn addition to early reperfusion therapy, a variety of medications are recommended in patients with STEMI by international guidelines2,20. The choice of anti-coagulation and antiplatelet therapies is dependent on the reperfusion strategy as well as the ischaemic and bleeding risks of the patient.

Box 5 | Multivessel disease: culprit- only or multivessel PCI

About half of patients with ST- segment elevation myocardial infarction (STEMI) receiving primary percutaneous coronary intervention (PCI) have multivessel disease261, but the optimal management of non- culprit substantial atherosclerotic lesions is still under debate. In the PRAMI trial262, over a mean follow- up of 23 months, multivessel PCI with complete revascularization was superior to culprit- only PCI in terms of a composite end point of cardiac death, myocardial infarction (MI) or refractory angina. Several other trials confirmed the favourable results of multivessel PCI compared with culprit- only PCI, but these advantages must be interpreted with caution, as the studies had some limitations. For example, repeat revascularization was included in composite end points of most of the studies. However, the decision to perform subsequent revascularization procedures in patients in the culprit- only arm could have been prompted (and thereby biased) by the knowledge of the existence of other stenosed vessels, as their presence would have been detected during the initial procedure263. By contrast, in the CULPRIT- SHOCK trial173, culprit- only PCI (with the option of staged PCI (a second planned PCI at a later time point) for non- culprit lesions) was significantly better than immediate multivessel PCI in terms of a composite end point of death or severe renal failure at 30 days. An exploratory analysis of 1-year mortality of this study did not show any significant difference between the two groups264. A 2015 focused update of the American College of Cardiology (ACC)–American Heart Association (AHA)–Society for Cardiovascular Angiography and Interventions (SCAI) guidelines for PCI in patients with STEMI gave a class IIb recommendation to consider PCI of non- culprit lesions in patients with multivessel disease who are haemodynamically stable either at the time of the primary PCI or as a planned staged procedure144. The European guidelines give a class IIa recommendation to consider revascularization of non- culprit lesions in patients with STEMI with cardiogenic shock at the time of the primary PCI and in haemodynamically stable patients routinely before hospital discharge2.


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Anticoagulation therapy. Anticoagulation therapy aims to inhibit thrombin formation or activity, which plays an important role in the pathophysiology of STEMI and during primary PCI. Several options are available to provide rapid effective anticoagulation to patients with STEMI being treated with primary PCI. Antithrombin III (AT3) is a peptide that inhibits several of the activated clotting factors. Unfractionated heparin binds to and increases the activity of AT3 and has some inhibi-tory effect on coagulation factors IXa, XIa and XIIa. Enoxaparin is a low molecular mass heparin and also binds to AT3. In the setting of primary PCI, these agents should be given intravenously2,20. Whereas the dose of unfractionated heparin may need to be adjusted on the basis of a measurement of the activated clotting time (the time until a clot is formed from a fixed vol-ume of blood under certain conditions), enoxaparin does not need monitoring and is given as a single bolus. Bivalirudin is a direct thrombin inhibitor and may be used in patients at high risk of bleeding or with heparin induced- thrombocytopenia.

Unless there is a clear indication for continued anti-coagulation therapy (such as atrial fibrillation, mechani-cal prosthetic valve or intraventricular thrombus, among others), routine full- dose anticoagulation therapy is gen-erally not indicated after PCI. Prophylactic doses for the prevention of venous thrombo- embolism may be used in patients with prolonged bed rest2.

Patients receiving fibrinolysis should also receive anticoagulation therapy until PCI is performed (if appli-cable) or for the duration of hospital stay (but without exceeding 8 days). Enoxaparin is preferred to unfrac-tionated heparin; in patients treated with streptokinase, fondaparinux (an anticoagulant that purely inhibits factor Xa) should be used2.

Antiplatelet therapy. Antiplatelet agents aim to prevent platelets from forming a thrombus and are, therefore, crucial for the treatment of patients during and after STEMI. The standard of care for antiplatelet therapy in STEMI is oral dual antiplatelet therapy combining life-long aspirin and an oral inhibitor of P2Y purinoceptor 12 (P2Y12; the predominant receptor in the ADP- stimulated prolonged platelet aggregation)146 for platelet aggrega-tion, which, as a rule, should be used for 12 months147. Detailed guidelines have been issued regarding the optimal duration of dual antiplatelet therapy148,149.

In all patients, aspirin should be given as soon as possible after diagnosis, and treatment should be maintained permanently at a low dose. There are three options for an oral P2Y12 inhibitor. Clopidogrel remains the drug of choice in patients at high risk of bleeding, particularly patients requiring lifelong oral anticoagu-lation therapy, or if the newer agents are not available, contraindicated or poorly tolerated. However, current guidelines2,20 recommend the potent oral P2Y12 inhibi-tors (ticagrelor or prasugrel) over clopidogrel, given the benefits of these agents compared with clopidogrel in large outcome trials150,151. Beneficial effects in redu cing ischaemic events, although with increased risk of bleed-ing, have been documented150,151. Prasugrel is contra-indicated in patients with a prior history of stroke or

transient ischaemic attacks and not recommended in patients of ≥75 years of age. In patients with a body weight ≤60 kg, the maintenance dose should be reduced.

Intravenous antiplatelet agents include glycopro-tein IIb/IIIa (GPIIb/IIIa; also known as integrin αIIb–integrin β3) receptor blockers and cangrelor, a P2Y12 inhibitor. Currently, GPIIb/IIIa receptor blockers are mostly used in the catheterization laboratory for bail-out to manage complications arising during PCI such as large thrombus, slow flow (delayed progression of the injected contrast medium through the coronary tree) or no reflow. Cangrelor has a rapid onset and offset of action and can reduce periprocedural ischaemic compli-cations, although it is associated with an increased risk of bleeding compared with clopidogrel152. Cangrelor may be considered in patients not pretreated with oral P2Y12 inhibitors at the time of PCI or in those who cannot swallow oral agents.

In patients receiving fibrinolysis, dual antiplatelet therapy should be restricted to lifelong aspirin and clopi-dogrel for 12 months, as prasugrel and ticagrelor have not been studied as adjuncts to fibrinolysis.

STEMI complicationsArrhythmia and conduction abnormality. The incidence of ventricular tachycardia (VT) and ventricular fibrilla-tion (VF) after STEMI has decreased since the establish-ment of routine early revascularization and β- adrenergic receptor blocker therapy153. However, contemporary studies report an almost 6% rate for the incidence of sustained VT or VF in patients with acute MI154,155. Early VT or VF within 48 hours after STEMI seems to be asso-ciated with increased in- hospital mortality but seems to have no effect on long- term prognosis156,157. Conversely, VT or VF that develops after 48 hours and in the absence of recurrent ischaemia is associated with worse progno-sis, mandating aggressive treatment as well as evaluation for implantation of a cardioverter–defibrillator158.

Similar to ventricular tachyarrhythmia, the occur-rence of conduction abnormalities and bradyarrhyth-mias associated with acute MI has decreased in the era of early revascularization159. More specifically, new onset of atrioventricular block in patient with STEMI has been reported to occur in 6.9% of patients with STEMI treated with thrombolytic therapy160, compared with a 3.2% incidence rate in patients treated with primary PCI161. Sinus or atrioventricular- nodal delay is mostly associ-ated with STEMI located in the inferior wall of the heart and can occur within the first hours and up to several days after the MI. Sinus bradycardia or various degrees of atrioventricular block occurring in the early phase of MI as a result of increased vagal tone respond well to atropine (an anticholinergic drug) and usually resolve within 24 hours162. Later occurrence of conduction delay may be associated with oedema and local accumulation of adenosine163. These abnormalities are usually asymp-tomatic but can also result in haemodynamic instabi lity. In the case of haemodynamic instability, temporary pac-ing may be required; however, most conduction abnor-malities due to inferior STEMI resolve within 2 weeks159. Atrioventricular block associated with anterior infarc-tion is mostly infra- Hisian (located further down in the


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conduction pathway), with new bundle branch block or hemiblock usually indicating extensive anterior MI2,159. In- hospital mortality and 30-day mortality have been reported to be higher in patients with atrioventricular block than in those who do not develop it, regardless of infarct location, whereas outcomes beyond 30 days seem similar across groups164.

Left ventricular thrombus. Data on the incidence of left ventricular thrombus detected by optimal imaging modalities range from as high as 15% in patients with STEMI to up to 25% in patients with anterior MI165. Although standard transthoracic echocardiography has low sensitivity, contrast echocardiography or car-diac MRI should be used if pre- test probability is high. Once left ventricular thrombus is detected, anticoagu-lation therapy (in addition to dual antiplatelet therapy) is essential, although it increases the bleeding risk.

Mechanical complications. Mechanical complications after acute MI include papillary muscle rupture and dysfunction, left ventricular aneurysm, ventricular sep-tal rupture and free wall rupture. These complications have become rare events in the era of primary PCI, with the current incidence reported to be <1%. A report from the APEX- AMI study documented rates of 0.51% for free wall rupture, 0.17% for ventricular septal rupture and 0.26% for papillary muscle rupture166. Nevertheless, these complications constitute a life- threatening emer-gency scenario mandating early diagnosis and urgent surgical referral. Initial symptoms range from dyspnoea to fulminant heart failure, cardiogenic shock and sud-den cardiac death. Any of these symptoms as well as the occurrence of a new heart murmur (an unusual sound caused by abnormal blood flow) should always prompt immediate echocardiography, which is the gold standard for the diagnosis of mechanical complications. In addi-tion, transfer to the intensive care unit is mandated. Once the diagnosis is confirmed, further treatment and timing of surgery should ideally be evaluated by a multi-disciplinary team. In case of haemodynamic instability or cardiogenic shock, the insertion of an IABP may be considered, whereas refractory circulatory failure should prompt percutaneous initiation of extracorporeal mem-brane oxygenation as a bridging therapy to manage the patient until definitive treatment is applied167,168.

Cardiogenic shock occurs in ~5–15% of patients, is one of the most powerful predictors of short- term and long- term outcomes after STEMI169–171 and remains the leading cause of death after acute MI171. Mechanical complications are rare causes of cardiogenic shock, as the most common underlying cause is left ventricular dysfunction. Evidence from randomized controlled trials in patients with cardiogenic shock is limited. Long- term follow- up of the SHOCK trial has shown that early revascularization was associated with increased sur-vival compared with initial medical stabilization172. In patients with multivessel disease presenting with STEMI and cardiogenic shock, culprit- only PCI was associated with a lower rate of the composite end point of death or severe renal failure leading to renal- replacement therapy than immediate multivessel PCI173. A beneficial effect in

terms of 30-day mortality of the insertion of an IABP in patients with STEMI with cardiogenic shock and planned early revascularization could not be confirmed by a trial that randomized 600 patients139. Thus, further randomized controlled trials are needed to evaluate optimal treatment strategies in patients with STEMI and cardiogenic shock.

Routine secondary prevention therapiesIn addition to anticoagulation and antiplatelet thera-pies, several pharmacological therapies should be con-sidered and established before discharge in patients with STEMI2.

The use of angiotensin- converting enzyme (ACE) inhibitors after MI was associated with a significant reduction in all- cause mortality and a significant reduc-tion in incidence of reinfarction174. However, data on ACE inhibitors in patients treated with primary PCI are scarce. The mechanisms by which ACE inhibitors reduce adverse events after MI include reducing ven-tricular remodelling after STEMI, decreasing sympa-thetic activity and increasing vagal tone, which may reduce the incidence of sudden death175.

The widespread use of β- adrenergic receptor block-ers (a class of antihypertensive drugs) after MI is based on several large clinical trials176–178, and a systematic review supports their use, showing reduced mortal-ity and morbidity179. β- Adrenergic receptor blockers after MI also improved survival and reduced nonfatal MI180,181. However, in a recent observational study, β- adrenergic receptor blocker therapy was not associ-ated with a reduction in all- cause mortality in patients with MI without heart failure or systolic dysfunction. This result suggests that not all patients presenting with MI would benefit from β- adrenergic receptor blocker treatment, especially those without heart failure or systolic dysfunction. Randomized controlled trials are necessary to confirm this finding182.

Lipid- lowering therapy is one of the most important parts of secondary prevention. Statins, which reduce cir-culating levels of cholesterol, are a well- established treat-ment for secondary prevention of CVD, as demonstrated by several randomized controlled trials183–186. A meta- analysis of >90,000 individuals in 14 randomized trials confirms the benefit of the use of statins after hospital admission with MI, with reductions in total mortality as well as further coronary events187. Further evidence is provided by a study of >105,000 patients who began a moderate- intensity or high- intensity statin therapy after hospitalization for MI; overall, 1.7% of patients had sta-tin intolerance, and 52.8% had high adherence to statin therapy. Results suggested an incidence of recurrent MI that was 36% higher in patients with intolerance and a 43% higher risk of CAD in patients with statin intoler-ance than in those with high statin adherence188, whereas the risk of mortality was similar across the groups over a median follow- up of 1.9–2.3 years.

Genetic studies have shown lower levels of LDL cho-lesterol and a reduced risk of CVD in individuals with loss- of-function mutations in PCSK9 (which encodes proprotein convertase subtilisin/kexin type 9, a protein that promotes the catabolism of LDL receptors, thereby


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increasing circulating levels of LDL particles)189. Drugs targeting PCSK9 include monoclonal antibodies (evo-locumab and alirocumab) and small interfering RNAs (inclisiran) and are associated with impressive reduc-tions (40–60%) of LDL cholesterol when combined with statin therapy190,191. A randomized placebo- controlled trial of evolocumab showed a 20% relative risk reduc-tion in cardiovascular events (cardiovascular death, MI or stroke) after a median follow- up of 2.2 years190, and a trial of alirocumab showed a 15% relative risk reduction in major cardiovascular events192. However, these drugs are currently not routinely prescribed to patients with STEMI owing in large part to their high cost.

Cardiac rehabilitation typically includes assessment of motivation to change lifestyle, education on goal plan-ning, referrals to other services (for example, dietary and smoking cessation advice), exercise with individual programmes and advice on relaxation and stress man-agement193. Systematic reviews have shown the benefit of cardiac rehabilitation in patients after MI, showing a reduction in all- cause and cardiovascular mortality between 13% and 25%194–196. However, the role of car-diac rehabilitation has been debated recently, after the RAMIT trial showed no significant beneficial effects of cardiac rehabilitation on survival following MI197. A recent study attempted to address the issue and showed a 46% lower mortality at 10 years in patients who completed rehabilitation than in those who did not complete it after treatment with primary PCI198.

Pre- discharge risk stratificationPatients with STEMI should have an evaluation of early and long- term risk of adverse cardiovascular events before hospital discharge, including assessment of the LVEF, severity of CAD and completeness of coronary revascularization2,20. Guidelines encourage the use of clinical scores such as the thrombolysis in myocardial infarction (TIMI) or GRACE scores for STEMI to assess early and long- term risk2,20,199. Both scores seem to per-form comparably for prediction of in- hospital death200, and the GRACE score for STEMI also provides progno-stic information for 6 months after discharge201. By con-trast, compared with non- ST-segment elevation-acute coronary syndrome (NSTE- ACS) guidelines, STEMI guidelines do not emphasize prognostication using biomarkers3,199. Several biomarkers have been reported to confer independent or complementary prognostic information after STEMI, including cTn76,202, BNP203, NT-proBNP204, midregional pro- ANP205, growth and differentiation factor 15 (reF.206), IL-1 receptor- like 1 (also known as ST2)207, glycated haemoglobin A1c (HbA1c)208 or biomarker panels209. However, besides the measurement of metabolic risk markers, such as LDL cholesterol and glucose, and renal function, no explicit recommenda-tions are given for the routine measurement of additional prognostic biomarkers after STEMI.

Quality of lifeThe major goals of treating patients with CAD are to reduce the risk of major adverse cardiovascular events, prolong life and improve patients’ symptoms, func-tional status and quality of life. In the setting of STEMI,

treatments are often directed towards improving sur-vival and preservation of viable myocardium to avert the development of heart failure. However, the effect of the MI on quality of life and the effect of treatments on recovery are also of great importance to patients. Real- world studies (studies with no or broad selection criteria with no specific intervention compared with randomized controlled trials with a generally well- specified popula-tion and treatment) have shown that ~20% of patients who were hospitalized for a STEMI have some degree of residual angina 1 year after their MI — a rate that is similar to that of patients recovering from NSTEMI and coronary revascularization in general210,211. Importantly, there is substantial variation in the risk of having resid-ual angina after an MI, with young age, CABG surgery, a high burden of pre- MI angina and depression as inde-pendent predictors of residual angina211 and poorer quality of life after MI212. Residual angina may have a particularly negative effect on the quality of life of young patients recovering from a STEMI, as it can impair the ability to work and fulfil everyday tasks. The transition from being completely healthy to being a patient with heart disease after MI may be especially difficult, and depression after acute MI, which is strongly associated with residual angina after an MI, is also more common in young patients and women213.

Historically, compared with balloon angioplasty alone, PCI with stenting decreases the risk of residual angina — at least in the intermediate term — probably through reduction in restenosis. In the Stent Primary Angioplasty for Myocardial Infarction trial — one of the few STEMI trials to examine quality of life — 21% of patients in the stent arm reported angina at 6 months after STEMI compared with 43% in the angioplasty arm214. In patients with STEMI and multivessel coro-nary disease, observational data suggest that complete revascularization (either during index hospitalization or staged) is associated with less angina and better quality of life than culprit- only PCI215. Smoking cessation after an MI is also associated with less angina and better quality of life at 1 year after MI, with residual angina rates of 29% in persistent smokers compared with 21% in those who quit after MI and 18% in patients who never smoked or quit before their MI216. Interestingly, participation in cardiac rehabilitation, which improves survival, has not been associated with better quality of life217.

Optimal medical therapy with antiplatelet agents, statins, β- adrenergic receptor blockers and ACE inhibi-tors has an important role in reducing the risk of recur-rent ischaemic events and improving survival. However, medical therapy has not been shown to reduce the risk of residual angina or improve quality of life211. Clearly, there is a role for antianginal medications in the post- MI patient who has residual angina, but a strategy of pre- emptive antianginal medications has not been tested in patients with STEMI.

OutlookThe development of novel antithrombotic strategies and percutaneous devices, combined with decreased delay from first medical contact to the catheterization lab-oratory, has led to a progressive and consistent reduction


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in mortality among patients with STEMI218,219. Despite these advances, ~20% of patients with acute MI expe-rience recurrent cardiovascular events within the fol-lowing year21. This observation demonstrates the need for the development of new therapeutic targets, such as inhibition of the inflammatory pathway, or meas-ures to improve microvascular perfusion, which should be coupled with techniques to identify patients who would benefit the most from treatment. Finally, as novel advancements begin to make their way into clin-ical guidelines, discrepancies between guideline- based treatment and daily practice in STEMI are accentuated in developing countries220. Thus, it is important to strive to close the gap in access to life- saving therapies, which will be a challenge for decades to come.

New strategies that target inflammationAs discussed earlier, inflammation plays an impor-tant part in atherogenesis and plaque evolution221. The CANTOS trial was the first to validate the inflamma-tory hypothesis in a large cohort of patients with CAD: targeting the IL-1β innate immune pathway with cana-kinumab (an anti- IL-1β human monoclonal antibody) led to a clinically meaningful 15% relative reduction in major cardiovascular events compared with placebo, regardless of the LDL level222. The CIRT trial evaluated a different approach to target inflammation, using a ther-apy with low- dose methotrexate; however, this therapy did not result in lower IL-1β, IL-6 or C- reactive protein (CRP) levels than placebo. The trial was stopped early and did not show a difference between the groups with regard to the composite end point of nonfatal MI, nonfatal stroke or cardiovascular death. Instead, methotrex-ate was associated with elevations in the levels of liver enzymes, reductions in leukocyte counts and haemato-crit levels and an increased incidence of non- basal-cell skin cancers223. One of the explanations for the conflict-ing results of the CANTOS and CIRT trials may be based on the fact that CANTOS included only patients with high residual inflammatory risk and limited the enrol-ment to those with persistently elevated high- sensitivity CRP levels, whereas CIRT did not screen for CRP levels. Both CIRT and CANTOS enrolled patients with athero-sclerosis who were in stable condition, and there are few data in the acute setting. Anakinra, an IL-1 receptor inhibitor, was evaluated in two small phase II studies among patients with acute MI, reducing high- sensitivity CRP levels224,225. In addition to the interleukin pathway, T cell activation signalling, synthetic inhibitors of the protein tyrosine phosphatase, low doses of IL-2 and infusion of autologous regulatory T cells are in devel-opment or represent future areas of research to target inflammation in ACSs226.

No reflow and reperfusion injurySome aspects of the pathophysiology of MI remain surprisingly refractory to successful treatment. The no- reflow phenomenon is a complication that can occur following coronary revascularization and is associated with an increased risk of cardiogenic shock, recurrence of MI and mortality227,228. Although the risk factors are well known (such as high thrombus burden, primary

PCI setting per se and ischaemic time), there are still no highly effective treatment options. Use of GPIIb/IIIa inhibitors and vasodilators has failed to demonstrate a clinical benefit in several observational studies and ran-domized trials229. Reducing the total ischaemic time by bringing the patient to the cardiac catheterization labora-tory as quickly as possible remains one of the most effec-tive ways to prevent the no- reflow phenomenon as well as reperfusion injury. To this end, devices that alert the patient to the presence of a heart attack may reduce the time from symptom onset to hospital admission and thereby total ischaemic time230,231. Although pharma-ceutical trials targeting reperfusion injury did not show any beneficial results with regard to clinical outcomes, evidence exists that remote ischaemic conditioning (that is, inducing ischaemia in a tissue distant from the heart) has a protective effect on the heart and improves clini-cal outcomes by reducing myocardial injury232. Greater understanding of the complex pathophysiology, includ-ing the mechanism of reperfusion injury, may identify additional targets to prevent the loss of the microvascu-lar integrity and increase vascular permeability. Despite numerous failures to date, the prevention and treatment of reperfusion injury, which directly affects infarct size, should remain a focus of future cardiovascular research.

Stem cell therapyStem cell therapy has been presented as a promising future therapeutic option over the past decade, particu-larly in cardiology233,234. Repairing damaged tissue fol-lowing an MI by injecting undifferentiated cells into the myocardium is an incredibly challenging strategy that could potentially limit the development of heart failure, regardless of the treatment administered before the PCI. However, there are many uncertainties with regard to this strategy. The regulatory mechanism of stem cell dif-ferentiation into cardiomyocytes remains unclear. Thus, which cell types should be used for cell transplantation, the mode of delivery, the optimal environment to guar-antee that stem cells differentiate into cardiomyocytes and the optimal timing for stem cell transplantation remain unclear. In addition, recent calls for retraction of journal articles and the pause of the related CONCERT- HF trial have contributed to the uncertainty about the role of stem cell therapy in heart failure after MI235.

Personalized medicine and artificial intelligenceRegardless of the pathway targeted, one of the challenges will be to identify and select the right population that may derive the greatest benefit from new treatments. Whereas trials draw inferences about populations, machine learning explores large data sets and uses algo-rithms that can make predictions regarding outcomes in individual patients. In health care, global interest in the potential of machine learning has increased236. In fact, deep learning algorithms have already demonstrated high accuracy in detecting left ventricular diastolic dysfunction on ECG237,238. Personalized benefit–risk estimates are another possible utilization of machine learning algorithms. Further, the use of machine learning models to define the population of interest, in everyday practice or in clinical trials, may change the way patients


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with ACS are stratified on the basis of their risk and may optimize the benefit–risk ratio for an individual patient.

Harmonizing the standard of careIn STEMI, therapeutic strategies may differ slightly according to the characteristics of each population or region239. Nevertheless, the American and European guidelines share the same reperfusion strategy recom-mendation based on a network of primary PCI- capable and non- PCI-capable hospitals20. This consensus is the result of years of accumulation of high- level evidence that has led to large- scale modification in national health- care policy to improve access to life- saving therapies. However, in the United States, more than one- third of the patients with STEMI transferred to a PCI- capable centre for primary PCI still fail to achieve a delay time ≤120 minutes despite estimated transfer times <60 minutes2,240.

There are many steps along the path from accu-mulating evidence regarding new practices to their widespread adoption241,242. For instance, educational programmes, based on survey data evaluating the gap between daily practice and guidelines, were crucial in adjusting and increasing the adherence to the evidence- based therapy220,243. This gap is known to be influenced by many factors, including cultural, educational, financial and geographical aspects of each region244.

An example of the effect of these efforts is the trans-formation of the management of ACS in Romania. In 2004, Romania had a staggering 20% in- hospital mortality in patients with STEMI. Despite having the lowest health-care budget in Europe, a 13% reduction in in-hospital STEMI mortality was achieved through the implementation of a modern primary PCI network

in 2011 (reF.245). Romania’s efforts serve as an example of what can be achieved in emerging countries and demon-strate that at least 5 years of hard work may be necessary to implement such strategies.

Although the adherence to guideline- recommended therapies and devices and access to a cardiac catheteri-zation laboratory are markedly lower among emerging countries than in developed countries, the numbers of patients, by contrast, continue to increase, with >70% of the cases of STEMI projected to occur in develop-ing regions in the next 10 years246. This estimate high-lights the urgent need to foster an effective system to promote and develop evidence- based revascularization recommendations and educational initiatives for these countries. The 10-year success with The Stent for Life Initiative, a nonprofit international organization of national cardiac societies and partnering stakeholders, is a leading example in this field220. This programme sup-ports the implementation of European STEMI guide-lines through a network of stakeholders, educational programmes and awareness campaigns247.

Several decades following the advent of PCI for MI, tremendous progress continues in the development of novel stents and haemodynamic support devices as well as intracoronary imaging techniques. There has been a parallel development of new therapeutic targets in the pharmacological field, such as improved antiplatelet and antithrombin agents, and the inflammation pathway may prove to be a valuable additional target to improve out-comes as well. The development of new analytic meth-ods may help clinical decision making and may further optimize the benefit–risk ratio in individual patients.

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AcknowledgementsS.G. acknowledges financial support from MEXT/JSPS KAKENHI 17K19669 and partly from 18H01726 and 19H03661. S.G. acknowledges financial support from Bristol- Myers Squibb from their independent research sup-port project (33999603) and financial support from the Vehicle Racing Commemorative Foundation and the Nakatani Foundation of measuring technologies in biomedical engineering.

Author contributionsIntroduction (B.V.); Epidemiology (D.S.P. and B.V.); Mechanisms/pathophysiology (R.M., B.V., S.G. and B.E.C.); Diagnosis, screening and prevention (V.K., H.A.K., D.C., E.G.,B.E.C. and B.V.); Management (P.G.S., B.E.C., T.K., H.S. and B.V.); Quality of life (D.J.C., S.V.A. and J.A.S.); Outlook (C.M.G., M.K. and B.V.); Overview of Primer (R.M.).

Competing interestsR.M. or her spouse has received institutional research grant support from Bayer, Beth Israel Deaconess, The Medicines Company, Bristol- Myers Squibb, Sanofi, CSL Behring, Eli Lilly, Medtronic, Novartis Pharmaceuticals, OrbusNeich and AstraZeneca; has received consulting fees from Abbott Laboratories, Abiomed, AstraZeneca, Bayer, Boston Scientific, CardioKinetix, Cardiovascular Systems, Medscape, Siemens Medical Solution, Spectranetics, The Medicines Company, Roivant Sciences, Volcano Corporation, CSL Behring, Janssen Pharmaceuticals, Merck & Co. and Osprey Medical; has served on a data safety monitoring board for Watermark Research Partners; holds equity in Claret Medical and Elixir Medical; and serves on advisory boards of Abbott Laboratories, Bristol- Myers Squibb, Boston Scientific Corporation, Covidien, Janssen Pharmaceuticals, The Medicines Company and Sanofi. S.G. received research fund-ing from Sanofi, Pfizer and Ono; is an associate editor for Circulation from the American Heart Association and is a member of the Steering Committee for Evolving Anticoagulation in AF and VTE programme at Medscape. J.A.S. declares ownership of the copyright to the Seattle Angina Questionnaire. All other authors declare no competing interests.

Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


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https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150009A.pdf

https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150009A.pdf

https://www.nih.gov/news-events/news-releases/statement-nhlbi-decision-pause-concert-hf-trial

https://www.nih.gov/news-events/news-releases/statement-nhlbi-decision-pause-concert-hf-trial

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