guidelinesforthemanagementofmyocardial infarction ... · working diagnosis and to guide the...

Review Article

Neth Heart J (2020) 28:116–130https://doi.org/10.1007/s12471-019-01344-6

Guidelines for themanagement ofmyocardialinfarction/injury with non-obstructive coronary arteries(MINOCA): a position paper from theDutch ACSworkinggroup

T. F. S. Pustjens · Y. Appelman · P. Damman · J. M. ten Berg · J. W. Jukema · R. J. de Winter · W. R. P. Agema ·M. L. J. van der Wielen · F. Arslan · S. Rasoul · A. W. J. van ’t Hof

Published online: 22 November 2019© The Author(s) 2019

Abstract Patients with myocardial infarction and non-obstructive coronary arteries (MINOCA), defined asangiographic stenosis <50%, represent a conundrumgiven the many potential underlying aetiologies. Pos-sible causes of MINOCA can be subdivided into coro-nary, myocardial and non-cardiac disorders. MINOCAis found in up to 14% of patients presenting with anacute coronary syndrome. Clinical outcomes includ-ing mortality, and functional and psychosocial status,are comparable to those of patients with myocardialinfarction and obstructive coronary arteries. However,many uncertainties remain regarding the definition,clinical features and management of these patients.This position paper of the Dutch ACS working groupof the Netherlands Society of Cardiology aims to stressthe importance of considering MINOCA as a dynamicworking diagnosis and to guide the clinician in themanagement of patients with MINOCA by proposinga clinical diagnostic algorithm.

T. F. S. Pustjens (�) · S. Rasoul · A. W. J. van ’t HofDepartment of Cardiology, Zuyderland Medical Centre,Heerlen, The [email protected]

Y. AppelmanDepartment of Cardiology, location VU University MedicalCentre, AmsterdamUMC, Amsterdam, The Netherlands

P. DammanDepartment of Cardiology, Radboud University MedicalCentre, Nijmegen, The Netherlands

J. M. ten Berg · F. ArslanDepartment of Cardiology, St Antonius Hospital,Nieuwegein, The Netherlands

J. W. JukemaDepartment of Cardiology, Leiden University MedicalCentre, Leiden, The Netherlands

Keywords Myocardial infarction · Non-obstructivecoronary arteries · MINOCA

Introduction

Up to 14% of the patients with acute myocardialinfarction (AMI) are found to have non-obstructivecoronary arteries, defined as coronary stenosis <50%[1]. The termmyocardial infarction (MI) with non-ob-structive coronary arteries (MINOCA) has been coinedfor this clinical entity, which represents a diagnosticand therapeutic dilemma since many patients aredischarged without a clear aetiology for the clinicalpresentation [2].

Despite the fact that this syndrome has been exam-ined in greater depth over the past few years, manyuncertainties remain regarding the pathophysiologyof the myocardial damage, the clinical features, man-

R. J. de WinterDepartment of Cardiology, location Academic MedicalCentre, AmsterdamUMC, Amsterdam, The Netherlands

W. R. P. AgemaDepartment of Cardiology, Jeroen Bosch Hospital,’s-Hertogenbosch, The Netherlands

M. L. J. van der WielenDepartment of Cardiology, location Bethesda, TreantZorggroep, Hoogeveen, The Netherlands

S. Rasoul · A. W. J. van ’t HofDepartment of Cardiology, Maastricht University MedicalCentre, Maastricht, The Netherlands

A. W. J. van ’t HofDepartment of Cardiology, Isala Hospital, Zwolle, TheNetherlands

116 Guidelines for the management of myocardial infarction/injury with non-obstructive coronary arteries. . .

https://doi.org/10.1007/s12471-019-01344-6

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agement and prognosis of these patients. As a re-sult, the patients may be treated inappropriately ornot treated at all.

On behalf of the Dutch ACS working group, we dis-cuss the importance of MINOCA and will present a di-agnostic algorithm to guide the general and interven-tional cardiologist which may lead to optimal treat-ment of this patient cohort.

Definition

The diagnosis MINOCA requires (1) the presence ofan AMI (according to the Fourth Universal Definitionof AMI, see Tab. 1), (2) non-obstructive coronary ar-teries on invasive coronary angiography, defined asno coronary stenosis ≥50% in any potential infarct-re-lated artery, and (3) no clinically overt specific causefor the acute presentation [2, 3].

Many terms have been coined to describe patientswith AMI or acute coronary syndrome (ACS) withnormal or near-normal coronary arteries, such asMINOCA, MINCA (MI with normal coronary arter-ies) [4] and INOCA (ischaemia and no obstructivecoronary artery disease) [5].

The term MINOCA is incorporated into the re-cently published Fourth Universal Definition of AMI.According to this, MINOCA (i.e. myocardial infarc-tion) indicates that an ischaemic mechanism is theunderlying cause for the myocyte injury. Others haveused the term MINOCA in an all-encompassing con-text to include all patients fulfilling the universalcriteria for AMI without obstructive coronary arterydisease (CAD) [2].

In light of this, Pasupathy et al. proposed a newterm called troponin-positive non-obstructive coro-nary arteries (TP-NOCA) that includes patients withcoronary disorders resulting in ischaemic necrosis,and myocardial and non-cardiac disorders resultingin myocardial injury [6]. Another proposed term isACSNNOCA (ACS with normal or near-normal coro-nary arteries) which encompasses all ACS patientswith non-obstructive coronary arteries (i.e. MINOCA/MINCA/INOCA).

Table 1 Fourth universal definition of myocardial infarc-tion

The fourth universal definition of acute myocardial infarction (AMI) definesAMI as the presence of:

1. acute myocardial injury with clinical evidence of acute myocardial is-chaemia, and

2. with detection of a rise and/or fall of cardiac troponin with at least onevalue above the 99th percentile upper reference limit, and

3. with at least one of the following:– symptoms of myocardial ischaemia– new ischaemic ECG changes– development of pathological Q waves– imaging evidence of new loss of viable myocardium or regional wall

motion abnormality in a pattern consistent with an ischaemic aetiology– the identification of a coronary thrombus by angiography or autopsy

There is much overlap between all these terms, in-cluding type 2MI [3]. The last-mentioned is also a het-erogeneous category that includes pathophysiologicalmechanisms comparable to MINOCA. From a clinicalpoint of view, it is extremely challenging (directly aftercoronary angiography) to make a clear distinction be-tween whether the patient with a suspected AMI andnon-obstructive coronary arteries suffers from my-ocardial injury, ischaemia or infarction.

Therefore, as the Dutch ACS working group, wepropose that MINOCA should not be considered asa ‘true’ diagnosis, but rather as a clinical dynamicworking diagnosis that needs further evaluation. Ifcoronary angiography during a suspected AMI showsnon-obstructive coronary arteries and there is noovert cause for the clinical presentation, the workingdiagnosis MINOCA could be made. In the furtherevaluation of the underlying mechanism of AMI it isimperative to exclude other clinically overt causes forthe elevated troponin (e.g. sepsis, hypotension andpulmonary embolism) and non-ischaemic mecha-nisms of myocyte injury (e.g. myocarditis). Viewed inthis way, which reflects clinical practice best, MINOCAcan represent both myocardial infarction andmyocar-dial injury with non-obstructive coronary arteries.

In this paper, the all-encompassing term MINOCAis used to describe the coronary, myocardial andnon-cardiac aetiologies, similar to the position pa-per on MINOCA of the European Heart Journal [2].Most importantly, MINOCA should be considered asa dynamic working diagnosis, which should encour-age the clinician to further evaluate the underlyingmechanism(s) in order to achieve patient-specifictreatments.

Clinical characteristics and assessment ofMINOCA

MINOCA can present with ST-elevation MI (STEMI)(approximately 1/3) or non-STEMI (approximately 2/3)[1]. As stated before, the causes of MINOCA can besubdivided into coronary, myocardial or non-cardiacrelated disorders (Tab. 2). In the 1980s, DeWood et al.reported that approximately 10% of patients with MIwere found to have non-obstructive CAD [7]. Cur-rently, the prevalence may be even higher in the eraof high-sensitivity cardiac troponin assays, because oftheir lower specificity to diagnose acute MI. A system-atic review by Pasupathy et al. indicates a MINOCAprevalence of 6% in ACS patients, with a wide rangeof 1–15% [1, 8–14]. This is mainly attributable to dif-ferences in study populations and the heterogeneityof its definition. A higher prevalence of MINOCA wasfound in younger patients (58.8% vs 61.3%, p< 0.001),females (43% vs 24%, p< 0.001), non-white patients(25% vs 12%, p< 0.0001) and in patients presentingwith non-STEMI (78% vs 51%, p<0.0001), comparedto AMI with obstructive CAD [1, 8, 10, 11, 14, 15].

Guidelines for the management of myocardial infarction/injury with non-obstructive coronary arteries. . . 117

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Table 2 Possible underlying aetiologies for myocardial is-chaemia with non-obstructive coronary arteries1. Coronarydisorders

Spontaneous coronary artery dissection

Plaque disruption

Coronary spasm

Microvascular dysfunction

Coronary thrombus/embolus

2. Myocardialdisorders

Myocarditis

Takotsubo cardiomyopathy

Hypertensive heart disease

Other cardiomyopathies (e.g. tachycardiomyopathy or useof cardiotoxins/chemotherapeutic agents)

3. Non-car-diac disorders

Stroke

Pulmonary embolism

Sepsis

Adult respiratory distress syndrome

End-stage renal failure

The VIRGO study [15] also showed that womenwere 5 times more likely to have MINOCA than men,and that these MINOCA patients had fewer traditionalcardiac risk factors, but more often had unconven-tional risk factors, such as (prior) drug use, hyperco-agulability syndrome, venous thromboembolism andautoimmune disorders. Female AMI patients withobstructive CAD were more likely to be menopausalor to have a history of gestational diabetes mellituscompared to those with MINOCA.

Although MINOCA patients have a lower cardiacrisk profile, there are conflicting data regarding theirprognosis. Safdar et al. described similar functionaland psychosocial outcomes. In addition, similar1- and 12-month mortality in both MINOCA andAMI with obstructive CAD [1-month: 1.1% and 1.7%(p= 0.43); 12-month: 0.6% and 2.3% (p= 0.68), re-spectively] were found, whereas Pasupathy et al. re-ported that mortality rates were significantly lower inthe MINOCA group compared to AMI with obstruc-tive CAD [in-hospital: 1.1% and 3.2% (p= 0.001); 12-month 3.5% and 6.7% (p=0.003), respectively] [1, 15].

An interesting finding by Bainey et al. was thatthe 1ne-year composite of death and/or reinfarc-tion rate among MINOCA patients with no angio-graphic evidence of CAD was significantly lower thanin MINOCA patients with stenosis <50% (3.9% and6.1%, [p= 0.028], respectively) [16]. In relation to this,independent predictors of adverse outcome werethree-vessel disease or left main stem involvement(stenoses ≥30% but <50%), high C-reactive proteinat hospital admission and elevated high-sensitivitycardiac troponin T levels [17, 18].

The previously mentioned data should be inter-preted with caution since the outcome of MINOCAstrongly depends on the underlying cause. Recently,the prognostic role of cardiac magnetic resonanceimaging (CMR) was assessed in MINOCA patients. Itwas found that a CMR diagnosis of cardiomyopathy

was an independent predictor for mortality, whereasa diagnosis of MI, myocarditis or a normal CMR wasnot [19].

To reveal the exact underlying aetiology ofMINOCA,a thorough patient history, physical examination, lab-oratory testing, imaging and invasive measurementsare needed, since MINOCA should be considered asa working diagnosis.

Cardiac causes of MINOCA: coronary disorders

Plaque disruption and plaque erosion

The most common pathologies associated with anACS are plaque rupture, erosion and calcified noduleswhich are present in 44%, 31% and 8% respectively[20].

Plaque formation starts with the formation of fattystreaks and intimal thickening, leading to fibrous capatheroma and eventually to fibrous cap thinning. Thisso-called thin-cap fibroatheroma can rupture.

In plaque erosion, there is an abundance of smoothmuscle cells without an extensive necrotic core, haem-orrhage or calcification. It differs from plaque rupture,as there is an absence of fibrous cap disruption.

Identification of vulnerable plaques on coronaryangiography can be challenging. Computed tomog-raphy (CT) angiography and intravascular coronaryimaging could play an important role in finding theseplaques in the future. Near-infrared spectroscopy-in-travascular ultrasound (IVUS) may help to quantifythe lipid content of the coronary plaque and could po-tentially be an important tool to predict future events.Besides, this imaging modality could possibly distin-guish whether the MINOCA event is caused by a vul-nerable plaque that has ruptured or whether CAD isabsent [21]. However, data on intravascular imagingin MINOCA patients is still sparse. In a prospectiveoptical coherence tomography (OCT) study among38 MINOCA patients, coronary plaque disruption andthrombus were present in 24% and 18%, respectively[22]. Reynolds et al. found similar results with IVUSin women with MINOCA, since plaque disruption wasobserved in 38% [23].

Treatment of MINOCA caused by plaque disruptionor plaque erosion should be managed according tostandard treatment recommendations for ACS [3].

Spontaneous coronary artery dissection

Spontaneous coronary artery dissection (SCAD) isa rare cause of ACS, characterised by a non-traumaticand non-iatrogenic separation of the coronary arte-rial wall with the creation of a false lumen filled withintramural haematoma [24].

SCAD is associated with younger age (~50 years), fe-male gender (~90%), fibromuscular dysplasia (FMD),pregnancy and the peripartum period in the absenceof conventional risk factors for coronary heart disease.


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The estimated prevalence of SCAD in ACS patients is1.7–4%. However, in women <50 years of age present-ing with ACS, the prevalence could be up to 25% [24,25]. With increasing awareness of SCAD and the morewidespread use of intravascular imaging, the diagno-sis SCAD seems to be made more frequently nowa-days.

A small proportion of SCAD cases is associatedwith connective tissue disease such as Marfan orEhlers-Danlos syndrome [26]. Furthermore, precip-itating stressors such as emotional stress, extremeValsalva-type manoeuvres and the induction of coro-nary spasm, can provoke the acute SCAD event [24,27, 28].

SCAD patients usually present with symptoms andsigns of ACS. Most cases are diagnosed at the time ofcoronary angiography with the presence of a radiolu-cent flap, dual lumen and contrast staining [29].

After the diagnosis of SCAD has been made, con-servative management based on expert opinionsshould be preferred [30–33]. In patients with ongo-ing ischaemia or haemodynamic instability, coronaryrevascularisation might be considered. However, thiscan be challenging due to the fragility of the vesselwall and is associated with high revascularisation fail-ure rates. At follow-up, routine recurrent coronaryangiography to determine SCAD healing should beavoided as the benefit does not outweigh the poten-tial risks (e.g. iatrogenic dissections). Further imagingto detect extra-coronary arteriopathies is advised,given the relationship between SCAD and FMD.

There are no guidelines regarding the optimalmedical management of SCAD, since randomisedcontrolled trials are lacking. The role of antiplatelettherapy in SCAD remains controversial, since theseagents potentially increase the bleeding risk [28]. Incontrast, others believe that, since the intimal tear inSCAD can be prothrombotic, dual antiplatelet ther-apy could be beneficial [24]. Lipid-lowering therapyshould only be prescribed to those patients with(pre-existing) dyslipidaemia, since atherosclerosis inSCAD is mostly absent and a small retrospectivestudy demonstrated potentially higher SCAD recur-rence with statins [34]. Ongoing prospective studiesmay further evaluate the usefulness and effects ofmedical therapy (Clinical Trials NCT02188069 andNCT02008786).

Coronary artery spasm

Vasospastic angina (VSA) occurs in 28% of patientspresenting with MINOCA [1]. However, earlier stud-ies evaluating VSA varied since there was no cleardefinition of VSA. The Coronary Vasomotion Disor-ders International Study Group (COVADIS) was estab-lished to internationally unify the diagnostic criteriafor VSA. These criteria included three core elements,namely (1) nitrate-responsive angina, (2) transient is-chaemic electrocardiogram (ECG) changes and (3) an-

giographic evidence of coronary artery spasm (>90%constriction). In the case of coronary microvascularspasm, no epicardial spasm is present during coro-nary provocation tests, but ECG changes and recog-nisable angina symptoms should be present.

Coronary provocation tests with acetylcholine orergonovine are not routinely performed, since theyare thought to be potentially dangerous. However,Montone et al. demonstrated in 80 MINOCA patientsthat this test could be performed safely directly aftercoronary angiography. A positive test was found in37 (46.2%) of the patients and was associated withworse prognosis [35]. Furthermore, a systematic re-view by Ciliberti et al. in 9444 patients showed that theoccurrence of both major (such as ventricular tachy-cardia or ventricular fibrillation) and minor (suchas transient bradycardia, advanced atrioventricularblock or paroxysmal atrial fibrillation) complicationsof pharmacological testing with acetylcholine or er-gonovine was low (0.8% and 4.7%, respectively) [36].

Patients with confirmed VSA can be treated withcalcium channel blockers and nitrates, with the for-mer shown to be an independent predictor of survivalwithout MI [37].

Coronary microvascular dysfunction

COVADIS lists the diagnostic criteria for coronary mi-crovascular angina (MVA) due to coronary microvas-cular dysfunction (MVD) as follows: (1) presence ofsymptoms suggestive of myocardial ischaemia, (2) ob-jective documentation of myocardial ischaemia, as as-sessed by currently available techniques, (3) absenceof obstructive CAD (stenosis <50%), and (4) confirma-tion of a reduced coronary blood flow reserve and/orinducible microvascular spasm [38].

The exact prevalence of MVA is unknown, but its in-cidence in postmenopausal women is high [39]. Sev-eral studies describe an occurrence rate of up to 50%in patients with chest pain and non-obstructive coro-nary arteries [39, 40]. However, there are large differ-ences between studies in relation to the definition ofMVD and the use of different diagnostic techniques.

Overall, the prognosis of patients with MVA is com-parable to that of patients with obstructive CAD. Theycontinue to have persistent symptoms, have a highprevalence of atherosclerosis, undergo repeat coro-nary angiographies, and they suffer from greater func-tional limitations [41, 42]. Besides, higher all-causemortality rates were observed compared to a referencepopulation without ischaemic heart disease [43].

Coronary microcirculation can be assessed byvarious invasive and non-invasive techniques (e.g.positron emission tomography, CMR and transtho-racic Doppler echocardiography). An impaired coro-nary flow reserve (CFR), documentation of coronarymicrovascular spasm, abnormal coronary microvas-cular resistance (IMR), or a coronary slow flow phe-nomenon can be objectivised by coronary angiogra-


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phy. A newer technique to assess MVD is the mea-surement of hyperaemic absolute coronary flow andresistance using thermodilution with a continuousintravenous saline infusion. This technique is opera-tor independent, more reliable and specific comparedto CFR and IMR. Recently, it was found to be feasi-ble, safe and reproducible, but its value in MVD iscurrently unknown [44].

Coronary thrombus or embolism

In practice, patients presenting with AMI with non-obstructive coronary arteries are stigmatised as hav-ing an AMI due to a coronary thrombus or embolus,without a solid explanation. Confirming this diagnosiscan be challenging.

Coronary thrombi or emboli may arise from ac-quired or inherited thromboembolic disorders. Exam-ples of acquired thromboembolic disorders includeatrial fibrillation, a left ventricular thrombus, valvularheart disease, malignancy-associated thrombophilia,antiphospholipid syndrome and systemic lupus ery-thematosus. Hereditary causes of thromboembolismare factor V Leiden, protein C or S deficiency, an-tithrombin deficiency, or hyperhomocysteinaemia[45, 46]. Thrombophilia screening yields positive re-sults in approximately 14% [1]. Factor V Leiden wasthe most prevalent inherited thrombotic disorder.However, this is based on small-scale and outdatedtrials [45–51].

Furthermore, MINOCA might be caused by a para-doxical embolism due to right-left shunting [2]. How-ever, this may be the case in only a very small subsetof MINOCA patients and clinical relevance seems lim-ited.

Cardiac causes: myocardial disorders

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy is also known as stresscardiomyopathy or ‘broken heart syndrome’; its pre-sentation is similar to that of AMI, but with no ob-structive CAD or plaque rupture on angiography. Itusually affects postmenopausal female patients and ismostly triggered by an intense emotional or extensivephysical trigger. It is characterised by transient, oftenlarge, regional left ventricular systolic dysfunctionwith, in the most common form (81.7%), akinesiaof almost the whole heart and hyperkinesia of thebasal walls. Furthermore, midventricular, basal andfocal forms of Takotsubo cardiomyopathy have beendescribed [52].

The exact underlying pathophysiological mecha-nism in Takotsubo cardiomyopathy remains unclear.A combination of catecholamine excess, coronaryartery spasm and MVD may play a role. It can be dif-ficult to distinguish Takotsubo cardiomyopathy fromAMI or acute myocarditis; hence coronary angiogra-

phy and left ventricular angiography or echocardio-graphy are necessary to confirm the diagnosis. OnCMR, myocardial oedema is commonly seen on T2-weighted sequences without detectable myocardialnecrosis after late gadolinium enhancement (LGE),which distinguishes it from myocarditis.

Although patients with Takotsubo cardiomyopathyrecover spontaneously within several weeks, the in-hospital and long-term adverse outcomes are similarto those of AMI. More interestingly, deformation, fi-brosis and metabolic indices remain impaired long af-ter left ventricular ejection fraction is recovered, whichresults in persistent heart failure symptoms [52, 53].

Currently, there are no guidelines on optimal med-ical treatment and its duration. Beta-blocker therapycan be useful to achieve adrenergic blockade, andother conventional heart failure therapies might beconsidered.

Myocarditis

Myocarditis is an inflammatory disease of the cardiacmuscle that is caused by a variety of infectious (e.g.adenoviruses, parvovirus B19, human herpesvirus6 and Coxsackie virus) and non-infectious conditions(e.g. immune-mediated or toxic). The clinical pre-sentation of acute myocarditis varies widely, rangingfrom fatigue and chest pain to cardiogenic shock andsudden death. Myocarditis in MINOCA is common,with a mean prevalence of 33% (Fig. 1; [1, 54, 55]).Recognition is important, since myocarditis can dete-riorate into fulminant heart failure or even end-stagedilated cardiomyopathy requiring a left ventricularassistant device or heart transplantation. Especiallygiant cell myocarditis is associated with poor clinicaloutcomes [56].

CMR can be useful in making the diagnosis of my-ocarditis, but endomyocardial biopsy should be thegold standard for the diagnosis of definite myocardi-tis. The timing of these additional investigations iscrucial, since myocarditis resolves in approximately50% of patients within 2–4 weeks [56]. Findings onCMR include patchy, mid-wall, or epicardial oedemaon T2-weighted sequences and mid-wall to epicardialscar after LGE and can be clearly distinguished fromchanges related to AMI (fibrosis).

Conventional treatment of myocarditis in patientswith haemodynamically stable heart failure consists ofdiuretics, angiotensin-converting enzyme inhibitorsor angiotensin receptor blockade, and beta-adrener-gic blockade [56]. In animal models with myocardi-tis, non-steroidal anti-inflammatory drugs were foundnot to be effective. Moreover, they were associatedwith heart failure exacerbation and increased mortal-ity [57, 58]. Patients with haemodynamically unstableheart failure may require intravenous inotropic agentsor mechanical cardiopulmonary support. In the caseof biopsy-proven infection-negative myocarditis, im-


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Fig. 1 Diagnosis madeby cardiac magnetic reso-nance imaging in patientswith myocardial ischaemiawith non-obstructive coro-nary arteries. MImyocardialinfarction, TTS Takotsubocardiomyopathy, HCM hy-pertrophic cardiomyopathy,DCM dilated cardiomyopa-thy

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munosuppressive therapy can be considered in spe-cific autoimmune forms.

Non-cardiac causes

Extra-cardiac causes of MINOCA which can result inmyocardial injury include (PE), (end-stage) renal fail-ure, sepsis, stroke and other forms of type 2 MI suchas anaemia and hyperthyroidism. They all can be as-sociated with chest pain, elevated cardiac enzymesand ECG changes. If PE is suspected, evaluation withthe help of the Wells score, D-dimer concentration,pulmonary CT angiography or ventilation/perfusionscintigraphy should be performed based on patient-specific presentation.

Management of MINOCA: proposal of adiagnostic algorithm

The dynamic working diagnosis MINOCA could bemade in those patients with suspected AMI, non-obstructive coronary arteries and no clinically overtcause for the acute presentation.

Consequently clinicians should be encouraged tostart further evaluation. Stigmatisation of these pa-tients, as having an MI due to coronary thromboem-bolism or as having non-cardiac chest pain, mustbe avoided. If the true underlying mechanism forthe event has been diagnosed, the working diagnosisMINOCA should be discarded and appropriate treat-ment should be started and related to the underlyingmechanism.

The interventional cardiologist is the first to be con-fronted with MINOCA at the catheterisation labora-tory. Left ventricular angiography or echocardiogra-phy should be performed directly after coronary an-

giography to detect wall motion abnormalities, pre-dominantly to reveal signs of Takotsubo cardiomyopa-thy.

If, after coronary angiography, the cause ofMINOCA is still unknown, re-evaluation by the useof a thorough patient history, physical examinationand laboratory assessment should be done, predom-inantly to exclude non-cardiac causes, various typesof type II MI and non-ischaemic mechanisms of themyocyte injury (e.g. myocarditis).

Traditional cardiovascular risk factors for coronaryheart disease may imply concealed atherosclerosisand thus endothelial dysfunction, which is a predic-tive factor for coronary artery spasm. In contrast,SCAD patients have fewer traditional cardiovascularrisk factors but this should be strongly consideredin young female patients. Elevated inflammatoryparameters or elevated D-dimer levels may suggestmyocarditis or PE, respectively. A positive familyor personal history for hypercoagulability may leadto suspicion of hereditary or acquired coagulationdisturbances.

Non-invasive imaging plays a pivotal role in the de-tection of the underlying cause for MINOCA. Echocar-diography is essential in the work-up of MINOCA toassess any form of structural heart disease, or thepresence of ASD, intracardiac thrombus, myocardialtumour or myxoma. Furthermore, CMR plays an im-portant role. Early CMR can differentiate betweenmy-ocardial inflammation, fibrosis and myocardial func-tion by T1- and T2-weighted imaging, LGE and (ECG-gated) cine imaging. Thirteen studies have evaluatedthe diagnostic yield of CMR and were able to finda definitive diagnosis in 71% of the patients (19% MI,33% myocarditis, 12% Takotsubo cardiomyopathy, 2%hypertrophic cardiomyopathy, 2% dilated cardiomy-


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Consider:1. Microvascular dysfun on2. Coronary spasm3. Type II MI

Regard as ACS, consider:1. Coronary spasm2. Coronary embolism3. Hypercoagulability

MINOCA

Invasive techniques Possible underlying causeLe ventricular angiography1

Takotsubo CMP

Reassessment of ICA Coronary artery disse on, missed occluded side branches

IVUS/OCT Atherosclerosis, plaque disrup on, plaque erosion

Intracoronary provoca n test

Coronary artery spasm

Myocardial flow or resistance test

Microvascular dysfun on

Noninvasive techniques Possible underlying causeLaboratory assessment2 Type II AMI, thrombophilia

Transthoracic echocardiography3

Takotsubo CMP, RWMA,PFO/ASD, intracardial thrombus, myocardial tumour or myxoma

CT-angiography Pulmonary embolism or aor c disse on

Suspected type I AMI

Invasive Coronary Angiography

Diagnosis confirmed

Treat underlying cause

Diagnosis not confirmed

CMR with LGE

NormalSugges ve for AMI

Consider:1. Myocard2. Takotsubo CMP3. Dilated CMP4. Hypertrophic CMP

Not sugges ve for AMI

aalNormaal

Reconsider add onal (non)invasive techniques

Fig. 2 Proposal for a diagnostic algorithm in patients withmyocardial ischaemia with non-obstructive coronary arteries.aUnless renal function <35ml/min per 1.73 m2. bHaemoglobin,C-reactive protein, leucocytes, oxygen saturation, D-dimers,(NT-pro) brain natriuretic peptide. c Within 48h. AMI acute my-ocardial infarction, MINOCA myocardial ischaemia with non-obstructive coronary arteries, ICA invasive coronary angiog-

raphy, CMP cardiomyopathy, IVUS intravascular ultrasound,OCT optical coherence tomography, RWMA regional wall mo-tion abnormalities, PFO patent foramen ovale, ASD atrial sep-tal defect, CT computed tomography, CMR cardiac mag-netic resonance imaging, LGE late gadolinium enhancement.ACS acute coronary syndrome

opathy, 3% other), as illustrated in Fig. 1 [4, 19, 54,59–68]. Based on these observations, we recommendroutine examination with CMR within 4 weeks afterhospital admission.

However, in 8–67% of patients no abnormalitiescould be found, which leads to a therapeutic dilemmafor clinicians [4, 23, 54, 59, 62, 64]. In these patients,

additional investigations such as those mentioned inFig. 2 may be considered.

In select cases, if no cause can be found, it can beuseful to perform CT angiography and/or intracoro-nary reactivity testing during the index procedure ora second procedure in the outpatient clinic to revealthe underlying cause of MINOCA. We recommend thisif:


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� There remains uncertainty regarding the presenceof coronary atherosclerosis or (spontaneous) coro-nary artery dissection (CT angiography)

� There is a need to detect the degree of coronaryatherosclerosis (CT angiography)

� There is a high suspicion of microvascular CAD (in-tracoronary reactivity testing)

� There is a high suspicion of VSA (intracoronary re-activity testing)

At the discretion of the interventional cardiologist,IVUS or OCT can be performed to determine thepresence of atherosclerosis, atherosclerotic plaquedisruption, plaque erosion, coronary dissection andcoronary thrombosis. In addition, vulnerable plaquescan be identified by measuring the fibrous cap thick-ness and the presence of a large necrotic core. Itmust be noted, as already mentioned, that coronaryplaque disruption and thrombus are highly prevalentin MINOCA [22]. Since the diagnosis of plaque disrup-tion has potential therapeutic implications, the use ofintravascular imaging is recommended. The herewithassociated higher costs, need for expertise and theextra time needed in the catheterisation laboratoryshould be taken into consideration.

To evaluate MVA or VSA, a combination of intra-coronary interventional diagnostic procedures canbe performed directly during the index procedureor a second procedure to assess the CFR (abnor-mal <2.0), IMR (abnormal ≥25) or FFR (abnormal≤0.80). If coronary MVD is absent [negative CFR andIMR, in the absence of significant epicardial stenosis(negative FFR)], acetylcholine testing can be per-formed to reveal epicardial or microvascular spasm[69]. This combined invasive diagnostic approach,including medical therapy, was recently evaluated inthe CorMicA trial in patients with stable angina pec-toris. It was concluded that this approach improvesangina symptoms and quality of life [70].

These techniques are safe in experienced hands.However, one should be aware of the potential com-plications (e.g. local bleeding complications, coronaryartery dissection or perforation, acute kidney injuryand stroke). Furthermore, CFR is highly influenced byage, blood pressure, heart frequency and contractility.Besides, it can be difficult to obtain good signals usingthe Doppler wire.

Altogether, both intravascular imaging and func-tional testing for detecting vasospasm or microvascu-lar resistance play an important role in detecting thetrue mechanism of MINOCA. What kind of testing ismost appropriate depends on the clinical presentationand the hospital resources. For example, intracoro-nary provocation testing may be the first choice ina patient with nocturnal angina pectoris and tran-sient ST-elevation presenting with non-obstructivecoronary arteries; on the other hand, if a patient withmultiple traditional cardiac risk factors is diagnosedwith subcritical stenoses, intracoronary imaging, and

CFR and IMR measurements provide the most infor-mation (e.g. degree of atherosclerosis, plaque ruptureor vulnerable plaque).

Future perspectives

The Stockholm Myocardial Infarction with NormalCoronaries (SMINC-2) study will provide insight intowhether or not early CMR can make a reliable diagno-sis in more than 70% of all MINOCA patients (ClinicalTrials NCT02318498) [71]. Furthermore, the ongoingMINOCA BAT (Clinical Trials NCT03686696) aims toprovide information on the usefulness of beta block-ers and angiotensin-converting enzyme inhibitorsor angiotensin receptor blockers in 3500 MINOCApatients.

Limitations

Several limitations should be addressed. First, thetermMINOCA can be interpreted in several ways, andthus studies vary widely regarding the inclusion cri-teria of MINOCA. Many terms have been coined todescribe patient with non-obstructive coronary arter-ies during an ACS. As the Dutch ACS working groupwe think use of an additional term will only lead toeven less clarity, and thereby suggest using the termMINOCA as a dynamic working diagnosis to describeall possible underlying causes (i.e. coronary, myocar-dial and non-coronary disorders).

Secondly, the 50% angiographic stenosis thresh-old in MINOCA is somewhat arbitrary, since it wasshown that the FFR was positive in a quarter of thepatients with angiographically considered non-ob-structive coronary arteries [72]. Although data onFFR testing in MINOCA patients is sparse, we agreewith the American Heart Association that, if FFR isused, only patients with FFR findings >0.80 should beincluded in a working diagnosis of MINOCA [73]. Be-sides, for prognostic purposes it would be importantto subdivide the MINOCA patients according to theirangiographic coronary status into those with normalcoronary arteries and mild CAD in future studies.

Third, since the MINOCA population is per defini-tion heterogeneous, it is a challenge to make a clear-cut diagnostic pathway for every MINOCA case. Forthis reason, we chose to make a general algorithmincluding all potentially useful diagnostic modalities.Depending on the clinical presentation and the hos-pital resources, a patient-specific diagnostic approachshould be made. However, CMR should play an im-portant role in this approach given the high diagnosticyield.

Conclusion

MINOCA is a common clinical entity in patientspresenting with AMI and represents many possibleaetiologies that can be challenging to detect. By


Review Article

proposing a clinical diagnostic algorithm, we aim toencourage the clinician to find the underlying causeof MINOCA, since MINOCA should be regarded asa dynamic working diagnosis including coronary,myocardial and non-coronary disorders.

Conflict of interest T.F.S. Pustjens, Y. Appelman, P. Damman,J.M. ten Berg, J.W. Jukema, R.J. de Winter, W.R.P. Agema,M.L.J. van der Wielen, F. Arslan, S. Rasoul and A.W.J. van’t Hofdeclare that they have no competing interests.

Open Access This article is distributed under the terms ofthe Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which per-mits unrestricted use, distribution, and reproduction in anymedium, provided you give appropriate credit to the origi-nal author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made.

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