coronary heart disease...coronary artery disease was evident in 237 publications (figure 1). these...

861

Contemporary management strategies of acute ST-segment–elevation myocardial infarction (STEMI)

are based on the pioneering early angiographic studies of DeWood and colleagues,1 who demonstrated an occluded coronary artery in almost 90% of these patients. Accordingly, the ‘open artery’ management strategy was used, initially with the use of thrombolytic therapy and subsequently with per-cutaneous coronary interventions. In contrast, early angiog-raphy in patients with non–ST-segment–elevation myocardial infarction (NSTEMI) showed an occluded vessel in fewer than a third of these patients,2 so that strategies focusing on

maintaining arterial patency were developed. However, both of these acute myocardial infarction (MI) angiographic stud-ies1,2 demonstrated the presence of significant obstructive coronary artery disease in >97% of these MI patients, thus underscoring the importance of obstructive coronary athero-sclerotic disease in this condition.

Clinical Perspective on p 870

With the widespread use of coronary angiography in the early clinical management of MI, multicenter MI registries have evolved and reported that as many as 10% of MI patients

Background—Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a puzzling clinical entity with no previous evaluation of the literature. This systematic review aims to (1) quantify the prevalence, risk factors, and 12-month prognosis in patients with MINOCA, and (2) evaluate potential pathophysiological mechanisms underlying this disorder.

Methods and Results—Quantitative assessment of 28 publications using a meta-analytic approach evaluated the prevalence, clinical features, and prognosis of MINOCA. The prevalence of MINOCA was 6% [95% confidence interval, 5%–7%] with a median patient age of 55 years (95% confidence interval, 51–59 years) and 40% women. However, in comparison with those with myocardial infarction associated with obstructive coronary artery disease, the patients with MINOCA were more likely to be younger and female but less likely to have hyperlipidemia, although other cardiovascular risk factors were similar. All-cause mortality at 12 months was lower in MINOCA (4.7%; 95% confidence interval, 2.6%–6.9%) compared with myocardial infarction associated with obstructive coronary artery disease (6.7%, 95% confidence interval, 4.3%–9.0%). Qualitative assessment of 46 publications evaluating the underlying pathophysiology responsible for MINOCA revealed the presence of a typical myocardial infarct on cardiac magnetic resonance imaging in only 24% of patients, with myocarditis occurring in 33% and no significant abnormality in 26%. Coronary artery spasm was inducible in 27% of MINOCA patients, and thrombophilia disorders were detected in 14%.

Conclusions—MINOCA should be considered as a working diagnosis with multiple potential causes that require evaluation so that directed therapies may improve its guarded prognosis. (Circulation. 2015;131:861-870. DOI: 10.1161/CIRCULATIONAHA.114.011201.)

Key Words: coronary artery disease ◼ coronary vasospasm ◼ magnetic resonance ◼ mortality ◼ myocardial infarction ◼ physiopathology ◼ thrombophilia

© 2015 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.011201

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Received May 16, 2014; accepted December 29, 2014.From Discipline of Medicine, University of Adelaide, South Australia (S.P., R.P.D., R.T., J.F.B.); Cardiology Department, Queen Elizabeth Hospital,

Adelaide, South Australia (S.P., R.P.D., R.T., J.F.B.); Discipline of Psychiatry, University of Adelaide, South Australia (T.A.); Center for Outcomes Research and Evaluation (CORE), Yale-New Haven Hospital, New Haven, CT (R.P.D.); Department of Internal Medicine, Yale School of Medicine, New Haven, CT (R.P.D.); and Cardiology Department, Lyell McEwin Hospital, Adelaide, South Australia (J.F.B.).

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA. 114.011201/-/DC1.

Correspondence to John F. Beltrame, BSc, BMBS, PhD, Discipline of Medicine, Queen Elizabeth Hospital, University of Adelaide, 28 Woodville Rd, Woodville South, Adelaide, SA, Australia 5011. E-mail [email protected]

Systematic Review of Patients Presenting With Suspected Myocardial Infarction and Nonobstructive

Coronary ArteriesSivabaskari Pasupathy, BSc(Hons); Tracy Air, BA (Hons), M.Biostatistics;

Rachel P. Dreyer, BSc(Hons), PhD; Rosanna Tavella, BSc(Hons), PhD; John F. Beltrame, BSc, BMBS, PhD

Coronary Heart Disease

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862 Circulation March 10, 2015

have no evidence of obstructive coronary artery disease.3 These patients with MI with nonobstructive coronary arteries (MINOCA)4 represent a conundrum because the underlying cause of their MI is not immediately apparent. Furthermore, whether they have similar clinical features and outcomes as patients with MI with obstructive coronary artery disease (MI-CAD) is unclear. Ascertaining whether MINOCA is a distinct clinical entity with specific clinical features, out-comes, and pathophysiological mechanisms is paramount to determining the appropriate management strategy for these patients, yet to date there is no systematic review of the pub-lished literature concerning these patients. Furthermore, given the limited investigation of these patients, it is not surprising that there are no professional guidelines on the management of MINOCA.

Accordingly, the primary objectives of this system-atic review are to detail the clinical attributes of these patients by systematically evaluating the published lit-erature in regards to (1) the prevalence, clinical features, and 12-month prognosis of MINOCA patients, and (2) the major underlying pathophysiological mechanisms respon-sible for this disorder.

MethodsThis study used a comprehensive structured systematic approach that included a methodical literature search, well-defined inclusion crite-ria for MINOCA, extraction of available raw data, and pooling of the data to determine the frequency of each of the predetermined study end points.

Published Literature SearchAn unrestricted literature search was conducted using PubMed and Embase. The search terms in each of these databases and the subsequent evaluation process are summarized in Figure 1. In brief, searches were conducted in both databases focusing on the terms ‘myocardial infarction,’ ‘nonobstructive,’ and ‘angiog-raphy.’ Only original human clinical research studies published in English were considered. However, the references in recent key review articles were also crosschecked with the database searches to ensure a comprehensive source of original papers. A search of the Cochrane database revealed no relevant systematic reviews on this topic.

Systematic Assessment of the Available LiteratureOf the original human MI research studies (1033 publications) between 1966 and 2013 (inclusive), reference to nonobstructive coronary artery disease was evident in 237 publications (Figure 1). These articles were reviewed for the following prespecified inclu-sion and exclusion criteria by 2 of the investigators (S.P., R.T.).

Inclusion CriteriaFor consideration in this meta-analysis, it was essential for the follow-ing criteria to be documented in the protocol of the published study:

1. Evidence of an MI5 as defined by (1) significant elevation of a cardiac biomarker and (2) at least 2 of the following – isch-emic symptoms, new ST/T changes, or new left bundle-branch block.

2. Qualitative coronary angiography findings to allow determina-tion of the presence/absence of obstructive coronary artery disease.

MINOCA was defined as the presence of an MI (as per the above criteria) in the absence of obstructive coronary artery disease (ie, no epicardial vessel with a stenosis ≥50% on angiography). Those MI

patients with significant obstructive coronary artery disease (at least 1 stenosis ≥50%) were designated as MI-CAD. The decision to use a <50% lesion threshold to delineate nonobstructive CAD from the obstructive CAD is based on the following rationale: (1) well estab-lished criteria in clinical guidelines,6 accordingly (2) it is the most frequently used definition in published angiographic studies, (3) con-sidering the limitations of angiography, the presence of angiographic smooth vessels does not exclude the presence of significant athero-sclerosis, (4) attention should be focused on why myocardial infarc-tion/injury has occurred in the absence of a functionally obstructive lesion, and (5) the more inclusive definition allows future prognostic studies to determine whether there is clinical utility in delineating those with angiographically smooth vessels from those with minor CAD.

Exclusion CriteriaPublications were excluded from further consideration if

1. coronary angiography was not performed in the context of an MI admission,

2. Tako-tsubo cardiomyopathy or myocarditis were the primary focus of the article,

3. there was no original data or the data were reproduced from a former study, and

4. isolated case report format.

Using these inclusion and exclusion criteria, 152 original MI pub-lications had sufficient data to clearly identify those patients with MINOCA. Further analysis was dependent on the specific objectives of this study, namely (1) determining the clinical (primary objective) or (2) pathophysiologic (secondary objective) attributes of MINOCA (Figure 1). The studies used in the analyses are listed in Table I in the online-only Data Supplement.

Because the primary objective requires a representative sample to quantitatively assess the clinical attributes of MINOCA, only publications that recruited (1) at least 100 patients with MI, and (2) consecutive MI patients, were included in the analysis. The specific definitions used in these studies for the various cardio-vascular risk factors are listed in Table II in the online-only Data Supplement.

For the second objective, original studies fulfilling the above inclu-sion/exclusion criteria were included if they performed systematic diagnostic evaluations on a group of MINOCA patients with the intention of exploring the underlying pathophysiologic mechanism/s responsible for the MI. These included myocardial imaging studies such as cardiac magnetic resonance (CMR) imaging and functional studies such as provocative spasm testing and thrombophilia screen-ing (Figure 1). For consistency, the total frequency of each abnor-mal pathophysiologic investigation was documented although it is acknowledged that the findings may be time-dependent. Accordingly, the results of early investigations (ie, within 6 weeks of MI) are also described.

Data Extraction and AnalysisThe end points evaluated in the primary objective included (1) prevalence of MINOCA, (2) clinical features including age, sex, MI type (STEMI or NSTEMI), cardiovascular risk factors, and (3) prognosis (including in-hospital and 12-month all-cause mor-tality). Data for these end points were pooled and analyzed using random effects meta-analysis models.7 This conservative approach assumes that individual studies are estimating different treatment effects. Heterogeneity in the study estimates were assessed using I2 statistics8 with larger values indicating increasing heterogeneity between studies. In addition, for studies including both MINOCA and MI-CAD patients, the summary odds ratios (ORs) or mean dif-ference and exact 95% confidence intervals (95% CI) were calcu-lated. Data from the pathophysiologic mechanistic publications was more limited so that qualitative assessment could only be under-taken. This involved pooling of frequency data from studies with similar end points. All analyses were performed using STATA (ver-sion 12, College Station, Tex.)

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ResultsFrom the 152 MINOCA publications identified on PubMed and Embase, we embarked on (1) quantitative assessment of 28 studies to evaluate the clinical attributes of the condition and (2) qualitative evaluation of 46 studies that focused on its pathophysiologic attributes (Figure 1 and Table I in the online-only Data Supplement). These clinical and pathophysiologic attributes of MINOCA are detailed below.

PrevalenceThe prevalence of MINOCA was determined from 27 large clinical trials/registries involving 176 502 consecutive MI patients who had coronary angiography performed. These studies reported a prevalence of MINOCA ranging from 1%

to 14% with an overall prevalence calculated at 6% (95% CI, 5%–7%), based on random effects analysis (Figure 2). The I2 statistic was estimated to be 99%.

Clinical Features

SexIn the 15 publications reporting gender (n=11 334), pooled analyses revealed that only 40% (95% CI, 33%–46%) of MINOCA patients were women. However pooled analysis of 10 studies that recruited both MINOCA (n=5322) and MI-CAD (n=70 253) patients, revealed an over-representation of women with MINOCA (43%; 95% CI, 35%–51%) rela-tive to that observed with MI-CAD (24%; 95% CI, 19%–30%; Table 1).

Figure 1. Flow diagram of study selection process. AMI indicates acute myocardial infarction; CAD, coronary artery disease; CMR, cardiac magnetic resonance; Echo, echocardiography; and MINOCA, myocardial infarction with nonobstructive coronary arteries.




AgeSufficient data were available in 13 studies (n=9986) to deter-mine the pooled mean age of MINOCA patients. This was calculated to be ≈55 years (95% CI, 51–59 years) with no significant heterogeneity between studies as estimated by the I2 statistic. In 6 publications, data on age were available for both MINOCA (n=3927) and MI-CAD (n=48 082) patients, with the respective pooled mean ages between 58.8 (95% CI, 51.6–66.1 years) and 61.2 years (95% CI, 52.2–70.4 years). Analysis of these comparative studies confirmed that patients with MINOCA were younger than those with MI-CAD. This analysis may have underscored this difference because the 6 studies included in this comparison recruited MINOCA patients at the upper age spectrum of the overall MINOCA cohort (Table 1).

Cardiovascular Risk FactorsBy evaluating comparative studies that included both MINOCA and MI-CAD patients, the relative frequencies of cardiovascular risk factors were determined. These are summarized in Table 1 along with the cardiovascular risk profile from all available MINOCA studies. Results reported within this section will be confined to the comparative stud-ies. Compared with MI-CAD patients, those with MINOCA were less likely to have hyperlipidemia (32% [95% CI, 30%–59%] versus 21% [95% CI, 6%–35%], respectively; OR, 0.63; P<0.001). However, it is noteworthy that the prevalence of hyperlipidemia among MINOCA patients in these comparative studies was considerably lower than that observed for the overall MINOCA cohort (33%; 95% CI, 25%–41%). Other cardiovascular risk factors including hypertension, diabetes mellitus, smoking, and family history

of premature coronary artery disease were similar between the groups (Table 1).

Infarct ECG FindingsTen studies (n=1998) documented the prevalence of an acute STEMI presentation among MINOCA patients.

0.0 0.1 0.2

Overall (I-squared = 99%, p=0.000)

Sharifi, 1995 Zimmerman, 1995

Hochman, 1999 Gehani, 2001

Hung, 2003 Germing, 2005

Larsen, 2005 Patel, 2006

Strunk, 2006 Widimsky, 2006

Larson, 2007 Ahmar, 2008

Ong, 2008 Baccouche, 2009

Gehrie, 2009 Frycz−Kurek, 2010

Uchida, 2010 Kang, 2011

Leurent, 2011 Tritto, 2011

Agewall, 2012 Aldrovandi, 2012

Hamdan, 2012 Rhew, 2012

Sun, 2012Collste, 2013 Larsen, 2013 0.04 (0.03, 0.04) 4.07

0.28 (0.25, 0.31) 4.060.06 (0.06, 0.07) 3.680.02 (0.00, 0.03) 3.860.08 (0.07, 0.10) 2.310.09 (0.04, 0.14) 4.040.04 (0.03, 0.04) 2.690.07 (0.03, 0.11) 2.690.05 (0.04, 0.06) 3.960.04 (0.03, 0.05) 3.590.13 (0.11, 0.16) 4.090.04 (0.04, 0.05) 2.730.08 (0.04, 0.12) 4.110.03 (0.03, 0.03) 4.110.10 (0.09, 0.10) 4.110.14 (0.12, 0.16) 3.710.10 (0.07, 0.13) 3.090.06 (0.07, 0.07) 3.790.04 (0.03, 0.05) 3.970.03 (0.02, 0.04) 3.970.08 (0.05, 0.10) 3.430.09 (0.08, 0.09) 4.110.07 (0.07, 0.08) 4.080.06 (0.04, 0.08) 3.680.10 (0.06, 0.14) 2.670.05 (0.04, 0.06) 3.990.07 (0.06, 0.07) 4.050.04 (0.04, 0.05) 4.100.01 (0.00, 0.02) 4.070.06 (0.05, 0.07) 100.00

Proportion (95% CI) % Weight

Note: Weights are from random effects analysis

Figure 2. Prevalence of myocardial infarction with nonobstructive coronary arteries (MINOCA). Forest plot of published studies examining the prevalence of MINOCA using random effects meta-analysis. Data presented as percentage (%) and 95% confidence intervals (CI; %).

Table 1. Cardiovascular Risk Factors in Patients With MINOCA or MI-CAD

Comparative Studies

All MINOCA StudiesRisk Factors

MI-CAD% (95% CI)

MINOCA% (95% CI)

Mean difference/OR

(95% CI) &P Value

Age 61.3(52.2, 70.4)

58.8(51.6, 66.1)

4.1 (2.9,5.4)P<0.001

54.7(50.5, 58.7)

Women 24%(19%, 30%)

43%(35%, 51%)

2.1 (1.7, 2.7)P<0.001

40%(33%, 46%)

Hyperlipidemia 32%(15%, 48%)

21%(6%, 35%)

0.6 (0.5, 0.7)P<0.001

33%(25%, 41%)

Hypertension 45%(30%, 59%)

52%(41%, 62%)

1.3 (0.9, 1.9)P=0.183

44%(38%, 50%)

Diabetes mellitus

22%(14%, 29%)

15%(9%, 20%)

0.8 (0.5, 1.3)P=0.333

13%(11%, 16%)

Smoking 39%(26%, 52%)

42%(33%, 51%)

1.1 (0.7, 1.5)P=0.785

42%(36%, 48%)

Family history 27%(10%, 43%)

21%(5%, 38%)

1.0 (0.7, 1.3)P=0.794

28%(17%, 39%)

Data presented as either mean or percentage (%) with 95% confidence intervals (CI; %) where appropriate. MI-CAD indicates myocardial infarction with coronary artery disease; MINOCA, myocardial infarction with nonobstructive coronary arteries; and OR, odds ratio.




Pooled analysis revealed that 33% (95% CI, 22%–44%) presented with features of STEMI (Figure 3). Accordingly, approximately two-thirds of patients were categorized with NSTEMI.

Angiographic FindingsBy definition, MINOCA patients have <50% lesions on angiography. The relative frequency of smooth vessels (ie, no lesions visible on angiography) compared with minor irregularities on angiography was assessed in 5 clinical tri-als with 1046 MINOCA patients (Figure I in the online-only Data Supplement). Among the MINOCA patients, the preva-lence of smooth vessels on angiography was 51% (95% CI, 39%–61%). Importantly, the I2 test confirmed the presence of significant heterogeneity among these studies.

PrognosisStudies assessing prognosis in patients with MINOCA were considerably heterogeneous in their follow-up period, and few reported the prevalence of cardiac mortality or rein-farction. Overall, 8 studies reported all-cause mortality in patients with MINOCA, including in-hospital (5 stud-ies, n=9564), and 12 months (4 studies, n=1924) after MI. Pooled meta-analysis of these studies revealed an all-cause in-hospital and 12-month mortality of 0.9% (95% CI, 0.5%–1.3%) and 4.7% (95% CI, 2.6%–6.9%), respectively. In 6 of these 8 studies, all-cause mortality was assessed in both MINOCA and MI-CAD patients, thereby allowing compari-sons of the relative mortality between these forms of MI. As shown in Table 2, although the in-hospital mortality and 12-month mortality were lower in MINOCA patients, the findings remain of concern considering the limited clinical attention received by these patients.

Potential Pathophysiological MechanismsOf the 81 original publications investigating the potential mechanisms responsible for MI in MINOCA patients, 46 used three distinct approaches, including (1) assessment of

structural myocardial dysfunction with CMR imaging (26 publications), (2) provocative coronary artery spasm testing (15 publications), and (3) thrombophilia screening (8 publi-cations, including 3 of the spasm studies). The remaining 35 publications used more heterogeneous approaches investigat-ing isolated aspects of MINOCA and were therefore not con-ducive to pooled analysis.

Structural Myocardial DysfunctionPooled analyses of the 26 CMR imaging publications involving MINOCA patients revealed features consis-tent with a subendocardial infarct on delayed hyper-enhancement in only 24% of 1801 MINOCA patients studied. The most common finding in the CMR imaging studies was myocarditis, with 33% of the 1676 MINOCA patients having features of this condition. Other myocar-dial abnormalities reported in the MINOCA CMR imag-ing studies included Tako-tsubo cardiomyopathy (18% of 1529 patients), hypertrophic cardiomyopathy (3% of 1074 patients), dilated cardiomyopathy (2% of 625 patients), and other causes (7% of 760 patients) such as pericarditis and amyloidosis. Importantly, 26% of 1592 MINOCA patients

Table 2. All-Cause Mortality in Patients With MINOCA or MI-CAD

Comparative Studies

All MINOCA Studies

All-Cause Mortality

MI-CAD% (95% CI)

MINOCA% (95% CI)

OR (95% CI)P Value

In-hospital 3.2%(1.8%, 4.6%)

1.1%(-0.1%, 2.2%)

0.37 (0.2–0.67)P=0.001

0.9%(0.5%, 1.3%)

12-month 6.7%(4.3%, 9.0%)

3.5%(2.2%, 4.7%)

0.59 (0.41–0.83)P=0.003

4.7%(2.6%, 6.9%)

Data presented as percentage (%) and 95% confidence intervals (%) with odds ratio (OR) and P values. MI-CAD indicates myocardial infarction with coronary artery disease; and MINOCA, myocardial infarction with nonobstructive coronary arteries

0.0 0.2 0.4 0.6 0.8 1.0

Overall (I-squared = 95.4%%, p=0.000)

Sharifi, 1995

Hochman, 1999

Germing, 2005

Strunk, 2006

Ong, 2008

Frycz-Kurek, 2010

Uchida, 2010

Kang, 2011

Sun, 2012

Rossini, 2013


0.21 (0.17, 0.27) 11.56

1.00 (0.29, 1.00) 5.51

0.36 (0.31, 0.41) 11.57

0.15 (0.02 ,0.45) 8.25

0.38 (0.35, 0.41) 11.73

0.07 (0.01,0.22) 10.72

0.53 (0.35,0.71) 9.10

0.22 (0.10,0.39) 9.91

0.64 (0.58, 0.69) 11.46

0.00 (0.00, 0.27) 10.19

0.33 (0.22 , 0.44) 100.00

NOTE: weights are from random effects analysis

Figure 3. Prevalence of acute ST-segment–elevation myocardial infarction (STEMI) presentation in myocardial infarction with nonobstructive coronary arteries (MINOCA). Forest plot of published studies examining the frequency of STEMI presentation in patients with MINOCA, using a random effects meta-analysis. Data presented as percentage (%) and 95% confidence intervals (CI; %).




undergoing contrast CMR imaging did not have detectable myocardial abnormalities.

Of the above investigations, 16 CMR studies were under-taken within 6 weeks of the MI (Table III in the online-only Data Supplement). These reported similar frequencies in abnormal CMR findings, including subendocardial infarct (24%), myocarditis (38%), Tako-tsubo cardiomyopathy (16%), and no significant abnormality (21%).

Coronary Artery SpasmProvocative spasm testing was undertaken in 14 studies involving MINOCA patients (Table 3). Of the 402 MINOCA patients in the pooled dataset, 28% had inducible spasm. In 8 studies (n=298), provocative testing was performed within 6 weeks of an MI and 28% had inducible spasm. In 4 stud-ies (n=90), provocation testing was undertaken in MINOCA patients with an old myocardial infarct (ie, MI≥6 weeks) and spasm was provoked in 34% of patients (Table 3).

Thrombophilia DisordersAs summarized in Table 4, 8 publications examined the presence of inherited thrombotic disorders in patients with MINOCA, with most undertaken in the early postinfarction period. Pooled analyses revealed the following abnormalities within the coagulation pathway: activated protein C resistance or factor V Leiden in 12% of 344 patients, protein C/protein

S deficiency in 3% of 189 patients, and factor XII deficiency in 3% of 163 patients. Overall, 14% of the 378 MINOCA patients who underwent thrombophilia screening had evi-dence of an inherited thrombotic disorder.

DiscussionThis detailed systematic review provides the first compre-hensive overview of patients with MINOCA. It demonstrates that MINOCA has (1) a 6% prevalence of all MI presenta-tions, (2) no diagnostic distinguishing clinical presentation features compared with MI-CAD, (3) a better 12-month all-cause mortality compared with MI-CAD, although its prognosis should be considered as guarded, and (4) struc-tural dysfunction, coronary spasm, and thrombotic disorders as some potential underlying causes. Given that MINOCA has similar features to MI-CAD, a guarded prognosis, and multiple potential causes, it should be considered a work-ing diagnosis that requires further evaluation of the potential underlying causes because these may have important clinical implications.

MINOCA Patients Do Not Have a Distinguishing Clinical PresentationPatients with MINOCA may present with STEMI or NSTEMI, with two-thirds presenting as the latter. Compared

Table 3. Provocative Spasm Testing in Patients With MINOCA

PublicationsNo. of Patients

in the Study Provocation Test Spasm Definition

Provoked/SpontaneousSpasm, n (%)

Early provocative spasm testing (within 6 wk of acute myocardial infarction)

Bory, 1988 59 iv ergot ≥50% constriction on angio 2/59 (3%)

Fukai, 1993 21 iv ergot ≥75% constriction on angio 13/16 (81%)

Dacosta, 2001 91 iv ergot ≥70% constriction on angio 11/71 (15%)

Wang, 2002 23 ic ergot ≥90% constriction on angio 17/23 (74%)

Hung, 2003 19 ic ergot ≥70% constriction on angio 18/19 (95%)

Dacosta, 2004 82 iv ergot ≥70% constriction on angio 13/82 (16%)

Abid, 2012 21 iv ergot ≥70% constriction on angio 5/21 (24%)

Ong, 2008 7 ic acetylcholine ≥75% constriction on angio 4/7 (57%)

Total (provocative spasm testing <6 wks) (83/298) 28%

Late provocative spasm testing (≥6 wk after myocardial infarction)

Legrand, 1982 18 iv ergot Chest pain & ST elevation 6/18 (33%)

Raymond, 1988 74 iv ergot ≥75% constriction on angio 5/16 (31%)

Ammann, 2000 23 Hyperventilate ST elevation 0/23 (0%)

Kim, 2005 33 iv ergot RWMA on echocardiography 20/33 (61%)

Total (provocative spasm testing ≥6 wks) (31/90) 34%

Undefined timing for provocative spasm testing (relative to myocardial infarction)

Salem, 1985 10 iv ergot Chest pain & ST elevation 0/7 (0%)

Verheugt, 1987 21 iv ergot NR 0/7 (0%)

Provocative spasm testing in cocaine induced MINOCA patients

*Kossowsky, 1989 5 cold pressor NR 0%

Overall pooled spasm 114/402 (28%)

Data presented as n (%). angio indicates coronary angiography; ergot, ergonovine; ic, intracoronary; iv, intravenous; MINOCA, myocardial infarction with nonobstructive coronary arteries; NR, not recorded; and RWMA, regional wall motion abnormality.

*Kossowsky et al was ignored from the calculations because it represents the cohort of cocaine abuse patients.




with MI-CAD patients, those with MINOCA tend to be younger, predominantly male (although women are over-represented relative to those with MI-CAD, 40% versus 25%, respectively) with significant cardiovascular risk fac-tors, although less often have hyperlipidemia (Table 1). Thus although there are statistical differences in the clinical profile of patients with MINOCA, there are no clinically distinguish-ing characteristics or risk factors that can easily delineate these patients from those with MI-CAD based on a systemic review of the literature. Specific future studies examining details of the clinical history may be more discerning. Once coronary angiography is performed and defines the MINOCA patients, completely smooth (ie, normal) coronary arteries are observed in only half of the patients, with many having minor irregularities thereby justifying the designation MINOCA. The clinical importance of delineating MINOCA patients with angiographically smooth coronary arteries from those with only mild irregularities needs to be clarified in future prognostic studies. The only published MINOCA study that has undertaken this comparison examined 12-month all-cause mortality and reported poorer outcomes in those with smooth coronaries, however sample size was small (24 deaths in total).9 If future studies demonstrate different outcomes in these angiographic subgroups, then it will be justifiable to clinically delineate them.

MINOCA Patients Have a Guarded PrognosisPatients with MINOCA have a significantly reduced all-cause mortality compared with those with MI-CAD, including a 63% lower in-hospital mortality and 41% lower 12-month mortality (Table 2).

Although these findings may be reassuring, the 4.7% (95% CI, 2.6%–6.9%) 12-month all-cause mortality for patients with MINOCA is of concern when compared with other published prognostic studies. Firstly, the Korean MI Registry10 evaluated 12-month all-cause mortality in 8510 consecutive MI patients, reporting a 3.1% mortality in those with MINOCA, 3.2% in those with single or double vessel coronary artery disease, and 6.5% in those with triple vessel disease or a significant left main coronary artery stenosis. Secondly, patients with stable

chest pain (ie, no previous MI) and normal smooth coronar-ies on angiography have a 0.2% annual all-cause mortality, whereas those with only minor luminal irregularities have a 0.3% annual all-cause mortality.11 Accordingly, MINOCA patients appear to have a poorer prognosis than those with stable chest pain and nonobstructive coronary artery disease, and more akin to those with an MI and single/double ves-sel coronary artery disease. Thus their prognosis should be considered somewhat guarded despite being better than those with MI-CAD.

MINOCA – A Heterogeneous Working Diagnosis With Some Treatable CausesSimilar to the diagnosis of heart failure, MINOCA should not be considered as a specific diagnosis but a heteroge-neous working diagnosis that requires further evaluation to elucidate potential underlying causes. Identifying the cause of MINOCA is important because it may have prognostic implications (eg, identification of a cardiomyopathy), but even more importantly it may require institution of specific therapies to treat the underlying cause. Important MINOCA-related diagnoses that may warrant specific targeted therapies include structural myocardial dysfunction (such as cardio-myopathies), coronary spasm, and thrombophilia disorders. These are further discussed below.

Structural Myocardial DysfunctionThe detection of structural heart disease with CMR imag-ing in patients with MINOCA syndrome can reveal cardio-myopathies such as Tako-tsubo, hypertrophic, or dilated cardiomyopathy (Figure 4). Although Tako-tsubo cardiomy-opathy is an important diagnosis considering its prognostic implications, currently there are no specific therapies for this condition. In contrast, hypertrophic and dilated cardio-myopathy (although seldom detected in MINOCA patients) have important management strategies/therapies that can influence patient outcomes. Accordingly, detection of these treatable conditions further justifies the routine use of CMR imaging in patients with MINOCA because it is the optimal diagnostic imaging modality for delineating cardiac struc-tural disorders in this condition.

Table 4. Thrombophilia Screening in Patients With MINOCA

PublicationsNo. of Patients in

the StudyAPCR/

Factor V LeidenProtein C/S Deficiency

FactorXII Deficiency

Thrombotic Disorders,

n (%)

Brecker, 1993 12 NE 0 NE 0/12 (0%)

DaCosta, 1998* 22 2 1 1 4/22 (18%)

Lande, 1998 26 3 2 NE 5/14 (36%)

Mansourati, 2000 107 13 NE NE 13/107 (12%)

Van de Water,2000 60 8 NE NE 8/60 (13%)

DaCosta, 2001 91 7 1 1 9/73 (13%)

DaCosta, 2004 82 8 1 3 12/78 (15%)

Abid, 2012 21 2 1 0 4/12 (33%)

Overall 41/344 (12%) 5/189 (2.6%) 4/163 (2.5%) 51/356 (14%)

Data presented as n (%). APCR indicates activated protein C Resistance; MINOCA, myocardial infarction with nonobstructive coronary arteries; and NE, not examined.

*Dacosta et al (1998) was ignored from the calculations because the same patient cohort was again used in Dacosta et al (2004).




Myocarditis is an important cause of MINOCA that is opti-mally diagnosed by CMR imaging. It accounts for approxi-mately a third of MINOCA cases and provides a definitive diagnosis that may have prognostic implications, although generally it requires only conservative management.

Another important MINOCA subgroup detected by CMR imaging are those with a subendocardial infarct pattern on delayed hyper-enhancement images. The infarct may arise from transient occlusive coronary spasm or thrombosis.12

Coronary SpasmMore than a quarter of patients with MINOCA undergoing pro-vocative spasm testing have inducible spasm. Unfortunately there are no suitable studies directly comparing provocative spasm testing between MINOCA and MI-CAD patients, although several have reported inducible spasm in 20% to 80% of MI-CAD patients.13,14 Thus the relative contribution of coronary spasm to the pathophysiology of MINOCA requires further investigation.

There are several interesting observations in relation to pro-vocative spasm testing findings in patients with MINOCA. First, there is no time-dependence for inducible spasm among MINOCA patients (Table 3), whereas MI-CAD patients with a recent (<6 weeks) infarct are more likely to have inducible spasm than those with an old (>6 weeks) infarct. Whether the persistent inducible spasm in MINOCA patients reflects an underlying vasospastic predisposition is open to specula-tion. Second, there appears to be an ethnic predisposition to coronary spasm in patients with a recent myocardial infarct,14 particularly among Japanese patients.15 Fukai et al16 from Japan reported an 81% prevalence of inducible spasm in patients with MINOCA, whereas studies from Europe17–20 and the United States21,22 have a pooled prevalence of only 14%. Interestingly, other Asian-based studies23,24 also report a high prevalence of inducible spasm (Table 3). Finally, cocaine may induce coronary spasm and should be considered as a potential cause of MINOCA, however a recent large registry reported that cocaine use was associated with only 0.9% of MI cases.25

The above findings relating to coronary spasm in MINOCA are exploratory and require further investigation because the data are heterogeneous with the studies differing in their study design, provocation stimulus, and coronary spasm defini-tion. In particular, ergonovine provocation is less often used because it is no longer available in some countries and ace-tylcholine has become the preferred provocation stimulus. Despite these study differences, the importance of coronary spasm as a potential cause of MINOCA must not be over-looked as it appears to occur frequently and the use of calcium channel blockers is an independent determinant of survival in patients with coronary spasm.26

Thrombophilia DisordersAs summarized in Table 4, genetic thrombophilia disorders have been observed in MINOCA. Factor V Leiden is a single point mutation with a prevalence of 3% to 7% in Western populations27 but was observed in 12% of MINOCA patients. Furthermore, comparative studies with MI-CAD patients also report a higher prevalence in MINOCA (Mansourati et al28: 4.5% versus 12.1%; and Van de Water et al29: 4.3% versus 11.7%, respectively). Protein C & S deficiency are autosomal dominant disorders with a population prevalence of 0.1% to 1%,27 yet occur in 2.6% of MINOCA patients and similarly those with MI-CAD.30

These associations with the genetic thrombophilia dis-orders are based on small studies and require confirmation with larger multicenter prospective studies. Furthermore, investigation of acquired thrombophilia disorders should be considered because these may also occur in the context of acute MI and could exacerbate the genetic disorders. Irrespective of the prevalence of these thrombophilia disor-ders in MINOCA, their detection may influence subsequent management thereby justifying their routine evaluation in patients with MINOCA.

LimitationsThe results from this structured systematic review should be interpreted in the context of several potential limitations. First, the analysis is dependent on the available published data and is thus limited by publication bias, patient selec-tion bias, suboptimal definitions for cardiovascular risk fac-tors, retrospective analyses, and applicability of historical publications to contemporary practice. Second, there is sig-nificant heterogeneity between the studies included in the meta-analysis although the random effects model approach used in this study is less influenced by this pitfall. Third, the second objective, which focused on pathophysiological studies, did not lend itself to quantitative meta-analysis but a qualitative evaluation of published data. This was neces-sary because there were differences in patient recruitment, methods of investigation, and definitions of a positive result, for each of the respective studies involving CMR imag-ing, provocative spasm testing, and genetic thrombophilia disorders.

ConclusionsThis systematic review provides an important reference point for further research and development of MINOCA. It

Figure 4. Cardiac magnetic resonance (CMR) imaging findings in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA). Bar graph of published studies showing the diagnostic significance of CMR imaging in MINOCA patients. Data presented as percentage (%). AMI indicates acute myocardial infarction; MC, Myocarditis; TTC, Tako-tsubo cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; and NAD, diagnosis not available.




demonstrates that the condition is not uncommon, has no delineating clinical presentation, a guarded 12-month prog-nosis, and multiple potential causes with some amenable to specific therapies. Despite this, there are no guidelines regard-ing the management of these patients and limited insights into the contemporary management undertaken (if any) in affected patients. Based on the findings of this systematic review, we would propose that MINOCA be considered a working diag-nosis that requires routine evaluation for treatable underlying causes. This may include CMR imaging, provocative spasm testing, and thrombophilia assessment. Further research is required to define the optimal therapy in MINOCA patients who do not have an identifiable underlying cause. These strat-egies may potentially improve the guarded prognosis in these patients.

AcknowledgmentsDr Stuart Howell, Senior Statistician, provided statistical support; Mick Draper, Librarian, assisted with the literature search; and Thomas Sullivan, Senior Statistician, provided statistical support.

DisclosuresNone.

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CLINICAL PERSPECTIvEThis article systematically summarizes the published literature concerning patients with myocardial infarction with nonob-structive coronary arteries. These patients account for 6% of all those experiencing an acute myocardial infarct. Although they have a similar prevalence for many risk factors to those with myocardial infarction associated with obstructive coronary artery disease, in comparison they tend to be younger, more often female, and less likely to have hyperlipidemia. Moreover, although their prognosis is better than those with obstructive coronary artery disease, it remains guarded with an all-cause mortality of 4.7% (95% confidence interval, 2.6%–6.9%) at 12 months. The key clinical practice implication from this study is that myocardial infarction with nonobstructive coronary arteries should be considered as a working diagnosis that necessi-tates further investigation for an underlying cause (ie, similar to that required for a heart failure diagnosis). Important causes include myocarditis, Tako-tsubo cardiomyopathy, vasospastic angina, and hereditary thrombophilia disorders, all of which require different management strategies. Cardiac magnetic resonance imaging is a useful initial investigation to delineate some of these causes. Assessment for coronary artery spasm and thrombophilia disorders should also be considered. The importance of identifying these causes resides with the potential to use effective therapies that otherwise may not have been considered and that may impact on prognosis (eg, calcium channel blockers for coronary spasm). Accordingly, there is the potential to reduce the guarded prognosis in these patients.

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SUPPLEMENTAL MATERIAL

Systematic Review of patients presenting with suspected Myocardial Infarction

and Non-Obstructive Coronary Arteries (MINOCA)

Authors: Sivabaskari Pasupathy B.Sc (Hons), Tracy Air B.A (Hons), M.Biostatistics,

Rachel P. Dreyer. B.Sc.(Hons) PhD, Rosanna Tavella B.Sc.(Hons) PhD, John F.

Beltrame B.Sc, BMBS, FRACP, PhD, FESC, FACC, FAHA, FCSANZ

Supplemental Table 1: Studies Utilised in MINOCA Systematic Analysis

Supplemental Table 2: Cardiovascular Risk Factor Definitions

Supplemental Table 3: Summary of CMR Findings in MINOCA Publications

Supplemental Figure 1: Prevalence of ‘normal’ smooth coronary arteries in

MINOCA

Supplemental Table 1: Studies Utilised in MINOCA Systematic Analysis

The publications listed below are those selected to evaluate objective A (clinical

characteristics) and B (pathophysiological mechanism) in this systematic review, as

summarised in Figure-1. Each study has been allocated a study number* and where

they are utilised in data analysis is detailed under Figures and Tables#.

Objective A: Clinical study cohort

Study

Number*

Study Reference

Figures &

Tables#

A-1 Agewall S, Daniel M, Eurenius L, Ekenback C, Skeppholm M, Malmqvist K, Hofman-

Bang C, Collste O, Frick M, Henareh L, Jernberg T, Tornvall P. Risk factors for

myocardial infarction with normal coronary arteries and myocarditis compared with

myocardial infarction with coronary artery stenosis. Angiology. 2012;63:500-503

Figure 2

Table 1

Appendix 3

A-2 Ahmar W, Lefkovits J. Acute st elevation myocardial infarction with angiographically

normal coronary arteries: Causes and outcomes. International Journal of Cardiology.

2008;128:131-133

Figure 2

Table 1

A-3 Aldrovandi A, Cademartiri F, Arduini D, Lina D, Ugo F, Maffei E, Menozzi A, Martini C,

Palumbo A, Bontardelli F, Gherli T, Ruffini L, Ardissino D. Computed tomography

coronary angiography in patients with acute myocardial infarction without significant

coronary stenosis. Circulation. 2012;126:3000-3007

Figure 2

A-4 Baccouche H, Mahrholdt H, Meinhardt G, Merher R, Voehringer M, Hill S, Klingel K,

Kandolf R, Sechtem U, Yilmaz A. Diagnostic synergy of non-invasive cardiovascular

magnetic resonance and invasive endomyocardial biopsy in troponin-positive patients

without coronary artery disease. Eur Heart J. 2009;30:2869-2879

Figure 2

A-5 Collste O, Sorensson P, Frick M, Agewall S, Daniel M, Henareh L, Ekenback C,

Eurenius L, Guiron C, Jernberg T, Hofman-Bang C, Malmqvist K, Nagy E, Arheden H,

Tornvall P. Myocardial infarction with normal coronary arteries is common and

associated with normal findings on cardiovascular magnetic resonance imaging:

Results from the stockholm myocardial infarction with normal coronaries study.

Journal of Internal Medicine. 2013;273:189-196

Figure 2

A-6 Frycz-Kurek AM, Gierlotka M, Gąsior M, Wilczek K, Lekston A, Kalarus Z, Polonski L.

Patients with no significant lesions in coronary arteries and st-segment elevation

myocardial infarction have worse outcome than patients with non-st-segment

elevation myocardial infarction: Analysis from pl-acs registry. Kardiol Pol.

2010;68:1211-1217

Figure 2&3

Table 1&2

A-7 Gehani AA, al-Mulla AW, Chaikhouni A, Ammar AS, Mahrous F, Tirkawi R, Ashraf A,

Hajar HA. Myocardial infarction with normal coronary angiography compared with

severe coronary artery disease without myocardial infarction: The crucial role of

smoking. J Cardiovasc Risk. 2001;8:1-8

Figure 2

Table 1

A-8 Gehrie ER, Reynolds HR, Chen AY, Neelon BH, Roe MT, Gibler WB, Ohman EM,

Newby LK, Peterson ED, Hochman JS. Characterization and outcomes of women and

Figure 2

Table 1&2

men with non-st-segment elevation myocardial infarction and nonobstructive coronary

artery disease: Results from the can rapid risk stratification of unstable angina

patients suppress adverse outcomes with early implementation of the acc/aha

guidelines (crusade) quality improvement initiative. Am Heart J. 2009;158:688-694

A-9 Germing A, Lindstaedt M, Ulrich S, Grewe P, Bojara W, Lawo T, Von Dryander S,

Jager D, Machraoui A, Mugge A, Lemke B. Normal angiogram in acute coronary

syndrome - preangiographic risk stratification, angiographic findings and follow-up.

International Journal of Cardiology. 2005;99:19-23

Figure 2&3

A-10 Hamdan R, Frangieh A, Kadri Z, Hajje F, Azar R, Salame E, Jaoude SA, Kassab R,

Badaoui G. What do we know about myocardial infarction with normal coronary

arteries? Gazzetta Medica Italiana Archivio per le Scienze Mediche. 2012;171:7-12

Figure 2

Table 1&2

A-11 Hochman JS, Tamis JE, Thompson TD, Weaver WD, White HD, Van de Werf F,

Aylward P, Topol EJ, Califf RM. Sex, clinical presentation, and outcome in patients

with acute coronary syndromes. Global use of strategies to open occluded coronary

arteries in acute coronary syndromes iib investigators. N Engl J Med. 1999;341:226-

232

Figure 2&3

A-12 Hung MJ, Cherng WJ, Kuo LT, Wang CH. Acute myocardial infarction in taiwanese

with angiographically normal coronary arteries: Role of coronary artery spasm. Acta

Cardiologica Sinica. 2003;19:31-38

Figure 2

Table 1

A-13 Kang WY, Jeong MH, Ahn YK, Kim JH, Chae SC, Kim YJ, Hur SH, Seong IW, Hong

TJ, Choi DH, Cho MC, Kim CJ, Seung KB, Chung WS, Jang YS, Rha SW, Bae JH,

Cho JG, Park SJ. Are patients with angiographically near-normal coronary arteries

who present as acute myocardial infarction actually safe? International Journal of

Cardiology. 2011;146:207-212

Figure 2&3

Table 1&2

A-14 Larsen AI, Galbraith PD, Ghali WA, Norris CM, Graham MM, Knudtson ML.

Characteristics and outcomes of patients with acute myocardial infarction and

angiographically normal coronary arteries. American Journal of Cardiology.

2005;95:261-263

Figure 2

Table 1&2

Appendix 3

A-15 Larsen AI, Nilsen DW, Yu J, Mehran R, Nikolsky E, Lansky AJ, Caixeta A, Parise H,

Fahy M, Cristea E, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D,

Stone GW. Long-term prognosis of patients presenting with st-segment elevation

myocardial infarction with no significant coronary artery disease (from the horizons-

ami trial). Am J Cardiol. 2013;111:643-648

Figure 2

Table 1&2

A-16 Larson DM, Menssen KM, Sharkey SW, Duval S, Schwartz RS, Harris J, Meland JT,

Unger BT, Henry TD. "False-positive" cardiac catheterization laboratory activation

among patients with suspected st-segment elevation myocardial infarction. Journal of

the American Medical Association. 2007;298:2754-2760

Figure 2

A-17 Leurent G, Langella B, Fougerou C, Lentz PA, Larralde A, Bedossa M, Boulmier D, Le

Breton H. Diagnostic contributions of cardiac magnetic resonance imaging in patients

presenting with elevated troponin, acute chest pain syndrome and unobstructed

coronary arteries. Archives of Cardiovascular Diseases. 2011;104:161-170

Figure 2

A-18 Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U. Coronary

artery spasm as a frequent cause of acute coronary syndrome: The caspar (coronary

artery spasm in patients with acute coronary syndrome) study. J Am Coll Cardiol.

Figure 2&3

2008;52:523- 527

A-19 Patel MR, Chen AY, Peterson ED, Newby LK, Pollack CV, Brindis RG, Gibson CM,

Kleiman NS, Saucedo JF, Bhatt DL, Gibler WB, Ohman EM, Harrington RA, Roe MT.

Prevalence, predictors, and outcomes of patients with non-st-segment elevation

myocardial infarction and insignificant coronary artery disease: Results from the can

rapid risk stratification of unstable angina patients suppress adverse outcomes with

early implementation of the acc/aha guidelines (crusade) initiative. Am Heart J.

2006;152:641-647

Figure 2

Table 1&2

A-20 Rhew SH, Ahn Y, Kim MC, Jang SY, Cho KH, Hwang SH, Lee MG, Ko JS, Park KH,

Sim DS, Yoon NS, Yoon HJ, Kim KH, Hong YJ, Park HW, Kim JH, Jeong MH, Cho

JG, Park JC, Kang JC. Is myocardial infarction in patients without significant stenosis

on a coronary angiogram as benign as believed? Chonnam medical journal.

2012;48:39-46

Figure 2

Table 1&2

A-21 Rossini R, Capodanno D, Lettieri C, Musumeci G, Limbruno U, Molfese M, Spatari V,

Calabria P, Romano M, Tarantini G, Gavazzi A, Angiolillo DJ. Long-term outcomes of

patients with acute coronary syndrome and nonobstructive coronary artery disease.

Am J Cardiol. 2013;112:150-155

Figure 3

Appendix 3

A-22 Sharifi M, Frohlich TG, Silverman IM. Myocardial infarction with angiographically

normal coronary arteries. Chest. 1995;107:36-40

Figure 2&3

Table 1

Appendix 3

A-23 Strunk B, Shaw RE, Bull S, Adams J, Baer M, Gershengorn K, Kao A, Keeffe B, Sklar

J, Sperling D, Sperling R, Wexman M, Young J. High incidence of focal left ventricular

wall motion abnormalities and normal coronary arteries in patients with myocardial

infarctions presenting to a community hospital. Journal of Invasive Cardiology.

2006;18:376-381

Figure 2&3

Table 1

A-24 Sun J, Zhang W, Zeng Q, Dong S, Sun X. Three-year follow-up in patients with acute

coronary syndrome and normal coronary angiography. Coronary Artery Disease.

2012;23:162-166

Figure 2&3

A-25 Tritto I, Bovelli D, Castelli M, Patella M, Cerasa MF, Ciliberti G, Bazzucchi M, Dominici

M, Boschetti E, Ambrosio G. Comparison between takotsubo and acute myocardial

infarction with normal coronary arteries: A retrospective study. European Heart

Journal. 2011;32:1058-1059

Figure 2

A-26 Uchida Y, Uchida Y, Sakurai T, Kanai M, Shirai S, Oshima T, Koga A, Matsuyama A,

Tabata T. Fluffy luminal surface of the non-stenotic culprit coronary artery in patients

with acute coronary syndrome: An angioscopic study. Circ J. 2010;74:2379-2385

Figure 2&3

A-27 Widimsky P, Stellova B, Groch L, Aschermann M, Branny M, Zelizko M, Stasek J,

Formanek P. Prevalence of normal coronary angiography in the acute phase of

suspected st-elevation myocardial infarction: Experience from the prague studies.

Can J Cardiol. 2006;22:1147-1152

Figure 2

Table 1

Appendix 3

A-28 Zimmerman FH, Cameron A, Fisher LD, Grace NG. Myocardial infarction in young

adults: Angiographic characterization, risk factors and prognosis (coronary artery

surgery study registry). Journal of the American College of Cardiology. 1995;26:654-

661

Figure 2

Objective-B Pathophysiology Study Cohort

Study

Number*

Study Reference

Figures &

Tables#

B-1 Abid L, Bahloul A, Frikha Z, Mallek S, Abid D, Akrout M, Hentati M,

Kammoun S. Myocardial infarction and normal coronary arteries: The

experience of the cardiology department of sfax, tunisia. Internal Medicine.

2012;51:1959-1967

Table 3&4

B-2 Ahmed H, Mohammed N, Alsaileek A. The role of delayed contrast-

enhanced cardiac magnetic resonance in the differential diagnosis between

myocarditis and myocardial infarction. Journal of the Saudi Heart

Association. 2010;22:103

Figure 4

Appendix 4

B-3 Aldrovandi A, Cademartiri F, Arduini D, Lina D, Ugo F, Maffei E, Menozzi A,

Martini C, Palumbo A, Bontardelli F, Gherli T, Ruffini L, Ardissino D.

Computed tomography coronary angiography in patients with acute

myocardial infarction without significant coronary stenosis. Circulation.

2012;126:3000-3007

Figure 4

Appendix 4

B-4 Ammann P, Marschall S, Kraus M, Schmid L, Angehrn W, Krapf R, Rickli H.

Characteristics and prognosis of myocardial infarction in patients with

normal coronary arteries. Chest. 2000;117:333-338

Table 3

B-5 Assomull RG, Lyne JC, Keenan N, Gulati A, Bunce NH, Davies SW,

Pennell DJ, Prasad SK. The role of cardiovascular magnetic resonance in

patients presenting with chest pain, raised troponin, and unobstructed

coronary arteries. European Heart Journal. 2007;28:1242-1249

Figure 4

Appendix 4

B-6 Avegliano GP, Huguet M, Costabel JP, Kuschnir P, Thierer J, de Lima AA,

Sanchez G, Petit M, Frangi AA, Ronderos R. Cardiac magnetic resonance

imaging in patients with chest pain, high troponin levels and absence of

coronary artery obstruction. Revista Argentina de Cardiologia. 2011;79:226-

230

Figure 4

Appendix 4

B-7 Baccouche H, Mahrholdt H, Meinhardt G, Merher R, Voehringer M, Hill S,

Klingel K, Kandolf R, Sechtem U, Yilmaz A. Diagnostic synergy of non-

invasive cardiovascular magnetic resonance and invasive endomyocardial

biopsy in troponin-positive patients without coronary artery disease. Eur

Heart J. 2009;30:2869-2879

Figure 4

Appendix 4

B-8 Bellenger NG, Peebles C, Harden S, Dawkins K, Curzen N. Troponin-

positive chest pain with unobstructed coronary arteries: A role for delayed

enhanced cardiovascular magnetic resonance in the diagnosis of non-st

elevation myocardial infarction. J Invasive Cardiol. 2006;18:594-598

Figure 4

Appendix 4

B-9 Bhatti L, Kim HW, Parker M, Macwar R, Kim RJ. Rate of acute myocardial

infarction in patients with troponin-positive chest pain and unobstructed

Figure 4

Appendix 4

coronary arteries. Journal of Cardiovascular Magnetic Resonance.

2013;15:380-381

B-10 Bory M, Joly P, Bonnet JL, Djiane P, Serradimigni A. Methergin(registered

trademark) testing with angiographically normal coronary arteries. American

Journal of Cardiology. 1988;61:298-302

Table 3

Appendix 4

B-11 Boussel L, Gamondes D, Staat P, Elicker BM, Revel D, Douek P. Acute

chest pain with normal coronary angiogram: Role of contrast-enhanced

multidetector computed tomography in the differential diagnosis between

myocarditis and myocardial infarction. Journal of Computer Assisted

Tomography. 2008;32:228-232

Figure 4

Appendix 4

B-12 Brecker SJD, Stevenson RN, Roberts R, Uthayakumar S, Timmis AD,

Balcon R. Acute myocardial infarction in patients with normal coronary

arteries. British Medical Journal. 1993;307:1255-1256

Table 4

B-13 Cheriaa S, Passefort S, Safar B, Payot L, Cymbalista M, Cattan S, Gryman

R, Milleron O. Diagnostic value of cardiac magnetic resonance imaging in

patients presenting with chest pain, troponin elevation and unobstructed

coronary arteries. European Heart Journal. 2012;33:50

Figure 4

Appendix 4

B-14 Chopard R, Jehl J, Dutheil J, Genon VD, Seronde MF, Kastler B, Schiele F,

Meneveau N. Evolution of acute coronary syndrome with normal coronary

arteries and normal cardiac magnetic resonance imaging. Archives of

Cardiovascular Diseases. 2011;104:509-517

Figure 4

Appendix 4

B-15 Christiansen JP, Edwards C, Sinclair T, Armstrong G, Scott A, Patel H, Hart

H. Detection of myocardial scar by contrast-enhanced cardiac magnetic

resonance imaging in patients with troponin-positive chest pain and minimal

angiographic coronary artery disease. Am J Cardiol. 2006;97:768-771

Figure 4

Appendix 4

B-16 Collste O, Sorensson P, Frick M, Agewall S, Daniel M, Henareh L,

Ekenback C, Eurenius L, Guiron C, Jernberg T, Hofman-Bang C, Malmqvist

K, Nagy E, Arheden H, Tornvall P. Myocardial infarction with normal

coronary arteries is common and associated with normal findings on

cardiovascular magnetic resonance imaging: Results from the stockholm

myocardial infarction with normal coronaries study. Journal of Internal

Medicine. 2013;273:189-196

Figure 4

Appendix 4

B-17 Da Costa A, Isaaz K, Faure E, Mourot S, Cerisier A, Lamaud M. Clinical

characteristics, aetiological factors and long-term prognosis of myocardial

infarction with an absolutely normal coronary angiogram: A 3-year follow-up

study of 91 patients. European Heart Journal. 2001;22:1459-1465

Table 3&4

B-18 Da Costa A, Tardy B, Haouchette K, Mismetti P, Cerisier A, Lamaud M,

Guyotat D, Isaaz K. Long term prognosis of patients with myocardial

infarction and normal coronary angiography: Impact of inherited coagulation

Table 3&4

disorders. Thrombosis and Haemostasis. 2004;91:388-393

B-19 Dacosta A, Tardy-Poncet B, Isaaz K, Cerisier A, Mismetti P, Simitsidis S,

Reynaud J, Tardy B, Piot M, Decousus H, Guyotat D. Prevalence of factor v

leiden (apcr) and other inherited thrombophilias in young patients with

myocardial infarction and normal coronary arteries. Heart. 1998;80:338-340

Table 4

B-20 Eitel I, Behrendt F, Schindler K, Kivelitz D, Gutberlet M, Schuler G, Thiele

H. Differential diagnosis of suspected apical ballooning syndrome using

contrast-enhanced magnetic resonance imaging. European Heart Journal.

2008;29:2651-2659

Figure 4

Appendix 4

B-21 Fukai T, Koyanagi S, Takeshita A. Role of coronary vasospasm in the

pathogenesis of myocardial infarction: Study in patients with no significant

coronary stenosis. Am. Heart J. 1993;126:1305-1311

Table 3

B-22 Gerbaud E, Harcaut E, Coste P, Erickson M, Lederlin M, Labeque JN,

Perron JM, Cochet H, Dos Santos P, Durrieu-Jais C, Laurent F, Montaudon

M. Cardiac magnetic resonance imaging for the diagnosis of patients

presenting with chest pain, raised troponin, and unobstructed coronary

arteries. International Journal of Cardiovascular Imaging. 2012;28:783-794

Figure 4

Appendix 4

B-23 Habibian M, Luis S, Luis C, Courtney A, Hamilton-Craig C, Strugnell W,

Hansen M, Slaughter R, Raffel O. Comparison of the utility of transthoracic

echocardiographic and cardiac magnetic resonance imaging in patients

presenting with troponin positive chest pain with unobstructed coronary

arteries. Heart Lung and Circulation. 2011;20:S165

Figure 4

Appendix 4

B-24 Hung MJ, Cherng WJ, Kuo LT, Wang CH. Acute myocardial infarction in

taiwanese with angiographically normal coronary arteries: Role of coronary

artery spasm. Acta Cardiologica Sinica. 2003;19:31-38

Table 3

B-25 Indrajith M, Butterly S, Amin J, Jesuthsan B, Ng A, Ngai S, Wang W. The

utility of cardiac mri in patients presenting with myocardial injury without

obstructive coronary artery disease. Heart Lung and Circulation.

2011;20:S195

Figure 4

Appendix 4

B-26 Kim MH, Park EH, Yang DK, Park TH, Kim SG, Yoon JH, Cha KS, Kum DS,

Kim HJ, Kim JS. Role of vasospasm in acute coronary syndrome - insights

from ergonovine stress echocardiography. Circulation Journal. 2005;69:39-

43

Table 3

B-27 Kossowsky WA, Lyon AF, Chou SY. Acute non-q wave cocaine-related

myocardial infarction. Chest. 1989;96:617-621

Table 3

B-28 Lande G, Dantec V, Trossaert M, Godin JF, Le Marec H. Do inherited

prothrombotic factors have a role in myocardial infarction with normal

coronary arteriogram? J Intern Med. 1998;244:543-544

Table 4

B-29 Laraudogoitia Zaldumbide E, Perez-David E, Larena JA, Velasco del

Castillo S, Rumoroso Cuevas JR, Onaindia JJ, Lekuona Goya I, Garcia-

Fernandez MA. The value of cardiac magnetic resonance in patients with

acute coronary syndrome and normal coronary arteries. Rev Esp Cardiol.

2009;62:976-983

Figure 4

Appendix 4

B-30 Legrand V, Deliege M, Henrard L. Patients with myocardial infarction and

normal coronary arteriogram. Chest. 1982;82:678-685

Table 3

B-31 Leurent G, Langella B, Fougerou C, Lentz PA, Larralde A, Bedossa M,

Boulmier D, Le Breton H. Diagnostic contributions of cardiac magnetic

resonance imaging in patients presenting with elevated troponin, acute

chest pain syndrome and unobstructed coronary arteries. Archives of

Cardiovascular Diseases. 2011;104:161-170

Figure 4

Appendix 4

B-32 Luis SA, Luis CR, Habibian M, Courtney A, Hamilton-Craig C, Strugnell W,

Poon K, Slaughter R, Raffel OC. Comparison of the diagnostic role of

transthoracic echocardiographic and cardiac magnetic resonance imaging

in patients presenting with troponin positive chest pain and unobstructed

coronary arteries. European Heart Journal, Supplement. 2012;14:A17

Figure 4

Appendix 4

B-33 Mahmoudi M, Harden SP, Abid N, Peebles C, Nicholas Z, Jones T,

McKenzie D, Curzen N. Troponin-positive chest pain with unobstructed

coronary arteries: Definitive differential diagnosis using cardiac mri. British

Journal of Radiology. 2012;85:e461-e466

Figure 4

Appendix 4

B-34 Mansourati J, Da Costa A, Munier S, Mercier B, Tardy B, Ferec C, Isaaz K,

Blanc JJ. Prevalence of factor v leiden in patients with myocardial infarction

and normal coronary angiography. Thrombosis and Haemostasis.

2000;83:822-825

Table 4

B-35 McAlindo E, Port AG, Chiarelll A, Cincott G, Lawto C, Bucciarelli-Ducc C.

The role of cardiovascular mri in troponin positive acute coronary

syndromes with unobstructed coronary arteries. Heart. 2012;98:A72-A73

Figure 4

Appendix 4

B-36 Monney PA, Sekhri N, Burchell T, Knight C, Davies C, Deaner A, Sheaf M,

Baithun S, Petersen S, Wragg A, Jain A, Westwood M, Mills P, Mathur A,

Mohiddin SA. Acute myocarditis presenting as acute coronary syndrome:

Role of early cardiac magnetic resonance in its diagnosis. Heart.

2011;97:1312-1318

Figure 4

Appendix 4

B-37 Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U. Coronary

artery spasm as a frequent cause of acute coronary syndrome: The caspar

(coronary artery spasm in patients with acute coronary syndrome) study. J Am Coll

Cardiol. 2008;52:523- 527

Table 3

B-38 Pellaton C, Monney P, Ludman AJ, Schwitter J, Eeckhout E, Hugli O, Muller

O. Acute coronary syndromes or myocarditis in young people: A difficult

Figure 4

Appendix 4

daily diagnostic challenge. European Heart Journal. 2012;33:624

B-39 Pelloni E, Andriani M, Bodoni LL, Grasso C, Fanelli AL, Iacovino M,

Marchetti M, Davini O, Marra S. Patients with acute coronary syndrome and

normal coronary arteries: The role of cardiac magnetic resonance. Giornale

Italiano di Cardiologia. 2012;13:177S

Figure 4

Appendix 4

B-40 Raymond R, Lynch J, Underwood D, Leatherman J, Razavi M. Myocardial

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1988;11:471-477

Table 3

B-41 Reynolds HR, Srichai MB, Iqbal SN, Slater JN, Mancini GBJ, Feit F, Pena-

Sing I, Axel L, Attubato MJ, Yatskar L, Kalhorn RT, Wood DA, Lobach IV,

Hochman JS. Mechanisms of myocardial infarction in women without

angiographically obstructive coronary artery disease. Circulation.

2011;124:1414-1425

Figure 4

Appendix 4

B-42 Salem BI, Haikal M, Zambrano A. Acute myocardial infarction with 'normal'

coronary arteries: Clinical and angiographic profiles, with ergonovine

testing. Texas Heart Institute Journal. 1985;12:1-7

Table 3

B-43 Swarbrick D, Das R, Child NM. Diagnostic yield of early versus late

outpatient cardiac mri in suspected acute coronary syndrome in patients

with normal coronary arteries. Journal of Cardiovascular Magnetic

Resonance. 2013;15:53-54

Figure 4

Appendix 4

B-44 Van De Water NS, French JK, Lund M, Hyde TA, White HD, Browett PJ.

Prevalence of factor v leiden and prothrombin variant g20210a in patients

age <50 years with no significant stenoses at angiography three to four

weeks after myocardial infarction. Journal of the American College of

Cardiology. 2000;36:717-722

Table 4

B-45 Verheugt FW, ten Cate JW, Sturk A, Imandt L, Verhorst PM, van Eenige

MJ, Verwey W, Roos JP. Tissue plasminogen activator activity and

inhibition in acute myocardial infarction and angiographically normal

coronary arteries. Am J Cardiol. 1987;59:1075-1079

Table 3

B-46 Wang C-H, Kuo L-T, Hung M-J, Cherng W-J. Coronary vasospasm as a

possible cause of elevated cardiac troponin i in patients with acute coronary

syndrome and insignificant coronary artery disease. Am Heart J.

2002;144:275-281

Table 3

Supplemental Table 2: Cardiovascular Risk Factor Definitions

Risk factor

Self reported

Publications

Specific Definition

Publications

Not specified

Publications

Hypertension A-6, A-7, A-27 Admission BP <140/80mmHg

A-6, A-12, A-13, A-15, A-20,

A-27

A-1, A-2, A-8, A-10, A-14,

A-19

Hyperlipidemia A-6, A-15 Total cholesterol >240mg/dl

A-17

Total cholesterol >93.6mg/dl

A-18, A-25

A-1, A-2, A-8, A-10, A-13,

A-14, A-19, A-20, A-27

Diabetes A-17, A-25 Fasting glucose >126mg/dl

A-6, A-13, A-20

A-1, A-2, A-8. A-10, A-14,

A-15, A-27

Current Smoker A-7, A-8, A-19, A-20 10 cigs/day for > 1 year

A-17

A-1, A-2, A-6, A-10, A-13,

A-14, A-15, A-27

Family History - -

A-1, A-2, A-10, A-13, A-14,

A-29, A-20,

Supplemental Table 3: Summary of CMR Findings in MINOCA Publications

Study Features

MI Myocardit

is Takotsubo HCM DCM Other

No abnormali

ty

All

(Diagnosis/Total

MINOCA CMR)

24%

429/1,801

33%

562/1,676

18%

277/1,529

3%

38/1,074

2%

12/625

7%

50/760

26%

415/1,592

Early ( <6 wks)

(Diagnosis/Total

MINOCA CMR)

24%

285/1,167

38%

400/1,066

16%

171/1,083

3%

23/779

2%

8/358

6%

30/480

21%

229/1,066

Late (>6 Wks)

(Diagnosis/Total

MINOCA CMR)

18%

52/290

23%

66/290

27%

41/151

NE

2%

1/60

NE 56%

130/231

Undefined

(Diagnosis/Total

MINOCA CMR)

27%

92/344

30%

96/320

22%

65/295

5%

15/295

1%

3/207

7%

20/280

19%

56/295

Data represented as % (n). MI, Acute Myocardial Infarction; HCM, Hypertrophic

cardiomyopathy; DCM, Dilated cardiomyopathy; MINOCA, Myocardial Infarction with Non

Obstructive Coronary Arteries; CMR, Cardiac Magnetic Resonance Imaging; NE, Not

examined.

Supplemental Figure 1: Prevalence of ‘normal’ smooth coronary arteries in

MINOCA

0.0 0.2 0.4 0.6 0.8 1.0

Overall (I-squared = 84.6%, p=0.000)

Sharifi, 1995

Larsen, 2005

Widimsky, 2006

Agewall, 2012

Rossini, 2013 0.47 (0.41,0.53) 28.48

0.46 (0.17,0.77) 10.29

0.74 (0.57, 0.87) 20.22

0.37 (0.34, 0.41) 30.06

0.58 (0.27, 0.85) 10.94


0.51 (0.39, 0.61) 100.00

Sivabaskari Pasupathy, Tracy Air, Rachel P. Dreyer, Rosanna Tavella and John F. BeltrameNonobstructive Coronary Arteries

Systematic Review of Patients Presenting With Suspected Myocardial Infarction and

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2015 American Heart Association, Inc. All rights reserved.

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