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Risk Factors and Markers for Acute Myocardial Infarction With Angiographically Normal Coronary Arteries

      Myocardial Infarction with normal coronary arteries (MINCA) is common with a prevalence of 1% to 12% of all myocardial infarctions. The pathogenic mechanisms of MINCA are still unknown, but endothelial dysfunction has been suggested as a possible cause. To investigate risk factors and markers for MINCA, we conducted a case–control study. Considering the reported low prevalence of classical risk factors for coronary heart disease (CHD) in some but not all studies, our hypothesis was that endothelial function and intima–media thickness (IMT) were better, respectively lower, than CHD controls. One hundred patients with MINCA fulfilling diagnostic criteria according to the European Society of Cardiology/American Collage of Cardiology/American Heart Association universal definition of myocardial infarction with myocarditis excluded by cardiac magnetic resonance imaging were investigated. Risk factors, endothelial function (EndoPAT), and IMT were compared to gender- and age-matched patients with myocardial infarction and CHD, respectively healthy controls. Smoking, hypertension, impaired glucose tolerance and diabetes mellitus, inflammatory disease, and psychiatric disorders were more common in patients with MINCA than in healthy controls. In contrast to patients with CHD, the lipid profile was antiatherogenic with low low-density lipoprotein and high high-density lipoprotein cholesterol. There were no major differences between the groups regarding endothelial function and IMT that were in the normal range. In conclusion, the present study showed that MINCA was associated with many established cardiovascular risk factors without major differences in atherosclerosis markers. MINCA patients recalled a high prevalence of emotional stress before admission that together with previous psychiatric vulnerability and female gender speaks strongly in favor of Takotsubo syndrome being an important cause of MINCA.
      To investigate risk factors and markers for myocardial infarction with normal coronary arteries (MINCA), we conducted a case–control study. In the Stockholm Myocardial Infarction with Normal Coronaries (SMINC) study, we compared patients with MINCA with age- and gender-matched patients with coronary heart disease (CHD) and healthy controls. Considering a reported low prevalence of classical risk factors for CHD in some but not all studies,
      • Larsen A.I.
      • Galbraith P.D.
      • Ghali W.A.
      • Norris C.M.
      • Graham M.M.
      • Knudtson M.L.
      APPROACH Investigators
      Characteristics and outcomes of patients with acute myocardial infarction and angiographically normal coronary arteries.
      • Larsen A.I.
      • Nilsen D.W.
      • Yu J.
      • Mehran R.
      • Nikolsky E.
      • Lansky A.J.
      • Caixeta A.
      • Parise H.
      • Fahy M.
      • Cristea E.
      • Witzenbichler B.
      • Guagliumi G.
      • Peruga J.Z.
      • Brodie B.R.
      • Dudek D.
      • Stone G.W.
      Long-term prognosis of patients presenting with ST-segment elevation myocardial infarction with no significant coronary artery disease (from the HORIZONS-AMI trial).
      • Raymond R.
      • Lynch J.
      • Underwood D.
      • Leatherman J.
      • Razavi M.
      Myocardial infarction and normal coronary arteriography: a 10 year clinical and risk analysis of 74 patients.
      our hypothesis was that endothelial function and intima–media thickness (IMT) were better, respectively lower, than CHD controls.

      Methods

      From June 2007 to May 2011, a total of 176 patients were screened at five coronary care units in the Stockholm metropolitan area. Patients aged from 35 to 70 years fulfilling the diagnostic criteria of acute myocardial infarction and a coronary angiogram with no or minimal signs of atheromatosis were eligible for the study; thus patients with Takotsubo Syndrome (TS) were included. Minimal atheromatosis was defined as small irregularities in the coronary vessel wall, giving rise to <30% reduction of the vessel lumen with all coronary angiograms independently examined by a second angiographer. Acute myocardial infarction was diagnosed according to the European Society of Cardiology/American Collage of Cardiology/American Heart Association universal definition of myocardial infarction,
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • Simoons M.L.
      • Chaitman B.R.
      • White H.D.
      • Thygesen K.
      • Alpert J.S.
      • White H.D.
      • Jaffe A.S.
      • Katus H.A.
      • Apple F.S.
      • Lindahl B.
      • Morrow D.A.
      • Chaitman B.R.
      • Clemmensen P.M.
      • Johanson P.
      • Hod H.
      • Underwood R.
      • Bax J.J.
      • Bonow J.J.
      • Pinto F.
      • Gibbons R.J.
      • Fox K.A.
      • Atar D.
      • Newby L.K.
      • Galvani M.
      • Hamm C.W.
      • Uretsky B.F.
      • Steg P.G.
      • Wijns W.
      • Bassand J.P.
      • Menasche P.
      • Ravkilde J.
      • Ohman E.M.
      • Antman E.M.
      • Wallentin L.C.
      • Armstrong P.W.
      • Simoons M.L.
      • Januzzi J.L.
      • Nieminen M.S.
      • Gheorghiade M.
      • Filippatos G.
      • Luepker R.V.
      • Fortmann S.P.
      • Rosamond W.D.
      • Levy D.
      • Wood D.
      • Smith S.C.
      • Hu D.
      • Lopez-Sendon J.L.
      • Robertson R.M.
      • Weaver D.
      • Tendera M.
      • Bove A.A.
      • Parkhomenko A.N.
      • Vasilieva E.J.
      • Mendis S.
      • Bax J.J.
      • Baumgartner H.
      • Ceconi C.
      • Dean V.
      • Deaton C.
      • Fagard R.
      • Funck-Brentano C.
      • Hasdai D.
      • Hoes A.
      • Kirchhof P.
      • Knuuti J.
      • Kolh P.
      • McDonagh T.
      • Moulin C.
      • Popescu B.A.
      • Reiner Z.
      • Sechtem U.
      • Sirnes P.A.
      • Tendera M.
      • Torbicki A.
      • Vahanian A.
      • Windecker S.
      • Morais J.
      • Aguiar C.
      • Almahmeed W.
      • Arnar D.O.
      • Barili F.
      • Bloch K.D.
      • Bolger A.F.
      • Botker H.E.
      • Bozkurt B.
      • Bugiardini R.
      • Cannon C.
      • de Lemos J.
      • Eberli F.R.
      • Escobar E.
      • Hlatky M.
      • James S.
      • Kern K.B.
      • Moliterno D.J.
      • Mueller C.
      • Neskovic A.N.
      • Pieske B.M.
      • Schulman S.P.
      • Storey R.F.
      • Taubert K.A.
      • Vranckx P.
      • Wagner D.R.
      Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial InfarctionAuthors/Task Force Members ChairpersonsBiomarker SubcommitteeECG SubcommitteeImaging SubcommitteeClassification SubcommitteeIntervention SubcommitteeTrials & Registries SubcommitteeTrials & Registries SubcommitteeTrials & Registries SubcommitteeTrials & Registries SubcommitteeESC Committee for Practice Guidelines (CPG)Document Reviewers
      Third universal definition of myocardial infarction.
      and the diagnosis of TS was based on the Mayo clinic diagnostic criteria.
      • Prasad A.
      • Lerman A.
      • Rihal C.S.
      Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction.
      Patients with a history of structural heart disease, CHD, pacemaker, severe chronic obstructive pulmonary disease with hypoxemia due to acute exacerbation, severe renal failure (serum creatinine >150 μmol/L), or lack of sinus rhythm on admission were excluded. Medical records of all patients were examined by a cardiologist unrelated to the study to exclude patients not fulfilling the criteria for myocardial infarction. The first 100 patients underwent computed tomography (CT) of the chest to exclude pulmonary embolism, but because all turned out negative, the protocol was changed to measurement of d-dimer and CT only in case of high suspicion of pulmonary embolism. Cardiac magnetic resonance (CMR) imaging was performed in 152 patients mainly to exclude myocarditis. The screening process, including CMR results, has been described.
      • 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.
      Subsequently a total of 100 patients with MINCA were included (Figure 1).
      Figure thumbnail gr1
      Figure 1CONSERT diagram of inclusion of patients with MINCA.
      All 100 patients with MINCA were individually matched by gender and age (within ± 5 years) to 2 control groups: patients with myocardial infarction with CHD and healthy controls. Matching CHD controls were recruited during hospital stay or at follow-up at the respective coronary care unit. Healthy controls were recruited from the Stockholm population registry (2007 to 2008) or from the computer-based medical record system TAKE CARE containing all citizens in Stockholm (2009 to 2012). The controls were selected randomly by date of birth and gender to match cases and contacted for participation by an invitation letter followed by a telephone call. Ten missing healthy controls were recruited among staff, relatives, and controls' friends. The participation proportion was approximately 50%. All healthy controls were free of symptomatic CHD and performed a normal exercise stress test.
      The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice and was approved by the Stockholm Ethics Committee. For inclusion, patients were asked to give written informed consent. Each patient was assigned a study identification number, and a record for information was established and kept secured at the Cardiology Unit at Karolinska University Hospital in Solna, Sweden.
      Smoking was defined as any active regular use and ex smoking as any history of regular use. Hypertension and hyperlipidemia were defined as previously diagnosed and medically treated. Diabetes mellitus was defined as previously diagnosed. Inflammatory diseases included diagnosed asthma, chronic obstructive pulmonary disease, rheumatologic diseases, pancreatitis, hepatitis, primary biliary cirrhosis, diverticulitis, collagenous colitis, and chronic tooth infection. Osteoarthritis was not included. Psychiatric disorders included depression, anxiety disorder, sleeping disorder, bipolar disorder, anorexia, social phobia, attention deficit disorder, and chronic fatigue syndrome. Thromboembolic disorders included previous thromboembolic diagnoses and known coagulopathy. Medical records were retrospectively examined by 2 of the authors (MD, CE) searching for evidence of physical and emotional stress precipitating the acute event and to confirm information regarding inflammatory diseases and psychiatric disorders.
      The following data, analyzed by routine clinical chemistry, were acquired from medical records at admission for patients with MINCA and CHD controls; plasma C-reactive protein (mg/l), fasting plasma triglycerides (mmol/l), fasting plasma cholesterol (mmol/l), fasting plasma low-density lipoprotein (LDL) cholesterol (mmol/l), and fasting plasma high-density lipoprotein (HDL) cholesterol (mmol/l). Peak troponin (I or T; μg/l) or high-sensitive troponin T (ng/l) ratios were calculated relatively to the upper limit of normal. An oral glucose tolerance test was performed 2 to 3 days after admission or 6 weeks after discharge by determination of the plasma concentration of glucose (mmol/l) 2 hours after ingestion of 75-g glucose dissolved in 150 ml of water. A plasma glucose concentration >7.8 mmol/l was considered impaired glucose tolerance (IGT). Corresponding blood chemistry was analyzed at the study visit for the healthy controls. Additional blood sampling was performed at the time of a 3-month follow-up visit for patients with MINCA and CHD controls and at the study visit for the healthy controls. Plasma was stored at −80 C for subsequent analyses. Analysis of NT-proBNP (ng/l) was performed 3 months after the acute event by an electrochemical luminescence technique (Roche) to determine myocardial dysfunction.
      Endothelial function was measured 3 months after the acute event with EndoPAT (Itamar-Medical Ltd), a specialized device for assessment of endothelial function. The EndoPAT system is based on peripheral arterial tone (PAT) signal technology; a noninvasive plethysmographic method measuring pulsatile volume changes in the digital bed. The test is user independent and automatically calculated and was performed in a thermoneutral and quiet surrounding avoiding pretest consumption of caffeine and smoking. The test quantifies endothelium-mediated changes in vascular tone elicited by a 5-minute occlusion of the brachial artery using a standard blood pressure cuff inflated to a suprasystolic pressure. When the cuff is deflated, the surge
      • Poredos P.
      • Jezovnik M.K.
      Testing endothelial function and its clinical relevance.
      of blood flow causes an endothelium-dependent flow-mediated dilatation leading to reactive hyperemia and an increase in the PAT signal amplitude. Measurements from the contralateral probe are used to control for non–endothelial-dependent changes in vascular tone. The postocclusion to preocclusion ratio, called EndoScore or reactive hyperemia index (RHI), is calculated with specialized software.
      • Poredos P.
      • Jezovnik M.K.
      Testing endothelial function and its clinical relevance.
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • Creager M.A.
      • Deanfield J.
      • Ganz P.
      • Hamburg N.M.
      • Luscher T.F.
      • Shechter M.
      • Taddei S.
      • Vita J.A.
      • Lerman A.
      The assessment of endothelial function: from research into clinical practice.
      Two-dimensional images of the left and right common carotid artery (CCA) were acquired, using an ultrasound scanner (Vivid 7; General Electric [GE], New York) equipped with a 12-MHz transducer, 3 months after the acute event. From each CCA, a long-axis cine loop of 3 beats and 3 diastolic images at the time of the electrocardiographic R-wave was stored digitally on magnet-optic discs for offline analysis. The IMT of the CCA far wall was measured in 3 diastolic images from each side using GE semiautomatic IMT analysis software. A 10-mm region of interest was manually placed starting 1 cm proximal to the carotid bulb. The intima–media borders of the far wall, toward the lumen and the adventitia, were identified automatically by the program. Manual correction was not performed, and in case of suboptimal tracking, the region of interest could be adjusted somewhat or another diastolic frame chosen. IMT was calculated as mean of 3 semiautomatic measurements.
      • Vermeersch S.J.
      • Rietzschel E.R.
      • De Buyzere M.L.
      • Van Bortel L.M.
      • D'Asseler Y.
      • Gillebert T.C.
      • Verdonck P.R.
      • Segers P.
      Validation of a new automated IMT measurement algorithm.
      A mean of the results of IMT of the left and right CCA was calculated and used for comparison between the groups.
      The primary end point was endothelial function measured by EndoPAT. A sample size estimation, using RHI as a continuous variable, was performed after investigation of 41 patients with MINCA and 23 CHD controls that showed an absolute 0.27% larger RHI in patients with MINCA. A number of 100 patients with MINCA and 100 CHD controls were calculated to give the study a power of 83% to show that patients with MINCA had larger RHI than CHD controls (p <0.05).
      Values are presented as mean ± standard deviation (SD), percent (%), or interquartile range (IQR). Group-wise comparisons were made by the Mann–Whitney U test or the Kruskal–Wallis test for continuous variables. A chi-square test was used for categorical data. A p value of <0.05 was considered significant.

      Results

      The mean age of patients with MINCA and controls was 58 to 59 years. The vast majority were women (72%). Twenty-five percent of the patients with MINCA fulfilled all Mayo Clinic diagnostic criteria for TS. Another 19% showed less prominent abnormal ventricular wall motion (regional hypokinesia/akinesia/dyskinesia) on imaging with left ventriculography or echocardiography, suggestive of TS in regression or a milder state. Fifty-six percent of all patients with MINCA had a history of physical or emotional stress before admission. Eighteen percent of the patients with MINCA, respectively 41% of the CHD controls presented with ST-elevation. The relative troponin levels were similar in CHD controls compared to patients with MINCA (Table 1).
      Table 1Characteristics of myocardial infarction with normal coronary arteries (MINCA) patients compared to coronary heart disease (CHD), respectively healthy controls
      MINCA

      n=100
      CHD

      n=100
      Healthy control

      n=100
      MINCA vs CHD

      (p-value)
      MINCA vs control

      (p-value)
      Age (years)58 ± 859 ± 859 ± 8--
      Women72 %72 %72 %--
      BMI (kg/m2)26 ± 527 ± 525 ± 40.0370.557
      Heart rate (bpm)74 ± 1575 ± 1469 ± 150.706n.a.
      Systolic blood pressure (mm Hg)147 ± 27149 ± 27128 ± 170.492n.a.
      Troponin, ratio to normal110 ± 176275 ± 560-0.642-
      C-reactive protein > 5 μg/L16 %13 %5 %0.6990.010
      Smoker21 %33 %7 %0.0560.004
      Ex-smoker29 %34 %40 %0.4470.102
      Hypertension37 %46 %17 %0.1960.001
      Hyperlipidemia9 %20 %4 %0.0270.152
      Diabetes mellitus4 %10 %0 %0.0960.043
      Impaired glucose tolerance and diabetes mellitus39 %55 %20 %0.0290.004
      Migraine14 %13 %13 %0.8360.836
      Thrombembolic disorder6 %1 %2 %0.0540.149
      Inflammation30 %20 %10 %0.102<0.001
      Psychiatric disorder20 %11 %3 %0.079<0.001
      Triglycerides (mmol/L)

      (mg/dl)
      1.0 ± 0.5

      89 ± 44
      1.4 ± 0.7

      124 ± 62
      1.0 ± 0.6

      89 ± 53
      <0.0010.096
      Cholesterol (mmol/L)

      (mg/dl)
      5.1 ± 1.0

      197 ± 39
      5.4 ± 1.1

      209 ± 43
      5.6 ± 1.0

      217 ± 39
      0.092<0.001
      Low density lipoprotein cholesterol (mmol/L)

      (mg/dl)
      3.0 ± 0.8

      116 ± 31
      3.5 ± 0.9

      135 ± 35
      3.6 ± 0.8

      139 ± 31
      0.002<0.001
      High density lipoprotein cholesterol (mmol/L)

      (mg/dl)
      1.6 ± 0.5

      62 ± 19
      1.3 ± 0.4

      50 ± 16
      1.6 ± 0.5

      62 ± 19
      <0.0011.000
      Bold value indicates p ≤ 0.05.
      Clinical characteristics of patients with MINCA and their respective controls are presented and compared in Table 1. Body mass index (BMI) was lower and treatment for hyperlipidemia was less frequent in patients with MINCA than in CHD controls. Present smoking tended to be less frequent in patients with MINCA than in CHD controls but was more common than in healthy controls. The prevalence of treatment for hypertension was similar in patients with MINCA and CHD controls but higher than in healthy controls. A history of diabetes mellitus was more common in patients with MINCA than in healthy controls, whereas the combination of IGT and a history of diabetes mellitus was less frequent in patients with MINCA than in CHD controls but more common than in healthy controls. A history of inflammatory disease and psychiatric disorders was more common in patients with MINCA than in healthy controls. Plasma triglycerides were lower in patients with MINCA than in CHD controls. Plasma LDL cholesterol was lower in patients with MINCA than in both CHD and healthy controls, whereas plasma HDL cholesterol was greater in patients with MINCA than in CHD controls. Patients with MINCA fulfilling all Mayo clinic diagnostic criteria for TS had similar characteristics compared to patients with MINCA without any criteria except for female gender and psychiatric disorders that were more common in TS (Table 2).
      Table 2Characteristics, markers of atherosclerosis and myocardial dysfunction of myocardial infarction with normal coronary arteries patients divided into patients fulfilling all Mayo clinic diagnostic criteria for Takotsubo Syndrome and lacking all criteria for Takotsubo
      Takotsubo

      Yes

      n=25
      Takotsubo

      No

      n=56
      p-value
      Age (years)59 ± 857 ± 80.194
      Female gender100 %57 %<0.001
      BMI (kg/m2)25 ± 426 ± 40.170
      Smoker28 %14 %0.142
      Hypertension36 %39 %0.779
      Hyperlipdemia8 %13 %0.552
      Diabetes mellitus4 %4 %0.925
      Impaired glucose tolerance and diabetes mellitus35 %32 %0.814
      Migraine4 %20 %0.067
      Thrombembolic disorder4 %9 %0.434
      Inflammation32 %23 %0.405
      Psychiatric disorder40 %11 %0.002
      Reactive hyperemia index2.27 ± 0.49 %2.19 ± 0.71 %0.408
      Intima-media thickness (mm)0.73 ± 0.130.70 ± 0.140.238
      N-terminal pro brain natriuretic peptide (ng/L)152 ± 181123 ± 1090.523
      Bold value indicates p ≤ 0.05.
      There were no significant differences between patients with MINCA and the 2 respective controls groups regarding the atherosclerosis markers RHI and IMT. However, both RHI and IMT medians and distributions in patients with MINCA were similar to healthy controls but tended to deviate from CHD controls (Table 3 and Figures 2 and 3). NT-proBNP was lower in patients with MINCA than in CHD controls but greater than in healthy controls (Table 3 and Figure 4). There were no differences in markers of atherosclerosis between patients with MINCA fulfilling all compared with none of the Mayo clinic diagnostic criteria (Table 2).
      Table 3Markers of atherosclerosis and myocardial dysfunction of myocardial infarction with normal coronary arteries (MINCA) patients compared to coronary heart disease (CHD), respectively healthy controls
      MINCACHDControlMINCA vs CHDMINCA vs Control
      Reactive hyperemia index2.2 ± 0.7 %2.1 ± 0.6 %2.3 ± 0.6 %p = 0.141p = 0.639
      Intima-media thickness (mm)0.71 ± 0.120.74 ± 0.160.70 ± 0.12p = 0.216p = 0.855
      N-terminal pro brain natriuretic peptide (ng/L)133 ± 129274 ± 46068 ± 74p = 0.001P < 0.001
      Bold value indicates p ≤ 0.05.
      Figure thumbnail gr2
      Figure 2Endothelial function measured as RHI in percent (%) in patients with MINCA compared to CHD, respectively healthy controls presented as box plots with median, interquartile, and nonoutlier range. KW-H = Kruskal–Wallis statistical test.
      Figure thumbnail gr3
      Figure 3IMT (mm) in patients with MINCA compared to CHD, respectively healthy controls presented as box plots with median, interquartile, and nonoutlier range. KW-H = Kruskal–Wallis statistical test.
      Figure thumbnail gr4
      Figure 4Myocardial dysfunction measured as NT-proBNP (ng/l) in patients with MINCA compared to CHD, respectively healthy controls presented as box plots with median, interquartile, and nonoutlier range. KW-H = Kruskal–Wallis statistical test.

      Discussion

      The main finding of the SMINC study was that patients with MINCA had several established cardiovascular risk factors, mainly smoking, hypertension, IGT and diabetes mellitus, inflammatory disease, and psychiatric disorders. In contrast to patients with CHD, the lipid profile was antiatherogenic with low LDL and high HDL cholesterol. Our hypothesis that endothelial function and IMT was better, respectively lower, than CHD controls could not be proven. However, patients with MINCA were similar to healthy controls in both atherosclerosis markers, indicating a normal vascular structure and function.
      Our primary end point RHI did not differ significantly between patients with MINCA and CHD controls despite sufficient power of the study. Because mean RHI was in the normal range for all groups, one can speculate if endothelial function could have been affected by medical therapy, thus improving endothelial function in CHD controls. It can also be speculated that the high number of STEMI controls might have influenced the results by having less atherosclerosis than a more mixed sample of CHD controls. Another factor of importance for the interpretation of the results of the endothelial function test was that the cardiovascular risk factor profile was similar in patients with MINCA and CHD controls.
      • Poredos P.
      • Jezovnik M.K.
      Testing endothelial function and its clinical relevance.
      • Rubinshtein R.
      • Kuvin J.T.
      • Soffler M.
      • Lennon R.J.
      • Lavi S.
      • Nelson R.E.
      • Pumper G.M.
      • Lerman L.O.
      • Lerman A.
      Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events.
      The prevalence of migraine was similar in all groups in our study. One study has indicated a possible association between endothelial dysfunction and increased vasomotor tone,
      • Martin E.A.
      • Prasad A.
      • Rihal C.S.
      • Lerman L.O.
      • Lerman A.
      Endothelial function and vascular response to mental stress are impaired in patients with apical ballooning syndrome.
      whereas other authors have shown more migraine in patients with MINCA.
      • Raymond R.
      • Lynch J.
      • Underwood D.
      • Leatherman J.
      • Razavi M.
      Myocardial infarction and normal coronary arteriography: a 10 year clinical and risk analysis of 74 patients.
      Considering the lack of migraine and the normal endothelial function, increased vasomotor tone is not likely to be a major mechanism behind MINCA.
      In our study, 1/4 of the patients presented with typical signs of TS, whereas in another MINCA study, only 8% had typical signs of TS.
      • Larsen A.I.
      • Nilsen D.W.
      • Yu J.
      • Mehran R.
      • Nikolsky E.
      • Lansky A.J.
      • Caixeta A.
      • Parise H.
      • Fahy M.
      • Cristea E.
      • Witzenbichler B.
      • Guagliumi G.
      • Peruga J.Z.
      • Brodie B.R.
      • Dudek D.
      • Stone G.W.
      Long-term prognosis of patients presenting with ST-segment elevation myocardial infarction with no significant coronary artery disease (from the HORIZONS-AMI trial).
      This difference is most likely due to the lower percentage of women in the latter study. Unfortunately, we did not measure catecholamines at admission but collected information regarding emotional stress preceding admission. Another 1/5 of the patients had atypical wall motion of the left ventricle together with mental stress, suggestive of TS. One can speculate if there are different degrees of TS, some with milder affection of left ventricular function. Taken into account that TS is reversible, timing is crucial for fulfilling the diagnostic criteria, suggesting an even larger proportion of TS in this group of patients with MINCA. A history of psychiatric disorders was also more common in the MINCA group than in the healthy control group. Previous studies of TS have shown that emotional stress can precipitate severe reversible left ventricular dysfunction in patients without CHD. Exaggerated sympathetic activity is probably central to the cause of this syndrome.
      • Wittstein I.S.
      • Thiemann D.R.
      • Lima J.A.
      • Baughman K.L.
      • Schulman S.P.
      • Gerstenblith G.
      • Wu K.C.
      • Rade J.J.
      • Bivalacqua T.J.
      • Champion H.C.
      Neurohumoral features of myocardial stunning due to sudden emotional stress.
      Finally, most patients with MINCA being women could also support TS to be an important cause of MINCA.
      Interestingly, levels of NT-proBNP were considerably higher in the patients with MINCA than in healthy controls, implying residual myocardial stress. In TS, left ventricular dysfunction is totally reversible within 3 months. The finding could be explained by sustained diastolic dysfunction in TS
      • Ahtarovski K.A.
      • Iversen K.K.
      • Christensen T.E.
      • Andersson H.
      • Grande P.
      • Holmvang L.
      • Bang L.
      • Hasbak P.
      • Lonborg J.T.
      • Madsen P.L.
      • Engstrom T.
      • Vejlstrup N.G.
      Takotsubo cardiomyopathy, a two-stage recovery of left ventricular systolic and diastolic function as determined by cardiac magnetic resonance imaging.
      after a normalized left ventricular systolic function or it could be an effect of myocardial dysfunction secondary to myocardial scarring.
      A history of inflammatory disease was more common in patients with MINCA than in healthy controls. Further support for inflammation as a possible cause was the exaggerated increase in C-reactive protein at admission. Hypercoagulability due to inflammation has been reported as a possible reason for MINCA. There are some case reports with patients presenting with MINCA during exacerbation of systemic inflammatory disease without evidence of coronary vasculitis,
      • Badui E.
      • Valdespino A.
      • Lepe L.
      • Rangel A.
      • Campos A.
      • Leon F.
      Acute myocardial infarction with normal coronary arteries in a patient with dermatomyositis. Case report.
      whereas others have identified a secondary myocarditis.
      • Jasmin R.
      • Ng C.T.
      • Sockalingam S.
      • Yahya F.
      • Cheah T.E.
      • Sadiq M.A.
      Myocardial infarction with normal coronaries: an unexpected finding in a 13-year-old girl with systemic lupus erythematosus.
      Some previous studies have shown significantly greater number of patients with febrile infections, mainly upper airway infections, within 2 weeks before admission of MINCA,
      • 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.
      but again, those studies were conducted on younger patients (<50 years) in whom a high rate of myocarditis could be expected. Other authors have suggested links with specific infections such as cytomegalovirus or Helicobacter pylori.
      • Kardasz I.
      • De Caterina R.
      Myocardial infarction with normal coronary arteries: a conundrum with multiple aetiologies and variable prognosis: an update.
      The condition of inflammation and hypercoagulability needs to be further elaborated in future studies of MINCA.
      The main strength of this study was the uniform study group compared with previous reports.
      • Larsen A.I.
      • Galbraith P.D.
      • Ghali W.A.
      • Norris C.M.
      • Graham M.M.
      • Knudtson M.L.
      APPROACH Investigators
      Characteristics and outcomes of patients with acute myocardial infarction and angiographically normal coronary arteries.
      • Larsen A.I.
      • Nilsen D.W.
      • Yu J.
      • Mehran R.
      • Nikolsky E.
      • Lansky A.J.
      • Caixeta A.
      • Parise H.
      • Fahy M.
      • Cristea E.
      • Witzenbichler B.
      • Guagliumi G.
      • Peruga J.Z.
      • Brodie B.R.
      • Dudek D.
      • Stone G.W.
      Long-term prognosis of patients presenting with ST-segment elevation myocardial infarction with no significant coronary artery disease (from the HORIZONS-AMI trial).
      • Raymond R.
      • Lynch J.
      • Underwood D.
      • Leatherman J.
      • Razavi M.
      Myocardial infarction and normal coronary arteriography: a 10 year clinical and risk analysis of 74 patients.
      This was mainly achieved by excluding myocarditis with CMR but also excluding tachyarrhythmia and other causes of type 2 myocardial infarction.
      • Collste O.
      • Sorensson P.
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      • Daniel M.
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      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.
      This study has different limitations. The age limitation of patients to 35 to 70 years might have caused selection bias by excluding younger and older patients from participation. For example, some younger patients with the clinical assessment of myocarditis might not have been examined with coronary angiography and CMR and therefore misdiagnosed and not screened for the study. Also, patients with previous CHD have been reported with TS but excluded from this study. Participation rate would also influence selection bias. Information retrospectively collected from medical records such as medical history and presence of risk factors struggles with recall bias and loss of information. There is also a possibility that TS patients were more likely to report stress after being informed about their diagnosis. The probably heterogeneous group of patients forming MINCA might have confounded the results. Patients with thrombotic etiology are very likely to have different characteristics than patients with TS. Finally, the lack of intravascular imaging is a limitation because it could have documented vulnerable plaques not visible on coronary angiography. However, CT angiography was performed in a subset of patients showing that patients with MINCA and controls were comparable regarding plaque burden.
      • Brolin E.B.
      • Jernberg T.
      • Brismar T.B.
      • Daniel M.
      • Henareh L.
      • Ripsweden J.
      • Tornvall P.
      • Cederlund K.
      Coronary plaque burden, as determined by cardiac computed tomography, in patients with myocardial infarction and angiographically normal coronary arteries compared to healthy volunteers: a prospective multicenter observational study.

      Acknowledgment

      The authors thank Kerstin Höglund, from the Cardiovascular Research Unit at Karolinska University Hospital, Solna, Sweden.

      Disclosures

      The authors have no conflicts of interest to disclose.

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