ORIGINAL ARTICLE

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is defined as a condition sugges­tive of myocardial infarction in the absence of obstruc­tive coronary arteries on angiography (angiographi­cally normal coronary arteries or coronary artery stenosis < 50%). This entity has gained renewed in­terest in recent years based on studies aimed at clari­fying its pathophysiology and differentiating it from other causes of non-ischemic myocardial injury such as Takotsubo cardiomyopathy and myocarditis. (1) The diagnosis is often suspected during hospitaliza­tion and is confirmed later or not. Cardiology societies worldwide have agreed to use the term MINOCA to describe a working diagnosis for ischemic cardiomyo­pathy which encompasses various causes, including plaque rupture, coronary artery spasm, coronary em­bolism, spontaneous coronary artery dissection, and microvascular dysfunction. ((2)-5) The optimal treat­ment and prognosis for these patients are still uncer­tain.

Many studies that describe the characteristics of MINOCA are based on retrospective data and do not differentiate its diagnosis from other causes of non-is­chemic myocardial injury. Therefore, the conclusions drawn from these studies may be erroneous. (6-8)

The aim of this study was to describe the charac­teristics and in-hospital outcome of MINOCA patients in high-complexity centers of Argentina.

ReSCAR was a prospective cohort study conducted in high complexity medical centers in Argentina, mostly located in Buenos Aires metropolitan area. The study was conceived, designed and conducted by the Council on Cardiovascular Emergency Care of the Argentine Society of Cardiology to describe the spectrum of acute coronary syndromes (ACS), particularly the in-hospital features and one-year outcome. The protocol was designed with a focus on including vari­ables for describing MINOCA.

The participating centers should have the availability to measure high-sensitivity cardiac troponins and perform coronary angiography in order to standardize the diagnosis of myocardial infarction according to the current criterion. (5)(5) The Argentine Society of Cardiology invited all centers in Argentina to participate in the study.

The diagnosis of MINOCA was assigned by the principal investigator of the center when the patient was discharged. The definition used was the one suggested by the Fourth Universal Definition of Myocardial Infarction which is currently shared by the Consensus Statement of the Argentine Society of Cardiology. (4,5)

MINOCA was considered a clinical-angiographic syndrome characterized by:

1. A rise and/or fall of high-sensitivity cardiac troponin values with at least one value above the 99th percentile upper reference limit and at least one of the following: symptoms of myocardial ischemia, new significant electrocardiographic changes, development of pathological Q waves, evidence of loss of viable myocardium or regional wall motion abnormality in imaging tests, or identification of intracoronary thrombus by angiography or autopsy.
2. Non-obstructive coronary artery disease: defined as absence of coronary artery stenosis ≥ 50%.
3. Absence of alternative diagnoses of myocardial injury (sepsis, pulmonary embolism, aortic dissection, etc.).

Given that previous registries have reported a prevalence of around 10% for MINOCA, (6910) we planned to include 1000 ACS patients from January to August 2022. This would allow us to obtain approximately 100 patients with MINOCA for the analysis and comparison with other coronary syndromes.

We included consecutive patients > 18 years of age who were admitted to the coronary care unit for an acute coronary syndrome (ACS) and a final diagnosis at discharge of ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina, type 2 my­ocardial infarction, or MINOCA. Patients with a diagnosis of ACS on admission and final diagnosis of myocarditis of Takotsubo were also included.

Data were collected from the information recorded in an electronic case report form in the RedCap platform. (11) Ac­cess to the data was controlled by the group that organized the registry to ensure confidentiality.

The collected data included the patient's medical his­tory, clinical information upon admission, laboratory tests, electrocardiogram, coronary angiography, and other tests conducted during hospitalization. In-hospital complications and medications on admission and discharge were recorded. For data analysis, high-sensitivity cardiac troponins (T and I) are expressed as multiples of the 99th percentile (99px) to separate the values of the different cut-off points for each center and make them comparable. Analysis of the data cor­responding to the pre-specified 12-month follow-up period is ongoing and was collected through telephone contact and medical records. For further information on the protocol, please refer to the already published ReSCAR registry. (12)

All the statistical calculations were performed using IBM SPSS 25.0 software package. Discrete variables were ex­pressed as frequencies and percentages. Continuous vari­ables were expressed as mean ± standard deviation, or median and interquartile range, according to their distri­bution. The chi square test or Fisher's exact test were used to compare the categorical variables, and continuous vari­ables were analyzed using the Student's t test or the Mann- Whitney test according to their distribution. A type I error < 5% (two-tailed p value < 0.05) was considered statistically significant.

All the patients gave their informed consent before partici­pating in the study. The consent was submitted for approval by the institutional review board of each center, which is under the regulations of the Central Review Board of the Argentine Society of Cardiology.

The investigators implemented measures to protect the confidentiality of all the information according to the Argen­tine Law on Protection of Personal Data No. 25326, so that the identity of the patients and all their personal data will remain anonymous and only the researchers and the mem­bers of the learning, teaching and research ethics committee would have access to these data, if required.

The study was conducted following national ethical standards (Law No. 3301 of the city of Buenos Aires, Na­tional Law for Good Clinical Practice in Research on Human Subjects, and the Declaration of Helsinki, among others).

A total of 984 patients from 15 centers were included between January and August 2022. Of the 104 pa­tients (10.6%) without significant coronary artery stenoses, 85 (8.6%) had a final diagnosis of MINOCA.

Median age of MINOCA patients was 65 years (53- 73) and 51.8% were women. The general character­istics of MINOCA patients are displayed in Table 1. Among coronary risk factors, 55 patients had hyper­tension (64.7%), 9 patients had diabetes (10.6%), 44 had dyslipidemia (51.8%), 23 were current smokers (27.1%), and 7 had a family history of cardiovascular disease (8.2%). Regarding women-specific risk factors (n= 43), 1 patient had a history of gestational diabe­tes (2.3%), 1 had a hypertensive disorder of pregnancy (2.3%), and median age of menopause was 52 years (48-55). Active or recent cancer was the most common comorbidity and was present in 5 patients (5.9%), while 4 patients had chronic kidney disease (4.7%). Almost a quarter (23.5%) of the patients had a his­tory of coronary artery disease, which was associated with the presence of coronary artery stenoses <50% on coronary angiography. Ten patients had a his­tory of myocardial infarction (11.8%) and 9 patients had undergone percutaneous coronary intervention (9.5%). Eight patients had a history of atrial fibrilla­tion (9.4%) and 3 had heart failure (3.5%). Compared to patients with myocardial infarction and significant coronary artery obstructions, patients with MINOCA had a higher proportion of female gender (51.8% vs. 20.4%, p < 0.001), and lower prevalence of diabetes (10.6% vs. 26.8%, p<0.001), tobacco use (27.1% vs. 47.3%, p = 0.012) and previous myocardial infarction (11.8% vs. 24.7%, p = 0.006), but a a trend to higher prevalence of chronic angina (8.2 vs. 3.8%, p = 0.084).

On admission, 95.3% of the patients were hemo­dynamically stable and without heart failure. There were no ischemic changes in the electrocardiogram in 71.8% of the cases. Among abnormal electrocar­diograms, T-wave changes were the most common (12.9%), followed by ST-segment depression (8.2%), and only 2.4% presented with ST-segment elevation. Median high-sensitivity cardiac troponin levels on admission were 2.42 times above the 99th percentile of the reference values (0.85-10.21). Median left ven­tricular ejection fraction was 60% (55-64%). Median GRACE score was 115 (98-138) and median CRU­SADE score was 23 (14-31). Compared to patients with myocardial infarction with obstructive coronary arteries, patients with MINOCA presented with lower GRACE score (115 vs. 135, p < 0.001) (Table 2).

When the angiographic characteristics were ana­lyzed, 62 patients (72.9%) had normal coronary ar­teries and 23 patients (27%) had coronary stenoses < 50%. Although the median troponin level was high­er in patients with coronary artery obstructions than in those with normal coronary arteries, this difference was not statistically significant. Additionally, the pro­portion of patients with normal electrocardiograms was not statistically different between the two groups (Table 3).

The additional tests performed to patients with suspected MINOCA included cardiac magnetic reso­nance imaging in 16 patients (18.8%) during hospitali­zation and computed tomography coronary angiogra­phy in 8 (9.4%). Intracoronary spasm provocation test was performed in only one patient. Intravascular ultrasound (IVUS) or optical coherence tomography (OCT) were not performed in any patient. One patient underwent non-invasive assessment of endothelial dysfunction, and another patient underwent myocar­dial perfusion SPECT imaging.

The final diagnosis of the MINOCA mechanism as­signed by the principal investigator of each center was microvascular dysfunction in 52 patients (61.2%), coro­nary spasm in 18 patients (21.5%), plaque accident in 6 patients (7.1%), coronary artery dissection in 3 patients (3.5%), and coronary embolism in 1 patient (1.2%). The mechanism was not assigned in 5 patients.

Median length of hospital stay was 3 days (2-4). Atrial fibrillation was the most common complica­ tion (4 patients). Two patients had recurrent angina or reinfarction, 1 patient had ventricular tachycardia/ fibrillation (VT/VF) and 3 patients had signs of heart failure. There were no bleeding events BARC ≥ type 2. No deaths were reported. Compared to patients with myocardial infarction with obstructive coronary ar­teries, MINOCA patients had fewer ischemic events (death/infarction/stroke 1.2% vs. 7.9%, p=0,021) and a trend to fewer bleeding events BARC ≥ type 2 (0 vs. 4.2%, p = 0.061) during hospitalization (Table 4).

At hospital discharge, aspirin was prescribed to 62 patients (72.9%) and P2Y12 receptor inhibitors to 23 (27.1%) patients. Dual antiplatelet therapy was pre­scribed to 22 patients (22.9%) (Table 5).

Table 1. General characteristics of the population with MINOCA

BMI: body mass index; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; IQR: interquartile range; MINOCA: myocardial infarction with non-obstructive coronary arteries; TIA: transient ischemic attack

Our study shows a prevalence of MINOCA of 8.6% in hospitalized patients with suspected ACS. We would like to highlight some of our findings.

First, in our registry, the prevalence of non-ob­structive coronary arteries on coronary angiography among all patients hospitalized for ACS was 10.6%, which is similar to the one reported in other registries. Gehrie et al. found a prevalence of 10% in patients with non-ST-segment elevation ACS in a retrospective analysis of the CRUSADE registry. (13) In the analy­sis of MINOCA in the retrospective ACTION registry- GWTG (9) and the extensive meta-analysis of MINO­CA by Pasupathy et al., the incidence reported was 6%. (6) In Argentina, the CONAREC XVII Registry on ACS found that 2.8% of patients had no coronary artery stenoses on angiography and 7.7% had moder­ate obstructions. (14) In all these registries, the term MINOCA is used as a working diagnosis, which means that it does not exclude conditions such as Takotsubo or myocarditis, but rather includes them as possible causes of MINOCA. In our registry, we attempted to exclude non-ischemic injuries and found a prevalence of MINOCA of 8.6%.

Second, half of the MINOCA patients in this regis­try are women. The proportion of women in this reg­istry is similar to that of other registries, but differs from registries of myocardial infarction with signifi­cant epicardial lesions, where the proportion of women is lower. (6, 15, 16) The age found in our registry is sim­ilar to that of patients with myocardial infarction with obstructive coronary arteries but differs from that de­scribed in other registries, where the age of MINOCA patients was lower than that of patients with signifi­cant coronary artery disease. (9, 17)

Table 2. Characteristics on admission

HR: heart rate; IQR: interquartile range; LBBB: left bundle branch block; LVEF: left ventricular ejection fraction; MINOCA: myocardial infarction with non-obstructive coronary arteries; RDW: red cell distribution width; SBP: systolic blood pressure.

Table 3. Comparison of troponin levels and ECG in MINOCA patients with or without coronary artery disease on angiography.

*High-sensitive cardiac troponins expressed as multiples of p99. Median (P25-75) CAD: coronary artery disease; ECG: electrocardiogram; MINOCA: myocardial infarction with non-obstructive coronary arteries; NS: non-significant.

Third, in our registry the prevalence of traditional coronary risk factors is lower than the one found in myocardial infarctions with epicardial coronary artery disease. It is worth noting that the prevalence of dia­betes is lower, which is consistent with other MINO­CA registries. (7, 18) This registry also collected data on women-specific risk factors, such as hypertensive disorders of pregnancy, gestational diabetes, and men­opause-related factors. The prevalence of these risk factors was lower than that described in other regis­tries such as the VIRGO study, a registry of coronary syndromes in patients < 55 years with a special focus on nontraditional risk factors. (18) There may be a data collection bias related to the lack of routine ask­ing about women-specific risk factors.

Fourth, most MINOCA patients presented as non- ST-segment elevation ACS with moderate elevation of cardiac troponins on admission and clinical stability. Although the risk estimated by the GRACE score was moderate, the rate of in-hospital events was low and there were no in-hospital deaths. Similarly, we could not confirm in our registry that the presence of cor­ onary artery disease is associated with a worse out­come during hospitalization, as some registries have previously described. (19) The question of long-term outcomes remains, and we hope to answer it when we complete the analysis of the one-year follow-up.

Fifth, most MINOCA patients did not undergo ad­ditional tests during hospitalization to determine the etiology. This is particularly striking for cardiac mag­netic resonance imaging, considered essential for the diagnosis of MINOCA, which was performed in only 18.8% of patients. It is possible that cardiac magnetic resonance imaging was not performed during hos­pitalization due to unavailability at the center or to avoid prolonging hospitalization for low-risk patients. It is also possible that the test was performed after discharge. Furthermore, it can be hypothesized that intravascular diagnostic tests or intracoronary spasm provocation tests are not widely available in our set­ting, and noninvasive methods for diagnosing coro­nary artery spasm or microvascular dysfunction are not widely used or known. Nevertheless, it is also true that the etiologic diagnosis of MINOCA begins during hospitalization and is often completed in the outpa­tient setting. The Argentine Consensus Statement on MINOCA, recently published, can assist in the initial management and diagnosis of these patients. (4) Due to the low rate of tests performed during hospitaliza­tion, the population described in this registry may be more indicative of a working diagnosis than of a con­firmed diagnosis of MINOCA.

However, the main etiologic diagnosis ascribed by the investigator of each center was microvascular dys­function in 62.1% of the cases. According to several studies that further investigate the etiology of MI­NOCA using a combination of cardiac magnetic reso­nance imaging and intravascular imaging, at least half of MINOCA cases are due to plaque injury, followed by coronary artery spasm and cases of undetermined etiology, while spontaneous coronary artery dissection and embolism are less common. (19, 20) The possible causes of MINOCA may still be unknown or confused with INOCA (ischemia without obstructive coronary artery disease), a condition in which microvascular dysfunction is very common.

Finally, there is little evidence on the optimal treatment for MINOCA after discharge from the in­dex hospitalization. Dual antiplatelet therapy has not been shown to reduce events, and the use of statins, renin-angiotensin-aldosterone system antagonists, and beta-blockers may have a protective effect. (21-24) In our registry, the use of dual antiplatelet therapy at discharge was significantly higher than at admis­sion, but was used in only 22.9% of patients, which is related to the etiologic diagnosis assigned. Secondary prevention with statins was high and, together with beta blockers, prescription was greater than on admis­sion

The strength of our registry lies in its prospective description of MINOCA, providing data that are hard to obtain from retrospective analyses of registries de­signed with different objectives. Post-discharge moni­toring of patients will provide data on long-term out­come. We expect that this study will help to generate hypotheses for future research to clarify the prognosis and optimal treatment of patients with MINOCA.

Table 4. Complications during hospitalization

IQR: interquartile range; MV: mechanical ventilation; TIA: transient ischemic attack; VF: ventricular fibrillation; VT: ventricular tachycardia.

Table 5. Medication on admission and discharge

ACEI: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNI: angiotensin receptor neprilysin inhibitor; P2Y12i: P2Y12 receptor inhibitor

Due to the requirement of signing an informed con­sent form and the nature of this registry, we can­not guarantee the consecutive inclusion of patients. Therefore, the prevalence found in our study may not accurately reflect reality. The involvement of cent­ers primarily located in the Buenos Aires metropoli­tan area may result in data not representative of the entirety of Argentina. In addition, the interpretation of the coronary angiograms was the responsibility of the investigators at each center and not of a central group. In any case, we believe that the registry rep­resents the characteristics of hospitalized patients in "real life".

In this registry, patients with MINOCA represent a significant proportion of those with ACS. The rate of in-hospital complications, including mortality, was low. There seems to be a strong opportunity for further investigations to confirm the diagnosis, pathophysiological mechanisms, and treatment of MINOCA.

https://creativecommons.org/licenses/by-nc-sa/4.0/

CEMIC: Mirza Rivero, Mayra Meza, Sol Kersten, Carlos Boissonnet.

CEMEP: Gerardo Filippa.

Clínica Olivos: Fernando Guardiani, Sebastian Nani.

Fundación Favaloro: Ernesto Duronto, Gastón Procopio, Camila Marian Abud, Santiago Andrés Ahuad Calvelo.

Hospital Austral: Jorge Bilbao, Nicolás Torres.

Hospital Británico: Mauro Gingins, Gisela Gomez, Federico Deveter.

Hospital de Clínicas: Sandra Swieszkowski, Martin Aladio, Maia Matsudo.

Hospital Durand: Valentín Roel.

Hospital Naval: Guillermo Perez.

ICBA: Juan P Costabel, Julian Feder, Alan Sigal.

Instituto Médico de la Ribera: Valerio Pessano, Juan Pablo Larralde

Sanatorio Anchorena San Martín: Leandro Rodriguez. Juan Manuel Souto.

Sanatorio Finochietto: Diego Crippa.

Sanatorio Güemes: Ricardo Villareal, Joaquín Perea, Agustina Saucedo, Elena Vargas.

Sanatorio Trinidad de Palermo: Federico Cardone.