The association between acute myocardial infarction (AMI) and obstructive coronary artery disease, which is found in more than 90% of AMI patients, has been known for a long time.¹ However, nearly 10% of AMI patients do not have obstructive plaques, a finding that has been reproduced in several studies.^{2 - 4} A clinical presentation with symptoms, electrocardiographic and laboratory changes typical of AMI, in the absence of obstructive coronary atherosclerosis, had long been considered as false positive.⁵ However, more recent studies have reported that the prognosis of these patients may not be favorable, with rates of mortality and major adverse cardiovascular events (MACE) similar to those of patients with obstructive disease.⁶

For this reason, the term MINOCA (myocardial infarction with non-obstructive coronary arteries) has been introduced to describe AMI patients without significant coronary artery disease, and already included in the fourth Universal Definition of Myocardial Infarction.⁷

Several mechanisms have been proposed for the development of MINOCA, including the rupture of a nonobstructive plaque, coronary thromboembolism, other type 2 myocardial infarctions and vasospasm. Myocarditis and Takotsubo syndrome can cause nonischemic myocardial injury, with clinical features similar to those of acute coronary syndrome.⁸

Considering the myriad of possible diagnoses and the lack of scientific evidence,⁹ the ideal therapeutic approach to these patients is still uncertain. It has been strongly recommended the investigation, identification, and treatment of the underlying disease. Likewise, the clinical course and prognosis of MINOCA patients is also heterogeneous; while most patients recover from the disease without any cardiac sequelae, a worrying minority of patients have an unfavorable course, with a one-year mortality rate of nearly 5%.¹⁰ Therefore, improving the prognostic stratification of patients with MINOCA is highly needed. The Global Registry of Acute Coronary Events (GRACE) score has been widely used for stratification of in-hospital mortality at 1 and 3 years after acute coronary syndrome.^{11 - 13}

The present study aimed to describe characteristics of patients admitted for MINOCA to a single center during a four-year period (from 2014 to 2017). In addition, the study aimed to evaluate the GRACE score for prognostic stratification of patients with MINOCA during a one-year follow-up.

This was a retrospective, observational, single-center, cohort study that included consecutive patients admitted to a Cardiology unit with a diagnosis of MINOCA, from January 01, 2014 to December 01, 2017. The diagnosis of MINOCA was established by the researchers after review of patients’ clinical records, according to the European Society of Cardiology (ESC) criteria:⁸ to fulfill the fourth Universal Definition of Myocardial Infarction criteria for AMI;⁷ absence of obstructive epicardial coronary artery disease (absence of stenosis greater than 50%); and absence of a clinically overt specific cause for the acute presentation. Patients with suspected myocarditis (pleuritic pain, increase in inflammatory markers, respiratory infection, or gastrointestinal infection in the last four weeks) or with a diagnosis of myocarditis confirmed by cardiac magnetic resonance (CMR) (according to the ESC Working Group criteria),¹⁴ and patients with suspected Takotsubo syndrome (according to the InterTAK diagnostic criteria established in the International Expert Consensus Document on Takotsubo Syndrome)¹⁵ were excluded. A flowchart of patients’ selection process is depicted in Figure 1 .

Figure 1

Demographic, clinical, laboratory, electrocardiographic, echocardiographic, and angiographic data, as well as information on treatment during hospitalization were collected from patients’ medical records.

Dyslipidemia was defined as increased levels of low-density lipoprotein (LDL) cholesterol in patients taking lipid-lowering drug, or LDL levels at admission that would qualify patients for lifestyle changes and/or pharmacological therapy, according to the 2019 ESC guidelines for management of dyslipidemias.¹⁶ All patients had access to echocardiography at hospital admission and prior to discharge, and we also investigated whether patients underwent CMR. CMR was considered of diagnostic value when it enabled the identification of MINOCA etiology or determined an ischemic cause of MINOCA (detection of subendocardial or transmural scarring), even when the mechanism of infarction could not be completely elucidated.

The final diagnosis of MINOCA was established by the investigators after revision of clinical data and results of complementary tests. Cardioembolic stroke was defined as the presence of a predisposing factor (atrial fibrillation without hypocoagulation, thrombophilia, heart valve disease), combined with an image suggestive of intracoronary thrombus that was not adherent to the plaque, or subendocardial or transmural delayed contrast enhancement. Diagnosis of spasm was defined based on documentation of previous spontaneous episodes of rest angina, associated with ST-segment changes that responded promptly to short-acting nitrates.⁸ Plaque disruption and spontaneous coronary dissection were confirmed by intracoronary imaging (intravascular ultrasound or optical coherence tomography).⁸ Cases where CMR revealed a contrast enhancement pattern compatible with subendocardial or transmural infarction were classified as of ischemic cause with uncertain mechanism. The final diagnosis of MINOCA was classified as unknown when patients did not meet the criteria described above.

The one-year follow-up was conducted by means of review of medical records for the occurrence of the following outcomes – all-cause mortality and MACE (a composite of all-cause mortality and hospitalization due to cardiovascular disease, namely AMI, stroke, acute limb ischemia, or heart failure). The causes of readmission were determined according to medical records.

The GRACE 2.0 risk score was calculated at admission using a validated algorithm.¹³

Statistical analysis was performed using the IBM SPSS-statistics, version 25. The level of significance was set at 5%. The sample was described using descriptive statistics. Categorical variables were described as percentage. Normality of quantitative variables was verified by the Kolmogorov-Smirnov test with Lilliefors correction. These variables showed a non-Gausssian distribution and were described as median and interquartile range (IQR). Using a non-parametric analysis, the quantitative variables were analyzed using the Mann-Whitney test. The discriminatory power of the GRACE score for the prediction of cardiovascular events was assessed by ROC curve analysis. The maximum Youden index was used to determine the cutoff points for GRACE score that would best predict the occurrence of primary and secondary outcomes.

Characteristics of our patients with diagnosis of MINOCA are similar to those described in several international studies.^{2 - 4 , 6 , 17 - 19} A recent systematic review of records of patients with MINOCA reported a mean age of 55 years,⁶ and higher prevalence of female patients,^{2 - 4 , 6 , 17 - 19} suggesting sex-related or hormone effects on the pathophysiology of the disease.⁸ However, contrary to our findings, some international studies have described a lower frequency of classical cardiovascular risk factors in these patients.^{18 , 19} Our study showed a high prevalence of dyslipidemia and arterial hypertension in our sample, which was already reported in a previous Portuguese study.¹⁷ As compared with the population of the Portuguese Registry of Acute Coronary Syndromes,²⁰ our sample shows some similarities, such as mean age (66 ±13 years), and prevalence of arterial hypertension (66.9%) and dyslipidemia (57.2%), and differed especially in sex distribution and prevalence of smoking (28.5%), diabetes mellitus (31.9%), and history of AMI (17.9%). These findings may reflect a higher prevalence of MINOCA associated with atherosclerotic disease in the Portuguese population, which is difficult to be confirmed in our study due to the small proportion of patients whose cause of MINOCA could be confirmed, despite similar mortality rates to other series.²¹

In our sample, the prognosis was similar to that previously described in other observational studies. Kang et al.¹⁰ also reported an annual MACE rate of 7.8%, which was comparable to that observed in the comparative sample of acute coronary syndrome patients with one or two-vessel disease. Pasupathy et al.,⁶ in a systematic review of studies on MINOCA patients, described a 12-month all-cause mortality rate of 4.7%. More recently, the COAPT study²² presented even more worrying results – an all-cause mortality rate of 3.9% and 12.6% likelihood of occurrence of the composite endpoint of cardiac death and cardiovascular rehospitalization within one year.

A variable clinical course has been reported in previous studies; while most patients have a favorable course, without myocardial function sequelae, a significant proportion of patients develop MACE in short term. In light of the difficulty in establishing an etiological diagnosis in all patients, and the clinical dilemma in identifying which patients would require a closer follow-up and more aggressive secondary prevention therapy, the prognostic stratification is crucial. Numerous studies have proposed several prognostic markers, but with heterogeneous results – female sex, history of smoking, atrial fibrillation, previous AMI, ST-segment elevation at admission,^{18 , 23} age, diabetes, previous stroke, peripheral arterial disease, chronic obstructive pulmonary disease, neoplasms, reduced ejection fraction, levels of LDL, creatinine and C-reactive protein,¹⁸ and number of coronary arteries with stenosis less than 50%.²⁴

The GRACE score is an ideal prognostic stratification tool in these patients. The instrument allows an objective quantification of the risk, making it more practical for clinicians when compared with a wide range of markers difficult to be integrated. Also, there is ample scientific evidence on the use of this risk stratification score in acute coronary syndrome.^{11 - 13} Also, it has been widely use in clinical practice even for risk stratification of patients with MINOCA, before being submitted to catheterization.¹² Our study showed that the GRACE score is associated with one-year MACE. The cut-off points revealed by our statistical analysis are similar to those suggested by the ESC guidelines on the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.¹² The authors suggest that MINOCA patients with a GRACE score < 109 would be classified as “low risk”, a GRACE score of 109-139 would indicate an “intermediate risk” (already at a high risk of one-year MACE) and those with a GRACE score ≥140 would be classified as “high risk” (at high risk of one-year mortality). Therefore, an AMI patient, regardless of the presence of obstructive coronary artery disease, would be categorized into a risk group (low, intermediate, or high). However, independent of such classification, the active investigation for the etiologic diagnosis and appropriate therapy is always indicated.

CMR is an essential tool in the diagnosis of MINOCA. When performed in the acute phase of the disease (ideally in the first seven days of presentation),²⁵ the test allows the diagnosis in up to 87% of patients, changes the diagnosis made by cardiologists in nearly 52% of patients, and contributes to the definition of the best therapeutic strategy for the patient.²⁶ In our study, CMR had a lower diagnostic value, since it was performed in outpatient regimen in most cases, and did not allow the detection of perilesional edema using T2-weighted sequences or changes in segmental contractility in acute phase.^{8 , 27} The low percentage of patients who underwent CMR in our study may be explained by the low accessibility of this test in our center. Similarly, although intravascular ultrasound and optical coherence tomography are essential tools for diagnosis of plaque disruption and spontaneous coronary dissection,⁸ these are not readily accessible in clinical practice in our institution.

In the present study, secondary prevention therapy was prescribed at discharge based on clinical suspicion of the disease and following the current ESC recommendations.⁸ Most patients were prescribed ACE inhibitors, ARBs, betablocker, and statins. However, considering the lack of robust scientific evidence, the benefit of using traditional therapies in secondary prevention in this population, with different diagnosis, is questionable. The MINOCA BAT trial aims to randomly assign more than 5,600 MINOCA patients to receive ACE inhibitor/ARBs plus betablocker versus placebo and evaluate one-year mortality rate and other cardiovascular events in one year. The use of these medications in this population can be considered reasonable according to recent findings reported in an observational study of MINOCA patients recorded in the SWEDEHEART registry,²⁸ suggesting long-term beneficial effects of ACE inhibitors and ARBs, and possibly betablockers in preventing cardiovascular events in these patients.

This was a single-center, retrospective study, and limitations inherent to this study design should be considered, including a possible selection bias of patients. The small sample size and the short study period may affect the strength of our findings. In addition, since this was a retrospective study based on clinical records, a possible underreporting of endpoints cannot be ruled out. The low rate of identification of the cause of MINOCA may also bias the results, since it is not possible to determine the number of patients whose MINOCA was not related to vessel disease (as in case of myocarditis and Takotsubo syndrome). Besides, the cause of death of patients with definite diagnosis of MINOCA was unknown, which may limit the interpretation of the results.

This study highlights the diversity of causes and heterogeneous prognosis of MINOCA, which depends on the etiology and, in most cases, is not benign. The GRACE score at admission was shown a useful tool to identify those patients with a less favorable prognosis, with a good discriminatory ability in predicting the occurrence of events during the follow-up of our sample.

Due to the heterogeneity of patients with MINOCA, multicenter studies using specific protocols for the etiological diagnosis, prognosis and therapeutic guidance are needed to establish the best therapeutic strategies tailored to the prognosis of each patient.