MI WITH NORMAL CORONARIES

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a syndrome characterized by clinical evidence of acute myocardial infarction (AMI) according to the fourth universal definition with normal or near-normal coronary arteries on angiography.^[1] Data from large contemporary registries demonstrate that the prevalence of MINOCA among MI patients is 6–8%.^[1]

The absence of obstructive coronary stenosis along with the results deriving from early studies supported the common feeling among physicians that the prognosis of MINOCA was benign.^[2] Results from more recent studies did not confirm this belief. Indeed, in an excellent meta-analysis, Pasupathy et al.^[3]demonstrated that all-cause mortality at 1 year was lower in MINOCA compared with myocardial infarction and obstructive coronary artery disease (MICAD) (4.7% vs. 6.7%), but not negligible considering that patients with angina without recent AMI and obstructive coronary artery disease have an annual mortality of 0.3%.^[4] Of note, in the prospectively conducted Korean MI Registry, MINOCA patients had an equivalent 12-month all-cause mortality to those with an AMI associated with single- or double-vessel coronary artery disease.^[5]Furthermore, a retrospective analysis of 13 800 patients presenting with non-ST elevation MI enrolled in the ACUITY trial demonstrated that MINOCA had a higher mortality at 1 year (4.7% vs. 3.6%) compared with MICAD, although mainly driven by non-cardiac mortality.^[6] Long-term prognosis of MINOCA is also not favourable. Indeed, in an observational study of MINOCA patients recorded in the SWEDEHEART registry, at a mean follow-up of 4.1 years, mortality was 13.4% (with only 43.0% of deaths classified as cardiovascular), 7.1% of patients experienced another myocardial infarction, 4.3% had an ischaemic stroke, 6.4% were hospitalized for heart failure, and hospitalization for bleeding occurred in 3.6%.^[7]

In this issue of the European Heart Journal, Dreyer et al.^[8] assessed the prognosis of MINOCA compared with MICAD at 1 year in an observational cohort study enrolling patients aged >65 years (mean age 75.6 years) from the National Cardiovascular Data Registry CathPCI Registry with linkage to the Centers for Medicare and Medicaid Services (CMS) claims data. This study included 286 780 patients admitted with a diagnosis of AMI, with 5.9% of patients presenting MINOCA. The authors have to be congratulated for publishing the hitherto largest study evaluating the prognosis of patients with MINOCA. The authors demonstrated that the 12-month rates of major adverse cardiac events (MACEs) (18.7% vs. 27.6%), mortality (12.3% vs. 16.7%), and re-hospitalization for AMI (1.3% vs. 6.1%) and for heart failure (5.9% vs. 9.3%) were significantly lower for MINOCA vs. MICAD patients, while they were similar for re-hospitalization for stroke (1.6% vs. 1.4%). Thus, this study clearly confirms that MINOCA patients have a guarded prognosis, with a significant risk of mortality and recurrent MACEs, although this is lower as compared with that observed in MICAD.

The study by Dreyer et al. enrolled patients >65 years old to enable linkage to CMS data and, as a consequence, the mean age of the study population (~75 years) is significantly higher compared with that in previous MINOCA studies. Indeed, MINOCA patients are usually younger, and a large systematic review showed that the average age of patients with MINOCA was lower as compared with that of patients with MICAD.^[3] Not surprisingly, an older age represents an independent predictor for all-cause mortality and occurrence of MACEs in MINOCA.^[9] At the other extreme, in the VIRGO study^[10] enrolling 2690 younger patients aged <55 12-month="" 2.3="" a="" along="" ami="" and="" compared="" demonstrated="" for="" higher="" low="" micad="" minoca="" mortality="" of="" other="" p="" patients="" prevalence="" registries.="" similar="" vs.="" with="" years="">

Unfortunately, the study by Dreyer et al.,^[8] similarly to several previous studies, does not provide any insight into the prognosis across the different causes of MINOCA. Indeed, multiple mechanisms are involved in the pathogenesis of MINOCA and it is likely that prognosis may vary substantially according to the underlying cause. A study by Dastidar et al.^[11] demonstrated that cardiac magnetic resonance (CMR) was able to identify the mechanism of MINOCA in 75% of patients, and mortality at 3.5 years of follow-up among patients with normal CMR was only 2%. Another study by Montone et al.^[12] enrolling 80 patients with a diagnosis of MINOCA, excluding causes other than suspected coronary vasomotor disorders, demonstrated that an invasive provocative test with acetylcholine or ergonovine was positive in 46.2% of patients. After a median follow-up of 36 months, patients with a positive test had significantly higher rates of all-cause death, cardiac death, and readmission for acute coronary syndrome, as well as a worse angina status when compared with patients with a negative test. The negative prognostic value of positive provocative tests was mainly related to the induction of epicardial spasm rather than microvascular spasm, and, accordingly, a dose reduction or discontinuation of calcium channel blockers was associated with mortality, supporting the crucial role of epicardial spasm in the occurrence of fatal events in this subset of patients.

What has been said above leads to the inescapable conclusion that patients presenting with MINOCA represent a heterogeneous cohort of patients with a prognosis that, on average, is guarded, but it varies substantially depending on the aetiology. An optimal medical treatment can only be based on the full knowledge of the underlying cause (Figure 1). Accordingly, the diagnosis of MINOCA should prompt further investigations in order to ascertain its cause as we have previously proposed,^[2] while cardiologists tend to lose interest in patients without epicardial stenoses. MINOCA can indeed be caused by disruption of a non-obstructive atherosclerotic plaque, functional alterations of the coronary circulation, and coronary microembolism; it can also be caused by Takotsubo syndrome or myocarditis with an infarction-like presentation,^[13]although in these two settings troponin release is probably caused by a combination of myocardial necrosis and myocardial injury.^[1] An accurate diagnosis obviously impacts on treatment. For instance, an observational study of MINOCA patients recorded in the SWEDEHEART registry failed to find a positive effect of dual antiplatelet therapy on outcome.^[7] Lack of efficacy probably depends on the fact that patients with MINOCA caused by disruption of a non-obstructive atherosclerotic plaque were under-represented in this patient population.

Figure 1.

Specific treatment of myocardial infarction with non-obstructive coronary arteries (MINOCA) based on the underlying pathogenic mechanism. (A) Optical coherence tomography showing a plaque rupture; (B) intracoronary acetylcholine test showing a spasm of the left anterior descending coronary artery; (C) cardiac magnetic resonance imaging of myocarditis typically localized to the subepicardial regions of the left ventricle; (D) left ventricle angiogram of Takotsubo syndrome showing typical apical ballooning; (E) on the left, transthoracic echocardiogram showing a thrombus in the left atrium; on the right, thrombus retrieved using a manual thrombus aspiration coronary catheter. ACE-i, angiotensin-converting enzyme inhibitors; HF, heart failure.

In conclusion, patients with MINOCA have a guarded prognosis; indeed, one in five patients with MINOCA and age >65 years suffers a major adverse event over 12 months.^[8] These patients should not be overlooked, as an accurate aetiological diagnosis is the foundation of an appropriate treatment, which can substantially improve their prognosis (Figure 1). Pears and apples are both fruits, but they have a different flavour and taste. Precision medicine means, first of all, providing an accurate aetiological diagnosis.