Guidelines for the management of myocardial infarction/injury with non-obstructive coronary arteries (MINOCA): a position paper from the Dutch ACS working group

Up to 14% of the patients with acute myocardial infarction (AMI) are found to have non-obstructive coronary arteries, defined as coronary stenosis <50% [1]. The term myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) has been coined for this clinical entity, which represents a diagnostic and therapeutic dilemma since many patients are discharged without a clear aetiology for the clinical presentation [2].

Despite the fact that this syndrome has been examined in greater depth over the past few years, many uncertainties remain regarding the pathophysiology of the myocardial damage, the clinical features, management and prognosis of these patients. As a result, the patients may be treated inappropriately or not treated at all.

On behalf of the Dutch ACS working group, we discuss the importance of MINOCA and will present a diagnostic algorithm to guide the general and interventional cardiologist which may lead to optimal treatment of this patient cohort.

The diagnosis MINOCA requires (1) the presence of an AMI (according to the Fourth Universal Definition of AMI, see Tab. 1), (2) non-obstructive coronary arteries on invasive coronary angiography, defined as no coronary stenosis ≥50% in any potential infarct-related artery, and (3) no clinically overt specific cause for the acute presentation [2, 3].

Many terms have been coined to describe patients with AMI or acute coronary syndrome (ACS) with normal or near-normal coronary arteries, such as MINOCA, MINCA (MI with normal coronary arteries) [4] and INOCA (ischaemia and no obstructive coronary artery disease) [5].

The term MINOCA is incorporated into the recently published Fourth Universal Definition of AMI. According to this, MINOCA (i.e. myocardial infarction) indicates that an ischaemic mechanism is the underlying cause for the myocyte injury. Others have used the term MINOCA in an all-encompassing context to include all patients fulfilling the universal criteria for AMI without obstructive coronary artery disease (CAD) [2].

In light of this, Pasupathy et al. proposed a new term called troponin-positive non-obstructive coronary arteries (TP-NOCA) that includes patients with coronary disorders resulting in ischaemic necrosis, and myocardial and non-cardiac disorders resulting in myocardial injury [6]. Another proposed term is ACSNNOCA (ACS with normal or near-normal coronary arteries) which encompasses all ACS patients with non-obstructive coronary arteries (i.e. MINOCA/MINCA/INOCA).

There is much overlap between all these terms, including type 2 MI [3]. The last-mentioned is also a heterogeneous category that includes pathophysiological mechanisms comparable to MINOCA. From a clinical point of view, it is extremely challenging (directly after coronary angiography) to make a clear distinction between whether the patient with a suspected AMI and non-obstructive coronary arteries suffers from myocardial injury, ischaemia or infarction.

Therefore, as the Dutch ACS working group, we propose that MINOCA should not be considered as a ‘true’ diagnosis, but rather as a clinical dynamic working diagnosis that needs further evaluation. If coronary angiography during a suspected AMI shows non-obstructive coronary arteries and there is no overt cause for the clinical presentation, the working diagnosis MINOCA could be made. In the further evaluation of the underlying mechanism of AMI it is imperative to exclude other clinically overt causes for the elevated troponin (e.g. sepsis, hypotension and pulmonary embolism) and non-ischaemic mechanisms of myocyte injury (e.g. myocarditis). Viewed in this way, which reflects clinical practice best, MINOCA can represent both myocardial infarction and myocardial injury with non-obstructive coronary arteries.

In this paper, the all-encompassing term MINOCA is used to describe the coronary, myocardial and non-cardiac aetiologies, similar to the position paper on MINOCA of the European Heart Journal [2]. Most importantly, MINOCA should be considered as a dynamic working diagnosis, which should encourage the clinician to further evaluate the underlying mechanism(s) in order to achieve patient-specific treatments.

MINOCA can present with ST-elevation MI (STEMI) (approximately 1/3) or non-STEMI (approximately 2/3) [1]. As stated before, the causes of MINOCA can be subdivided into coronary, myocardial or non-cardiac related disorders (Tab. 2). In the 1980s, DeWood et al. reported that approximately 10% of patients with MI were found to have non-obstructive CAD [7]. Currently, the prevalence may be even higher in the era of high-sensitivity cardiac troponin assays, because of their lower specificity to diagnose acute MI. A systematic review by Pasupathy et al. indicates a MINOCA prevalence of 6% in ACS patients, with a wide range of 1–15% [1, 8‐14]. This is mainly attributable to differences in study populations and the heterogeneity of its definition. A higher prevalence of MINOCA was found in younger patients (58.8% vs 61.3%, p < 0.001), females (43% vs 24%, p < 0.001), non-white patients (25% vs 12%, p < 0.0001) and in patients presenting with non-STEMI (78% vs 51%, p < 0.0001), compared to AMI with obstructive CAD [1, 8, 10, 11, 14, 15].

The VIRGO study [15] also showed that women were 5 times more likely to have MINOCA than men, and that these MINOCA patients had fewer traditional cardiac risk factors, but more often had unconventional risk factors, such as (prior) drug use, hypercoagulability syndrome, venous thromboembolism and autoimmune disorders. Female AMI patients with obstructive CAD were more likely to be menopausal or to have a history of gestational diabetes mellitus compared to those with MINOCA.

Although MINOCA patients have a lower cardiac risk profile, there are conflicting data regarding their prognosis. Safdar et al. described similar functional and psychosocial outcomes. In addition, similar 1‑ and 12-month mortality in both MINOCA and AMI with obstructive CAD [1-month: 1.1% and 1.7% (p = 0.43); 12-month: 0.6% and 2.3% (p = 0.68), respectively] were found, whereas Pasupathy et al. reported that mortality rates were significantly lower in the MINOCA group compared to AMI with obstructive CAD [in-hospital: 1.1% and 3.2% (p = 0.001); 12-month 3.5% and 6.7% (p = 0.003), respectively] [1, 15].

An interesting finding by Bainey et al. was that the 1ne-year composite of death and/or reinfarction rate among MINOCA patients with no angiographic evidence of CAD was significantly lower than in MINOCA patients with stenosis <50% (3.9% and 6.1%, [p = 0.028], respectively) [16]. In relation to this, independent predictors of adverse outcome were three-vessel disease or left main stem involvement (stenoses ≥30% but <50%), high C‑reactive protein at hospital admission and elevated high-sensitivity cardiac troponin T levels [17, 18].

The previously mentioned data should be interpreted with caution since the outcome of MINOCA strongly depends on the underlying cause. Recently, the prognostic role of cardiac magnetic resonance imaging (CMR) was assessed in MINOCA patients. It was found that a CMR diagnosis of cardiomyopathy was an independent predictor for mortality, whereas a diagnosis of MI, myocarditis or a normal CMR was not [19].

To reveal the exact underlying aetiology of MINOCA, a thorough patient history, physical examination, laboratory testing, imaging and invasive measurements are needed, since MINOCA should be considered as a working diagnosis.

Extra-cardiac causes of MINOCA which can result in myocardial injury include (PE), (end-stage) renal failure, sepsis, stroke and other forms of type 2 MI such as anaemia and hyperthyroidism. They all can be associated with chest pain, elevated cardiac enzymes and ECG changes. If PE is suspected, evaluation with the help of the Wells score, D‑dimer concentration, pulmonary CT angiography or ventilation/perfusion scintigraphy should be performed based on patient-specific presentation.

The dynamic working diagnosis MINOCA could be made in those patients with suspected AMI, non-obstructive coronary arteries and no clinically overt cause for the acute presentation.

Consequently clinicians should be encouraged to start further evaluation. Stigmatisation of these patients, as having an MI due to coronary thromboembolism or as having non-cardiac chest pain, must be avoided. If the true underlying mechanism for the event has been diagnosed, the working diagnosis MINOCA should be discarded and appropriate treatment should be started and related to the underlying mechanism.

The interventional cardiologist is the first to be confronted with MINOCA at the catheterisation laboratory. Left ventricular angiography or echocardiography should be performed directly after coronary angiography to detect wall motion abnormalities, predominantly to reveal signs of Takotsubo cardiomyopathy.

If, after coronary angiography, the cause of MINOCA is still unknown, re-evaluation by the use of a thorough patient history, physical examination and laboratory assessment should be done, predominantly to exclude non-cardiac causes, various types of type II MI and non-ischaemic mechanisms of the myocyte injury (e.g. myocarditis).

Traditional cardiovascular risk factors for coronary heart disease may imply concealed atherosclerosis and thus endothelial dysfunction, which is a predictive factor for coronary artery spasm. In contrast, SCAD patients have fewer traditional cardiovascular risk factors but this should be strongly considered in young female patients. Elevated inflammatory parameters or elevated D‑dimer levels may suggest myocarditis or PE, respectively. A positive family or personal history for hypercoagulability may lead to suspicion of hereditary or acquired coagulation disturbances.

Non-invasive imaging plays a pivotal role in the detection of the underlying cause for MINOCA. Echocardiography is essential in the work-up of MINOCA to assess any form of structural heart disease, or the presence of ASD, intracardiac thrombus, myocardial tumour or myxoma. Furthermore, CMR plays an important role. Early CMR can differentiate between myocardial inflammation, fibrosis and myocardial function by T1- and T2-weighted imaging, LGE and (ECG-gated) cine imaging. Thirteen studies have evaluated the diagnostic yield of CMR and were able to find a definitive diagnosis in 71% of the patients (19% MI, 33% myocarditis, 12% Takotsubo cardiomyopathy, 2% hypertrophic cardiomyopathy, 2% dilated cardiomyopathy, 3% other), as illustrated in Fig. 1 [4, 19, 54, 59‐68]. Based on these observations, we recommend routine examination with CMR within 4 weeks after hospital admission.

However, in 8–67% of patients no abnormalities could be found, which leads to a therapeutic dilemma for clinicians [4, 23, 54, 59, 62, 64]. In these patients, additional investigations such as those mentioned in Fig. 2 may be considered.

In select cases, if no cause can be found, it can be useful to perform CT angiography and/or intracoronary reactivity testing during the index procedure or a second procedure in the outpatient clinic to reveal the underlying cause of MINOCA. We recommend this if:

At the discretion of the interventional cardiologist, IVUS or OCT can be performed to determine the presence of atherosclerosis, atherosclerotic plaque disruption, plaque erosion, coronary dissection and coronary thrombosis. In addition, vulnerable plaques can be identified by measuring the fibrous cap thickness and the presence of a large necrotic core. It must be noted, as already mentioned, that coronary plaque disruption and thrombus are highly prevalent in MINOCA [22]. Since the diagnosis of plaque disruption has potential therapeutic implications, the use of intravascular imaging is recommended. The herewith associated higher costs, need for expertise and the extra time needed in the catheterisation laboratory should be taken into consideration.

To evaluate MVA or VSA, a combination of intracoronary interventional diagnostic procedures can be performed directly during the index procedure or a second procedure to assess the CFR (abnormal <2.0), IMR (abnormal ≥25) or FFR (abnormal ≤0.80). If coronary MVD is absent [negative CFR and IMR, in the absence of significant epicardial stenosis (negative FFR)], acetylcholine testing can be performed to reveal epicardial or microvascular spasm [69]. This combined invasive diagnostic approach, including medical therapy, was recently evaluated in the CorMicA trial in patients with stable angina pectoris. It was concluded that this approach improves angina symptoms and quality of life [70].

These techniques are safe in experienced hands. However, one should be aware of the potential complications (e.g. local bleeding complications, coronary artery dissection or perforation, acute kidney injury and stroke). Furthermore, CFR is highly influenced by age, blood pressure, heart frequency and contractility. Besides, it can be difficult to obtain good signals using the Doppler wire.

Altogether, both intravascular imaging and functional testing for detecting vasospasm or microvascular resistance play an important role in detecting the true mechanism of MINOCA. What kind of testing is most appropriate depends on the clinical presentation and the hospital resources. For example, intracoronary provocation testing may be the first choice in a patient with nocturnal angina pectoris and transient ST-elevation presenting with non-obstructive coronary arteries; on the other hand, if a patient with multiple traditional cardiac risk factors is diagnosed with subcritical stenoses, intracoronary imaging, and CFR and IMR measurements provide the most information (e.g. degree of atherosclerosis, plaque rupture or vulnerable plaque).

The Stockholm Myocardial Infarction with Normal Coronaries (SMINC-2) study will provide insight into whether or not early CMR can make a reliable diagnosis in more than 70% of all MINOCA patients (Clinical Trials NCT02318498) [71]. Furthermore, the ongoing MINOCA BAT (Clinical Trials NCT03686696) aims to provide information on the usefulness of beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 3500 MINOCA patients.

Several limitations should be addressed. First, the term MINOCA can be interpreted in several ways, and thus studies vary widely regarding the inclusion criteria of MINOCA. Many terms have been coined to describe patient with non-obstructive coronary arteries during an ACS. As the Dutch ACS working group we think use of an additional term will only lead to even less clarity, and thereby suggest using the term MINOCA as a dynamic working diagnosis to describe all possible underlying causes (i.e. coronary, myocardial and non-coronary disorders).

Secondly, the 50% angiographic stenosis threshold in MINOCA is somewhat arbitrary, since it was shown that the FFR was positive in a quarter of the patients with angiographically considered non-obstructive coronary arteries [72]. Although data on FFR testing in MINOCA patients is sparse, we agree with the American Heart Association that, if FFR is used, only patients with FFR findings >0.80 should be included in a working diagnosis of MINOCA [73]. Besides, for prognostic purposes it would be important to subdivide the MINOCA patients according to their angiographic coronary status into those with normal coronary arteries and mild CAD in future studies.

Third, since the MINOCA population is per definition heterogeneous, it is a challenge to make a clear-cut diagnostic pathway for every MINOCA case. For this reason, we chose to make a general algorithm including all potentially useful diagnostic modalities. Depending on the clinical presentation and the hospital resources, a patient-specific diagnostic approach should be made. However, CMR should play an important role in this approach given the high diagnostic yield.

MINOCA is a common clinical entity in patients presenting with AMI and represents many possible aetiologies that can be challenging to detect. By proposing a clinical diagnostic algorithm, we aim to encourage the clinician to find the underlying cause of MINOCA, since MINOCA should be regarded as a dynamic working diagnosis including coronary, myocardial and non-coronary disorders.