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Sex-specific and ethnicity-specific differences in MINOCA

Sarena La, John Beltrame & Rosanna Tavella, R. Sex-specific and ethnicity-specific differences in MINOCA. Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-023-00927-6

Abstract

Suspected myocardial infarction with non-obstructive coronary arteries (MINOCA) has received increasing attention over the past decade. Given the heterogeneity in the mechanisms underlying acute myocardial infarction in the absence of obstructive coronary arteries, the syndrome of MINOCA is considered a working diagnosis that requires further investigation after diagnostic angiography studies have been performed, including coronary magnetic resonance angiography and functional angiography. Although once considered an infrequent and low-risk form of myocardial infarction, recent data have shown that the prognosis of MINOCA is not as benign as previously assumed. However, despite increasing awareness of the condition, many questions remain regarding the diagnosis, risk stratification and treatment of MINOCA. Women seem to be more susceptible to MINOCA, but studies on the sex-specific differences of the disease are scarce. Similarly, ethnicity-specific factors might explain discrepancies in the observed prevalence or underlying pathophysiological mechanisms of MINOCA but data are also scarce. Therefore, in this Review, we provide an update on the latest evidence available on the sex-specific and ethnicity-specific differences in the clinical features, pathophysiological mechanisms, treatment and prognosis of MINOCA.

Introduction

The diagnosis and management of acute myocardial infarction (MI) has progressed substantially in the past four decades owing, in part, to innovations in the assessment of coronary artery disease (CAD), including the widespread use of coronary angiography. However, patients fulfilling the clinical criteria of acute MI but with non-obstructive coronary arteries on angiography present a conundrum. This clinical scenario was first documented >80 years ago and, until the past decade, these patients were often overlooked as having a ‘false-positive’ MI with a presumptive favourable prognosis. Accordingly, a clear definition of this entity and increased clinical recognition have been warranted, particularly considering the extensive potential causes underlying its presentation.

The term MINOCA, the acronym for ‘MI with non-obstructive coronary arteries’, was first coined in 2013 (ref. 4) and, in 2015, Pasu- pathy et al. presented a benchmark systematic review that defined the characteristics of patients with MINOCA. This report drummed up clinical interest in the field, which ultimately led to the publication of diagnostic criteria for MINOCA by the ESC (Box 1). Subsequently, in the fourth universal definition of MI, a delineation between myocardial injury (elevated plasma troponin levels) and MI (myocardial injury owing to ischaemia) was emphasized, in which non-ischaemic condi- tions, including myocarditis or Takotsubo syndrome, would no longer fall under the definition of MI. These concepts were incorporated into the 2019 AHA Scientific Statement, which stated that the term ‘MINOCA’ should be reserved for patients in whom there is an ischae- mic basis for their presentation (that is, true MINOCA) as opposed to myocardial injury that is attributable to non-ischaemic mechanisms (known as MINOCA mimickers). Therefore, the working diagnosis approach in patients with suspected MINOCA is to first exclude those with non-ischaemic conditions, and then identify the underlying cause of myocardial ischaemia in those with true MINOCA (Fig. 1).

In this Review, we provide a detailed update of the clinical features, pathophysiology, diagnosis and management of MINOCA, with a specific focus on sex-related and ethnicity-related differences in their presentation as well as the socioeconomic factors that influence the disease course. Although we should ideally focus on patients with true MINOCA, much of the available literature utilizes the term ‘MINOCA’ in a generic context (that is, without the exclusion of MINOCA mimickers). Accordingly, this Review will include generic MINOCA studies in which both true MINOCA and MINOCA mimickers have not been distinguished.

Prevalence and clinical presentation

The prevalence of MINOCA is estimated to be 1–14% (overall prevalence 6%) of the population of patients with acute MI; this large range in prevalence is in part due to variations in the definition of MINOCA. The available studies consistently show that, compared with patients with MI and CAD (MICAD), patients with MINOCA are younger (mean age 59 years for MINOCA versus 61 years for MICAD) and more likely to be female (43% for MINOCA versus 24% for MICAD) but are less likely to present with traditional cardiovascular risk factors such as hypertension, dyslipidaemia, diabetes mellitus and a history of smoking. ST-segment elevation MI (STEMI) accounts for one-third of MINOCA cases and is associated with an increased risk of in-hospital death. A lower peak of cardiac troponin concentration in plasma has been observed in patients with MINOCA compared with patients with MICAD. Of note, patients with MINOCA have circadian rhythm variations that are similar to those observed in patients with MICAD, such as an increased risk of disease onset in early mornings and on Mondays, which points to the role of stress-related triggers in the pathophysiology of MINOCA and MICAD. A small increase in the incidence of MINOCA has also been observed during the summer and autumn seasons.

Pathophysiological mechanisms

Numerous mechanisms are involved in the pathophysiology of a true MINOCA diagnosis, including coronary artery spasm and microvascular dysfunction, coronary artery plaque disruption, spontaneous coronary thrombosis or embolism, spontaneous coronary artery dissection (SCAD), and supply–demand mismatch (Fig. 1).

Epicardial coronary artery spasm

Myocardial ischaemia can be caused by subtotal or total occlusion (defined as ≥90% constriction) of an epicardial coronary artery from coronary artery spasm. In vasospastic angina, coronary artery occlusion is typically transient; however, with prolonged vasospastic occlusion, MI might ensue. The reported prevalence of MINOCA in the literature ranges from 47% to 73%, which is largely attributable to differences in diagnostic approaches and definitions. Although spontaneous episodes of coronary artery spasm can be observed during coronary angiography, provocative spasm testing is required for a definitive diagnosis, yet few studies involving patients with MINOCA have routinely performed this invasive procedure. In a study that performed provocative spasm testing in 80 patients with stable true MINOCA, epicardial coronary artery spasm was inducible in 65% of the cohort. Identifying coronary artery spasm as the underlying mechanism for MINOCA is important given the potential adverse events associated with the condition (including malignant arrhythmias and cardiac arrest) and the effectiveness of calcium channel blocker therapy in preventing spasm and MI.

Coronary microvascular dysfunction

Coronary microvascular dysfunction has traditionally been defined on the basis of an impaired coronary microvascular vasodilatory response to physiological (exercise or tachycardia) or pharmacological (adenosine) stimuli. Coronary microvascular dysfunction can potentially contribute to the pathogenesis of MINOCA; however, the related clinical disorders have typically been described primarily in patients with stable angina. Microvascular angina refers to patients with non-obstructive CAD and an impaired coronary flow, whereas microvascular spasm has been established as a hyper-reactive microvascular constrictor response to acetylcholine during provocative spasm testing and in the absence of epicardial coronary artery spasm. Theoretically, however, microvascular spasm and epicardial coronary artery spasm could coexist. Finally, the coronary slow flow phenomenon, observable on angiography, is characterized as delayed distal vessel opacification in the absence of obstructive coronary artery vessel disease, which results in increased microvascular resistance and is usually assessed by thrombolysis in myocardial infarction (TIMI) frame counts. These three microvascular pathophysiological entities have been described in patients with MINOCA. Microvascular dysfunction can be a cause of ischaemia but can also occur as a consequence of myocardial injury; further studies are needed to understand the role of coronary microvascular dysfunction in MINOCA.