INTRODUCTION — Most cases of acute myocardial infarction (MI) are caused by rupture or erosion of an atherosclerotic plaque associated with subsequent thrombus formation [1]. Other causes include a supply-demand mismatch in the presence or absence of a significant stenoses. (See "Angina pectoris: Chest pain caused by fixed epicardial coronary artery obstruction", section on 'Pathophysiology of myocardial ischemia' and "Mechanisms of acute coronary syndromes related to atherosclerosis".)
This topic will discuss the potential causes of MI that occur in the absence of obstructive atherosclerosis.
DEFINITIONS — MI is defined as a clinical (or pathologic) event in the setting of myocardial ischemia in which there is evidence of myocardial injury [2,3]. The diagnosis is secured when there is a rise and/or fall of troponin, along with supportive evidence in the form of typical symptoms, suggestive electrocardiographic changes, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. (See "Diagnosis of acute myocardial infarction", section on 'Definitions'.)
MI with no obstructive coronary atherosclerosis (MINOCA) is a distinct clinical syndrome characterized by evidence of MI with normal or near normal coronary arteries on angiography (stenosis severity ≤50 percent) in the absence of obvious noncoronary causes of MI like a severe hemorrhage or severe respiratory failure [4]. There are several well-defined causes/pathophysiologic mechanisms for MINOCA; the prognosis and management differs for each of these.
PREVALENCE — In a systematic review of studies, the prevalence of myocardial infarction with no obstructive coronary atherosclerosis among patients with acute myocardial infarction was between 1 and 14 percent with a mean of 6 percent [5]. However, prevalence varied widely across the studies.
PROGNOSIS — Given the heterogeneity of causes, studies of the prognosis of patients with myocardial infarction with no obstructive coronary atherosclerosis (MINOCA) are of limited value, as prognosis may be influenced by the cause as well as the degree of myocardial damage associated with the MI. In a meta-analysis of eight studies that reported all-cause mortality in patients with MINOCA, in-hospital mortality was 0.9 percent and 12-month mortality was 4.7 percent [5]. When restricted to studies directly compared MINOCA and MI due to obstructive coronary artery disease, in-hospital and 12-month mortality was lower in MINOCA patients (1.1 versus 3.2 percent and 3.5 versus 6.7 percent, respectively). Of interest, reduced left ventricular ejection fraction, nonobstructive coronary artery disease, use of beta blockers during follow-up, and ST-segment depression on the admission electrocardiogram are significant predictors of long-term prognosis [6].
CAUSES — Myocardial infarction with no obstructive coronary atherosclerosis (MINOCA) is a syndrome with many causes [4]. They may involve the epicardial vessels and/or the coronary microcirculation. The subdivision into epicardial and microvascular causes is somewhat arbitrary but allows for one way to think about them.
Epicardial
Coronary artery spasm — Coronary artery spasm, as seen in “variant angina,” usually occurs at a localized segment of an epicardial artery, but sometimes involves two or more segments of the same (multifocal spasm) or of different (multivessel spasm) coronary arteries. It may also involve diffusely one or multiple coronary branches [7]. Coronary artery spasm is discussed in detail elsewhere. (See "Vasospastic angina".)
Among studies in patients with MINOCA, the reported prevalence of coronary spasm is extremely variable (3 to 95 percent) and this has been attributed to the different stimuli/provocative tests used to diagnose spasm, and different definitions of spasm.
Myocardial bridging, per se, is unlikely to cause MINOCA. However, it can predispose the affected artery to spasm. MINOCA patients with bridging seen on coronary angiography should be considered for provocative testing.
Acute thrombosis at the site of non-obstructive eccentric plaque thrombosis — Many atherosclerotic plaques expand outward rather than encroaching on the arterial lumen. These "positively-remodelled" plaques are often lipid rich and have a thin fibrous cap; they are vulnerable to rupture into the lumen [1,8,9]. Transient and partial thrombosis at the site of a non-obstructive plaque with subsequent spontaneous fibrinolysis and distal embolization may be one of the mechanisms responsible for the occurrence of MINOCA. Similarly, coronary erosion with loss of surface endothelium, possibly due to hyaluronan and neutrophil accumulation, can also cause MINOCA [1,10]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)
The reason for these cases to be labeled as MINOCA is that angiography is of limited utility for the purpose of elucidating plaque-related thrombosis as a cause of thrombosis due to its low resolution as well as the fact that it does not interrogate the lumen of the vessel. Thus, intracoronary imaging modalities are crucial in this setting. Plaque rupture or erosion has been diagnosed by intravascular ultrasound in about 40 percent of women with MINOCA [11]. Optical coherence tomography, due to its high resolution, may provide additional information [9,12].
As MINOCA is associated with a risk of recurrent cardiovascular events over time, comparable with that of patients with acute coronary syndromes (ACS) and obstructive atherosclerosis [5,13,14], these patients require dual antiplatelet treatment for 12 months and statins. In particular, long-term lipid-lowering therapy with statins after MI is associated with a significant increase of the fibrous-cap thickness, paralleling the reduction of the lipid content of the plaque [15]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
Spontaneous coronary artery dissection — Spontaneous coronary artery dissection (SCAD) is more common among young women, and sex-related hormones play an important pathogenetic role. SCAD is frequently associated with fibromuscular dysplasia in other vascular beds. In the majority of cases, it is obstructive, and the diagnosis can be based on coronary angiography; in other less obvious cases, intravascular imaging is necessary for an accurate diagnosis. Percutaneous interventions are limited to patients with electrical or hemodynamic instability, as the dissection tends to heal spontaneously over time [16]. (See "Spontaneous coronary artery dissection".)
Microvascular
Takotsubo cardiomyopathy — Takotsubo or stress cardiomyopathy is characterized by apical ballooning of the left ventricle in the absence of obstructive coronary artery disease (CAD). The prevalence of Takotsubo cardiomyopathy is reported to range between 1.2 and 2.2 percent of all ACS cases and women in the post-menopausal age are affected most frequently [17,18]. This issue is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)
Coronary microvascular dysfunction — Coronary microvascular dysfunction, also referred to as cardiac syndrome X or angina pectoris with normal coronary arteries, is a process characterized by transient myocardial ischemia, as indicated by ST-segment changes and angina as well as either spontaneous or induced by intracoronary administration of acetylcholine, in the absence of obstructive CAD and epicardial spasm [19]. About 25 percent of patients with ACS and no obstructive CAD have evidence of coronary microvascular dysfunction, although an increase of troponin is infrequent [20]. This topic is discussed in detail elsewhere. (See "Microvascular angina: Angina pectoris with normal coronary arteries".)
Viral myocarditis — Adenoviruses, parvovirus B19 (PVB19), human herpesvirus 6, and Coxsackie virus are considered the most common causes of viral myocarditis, which accounts for about one-third of cases of patients with MINOCA. Viral myocarditis is discussed in detail elsewhere. (See "Myocarditis: Causes and pathogenesis" and "Clinical manifestations and diagnosis of myocarditis in adults".)
Coronary artery embolism — Coronary artery embolism (CE) is an uncommon cause of acute MI that often affects the microcirculation, although angiographically visible embolization of epicardial coronary artery branches may occur. It should be suspected in patients with MINOCA and one of the following conditions associated with high risk of systemic embolism: prosthetic heart valves, atrial fibrillation (AF), dilated cardiomyopathy with apical thrombus, rheumatic heart disease with mitral stenosis, infective endocarditis, and atrial myxoma. Paradoxical embolism is a rare cause of MINOCA. Importantly, in patients in whom paradoxical embolism is suspected, coronary angiography needs to be carefully analyzed for the identification of amputation (also called “stops”) of distal (peripheral) coronary branches. Transthoracic, transesophageal, and contrast-enhanced echocardiography are the cornerstone methods for detection of cardiac sources of embolism as causes of MINOCA. (See "Cardiac tumors" and "Postoperative complications among patients undergoing cardiac surgery", section on 'Myocardial infarction' and "Echocardiography in detection of cardiac and aortic sources of systemic embolism", section on 'Potential sources of emboli'.)
Criteria for the diagnosis of coronary artery embolism have been proposed (table 1).
The prevalence and features of CE–related MI were evaluated in a study of 1776 patients with a first MI who underwent diagnostic coronary arteriography and transthoracic echocardiography [21]. Criteria for the clinical diagnosis of definite or probable CE were established. The following findings were noted:
●The prevalence of CE was 2.9 percent; of these, about 15 percent had multivessel CE.
●AF was the most common cause of CE (73 percent). Other causes included cardiomyopathy and valvular heart disease.
●In a propensity score-matched analysis, patients with CE had a higher incidence of cardiac death than those in the non-CE group (hazard ratio 9.29, 95% confidence interval 1.13-76.5).
Distal coronary artery embolism can occur in patients with coronary artery aneurysms, which can be detected by routine coronary angiography. Intravascular ultrasound or optical coherence tomography can provide additional information as to whether the aneurysm(s) is a potential source of thrombus.
CLINICAL FEATURES — The clinical presentation of MINOCA is similar to that of acute coronary syndrome patients with obstructive coronary artery disease [5]. However, MINOCA patients are younger and more often women [5,13]. In one large systematic review, women accounted for about 40 percent of patients and the pooled mean age was about 55 years [5]. Traditional risk factors for cardiovascular disease (diabetes, smoking, hypertension, and family history) were similar between patients with MI with atherosclerosis and those with MINOCA, with the exception of hyperlipidemia, which occurred less often (21 versus 32 percent). (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Clinical presentation'.)
In patients with MINOCA, the results of electrocardiograph and biomarker testing mimic those of patients with atherosclerotic coronary obstruction. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Electrocardiogram assessment' and "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Cardiac biomarkers and other laboratory testing'.)
DIAGNOSIS — For patients meeting the definition of acute MI (see 'Definitions' above and "Diagnosis of acute myocardial infarction", section on 'Definitions'), the diagnosis of MINOCA is made based on the finding of no major luminal irregularities at the time of coronary angiography (ie, no lesions obstructing the luminal diameter by more than 50 percent). The diagnosis of MINOCA cannot be made without coronary angiography having been performed.
DETERMINING THE CAUSE — For patients who meet the diagnostic criteria for myocardial infarction with no obstructive coronary atherosclerosis (MINOCA) (see 'Diagnosis' above), we recommend that an attempt be made to establish the specific cause/triggering mechanism, as prognosis and management varies with the cause. (See 'Causes' above.).
Our approach to elucidating the cause of MINOCA uses information in the patient’s history as well as that from an assessment of left ventricular (LV) wall motion, preferably with transthoracic echocardiography (TTE). If TTE has not been performed before coronary angiography, it can be performed in the catheterization laboratory or left ventriculography can be performed as a substitute. However, information from the history, coronary angiography, or evaluation of LV wall motion, is neither sensitive nor specific for a particular cause.
The following are a few examples of the way in which the history or assessment of LV wall motion may direct the evaluation.
●Patients with a chronic pattern of recurrent episodes of chest pain suggesting episodic angina are more likely to have vasospasm than other diagnoses.
●Regional wall motion abnormalities may indicate that an epicardial cause of MINOCA, such as vasospasm or thrombosis, on a nonobstructive atherosclerotic plaque is likely.
●Left ventriculography or echocardiography showing apical ballooning with akinesis or dyskinesis of the apical one-half to two-thirds of the LV suggests Takotsubo cardiomyopathy.
●Coronary artery embolism should be considered in patients with prosthetic heart valves, chronic atrial fibrillation, dilated cardiomyopathy with apical thrombus, infective endocarditis, and atrial myxoma.
Aside from coronary angiography and assessment of LV wall motion, the following tests may be useful for elucidating the cause of MINOCA: optical coherence tomography (OCT) or intravascular ultrasound (IVUS); acetylcholine (Ach) or ergonovine challenge; cardiac magnetic resonance imaging with contrast material (CMR/CM); endomyocardial biopsy; contrast enhanced echocardiography and transesophageal echocardiography; and testing for markers of thrombophilia (eg, protein C and S deficiency, as well as enhanced Factor VII activity). The sequence in which these tests are performed depends on the likelihood of the cause based on the history and evaluation of LV wall motion.
If coronary angiography is abnormal but reveals less than 50 percent luminal obstruction and/or nonocclusive thrombus, we often perform IVUS or OCT to identify subcritical plaque fissure or erosion and thrombus or spontaneous coronary artery dissection. These studies are performed before the patient is discharged from the catheterization laboratory. (See 'Acute thrombosis at the site of non-obstructive eccentric plaque thrombosis' above.)
If coronary angiography reveals normal or near normal epicardial arteries and the history suggests coronary artery spasm or if IVUS/OCT has not been helpful, we consider provocative testing with intracoronary Ach or ergonovine. This test is performed before the patient is discharged from the catheterization laboratory. It should be kept in mind that the diagnosis of coronary artery spasm does not require confirmation of spasm with provocative testing. Provocative testing is performed only when the diagnosis of variant angina is suspected, but not firmly established. Provocative testing may also suggest a diagnosis of microvascular dysfunction. (See 'Coronary microvascular dysfunction' above.) At present, pharmacologic provocative testing is not frequently performed and should be employed only by experienced teams. (See "Vasospastic angina", section on 'Diagnosis'.) Finally, intracoronary Ach test may suggest coronary microvascular dysfunction as the cause of MINOCA.
If a cause of MI has not been identified in the catheterization laboratory with the above strategy, additional testing can be performed. If the history or echocardiogram suggests Takotsubo cardiomyopathy or myocarditis, CMR/CM may be helpful to confirm the diagnosis. If clinical data suggest coronary microembolism, transthoracic or transesophageal echocardiography or contrast-enhanced echocardiography is required to detect a cardiac source of embolism.
MANAGEMENT — The management of myocardial infarction with no obstructive coronary atherosclerosis (MINOCA) is specific to the underlying cause, if determined (see 'Causes' above). For patients who have some evidence of atherosclerotic disease in the coronary circulation and no other cause for MINOCA has been found, we believe it is reasonable to assume the patient has had an acute coronary syndrome attributable to atherosclerotic disease and discharge the patient on aspirin, a platelet P2Y12 receptor blocker, beta blocker, and a statin. (See "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction", section on 'Summary and recommendations'.)
An observational study from the SWEDEHEART registry included 9466 consecutive unique patients with MINOCA [22]. During the follow-up of a mean of 4.1 years, 2183 (23.9 percent) patients experienced a major adverse cardiac event. The hazard ratios (95% CI) for major adverse cardiac events were 0.77 (0.68 to 0.87), 0.82 (0.73 to 0.93), and 0.86 (0.74 to 1.01) in patients on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and beta blockers, respectively. For patients on dual antiplatelet therapy followed for one year, the hazard ratio was 0.90 (0.74 to 1.08). The authors showed long-term beneficial effects of treatment with statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on outcome in patients with MINOCA, a trend toward a positive effect of beta blocker treatment, and a neutral effect of dual antiplatelet therapy. Each of the treatments might have a beneficial effect in a specific patient subset with a common cause of MINOCA, while the effect may be diluted in the whole MINOCA population. Thus, the observational nature of this study makes us uncertain of the potential magnitude of the benefit or lack of benefit of these interventions. For the time being, the major effort remains an accurate diagnosis of the underlying cause of MINOCA, which can be obtained in the vast majority of patients using intravascular imaging, provocative coronary testing, and CMR. This is the key premise for a personalized form of treatment.
RECOMMENDATIONS OF OTHERS — A European Society of Cardiology working group has published a position paper on myocardial infarction with non-obstructive coronary arteries [23]. The content of that paper is similar to the content of this topic review.
SUMMARY
●Definitions – Myocardial infarction with no obstructive coronary atherosclerosis (MINOCA) is a syndrome with multiple potential causes. (See 'Definitions' above.)
●Prevalence – The prevalence of MINOCA among all cases of MI is about 6 percent and ranges between 1 and 14 percent. (See 'Prevalence' above.)
●Determining the cause – The cause of MINOCA, if not apparent, can often be secured using an algorithmic approach. (See 'Determining the cause' above.)
●Prognosis – The prognosis is variable, depending on the cause, and in many cases, it is similar to that of MI with obstructive atherosclerosis. (See 'Prognosis' above.)
●Management – The management of the patient is determined by the cause, if one is identified. (See 'Management' above.)
