Management Strategies for Myocardial Infarction with Unobstructed Coronary Arteries

The pathophysiology, treatment, and outcomes of acute myocardial infarction (MI) vary depending on the presence or absence of obstructive coronary artery disease (CAD) or coronary dissection at the time of invasive coronary angiography.

This review focuses on myocardial infarction with unobstructed coronary arteries (MINOCA) syndrome, a myocardial infarction characterized by the absence of 50% or greater stenosis in all major epicardial coronary arteries on coronary angiography. This clinical picture encompasses patients without coronary atherosclerosis and those with mild to moderate non-obstructive atherosclerotic disease.

Uniform diagnostic criteria have been established for MINOCA to differentiate it from AMI with obstructive coronary artery disease (MI-CAD). MINOCA is a provisional diagnosis assigned at the time of coronary angiography in patients who meet the criteria for the universal definition of MI, with <50% diameter stenosis in all major epicardial coronary arteries, and in the absence of an alternative cause. specific for the clinical presentation, such as myocarditis or pulmonary embolism.

The syndrome occurs in approximately 6-8% of patients with spontaneous myocardial infarction who are referred for coronary angiography, and is substantially more common among women with myocardial infarction than among male patients.

The clinical presentations of MINOCA are often indistinguishable from myocardial infarction with obstructive coronary artery disease (MI-CAD).

The majority of MINOCA patients (83.1%) present with non-ST segment elevation MI (NSTEMI), but ST segment elevations can occur and are associated with an increased risk of in-hospital mortality.

The prevalences of traditional cardiovascular risk factors, such as dyslipidemia, diabetes mellitus, and smoking, are lower in patients with MINOCA compared with IM-CAD. However, 75% of MINOCA patients have at least one traditional cardiovascular risk factor.

The prognosis after MINOCA is more favorable than after IM-CAD. Still, MINOCA can be fatal, and prehospital deaths with histologic evidence of acute MI and unobstructed coronary arteries have been reported in the modern era. Patients may develop cardiogenic shock, ventricular arrhythmias, and in rare cases, mechanical complications such as cardiac rupture.

The post-discharge prognosis of patients after MINOCA is worse than that of patients without MI but more favorable than after IM-CAD.

> Short and long term mortality

At one year of follow-up, MINOCA mortality is 2 to 5%. Among people aged 65 years and older, the risk of adverse outcomes is even higher, with mortality as high as 12% at 1 year of follow-up.

> Reinfarction

Reinfarction occurs in 1.3-2.6% of patients at one year and in 7.1% at 4 years. 21.6% of these patients died during a median follow-up of 38 months, with no difference in mortality between those with and without progression of atherosclerosis.

> Major adverse cardiovascular events

Major adverse cardiovascular events (MACE), including all-cause mortality as well as hospitalization for myocardial infarction, ischemic stroke, or heart failure, occur at a considerable rate in patients with MINOCA. Clinicians should follow MINOCA patients closely in the years after discharge, as with other myocardial infarction patients.

> Risk factors for adverse outcomes

Risk factors associated with long-term MACE after MINOCA appear to be similar to those associated with poor outcomes after IM-CAD, including ST-segment elevation on the presentation electrocardiogram (ECG), older age, cardiac ejection fraction. reduced left ventricle, diabetes mellitus, hypertension, smoking, previous myocardial infarction, stroke, peripheral arterial disease, chronic obstructive pulmonary disease, chronic kidney disease and lower total cholesterol.

> Quality of Life

Physical capacity and quality of life are decreased after MINOCA. Nearly 25% of MINOCA patients reported angina 1 year after myocardial infarction, a similar proportion to IM-CAD patients.

The pathogenesis of MINOCA is heterogeneous and may include atherosclerotic plaque rupture or erosion, coronary thromboembolism, coronary spasm, and, rarely, coronary dissection. ( Figure 1 ). In some cases, patients may have a provisional diagnosis of MINOCA, but are ultimately assigned a diagnosis of takotsubo syndrome, acute myocarditis, or nonischemic cardiomyopathy after additional testing. These patients are not considered to have MINOCA once an alternative nonischemic diagnosis has been established.

> Rupture and erosion of the atherosclerotic plaque

Coronary atherosclerosis is a common cause of MINOCA, as demonstrated by intracoronary imaging studies. The responsible atherosclerotic plaques are usually smaller than in patients with obstructive IM-CAD. Plaque rupture exposes the tissue factor and thrombogenic contents of the lipid-rich necrotic core to the bloodstream, promoting local thrombus formation.

Plaque erosion, another possible atherosclerotic mechanism of MINOCA, is characterized by the formation of thrombi overlying a site of bare superficial endothelium that in turn overlies a fibrous plaque, rather than a lipid plaque.

There are several potential mechanisms by which plaque rupture and erosion can lead to MINOCA: transient vessel occlusion at the rupture site before intrinsic thrombolysis, distal embolization of part or all of the thrombus with occlusion of small vessels that not angiographically evident, or flush occlusion of the ostium of a side branch that is also not apparent on invasive angiography. In some cases, the thrombus may be identified only retrospectively, such as after cardiac magnetic resonance imaging (CMR) demonstrates an infarction in a corresponding coronary territory. Such patients may receive an initial diagnosis of MINOCA that ultimately turns out to be incorrect.

In clinical practice, intravascular imaging is essential to visualize plaque rupture, thrombus, or culprit plaques at various stages of healing after injury, including intraplaque cavities and healing layered plaques.

> Coronary artery embolism

Coronary artery embolism is a cause of MINOCA. An intracardiac thrombus may form in the left atrium, left atrial appendage, or left ventricle in the setting of stasis due to atrial fibrillation, ventricular dysfunction, or left ventricular noncompaction. Subsequent migration of the thrombus to the epicardial coronary arteries can cause myocardial infarction.

> Coronary artery spasm

Among MINOCA patients who underwent routine provocation testing with intracoronary acetylcholine or ergonovine, 24-70% showed evidence of epicardial or microvascular coronary spasm. Epicardial spasm is defined by vasoconstriction of at least 90% in response to provocative testing. Microvascular spasm is defined by recapitulation of symptoms with ECG changes in response to challenge without epicardial spasm.

Given the prevalence of coronary spasm in MINOCA, spasm can be inferred as the cause in the absence of dedicated provocative testing when regional infarction or edema is observed by CMR and no culprit coronary lesion is identified by intracoronary imaging.

> Spontaneous coronary artery dissection

Spontaneous coronary artery dissection (SCAD) is a rare cause of MINOCA. In SCAD, the spontaneous development of an intramural hematoma narrows the true lumen, occludes the side branches, or both, leading to myocardial infarction. Although SCAD is not atherosclerotic, it frequently appears as severe coronary narrowing on coronary angiography and is therefore an angiographic diagnosis that is not compatible with MINOCA.

> Coronary microvascular disease

Theoretically, coronary microcirculation may contribute to the development of MINOCA, either due to fixed resistance or lack of vasodilation in the context of increased myocardial oxygen demand. Coronary artery spasm frequently coexists with coronary microvascular disease. The prevalence of coronary microvascular disease in MINOCA is difficult to establish because testing is performed after an MI event has occurred and myocardial edema associated with MI has the potential to impair microvascular function.

Additional research is needed to define the contribution of coronary microvascular disease to the pathophysiology of MINOCA.

> Type 2 myocardial infarction and mismatch between supply and demand

Disturbances of myocardial oxygen supply and demand can lead to infarction, even in the absence of plaque rupture or angiographically obstructive CAD. This may occur in the setting of hypotension, hypertension, tachycardia, bradycardia, or profound anemia, with or without epicardial or microvascular CAD.

Several cardiac conditions associated with chest discomfort and elevated troponin levels, particularly takotsubo syndrome, myocarditis, and pulmonary embolism, can mimic the clinical presentation of MI. These conditions may be misclassified as MINOCA.

> Takotsubo syndrome

Takotsubo syndrome is a reversible syndrome of left ventricular dysfunction that can mimic the presentation of an acute MI, with elevated troponins, ischemic ECG changes, and symptoms. Takotsubo syndrome typically occurs in postmenopausal women, is preceded by a physical or emotional stressor, and causes left ventricular wall motion abnormalities that are out of proportion to peak troponin concentration.

B-type natriuretic peptide is usually elevated. The pathophysiology of takotsubo syndrome is not completely understood, but it is not believed to be caused by atherosclerotic vascular disease and is therefore considered distinct from myocardial infarction. The dominant mechanisms appear to be neurohormonal stunning and/or microvascular spasm, with the autonomic nervous system contributing significantly to the pathophysiology. Some patients may have a form of hypertrophic cardiomyopathy with dynamic outflow tract obstruction and increased afterload as a cause or contributor to takotsubo syndrome.

Careful review of coronary angiography is paramount in patients with suspected takotsubo syndrome, because SCAD of the left anterior descending coronary artery after expert angiographic review has been reported in a small proportion of these patients. Once the diagnosis of takotsubo syndrome has been confirmed, the term MINOCA no longer applies.

> Myocarditis

Myocarditis is a common cause of chest pain and troponin elevation in patients assigned a provisional diagnosis of MINOCA. A final diagnosis of myocarditis replaces the provisional MINOCA designation prior to CMR. However, it should be noted that coronary artery spasm is sometimes seen in cases of imaging-confirmed myocarditis.

> Pulmonary embolism

Pulmonary embolism (PE) should be considered in all patients with a provisional diagnosis of MINOCA, because PE is a life-threatening diagnosis that can cause chest pain, dyspnea, and elevated troponin concentrations. A history of recent immobility, long-distance travel, surgery, cancer, or calf pain may be useful clues to identify individuals with a high likelihood of PD. Unexplained tachycardia, tachypnea, or hypoxia should prompt D-dimer measurement or computed tomography pulmonary angiography to evaluate this alternative diagnosis before or after coronary angiography.

Optimal MINOCA treatment is expected to vary depending on the underlying mechanism of infarction. A systematic approach to evaluation is crucial to confirm the diagnosis of myocardial infarction and identify the underlying pathophysiology. A clinical algorithm was proposed in the 2019 American Heart Association scientific statement on MINOCA for this purpose ( Figure 2 ). This algorithm emphasizes careful review of coronary angiography, routine evaluation of left ventricular function with echocardiography or ventriculography, and contrast-enhanced CMR to diagnose myocarditis or identify the territory of acute MI or injury.

Intracoronary imaging with optical coherence tomography (OCT) or intravascular ultrasound (IVUS) should be considered at the time of diagnostic coronary angiography to identify culprit atherosclerotic lesions. Some operators may prefer to employ OCT as a separate diagnostic procedure, for example, after CMR has identified an area of ​​late gadolinium enhancement or regional myocardial edema, or at a minimum has ruled out myocarditis. Microvascular or epicardial coronary spasm testing may also be considered because the results could alter long-term medical therapy.

> Practical considerations about images

Intracoronary imaging with OCT or IVUS provides important information in the diagnostic evaluation of patients with MINOCA. However, selecting which glass(es) to image can be challenging, as the culprit glass cannot be reliably identified in many cases. In previous studies of patients with IM-CAD, ST depressions and T wave inversions on the ECG identified the correct culprit coronary vessel in only 60% and 84% of cases, respectively.

> Cardiac magnetic resonance imaging

Although CMR is essential for obtaining information about MINOCA, delays from the onset of ischemic symptoms to CMR, as well as the specific CMR sequences obtained, may affect the diagnostic performance of this modality. Studies highlight the critical importance of timely imaging in patients with MINOCA, ideally during the index hospitalization, as delays in imaging can lead to missed findings of myocardial edema or myocarditis.

> Provocation tests for coronary spasm

Provocative testing for coronary spasm may be considered at the time of diagnostic angiography for MINOCA or during subsequent invasive evaluation. Contemporary testing approaches involve administration of a bolus dose or an intracoronary infusion of acetylcholine or ergonovine. Despite concerns about the safety of provocative testing in the setting of acute myocardial infarction, emerging data support the relative safety of coronary reactivity testing for spasm among patients presenting with MINOCA.

> Coronary computed tomography angiography

Although coronary computed tomography angiography (CCTA) can identify the presence and extent of coronary atherosclerosis, the resolution of the images is currently not sufficient to identify culprit plaque rupture.

The performance of CCTA in MINOCA is low and its role in the diagnostic evaluation of MINOCA is currently limited. One clinical scenario in which CCTA may be useful is to assist in the decision to prescribe statin therapy to a MINOCA patient with angiographically normal coronary arteries.

> Role of revascularization

Currently, the preferred treatment for MINOCA is medical therapy.

Infrequently, intracoronary imaging in a patient with MINOCA may reveal substantial plaque burden, and a practitioner may choose to perform percutaneous coronary intervention in these cases. The benefits of doing so are still unclear.

Although this clinical scenario has never been specifically studied, a similar clinical syndrome is MI caused by thrombotic coronary occlusion due to erosion of a small plaque. In plaque erosion, a medical management strategy, with or without aspiration thrombectomy, but without stenting, conferred excellent long-term results.

> Medical therapy

Clinical practice guidelines for secondary prevention of MI are largely based on data from patients with IM-CAD. There are no specific medications known for optimal secondary prevention of MINOCA, and clinical trials are urgently needed. Consequently, medications for secondary prevention of myocardial infarction are administered less frequently at discharge after a diagnosis of MINOCA than IM-CAD, and with heterogeneity in clinical practice indicative of balance in the medical community.

In the absence of randomized controlled trials, observational studies provide key information about the best medical therapy. Statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were associated with lower rates of long-term MACE. Beta blockers (BB) were associated with a trend toward benefit while no reduction in MACE was observed with dual antiplatelet therapy. Although the administration of calcium channel blockers is reasonable in patients with coronary spasm as a presumed mechanism of infarction, their role in unselected patients with MINOCA remains uncertain.