Introduction

Current management of acute myocardial infarction (MI) is based on a prompt diagnosis and immediate revascularization through a diagnostic coronary angiography and subsequent revascularization, mostly percutaneous interventions.¹ About 90% of patients presenting with ST-segment elevation MI have an explanatory coronary artery stenosis or occlusion.² For these patients, the role of atherosclerosis and the benefits of cardioprotective medications have been well-established.

The remaining 10%, however, have an acute myocardial injury without a documented, related obstructive coronary artery lesion.^3,4 This subgroup, currently referred to as myocardial infarction with nonobstructive coronary arteries (MINOCA), was considered a benign entity requiring little or no therapeutic attention. Over the recent years however, evidence has emerged that the associated morbidity and mortality of MINOCA demands more efficient diagnostic and therapeutic approaches.⁵ Yet MINOCA remains a diagnostic and therapeutic dilemma due to the paucity of studies evaluating these patients.

Clinical Features and Diagnosis

Patients presenting with MINOCA have a lower incidence of dyslipidemia and appear to be younger and more often female; however, neither their risk profile nor their clinical presentation differ from patients presenting with an acute MI and obstructive coronary artery disease.³

The diagnosis of MINOCA, as defined by the European Society of Cardiology (ESC) working group, requires

1. clinical and/or biochemical evidence of acute MI with increased biomarkers for myocardial injury and electrocardiographic changes,
2. the exclusion of obstructive coronary artery disease as defined by a coronary stenosis <50% (either invasively or with computed tomography angiography), and
3. no other apparent cause for the acute presentation.⁶

Once this preliminary diagnosis is established, it should remain a "working diagnosis," requiring further evaluation.

Acute pulmonary embolism should be high on the list of differential diagnoses. CT pulmonary angiography performed in 100 consecutive patients with MINOCA however yielded no positive tests and is thus not recommended as a routine practice.⁷

The Role of CMR in MINOCA

Cardiovascular magnetic resonance (CMR) has emerged as the gold standard for noninvasive assessment of the heart due to its safety, inter-observer consistency, quantitative accuracy, and ability to characterize the myocardium. Accordingly, CMR is a key diagnostic tool in the evaluation of patients presenting with MINOCA.⁸

In a prospective study of 125 consecutive patients presenting with MINOCA, Pathik et al. were able to provide a specific diagnosis in 87% of their patients. Among them, 37% were diagnosed with acute myocarditis, and 27% were found to have Takotsubo cardiomyopathy. Another 21% were diagnosed with an acute MI, 1% revealed apical hypertrophy, and 2% were diagnosed with a dilated cardiomyopathy.⁹ These results were supported by a recent meta-analysis of 26 CMR publications reasserting myocarditis as the leading diagnosis in patients with MINOCA.³ CMR is therefore strongly recommended by various experts and the ESC's task force when evaluating patients with the working diagnosis of MINOCA. CMR is recommended within 7 days of presentation because delayed imaging can sometimes result in some features no longer being evident.¹⁰

Acute MI

Possible causes of MINOCA include plaque rupture, plaque erosion, or plaque ulceration with spontaneous autolysis of the associated intracoronary thrombus, leaving a seemingly benign appearing lesion during index angiography. Reynolds et al. were able to identify a plaque rupture or ulceration as a cause for MINOCA in 38% of patients presenting with MINOCA using intravascular imaging. The noninvasive diagnosis of acute MI can be made using CMR if there is late gadolinium enhancement (LGE) in a subendocardial or transmural pattern corresponding to a vascular territory. Moreover, T2 weighted imaging with a high regional signal serves as evidence for the perilesional edema, thereby verifying an acute rather than chronic event (Figure 1).¹¹ Based on the delayed-enhancement magnetic resonance imaging trial, test sensitivity reached 99% for detecting acute MI and 94% for detecting chronic MI. Lastly, in the presence of LGE, the correct location and culprit artery were identified in 97-100% of cases.^12-13

Figure 1

The diagnosis of an acute MI in MINOCA may have important implications. If performed acutely and with a CMR showing edema in a coronary regional distribution pattern, the diagnosis of acute MI could be established despite the lack of a persisting explanatory stenosis. Secondary prevention would then be indicated. Edema in a non-coronary distribution (predominant subepicardial edema), on the other hand, would exclude MI.

Myocarditis

Most clinicians still consider endomyocardial biopsy as the reference standard for the diagnosis of myocarditis, which is not without risk, however. In addition, despite multiple biopsies of the left and right ventricle, the diagnostic accuracy remains modest at best. Current guidelines recommend biopsy only in specific cases such as acute heart failure. Therefore, clinicians lean toward a noninvasive technique such as CMR.⁸

The Lake Louise Criteria approach consists of late enhancement sequences, T2-weighted edema images, and T1-weighted sequences before and after contrast injection (early enhancement). Diagnosis of myocarditis requires at least two of the following:

1. The presence of myocardial edema
2. Capillary leaks and hyperemia
3. Necrosis/fibrosis¹⁴

The Lake Louise Criteria have been developed for acute rather than chronic myocarditis, underscoring the necessity for early rather than late imaging in such patients (Figure 2).

Figure 2

Recently, novel quantitative T1 and T2 mapping techniques, including the quantification of extracellular volume, have emerged as new techniques in the characterization of the myocardium and were found to overcome some of the limitations of the Lake Louise Criteria. T2 times were found to be elevated in acute myocarditis, again identifying edema as the prime indicator of acute disease.¹⁵

Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a type of non-ischemic cardiomyopathy in which there is a sudden and reversible myocardial stunning in the absence of occlusive coronary artery disease.¹⁶ CMR has become a useful tool for noninvasive assessment of these patients.

Cine sequences allow for the assessment of LV contractility and function. Contractile anomalies typically affect the anterior, inferior, and lateral walls equally and extend beyond a single epicardial vascular territory. Although the classic Takotsubo consists of apical ballooning, assuming a Japanese "octopus pot" like shape, as many as 40% have atypical locations. Figure 3 shows an example.

Figure 3

Myocardial edema is readily identified using T2-weighted images. The area of edema typically matches the dysfunctional segments of the myocardium and also extends beyond a single epicardial vascular territory. The combination of an extensive non-coronary wall motion abnormality with edema and the absence of ischemic scars provide solid evidence for Takotsubo cardiomyopathy.¹⁷ T2 mapping technique may offer a more robust alternative to the assessment of edema.

LV segments show diffuse yet no regional perfusion deficits in first-pass perfusion images and typically no areas of high signal intensity in LGE images because there is no irreversible myocardial injury.¹⁸

Overall, CMR diagnosis is favoured with the presence of marked LV ballooning and myocardial edema in the absence of significant LGE. Complications may present in the acute phase, including LV outflow obstruction, acute heart failure, and arrhythmia, and recent data indicate that the overall prognosis may not be favourable.¹⁹

Normal CMR

In a number of studies, including a meta-analysis of 26 CMR studies investigating patients with MINOCA, 8-26% had a completely normal CMR devoid of LGE, edema, or perfusion defects. The timing of CMR may be a factor, and finding an alternate diagnosis for the rise in troponin becomes relevant. To date, no studies have addressed this population, and their management remains unclear.⁸

Coronary Artery Spasm and Thrombophilia

Coronary artery spasm with resultant transient myocardial injury and chest pain have been reported in up to a third of patients presenting with MINOCA.²⁰ The prevalence is higher amongst Asians, with a reported frequency of 81% in Japanese patients and 61% in Korean patients presenting with MINOCA.²² The diagnosis of coronary artery spasm is based on intracoronary provocative tests using acetylcholine or ergonovine. Intracoronary provocative tests were originally understood to be potentially dangerous, but Montone et al. demonstrated that the tests are safe and informative because patients with a positive test had a higher occurrence of all-cause mortality, and in particular cardiac mortality, when compared with the patients with a negative test.²³ This comes as no surprise given previous studies showing that failure to initiate a calcium-channel blocker in this population is an independent predictor of mortality.²⁴

Thrombophilia including coronary embolism have previously been reported in up to 14% of patients presenting with MINOCA. Factor V Leiden, protein C and protein S deficiency, and Factor XII deficiency were identified as the heritable causes, and malignancy and systemic lupus erythematous were identified as acquired causes.⁶

Treatment

To date, there are no randomized clinical trials evaluating different treatments in MINOCA patients. Observational data from the SWEDEHEART registry demonstrated an 18% reduction in major adverse cardiac events (MACE) with the introduction of an angiotensin-converting enzyme inhibitor/ angiotensin-receptor blocker as well as a 23% reduction in MACE with statin therapy. Both beta-blockers and dual antiplatelet therapy were associated with a 14% and 10% reduction in MACE; however, they did not reach statistical significance.²⁵ In the absence of systematic evaluation, the ESC currently proposes empiric treatment with aspirin, statins, and, in cases of vasospasm, calcium-channel blockers assuming the potential underlying mechanisms include coronary plaque disruption, coronary spasm, and thromboembolism.⁸

Prognosis

MINOCA was once recognized as a benign entity, but present data suggest that the prognosis for patients with MINOCA is more guarded. In a recent meta-analysis, all-cause mortality was reported at a rate of 0.9% at 30 days and 4.7% at 12 months. Although these are lower than the rates associated with MI and obstructive coronary disease (3.2% at 30 days and 6.7% at 12 months), they are similar to the rates quoted for patients with single or double vessel disease who have had a previous MI. As such, clinical recognition of this patient subgroup is essential, and evaluating the underlying cause is paramount.³ Because of the wide scope of underlying causes, more research is warranted on an early diagnostic workup in patients with MINOCA.

References

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Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pericardial Disease, Prevention, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Magnetic Resonance Imaging, Nuclear Imaging, Chronic Angina

Keywords: Myocarditis, Takotsubo Cardiomyopathy, Acute Coronary Syndrome, Heart Failure, Diagnostic Imaging, Acetylcholine, Acute Disease, Aged, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Arrhythmias, Cardiac, Aspirin, Atherosclerosis, Biomarkers, Biopsy, Calcium Channel Blockers, Cardiomyopathy, Dilated, Chest Pain, Cicatrix, Angiography, Constriction, Pathologic, Coronary Artery Disease, Coronary Stenosis, Coronary Vasospasm, Diagnosis, Differential, Dyslipidemias, Edema, Electrocardiography, Embolism, Ergonovine, Factor V, Factor XII Deficiency, Gadolinium, Heart Ventricles, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperemia, Hypertrophy, Incidence, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Muscle, Skeletal, Myocardial Infarction, Myocardial Stunning, Myocarditis, Myocardium, Neoplasms, Octopodiformes, Pericardial Effusion, Prospective Studies, Protein C, Protein S Deficiency, Pulmonary Embolism, Registries, Secondary Prevention, Spasm, Thromboembolism, Thrombosis, Troponin, Ventricular Septum

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