Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA)

Article, see p 1481

Myocardial infarction with nonobstructive coronary arteries (MINOCA) is clinically defined by the presence of the universal acute myocardial infarction (AMI) criteria, absence of obstructive coronary artery disease (≥50% stenosis), and no overt cause for the clinical presentation at the time of angiography (eg, classic features for takotsubo cardiomyopathy). With the more frequent contemporary use of coronary angiography in AMI, clinicians have been regularly confronted with this puzzling problem and seeking guidance in its management. An article by Lindahl et al in this issue of Circulation represents a major step forward in MINOCA and thereby warrants taking stock of the past, present, and future management strategies of this intriguing condition.

The Past

The pioneering early angiography studies of DeWood et al demonstrated that ST-segment–elevation myocardial infarction was often associated with an occluded epicardial artery, but this occurred less frequently in non–ST-segment–elevation myocardial infarction, although in both conditions obstructive coronary artery disease was evident in >95% of patients. These findings underscored the importance of the underlying atherothrombotic process and provided the impetus for major advances in AMI management over the next 35 years. However, when angiography failed to reveal the presence of obstructive atheroma or thrombosis in patients with clinical criteria for ST-segment–elevation myocardial infarction, some clinicians labeled these patients as having a false-positive ST-segment–elevation myocardial infarction diagnosis. Such a label implies that an AMI has not occurred (despite the clinical presentation) and therefore no further diagnostic investigation or cardiac therapy is required.

To avoid such diagnostic complacency, the diagnosis of MINOCA was coined with an emphasis on investigating these patients to identify the underlying cause of their AMI presentation. Providing a label for this clinical syndrome was the first key step in improving the management of these patients because MINOCA was promoted as a working diagnosis that necessitated the identification of an underlying cause, much the same as a diagnosis of heart failure or anemia requires such action. This was further emphasized in the first position statement on this disorder, although it has yet to be incorporated into AMI guidelines.

The Present

With the concept of MINOCA established, the next key step in its management was to identify the potential underlying causes and optimal diagnostic pathway in evaluating these patients. Potential underlying mechanisms include coronary causes such as coronary spasm, coronary microvascular dysfunction, plaque disruption, spontaneous coronary thrombosis/emboli, and coronary dissection; myocardial disorders, including myocarditis, takotsubo cardiomyopathy, and other cardiomyopathies; and noncardiac causes, for example, pulmonary embolism. Multiple diagnostic pathways have been proposed to evaluate patients with MINOCA, with early cardiac magnetic resonance imaging (CMRI) being a central investigation in most pathways because of its ability to detect common causes. Indeed, recent reports claimed that CMRI identifies the underlying cause in as many as 87% of patients with MINOCA. Other investigations include provocative spasm testing, screening for thrombophilia disorders, and intravascular ultrasound; however, routine screening for pulmonary embolism with computed tomographic pulmonary angiography is of very limited value.

Contemporary research studies of MINOCA have evaluated the prognosis of these patients, reporting a 12-month all-cause mortality of 4.7% (95% confidence interval, 2.6–6.9), with comparative studies consistently demonstrating a better prognosis than for those who experience AMI associated with obstructive coronary artery disease. Moreover, Kang et al confirmed that 12-month major adverse cardiac events (MACE; death and myocardial infarction) in patients with MINOCA were comparable to patients with AMI associated with single- or double-vessel coronary artery disease. In addition to these MACE outcomes, Grodzinsky et al demonstrated that 25% of patients with MINOCA continued to experience angina 12 months after AMI, which is equivalent to the rate in those with AMI associated with obstructive coronary artery disease.

Considering the guarded prognosis of patients with MINOCA, the next beckoning question is, What therapies should be recommended? Currently, there are no randomized trials addressing this question. However, the article by Lindahl et al published in this issue of Circulation provides the first insight into potential long-term medical therapy in the management of MINOCA. Using the strength of the internationally acclaimed SWEDEHEART Registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapy), the authors have garnered a large cohort of consecutive patients with MINOCA (n=9466) and used a stratified propensity score analysis approach to examine the effect of 4 conventional postinfarct therapies (statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dual antiplatelet therapy) on long-term MACE (defined as all-cause mortality, AMI hospitalization, ischemic stroke, and heart failure). A secondary objective was to examine the impact of these therapies on bleeding events. The key study findings include (1) a reduced hazard ratio of MACE with the use of statins (hazard ratio=0.77; 95% confidence interval, 0.68–0.87) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (hazard ratio=0.82; 95% confidence interval, 0.73–0.93) with a trend observed in β-blocker therapy (hazard ratio=0.86; 95% confidence interval, 0.74–1.01) and (2) no associated benefit with the use of dual antiplatelet therapy but a trend toward an increased bleeding rate.

Although a nonrandomized study with important limitations (see below), this study is a game changer because for the first time there are data (rather than opinion) on potential beneficial therapies to reduce MACE in patients with MINOCA. Accordingly, clinicians can no longer dismiss patients with MINOCA as having false-positive AMIs but need to consider the potential benefit of statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in these patients. Hence, the study is a major step forward in the recognition and management of MINOCA.

As indicated by the authors, important limitations in this retrospective cohort study are the heterogeneous nature of MINOCA and that no investigations to identify the underlying causes were routinely performed in this cohort. Although clinically overt causes were excluded because study inclusion was based on discharge diagnosis, less conspicuous presentations may have been overlooked. For example, in a meta-analysis of 5 studies involving 556 patients with MINOCA, Tornvall et al demonstrated that 33% had CMRI evidence of myocarditis despite fulfilling the diagnostic criteria for AMI. Hence, in the above analysis, up to one third of the patients treated with statin or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers may have had myocarditis, for which the benefits of these therapies are unclear. If CMRI were performed on all patients and the therapies were targeted to those patients with MINOCA with evidence of true myocardial infarction, perhaps the observed benefits would have been even greater.

The Future

The Lindahl et al study has provided direction for the next key step in the management of MINOCA, namely a multicenter randomized controlled trial confirming the benefits of these conventional therapies on MACE. With a prospectively designed trial, there is an opportunity for a more targeted therapeutic approach by identifying the underlying cause with screening investigations. Confirmation of the above findings would mandate the evaluation of patients with MINOCA and the initiation of secondary prevention therapies. This would not only be paradigm shifting in relation to the treatment of MINOCA but also provoke a re-evaluation of the mechanisms for these beneficial agents in the context of minimal or no atherosclerotic disease.

This trial design also highlights an evolving problem in MINOCA publications relating to the generic and specific uses of the term. In the position paper, the term MINOCA is used in an all-encompassing context to include all patients fulfilling the universal criteria for AMI without obstructive coronary artery disease and no clinically overt cause for the presentation at the time of coronary angiography. As described above, this should initiate further investigation such as CMRI to identify the underlying cause. However, the term MINOCA is also being used in a more specific context to exclusively describe patients with evidence of ischemia-related myocardial necrosis (as the name implies). This dual interpretation of the MINOCA term will cause confusion in the future, especially if specific therapies are identified for ischemic-related MINOCA. Thus, a revision of the nomenclature is warranted, and perhaps the generic form of the term should be replaced with a broader label (eg, troponin-positive nonobstructive coronary arteries [TP-NOCA]) that encompasses patients with coronary disorders resulting in ischemic necrosis (ie, MINOCA), as well as structural myocardial disorders and noncardiac disorders (Figure). Future position papers should address this important issue in this rapidly evolving field.

Figure. Troponin-positive nonobstructive coronary arteries. MINOCA indicates myocardial infarction with nonobstructive coronary arteries.