Troponin elevation in patients with non-obstructive coronary artery disease: just a bystander or life threatening?

This editorial refers to ‘Evaluations of coronary microvascular dysfunction in a patient with thrombotic microangiopathy and cardiac troponin elevation: a case report’, by K. Otsuka et al., https://doi.org/10.1093/ehjcr/ytac318.

Elevation of serum troponin as a specific marker of myocardial necrosis, in the absence of significant obstruction in the epicardial coronary arteries, is a disease entity known as myocardial infarction with non-obstructive coronary arteries (MINOCA).^1,2 Myocardial infarction with non-obstructive coronary arteries is postulated to encompass a group of heterogeneous conditions with different mechanisms of pathology but with the following three common essential criteria: (i) a diagnosis of acute myocardial infarction (AMI) defined as an elevation in serum troponin and symptoms or ECG alterations typical for AMI, (ii) no significant obstructive coronary disease, and (iii) no clinical findings of other specific conditions that can cause AMI.³ Traditionally, the diagnosis of MINOCA required exclusion of significant coronary artery disease by invasive coronary angiography. While the prognosis and predictors for MINOCA patients remain unclear, this disease entity isn’t always benign. As the management and prognosis in MINOCA are closely related to the underlying aetiology, the identification of the causes is important and frequently requires additional investigations beyond conventional invasive coronary angiography. Recent advances in non-invasive diagnostic tools including the evolution of advanced imaging techniques have enabled detection of significant coronary artery disease, cardiac ischaemia, and necrosis.^1,2 The diagnosis of ischaemia with non-obstructive coronary arteries (INOCA) has the pre-requisites of angina, hence though to be more of a chronic rather than an acute condition, and the presence of cardiac ischaemia on functional testing, elevated serum troponin, and the exclusion of epicardial coronary artery stenosis.^1,2 While there are some proposed features that can guide the classification between INOCA and MINOCA, classification in the clinical setting is not always clear cut given the fair degree of overlap between the two entities and a lack of clearly defined characteristics which differentiates INOCA vs. MINOCA. Both these disease entities may possibly represent different points along a continuum since there is also the potential for INOCA to evolve into an ACS/MINOCA. The overlap between these two entities and significant knowledge gaps relating to patient phenotypes and mechanistic understanding of INOCA frequently poses a diagnostic challenge in the clinical setting.⁴ Refer to Table 1.

Otsuka and colleagues⁵ presented a case with a combination of features supporting both an INOCA and MINOCA classification and highlighted the use of various non-invasive imaging modalities in the diagnostic process. The case featured had presented with dyspnoea but was noted to have fever, jaundice, petechiae, purpuric rash involving the toes, renal impairment, and thrombocytopenia. The initial ECG demonstrated ST depression in leads V5 and V6 in association with a significant serum troponin elevation consistent with an AMI, i.e. non-ST-elevation myocardial infarction (NSTEMI). Transthoracic echocardiography also demonstrated hypokinesis of the inferior wall but overall preserved left ventricular systolic function consistent with the differential diagnosis of an AMI. These findings were in keeping with an acute condition hence favouring a MINOCA classification. The patient was diagnosed with thrombotic microangiopathy due to sepsis resulting in microvascular angina (MVA). Unfortunately, due to the critical status of the patient and the thrombocytopenia, an invasive coronary angiography could not be performed early in the admission to assess for significant coronary lesions.⁵ Otsuka and colleagues utilized a well-described but limited method of measuring the coronary flow reserve using echocardiography to demonstrate myocardial ischaemia with a coronary flow reserve of 1.7 on day seven following admission to the hospital and tracked progression of coronary flow reserve in response to treatment demonstrating normalization of coronary flow reserve to 2.5 at day 30.^2,6 Findings on invasive coronary angiography at day 10 post-presentation (when the patient was more medically stable) excluded anatomically significant coronary artery disease. Cardiac magnetic resonance imaging also did not demonstrate any evidence of late gadolinium enhancement in the myocardium effectively excluding myocardial necrosis (a common finding following a myocardial infarction). Both these findings excluded significant coronary artery disease as the cause of the troponin increase and symptoms at presentation.⁵ Thus, Otsuka and colleagues classified their patient as having INOCA in accordance to the recent definition of INOCA proposed by the EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries.²

This case highlights one of the fundamental challenges in differentiating between INOCA and MINOCA in the clinical setting. All the features of INOCA can be accounted in this case, with myocardial ischaemia proposed to have been due to thrombotic microangiopathy and vascular damage as evidenced by arteriolar and capillary thrombosis in association with characteristic abnormalities in the endothelium and vessel wall due to systemic sepsis.⁷ Diagnostic criteria for MVA have been published previously by the COVADIS group⁸ and include the following: symptoms of myocardial ischaemia with angina during rest or effort, the absence of obstructive coronary artery disease as shown with coronary artery CT or invasive angiography (<50% diameter reduction or FFR > 0.80), objective proof of myocardial ischaemia with a functional imaging test, and impaired coronary microvascular function with an impaired coronary flow reserve < 2.0 determined with invasive or non-invasive measures.^2,8 Interestingly, the MVA changes in INOCA are typically believed to be more stable and chronic (several weeks or longer) with symptoms suggesting ischaemic heart disease such as chest discomfort with both classic (e.g. angina pectoris) and atypical features in terms of location, quality, and inciting factors.⁴ The acute clinical picture in this case is not typical for INOCA and more consistent with MINOCA. The diagnosis of INOCA was favoured by the authors based on the available supportive evidence, i.e. absence of significant stenoses of the epicardial coronary arteries and lack of any evidence of myocardial necrosis. Furthermore, the underlying illness, i.e. thrombotic microangiopathy due to sepsis, supported a diagnosis of INOCA since one of the postulated mechanisms for INOCA involves decreased coronary flow reserve and elevated platelet reactivity. In this instance, the authors offer the explanation that the sepsis induced thrombotic microangiopathy, resulting in myocardial ischaemia which accounts for the clinical picture of MVA, symptoms, raised serum troponin levels, ECG alterations, and echocardiographic findings.

This case highlights that the recent diagnostic criteria proposed by the EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries may still be inadequate in being able to definitively categorize INOCA vs. MINOCA.⁴ The utility of multi-modality imaging, in this instance, was able to clarify the mechanism and pathophysiology underlying the clinical presentation, hence helpful in the overall diagnostic process. Transthoracic Doppler echocardiography was used to demonstrate the presence of coronary microvascular dysfunction detected as reduced coronary flow reserve and cardiac magnetic resonance imaging used to excluded the presence of any myocardial necrosis, hence excluding the diagnosis of a myocardial infarct. Positron emission tomography would also have been helpful in this instance but was unfortunately not available. Ultimately, the integration of all the investigative findings allowed for the final diagnosis to be made. However, the acuity of the onset of the symptoms is not accounted for.

This case also serves to emphasize that MINOCA/INOCA may not necessarily be a benign condition and prognosis is very much dependent of the underlying aetiology and early institution of treatment. CMD in the absence of significant coronary artery disease has been associated with a two–four-fold increase of the cardiovascular event rate.^1,2 Nonetheless, the utility of multi-modality imaging still requires the judicious choice of the imaging modalities selected and should be tailored to the specific individual case dependent on the underlying aetiology.

In conclusion, the overlap between the clinical syndromes defining INOCA and MINOCA, significant knowledge gaps relating to patient phenotypes, and our current mechanistic understanding of INOCA highlight the need for a more uniform definition for INOCA given the likelihood that multiple mechanisms may contribute to INOCA.⁴ An improved understanding of these conditions and specific phenotyping beyond symptoms and ischaemia and data from additional large prospective cohorts are clearly still needed to help shape more definitive diagnostic criteria for INOCA/MINOCA.

Lead author biography

Dr. Christoph Sinning is senior physician at the Department of Cardiology at the University Heart & Vascular Center Hamburg, Germany. His main areas of work are cardiovascular imaging with a focus on echocardiography, treatment of adults with congenital heart disease and cardiac devices like pacemaker and ICD. The current scientific work is focussing on the use of echocardiography in detecting outcome of patients undergoing EP procedures and improving detection of candidates for cardiac resynchronisation therapy. In addition an area of scientific work is outcome of advanced heart failure in adults with congenital heart disease.

Acknowledgements

None.

Funding: None declared.

References

Author notes