Insights to advance our management of myocardial ischemia: From obstructive epicardial disease to functional coronary alterations

1. Obstructive epicardial disease, functional vasospasm and microvascular disorders

Myocardial ischemia may result from both structural (fixed obstructive lesions) and functional (dynamic vasomotor dysfunction) disorders of the epicardial coronary arteries and/or coronary microvascular circulation. Most attention clinically has centered on the diagnosis and treatment of epicardial coronary artery disease (CAD), though stenosis severity does not predict prognosis, and myocardial ischemia with no obstructive CAD (INOCA), defined as the signs and symptoms of ischemia without CAD, is observed in about half of the patients undergoing clinically indicated coronary angiograms 1. The most common mechanisms responsible for INOCA appear to include coronary artery spasm (epicardial or microvascular) and coronary microvascular disorders alone or in combination. While there is growing scientific and clinical acceptance of INOCA as a distinct entity that is highlighted in cardiology professional society guidelines, challenges remain in advancing both the diagnosis and management of patients with INOCA, most of whom are women.

Recently, the Coronary Vasomotor Disorders International Study Group (COVADIS) invited leading experts to address strategies to enhance our clinical understanding of INOCA, with an emphasis on the management of coronary vasomotor disorders. Under-recognition of coronary vasomotor disorders, distinguishing different presentations of angina due to vasospasm and/or abnormal microvascular vasodilatation, developing invasive/non-invasive testing and treatment protocols, integrating diagnostic protocols into cardiologists’ workflow and trials to inform guideline development were identified as key knowledge gaps and will be briefly addressed in this Viewpoint article. We emphasize also that epicardial coronary obstruction and INOCA are not mutually exclusive causes of ischemia, and both may coexist clinically—often in the same patient.

Also critically important is the lack of knowledge about the clinical course of INOCA patients that was recently advanced by CIAO-ISCHEMIA, an ancillary study of the ISCHEMIA trial. CIAO ISCHEMIA, by most of the same ISCHEMIA investigators, described the natural history of symptoms and ischemia among patients screened for ISCHEMIA with abnormal stress imaging but no obstructive CAD. The outcome of interest was the association between changes in angina (Seattle Angina Questionnaire Angina Frequency score) and changes in echocardiographic wall motion evidence for ischemia. CIAO participants were more often female (66% vs. only 26% of ISCHEMIA participants with obstructive CAD) but the magnitude of ischemia was not different (median 4 ischemic segments) between these cohorts. At enrollment, ischemia magnitude and angina were not significantly correlated in either the CIAO (e.g., INOCA) or ISCHEMIA (obstructive CAD) participants. Unfortunately, follow-up stress echocardiography was not part of ISCHEMIA. But at 1-year, a stress echocardiogram became normal in half of CIAO participants as about a quarter had moderate or severe persisting ischemia, while angina outcomes improved in almost half and worsened in only 14%. Most interesting was the observation that change in ischemia over 1 year was not correlated with change in angina. The investigators concluded that although improvements in ischemia and in angina were common without obstructive CAD, they were not correlated.

These results highlight the complex pathophysiology and the multifactorial mechanisms of ischemic heart disease and the difficulty of attempting to assess outcomes. Mechanisms and diagnostic evaluation of ischemic heart disease in those with or without obstructive CAD and in those with persistent angina following revascularization, and the optimal approach to analyze and manage these patients, represent knowledge gaps for future trials to address.

COVADIS has developed consensus nomenclature statements, created registries, and fostered clinical trials for coronary vasomotor disorders, thereby raising awareness of the importance of coronary vasomotor dysfunction in pathogenesis of angina. COVADIS established criteria for vasospastic (Table 1), and microvascular angina (Table 2), and has endorsed performing “functional” angiography vs. only anatomic coronary angiography, quantifying vascular responses in addition to obstructive disease only, however other terminologies also exist. Pharmacologic trials and the CorMICA randomized trial have suggested treatment targets and approaches for diagnosis and management of patients without obstructive CAD, prompting guideline changes. Important challenges remain to better elucidate how best to identify and treat mechanisms of ischemia not necessarily caused by obstructive epicardial CAD and functional coronary disorders.