Clinical Relevance of Ischemia with Nonobstructive Coronary Arteries According to Coronary Microvascular Dysfunction

Abstract

Background In the absence of obstructive coronary stenoses, abnormality of noninvasive stress tests (NIT) in patients with chronic coronary syndromes may indicate myocardial ischemia of nonobstructive coronary arteries (INOCA). The differential prognosis of INOCA according to the presence of coronary microvascular dysfunction (CMD) and incremental prognostic value of CMD with intracoronary physiologic assessment on top of NIT information remains unknown. Methods and Results From the international multicenter registry of intracoronary physiologic assessment (ILIAS [Inclusive Invasive Physiological Assessment in Angina Syndromes] registry, N=2322), stable patients with NIT and nonobstructive coronary stenoses with fractional flow reserve >0.80 were selected. INOCA was diagnosed when patients showed positive NIT results. CMD was defined as coronary flow reserve ≤2.5. According to the presence of INOCA and CMD, patients were classified into 4 groups: group 1 (no INOCA nor CMD, n=116); group 2 (only CMD, n=90); group 3 (only INOCA, n=41); and group 4 (both INOCA and CMD, n=40). The primary outcome was major adverse cardiovascular events, a composite of all-cause death, target vessel myocardial infarction, or clinically driven target vessel revascularization at 5 years. Among 287 patients with nonobstructive coronary stenoses (fractional flow reserve=0.91±0.06), 81 patients (38.2%) were diagnosed with INOCA based on positive NIT. By intracoronary physiologic assessment, 130 patients (45.3%) had CMD. Regardless of the presence of INOCA, patients with CMD showed a significantly lower coronary flow reserve and higher hyperemic microvascular resistance compared with patients without CMD (P<0.001 for all). The cumulative incidence of major adverse cardiovascular events at 5 years were 7.4%, 21.3%, 7.7%, and 34.4% in groups 1 to 4. By documenting CMD (groups 2 and 4), intracoronary physiologic assessment identified patients at a significantly higher risk of major adverse cardiovascular events at 5 years compared with group 1 (group 2: adjusted hazard ratio [HR_adjusted], 2.88; 95% CI, 1.52-7.19; P=0.024; group 4: HR_adjusted, 4.00; 95% CI, 1.41-11.35; P=0.009). Conclusions In stable patients with nonobstructive coronary stenoses, a diagnosis of INOCA based only on abnormal NIT did not identify patients with higher risk of long-term cardiovascular events. Incorporating intracoronary physiologic assessment to NIT information in patients with nonobstructive disease allowed identification of patient subgroups with up to 4-fold difference in long-term cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Keywords: coronary flow reserve; coronary microvascular disease; ischemia with nonobstructive coronary arteries; myocardial ischemia; prognosis.

Figure 1. Study flow.

CAD indicates coronary artery disease; CFR, coronary flow reserve; CMD, coronary microvascular disease; FFR, fractional flow reserve; ILIAS, Inclusive Invasive Physiological Assessment in Angina Syndromes; INOCA, ischemia with nonobstructive coronary arteries; and PCI, percutaneous coronary intervention.

Figure 2. Prognostic impact of ischemia with nonobstructive coronary arteries and coronary microvascular disease.

The cumulative incidence of major adverse cardiovascular event at 5 years were compared according to presence of (A) ischemia with nonobstructive coronary arteries and (B) coronary microvascular disease. Adjusted covariates in the multivariable model included age, sex, diabetes, hyperlipidemia, and previous percutaneous coronary intervention. CMD indicates coronary microvascular disease; HR, hazard ratio; INOCA, ischemia with nonobstructive coronary arteries; and MACE, major adverse cardiovascular event.

Figure 3. Comparison of major adverse cardiovascular event at 5 years according to stress tests results and presence of coronary microvascular disease.

Kaplan–Meier curve are shown for the 4 groups of patients according to ischemia with nonobstructive coronary arteries and coronary microvascular disease. Adjusted covariates in multivariable model included age, sex, diabetes, hyperlipidemia, and previous percutaneous coronary intervention. CMD indicates coronary microvascular disease; HR, hazard ratio; INOCA, ischemia with nonobstructive coronary arteries; and MACE, major adverse cardiovascular event.

Figure 4. Long‐term prognostic implication of ischemia with nonobstructive coronary arteries and coronary microvascular disease.

Symptomatic patients with stable ischemic heart disease who underwent of noninvasive stress tests and intracoronary coronary physiologic assessment were evaluated. The patients were stratified according to the presence of ischemia with nonobstructive coronary arteries and coronary microvascular disease. In the overall population, 28.2% showed positive of noninvasive stress tests results and 45.3% had coronary microvascular disease. Patients with coronary microvascular disease showed a significantly increased risk of major adverse cardiovascular event at 5 years, regardless of noninvasive stress tests results. These findings indicate that the differential prognostic impact of endotype of ischemia with nonobstructive coronary arteries which support the necessity of intracoronary physiologic assessment. CAD indicates coronary artery disease; CMD, coronary microvascular disease; HR, hazard ratio; ILIAS, Inclusive Invasive Physiological Assessment in Angina Syndromes; INOCA, ischemia with nonobstructive coronary arteries; MACE, major adverse cardiovascular event; and NIT, noninvasive stress test.