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.

Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options

“…In the setting of significant epicardial artery stenosis, the additional resistance from coexisting CMD further limits maximal coronary blood flow [ 135 ]. Notably, CMD, with or without vasospastic angina, is one of the major endotypes of myocardial ischemia without obstructive CAD, which, when present, results in a significantly worsened prognosis with a higher risk of major adverse CV events at 5 years [ 136 ]. In a recent retrospective cross-sectional study involving an unselected population of T2DM patients experiencing chest pain and non-obstructive CAD, 72.1% of the 129 studied diabetic patients had an endothelial-dependent or -independent CMD, which was associated with a linear increase of HbA1c amongst women but not men [ 137 ].…”

Effect of nonobstructive coronary stenosis on coronary microvascular dysfunction and long‐term outcomes in patients with INOCA

“…CFR was higher in patients with <20% and 0% stenosis than in 20%–49% and 1%–40% stenosis, respectively, 18,42 both studies demonstrated the association of CFR with adverse outcomes among women with suspect ischemia 18 and patients with diabetes, 42 but these studies did not study the effect of nonobstructive stenosis on CMD. In addition, a recent study showed that angiographic coronary diameter stenosis was not associated with the presence of CMD in INOCA 43 …”

“…In addition, a recent study showed that angiographic coronary diameter stenosis was not associated with the presence of CMD in INOCA. 43 …”

“… 18 In a multicenter registry of intracoronary physiologic assessment in INOCA patients, CMD was associated with an increased risk of MACE at 5 years of follow‐up. 43 …”

“…In the WISE study, the evaluation of CMD by CFR improved the prediction of MACE regardless of the presence or absence of obstructive (≥50% stenosis) CAD 18 . In a multicenter registry of intracoronary physiologic assessment in INOCA patients, CMD was associated with an increased risk of MACE at 5 years of follow‐up 43 …”