IMR-Ach: normal reference and its implications in different ANOCA endotypes

Aims While IMR derived from adenosine (IMR-Ado) is a key parameter for assessing microvascular function in ANOCA, the clinical utility of IMR values derived from acetylcholine (IMR-Ach) remains underexplored. The aims is to identify normal and pathological values of IMR-Ach to better characterize the pathological mechanisms underlying microvascular dysfunction. Methods and results This study is a sub-analysis of the Micro-SNAPE registry, which enrolled 1,001 ANOCA patients who underwent invasive assessment of coronary flow, pressure, resistance, and spasm provocation testing using a standardized protocol. The upper reference limit for IMR-Ach was defined using a frequentist approach as the 95th percentile of values observed in a subgroup of patients with normal hemodynamics and no history of stenting, myocardial infarction, or heart failure. Patients were categorized into two groups based on IMR-Ach values (Abnormal vs. Normal IMR-Ach), clinical and hemodynamic parameters were compared between groups. The prevalence of different ANOCA endotypes was also assessed and compared between groups. The IMR-Ach cutoff for normality was 33.6 UI, with 321 patients (32.1%) exhibiting elevated IMR ach values. Patients with abnormal IMR-Ach were older (p < 0.01) and more likely to be male (p < 0.01). They had lower CFR-Ach values (1.62 ± 0.73 vs. 3.09 ± 1.77, p < 0.01) but comparable CFR-Ado values (3.55 ± 1.76 vs. 3.47 ± 1.93, p = 0.147). IMR-Ado was significantly higher in patients with abnormal IMR-Ach (25.88 ± 15.48 vs. 17.31 ± 10.15, p < 0.01), a positive and significant association between IMR-Ach and IMR-Ado was found (β = 0.206 ± 0.018, std. β = 0.359, p < 0.01). Endotypes characterized by elevated IMR-Ado were more prevalent in patients with abnormal IMR-Ach (High resistance: 19.1% vs. 8.9%, p < 0.01; Compensated high resistance: 10.9% vs. 2.5%, p < 0.01). Conversely, according to COVADIS criteria, microvascular and epicardial spasm endotypes were more frequent in patients with normal IMR-Ach values (microvascular spasm: 23.8% vs. 19.4%, p < 0.01; epicardial spasm: 13.7% vs. 6.8%, p < 0.01). When stratified by hemodynamic parameters, patients with abnormal IMR-Ach showed a higher prevalence of endothelial dysfunction (37.8% vs. 4.8%, p < 0.01) and hemodynamic microvascular spasm (IMR-Ach > IMR-rest: 11.2% vs. 3.3%, p < 0.01). In contrast, ischemic ECG changes and angina during ach infusion were more common among patients with normal IMR-Ach (p =0.036 and p<0.01 respectively), consistent with the higher prevalence of the “ischemia without hemodynamic abnormalities” endotype (9.6% vs. 3.1%, p < 0.01). Conclusions An abnormal IMR-Ach may represent an early marker of endothelial dysfunction and microvascular spasm. A normal IMR-Ach value, despite the presence of acetylcholine-induced chest pain and ST-segment changes, should discourage a diagnosis of microvascular spasm suggesting alternative ischemia-related mechanisms.