Clinical significance and pathophysiological underpinnings of isolated high microvascular resistance in ANOCA: a comprehensive phenotypic analysis from the multicenter J-CMD registry

Background Coronary microvascular dysfunction (CMD) is now recognized as a primary driver of symptoms and adverse outcomes in patients with angina and non-obstructive coronary artery disease (ANOCA). While the 2024 ESC guidelines have formally introduced isolated elevations in the index of microcirculatory resistance (IMR) as a distinct CMD endotype, its specific clinical relevance and underlying pathophysiological drivers remain poorly characterized. This study sought to elucidate the phenotypic profile and clinical burden of this endotype within a large-scale, prospective registry. Methods We performed a detailed analysis of 1,014 patients from the prospective, multicenter J-CMD Registry who underwent comprehensive invasive physiological assessment. Patients were stratified into four distinct endotypes based on coronary flow reserve (CFR; threshold 2.5) and IMR (threshold 25): Non-CMD (n=598), Isolated High IMR (n=155; representing 37.3% of the CMD cohort), Functional CMD (n=131), and Structural CMD (n=130). Clinical characteristics, serum biomarkers, and detailed echocardiographic parameters were juxtaposed across these groups to identify phenotype-specific correlates. Results While advanced age was a universal feature across all CMD phenotypes, hypertension emerged as a potent and specific determinant of both high IMR endotypes. Despite having a preserved CFR, the Isolated High IMR group exhibited evidence of adverse structural and functional remodeling, characterized by significantly larger left atrial diameters (36.0 vs. 34.0 mm; p=0.03) and more pronounced diastolic impairment (E/e' ratio: 9.1 vs. 8.2, p<0.001) compared to the Non-CMD group. Notably, NT-proBNP levels remained comparable, suggesting that these microvascular changes precede overt heart failure. Paradoxically, Seattle Angina Questionnaire scores revealed a severe and uniform symptomatic burden across all CMD endotypes, irrespective of CFR preservation. Multivariable logistic regression confirmed that age (OR 1.24; p=0.008), hypertension (OR 1.80; p=0.004), and E/e′ (OR 1.06; p=0.04) were independent predictors specifically associated with the Isolated High IMR phenotype. Furthermore, clinical determinants incorporating age >63 years, hypertension, and E/e′ >8.5 demonstrated a stepwise increase in the odds of Isolated High IMR according to the number of the components. Conclusion Isolated High IMR represents a distinct, clinically significant CMD endotype intrinsically linked to hypertensive remodeling and subclinical diastolic dysfunction. Crucially, the symptomatic impairment in these patients is as debilitating as that seen in other CMD forms, despite a seemingly "normal" coronary flow reserve. These findings underscore the necessity of incorporating IMR into routine diagnostic algorithms to avoid underdiagnosing high-risk ANOCA patients and highlight the need for targeted therapeutic strategies addressing microvascular resistance.