Continuous Angiography-Derived Microvascular Resistance and Non-Linear Cardiovascular Event Risk

Background: Current clinical guidelines dichotomize coronary microvascular dysfunction (CMD) using a binary angiography-derived index of microcirculatory resistance (angio-IMR) cutoff of ≥25 units to define abnormal microvascular resistance. However, this threshold may obscure continuous, non-linear relationships between microvascular resistance and major adverse cardiovascular events (MACE), potentially misclassifying intermediate-risk patients. We performed a restricted cubic spline (RCS) meta-analysis to characterize the continuous dose-response relationship between angio-IMR and MACE risk across diverse cardiovascular populations. Methods: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library from inception to March 2026 to identify relevant studies and identified 13 studies (2021-2026) reporting angio-IMR and MACE outcomes in 2,712 patients (561 MACE events, follow-up 12-60 months). Populations included ST-elevation myocardial infarction (STEMI, 4 studies) ischemia with non-obstructive coronary arteries (INOCA, 2 studies), myocardial infarction with non-obstructive coronary arteries (MINOCA), anterior STEMI, diabetic chronic coronary syndrome, calcified coronary artery disease, and post-percutaneous coronary intervention cohorts. We pooled binary hazard ratios (HRs) for IMR ≥25 using random-effects models with inverse-variance weighting and fitted five-knot RCS models (knots: 10, 16, 22, 32, 42 units) to continuous IMR values. Non-linearity was assessed via likelihood ratio testing. Publication bias was evaluated using Egger's regression test. Results: Pooled binary HR for IMR ≥25 was 4.30 (95% CI 3.47-5.33, I 2 =0%). RCS analysis revealed trending non-linearity (p=0.095) with a "microvascular cliff" identified at IMR ≈16 units—the inflection point of maximum curvature where HR acceleration begins exponentially (HR=1.45 at this threshold). At the guideline cutoff of IMR=25, HR reached 3.53, indicating substantial risk accumulation occurs before the conventional threshold. Critically, patients with IMR 16-24 units, currently classified as "normal," already demonstrate significantly elevated MACE risk compared to those with IMR <16. No significant publication bias was detected (Egger's intercept=2.42, p=0.104). Conclusions: The binary IMR ≥25 cutoff is biologically arbitrary and systematically misclassifies intermediate-risk patients with subclinical microvascular dysfunction. The microvascular cliff at IMR ≈16 supports adoption of continuous risk stratification paradigms for CMD rather than dichotomous classification. These findings challenge current diagnostic criteria and suggest that earlier intervention thresholds (IMR ≥16) may substantially improve risk prediction and guide therapeutic decision making in patients with microvascular disease across diverse clinical presentations.