"Normal-low" coronary flow reserve unmasks a pre-HFpEF phenotype in non-cardiac chest pain in ANOCA: insights from the J-CMD registry

Background Patients with angina with non-obstructive coronary arteries (ANOCA) who lack vasomotor dysfunction or physiological ischemia during interventional diagnostic procedures (IDP) are frequently categorized as having "non-cardiac chest pain" (NCCP). This label often leads to the cessation of cardiac care, and consequently, their potential cardiac pathology may be overlooked. We hypothesized that within this NCCP population, a lower coronary flow reserve (CFR)—even when within the clinically "normal" range defined by current IDP—harbors distinct characteristics indicative of a subclinical pre-heart failure with preserved ejection fraction (HFpEF) state. Methods We analyzed 447 symptomatic patients from the prospective, multicenter J-CMD Registry. NCCP was definitively diagnosed based on a comprehensive IDP protocol, requiring negative results for all of the following: 1) vasomotor dysfunction (negative acetylcholine or ergonovine spasm provocation testing), 2) normal CFR (≥ 2.0), and IMR (< 25), and 3) epicardial physiological ischemia (FFR > 0.80). This cohort, representing true “NCCP” from a current IDP perspective, was stratified into three groups based on CFR tertiles obtained during IDP: Normal-Low (NL; 2.0–3.3, n = 145), Normal-Middle (NM; 3.4–5.1, n = 154), and Normal-High (NH; ≥ 5.2, n = 148). Biomarkers, echocardiographic parameters, and Seattle Angina Questionnaire (SAQ) scores were compared across the groups. Results Despite all ANOCA subjects being classified as NCCP by current IDP criteria (CFR ≥ 2.0, IMR < 25, FFR > 0.80, and no epi/microvascular spasm), the NL-CFR group exhibited distinct signs of cardiac stress and diastolic dysfunction. Specifically, the NL group demonstrated significantly higher NT-proBNP levels (NL: 1.86 [1.60–2.30] vs. NM: 1.70 [1.40-2.06] vs. NH: 1.73 [1.38–2.02], Log10 pg/mL, p = 0.008). Echocardiographic findings revealed significantly elevated filling pressures (E/e’; NL:9.0 [7.1–11.8] vs. NM:8.7 [7.0–10.8] vs. NH:8.0 [6.5–9.7], p = 0.010) and impaired relaxation (E/A; NL:0.83 [0.67–1.02] vs. NM:0.93 [0.75–1.25] vs. NH:0.96 [0.76–1.20], p = 0.006) in the NL group compared to the other groups. While clinical symptoms measured by SAQ showed a high symptomatic burden across the cohort, no statistically significant differences were observed between tertiles (p > 0.05 for all SAQ domains). Conclusions Among ANOCA patients labeled as NCCP based on IDP results, a "Lower-Normal" CFR (2.0–3.3) is not a benign finding but is significantly associated with subclinical diastolic dysfunction and increased myocardial wall stress. These findings suggest that a lower-normal CFR identifies a latent "pre-HFpEF" phenotype, challenging the current "non-cardiac" designation and underscoring the need for clinical vigilance beyond current IDP-based diagnostic criteria.