Nelson, Micheal D

ABSTRACT Background The brain–heart axis is central to vascular health, yet no imaging biomarkers capture integrated dysfunction across neural and coronary microvascular networks. Although coronary microvascular dysfunction links to cognitive decline, neural correlates connecting cerebral efficiency with coronary physiology remain unclear. Objectives To determine whether the Unified Structural and Functional Connectivity (USFC)—a multimodal magnetic resonance imaging (MRI) “traffic map” of brain network efficiency—predicts coronary endothelial function and cognition in women with ischemia and no obstructive coronary artery disease (INOCA). Methods Thirty‐three women with suspected INOCA from the Women's Ischemia Syndrome Evaluation (WISE) study (NCT03876223) underwent invasive coronary function testing, cardiac MRI, cognitive evaluation, and multimodal brain MRI. USFC, structural connectivity (SC), and functional connectivity (FC) were computed for predefined 10 backbone pathways. Support vector regression and logistic classification assessed predictive performance. Results USFC explained 16%–20% more variance in coronary endothelial function, myocardial perfusion reserve, and cognition than SC or FC alone ( p < 0.05). Connectivity between the left caudate–superior medial orbital gyrus and right calcarine–inferior occipital gyrus emerged as robust predictors of crystallized cognition ( r = –0.78, p FDR < 0.05) and coronary endothelial function ( r = 0.70, p FDR < 0.05), respectively. USFC also best discriminated low versus high coronary blood flow (area under the ROC curve [AUC]: USFC 0.622 vs. SC 0.349 and FC 0.425; p < 0.05). Conclusions USFC identifies neuro–cardiac pathways linking cerebral efficiency with coronary endothelial function. These results introduce a sensitive biomarker of systemic vulnerability, highlighting occipital and frontostriatal pathways as shared substrates of dysfunction. USFC offers a mechanistic framework for detecting vascular risk across metabolically demanding tissues. Trial Registration ClinicalTrials.gov identifier: NCT03876223