Bairey Merz, C Noel

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

Background: Coronary microvascular dysfunction results in angina and adverse outcomes in patients with evidence of ischemia and nonobstructive coronary artery disease; however, no specific therapy exists. CD34+ cell therapy increases microvasculature in preclinical models and improves symptoms, exercise tolerance, and mortality in refractory angina patients with obstructive coronary artery disease. The objective of this research was to evaluate the safety, tolerability, and efficacy of intracoronary CD34+ cell therapy in patients with coronary microvascular dysfunction. Methods: We conducted a 2-center, 20-participant trial of autologous CD34+ cell therapy (protocol CLBS16-P01; NCT03508609) in patients with ischemia and nonobstructive coronary artery disease with persistent angina and coronary flow reserve ≤2.5. Efficacy measures included coronary flow reserve, angina frequency, Canadian Cardiovascular Society angina class, Seattle Angina Questionnaire, SF-36, and modified Bruce exercise treadmill test obtained at baseline and 6 months after treatment. Autologous CD34+ cells (CLBS16) were mobilized by administration of granulocyte-colony stimulating factor 5µg/kg/day for 5 days and collected by leukapheresis. Participants received a single intracoronary left anterior descending infusion of isolated CD34+ cells in medium that enhances cell function. Results: Coronary flow reserve improved from 2.08±0.32 at baseline to 2.68±0.79 at 6 months after treatment ( P <0.005). Angina frequency decreased ( P <0.004), Canadian Cardiovascular Society class improved ( P <0.001), and quality of life improved as assessed by the Seattle Angina Questionnaire ( P ≤0.03, all scales) and SF-36 ( P ≤0.04, all scales). There were no cell-related serious adverse events. Conclusions: In this pilot clinical trial of microvascular angina, patients with ischemia and nonobstructive coronary artery disease receiving intracoronary infusion of CD34+ cell therapy had higher coronary flow reserve, less severe angina, and better quality of life at 6 months. The current study supports a potential therapeutic role for CD34+ cells in patients with microvascular angina. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03508609.

Nonobstructive coronary artery disease (CAD) in women is associated with adverse cardiovascular (CV) outcomes; however, information regarding genetic variants that predispose women to nonobstructive CAD is lacking. Women from the Women's Ischemia Syndrome Evaluation (WISE) Study and the St. James Women Take Heart (WTH) Study were genotyped with the Cardio-MetaboChip. WISE enrolled women with symptoms and signs of ischemia referred for coronary angiography; WTH enrolled asymptomatic, community-based women without heart disease. Analyses were conducted with a case (WISE) - control (WTH) design and multivariate logistic regression models to investigate genetic variation associated with likelihood of nonobstructive CAD. One genetic marker, single nucleotide polymorphism (SNP) rs2301753 on chromosome 6 in RNF39, achieved chip-wide significance for nonobstructive CAD ( P < 9.5 × 10−7). After adjusting for baseline characteristics, we found no variants achieved chip-wide significance. However, SNP rs2301753 on chromosome 6 in RNF39 was associated with reduced likelihood of nonobstructive CAD [odds ratio (OR) 0.42 and 95% confidence interval (CI) of 0.29 to 0.68], at a nominal level of P = 5.6 × 10−6, while SNP rs12818945 in the ATP2B1 locus on chromosome 12 was associated with increased odds for nonobstructive CAD (OR 2.38 and 95% CI of 1.63 to 3.45) and nominal P = 5.8 × 10−6. The functions of RNF39 and ATP2B1 raise the possibility that genes involved in cardio-dysfunction may contribute to nonobstructive CAD in Caucasian women and may provide insights into novel approaches for therapy and prevention. If replicated, incorporation of these genetic variants into diagnostic evaluation may identify women at high risk for nonobstructive CAD.