Abstract Body (Do not enter title and authors here): Background
Coronary microvascular dysfunction (CMD) is a cause of ischemia with non-obstructive coronary arteries (INOCA), but mechanisms underlying CMD are not well understood. We previously reported a proinflammatory whole blood transcriptional signature among INOCA patients with versus without CMD. Here we sought to broadly identify pathways beyond inflammation with potential relevance to CMD mechanisms.

Methods
We prospectively enrolled females with ischemic symptoms or myocardial ischemia on stress testing who underwent invasive coronary angiography with <50% stenosis in all major epicardial vessels. CMD was defined as coronary flow reserve (CFR) <2.5 measured invasively by bolus thermodilution. Whole blood RNA was collected at the time of coronary angiography and sequenced. Differential transcript expression analyses adjusted for age were performed using DESeq2 with CFR as binary and continuous variables. Ingenuity Pathway Analysis (IPA) was performed to identify differentially expressed canonical pathways with nominal p-values <0.05 and a z-score ≥|2|.

Results
Seven of 28 women with INOCA (mean age 60 ± 8.4 years, 82% white, 32% Hispanic/Latino ethnicity) had CMD. When CFR (median 3.2 [IQR 2.5-4.2]) was analyzed as a continuous variable, 55 pathways were differentially expressed: 6 related to cell adhesion and migration signaling (e.g., integrin signaling) and 13 metabolic processes (e.g., PI3K/AKT signaling). All cell adhesion and migration pathways (Figure, Panel A) and 11/13 metabolic pathways (Panel B) were upregulated with lower CFR. As previously reported, 18/19 pathways related to inflammation were upregulated (Panel C). The remaining 17 pathways were related to the immune response to specific pathogens, the cell cycle and tumorigenesis, and signaling in the gastrointestinal, nervous, and endocrine systems.

Conclusion
Pathways related to cell signaling, metabolism, and inflammation were primarily upregulated among women with INOCA and CMD versus those without CMD. Further research is needed to explore transcriptional profiles implicated in the pathogenesis of CMD in INOCA.