Mechanistic Links of Insular Cortex Iron to Cardiac Function, Brain Atrophy, Connectivity and Cognition in Women with Microvascular Dysfunction

Motivation: Excessive brain iron accumulation is a critical issue linked to neurodegeneration and disrupted connectivity, increasing the risk of pathological aging and highlighting the need to understand these mechanisms for improving clinical outcomes. Goal(s): To examine how cortical and deep-gray-matter iron connects cardiac and cognitive dysfunction with brain atrophy and altered-connectivity in women with suspected coronary-microvascular-dysfunction (CMD). Approach: Forty-five women underwent clinical, cognitive, cardiac/brain MRI assessments, utilizing sequential mediation analysis to explore pathways from iron to atrophy, connectivity, and cardiac/cognitive outcomes. Results: Insular cortex iron emerged as a key pathway linking cardiac/cognitive function to atrophy and connectivity, highlighting its role in CMD-related heart-brain interactions. Impact: This study identifies insular-cortex iron as a potential biomarker linking cardiac and cognitive function in CMD. These findings could guide future interventions targeting brain iron to mitigate cardiovascular and cognitive risks, prompting new research on heart-brain interactions in women's health.