Unified framework elucidates microvascular and neurovascular mechanisms in diabetic silent myocardial ischemia

Diabetic silent myocardial ischemia (DSMI) is a life-threatening cardiovascular complication where impaired myocardial perfusion occurs without symptoms, often underappreciated clinically. Current understanding struggles to fully integrate the dual pathology of coronary microvascular dysfunction and neurocardiac signaling disruption. Chronic hyperglycemia drives endothelial and smooth-muscle cell damage via oxidative stress, AGE accumulation, and mitochondrial dysfunction, reducing NO bioavailability and capillary integrity. Simultaneously, diabetic neuropathy blunts pain perception and disrupts neurovascular coupling, leaving ischemia undetected. This review addresses the critical gap by synthesizing these converging pathological axes into a novel, unified mechanistic framework.

This comprehensive review synthesizes current mechanistic knowledge on diabetic silent myocardial ischemia (DSMI) by integrating findings from diverse studies. It critically evaluates the interplay between coronary microvascular dysfunction and neurocardiac signaling disruption. The authors propose a novel unified framework to explain the underlying pathology, identify candidate biomarkers, and pinpoint actionable therapeutic targets based on existing literature. The review also proposes testable mechanistic hypotheses and directions for future translational research to accelerate early diagnosis and disease-modifying interventions.

The review identifies two converging pathological axes in DSMI: coronary microvascular dysfunction and neurocardiac signaling disruption. Chronic hyperglycemia drives oxidative stress, advanced glycation end-product (AGE) accumulation, and mitochondrial dysfunction, impairing NO bioavailability, coronary flow reserve, and capillary integrity. Concurrently, diabetic neuropathy attenuates nociceptive transmission and disrupts neurovascular coupling. At the molecular level, dysregulated INSR, AT1R, TLR4, AMPK, and TRP channel signaling perpetuate endothelial injury, vascular inflammation, and neural dysfunction. Critically, mtROS overproduction, impaired mitochondrial biogenesis, and altered mitochondrial dynamics are highlighted as shared mechanistic nodes linking both axes. The review proposes several candidate biomarkers: urinary 8-OHdG, NT-proBNP, heart rate variability indices, and coronary flow reserve by cardiac PET/CMR. It also identifies actionable therapeutic targets.

These include mitochondria-directed antioxidants (MitoQ, SS-31), SGLT2 inhibitors, GLP-1 receptor agonists, TLR4 antagonists, and TRPV1 modulators.