Microvasc Res. 2026 Jun 21:104983. doi: 10.1016/j.mvr.2026.104983. Online ahead of print.
ABSTRACT
Diabetic silent myocardial ischemia (DSMI) represents a clinically underappreciated yet life-threatening cardiovascular complication in which impaired myocardial perfusion occurs without recognisable symptoms. Two converging pathological axes underlie this phenotype: coronary microvascular dysfunction and neurocardiac signalling disruption. Chronic hyperglycaemia drives oxidative stress, advanced glycation end-product (AGE) accumulation, and mitochondrial dysfunction in endothelial and smooth-muscle cells, collectively impairing nitric oxide (NO) bioavailability, coronary flow reserve, and capillary integrity. Simultaneously, diabetic peripheral and autonomic neuropathy attenuates nociceptive transmission and disrupts neurovascular coupling, blunting the perception of ischaemic pain. At the molecular level, dysregulated insulin receptor (INSR), angiotensin II type 1 receptor (AT1R), toll-like receptor 4 (TLR4), AMP-activated protein kinase (AMPK), and transient receptor potential (TRP) channel signalling converge to perpetuate endothelial injury, vascular inflammation, and neural dysfunction. Critically, emerging evidence implicates mitochondrial reactive oxygen species (mtROS) overproduction, impaired mitochondrial biogenesis, and altered mitochondrial dynamics as shared mechanistic nodes linking both axes. This review synthesises current mechanistic knowledge within a novel unified framework, proposes candidate biomarkers-including urinary 8-OHdG, NT-proBNP, heart rate variability indices, and coronary flow reserve by cardiac PET/CMR-and identifies actionable therapeutic targets, including mitochondria-directed antioxidants (MitoQ, SS-31), SGLT2 inhibitors, GLP-1 receptor agonists, TLR4 antagonists, and TRPV1 modulators. Testable mechanistic hypotheses and directions for future translational research are proposed to accelerate early diagnosis and disease-modifying intervention in high-risk diabetic patients.
PMID:42324025 | DOI:10.1016/j.mvr.2026.104983