Abstract Body: Background: Cardiac autonomic neuropathy, coronary microvascular dysfunction, and metabolic dysregulation are recognized features of diabetic cardiomyopathy, yet the relationships among these processes remain unclear.
Hypothesis: Cardiac neuropathy is an early driver of cardiac dysfunction in diabetic cardiomyopathy.
Methods: Diabetes was induced in mice with streptozotocin. Cardiac innervation, capillary architecture, and systolic and diastolic function were assessed across disease progression. Single-nucleus RNA sequencing was used to define endothelial transcriptional responses, and MERFISH spatial transcriptomics was used to evaluate relationships between vascular organization and cardiomyocyte metabolic state. Histology and electron microscopy were used to quantify tissue lipid accumulation. Sarm1 knockout mice were used to test whether blocking axonal degeneration alters cardiac remodeling in diabetes.
Results: Diabetic hearts developed early cardiac neuropathy, with axon length density reduced by ~30–33% at 4 weeks, preceding microvascular remodeling and systolic and diastolic dysfunction. Although capillary length density was largely unchanged, diabetic hearts developed increased capillary spacing at 8 weeks, consistent with focal under-vascularized regions. Single-nucleus RNA sequencing identified endothelial upregulation of neurovascular signaling genes, including Ntn1 and Chrm3, together with endothelial dysfunction programs; similar signatures were present in denervated human transplant hearts with cardiac allograft vasculopathy. MERFISH revealed regional cardiomyocyte metabolic heterogeneity associated with endothelial proximity and hypoxic gene signatures in poorly vascularized regions. Diabetic hearts also showed increased lipid accumulation. Sarm1 deletion prevented cardiac neuropathy, improved cardiac function, and reduced lipid droplet accumulation by 29% despite similar systemic metabolic status.
Conclusions: These findings support cardiac neuropathy as a potential early driver linking spatial microvascular dysfunction to metabolic remodeling in diabetic cardiomyopathy and identify SARM1 as a candidate therapeutic target.