Progression of diabetic cardiomyopathy exhibits alterations in cardiac function andstructure and macrophages composition

Background: Diabetic cardiomyopathy (DbCM) is defined as a cardiac dysfunction derived from diabetes mellitus (DM) without the presence of coronary artery diseases and hypertension. However, there are no specific treatments for DbCM, and the uniqueness of DbCM remains controversial. Therefore, this study aimed to understand the characteristics of DbCM using longitudinal follow-up echocardiography and single-nuclei RNA sequencing.

Method: DbCM murine model was established using a high-fat diet (HFD) and a single dose of 100 mg/kg streptozotocin (STZ). Echocardiography was used for longitudinal follow-up of cardiac function and structure. Single-nuclei RNA sequencing (snRNA-seq) was performed to decipher the progression of DbCM. Then, pathway analysis was conducted, along with RT-qPCR and Western blotting.

Results: HFD/STZ mice recapitulated the DbCM phenotype, particularly diastolic dysfunction and left ventricular hypertrophy, after 24 weeks of follow-up. Interestingly, the MV E/A ratio significantly decreased in HFD/STZ mice at 8 weeks of study (p < 0.05) compared to controls. Left ventricular posterior wall thickness was increased in HFD/STZ mice (p < 0.0001). The results of snRNA-seq showed an influx of macrophages into diabetic hearts, and the dysregulated inflammatory pathway was one of the critical drivers in DbCM progression. Moreover, the chronic hyperglycaemic condition resulted in induced interferon regulatory factor 7 (Irf7) gene expression, which is a stress-inducible factor. Gene expression of Irf7 showed significantly higher levels in diabetic heart tissue vs. controls (p < 0.01) and high (D-glucose)-glucose vs. osmotic control (L-glucose)-treated pro-repairing macrophages (p < 0.01).

Conclusion: Diabetic cardiomyopathy mice reveal multifaceted characteristics, including diastolic dysfunction, cardiac hypertrophy, and immune inflammation in the heart. These suggest therapeutic targets for modulating diabetic cardiomyopathy progression by immunomodulatory therapies.