Calcium dysregulation in diabetic cardiomyopathy & heart failure with preserved ejection fraction.

Diabetes is a major risk factor for cardiovascular disease, and heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF), which is the most prevalent form of HF in patients with type 2 diabetes (T2D). However, the mechanisms behind diabetes-induced cardiomyopathy (DbCM) are complex and remain poorly understood. Insulin resistance resulting from diabetes has been shown to contribute to cardiac impairment, leading to diastolic dysfunction and hypertrophy. Studies have shown that the impairment of calcium (Ca2+)-handling cardiac proteins, such as sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and ryanodine receptor type 2 (RyR2), may act as key drivers behind the development of DbCM and its progression to HF. However, further studies are needed to fully understand their impact. This review focuses on the intersection of diabetes and HFpEF at the molecular level, showing how insulin resistance contributes to cardiac impairment, and the critical role of Ca2+ -handling proteins in DbCM progression. Due to the limited understanding and the complexity of DbCM, there are currently no viable cures that reverse disease progression in DbCM or HFpEF. However, adeno-associated virus (AAV)- mediated gene therapies show promise for treating diabetes-induced cardiomyopathy. This review discusses molecular pathways affected under DbCM and HFpEF conditions as well as potential treatments in both preclinical and clinical trials to analyze their effectiveness.