An Update on Molecular Modes Implicated in Diastolic Impairment in Early Diabetic Cardiomyopathy; Probable Modes of Therapy &Avoidance-A Narrative Review

Abstract

In case of diabetic patients cardiomyopathy is a significant etiology of heart failure (HF); howeverno clarification exists regarding its pathophysiology. Myocardial hypertrophy as well as diastolic impairment are the logo for Diabetic cardiomyopathy (DbCM), whereas systolic function gets impacted in the latter phase of this disease. Previously we had reviewed Diabetic cardiomyopathy (DbCM with emphasis on epigenetic alterations ,miR changes apart from adipocyte impairment in HF induction, role of SGLT2 hampering agents in beneficial Cardiovascular Outcome Trials (CVOT’s)and renal benefits, role of sirtuins in macrophage Polarization for Diabesity therapy .Here our aim was to posit the pathophysiological mode implicated in myocardial hypertrophy and escalated myocardial stiffness resulting in diastolic impairment .This myocardial stiffness takes place from cellular and extracellular matrix(ECM ) stiffness &cell- matrix crosstalk. Escalated inherent cardiomyocytes stiffness plausibly is the maximum significant cause responsible for myocardial stiffness. It leads to dysfunctional cardiomyocytes cytoskeleton stiffness. Various other modes are implicatedbyT2DM; particularly having significant influence on myocardial stiffening i.e dysfunctional nitric oxide (NO), coronary microvascular impairment, escalated inflammation, as well as Oxidative stress(OS), myocardial Sodium –glucose specific cotransporter 2(SGLT2) modulated actions. Greater insight aids in planning better therapy.Anti diabeticagents, SGLT2 hampering agents have revealed newer ways of benefit ,like sirtuins action , upregulation of nutrient deprivation signaling in addition to downregulation of nutrient surplus signaling, escalated expression &activity of AMP-activated protein kinase(AMPK), Sirtuins (SIRT1), SIRT3 andSIRT6, & Peroxisome Proliferator Activated Receptor γCoactivator -1α(PGC-1α) ,reduction in activation of mammalian target of rapamycin inhibitors (mTOR). Recently Ghosh et al. (2023),advocated targeting sarcoplasmic / cytosolic endoplasmic reticulum Ca2+ -ATPase(SERCA2) ,use of imeglimin which escalates insulin action& along with reverses Pancreatic βcells impairment ,use of anti oxidants, angiotensin receptor neprilysin hampering agents(ARNi),NO stimulating agents. More work is being done regarding combination of empagliflozin with linagliptin &others like semaglutide with .Gradually we will get answers by getting more insight.