The role of hyperglycaemia in the development of diabetic cardiomyopathy

Magali Samia El Hayek, Laura Ernande, Jean-Pierre Benitah, Ana-Maria Gomez, Laetitia Pereira

Diabetes mellitus is a metabolic disorder with a chronic hyperglycaemic state. Cardiovascular diseases are the primary cause of mortality in patients with diabetes. Increasing evidence supports the existence of diabetic cardiomyopathy, a cardiac dysfunction with impaired cardiac contraction and relaxation, independent of coronary and/or valvular complications.

Diabetic cardiomyopathy can lead to heart failure. Several preclinical and clinical studies have aimed to decipher the underlying mechanisms of diabetic cardiomyopathy. Among all the co-factors, hyperglycaemia seems to play an important role in this pathology. Hyperglycaemia has been shown to alter cardiac metabolism and function through several deleterious mechanisms, such as oxidative stress, inflammation, accumulation of advanced glycated end-products and upregulation of the hexosamine biosynthesis pathway. These mechanisms are responsible for the activation of hypertrophic pathways, epigenetic modifications, mitochondrial dysfunction, cell apoptosis, fibrosis and calcium mishandling, leading to cardiac stiffness, as well as contractile and relaxation dysfunction.

This review aims to describe the hyperglycaemic-induced alterations that participate in diabetic cardiomyopathy, and their correlation with the severity of the disease and patient mortality, and to provide an overview of cardiac outcomes of glucose-lowering therapy.

Diabetes, Glucose, Cardiomyopathy

• AGE: advanced glycated end-product
• ATPv: adenosine triphosphate
• CaMKII: calmodulin kinase II
• CI: confidence interval
• DM: diabetes mellitus
• DPP4: dipeptidyl-peptidase-4
• GLP-1: glucagon-like peptide-1
• GRK2: β-adrenergic receptor kinase
• HbA1c: glycated haemoglobin
• HF: heart failure
• HFpEF: heart failure with preserved ejection fraction
• HFrEF: heart failure with reduced ejection fraction
• HR: hazard ratio
• MACE3: three-point major adverse cardiovascular events
• O-GlcNAc: O-linked-N-acetylglucosamine
• O-GlcNAcylation: O-linked-N-acetylglucosaminylation
• ROS: reactive oxygen species
• SERCA: sarco/endoplasmic reticulum Calcium adenosine triphosphatase
• SGLT2: sodium/glucose co-transporter 2

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