Cardiomyopathy Associated with Diabetes: The Central Role of the Cardiomyocyte

Abstract

The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%-80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal glycemic control is not sufficient to prevent DCM, which derives from heart remodeling and geometrical changes, with both consequences of critical events initially occurring at the cardiomyocyte level. Cardiac cells, under hyperglycemia, very early undergo metabolic abnormalities and contribute to T helper (Th)-driven inflammatory perturbation, behaving as immunoactive units capable of releasing critical biomediators, such as cytokines and chemokines. This paper aims to focus onto the role of cardiomyocytes, no longer considered as "passive" targets but as "active" units participating in the inflammatory dialogue between local and systemic counterparts underlying DCM development and maintenance. Some of the main biomolecular/metabolic/inflammatory processes triggered within cardiac cells by high glucose are overviewed; particular attention is addressed to early inflammatory cytokines and chemokines, representing potential therapeutic targets for a prompt early intervention when no signs or symptoms of DCM are manifesting yet. DCM clinical management still represents a challenge and further translational investigations, including studies at female/male cell level, are warranted.

Keywords: cardiomyocytes; cardiomyopathy; chemokines; diabetes; inflammation; therapy.

Figure 1

Glycotoxicity/lipotoxicity-induced events at cardiomyocyte level. A “maladaptive” proinflammatory response occurs in cardiomyocytes under persistent stressful challenge, like diabetes. Each box depicts intracellular processes leading to diabetic cardiomyopathy. FA: fatty acids; AGE: advanced glycated end products; NO: nitric oxide; ROS: reactive oxygen species.

Figure 2

Detrimental event cascade leading to cardiac tissue injury. Chronic hyperglycemia triggers oxidative stress mediators and inflammasome assembly, leading to cell apoptosis and the release of cytokines and chemokines, which perpetuate inflammation. ROS: reactive oxygen species; DAMP: damage-associated molecular pattern; NLRP3: nucleotide-binding oligomerization domain like receptor pyrin domain containing 3. IL: interleukin.