Heart Failure And Type 2 Diabetes Mellitus: Neurohumoral, HistologicalAnd Molecular Interconnections

Figures

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  Fig. (1). Mechanisms involved in development of heart failure in diabetes mellitus. The development of HF in T2DM involves a myriad combination of interconnected changes that can be schematically presented as cardiac and extracardiac mechanisms. Extracardiac mechanisms include alterations in SNS and RAAS, arginine-vasopressin and natriuretic peptide system, and endothelial dysfunction. Cardiac mechanisms involve alterations in myocardial energy metabolism and calcium metabolism, cardiomyocyte hypertrophy and death, and extracellular matrix remodeling. These mechanisms aimed to be compensatory over time, leading to pathological myocardial remodeling and HF progression.

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  Fig. (2). Schematic illustration of major disturbances of cardiomyocyte calcium metabolism in the diabetic heart. Disturbances in Ca2+ metabolism occur due to various factors, among which are the impaired activity of L-type Ca2+ channels, sarcoplasmic reticulum Ca2+ ATPase, type 2 ryanodine receptor, Na+/Ca2+ exchanger, and altered mitochondrial function.

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  Fig. (3). Schematic illustration of main signaling pathways regulating myocardial hypertrophy in diabetes mellitus. Systemic hyperglycemia and hyperlipidemia promote chronic low-grade inflammation that leads to activation of toll-like receptors that trigger p38 and JNK signaling pathways. Systemic inflammation also stimulates cytokine release, among which is tumor necrotic factor-α that may induce cardiomyocyte hypertrophy through modulation of nuclear factor-κB signaling. Lipotoxicity and glucotoxicity induce oxidative stress and endothelial dysfunction resulting in reduced nitric oxide bioavailability and decreased activity of the nitric oxide–cyclic guanosine monophosphate–protein kinase G pathway. Protein kinase G inhibition results in loss of its protective effect against cardiomyocyte hypertrophy.