Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity

Abstract

Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.

Keywords: diabetes mellitus; heart failure; myocytes, cardiac; peroxisome proliferator-activated receptors; renin-angiotensin system.

Fig. 1

Pathophysiological mechanisms of diabetic cardiomyopathy. Hyperglycemia, insulin resistance, and hyperinsulinemia induce cardiac insulin resistance and metabolic disorders that increase mitochondria dysfunction, oxidative stress, AGEs, impairment of mitochondria Ca²⁺ handling, inflammation, activation of RAAS, autonomic neuropathy, endoplasmic reticulum stress, cardiomyocyte death, as well as microvascular dysfunction. These pathophysiological abnormalities promote cardiac stiffness, hypertrophy, and fibrosis, resulting in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. Abbreviations: AGEs, advanced glycation end-products; RAAS, renin-angiotensin-aldosterone system.

Fig. 2

The molecular proteins and signaling pathways in hyperglycemia- and insulin resistance-diabetic cardiomyopathy. Increased PKC, MAPK, NF-κB, SGLT2, O-GlcNAc and CREM signaling, dysregulation of miRNA and exosomes, and reduction of AMPK, PPAR-γ and Nrf2 induce cardiac insulin resistance, subcellular component abnormalities, metabolic disorders, and structural changes, resulting in diabetic cardiomyopathy. Abbreviations: AMPK, AMP-activated protein kinase; PPAR, peroxisome proliferator-activated receptor; Nrf2, nuclear factor erythroid 2-related factor 2; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; SGLT2, sodium-glucose cotransporter-2; O-GlcNAc, O-linked N-acetylglucosamine; CREM, cyclic adenosine 5′-monophosphate-responsive element modulator; miRNA; microRNA.