Diabetic Cardiomyopathy

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.

Potential Role of Antihypertensive Medications in Preventing Excessive Arterial Stiffening

“…Transforming growth factor beta 1 (TGF-β1)/Smad signaling can stimulate synthesis of ECM proteins including collagens and fibronectin [17]. Increased TGF-β1 increases synthesis and accumulation of ECM proteins partly by associated increases in matrix metalloproteinases (MMPs) [18], which degrade elastin. [18].…”

“…Increased TGF-β1 increases synthesis and accumulation of ECM proteins partly by associated increases in matrix metalloproteinases (MMPs) [18], which degrade elastin. [18]. Excessive arterial stiffening is a complex property that is also mediated by abnormal ECM and matrix-cell interactions [19].…”

“…The signaling pathways of the mitochondrial monoamine oxidase, cyclooxygenase 2, and p66Shc signaling are also involved in Ang II-induced activation of NOX induction and oxidative stress in arterial tissues [33]. Some other sources of ROS include peroxisomal β-oxidation of fatty acids, arachidonic acid metabolism, xanthine oxidase, microsomal P-450 enzymes, and pro-oxidant heme molecule that have been recognized to contribute to arterial stiffening and hypertension [18]. Therefore, increased ROS and oxidative stress impair deoxyribonucleic acid, lipid, protein, as well as mitochondrial function.…”

“…PVAT produces some protective substances such as adiponectin, which helps maintain normal physiological arterial function [38, 39]. However, in individuals with obesity and insulin resistance there is increased release of pro-inflammatory adipokines including interleukin-6, interleukin-8, tumor necrosis factor alpha, as well as toll-like receptor-4 [18]. Activated nuclear factor kappa B (NF-κB) is regarded as an important mechanism on increased arterial stiffening.…”

“…Activated nuclear factor kappa B (NF-κB) is regarded as an important mechanism on increased arterial stiffening. While p50 and p65 subunits of NF-κB are maintained in the cytoplasm, phosphorylation of NF-κB promotes translocation of the heterodimer to the nucleus and release of pro-inflammatory cytokines [18]. Macrophages are an important driver of vascular inflammation and associated increased arterial stiffness.…”