Abstract
The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.
Key points
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Diabetic cardiomyopathy is characterized by adverse structural remodelling (including cardiac hypertrophy and fibrosis), early-onset diastolic dysfunction and late-onset systolic dysfunction.
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At present, treatment regimens for diabetes-associated cardiovascular disease rely on conventional therapies that focus on optimizing glycaemic control, lowering lipid levels and reducing oxidative stress.
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Pathophysiological factors that contribute to diabetic cardiomyopathy include metabolic disturbances, insulin resistance, formation and crosslinking of advanced glycation end products, mitochondrial damage, oxidative stress, inflammation and cell death.
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Several new potential treatment strategies that target myocardial fibrosis, inflammation, oxidative stress and insulin resistance have shown promising results in preclinical studies but require validation in randomized clinical trials.
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Acknowledgements
The work of the authors is supported in part by grants from the NIH (1R01-HL-125877-01), the American Diabetes Association (1-15-BS-018, 1-18-IBS-082 and 1-13-JF-53), the UofL–China Paediatric Research Exchange Program at the University of Louisville, USA, and a Pilot Award from Norton Children’s Hospital Foundation & Norton Healthcare Foundation. The authors thank N. Mellen (Department of Neurology, University of Louisville School of Medicine, Louisville, KY, USA) for help editing the manuscript.
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Y.T., Z.Z. and L.C. researched data for the article and wrote the manuscript. Y.T., C.Z., K.A.W., B.B.K. and L.C. contributed substantially to the discussion of its contents. All authors reviewed and edited the manuscript before submission.
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Glossary
- Insulin resistance
-
Impaired signal transduction and biological actions in response to insulin stimulation.
- β-oxidation
-
Catabolic process that takes place in the mitochondria to generate energy by breaking fatty acid molecules into acetyl coenzyme A, which enters the tricarboxylic acid cycle that generates reduced NAD and reduced flavin adenine dinucleotide, which are co-enzymes used in the electron transport chain.
- Advanced glycation end products
-
(AGEs). Protein or lipid molecules that are modified by glycation when exposed to sugars; AGEs can induce cardiovascular injury through crosslinking of extracellular matrix molecules and by engaging the receptor for AGEs (RAGE) on cardiac cells.
- Reactive oxygen species
-
(ROS). By-products of cellular respiration comprising unstable chemical species containing oxygen, including superoxide and hydroxyl radical; ROS have important roles in cell signalling and homeostasis but can induce cellular damage when dysregulated.
- Reactive nitrogen species
-
(RNS). Reactive compounds derived from nitric oxide, including nitroxyl anion and nitrosonium cation, that are critical for the physiological regulation of living cells but can induce cellular damage when dysregulated.
- Oxidative stress
-
An imbalance between the production of free radicals and the biological system’s capacity to detoxify the reactive intermediates with antioxidants. Oxidative stress is a common pathogenic mechanism in many diseases.
- Endoplasmic reticulum (ER) stress
-
The endoplasmic reticulum (ER) is a major organelle in which proteins are synthesized, folded, modified and delivered to their final intracellular or extracellular destination. Increased stress on this system results in the accumulation of unfolded proteins in the ER lumen.
- Autophagy
-
A regulated cellular process that removes unnecessary or dysfunctional cellular components by lysosome-mediated or vacuole-mediated degradation and recycling.
- Extracellular matrix
-
(ECM). A complex network of extracellular material such as proteins and polysaccharides that are secreted locally by cells and remain crosslinked with each other to provide structural, adhesive and biochemical signalling support.
- Inflammasome
-
Multiprotein intracellular complex that can sense a variety of physiological and pathological stimuli and in response can activate the highly pro-inflammatory cytokines IL-1β and IL-18.
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Tan, Y., Zhang, Z., Zheng, C. et al. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol 17, 585–607 (2020). https://doi.org/10.1038/s41569-020-0339-2
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DOI: https://doi.org/10.1038/s41569-020-0339-2
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