1 Wilson AJ, et al. Heart 2017;0:1–7. doi:10.1136/heartjnl-2017-311448 Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting Adam J Wilson, 1 Eleanor K Gill, 1,2 Rawan A Abudalo, 1,2 Kevin S Edgar, 1 Chris J Watson, 1 David J Grieve 1,2 ABSTRACT Despite being frst described 45 years ago, the existence of a distinct diabetic cardiomyopathy remains controversial. Nonetheless, it is widely accepted that the diabetic heart undergoes characteristic structural and functional changes in the absence of ischaemia and hypertension, which are independently linked to heart failure progression and are likely to underlie enhanced susceptibility to stress. A prominent feature is marked collagen accumulation linked with infammation and extensive extracellular matrix changes, which appears to be the main factor underlying cardiac stiffness and subclinical diastolic dysfunction, estimated to occur in as many as 75% of optimally controlled diabetics. Whether this characteristic remodelling phenotype is primarily driven by microvascular dysfunction or alterations in cardiomyocyte metabolism remains unclear. Although hyperglycaemia regulates multiple pathways in the diabetic heart, increased reactive oxygen species (ROS) generation is thought to represent a central mechanism underlying associated adverse remodelling. Indeed, experimental and clinical diabetes are linked with oxidative stress which plays a key role in cardiomyopathy, while key processes underlying diabetic cardiac remodelling, such as infammation, angiogenesis, cardiomyocyte hypertrophy and apoptosis, fbrosis and contractile dysfunction, are redox sensitive. This review will explore the relative contributions of the major ROS sources (dysfunctional nitric oxide synthase, mitochondria, xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidases) in the diabetic heart and the potential for therapeutic targeting of ROS signalling using novel pharmacological and non- pharmacological approaches to modify specifc aspects of the remodelling phenotype in order to prevent and/or delay heart failure development and progression. INTRODUCTION Diabetes is becoming alarmingly prevalent and is characterised by elevated cardiovascular risk, and specifically chronic heart failure (CHF), largely due to hypertension or ischaemia, with poor prognosis and survival. 1 While the existence of distinct cardio- myopathy remains controversial, the diabetic heart displays major structural changes independent of coronary disease which underlie CHF progression and enhanced susceptibility to stress. 2 Prominent features are inflammation and collagen accumula- tion linked with major extracellular matrix (ECM) changes, underlying subclinical diastolic dysfunc- tion observed in many optimally controlled type 1/2 diabetics (T1D/T2D). 3 Despite appreciation of distinct cardiac remodelling, CHF management remains similar between diabetics and non-dia- betics, following European Society of Cardiology guidelines. 4 Although some standard cardiac drugs (eg, angiotensin receptor blockers) confer direct benefit against fibrosis, 5 and novel antidiabetic ther- apies (eg, liraglutide, empagliflozin) reduce cardio- vascular mortality and hospitalisation, 6 they are not specifically indicated in diabetes, highlighting a need for tailored strategies. CARDIAC REMODELLING IN DIABETES Pathogenesis of diabetic cardiac remodelling Remodelling of the non-diabetic heart in response to pathophysiological stimuli (eg, hypertension, ischaemia) is largely driven by neurohumoral acti- vation, for example, renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. 7 Chronic or acute stress induces remodelling of cardiomyocytes, fibroblasts, endothelium, smooth muscle, and inflammatory cells, and distinct (mal) adaptation (eg, hypertrophy, apoptosis, collagen accumulation, ECM turnover, cytokine/chemo- kine signalling, autophagy, excitation-contraction coupling, oxidative metabolism), ultimately driving development/progression of CHF (figure 1). 7 While these processes are evident in diabetes, they gener- ally occur subclinically, thereby predisposing to stress. The diabetic heart is particularly charac- terised by ECM remodelling, the main drivers of which are matrix metalloproteinases (MMPs) and TIMPs (tissue inhibitors of MMPs), which are dysregulated, leading to collagen accumulation. 8 In diabetes, collagen synthesis and cross-linking are specifically promoted by advanced glycation end-products (AGEs), which upregulate profi- brotic signalling (eg, angiotensin II, transforming growth factor-β), largely dependent on cytokine/ chemokine secretion (eg, tumour necrosis factor-α, interleukin-1β), by infiltrating inflammatory cells. 9 Normally, such pathways interact with MMPs/ TIMPs to maintain ECM turnover, which becomes dysregulated in diabetes largely due to RAAS acti- vation. Such alterations promote ECM expansion/ dysregulation, which underlies cardiac stiffness and diastolic dysfunction, ultimately causing elevated wall stress, chamber dilatation, contractile dysfunc- tion and CHF. 3 Significantly, diabetes promotes cardiomyocyte hypertrophy by reactivating fetal genes (eg, β-myosin heavy chain, atrial natriuretic peptide). 10 Associated contractile dysfunction may be explained by altered cytoskeletal organisation Review To cite: Wilson AJ, Gill EK, Abudalo RA, et al. Heart Published Online First: [please include Day Month Year]. doi:10.1136/ heartjnl-2017-311448 1 Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK 2 British Society for Cardiovascular Research, Belfast, UK Correspondence to David J Grieve, Centre for Experimental Medicine, Queen’s University Belfast, Wellcome- Wolfson Building, 97 Lisburn Road, Belfast BT9 7AE, UK; d. grieve@qub.ac.uk Received 29 June 2017 Revised 24 August 2017 Accepted 24 August 2017 Heart Online First, published on September 27, 2017 as 10.1136/heartjnl-2017-311448 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BCS) under licence. on March 18, 2020 by guest. Protected by copyright. http://heart.bmj.com/ Heart: first published as 10.1136/heartjnl-2017-311448 on 27 September 2017. Downloaded from