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      Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

      , MD, PhD, , MD, PhD, , MD, PhD

      The Canadian Journal of Cardiology

      Pulsus Group

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          Abstract

          Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes.

          Résumé

          L’hypertension et le diabète de type 2 sont des affections concomitantes fréquentes. L’hypertension est deux fois plus fréquente chez les patients atteints de diabète que chez ceux qui n’en sont pas atteints. De plus, les patients atteints d’hypertension sont souvent résistants à l’insuline et sont plus susceptibles de souffrir de diabète que les personnes normotendues. Chez les diabétiques, la principale cause de morbidité et de mortalité est la maladie cardiovasculaire, qui est exacerbée par l’hypertension. En conséquence, le diabète et l’hypertension sont étroitement interreliés en raison de facteurs de risques similaires, comme la dysfonction endothéliale, l’inflammation vasculaire, le remodelage artériel, l’athérosclérose, la dyslipidémie et l’obésité. On observe un chevauchement important entre les complications cardiovasculaires du diabète et celles de l’hypertension liées principalement à des maladies microvasculaires et macrovasculaires. Des mécanismes communs, comme une stimulation du système rénine-angiotensine-aldostérone, un stress oxydatif, une inflammation et une activation du système immunitaire, sont susceptibles de contribuer à la relation étroite entre le diabète et l’hypertension. Dans cet article, nous abordons le diabète et l’hypertension comme des affections concomitantes et nous parlons des caractéristiques physiopathologiques des complications vasculaires associées à ces affections. Nous soulignons également certains mécanismes vasculaires qui prédisposent à ces deux affections, en mettant l’accent sur les produits finaux de glycation avancée, le stress oxydatif, l’inflammation, le système immunitaire et les micro-ARN. Finalement, nous présentons certaines connaissances sur les traitements actuels ciblant le diabète et les complications cardiovasculaires et nous présentons de nouveaux agents qui pourraient avoir un pouvoir vasoprotecteur chez les patients diabétiques.

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          Most cited references 76

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          The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.

          NF-kappaB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-kappaB is sequestered in the cytoplasm by inhibitory proteins, I(kappa)B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I(kappa)B, leading to its degradation and translocation of NF-kappaB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-alpha or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response.
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            Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I.

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              Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.

              To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Prospective observational study. 23 hospital based clinics in England, Scotland, and Northern Ireland. 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Primary predefined aggregate clinical outcomes: any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders. The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point. In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.
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                Author and article information

                Contributors
                Journal
                Can J Cardiol
                Can J Cardiol
                The Canadian Journal of Cardiology
                Pulsus Group
                0828-282X
                1916-7075
                1 May 2018
                May 2018
                : 34
                : 5
                : 575-584
                Affiliations
                Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom
                Author notes
                []Corresponding author: Dr Rhian M. Touyz, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Tel.: +44-141-330-7775; fax: +44-141-330-3360. rhian.touyz@ 123456glasgow.ac.uk
                Article
                S0828-282X(17)31214-X
                10.1016/j.cjca.2017.12.005
                5953551
                29459239
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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