Diabetes and the heart: mechanisms of cardiac injury, hypertension and heart failure. SAGLB.DIA u Date of approval: November 2017

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1 Diabetes and the heart: mechanisms of cardiac injury, hypertension and heart failure SAGLB.DIA u Date of approval: November 2017

2 Abbreviations ACS: acute coronary syndrome AGE: advanced glycoxidation end product APC: antigen-presenting cell BP: blood pressure CAD: chronic arterial disease CNS: central nervous system CVD: cardiovascular disease CVOT: cardiovascular outcomes trial DAMP: damage-associated molecular patterns ESRD: end-stage renal disease HDL: high density lipoprotein IFN: interferon IL: interleukin LDL: low density lipoprotein Lys: lysine MACE: major cardiovascular events MHC: major histocompatibility complex PAI-1: plasminogen activator inhibitor-1 PAMP: pathogen-associated molecular patterns PAR4: protease-activated receptor 4 ROS: radical oxygen species SNS: sympathetic nervous system TCR: T-cell receptor tpa: tissue plasminogen activator

3 Introduction Type 2 diabetes is associated with an increased risk of macrovascular disease, coronary heart disease, stroke and peripheral vascular disease 1 The pathophysiology linking diabetes and CVD is complex and multifactorial 2 This document aims to provide an overview of the mechanisms behind the relationship of diabetes with hypertension, acute coronary syndrome and heart failure 1. Laakso M. Diabetes Care 2010;33:442 9; 2. Dokken BB. Diabetes Spectr Care 2008;21:160 5

4 Select one:

5 Hypertension in diabetes Hypertension is present in 50% of patients with diabetes and significantly contributes to micro and macrovascular disease in these patients 1 Coexisting hypertension and diabetes are associated with: Doubling stroke or CVD risk 2 5- to 6-fold increase in risk for ESRD 3 Increased peripheral vascular disease 3 Increased lower extremity amputations 3 Increased retinopathy 3 Increased heart failure 2,3 1. Lastra G, et al. Endocrinol Metab Clin North Am 2014;43:102 22; 2. ESC Guidelines. Eur Heart J 2013;34: ; 3. Bakris GL, et al. Am J Kidney Dis 2000;36:646 61

6 Mechanisms of hypertension, inflammation and immunity in diabetes Angiotensin II Aldosterone Endothelin-1 Genes Salt Hypersensitive Stimuli BP CNS Low-grade infection PAMPs BP Tissue injury DAMPs Neo-antigens APCs CD80/86 CD28 MHC-II TCR T h 0 Vascular and kidney damage Inflammation Oxidative stress ROS IFN-γ IL-17 γδt T h 1 T h 17 T cell polarization IL-10 T reg T h 2 Idris-Khodja N, et al. Dual opposing roles of adaptive immunity in hypertension. Eur Heart J 2014;35: , by permission of Oxford University Press

7 Diabetes and acute coronary syndrome Patients with acute coronary syndrome and diabetes have been found to have worse outcomes than those without diabetes This may be due to the presence of other comorbidities including hypertension or renal insufficiency However, diabetes is also associated with a proinflammatory and prothrombotic state and an upregulation of platelet membrane proteins Fuster V & Farkouh ME. Circulation 2008;118:1607 8

8 Pathophysiology of arterial plaques in patients with ACS and diabetes Increased risk of arterial plaque rupture and thrombus formation

9 The impact of diabetes on thrombin, fibrin and plasmin

10 Heart failure in diabetes Approximately 20 40% of patients with heart failure also have diabetes 1 The major risk factors for heart failure are also present in diabetes including Obesity Hypertension Advanced age Dyslipidemia Coronary heart disease There has been some discussion on the inclusion of heart failure as a part of the MACE primary endpoint in CVOTs 2 However, some researchers would prefer that heart failure remain a separate primary endpoint as the underlying mechanism remains unclear 3 CVOT: cardiovascular outcome trial 1. Thomas MC. Curr Cardiol Rev 2016;12:249 55; 2. McMurray JJV, et al. Lancet Diab Endocrinol 2014;2:843 51; 3. Sattar N, et al. Diabetologia 2016;59:1333 9

11 Heart failure and diabetes Diabetes mellitus + + Chronic heart failure Adapted from Knops M & Doehner W. Am J Cardiol 2012;110:1070 1

12 Summary CVD has a significant impact on the morbidity and mortality associated with diabetes 1 Currently, while much is known about the relationship between insulin resistance, hypertension and cardiovascular injury, further research is required to determine the exact mechanisms associated with heart failure in diabetes 2 Patients with ACS and diabetes are at increased risk of plaque rupture due to increased thrombin generation associated with hypoglycemia, and other aspects of the pathophysiology of diabetes 3 Understanding the complex pathophysiology involved in CVD and diabetes will be crucial to developing effective treatments and preventative strategies that can target both diseases 1. Dokken BB. Diabetes Spectr 2008;21:160 5; 2. McMurray JJV, et al. Lancet Diab Endocrinol 2014;2: Sanon S, et al. Am J Cardiol 2012;110(Suppl.):13B 23B