ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD

The Task Force on Diabetes, Pre-Diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and Developed in Collaboration With the European Association for the Study of Diabetes (EASD)

Lars Rydén (ESC Chairperson) (Sweden); Peter J. Grant (EASD Chairperson) (UK); Stefan D. Anker (Germany); Christian Berne (Sweden); Francesco Cosentino (Italy); Nicolas Danchin (France); Christi Deaton (UK); Javier Escaned (Spain); Hans-Peter Hammes (Germany); Heikki Huikuri (Finland); Michel Marre (France); Nikolaus Marx (Germany); Linda Mellbin (Sweden); Jan Ostergren (Sweden); Carlo Patrono (Italy); Petar Seferovic (Serbia); Miguel Sousa Uva (Portugal); Marja-Riita Taskinen (Finland); Michal Tendera (Poland); Jaakko Tuomilehto (Finland); Paul Valensi (France); Jose Luis Zamorano (Spain); Jose Luis Zamorano (Chairperson) (Spain); Stephan Achenbach (Germany); Helmut Baumgartner (Germany); Jeroen J. Bax (Netherlands); Héctor Bueno (Spain); Veronica Dean (France); Christi Deaton (UK); Çetin Erol (Turkey); Robert Fagard (Belgium); Roberto Ferrari (Italy); David Hasdai (Israel); ArnoW. Hoes (Netherlands); Paulus Kirchhof (Germany UK); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Patrizio Lancellotti (Belgium); Ales Linhart (Czech Republic); Petros Nihoyannopoulos (UK); Massimo F. Piepoli (Italy); Piotr Ponikowski (Poland); Per Anton Sirnes (Norway); Juan Luis Tamargo (Spain); Michal Tendera (Poland); Adam Torbicki (Poland); William Wijns (Belgium); Stephan Windecker (Switzerland); Guy De Backer (Review Coordinator) (Belgium); Per Anton Sirnes (CPG Review Coordinator) (Norway); Eduardo Alegria Ezquerra (Spain); Angelo Avogaro (Italy); Lina Badimon (Spain); Elena Baranova (Russia); Helmut Baumgartner (Germany); John Betteridge (UK); Antonio Ceriello (Spain); Robert Fagard (Belgium); Christian Funck-Brentano (France); Dietrich C. Gulba (Germany); David Hasdai (Israel); Arno W. Hoes (Netherlands); John K. Kjekshus (Norway); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Eli Lev (Israel); Christian Mueller (Switzerland); Ludwig Neyses (Luxembourg); Peter M. Nilsson (Sweden); Joep Perk (Sweden); Piotr Ponikowski (Poland); Zeljko Reiner (Croatia); Naveed Sattar (UK); Volker Schächinger (Germany); André Scheen (Belgium);


Eur Heart J. 2013;34(39):3035-3087. 

In This Article

4. Molecular Basis of Cardiovascular Disease in Diabetes Mellitus

4.1 The Cardiovascular Continuum in Diabetes Mellitus

Type 2 diabetes mellitus is characterized by a state of long-standing IR, compensatory hyperinsulinaemia and varying degrees of elevated PG, associated with clustering of cardiovascular risk and the development of macrovascular disease prior to diagnosis (Figure 5). The early glucometabolic impairment is characterized by a progressive decrease in insulin sensitivity and increased glucose levels that remain below the threshold for a diagnosis of T2DM, a state known as IGT.

Figure 5.

Glycaemic continuum and cardiovascular disease.

The pathophysiological mechanisms supporting the concept of a 'glycaemic continuum' across the spectrum of IFG, IGT, DM and CVD will be addressed in the following sections. The development

of CVD in people with IR is a progressive process, characterized by early endothelial dysfunction and vascular inflammation leading to monocyte recruitment, foam cell formation and subsequent development of fatty streaks. Over many years, this leads to atherosclerotic plaques, which, in the presence of enhanced inflammatory content, become unstable and rupture to promote occlusive thrombus formation. Atheroma from people with DM has more lipid, inflammatory changes and thrombus than those free from DM. These changes occur over a 20–30 year period and are mirrored by the molecular abnormalities seen in untreated IR and T2DM.

4.2 Pathophysiology of Insulin Resistance in Type 2 Diabetes Mellitus

Insulin resistance has an important role in the pathophysiology of T2DM and CVD and both genetic and environmental factors facilitate its development. More than 90% of people with

T2DM are obese,[67] and the release of free fatty acids (FFAs) and cytokines from adipose tissue directly impairs insulin sensitivity (Figure 6). In skeletal muscle and adipose tissue, FFA-induced reactive oxygen species (ROS) production blunts activation of insulin receptor substrate 1 (IRS-1) and PI3K-Akt signalling, leading to down-regulation of insulin responsive glucose transporter 4 (GLUT-4).[68,69]

Figure 6.

Hyperglycaemia, insulin resistance, and cardiovascular disease. AGE = advanced glycated end-products; FFA = free fatty acids; GLUT-4 = glucose transporter 4; HDL-C = high-density lipoprotein cholesterol; LDL = low-density lipoprotein particles; NO = nitric oxide; PAI-1 = plasminogen activator inhibitor-1; PKC = protein kinase C; PPARy = peroxisome proliferator-activated receptor y; PI3K = phosphatidylinositide 3-kinase; RAGE = AGE receptor; ROS = reactive oxygen species; SR-B = scavenger receptor B; tPA = tissue plasminogen activator.

4.3 Endothelial Dysfunction, Oxidative Stress and Vascular Inflammation

FFA-induced impairment of the PI3K pathway blunts Akt activity and phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, resulting in decreased production of nitric oxide (NO), endothelial dysfunction,[70] and vascular remodelling (increased intima-media thickness), important predictors of CVD (Figure 6)..[71,72] In turn, accumulation of ROS activates transcription factor NF-κB, leading to increased expression of inflammatory adhesion molecules and cytokines.[69] Chronic IR stimulates pancreatic secretion of insulin, generating a complex phenotype that includes progressive beta cell dysfunction,[68] decreased insulin levels and increased PG. Evidence supports the concept that hyperglycaemia further decreases endothelium-derived NO availability and affects vascular function via a number of mechanisms, mainly involving overproduction of ROS (Figure 6).[73] The mitochondrial electron transport chain is one of the first targets of high glucose, with a direct net increase in superoxide anion (O2) formation. A further increase in O2 production is driven by a vicious circle involving ROS-induced activation of protein kinase C (PKC).[74] Activation of PKC by glucose leads to up-regulation of NADPH oxidase, mitochondrial adaptor p66Shc and COX-2 as well as thromboxane production and impaired NO release (Figure 6)..[75–77] Mitochondrial ROS, in turn, activate signalling cascades involved in the pathogenesis of cardiovascular complications, including polyol flux, advanced glycation end-products (AGEs) and their receptors (RAGEs), PKC and hexosamine pathway (HSP) (Figure 6). Recent evidence suggests that hyperglycaemia-induced ROS generation is involved in the persistence of vascular dysfunction despite normalization of glucose levels. This phenomenon has been called 'metabolic memory' and may explain why macro- and microvascular complications progress, despite intensive glycaemic control, in patients with DM. ROS-driven epigenetic changes are particularly involved in this process.[74,78]

4.4 Macrophage Dysfunction

The increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation and IR.[79] In addition, the insulin-resistant macrophage increases expression of the oxidized low-density lipoprotein (LDL) scavenger receptor B (SR-B), promoting foam cell formation and atherosclerosis. These findings are reversed by peroxisome proliferator-activated receptor gamma (PPARγ) activation, which enhances macrophage insulin signalling (Figure 6). In this sense it seems that macrophage abnormalities provide a cellular link between DM and CVD by both enhancing IR and by contributing to the development of fatty streaks and vascular damage.

4.5 Atherogenic Dyslipidaemia

Insulin resistance results in increased FFA release to the liver due to lipolysis. Therefore, enhanced hepatic very low-density lipoprotein (VLDL) production occurs due to increased substrate availability, decreased apolipoprotein B-100 (ApoB) degradation and increased lipogenesis. In T2DM and the metabolic syndrome, these changes lead to a lipid profile characterized by high triglycerides (TGs), low high-density lipoprotein cholesterol (HDL-C), increased remnant lipoproteins, apolipoprotein B (ApoB) synthesis and small, dense LDL particles (Figure 6).[80] This LDL subtype plays an important role in atherogenesis being more prone to oxidation. On the other hand, recent evidence suggests that the protective role of HDL may be lost in T2DM patients due to alterations of the protein moiety, leading to a pro-oxidant, inflammatory phenotype.[81] In patients with T2DM, atherogenic dyslipidaemia is an independent predictor of cardiovascular risk, stronger than isolated high triglycerides or a low HDL cholesterol.[80]

4.6 Coagulation and Platelet Function

In T2DM patients, IR and hyperglycaemia participate to the pathogenesis of a prothrombotic state characterized by increased plasminogen activator inhibitor-1(PAI-1), factor VII and XII, fibrinogen and reduced tissue plasminogen activator (tPA) levels (Figure 6).[82] Among factors contributing to the increased risk of coronary events in DM, platelet hyper-reactivity is of major relevance.[83] A number of mechanisms contribute to platelet dysfunction, affecting the adhesion and activation, as well as aggregation, phases of platelet-mediated thrombosis. Hyperglycaemia alters platelet Ca2+ homeostasis, leading to cytoskeleton abnormalities and increased secretion of pro-aggregant factors. Moreover, hyperglycaemia-induced up-regulation of glycoproteins (Ib and IIb/IIIa), P-selectin and enhanced P2Y12 signalling are key events underlying atherothrombotic risk in T1DM and T2DM (Figure 6).

4.7 Diabetic Cardiomyopathy

In patients with T2DM, reduced IS predisposes to impaired myocardial structure and function and partially explains the exaggerated prevalence of heart failure in this population. Diabetic cardiomyopathy is a clinical condition diagnosed when ventricular dysfunction occurs in the absence of coronary atherosclerosis and hypertension. Patients with unexplained dilated cardiomyopathy were 75% more likely to have DM than age-matched controls.[84] Insulin resistance impairs myocardial contractility via reduced Ca2+ influx through L-type Ca2+ channels and reverse mode Na2+/Ca2+ exchange. Impairment of phosphatidylinositol 3-kinases (PI3K)/Akt pathway subsequent to chronic hyperinsulinaemia is critically involved in cardiac dysfunction in T2DM.[85]

Together with IR, hyperglycaemia contributes to cardiac- and structural abnormalities via ROS accumulation, AGE/RAGE signalling and hexosamine flux.[84,86] Activation of ROS-driven pathways affects the coronary circulation, leads to myocardial hypertrophy and fibrosis with ventricular stiffness and chamber dysfunction (Figure 6).[86]

4.8 The Metabolic Syndrome

The metabolic syndrome (MetS) is defined as a cluster of risk factors for CVD and T2DM, including raised blood pressure, dyslipidaemia (high triglycerides and low HDL cholesterol), elevated PG and central obesity. Although there is agreement that the MetS deserves attention, there has been an active debate concerning the terminology and diagnostic criteria related to its definition.[87] However, the medical community agrees that the term 'MetS' is appropriate to represent the combination of multiple risk factors. Although MetS does not include established risk factors (i.e. age, gender, smoking) patients with MetS have a two-fold increase of CVD risk and a five-fold increase in development of T2DM.

4.9 Endothelial Progenitor Cells and Vascular Repair

Circulating cells derived from bone marrow have emerged as critical to endothelial repair. Endothelial progenitor cells (EPCs), a sub-population of adult stem cells, are involved in maintaining endothelial homeostasis and contribute to the formation of new blood vessels. Although the mechanisms whereby EPCs protect the cardiovascular system are unclear, evidence suggests that impaired function and reduced EPCs are features of T1DM and T2DM. Hence, these cells may become a potential therapeutic target for the management of vascular complications related to DM.[88]

4.10 Conclusions

Oxidative stress plays a major role in the development of micro- and macrovascular complications. Accumulation of free radicals in the vasculature of patients with DM is responsible for the activation of detrimental biochemical pathways, leading to vascular inflammation and ROS generation. Since the cardiovascular risk burden is not eradicated by intensive glycaemic control associated with optimal multifactorial treatment, mechanism-based therapeutic strategies are needed. Specifically, inhibition of key enzymes involved in hyperglycaemia-induced vascular damage, or activation of pathways improving insulin sensitivity, may represent promising approaches.