Article Text

Diabetic heart disease
Methods of accelerated atherosclerosis in diabetic patients
  1. Gerard Pasterkamp
  1. Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands
  1. Correspondence to Professor Gerard Pasterkamp, Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Room G02-523, Utrecht 3584CX, The Netherlands; g.pasterkamp{at}umcutrecht.nl

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Diabetic patients have an increased risk of cardiovascular disease (CVD), which is a major contributor to morbidity and mortality in the aging population, and have a more than twofold increase in the risk of dying from CVD.1 Even patients with pre-diabetes, as detected by abnormal glucose tolerance tests, have an increased risk of developing disabling stroke, peripheral artery disease, and myocardial infarction. Healthcare spending for people with diabetes is more than double the expenditure on those without diabetes, and a significant part of these costs is explained by CVD comorbidity. This article will focus on the effect of diabetes on the initiation and progression of arterial occlusive disease, preceded by a short outline of the enormous impact of this issue from a societal-economic perspective.

Diabetes, a major healthcare issue

The prevalence and associated costs of diabetes are expected to increase significantly. There are currently over 240 million people with diabetes worldwide. By 2025, the number of people with diabetes is expected to more than double in South-East Asia, the Eastern Mediterranean, the Middle East, and Africa (source: World Diabetes Foundation). The incidence is projected to rise by nearly 20% in Europe and 50% in North America. Worldwide more than 50% of people with diabetes are unaware of their condition and are therefore not treated. About 40% of people with diabetes will develop chronic kidney disease which further increases the risk of CVD and other complications. Evidence from observational studies shows that hyperglycaemia is an important risk factor for CVD; in people with diabetes (types 1 and 2) the risk of CVD increases with increasing concentrations of glycated haemoglobin (HbA1c), independently of clinical characteristics and other traditional risk factors.2

The economic impact of diabetes (types 1 and 2) is substantial. Health expenditure to treat and prevent diabetes and its complications is estimated to total €90 billion (£75 billion, US$120 billion) or approximately 10% of total health expenditure in EU countries. Healthcare expenditures and costs to treat diabetes and its comorbidities are increasing rapidly all over Europe. It seems the direct cost burden of a person with diabetes varies considerably across countries. Reports show that France, Germany, and the UK have considerably higher per patient diabetes costs than Italy and Spain, although comparisons between EU countries are hampered by the fact that disease incidence and healthcare cost registries are executed on a national basis. The total direct diabetes cost burden also varied substantially across countries in 2010 (France €12.9 billion, Germany €43.2 billion, Italy €7.94 billion, Spain €5.45 billion, and the UK £13.8 billion) (source: London School of Economics, http://www2.lse.uk). Around one-quarter of medical expenditure on diabetes is spent on treating long term complications of diabetes such as CVD.

These rapidly increasing costs reinforce the need to understand the pathogenesis of diabetes related CVD and to provide quality care for the management of diabetes and its complications.

Diabetes and arterial occlusive disease

Diabetes is a risk factor for most clinical presentations involving atherosclerotic lesion progression. Angina pectoris, myocardial infarction, stroke, ischaemic heart disease, and heart failure are the major complications resulting from diabetes. The risk of CVD increases significantly when combined with being overweight, which is common in type 2 diabetes. Patients suffering from diabetes often also suffer from progressive decline in kidney function, hypertension, and obesity, which are all part of the metabolic syndrome. There is sound experimental and clinical evidence supporting the view that the pathogenesis of CVD differs between diabetic patients and other risk groups. The association between vascular occlusive disease and diabetes differs for the various anatomical regions (coronary, peripheral, cerebral, and the abdominal aorta) affected by atherosclerotic disease. The impact of diabetes on vascular disease in these anatomical regions will now be discussed.

Coronary artery disease

Diabetic patients have a more than twofold increased risk of suffering from myocardial infarction when compared to people without diabetes. Outcomes are worse in diabetic patients for each manifestation of coronary artery disease (CAD). A decade ago in patients with known CAD and diabetes, the rate of myocardial infarction approached 45% over 7 years and 75% over 10 years.3 Treatment options have improved but diabetes is still associated with worse outcomes in the presence of established CVD.4 Compared with non-diabetic patients, diabetic patients who undergo percutaneous coronary interventions have more extensive and diffuse atherosclerotic disease. Following an interventional procedure diabetic patients are more likely to suffer in-hospital death and non-fatal myocardial infarction. Long term survival and freedom from myocardial infarction and coronary revascularisation is also reduced in diabetic patients undergoing coronary catheterisation.5 The more diffuse disease is also considered a causal factor that partly explains the high incidence of restenosis following a successful coronary intervention in diabetic patients. Drug eluting stent (DES) implantation has significantly reduced the restenosis rates due to neointimal hyperplasia compared with bare metal stents. However, despite the increasing use of DES, diabetes is still associated with an increased risk of restenosis and unfavourable clinical outcomes. A recent meta-analyses elucidated that from a total of 47 candidate variables for the development of stent thrombosis, diabetes proved to be a frequent predictor.6

Peripheral artery disease

A clear association exists between diabetes and increased prevalence of peripheral arterial disease (PAD). Patients with diabetes have a two- to fourfold increase in the rates of PAD. The risk increases with duration and severity of diabetes.7 In the presence of PAD, diabetes is associated with more lower extremity amputations. In addition, diabetic patients more commonly have infrapopliteal arterial occlusive disease. They also have a higher incidence of foot ulcers and distal necrosis, complicated by neuropathy which may further deteriorate extremity functions. This image of poor peripheral circulation strengthens the concept that restenosis is more prevalent in diabetic patients following peripheral transluminal angioplasty. However, this could be debated since diabetic patients with PAD have also shown similar restenosis primary and secondary patency rates compared with non-diabetic patients.8 These studies also confirmed that mortality and amputation rates are increased in patients with diabetes. This increased risk of mortality and amputation could distort the estimation of restenosis and patency rates.

Cerebral artery disease

The frequency of diabetes among patients presenting with stroke is three times more than that of matched controls.9 Duration of diabetes is independently associated with ischaemic stroke risk, after adjusting for other risk factors. The risk increases by 3% each year, and triples among people who have suffered from diabetes for more than 10 years.10 Diabetes may significantly affect the risk of stroke among younger patients. A 10-fold increase in the risk of stroke for diabetic patients under 55 years has been reported, but the large confidence interval of that particular study merits careful consideration.w1 In the Athero-Express cohort 18% of patients undergoing carotid endarterectomy (CEA) have type 2 diabetes. Diabetic patients who undergo carotid surgery are younger and have an increased risk of ipsilateral stroke during follow-up after a CEA procedure.11

Abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is traditionally considered a manifestation of atherosclerotic disease. Surprisingly, diabetic patients are protected against AAA formation. Diabetes appears to reduce the prevalence of AAA by almost half, as shown in a cohort of 73 451 veterans.w2 Recently, a retrospective cohort study in a population of 3.1 million patients confirmed that diabetes is indeed protective against the development of AAA with an odds ratio of 0.75 (95% CI 0.73 to 0.77).12 These large scale studies suggest that the pathogenesis may differ for aneurysmal disease and occlusive vascular disease. Several hypotheses have been generated that may explain this inverse relation between diabetes and AAA formation. One could hypothesise that expansive remodelling, a hallmark of progressive atherosclerotic disease in order to prevent luminal narrowing, is hampered in diabetic patients. Arterial remodelling is an effect of massive matrix turnover that requires inflammation and proteolytic activity and subsequent collagen breakdown and production. Diabetes may have an effect on the stability of collagen cross-links which impairs the effect of proteolytic enzymes and subsequent arterial expansion.13 Another mechanism explaining the protection from aneurysm development is that hyperglycaemia increases plasminogen activator inhibitor 1 (PAI-1) expression which subsequently attenuates AAA diameter in experimental AAA disease.w3

The inverse association between diabetes and AAA formation is intriguing and scientifically relevant since it may help us to understand the mechanisms that play a role in the prevention of AAA formation and arterial occlusive disease.

Pathogenesis of atherosclerotic disease and diabetes

The aetiology of atherosclerosis initiation and progression has been reviewed extensively. It is questioned, however, whether the pathogenetic mechanisms for atherosclerotic lesion development differ for diabetes versus other risk factors. People with type 2 diabetes often have comorbidities that together make up the metabolic syndrome.w4 The incidence of atherosclerotic disease is also increased in type 1 diabetes which is less frequently associated with other risk factors of CVD. Therefore, hyperglycaemia (figure 1) is the most prominent factor that distinguishes diabetes from the metabolic syndrome. Indeed, measures of glycaemic control have been associated with an increased risk of macrovascular complications in type 1 and type 2 diabetes.14 w5 w6 Other vascular abnormalities that have been associated with diabetes are increased free fatty acids and insulin resistance. Each provoke molecular mechanisms that contribute to vascular dysfunction. These include decreased nitric oxide release, increased oxidative stress and subsequent inflammatory responses, disturbances of intracellular signal transduction, and activation of receptors for advanced glycation end products (AGEs).9 The effect of hyperglycaemia on determinants of atherosclerotic plaque initiation or destabilisation will be discussed next.

Figure 1

Effect of hyperglycaemia on vascular biology and mechanisms by which atherosclerosis progression is accelerated. MMP, matrix metalloproteinase; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; TLR, toll-like receptor; VCAM, vascular cell adhesion molecule.

Hyperglycaemia, macrophage uptake, and foam cell formation

Both human and animal studies on the effect of type 2 diabetes on atherosclerotic disease are often confounded by co-existent changes in lipid profiles.14 There is evidence that the effects on endothelial and smooth muscle cells evoked by hyperglycaemia resemble characteristics induced by hyperlipidaemia.15 On a cellular level, glucose affects all cell types in the vascular wall. Vascular cell adhesion molecule (VCAM) expression is increased in hyperglycaemic conditionsw7—an effect that is also observed in the presence of AGE-RAGE (receptor for AGE) complexes.w8 However, results presented in the literature regarding the association between hyperglycaemia and endothelial cell activation have been conflicting.15

Macrophage receptors involved in the uptake of modified low density lipoprotein (LDL) have been demonstrated to be induced by glucose. Changes in Scavenger receptor A,w9 LOX-1,w10 CD36,w11 ABCA1, and ABCG1w12 play a role in cellular lipid transport, and expressions have been shown to be altered upon a glucose challenge, resulting in a net LDL cellular increase.

Diabetes and the stabilising smooth muscle cell

Smooth muscle cells contribute to plaque stabilisation by producing extracellular matrix proteins, such as collagen, that prevent the cap overlying the atheromatous lesion from rupturing. Smooth muscle cells also play a dominant role in the response to vascular injury that initiates restenosis. The observation that diabetic patients have a higher risk from coronary restenosis suggests that hyperglycaemic conditions may accelerate smooth muscle cell migration and proliferation. Such a stimulus would theoretically be beneficial when it comes to plaque stabilisation. Indeed smooth muscle cell proliferation is enhanced in atherosclerotic lesion development in diabetic swine.w13 Apoptosis of smooth muscle cells is impaired in diabetic patientsw14 which is also a feature that could contribute to plaque stabilisation.

Diabetes, inflammation, and proteolysis

Local inflammatory cell infiltration and subsequent increased proteolytic activity are major determinants of plaque destabilisation. There is substantial evidence that the general inflammatory response upon an exogenous or endogenous challenge is accelerated in type 1 and type 2 diabetes.15 w15 In type 2 diabetes the expression of adipokines in fat tissue and the subsequent effect on endothelial function and integrity has gained major interest.w16 Even short term exposure to hyperglycaemic conditions influences gene expression of inflammatory genes, an effect that is still observed when glucose values have been normalised.w17

The toll-like receptors (TLR) are the first line of defence, protecting the body against damaging exogenous and endogenous stimuli. The response of the TLR should be tightly regulated since an accelerated response can lead to an overwhelming induction of white blood cell activation with subsequent tissue damage due to the badly controlled inflammatory response. TLR have been shown to play an important role in cardiovascular biology. They play a role in restenosis, atherosclerosis, and ischaemia–reperfusion injury,16 all vascular pathologies that are highly prevalent in diabetic patients. Indeed, TLR 2 and TLR 4 play a role in diabetes induced vascular inflammation.w15 Animal experiments have shown that both TLR 2 and TLR 4 are involved in the accelerated inflammatory response in the presence of type 1 diabetes.17

The activation of macrophages and synthetic smooth muscle cells in the vasculature may induce proteolysis of the collagen skeleton of the extracellular matrix by matrix metalloproteinases (MMPs). High glucose concentrations induce increased expressions of MMP-1 and MMP-2 in endothelial cells, and MMP-9 in monocyte derived macrophages.w18 Vascular tissue harvested from patients with type 2 diabetes revealed increased MMP-9 activity.w19 MMP-9 has been shown to stimulate the formation of intraplaque haemorrhage in advanced atherosclerotic lesions.w20 This is of interest because intraplaque haemorrhage is the main feature of the unstable atherosclerotic lesion that has been associated with an increased risk of future cardiovascular events.w21

As mentioned earlier, studies on the effect of diabetes on vascular inflammatory responses are often confounded by a simultaneous effect of lipid metabolism. Recently, an intervention study was done to test two glucose lowering drugs, pioglitazone and glimepiride. The effect of both drugs was evaluated using positron emission tomography (PET)/CT scanning.w22 Although both treatments reduced fasting plasma glucose and HbA1c values comparably, pioglitazone, but not glimepiride, decreased atherosclerotic plaque inflammation. Pioglitazone significantly increased the high density lipoprotein cholesterol concentration which was a main determinant of the attenuation of plaque inflammation. Thus, experimental evidence clearly points to a strong effect of hyperglycaemia on inflammatory vascular responses and proteolytic activity. This imaging study, despite its small size, emphasises that human studies on the role of hyperglycaemia on vascular inflammation merit consideration when confounding by changes in lipid profiles is an issue.

Diabetes and glycation processes within the extracellular matrix

Hyperglycaemia initiates tissue damage that is observed in diabetes, either through repeated acute changes in cellular glucose metabolism, or through the long term accumulation of glycated biomolecules and AGEs.w23 AGEs represent a heterogeneous group of compounds formed by oxidative and non-oxidative reactions between proteins and sugar residues. Also, lipids, nucleic acids, or a combination, can be affected by glycation resulting in the formation of AGEs.

The formation of AGEs implicates reactive intermediates such as methylglyoxal. AGEs form cross-links on extracellular matrix proteins or react with their specific receptor RAGE, resulting in oxidative stress and proinflammatory signalling. Plasma concentrations of AGEs have been associated with incident CVD in diabetic patientsw24 and AGEs are implicated in a vascular inflammatory response.w25 Of major interest is the fact that AGEs modified proteins are partially resistant to proteolysis,w23 which means that AGE formation is a double sided coin with respect to determinants of plaque destabilisation. On the one side inflammation is induced, while on the other side proteolysis of matrix is prevented. This may explain the counterintuitive observation that diabetes is a major risk factor for vascular occlusive disease while it protects patients from aneurysm formation. Not all AGEs stabilise matrix cross-links. Future research on the role of specific AGEs may reveal targeted AGE products that play a role in the progression of vascular occlusive disease.

Diabetes and thrombosis

Induction of hyperglycaemia and hyperinsulinaemia in healthy subjects without diabetes increases platelet reactivity.w26 Consistent with this observation, improved glycaemic control has been associated with decreased platelet reactivity. Hyperglycaemia can increase platelet reactivity by inducing non-enzymatic glycation of proteins on the surface of the platelet. Such glycation decreases membrane fluidity and increases the propensity of platelets to activate. Although hyperglycaemia is the main hallmark of diabetes, abnormalities of lipid metabolism are uniformly observed. People with diabetes typically manifest hypertriglyceridaemia. Very low density lipoprotein (VLDL) that is rich in triglycerides increases platelet reactivity. Thus, both hyperglycaemia and hypertriglyceridaemia increase platelet reactivity in subjects with diabetes.w27 A study by Stegenga et al in six healthy individuals was undertaken to show the differential effects of hyperglycaemia on the occurrence of thrombotic events. The results showed that patients with hyperglycaemia due to insulin resistance are especially susceptible to thrombotic events by a concurrent insulin driven impairment of fibrinolysis and a glucose driven activation of coagulation.w28

Diabetes and collateral formation

Collaterals bridge a stenotic lesion in an attempt to restore perfusion of the ischaemic tissue. Bridging collaterals can be formed by arteriogenesis or angiogenesis, processes in which a local inflammatory response plays an essential role. Interventions that block the chemokine induced attraction of leucocytes or activation of the monocytes all inhibit collateral formation.w29 Considering the fact that diabetes is associated with increased pro-inflammatory activity, one could hypothesise that increased collateral formation would compensate for the stenosis related ischaemia. In contrast, diabetes is associated with poor collateralisation.w30 Despite the fact that VCAM induced leucocyte cell adhesion and proteolytic activity are enhanced, this does not result in improved collateralisation in diabetic patients. An explanation could be the concomitant increase in the expression of angiostatin and the decreased expression of vascular endothelial growth factor (VEGF) in the presence of diabetes, effects that reduce angiogenesis.w19 w31 Angiostatin is a plasminogen cleavage product that has gained attention as a therapeutic target in the field of oncology. A strong correlation has been observed between lesional expression of MMP-2 or MMP-9 and angiostatin,w19 suggesting that these proteases may have two roles in the process of collateralisation.

Diabetes and plaque characteristics: human studies

The composition of advanced atherosclerotic plaques in diabetic patients has been reported previously, and the data are summarised in table 1. The imaging and pathologic data show that there is a general tendency towards an increased prevalence of vulnerable plaque characteristics in diabetic patients. However, conclusions are often based on small scale studies and the imaging or pathological parameters are not always comparable. Here we briefly discuss some of the outcomes of the human pathological observational studies.

Table 1

Pathology and imaging studies on the association between plaque type and risk factor for diabetes

In a cohort of 180 symptomatic patients who underwent CEA, a higher collagen content and less mural thrombus were observed in diabetic patients.w32 In another study including asymptomatic patients, an increased macrophage content was demonstrated in plaques obtained from diabetic patients. The increased inflammatory phenotype was also observed in coronary plaques that were obtained from symptomatic patients.w33 They also reported significantly more thrombus and atheroma within diabetic plaques. Finally, Burke et al reported significantly larger necrotic core size and macrophage content within coronary artery plaques of diabetic patients who died suddenly.18

On the other hand, the Oxford plaque biobank studied 526 carotid plaques and could not observe any major differences in plaque characteristics between diabetic and non-diabetic patients,19 an observation that we recently confirmed in the Athero-Express cohort of over 1000 patients undergoing carotid surgery (unpublished data). We can only speculate what could explain the dissimilarities between these and the aforementioned studies. First, the pathology may differ between the carotid and coronary vascular tree. Intraplaque is more prevalent in carotid artery plaques than coronary artery plaques. Secondly, coronary plaques are obtained during catheterisation of patients who have suffered from a very recent event, in contrast to carotid surgery which is executed weeks to months after the primary event. We previously reported that plaques stabilise with an increasing delay between the cerebral event and surgery.w34 However, it is unlikely that the delay before surgery explains the inconsistencies among studies, since plaque stabilisation after an event does not differ between diabetic versus non-diabetic patients. Thirdly, the number of patients included in the studies summarised in table 1 merits careful consideration; often limited patient numbers have not allowed a control for other determinants of plaque characteristics such as age, gender, surgery delay, and medication use.

Summary

Diabetes is highly prevalent in patients suffering from CVD. With increasing age and body mass indices, the incidence of diabetes is likely to rise which will be paralleled by cardiovascular morbidity and mortality. There is sufficient evidence that hyperglycaemia influences vascular biology and endothelial function and subsequently accelerates atherosclerotic plaque formation. The concept that diabetes results in more unstable plaques is based on small scale observational studies and requires validation in larger study groups. There is clearly a need to understand better the mechanisms by which diabetes accelerates occlusive diseases in the coronary, cerebral and peripheral vascular bed, in order to improve quality of life, reduce complications, and thus limit healthcare costs.

Methods of accelerated atherosclerosis in diabetes: key points

  • Diabetes is associated with an increased risk of arterial occlusive disease in the coronary, cerebral, and peripheral vascular bed.

  • However, patients suffering from diabetes are protected against aneurysm formation.

  • Hyperglycaemia has, directly or indirectly, the following effects on the vascular wall:

    • Macrophage lipid uptake leading to foam cell formation

    • Endothelial dysfunction

    • Increased platelet activity

    • Increased proteolytic activity

    • Glycation of extracellular matrix

    • Stimulation of smooth muscle cell proliferation

    • Increased inflammatory activity

  • In advanced atherosclerotic disease, diabetes has often been associated with an increased prevalence of unstable inflammatory and lipid rich plaques. However, conflicting data have been reported, study numbers are small, and differences in plaque types among vascular territories may be present.

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Acknowledgments

Louise Catanzarini for carefully reading and editing the manuscript.

References

  1. Study including >800   000 individuals exploring the cause of death in diabetic patients.
  2. Nice review on the epidemiology and pathogenesis of diabetes induced atherosclerotic disease.
  3. Paper showing that the risk of stroke increases with the duration after onset of diabetes.
  4. Study in over 3 million individuals showing that the risk of suffering from abdominal aortic aneurysm formation is increased in smokers and decreased in diabetic patients.
  5. Paper studying the mechanism by which diabetes can protect against aneurysm formation.
  6. Review paper exploring the causal link between altered lipid metabolism in hyperglycaemic conditions.
  7. Nice review discussing the concept that hyperglycaemia and hyperlipidaemia independently exert a pro-atherogenic effect by similar mechanisms.
  8. Paper providing evidence that the first line of the innate immune defence, the toll-like receptors, is influenced by diabetes.
  9. Postmortem study in patients who died of CAD, revealing that coronary plaques have more unstable characteristics in diabetic patients.
  10. Large study involving >500 patients who underwent carotid surgery showing that plaque phenotype does not differ significantly between diabetes and non-diabetes patients.
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Footnotes

  • Contributors I am the only author and I wrote the paper.

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The author has no competing interests.

  • Provenance and peer review Commissioned; externally peer reviewed.

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