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▸ Additional references are
published online only. To view
these references please visit
the journal online (http://dx.
doi.org/10.1136/heartjnl-2011-
301172).
Department of Cardiology,
Experimental Cardiology
Laboratory, University Medical
Center Utrecht, Utrecht,
The Netherlands
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@umcutrecht.nl
To cite: Pasterkamp G.
Heart 2013;99:743–749.
Pasterkamp G. Heart 2013;99:743–749. doi:10.1136/heartjnl-2011-301172
DIABETIC HEART DISEASE
Methods of accelerated atherosclerosis in diabetic
patients
Gerard Pasterkamp
Diabetic patients have an increased risk of cardio-
vascular disease (CVD), which is a major contribu-
tor 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 toler-
ance 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 sig-
nificant part of these costs is explained by CVD
comorbidity. This article will focus on the effect of
diabetes on the initiation and progression of arter-
ial 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 cur-
rently over 240 million people with diabetes world-
wide. 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 concentra-
tions of glycated haemoglobin (HbA1c), independ-
ently 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 consider-
ably 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
Education in Heart
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 manage-
ment 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 compli-
cations 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 syn-
drome. There is sound experimental and clinical evi-
dence 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 infarc-
tion 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 dia-
betes, 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 percutan-
eous 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
743
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Education in Heart
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 dia-
betic patients. Drug eluting stent (DES) implant-
ation 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 out-
comes. A recent meta-analyses elucidated that from
a total of 47 candidate variables for the develop-
ment 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 four-
fold increase in the rates of PAD. The risk increases
with duration and severity of diabetes.7 In the pres-
ence 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, compli-
cated 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 sec-
ondary patency rates compared with non-diabetic
patients.8 These studies also confirmed that mortal-
ity and amputation rates are increased in patients
with diabetes. This increased risk of mortality and
amputation could distort the estimation of resten-
osis and patency rates.
Cerebral artery disease
The frequency of diabetes among patients present-
ing with stroke is three times more than that of
matched controls.9 Duration of diabetes is inde-
pendently 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
744 Pasterkamp G. Heart 2013;99:743–749. doi:10.1136/heartjnl-2011-301172
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 retro-
spective cohort study in a population of 3.1 million
patients confirmed that diabetes is indeed protec-
tive 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 dia-
betes and AAA formation. One could hypothesise
that expansive remodelling, a hallmark of progres-
sive 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 break-
down and production. Diabetes may have an effect
on the stability of collagen cross-links which
impairs the effect of proteolytic enzymes and subse-
quent arterial expansion.13 Another mechanism
explaining the protection from aneurysm develop-
ment is that hyperglycaemia increases plasminogen
activator inhibitor 1 (PAI-1) expression which sub-
sequently attenuates AAA diameter in experimental
AAA disease.w3
The inverse association between diabetes and
AAA formation is intriguing and scientifically rele-
vant 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 pro-
gression has been reviewed extensively. It is ques-
tioned, 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 asso-
ciated with other risk factors of CVD. Therefore,
hyperglycaemia (figure 1) is the most prominent
factor that distinguishes diabetes from the meta-
bolic 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 contrib-
ute to vascular dysfunction. These include
decreased nitric oxide release, increased oxidative
stress and subsequent inflammatory responses, dis-
turbances 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.
 Downloaded from http://heart.bmj.com/ on February 24, 2015 - Published by group.bmj.com
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 pro-
files.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 regard-
ing 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 stabilisa-
tion 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.
Pasterkamp G. Heart 2013;99:743–749. doi:10.1136/heartjnl-2011-301172
Education in Heart
The observation that diabetic patients have a higher
risk from coronary restenosis suggests that hyper-
glycaemic 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 pro-
liferation 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 con-
tribute to plaque stabilisation.
Diabetes, inflammation, and proteolysis
Local inflammatory cell infiltration and subsequent
increased proteolytic activity are major determi-
nants 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 condi-
tions 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 subse-
quent tissue damage due to the badly controlled
745
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Education in Heart
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 extracel-
lular 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 macropha-
ges.w18 Vascular tissue harvested from patients with
type 2 diabetes revealed increased MMP-9 activi-
ty.w19 MMP-9 has been shown to stimulate the for-
mation 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 dia-
betes on vascular inflammatory responses are often
confounded by a simultaneous effect of lipid metab-
olism. 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 scan-
ning.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 deter-
minant 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 vas-
cular inflammation merit consideration when con-
founding 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 biomole-
cules and AGEs.w23 AGEs represent a heteroge-
neous group of compounds formed by oxidative
and non-oxidative reactions between proteins and
sugar residues. Also, lipids, nucleic acids, or a com-
bination, can be affected by glycation resulting in
the formation of AGEs.
The formation of AGEs implicates reactive inter-
mediates such as methylglyoxal. AGEs form cross-
links on extracellular matrix proteins or react with
their specific receptor RAGE, resulting in oxidative
746 Pasterkamp G. Heart 2013;99:743–749. doi:10.1136/heartjnl-2011-301172
stress and proinflammatory signalling. Plasma con-
centrations of AGEs have been associated with inci-
dent 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 desta-
bilisation. On the one side inflammation is induced,
while on the other side proteolysis of matrix is pre-
vented. 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 occlu-
sive disease.
Diabetes and thrombosis
Induction of hyperglycaemia and hyperinsulinae-
mia in healthy subjects without diabetes increases
platelet reactivity.w26 Consistent with this obser-
vation, 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 hypertriglyceridae-
mia. Very low density lipoprotein (VLDL) that is
rich in triglycerides increases platelet reactivity.
Thus, both hyperglycaemia and hypertriglyceridae-
mia increase platelet reactivity in subjects with dia-
betes.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 inflamma-
tory 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, dia-
betes 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
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Education in Heart

concomitant increase in the expression of angiosta-
tin and the decreased expression of vascular endo-
thelial 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 pre-
viously, 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.
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 asymptom-
atic patients, an increased macrophage content
was demonstrated in plaques obtained from dia-
betic patients. The increased inflammatory pheno-
type was also observed in coronary plaques that
were obtained from symptomatic patients.w33 They
also reported significantly more thrombus and ath-
eroma 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 dissimi-
larities 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 cor-
onary 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

Table 1 Pathology and imaging studies on the association between plaque type and risk factor for diabetes
Study type Author Vascular bed Observation Diabetic patients (n)

Pathology Burke et al18 Coronary Inflammation + 66

Lipid +
Pathology Carter et al w35 Femoral Inflammation + 10
Plaque vessels +
Pathology Virmani et al w36 Coronary Inflammation + Review
Expansive remodelling
Pathology Sommeijer et al w37 Carotid Fibrosis + 11
Thrombosis +
Pathology Cardellini et al w38 Carotid TIMP3 − 23
MMP-9 +
Pathology He et al w39 Carotid ICAM-1 + 21
VCAM+MPO +
Pathology Mas et al w40 Carotid Non-esterified fatty acids + 19
Inflammation +
Pathology Purushothaman et al w33 Aorta Inflammation + 20
Plaque vessels +IPH +
Pathology Redgrave et al 19 Carotid No differences 53
MRI Esposito et al w41 Carotid High risk lesion type + 51
CT angiography Choi et al w42 Coronary Mixed plaques + 135
Calcified plaques +
Ultrasound Ostling et al w43 Carotid Echolucency + 47
MRI Wasserman et al w44 Carotid No difference in presence of lipid core 52
Ultrasound Jiminez et al w45 Coronary Constrictive remodelling + 45
Multislice CT Yun et al w46 Coronary More plaque burden, all plaque types 36
CT angiography Gao et al w47 Coronary More plaque burden, all plaque types 122
Ultrasound Inaba et al w48 Coronary More plaque progression with more lipid 42
FDG-PET Kim et al w49 Upper body Inflammation + 60
Optical coherence Feng et al w50 Coronary Calcification+thrombus and fibrous cap thickness: 25
tomography no difference
Multislice CT Djaberi et al w51 Coronary Calcified plaques—in type II diabetes 70
18
FFG-PET, F-fluorodeoxyglucose positron emission tomography; ICAM-1, intercellular adhesion molecule 1; IPH, intra-plaque haemorrhage; MMP, matrix metalloproteinase;
MPO, myeloperoxidase; VCAM, vascular cell adhesion molecule.

Pasterkamp G. Heart 2013;99:743–749. doi:10.1136/heartjnl-2011-301172 747

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Education in Heart
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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.
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
748 Pasterkamp G. Heart 2013;99:743–749. doi:10.1136/heartjnl-2011-301172
studies summarised in table 1 merits careful consid-
eration; 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 morbid-
ity 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 complica-
tions, and thus limit healthcare costs.
Acknowledgements Louise Catanzarini for carefully reading and
editing the manuscript.
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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Ann Vasc Surg 2008;22:481–91.
9 Creager MA, Luscher T. Diabetes and vascular disease. Circulation
2003;108:1527–32.
10 Banerjee C, Moon YP, Paik MC, et al. Duration of diabetes and
risk of ischemic stroke: the Northern Manhattan Study. Stroke
2012;43:1212–7. Published Online First: 1 March 2012.
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▸ Paper showing that the risk of stroke increases with the duration
after onset of diabetes.
11 Cunningham EJ. Long-term durability of carotid endarterectomy
for symptomatic stenosis and risk factors for late postoperative
stroke. Stroke 2002;33:2658–63.
12 Kent KC, Zwolak RM, Egorova NN, et al. Analysis of risk factors
for abdominal aortic aneurysm in a cohort of more than 3 million
individuals. J Vasc Surg 2010;52:539–48.
▸ 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.
13 Golledge J, Karan M, Moran CS, et al. Reduced expansion rate of
abdominal aortic aneurysms in patients with diabetes may be
related to aberrant monocyte-matrix interactions. Eur Heart J
2008;29:665–72.
▸ Paper studying the mechanism by which diabetes can protect
against aneurysm formation.
14 Chait A, Bornfeldt KE. Diabetes and atherosclerosis: is there a role
for hyperglycemia? J Lipid Res 2009;50(Suppl):S335–9.
▸ Review paper exploring the causal link between altered lipid
metabolism in hyperglycaemic conditions.
15 Kanter JE, Johansson F, LeBoeuf RC, et al. Do glucose and lipids
exert independent effects on atherosclerotic lesion initiation or
progression to advanced plaques? Circ Res 2007;100:769–81.
Pasterkamp G. Heart 2013;99:743–749. doi:10.1136/heartjnl-2011-301172
Education in Heart
▸ Nice review discussing the concept that hyperglycaemia and
hyperlipidaemia independently exert a pro-atherogenic effect by
similar mechanisms.
16 Arslan F, Kleijn DPD, Pasterkamp G. Innate immune signaling in
cardiac ischemia. Nature 2011;8:292–300.
17 Devaraj S, Tobias P, Kasinath BS, et al. Knockout of toll-like
receptor-2 attenuates both the proinflammatory state of diabetes
and incipient diabetic nephropathy. Arterioscler Thromb Vasc Biol
2011;31:1796–804.
▸ Paper providing evidence that the first line of the innate immune
defence, the toll-like receptors, is influenced by diabetes.
18 Burke AP, Kolodgie FD, Zieske A, et al. Morphologic findings of
coronary atherosclerotic plaques in diabetics: a postmortem study.
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▸ Postmortem study in patients who died of CAD, revealing that
coronary plaques have more unstable characteristics in diabetic
patients.
19 Redgrave JN, Lovett JK, Syed AB, et al. Histological features of
symptomatic carotid plaques in patients with impaired glucose
tolerance and diabetes (Oxford Plaque Study). Cerebrovasc Dis
2008;26:79–86.
▸ Large study involving >500 patients who underwent carotid
surgery showing that plaque phenotype does not differ
significantly between diabetes and non-diabetes patients.
749
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Methods of accelerated atherosclerosis in

diabetic patients
Gerard Pasterkamp

Heart 2013 99: 743-749

doi: 10.1136/heartjnl-2011-301172

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Material http://heart.bmj.com/content/suppl/2013/04/18/heartjnl-2011-301172.
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References This article cites 19 articles, 10 of which you can access for free at:
http://heart.bmj.com/content/99/10/743#BIBL

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