Übersichten
English version of „Ursachen und Risikofaktoren
der Arteriosklerose“
Gefässchirurgie 2013 · 18: 544–550
DOI 10.1007/s00772-013-1233-6
© Springer-Verlag Berlin Heidelberg 2013
E.S. Debus1 · G. Torsello2 · T. Schmitz-Rixen3 · I. Flessenkämper4 · M. Storck5 ·
H. Wenk6 · R.T. Grundmann7
1 Klinik und Poliklinik für Gefäßmedizin, Gefäßchirurgie – Endovaskuläre Therapie – Angiologie, Deutsches
Aortenzentrum Hamburg, Universitäres Herzzentrum GmbH, Universitätsklinikum Hamburg-Eppendorf
2 Klinik für Vaskuläre und Endovaskuläre Chirurgie, UKM Münster
3 Zentrum der Chirurgie, Klinik für Gefäß- und Endovascularchirurgie, Universitätsklinikum Frankfurt
4 Klinik für Gefäßmedizin, Zertifiziertes Gefäßzentrum Berlin Südwest, HELIOS Kliniken, Berlin
5 Abteilung Gefäß- und Thoraxchirurgie, Städtisches Klinikum Karlsruhe
6 Zentrum für Gefäßmedizin, Klinikum Bremen-Nord
7 Scientific coordinator of the DGG German Institute for Health Research in Vascular Medicine (DIGG)
Causes of arteriosclerosis
and the associated
risk factors
Arteriosclerosis encompasses all arterial
vascular diseases that are characterized by
fibrous changes in the blood vessel walls.
The term is often used synonymously for
atherosclerosis, although arteriosclerosis
is in fact a generic term applied to other
diseases as well. These include Monckeberg medial calcific sclerosis, arteriolosclerosis and other manifestations of pulmonary hypertension [1, 2]. Atherosclerosis is the most frequently occurring form
of arteriosclerosis. It is defined as a chronic inflammatory reaction of the vessel wall
in response to dyslipidemia and vascular
endothelial stress, with inflammatory recruitment of leukocytes and local stimulation of proinflammatory cytokine expression by vascular cells [3]. This chronic inflammatory process leads to the formation
of multifocal plaques and is detectable in
almost all vascular tree alterations of this
type. Despite this, the majority of plaques
are of no clinical relevance. However,
some can result in obstruction, thrombosis and embolisms and thereby cause atherothrombotic events such as myocardial infarction, stroke or peripheral artery
occlusive disease (PAOD). The factors involved in the atherosclerotic inflammation process have been reviewed by Ric-
cioni and Sblendorio [4] and include T
cells, macrophages, cytokines, chemokines, growth factors and thrombocytes.
The altered homeostasis leads to so-called
endothelial dysfunction, with modification of the antihemostatic properties of
the vessel wall, changes in vascular tone,
increased leukocyte adhesion and raised
endothelial permeability to LDL cholesterol. The current article reviews the epidemiology and manifestations of arteriosclerosis, as well as the risk factors associated with the disease and measures to prevent it.
Developmental stages
For the American Heart Association
(AHA), Stary et al. [5, 6] have classified
the morphological changes occurring in
atherosclerosis (as the most frequently observed form of arteriosclerosis) into six developmental stages based on histological and histochemical results. These
six stages fall into two groups: early developmental stages that are not associated
with clinical symptoms (type I to type III
lesions) and advanced lesions (types IV
to VI).
FType I lesions comprise microscopically and chemically detectable lipid deposits in the intima and the cell
reactions associated with these. Such
so-called initial lesions are most frequently observed in children, but can
also be seen in adults with low-­level
atherosclerosis or in vessels that are
resistant to lipid deposits. The histological changes in the intima are minimal; small isolated groups of macrophages containing lipid droplets
(macrophage foam cells) can be identified.
FType II lesions are characterized
by microscopically detectable ­fatty
streaks. These are visible as yellowish streaks, patches or spots on the
intimal surface of the arteries. Fatty streaks can be strained red by Sudan III or IV and are thus also referred to as sudanophilic lesions. Microscopically, type II lesions are more
clearly defined than type I lesions.
They consist primarily of neighboring layers of macrophage foam cells
and the intimal smooth muscle cells
are now also lipid laden. T lymphocytes can also be identified in type II
lesions, although they are not as nuGefässchirurgie 7 · 2013 | 1
Übersichten
merous as macrophages. The lipids are found primarily in the cells;
the extracellular space contains only
small quantities of weakly dispersed
lipids. Lipid composition is primarily cholesterol ester (77%), cholesterol
and phospholipid. In children, type II
lesions are generally the only microscopically delectable arterial changes.
Type II lesions are further subclassified into progression-prone and progression-resistant lesions. Progression-prone lesions are characterized
by the presence of smooth muscle
cells, excess extracellular matrix and
adaptive intimal thickening. The fatty
streak development stage can still be
revered by appropriate nutrition.
FType III lesions are also known as intermediate lesions because they re­
present the transition stage between
the reversible fatty streaks and atheroma (type IV lesions) [2]. Yet another name for these lesions is proatheroma. Histologically, type III lesions are
defined by microscopically visible extracellular lipid droplets and particles.
These frequently pool between layers
of smooth muscle cells at the generally colocalized sites of adaptive intimal
thickening.
FType IV lesions (atheromas) comprise a dense accumulation of extracellular lipids in an extensive but welldefined region of the intima. The
pooled lipids are referred to at the lipid core. Atheromas are termed advanced because they are the first lesions of this classification system that
are associated with severe disorganization of intimal structure. The usual smooth muscle cells and intracellular matrix are dispersed; between the
lipid core and the endothelial surface,
the intima contains macrophages
and smooth muscle cells with an excess of lipid droplets. The lipid core
is formed by enlargement and confluence of the individual extracellular
lipid pools that characterize type III
lesions. It is assumed that the increase
in lipids is a consequence of continual
plasma influx. The lipid core thickens
the artery walls primarily eccentrically. This means that the lumen of the
vessel may not necessarily be restrict-
2 | Gefässchirurgie 7 · 2013
ed; rather that the external vessel circumference is increased. Despite this,
type IV lesions have a high clinical
relevance. Since the region between
the lipid core and the endothelial surface contains proteoglycans and macrophage foam cells, with only isolated smooth muscle cells and little collagen, this area is prone to developing
fissures (type VI lesions). The general abundance of macrophages in advanced type IV lesions means that the
periphery of these can rupture.
FType V lesions are characterized by
the formation of prominent new fibrous connective tissue that is predominantly composed of collagen
and smooth muscle cells. If this new
tissue forms a fibrous cap covering
the lipid core, the lesion is also referred to as a fibroatheroma. These alterations cause narrowing of the vessels to differing degrees, but generally to a greater extent than type IV lesions. These lesions are also of clinical relevance, since they may develop
fissures, hematomas and/or thrombi
(type VI lesions).
FType VI or complex lesions result
from type IV and V lesions that have
developed one of the aforementioned
complications. Stary et al. [6] further
differentiate between type VIa (rupture of the surface), type VIb (hematoma or hemorrhage) and type VIc lesions (thrombosis). Type VI lesions
are responsible for the morbidity and
mortality associated with atherosclerosis: lesion rupture with consequent
intraluminal thrombosis plays a central role in the pathogenesis of acute
coronary syndrome; surface ruptures
in the region of the carotid artery bifurcation cause embolism or thrombosis with transient ischemic attacks.
The lumen of the vessel in complex
lesions can become so narrow that it
results in spontaneous closure of the
artery, thus causing mycardial infarction or stroke.
Risk factors
A global insight into the risk factors associated with the progression of atheroschlerosis is provided by the Tromsø Study.
In this field study, ultrasound measurements were taken on the right carotid artery of 1307 men and 1436 women, and
then repeated 13 years later [7]. The measured entities were intima-media thickness and total carotid plaque area. Age,
male gender, total cholesterol, HDL cholesterol deficiency, high systolic blood
pressure, high body mass index (BMI)
and smoking all prove to be risk factors
for the progression of atherosclerosis. The
risk factors specifically associated with an
increase in total plaque area were age, total cholesterol, systolic blood pressure and
smoking, whereas only total cholesterol
could predict progression of the intimamedia thickness. In light of the fact that
systolic blood pressure correlated with total plaque area but not with intima-media thickness, the authors concluded that
plaques and intima-media thickness represent different phenotypes of atherosclerosis and are related to the cardiovascular
risk factors in different ways.
The Rotterdam Study is another prospective cohort study that assessed intima-media thickness and plaque formation (using a score) by means of ultrasound measurements in the carotid artery [8]. In this investigation, measurements made in 3409 participants
(aged >55 years) showed strong correlations of age, smoking, total cholesterol and systolic blood pressure or hypertension with the progression of extracoronary atherosclerosis. Gender on the other hand had only a very weak influence.
The aforementioned risk factors for arteriosclerosis correspond to the risk factors associated with experiencing a heart
attack. The INTERHEART Study—a casecontrol study—used data from 262 centers in 52 countries to analyze the potentially modifiable risk factors for myocardial infarction [9]. The study included at
total of 12,461 events and 14,637 controls.
Significant causal factors were abnormal
lipid status, smoking, hypertension, diabetes, abdominal obesity and psychosocial factors. A cumulative effect of these
factors was also observed. A combination
of smoking, hypertension and diabetes
mellitus increased the risk of myocardial
infarction compared to individuals without these factors by the factor (odds ratio,
Abstract
OR) 13.01 and constituted approximately
half of all risks.
Gefässchirurgie 2013 · 18: 544–550 DOI 10.1007/s00772-013-1233-6
© Springer-Verlag Berlin Heidelberg 2013
Smoking
E.S. Debus · G. Torsello · T. Schmitz-Rixen · I. Flessenkämper · M. Storck · H. Wenk ·  
R.T. Grundmann
Despite the fact that smoking is a generally accepted risk factor for myocardial infarction or stroke, only relatively few
published studies have directly investigated the link between smoking and atherosclerosis. One of these is the Cardiovascular Health Study, which demonstrated
a direct relationship between atherosclerosis and present smoking, past smoking
and non-smoking. Using ultrasound measurements made on the carotid artery of
5166 older adults, it was shown that the
more intense the smoking habit, the thicker the internal and common carotid artery
walls and the more pronounced the stenosis of these vessels [10].
Based on carotid intima-media thickness measurements in a total of 12,953 participants aged between 45 and 65 years,
the Atherosclerosis Risk in Communities
Study [11] also prospectively investigated
this issue. These authors were additionally
able to demonstrate that passive smoking
has a harmful effect and raises the risk of
atherosclerosis. In both of the latter mentioned studies, the same results were also observed after adjustment for the presence of other risk factors (such as diabetes,
hypertension, LDL cholesterol). The Atherosclerosis Risk in Communities Study
went one step further and assessed the
progression of atherosclerosis by re-evaluating the cohort approximately 3 years
later using carotid artery ultrasound measurements [12]. The link between smoking
and atherosclerosis was confirmed. The
mean progression of intima-media thickness was 43,0 µm in smokers compared
to 28,7 µm in participants who had never smoked. The authors concluded that
smoking (and passive smoking) is associated with the progression of atherosclerosis—particularly in patients with other risk factors such as diabetes and hypertension.
LDL and HDL cholesterol
High total cholesterol, high LDL cholesterol, low HDL cholesterol and high levels
of triglyceride in the blood are all consid-
Causes of arteriosclerosis and the associated risk factors
Abstract
Background. The arterial vascular diseases
grouped under the term arteriosclerosis are
characterized by fibrous changes in the blood
vessel walls.
Aim of the study. This article reviews the epidemiology and manifestations of arteriosclerosis, as well as the risk factors associated
with developing the disease.
Materials and methods. The current article
is a literature-based review that considers important studies relating to arteriosclerosis.
Results. Atherosclerosis is the most common form of arteriosclerosis. The relevance
of atherosclerosis for the health care system is highlighted by the following ­figures:
in Germany, the prevalence of coronary
heart disease (CHD) amongst the population aged 65 years and older is measured at
18% for women and at 28% for men. In 2004,
CHD mortality rates were calculated to be
80.57 per 100,000 women and 149.21 per
100,000 men. According to the 1998 Feder-
ered risk factors for atherosclerosis [13].
According to a report from the Centers
for Disease Control and Prevention (CDC),
76% of the US population aged 18 years or
older was screened for high cholesterol levels in 2009. High levels were detected in every third (35%) individual [14]. A
study involving 6093 participants investigated the link between serum LDL cholesterol levels and the degree of atherosclerosis. The intensity of coronary artery calcification was assessed by CT and selected
as an estimate of coronary atherosclerosis [15]. LDL cholesterol values could be
correlated to the extent of artery calcification; in patients with an LDL cholesterol level exceeding 160 mg/dl, the relative
risk of developing a calcified plaque was
increased by 62%. The same patient cohort was also used to investigate the relationship between HDL cholesterol and
atherosclerosis [16]. Participants with an
HDL cholesterol level below 40 mg/dl had
significantly more pronounced calcification of the coronary artery than participants with high levels, whereas high HDL
cholesterol levels were associated with a
reduced risk of atherosclerosis. In the lat-
al Health Monitoring Report, around 3 million
people in Germany were affected by peri­
pheral artery occlusive disease (PAOD).
Conclusion. The prevalence of atherosclerosis has increased dramatically during the last
decade. In high-income countries like Germany, this increase is estimated at 13.1%. As for
the risk factors associated with PAOD, smoking has the greatest influence on disease development in high-income countries and
in relative terms, hypercholesterolemia the
least. In contrast to PAOD, data from the UK
suggest that the incidence of abdominal aortic aneurysm (AAA) is on the decline. Correspondingly, the age-adjusted AAA ­mortality
rate in England and Wales decreased from
40.4 per 100,000 inhabitants in 1997 to 25.7
per 100,000 in 2009.
Keywords
Arteriosclerosis · Atherosclerosis · Prevalence ·
Epidemiology · Risk factors
ter case, the inverse relationship between
HDL cholesterol levels and the intensity
of artery calcification was independent of
LDL cholesterol level.
Similar conclusions had already been
reached in the Healthy Women Study [17].
This investigation used CT data to correlate premenopausal risk factors with postmenopausal progression. Of the women
with premenopausal LDL cholesterol levels <100 mg/dl, 71% had no coronary artery calcification 8 years after the menopause, compared to only 20% of women with premenopausal LDL cholesterol levels >160 mg/dl. With premenopausal HDL cholesterol levels <45 mg/dl, 32%
of women had no coronary artery calcification, compared to 77% of the women
with premenopausal HDL cholesterol levels >60 mg/dl. In this study, smoking increased the risk of death due to calcification of the coronary artery in an additive
manner.
Since consideration of LDL cholesterol level alone leads to underestimation of
the atherogenic risk, it is normal practice to also measure the non-LDL cholesterol levels in patients with triglycerGefässchirurgie 7 · 2013 | 3
Übersichten
ide levels above 200 mg/dl. This value is
arrived at by subtracting HDL cholesterol from the total cholesterol level. Using
CT measurements, Orakzai et al. [18] correlated triglyceride, LDL and HDL cholesterol and non-HDL cholesterol levels
with the degree of coronary artery calcification in 1611 symptom-free participants
(mean age: 53 years, 67% males). Increases in the values of the lipid variables correlated with increased artery calcification
and multivariate analysis revealed that
non-HDL cholesterol was most strongly
associated with atherosclerosis. This confirms the clinical observations made in a
large meta-analysis of 38,153 patients undergoing statin therapy [19]. In this study,
non-HDL cholesterol was more strongly associated with the risk of severe cardiovascular events than LDL cholesterol
or apolipoprotein B. The German Heinz
Nixdorf Recall Study (3956 participants,
52% female, age 45–75 years) also correlated the degree of coronary artery calcification to lipid profile. Here it was shown
that of all lipoproteins, the levels of apolipoprotein B most closely correlated with
the extent of artery calcification—more
precisely than ratio of LDL to HDL cholesterol for example [20]. These results
pose the question of whether apolipoprotein B levels should also be measured for
assessment of the risk of atherosclerosis.
The authors of the Atherosclerosis Risk in
Communities (ARIC) Study [21] categorically reject this suggestion. This investigation involved 9026 obesity, metabolic
syndrome and diabetes patients, in whom
the rates of adverse cardiac events were recorded over a period of 10 years; apolipoproteins A and B provided no prognostic
information that exceeded the usefulness
of non-HDL and HDL cholesterol level
measurements.
Triglycerides
In a meta-analysis of 17 studies
(46,413 males/10.864 females), Hokanson and Austin [22] were able to clearly
demonstrate that high plasma triglyceride
levels increased the relative risk of an adverse cardiovascular event by 30% in men
and 75% in women. Adjustment for HDL
cholesterol and other risk factors reduced
these values, but still resulted in a statis-
4 | Gefässchirurgie 7 · 2013
tically significant relative risk increase of
14% in men and 37% in women. Another meta-analysis of a total of 10,158 CHD
events in 262,525 patients confirmed the
relationship between high triglyceride levels and the risk of CHD [23]. Nevertheless,
a direct atherogenic effect of triglyceride
has not yet been demonstrated [24]. The
importance of triglycerides as biomarkers
for cardiovascular risk is based on their
association with atherogenic residual lipid particles and apolipoprotein C3, a proinflammatory, proatherogenic protein
found in all classes of lipoprotein (overview in [24]).
Diabetes mellitus
In the case of inadequate insulin (e.g.
type 1 diabetes mellitus) and insulin resistance (e.g. obesity), the vasodilatory and
antioxidative functions of insulin are reduced, which, in turn, can increase the
risk of arteriosclerosis in diabetes sufferers. Insulin modulates the secretion of vasodilators such as NO and prostaglandin,
has an influence on the sympathetic nervous system and protects smooth muscle
cells from oxidative stress [25, 26].
In a randomized study of 58 non-diabetics and 56 patients with type 2 diabetes mellitus, Bonora et al. [27] assessed
the intima-media thickness of the carotid artery using ultrasound measurements.
The intima-media thickness was significantly increased in diabetics – independent of other risk factors such as smoking,
dyslipidemia or hypertension. An analogous result was reached by Frost et al. [28].
Again using measurements of intima-media thickness in the common carotid artery, the latter authors detected a greater degree of subclinical arteriosclerosis
in type 2 diabetes mellitus patients compared to controls within 1 year of the diabetes diagnosis. Significant observations
have also been reported for type 1 diabetes mellitus – even among young patients.
Compared to healthy controls, Faienza et
al. [26] showed increased carotid intimamedia thickness in children with type 1
diabetes mellitus and those who were severely overweight.
The fact that patients with diabetes are
at an increased risk of arteriosclerosis was
also confirmed by the investigations car-
ried out in the Framingham Study. Meigs
et al. [29] reported on 325 participants in
whom the degree of coronary artery calcification was determined by CT. In comparison to controls with normal glucose
tolerance, patients with impaired glucose
tolerance had increased coronary calcification, whereby the extent of calcification
was independent of the degree of glucose
intolerance. The most significant changes were observed in patients already diagnosed with type 2 diabetes mellitus; they
were less pronounced in patients whose
diabetes mellitus was discovered by an
oral glucose tolerance test and were smallest of all in participants with impaired
fasting blood glucose levels.
Obesity
De Michele et al. [30] investigated the relationship of common carotid artery intima-media thickness and cross-sectional area to obesity in 310 middle-aged female subjects. The positive correlation between weight and intima-media thickness
increased from normal weight, to overweight, to obesity (BMI >30 kg/m2) and a
larger vessel cross-sectional area was observed in obese women. The authors concluded that obesity is associated with preclinical atherosclerosis, particularly as
multivariate analysis demonstrated the
aforementioned correlation to be independent of age, blood pressure, dyslipidemia and fasting blood glucose level. The
relationship between intima-media thickness of the carotid artery and obesity was
also demonstrated among younger women without cardiovascular disease [31].
Furthermore, this correlation could not
only be demonstrated using intima-media thickness measurements, but also by
assessment of the degree of calcification of
the coronary arteries [32]. Another investigation confirmed the link between obesity and carotid intima-media thickness
in 100 never-smoking participants with
no evidence of vascular disease, normal
LDL cholesterol and blood glucose levels and normal blood pressure [33]. Using
carotid intima-media thickness measurements, this study demonstrated an association between hip and waist circumference (as an estimate of obesity) and the
progression of arteriosclerosis [34].
Pulmonary hypertension
Pulmonary hypertension induces shearing force-dependent disorganization and
injury of the endothelium with consequent proliferation of vascular cells. Hypertension has an influence on the membrane properties of lymphocytes, thrombocytes, macrophages, erythrocytes and
endothelial cells. This leads to an influence on the electrolyte transport systems,
the ion channels and the sodium, potassium and calcium pumps of these cells,
which, in turn, results in an increased
intracellular calcium concentration and
high blood pressure. The synthesis of collagen, elastin, fibronectins and proteoglycans in the vessel wall is stimulated as a response to the structural adaptation of the
cells to the increased pressure. Pulmonary
hypertension is thus considered an important and established risk factor for arteriosclerosis [35]. Despite this fact, clinically
successful antihypertensive therapy is not
necessarily accompanied by regression of
arteriosclerotic vessel alterations. For example, in the randomized placebo-controlled CAMELOT Study, 24 months of
amlodipine treatment led to a reduction
in ischemic coronary events, although this
clinical benefit could not be explained by
measurable improvements in the coronary vessel lumen [36]. The same conclusion was reached by the so-called PART 2
Study, which was able to demonstrate the
blood pressure lowering activity of rami­
piril compared to a placebo [37]. This prospective investigation revealed no differences between the two groups in terms of
common carotid artery wall strength or
carotid plaque score. These authors also
concluded that the positive effect of the
blood pressure lowering ACE inhibitor (in
terms of severe adverse coronary events)
cannot be equated to a reduction in arteriosclerotic changes. The clinical benefit
of this therapy may also be attributable to
the reduction of left ventricular hypertrophy or reversal of endothelial dysfunction,
for example. On the other hand, another
randomized trial – the SECURE Study –
used ultrasound measurements to demonstrate the effect of ramipril not just on
blood pressure, but also on the intimamedia thickness of the carotid artery [38].
It is possible that arteriosclerosis and
pulmonary hypertension are independent
risk factors for an adverse coronary event.
This is suggested by coronary artery CT
data assessing the presence of subclinical
atherosclerosis in a total of 44,052 symptom-free subjects, one third of whom had
hypertension. During an average followup time of 5.6 years, 902 (2%) cases of
death were recorded; the lowest rate of
events (1.6/1000 person-years) was observed among individuals without coronary artery calcification and the highest
rate among those with hypertension and
calcification (9.8/1000 person-years). The
death rate due to any cause increased with
the extent of coronary artery calcification,
although the risk was lower in participants
without hypertension than in those with
high blood pressure [39].
Conclusions for clinical practice
Atherosclerosis is the most common
form of arteriosclerosis. It is defined as a
chronic inflammatory reaction of the vessel wall in response to dyslipidemia and
vascular endothelial stress. Age, male
gender, total cholesterol, HDL cholesterol
deficiency, high systolic blood pressure,
high BMI, diabetes mellitus and smoking
have all been shown to be significant risk
factors for the progression of atherosclerosis. The clinical manifestations of atherosclerosis include CHD, arteriosclerosis
of the carotid artery and the arteries involved in cerebral circulation to result in
stroke or transitory ischemic attacks, as
well as PAOD including AAA. Overall, almost 7% of women and almost 10% of
men in Germany report that they have
been diagnosed as having CHD.
Corresponding address
Prof. Dr. E.S. Debus
Klinik und Poliklinik für Gefäßmedizin,
Gefäßchirurgie – Endovaskuläre
Therapie – Angiologie
Deutsches Aortenzentrum Hamburg
Universitäres Herzzentrum GmbH
Universitätsklinikum Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Germany
[email protected]
Compliance with ethical
guidelines
Conflict of interest. E.S Debus, G. Torsello, T. SchmitzRixen, I. Flessenkämper, M. Storck, H. Wenk and R.T.
Grundmann state that there are no conflicts of interest.
The accompanying manuscript does not include
­studies on humans or animals.
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