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Arterial Stiffness in Chronic Obstructive Pulmonary Disease
57
The preliminary 2 years follow-up results of the ARCADE study, the first
longitudinal study of cardiovascular risk and comorbidities in COPD, show an
increased rate of aortic PWV progression in COPD, independent of traditional
risk factors, suggesting an alternative mechanism for accelerated aortic
stiffness in COPD [27].
Arterial stiffness is accompanied by the augmentation of pulse pressure
with increased systolic pressure and decreased diastolic pressure. The
increased systolic pressure caused left ventricular hypertrophy and left
ventricular diastolic dysfunction [28]. It has been shown that COPD patients
have a high prevalence of left ventricular diastolic dysfunction, which is
associated with disease severity [29]. The decrease in diastolic pressure
reduces myocardial perfusion, causing local ischemia, even in the absence
of coronary atherosclerosis. Increased pulse pressure augments the pulsatility
in highly perfused organs, such as brain, predisposing to vascular rupture,
arterial wall alterations and thrombosis with possible hemorrhagic or
thrombotic strokes [28]. Hogaza et al. showed that reduced lung function
significantly increased the risk for ischemic stroke in patients who never
smoked [30]. Arterial stiffness in patients with COPD may be one of the links
between COPD and the increased prevalence of cardiac and vasculo-cerebral
complications.
MECHANISMS CONTRIBUTING TO ARTERIAL STIFFNESS
IN COPD
Factors and mechanisms that contribute to the increased arterial stiffness
in COPD are complex, intricate and incompletely elucidated. The presence of
common risk factors has been evaluated.
Age is associated with both arterial stiffness [10] and airflow limitation
[31, 32]. Smoking is the most important risk factor in COPD, but data
regarding its relationship with arterial stiffness in COPD are conflicting.
Several cross-sectional studies found no association between smoking status
and arterial stiffness [11, 15, 17]. These results were confirmed in a large
population, including 5002 men and women, of the Atherosclerosis Risk in
Communities (ARIC) cohort study that examined the relationship between
smoking habits and arterial stiffness at various arterial sites. The authors
concluded that the important adverse effects of smoking on the vasculature
may not include the stiffening of the arteries [33]. Nevertheless, acute and
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chronic effects of smoking on AIx were reported [34]. Current smoking
correlated with arterial stiffness, measured as aortic AIx, in COPD patients
[26].
Apart these risk factors, some common pathogenic mechanisms, linking
arterial alterations and COPD, have been investigated, including systemic
inflammation, increased oxidative stress, sympathetic nervous system over
activity, structural alteration of connective tissue and vascular calcification.
Many recent studies have suggested some interesting hypotheses that try
to explain the increased risk of vascular damage in COPD.
Systemic Inflammation
A large amount of data indicates that patients with COPD have a
systemic inflammatory response [6, 35] with increased concentration of
activated inflammatory cells and circulating mediators [36]. Activated
neutrophils release reactive oxygen species [37] and present an increased
expression of adhesion molecules [38]. Circulating monocytes, from patients
with COPD, release greater amounts of matrix metalloproteinase-9 (MMP9)
than those from controls [39].
Numerous systemic inflammatory mediators such as interleukin-6 (IL-6),
tumor necrosis factor-ɑ (TNF-α), interleukin- 1β (IL-1β) and C-reactive
protein (CRP), are also elevated in COPD [40]. CRP correlated with the
presence of COPD [41], and also, with the severity of lung function reduction
and the risk of hospitalization and death [42].
Systemic inflammation plays also a role in the pathogenesis of arterial
stiffness [43]. The activation of matrix proteinases induces elastin degradation
and fragmentation of basement membrane, with increased smooth muscle cell
migration and proliferation in the intima [43, 44]. Matrix metalloproteinases
(MMP) may have colagenolytic activity that results in production of uncoiled
stiffer collagen [43, 44].
CRP is stimulated by inflammatory cytokines, and it has an active role in
enhancing vascular inflammation and in altering endothelial function [43].
Endothelial dysfunction may stimulate the expression of proinflammatory
cytokines and cell adhesion molecules. Vascular inflammation induces
vascular fibrosis and smooth muscle cell proliferation, which subsequently
determine arterial stiffness [43].
The origin of systemic inflammation in COPD is not known, but several
hypotheses have been proposed, including passage of inflammatory mediators
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Arterial Stiffness in Chronic Obstructive Pulmonary Disease
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and cells from lungs into systemic circulation, tissue hypoxia, lung
hyperinflation, muscle dysfunction and bone marrow stimulation [45, 46].
Smoking may also increase inflammatory reactions [5].
Once stimulated, systemic inflammation may affect lungs and enhance the
chronic destructive process of COPD [45]. The target organs for inflammatory
reactions may be, at the same time, lungs and arteries [45].
The quantification of aortic inflammation noninvasively using 18F-FDG
PET, in a study that compared ex-smokers to COPD patients and subjects with
metabolic syndrome, showed that patients with COPD exhibited aortic
inflammation that fell between the aortic inflammation exhibited by ex-
smokers and that by metabolic syndrome patients. This method confirmed the
arterial inflammatory reaction and may allow in the future the evaluation of
arterial inflammation under anti-inflammatory drug therapy [47].
The relationship between inflammatory mediators and arterial stiffness
reported in clinical studies is conflicting. Sabit et al. found a positive
correlation between aortic PWV and Il-6 [15], whereas, in another study,
serum CRP concentrations correlated with augmentation pressure, in patients
with COPD [18]. However, other studies failed to demonstrate any association
of arterial stiffness with markers of inflammation in COPD patients [20, 48,
49]. The differences between studies, in methods used to assess arterial
stiffness or the involvement of patients with different phenotypes or degree of
COPD severity, may partly explain these discrepancies between them. Another
explanation may be related to the complex and incompletely understood
relationship between inflammation and arterial stiffness in COPD.
The Role of Oxidative Stress
In COPD, there is an increase in local pulmonary and systemic oxidative
stress. Circulating leucocytes in COPD produce greater amounts of reactive
oxygen species than those from normal subjects. Elevated plasma levels of
nitrotyrosine and products of lipid peroxidation, as markers of oxidative stress,
were found in COPD patients. In exacerbations of pulmonary disease,
concentration of oxidative stress mediators increases [50].
One of the most important deleterious effects of oxidative stress is the
inactivation of nitric oxide (NO). Impaired production or activity of NO alters
vasodilation and leads to an abnormal vascular tone, which increases arterial
stiffness [44]. Reactive oxygen species may increase systemic inflammation
and vascular smooth muscle cell proliferation [51]. Oxidative stress can also
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induce the expression of matrix-degrading enzymes, such as MMP-2 and
MMP-9 [51], involved in the degradation of extracellular matrix of the vessel
wall [43, 44]. All these mechanisms support the involvement of oxidative
stress in the impairment of vascular wall elasticity.
The Role of Hypoxia
Patients with COPD have intermittent or, in severe states, permanent
hypoxia. It has been shown that hypoxia may stimulate various reactions that
are also involved in vascular alterations and arterial stiffness, such as systemic
inflammation, oxidative stress, activation of renin-angiotensin system (RAS),
alteration in autonomic system and hemodynamic stress [5, 10].
Significant correlation between carotid-femoral PWV and PaO2 was
found in COPD patients, suggesting that hypoxia increases arterial stiffness
[17].
Alteration of Connective Tissue
Connective tissue is the main histological structure in both lungs and
arteries. Conditions that alter the elasticity of arteries may also reduce
pulmonary compliance.
In has been shown that emphysema severity, evaluated by computer
tomograph scanning, is related to carotid-radial PWV, independent of age, sex,
blood pressure, hypersensitive CRP, dyslipidemia, hypoxemia and airflow
obstruction [20].
Histologically, elastin fragmentation in arteries leads to arterial stiffness,
dilated and thicker arteries [6, 44], whereas in lungs, degradation of elastin and
increase in collagen induce emphysema and reduced pulmonary compliance
[6, 52]. Similarly, skin elastin alteration induces skin wrinkling, which has
been found to be associated with emphysema severity, independent of pack-
years smoked [6, 53]. Patients with Marfan’s syndrome have an increased risk
of aortic root stiffness, but they may also develop emphysema [6, 54].
Enhanced proteolytic activity, with elastin degradation, may be one of the
links between vascular alterations and emphysema. Increased levels of
circulating MMP -9 have been found in patients with arterial stiffness [55],
and also, in sputum [56] and bronchoalveolar lavage [57] of patients with
pulmonary emphysema.
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Arterial Stiffness in Chronic Obstructive Pulmonary Disease
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An autoimmune mechanism, linking vascular and pulmonary disease, has
been also proposed [58], because patients with COPD and emphysema have
increased B cell and T cell responses to elastin peptides, and increased levels
of circulating antielastin antibodies [6, 59].
Taking together all these mechanisms, we can conclude that an individual
with a genetic predisposition, under the stimulation of environmental factors
(infections, air pollution), may develop lung, skin and vascular connective
tissue damage.
Neurohormonal Activation
Increased sympathetic nervous activity, involving peripheral nerves and
cardiac autonomic system, has been reported in patients with COPD [60].
Depressed heart rate variability has been found in patients with COPD, as
compared to controls, showing impaired autonomic control [61, 62]. The
increase in sympathetic nervous activity was inversely related to the patients’
oxyhemoglobin saturation, and the administration of oxygen attenuated the
sympathetic overactivity [62]. Elevated heart rate has been reported in many
observations, and it is explained mainly by the overactivity of sympathetic
nervous system [60].
In healthy subjects, sympathetic activity is an independent determinant of
PWV and diastolic function [63]. In HARVEST study, participants were
divided into two groups, one with increased sympathetic activity, and another
with normal sympathetic activity. Subjects with sympathetic predominance
had impaired compliance [64].
The link between sympathetic overactivity and arterial stiffness may
involve multiple mechanisms. Sympathetic stimulation increases vascular
tone, but it can also contribute to vascular stiffness, independent of blood
pressure, inducing endothelial dysfunction, growth of vascular muscle and
consequently, fibrosis [65]. It can activate RAS that has an important role in
arterial stiffness pathophysiology, increasing blood pressure and inducing
vascular fibrosis [65].
COPD - A Model of Accelerating Ageing
Progressive limitation in air flow is observed with age in otherwise,
healthy individuals [66]. Moreover, lungs of elderly people develop
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progressive enlargement of distal airways and alveoli, fragmentation of elastin
fibers with reduced pulmonary elasticity, resulting in senile emphysema
[6, 67]. Similar findings, with altered elastin, increased collagen, vascular
diameter enlargement and wall stiffening, are found in age associated
arteriosclerosis [68].
Telomere length is a marker of ageing [6, 69]. Accelerating ageing is
accompanied by shortening of the DNA component of the telomere length, the
segments located at the end of the chromosomes that protect them from
degradation and recombination [6, 70].
Telomere length reduces with every cell cycle, but this process is
accelerated by oxidative stress and systemic inflammation, and may indicate
biological age [6, 71].
It has been shown that alveolar epithelial and endothelial cells, from
patients with emphysema, have greater telomeres shortening, compared to
subjects without emphysema. Alveolar cells, with shorter telomeres from
emphysematous lungs, had increased markers of senesces and apoptosis [72].
Telomere length has been correlated with cardiovascular risk factors,
including hypertension, dyslipidemia, obesity, smoking and an unhealthy
lifestyle [68]. A cross-sectional study showed that subjects, with increased
arterial stiffness, have shorter telomeres [73], and shorter telomeres have been
found in endothelial cells of patients with coronary artery disease, compared
with those of age-matched subjects, without coronary disease [6, 74].
Furthermore, telomere length is a predictor of cardiovascular events [75], and
increased telomere attrition is a predictor of cardiovascular mortality in elderly
men [76].
It was concluded that shortening of telomeres may induce increased
systemic inflammation, oxidative stress, alteration of connective tissue and
consequently, vascular stiffness and emphysema [6].
Klotho gene is considered the “ageing gene,” as animal models of
defective klotho gene develop accelerating ageing osteoporosis, severe
vascular calcification, skin wrinkling and emphysema [6, 68, 77]. COPD
patients may also develop similar systemic manifestations, as a consequence
of an accelerating ageing process.
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Arterial Stiffness in Chronic Obstructive Pulmonary Disease
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THERAPEUTIC IMPLICATIONS
As common pathogenic mechanisms are involved in vascular stiffness and
COPD, therapeutic strategies directed to these mechanisms, and with possible
efficacy for both vascular and pulmonary diseases, have been evaluated.
Inhaled bronchodilators (corticosteroids, beta-agonists,
parasympatholytics) have been evaluated in relation with cardiovascular
outcomes and with arterial stiffness. The combination fluticasone
propionate/salmeterol reduced the probability of having an adverse
cardiovascular event, when compared to fluticasone propionate or salmeterol
alone, or to placebo [78]. A lower rate of death was found in patients with
severe COPD, treated for two years with fluticasone propionate/salmeterol,
when compared with those treated with tiotropium [79]. One mechanism
involved in this favorable influence on cardiovascular outcome may be the
reduction of arterial stiffness.
In one small trial, Sabit et al. evaluated the effects of fluticasone
propionate/ salmeterol 500/50, in 14 patients with moderate-severe COPD, and
observed that treatment significantly reduced arterial stiffness at 8 weeks by
2.2 m/s [80].
However, in a multicenter, randomized, double-blind, placebo-controlled
study that compared the effects of fluticasone propionate/salmeterol 250/50
mg twice-daily and placebo on aortic pulse wave velocity after 12 weeks
of treatment, a statistically significant reduction in aortic PWV, between
fluticasone propionate/salmeterol and placebo, was reported only in patients
with high arterial stiffness [22].
Another study that compared the effect of the fluticasone furoate/
vilanterol 100/25 mg, with tiotropium bromide, 18 mg, on aortic PWV, found
no differences between the two therapies [81].
Beta-agonists may stimulate nitric oxide synthase, increase nitric
oxide and ameliorate vascular tone, while corticosteroids may reduce
systemic inflammation with favorable effects on both arterial stiffness and
atherosclerosis [22]. Nevertheless, the effects of corticoids on markers of
inflammation were not firmly confirmed [51, 22].
At present, the possible therapeutic benefice of beta-agonists and
corticoids on arterial stiffness and cardiovascular outcomes is not clearly
established.
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Statins
Statins have been discussed in relation with both cardiac and vascular
diseases.
In COPD, statins reduced hospitalizations from exacerbations, acute
coronary events and cardiovascular and respiratory mortality [6, 82]. Several
studies have shown a favorable effect of statins on arterial stiffness and central
hemodynamics [44, 83]. Statins’ effect may be mediated by the reduction of
LDL-cholesterol and of systemic inflammation [44, 83]. The administration of
statins reduced the risk of shorter telomeres for coronary heart disease in the
West of Scotland Coronary Prevention Trail [68], with a possible implication
in ageing related diseases.
Renin-Angiotensin-Aldosterone Blockers
RAS plays an important role in systemic inflammation and fibrosis, and it
is intensely studied in relation with arterial stiffness [43, 44]. RAS may also be
involved in pulmonary disease, as it is stimulated by hypoxia [84]. It may
contribute to pulmonary hypertension due to the vasoconstrictor effect and to
the proliferation [84, 85]. A lower activity of RAS was associated with an
improvement of the peripheral use of oxygen and respiratory muscle function
[84, 86]. The blockade of RAS may reduce the systemic inflammation
involved in both vascular [44] and pulmonary alterations [87].
In an experimental study in which angiotensin receptor blocker irbesartan
was administrated for 8 weeks in a mouse model of severe emphysema, the
authors reported an improvement in pulmonary compliance and pulmonary
function [88].
The blockers of RAS decrease arterial stiffness indirectly through the
reduction of blood pressure, but important data support also a direct role at the
level of the vascular wall [44, 68]. The evaluation of the efficacy of RAS
blockers in the treatment of arterial stiffness in COPD patients, and the
possible concomitant pulmonary favorable effect, requires further studies.
Exercise Training
Physical exercise may reduce arterial stiffness in COPD patients. In one
study, after 4 weeks of exercise, trained patients had reduced arterial stiffness,
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Arterial Stiffness in Chronic Obstructive Pulmonary Disease
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as compared to controls matched for age and lung function. The decrease in
arterial stiffness accompanied the reduction in systolic pressure and fasting
plasma glucose that occurred with exercise [44]. Another study showed an
improvement in aortic stiffness, after a 7 week standard multidisciplinary
pulmonary rehabilitation program for patients with COPD [44, 89].
In one study that evaluated the correlation between physical activity level
and aortic Aix, as a measure of arterial stiffness in COPD patients, a higher
level of physical activity favorably influenced arterial stiffness [49].
The favorable effects of exercise may be due to a reduction in sympathetic
tone and enhancement of vagal activity and a decrease in blood pressure [10].
Stimulation of nitric oxide production by the shear stress that accompanies
physical activity, with subsequent vasodilation, reduces blood pressure [10].
The decrease in blood glucose may reduce the activation of the RAS and the
synthesis of advanced glycation end products, with favorable effects on
vascular elasticity [10].
Nevertheless, in a recent study, a state-of-the-art interdisciplinary
pulmonary rehabilitation program failed to show an improvement in aortic
PWV and further larger studies are required to elucidate the influence of
physical activity on arterial stiffness, in COPD patients.
CONCLUSION
Patients with COPD have increased arterial stiffness when compared to
healthy controls. The mechanisms that link arterial stiffness and COPD are not
completely elucidated, but they seem to be complex and intricate, involving
systemic inflammation, oxidative stress, destruction of connective tissue,
hypoxia and neurohormonal activation.
Vascular alterations are extrapulmonary manifestation of COPD, which
is now considered a systemic disease. The association of COPD with
arterial stiffness, osteoporosis, skin wrinkling and biological markers of
ageing, suggest that COPD is accompanied by an accelerating ageing process.
Therapeutic interventions in COPD patients, such as physical exercise and
inhaled beta-agonists and corticoids may have a favorable effect on vascular
stiffness. The administration of cardio-protective drugs, such as statins and
angiotensin receptor agonists in COPD patients, seems to determine a
pulmonary benefit.
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Future studies aimed to elucidate the common pathogenic pathways of
arterial stiffness and COPD, should have an impact on the development of
common therapeutic strategies, for both pulmonary and vascular diseases.
REFERENCES
[1] Hansell AL, Walk JA, Soriano JB. What do chronic obstructive
pulmonary disease patients die from? A multiple cause coding analysis.
Eur Respir J 2003;22:809-814.
[2] Huiart S, Ernst P, Suissa S. Cardiovascular morbidity and mortality in
COPD. Chest 2005; 128:2640-2646.
[3] Sidney S, Sorel M, Quesenberry CP, DeLuise C, Lanes S, Eisner MD.
COPD and incident cardiovascular Chest 2005; 128:2068-2075.
[4] Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne
VM. Impaired lung function and mortality risk in men and women:
findings from the Renfrew and Paisley prospective population study.
BMJ 1996;313:711-715.
[5] Sin DD, Man SFP. Why are patients with chronic obstructive pulmonary
disease at increased risk of cardiovascular disease? The potential role of
systemic inflammation in chronic obstructive pulmonary disease.
Circulation 2003; 107:1514-1519.
[6] MacNee W, Maclay J, McAllister D. Cardiovascular injury and repair
in chronic obstructive pulmonary disease. Proc Am Thorac Soc
2008;5:824-833.
[7] Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C,
Hayoz D, et al. on behalf of the European Network for non-invasive
investigation of large arteries. Abridged version of the expert consensus
document on arterial stiffness. Artery Res 2007;1:2-12.
[8] Van Bortel L, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank
JK, De Backer T, et al. on behalf of the Artery Society, the European
Society of Hypertension Working Group on Vascular Structure and
Function and the European Network for Noninvasive Investigation of
Large Arteries. Expert consensus document on the management of aortic
stiffness in daily practice using carotid-femoral pulse wave velocity. J
Hypertens 2011; 30:445-448.
[9] Vlachopoulos C, Aznaouridis K, Stefanidis C. Prediction of
cardiovascular events and all-cause mortality with arterial stiffness: a
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