CHEST

Recent Advances in Chest Medicine

Arterial Stiffness in COPD Isabelle Vivodtzev, PhD; Renaud Tamisier, MD, PhD; Jean-Philippe Baguet, MD, PhD; Jean Christian Borel, PhD; Patrick Levy, MD, PhD; and Jean-Louis Pépin, MD, PhD

In patients with COPD, cardiovascular diseases are the most common concomitant chronic diseases, a leading cause of hospitalization, and one of the main causes of death. A close connection exists between COPD and cardiovascular diseases. Cardiovascular risk scores aim to predict the effect of cardiovascular comorbidities on COPD mortality, but there is a need to better characterize occult and suboccult cardiovascular disease, even in patients with mild to moderate COPD. Among various surrogate markers of cardiovascular risk, arterial stiffness plays a central role and is a strong independent predictor of cardiovascular events beyond classic cardiovascular risk factors. Its measurement is highly suitable, validated, and relatively easy to perform in routine COPD clinical practice. The growing awareness of the increased cardiovascular risk associated with COPD has led to a call for respiratory physicians to measure arterial pulse wave velocity in routine practice. Cross-sectional data establish elevated arterial stiffness as being independently linked to COPD. Candidate mechanisms have been proposed, but surprisingly, only limited data are available regarding the impact of the different COPD treatment modalities on arterial stiffness, although initial studies have suggested a significant positive impact. In this review, we present the various surrogate markers of cardiovascular morbidity in COPD and the central role of arterial stiffness and the underlying mechanisms explaining vascular remodeling in COPD. We also consider the therapeutic impact of COPD medications and exercise training on arterial stiffness and the assessments that should be implemented in COPD care and follow-up. CHEST 2014; 145(4):861–875 Abbreviations: AGE 5 advanced glycation end product; AIx 5 augmentation index; CRP 5 C-reactive protein; FMD 5 flowmediated vasodilatation; FSC 5 fluticasone propionate/salmeterol combination; ICS 5 inhaled corticosteroid; LABA 5 long-acting b-agonist; MMP-9 5 matrix metalloproteinase 9; NO 5 nitric oxide; PWV 5 pulse wave velocity; RAAS 5 renin-angiotensin-aldosterone system; TNF-a 5 tumor necrosis factor-a

is extensive evidence that COPD and carThere diovascular disease coexist, with each condition 1,2

complicating the prognosis of the other.3,4 Cardiovascular disease is the second cause of death after lung cancer in smokers with mild to moderate airway obstruction5 and reaches 27% to 30% in patients with COPD.1 In COPD, the risk of death is mainly influenced by the severity of airflow obstruction and, to a large extent, by concomitant chronic diseases.6-9 Composite scores Manuscript received August 2, 2013; revision accepted December 5, 2013. Affiliations: From the Université Grenoble Alpes (Drs Vivodtzev, Tamisier, Borel, Levy, and Pépin); INSERM HP2 (U1042) (Drs Vivodtzev, Tamisier, Borel, Levy, and Pépin); Grenoble University Hospital (Drs Vivodtzev, Tamisier, Borel, Levy, and Pépin); and Department of Cardiology (Dr Baguet), Grenoble University Hospital, Grenoble, France. Funding/Support: This work was supported by grants from the scientific council of AGIRàdom.

have been proposed to assess prognosis and to provide more comprehensive ways to anticipate COPD evolution.10,11 A disease-specific comorbidities index has been suggested to better characterize the risk of mortality in patients with COPD.11 Different COPD phenotypes have been described, depending on the severity of airflow limitation and the presence of cardiometabolic comorbidities.12,13 Persistent systemic inflammation, a key mechanism for cardiovascular disease progression, is also associated with poor outcomes in COPD.5,14 Thus, easy-to-use cardiovascular Correspondence to: Jean-Louis Pépin, MD, PhD, Grenoble University Hospital, EFCR Laboratory, 29 Ave Maquis du Grésivaudan, La Tronche, Grenoble, France; e-mail: JPepin@ chu-grenoble.fr © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1809

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tools are needed to better delineate relevant clusters of comorbidities in COPD.15 The measurement of global cardiovascular risk scores in addition to lung function tests improves risk stratification in COPD, with a better prediction of incident cardiovascular events and mortality.4 However, in patients at medium to high cardiovascular risk, identifying early changes in the cardiovascular system before the occurrence of major clinical events, such as myocardial infarction and stroke, is critical. Several subclinical markers have been validated in the general cardiovascular field, including carotid intima-media thickness, endothelial function, and arterial stiffness measurements. Among these markers, arterial stiffness has a strong predictive value for cardiovascular events beyond that of classic cardiovascular risk factors16 and is the most suited for use in routine clinical practice. In the meta-analysis of Vlachopoulos et al17 evaluating 15,877 subjects, arterial stiffness was a strong predictor of future cardiovascular events and all-cause mortality. In COPD, arterial stiffness has been independently associated not only with the severity of the disease but also with inflammation, oxidative stress, and high sympathetic tone, the common processes by which COPD leads to the development of vascular remodeling and, secondarily, to cardiovascular events.18,19 Additionally, exacerbations of COPD are generally associated with enhanced systemic inflammation and sympathetic activation, both of which are involved in the progression of arterial stiffness. Thus, existing data and candidate mechanisms suggest that elevated arterial stiffness in COPD could be used as a surrogate marker of severity. Surprisingly little information exists about the impact of the different COPD treatment modalities on arterial stiffness. Nevertheless, arterial stiffness improves after exercise training in patients with COPD,20,21 and inhaled therapies might also modulate vascular function.22 Because there is still some debate regarding the safety of inhaled medications, particularly the risk of cardiovascular death,23 more knowledge of their impact on arterial stiffness is of interest.

Surrogate Markers of Cardiovascular Morbidity in COPD Because cardiovascular risk scores may underestimate the risk of cardiovascular events, particularly in early prevention, and sophisticated combinations of biomarkers fail to improve the prediction of cardiovascular outcomes,24 several studies have investigated subclinical markers of cardiovascular risk in smokers and the COPD population. Among these, noninvasive measurements of carotid intima-media thickness, reflecting early atherosclerosis; modifica-

tions in endothelial function; and arterial stiffness have primarily been studied to obtain information about the structure of vascular walls and vascular function in COPD. Carotid Intima-Media Thickness The carotid intima-media thickness, a validated and reliable marker of atherogenesis,25 mainly refers to the measurement of a localized arterial segment. Bilateral carotid arteries are scanned with high-resolution B-mode ultrasonography to determine the mean maximal intima-media thickness.25 Reports show that individuals with airflow limitation (particularly smokers) have exaggerated atherosclerosis (intima-media thickness) compared with age-matched control subjects26,27 (Table 1). Atherosclerotic changes occur early in the COPD process. A large population-based study recently demonstrated an association between COPD and the presence of carotid artery wall thickening and, more specifically, lipid core-vulnerable carotid artery plaques.28 However, although very reliable, the highly technical nature and cost of the ultrasound system comprise major drawbacks to the widespread use of this technique,48 limiting access for large numbers of patients with COPD. Endothelial Function The endothelium is the key regulator of vascular homeostasis and is involved in a multitude of physiologic functions, including regulation of vasomotor tone and structure, inhibition or stimulation of vascular smooth muscle cell proliferation and migration, and thrombogenesis and fibrinolysis.49 Many methods are used to measure the functioning of the endothelium in humans.50 These techniques differ in terms of cost, accessibility, and interobserver reliability. In the context of COPD, whatever the technique used, studies consistently have shown endothelial dysfunction in a large proportion of patients with COPD29-32 (Table 1). In two studies, flow-mediated vasodilatation (FMD) measured after forearm occlusion was quantified at 3.8% ⫾ 3.1% in former smokers29 compared with 4.3% ⫾ 1.2% in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I/II COPD.32 FMD measured after upper-arm occlusion decreased from 19% ⫾ 3% in healthy nonsmoker subjects to 16% ⫾ 2% in ex-smokers and 11% ⫾ 3% in COPD. Using digital pulse amplitude augmentation in response to hyperemia,51 we demonstrated that 50% of patients with stable COPD exhibited endothelial dysfunction and that COPD exacerbation is associated with further deterioration in endothelial function. In the COPD literature, endothelial dysfunction is consistently associated not only with the severity of airway obstruction29-32 but also with a higher percentage

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Sabit et al19/2007

COPD (stable, n 5 75) vs healthy current or ex-smokers subjects (n 5 42)

Smokers (n 5 70), ex-smokers (n 5 70), and never smokers (n 5 54)

COPD (stable, n 5 106); GOLD stage I/II (n 5 38) vs stage III (n 5 26) vs stage IV (n 5 42)

Clarenbach et al32/2013a

Arterial stiffness (n 5 18) PWV measures Zureik et al33/2001

COPD (total, n 5 44); stable (n 5 34) vs during exacerbation (n 5 10)

Former smokers with COPD (n 5 107) vs former smokers without COPD (n 5 63). All patients: age ⱖ 60 y, smoking pack-y ⱖ 10 COPD (stable, n 5 60) vs matched smokers (n 5 20) and nonsmokers (n 5 20) with normal lung function

COPD (n 5 253) vs control subjects (n 5 920)

Smokers with airflow limitation (n 5 61) vs age-matched control smokers (n 5 122) vs control never smokers (n 5 122) without airflow limitation Aged 45-84 y without clinical cardiovascular disease (quintile on percentage of emphysema)

Study Population

Minet et al31/2012

Eickhoff et al30/2008

Endothelial function (n 5 4) Barr et al29/2007

Lahousse et al28/2013

Barr et al26/2012

IMT (n 5 3) Iwamoto et al27/2009

Marker and Study/Year

aPWV (SphygmoCor; AtCor Medical Pty Limited) AIx

cfPWV (Complior; Colson)

FMD after reactive hyperemia

RH-PAT

FMD after reactive hyperemia

(B-mode) ultrasound FMD after reactive hyperemia

High-resolution B-mode ultrasonography and high-resolution MRI scanning

High-resolution B-mode ultrasonography

High-resolution B-mode ultrasonography

Method

11.4 ⫾ 2.7 m/s vs 8.95 ⫾ 1.7 m/s 30.1 ⫾ 8.2 vs 25.9 ⫾ 6.2

11.7 ⫾ 2.5 m/s

4.3% ⫾ 1.2% vs 2.8% ⫾ 1.5% vs 2.0% ⫾ 1.3%

0.47 ⫾ 0.33 vs 0.28 ⫾ 0.19

11% ⫾ 3% vs 16% ⫾ 3% vs 19% ⫾ 3%

3.8% ⫾ 3.1%

IMT . 2.5 mm COPD vs controls: 75% vs 55%

0.778-0.897 mm

0.78 vs 0.73 vs 0.73 mm

Mean Value

Table 1—Studies Investigating Surrogate Markers of Cardiovascular Risk in COPD

(Continued)

PWV was negatively associated with FEV1 and FVC. For every 2.5 m/s increase in PWV, FEV1 decreased by 195 ⫾ 50 mL (P 5 .001). aPWV COPD . control across each decade. aPWV independently correlated with age, tobacco life-dose, and inflammatory markers (IL-6).

Endothelial dysfunction in COPD was associated with lower postbronchodilator FEV1 and emphysema. FMD COPD , smokers , nonsmokers; impaired FMD was strongly related to systemic inflammation and airway obstruction. Six-min walk distance, high FFMI, and hypercapnia were associated with endothelial dysfunction in COPD. FEV1 and physical activity showed an independent effect on endothelial function.

Smokers with airflow limitations have exaggerated atherosclerosis (association between IMT and predicted FEV1). Obstructive spirometry and upper-lobe emphysema were independently associated with increased IMT of the internal carotid artery. COPD has twice increased risk of carotid artery wall thickening vs control subjects with normal lung function and is an independent determinant of presence of lipid core, an indicator of a vulnerable plaque.

Main Result

Figure 4. Putative targets of reduction in arterial stiffness after therapeutic interventions in COPD. Green arrows show published data available in the COPD population on the effect of inhaled therapies (fluticasone propionate/salmeterol, fluticasone furoate/vilanterol, and tiotropium), rehabilitation, and oxygen supplementation. See Figure 2 legend for expansion of abbreviations. (Adapted with permission from Zieman et al.65)

the effect of rehabilitation programs in COPD in terms of cardiovascular outcomes and impact on arterial stiffness. Mechanisms for the reduction in arterial stiffness after rehabilitation programs have been suggested in pilot studies (Fig 4, green arrows). The role of physical activity in improving arterial compliance has been demonstrated in healthy men.96 Exercise training, by

reducing basal sympathetic activity, enhancing vagal activity, and restoring baroreflex sensitivity,87 might decrease BP. Furthermore, shear stress during or immediately after bouts of exercise may stimulate NO production, leading to vasodilatation and reductions in BP and sympathetic drive.97 Finally, the positive effect of exercise on glucose regulation would reduce activation of the RAAS and prevent AGE formation,

Figure 5. Effect of rehabilitation on arterial stiffness in COPD. A, Respective effects of a 4-wk rehabilitation program () and control period () on carotid-brachial PWV in COPD. PWV was significantly reduced by 2 1.1 m/s ( 2 10%) in trained patients compared with untrained patients ( P 5 .001). (Reproduced with permission from Vivodtzev et al.20) B, Effect of a 7-wk rehabilitation program on aortic PWV and in BP in COPD. Both were significantly reduced after training (aortic PWV, P , .05; BP, P , .01). See Figure 1 legend for expansion of abbreviation. (Adapted with permission from Gale et al.21) 872

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COPD (n 5 98); frequent (n 5 72) vs infrequent exacerbators (n 5 26) Stable state vs at exacerbation presentation in 55 patients

Patel et al43/2013

Ultrasound ABI

ABI

AIx (SphygmoCor)

BA compliance (ultrasonography and pulsed Doppler echocardiography)

AP and AIx (SphygmoCor)

aPWV (Vicorder)

cfPWV (Complior)

cfPWV (SphygmoCor)

Method

ABI , 0.9 (n 5 94) 0.9 , ABI , 1.3 (n 5 127) ABI . 1.3 (n 5 17)

25.7 vs 21.0 in men 33.6 vs 29.4 in women 1.11-1.13

26 ⫾ 16 1023 kPa vs 38 ⫾ 28 1023 kPa

AP: 17 ⫾ 1 mm Hg vs 14 ⫾ 1 mm Hg AIx: 31 ⫾ 2 vs 30 ⫾ 1

11.4 ⫾ 2.1 m/s vs 10.3 ⫾ 2.0 m/s 11.3 ⫾ 0.4 m/s vs 10.1 ⫾ 0.3 m/s

Patients with COPD have increased arterial stiffness and BP compared with control subjects matched for age and smoking status. Total arterial compliance and BA compliance were decreased in patients with COPD vs healthy subjects. FEV1 and Pao2 were related to BA compliance. AIx and COPD are only weakly associated. The adequacy of AIx as a measure of arterial stiffness in COPD is challenged. Percentage of emphysema and upperlobe emphysema is associated with decrements in ABI. Thirty-six percent of patients had abnormal values of ABI.

cfPWV was increased in patients with more severe COPD compared with mild and moderate groups. Airflow limitation and hypoxemia may increase arterial stiffness. Good reproducibility of aPWV on shortterm and mid-term duration, showing a constancy of cfPWV values. Patients with frequent COPD exacerbations have greater arterial stiffness than those with infrequent exacerbations. Arterial stiffness rises acutely during COPD exacerbations, particularly with airway infection.

7.3 ⫾ 2.9 m/s vs 9.9 ⫾ 3.3 m/s vs 12.7 ⫾ 3.9 m/s

11.1 ⫾ 1.9 m/s vs 11.2 ⫾ 2.3 m/s

Main Result

Mean Value

Data are presented as mean ⫾ SD. ABI 5 ankle-brachial index; AIx 5 augmentation index; AP 5 augmentation pressure; aPWV 5 aortic pulse wave velocity; BA 5 brachial artery; cfPWV 5 carotid-femoral pulse wave velocity; DBP 5 diastolic BP; FFMI 5 fat-free mass index; FMD 5 flow-mediated dilatation; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; IMT 5 intima-media thickness; MAP 5 mean arterial pressure; PWV 5 pulse wave velocity; RH-PAT 5 reactive hyperemia-peripheral arterial tonometry; SBP 5 systolic BP; UACR 5 urinary albumin-to-creatinine ratio. aA reduction of 1 m/s in PWV is clinically significant.15

Pecci et al47/2012

COPD (n 5 246); measurements 2 wk following hospitalization (78% for COPD exacerbation); smokers vs nonsmokers

COPD (n 5 494) from the 3,374 subjects from the Copenhagen City Heart Study vs subjects without COPD Aged 45-84 y without clinical cardiovascular disease (quintile on percentage of emphysema)

Janner et al46/2012

Barr et al26/2012

COPD (stable, n 5 25) vs age-matched healthy subjects

Boussuges et al45/2007

COPD (n 5 102) vs healthy control subjects matched for age and smoking status (n 5 103)

COPD (stable, n 5 38)

Vivodtzev et al42/2013

Other measures Mills et al44/2007

COPD (n 5 62): GOLD stage I/II (n 5 32) vs stage III/IV (n 5 30) vs control subjects matched for age and cigarette smoke exposure (n 5 22)

Study Population

Cinarka et al41/2013

Marker and Study/Year

Table 1—Continued

of emphysema32 (Table 1). Systemic inflammation as measured by C-reactive protein (CRP)30,52 or IL-6 and tumor-necrosis factor-a (TNF-a)31 has been linked with endothelial dysfunction in COPD. Finally, we found a significant link between 6-min walk distance and reactive hyperemia-peripheral arterial tonometry in COPD. Accordingly, Clarenbach et al,32 using the FMD method, suggested that preserved physical activity has a protective effect on endothelial function. Once again, the required expertise, cost of the systems, and lack of consensus on measurement methods are the main limitations to the routine daily use of this subclinical marker. Arterial Stiffness Arterial stiffness, which mainly refers to the properties of regional or segmental arteries, is the most widely used method for anticipating cardiovascular risk in COPD. In the current literature, we found 19 studies reporting measurements of arterial stiffness in COPD (Table 1). The majority of these studies used pulse wave velocity (PWV) measurements, which mainly reflect the intrinsic elasticity of the arterial wall and its anatomic dimensions. PWV is the ratio of the distance (m) to transit time (s) between two pressure waves recorded transcutaneously at two arterial sites (Fig 1). Arterial PWV is a useful and safe noninvasive method for assessing central arterial stiffness. In particular, carotid-femoral PWV is considered the gold standard by the European Society of Hypertension and European Society of Cardiology55 and is a strong predictor of future cardiovascular events and all-cause mortality, supporting its implementation in clinical research and daily practice.17 It should be noted, however, that substantial differences exist among values of PWV, depending on the commercially available devices used. Two methods have been established for the measurement of carotid-tofemoral propagation time: (1) the intersecting tangent foot-to-foot algorithm (eg, used by the SphygmoCor system; AtCor Medical Pty Limited) and (2) the point of maximum systolic upslope of the signal, as initially used in the Complior system (Colson).56 PWV values obtained with the foot-to-foot method may be greater than those obtained from the maximum slope, a difference likely to be related to the method but not to the variation of PWV with heart rate.56 In addition, various methods are used to measure the distance between arterial sites and, notably, the subtraction of the carotid artery length from the suprasternal notch-to-femoral straight distance (as used in the SphygmoCor system) or the carotid-to-femoral straight distance (as used, at least until recently, in the Complior system). The use of different devices for PWV measurements may account for up to 25% of changes

Figure 1. Carotid-femoral PWV measurement as usually measured with the foot-to-foot velocity method. PWV is the ratio of distance to transit time between two pressure waves recorded transcutaneously at two arterial sites (PWV 5 distance [m]/transit time [s]). The propagation time may also be measured from the point of maximum upstroke of the signal. Expert consensus on the measurement of aortic stiffness in daily practice using carotidfemoral PWV suggests that 80% of the direct carotid-femoral distance is the most accurate distance estimate.53 DL 5 delta length; Dt 5 delta time; PWV 5 pulse wave velocity. (Reprinted with permission from Schillaci et al.54)

in the PWV values.57,58 Accordingly, the expert consensus on the measurement of aortic stiffness in daily practice using carotid-femoral PWV suggests that 80% of the direct carotid-femoral distance is the most accurate distance estimate.53 Nevertheless, the various devices do not differ in their sensitivity to the type of intervention and in within-subject variability.56 The reproducibility of PWV during a 1-day session has been reported to be high in healthy subjects59 as well as in patients receiving hemodialysis60 and in those with end-stage renal disease.61 For sequential measurements of carotid-femoral PWV performed by two different operators, the intraobserver and interobserver reproducibility are also very good (r . 0.977), suggesting that the device can be used with confidence by multiple investigators. In COPD, we have recently confirmed with the Complior device good reproducibility for short-term (15 days) and mid-term (42 days) evaluations of PWV in stable patients.42 This result was close to the variability of PWV measurements found in studies investigating the effects of various interventions over time on PWV and included a control group.49 Nevertheless, it has been shown that arterial stiffness rises acutely during COPD exacerbation, particularly with airway

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infection, leading to the possibility of greater variability of the measurement during exacerbation.43 All studies are consistent, showing a significant increase in arterial stiffness in COPD compared with ex-smokers without airway obstruction and nonsmoker healthy control subjects (Table 1). Across studies and depending on the devices used for measurement (SphygmoCor, Complior, or Vicorder [Skidmore Medical Limited]), mean PWV was found to be between 8.7 ⫾ 1.5 m/s and 11.4 ⫾ 2.7 m/s in patients with COPD18,19,22,34-37,39-42 (and up to 12.7 ⫾ 3.9 m/s in GOLD stage III/IV COPD) compared with means between 7.3 ⫾ 2.9 m/s and 9.9 ⫾ 2.3 m/s in control subjects matched for age and cigarette smoke exposure.34-37,39-41 Lower values of PWV were found by Albu et al38 (7.02 ⫾ 0.82 m/s in patients with COPD vs 6.12 ⫾ 1.3 m/s in control subjects) that could be explained by differences in the assessment of PWV (using echotracking) and differences in the calculation of the distance between recording sites. As for endothelial dysfunction, during exacerbations, an impairment in vascular function has been shown,19 with an 11.4% increase above the stable state during the exacerbation period followed by incomplete recovery during convalescence.62 Maclay et al35 suggested that increased arterial stiffness in COPD was unlikely to be caused by abnormal endothelial function, but abnormalities in the vascular extracellular matrix may be an independent systemic feature of COPD. Finally, greater arterial stiffness leading to increased afterload has been associated with left ventricular dysfunction in COPD.36 Arterial PWV measurements are cheaper and easier to implement in clinical practice than are intimamedia thickness and endothelial function assessments. The main limitations are its variability with basal heart rate and the acute effects of food intake and caffeine. There are also divergences in the algorithms used for calculation of the pulse propagation.56 A new expert consensus on the measurement of aortic stiffness in daily practice using carotid-femoral PWV advises on standardized measurement procedures.53 Based on MRI studies, the use of 80% of the direct carotidfemoral distance is now considered the most accurate distance estimate, and 10 m/s is the new threshold for normal values of carotid-femoral PWV. Other indicators of arterial stiffness than PWV have been used in COPD. The augmentation index (AIx) measures the supplementary increase in BP during systole due to the reflection of the forward-traveling pressure waves from the peripheral circulation. One study using the AIx method confirmed the increase in arterial stiffness measured with PWV in COPD.44 On the contrary, in 494 patients of the Framingham cohort study, Janner et al46 reported that AIx and COPD were only weakly associated. Finally, brachial

artery compliance investigated by two-dimensional ultrasonography, pulsed Doppler echocardiography, the b-stiffness index, and the ankle-brachial index gave concordant information, showing a relationship with airflow obstruction45 and emphysema26 but with a noticeably weaker association than that provided by PWV.47 Finally, we note that measurements of arterial stiffness have also been reported in other chronic respiratory diseases, such as bronchiectasis and cystic fibrosis. Similarly to patients with COPD, one study using the AIx method suggested an increase in arterial stiffness in patients with bronchiectasis.63 On the other hand, in patients with cystic fibrosis, AIx was increased compared with control subjects but without a significant difference in PWV.64 This was observed for normal BP and was independent of diabetic status but associated with systemic inflammation.

Mechanisms of Elevated Arterial Stiffness in COPD Mechanisms leading to arterial stiffness have been extensively reviewed in the general cardiovascular literature,16,53,65,66 for chronic conditions such as kidney disease and metabolic diseases, and in sleep apnea syndrome.65,67-69 The main contributing factors consistently reported for arterial stiffness are aging, BP, metabolic disorders, chronic inflammation, and oxidative stress. Arteries (and more specifically, central arteries) stiffen with aging because of a degeneration of the media, an increase in collagen content, and dilation and hypertrophy of large arteries.70 Chronic elevated BP decreases vascular distensibility that changes mechanical vascular resilience, leading to an increase in pulsatile shear stress and pressure and, in turn, to endothelial dysfunction and vascular disease.71,72 Besides, the reduction in wall compliancy is likely to block key signaling pathways involved in this response, such as the nitric oxide (NO) pathway.73 In addition to structural alterations, the accumulation of advanced glycation end products (AGEs) can promote the development of arterial stiffness through impairment of endothelial function and promotion of inflammation.74 Chronic hyperglycemia and hyperinsulinemia increase the local activity of the renin-angiotensin-aldosterone system (RAAS) and expression of angiotensin type 1 receptor in vascular tissue, promoting the development of wall hypertrophy and fibrosis.75 Finally, genetic polymorphisms associated with increased arterial stiffening have been identified.76 Subsequently, vascular stiffening leads to structural and functional heart abnormalities by influencing the load imposed on the ventricles. The heart requires more energy for a given level of ejected flow that

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progressively induces cardiac hypertrophy.77 Another consequence is a decrease in heart perfusion due to increasing sensitivity of the coronary flow to the decline in systolic function.78 By influencing a number of these systemic factors, COPD may amplify the risk for cardiovascular events, and elevated arterial stiffness probably contributes to this risk69 (Fig 2, red arrows). Airway Obstruction and Hypoxia The severity of airway obstruction is consistently related to arterial stiffness in COPD18,33,34,36-39,43 (Table 1). In male ex-smokers, current smokers, and nonsmokers, Zureik et al33 reported that for every 195 ⫾ 50 mL decrease in FEV1, PWV increased by 2.5 m/s in an age- and height-adjusted analysis. Smoking is a classic risk factor for cardiovascular diseases. However, this risk is increased in smokers with COPD compared with smokers without airflow obstruction19,34 and more so in frequent COPD exacerbators as well as during the exacerbation.43 A possible mechanism explaining the additional effect of COPD on arterial stiffness, besides smoking itself, is hypoxia. Carotid-femoral PWV was significantly correlated with Pao2 in COPD, suggesting that significant hypoxemia leads to increased arterial stiffness.41 Chronic or intermittent hypoxia is frequently observed in COPD and is known to increase

systemic inflammation79 (and particularly IL-6 and CRP levels8,79), which has been linked to arterial stiffness and the occurrence of cardiovascular events in COPD.18,19 By stimulating proinflammatory cytokines and oxidative stress, hypoxia increases the production of cell adhesion molecules on the vascular endothelium, allowing circulating leukocytes to adhere to the vascular intima and augmenting the risk of atherosclerosis.65 Furthermore, alteration of cardiac autonomic function occurs, particularly in sedentary patients with COPD, and is related to Pao2.80 Alteration in the autonomic system leads to augmented heart rate and hemodynamic stress that consequently increase arterial stiffness. Finally, renal hormonal imbalance has been reported in COPD during hypoxic exacerbation as well as in normal subjects exposed to hypoxia.81 Activation of the RAAS by hypoxia would increase the collagen content of the extracellular matrix and promote vascular smooth muscle cell proliferation. Glomerular damage, evidenced by a heightened urinary albumin-to-creatinine ratio, is also related to increased aortic stiffness in COPD40 (Table 1). Emphysema The severity of emphysema has been found to be associated with arterial stiffness in COPD independently of airflow limitation, smoking, age, sex, BP,

Figure 2. Mechanisms by which arterial stiffness is increased in COPD. Black arrows show mechanisms leading to an increase in arterial stiffness previously demonstrated in the cardiovascular field. Red arrows show published data available in the COPD population. AGE 5 advanced glycation end product; CRP 5 C-reactive protein; I-cam 5 intercellular adhesion molecule-1; MF 5 macrophages; MMP 5 matrix metalloproteinase; NOS 5 nitric oxide synthase; ROS 5 reactive oxygen species; TGFB 5 transforming growth factor; TNFa 5 tumor necrosis factor-a; VSMC 5 vascular smooth muscle cell. (Adapted with permission from Zieman et al.65) 868

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dyslipidemia, inflammation, and hypoxemia, suggesting that a specific pathophysiologic mechanism links emphysema and arterial stiffness.18,26,37 An avenue for this mechanism is the inherited propensity for emphysema alongside arterial stiffness to develop in some patients with COPD. Increased systemic elastin degradation has been found in COPD, which is related to emphysema severity and arterial stiffness.39 The polymorphisms of gelatinase B (matrix metalloproteinase 9 [MMP-9]) stimulate the chemotactic agent that degrades the basement membrane (extracellular matrix). Changes in MMP-9 have been found in patients with emphysema, and serum levels of MMP-9 are increased in patients with COPD and arterial stiffness.18 It is likely that subjects with an emphysematous COPD phenotype have a systemic susceptibility to lung, skin, and arterial connective tissue damage.39 Inflammation and Oxidative Stress Systemic inflammation and oxidative stress are wellrecognized contributors to extrapulmonary features of COPD82 and have been suggested to be implicated in cardiovascular risk in patients with COPD.8 A correlation between arterial stiffness and systemic inflammation was found in four studies of COPD.18,19,22,42 CRP can interact with endothelial cells to simulate the production of IL-6 and endotheline-1 and alter NO production, contributing to the aforementioned endothelial dysfunction.30,31 Increased levels of IL-6 and TNF-a would increase expression of adhesion molecules on activated endothelium and facilitate the formation of atheromatous plaque. We should note that some studies20,21,35 failed to show a link between inflammation and arterial stiffness in COPD. Their results could be explained by the assessment techniques used, the targeted proteins,18 or, in some cases, the small number of inflammatory markers studied. The relationship between arterial stiffness and novel biomarkers of systemic inflammation and biochemical markers of cardiac dysfunction or respiratory exacerbation need to be further investigated in COPD.69 COPD Accelerates Aging and Facilitates the Occurrence of Comorbidities Increased arterial stiffness is part of the normal aging process.66 As expected, arterial stiffness measurements correlate with age in COPD, but COPD also appears to accelerate aging.69,83 Shorter telomeres, a marker of aging, are present in blood leukocytes from patients with COPD and in the lung cells of patients with emphysema.84 Furthermore, cellular senescence (cell cycle arrest) has been found to increase with the severity of inflammation in emphy-

sema. Moreover, endothelial cell senescence plays a role in atherosclerosis.85 Systemic complications of COPD may contribute to a premature aging effect on arterial stiffness.86 COPD is associated with sympathetic overactivation and decreased baroreflex sensitivity, which both can participate in raising BP.87 In turn, systemic hypertension stimulates excessive collagen production and intima-medial thickening in response to increased wall stress.65 Furthermore, an association between metabolic parameters (glycemia and cholesterolemia) and arterial stiffness has been observed in COPD.34,42 Chronic hyperglycemia may activate the RAAS and increase the expression of angiotensin type 1 receptor in vascular tissue, thus, promoting the development of arterial wall hypertrophy and fibrosis.75 Finally, the formation of AGEs in the blood resulting from hyperglycemia has been positively correlated with PWV.88 AGEs form irreversible cross-links within collagen, making it stiffer, reducing the elastic properties of cell matrix, and increasing inflammatory cytokines and oxidative stress.65 A relationship between arterial stiffness and BP or poor glucose regulation has been reported early in the disease process, long before the occurrence of established type 2 diabetes mellitus or cardiovascular diseases. Because there is growing evidence that COPD predisposes patients to metabolic syndrome,86 this mechanism and the role of elevated arterial stiffness should be studied further. Do Therapeutic Interventions in COPD Have an Impact on Arterial Stiffness? Current Literature and Future Research Directions To our knowledge, only four studies evaluated the effects of inhaled therapies or exercise training programs on arterial stiffness in COPD (Fig 3, Table 2). Furthermore, only one additional study investigated the acute effect of oxygen supplementation on arterial stiffness in COPD.90 Inhaled Treatments The effects of long-acting b-agonist (LABA) and inhaled corticosteroid (ICS) therapy on arterial stiffness in patients with COPD was first investigated in 2007 but only reported in abstract form.91 In this study, an 8-week fluticasone proprionate/salmeterol combination (FSC) treatment resulted in a decrease in arterial stiffness in patients with moderate to severe COPD associated with a reduction in mean arterial pressure and an increase in FEV1. This result was confirmed by another study showing that FSC reduces aortic PWV in a per-protocol analysis of patients with moderate to severe COPD (Fig 3A).22 The effects

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Figure 3. Effect of inhaled therapies on arterial stiffness in COPD. A, Respective effects of FSC () and placebo () on aPWV change from baseline. Data are presented as mean ⫾ SE. No statistical difference was observed between FSC and placebo at the end point (12 weeks) (P 5 .065). B, Effect of FSC on aPWV change from baseline, depending on tertile of baseline aPWV. Tertiles 1 (), 2 (), and 3 () were , 8.7, . 8.7 to ⱕ 10.9, and . 10.9 m/s at baseline, respectively. There was a statistical reduction in aPWV in tertile 3 (21.1 m/s, P 5 .05), suggesting a greater effect of inhaled therapies in patients with higher aPWV at baseline. aPWV 5 aortic pulse wave velocity; FSC 5 fluticasone propionate/salmeterol combination. See Figure 1 legend for expansion of other abbreviation. (Adapted with permission from Dransfield et al.22)

were greater and significant only in patients with elevated arterial stiffness at baseline (aortic PWV ⱖ 11 m/s, post hoc analysis) (Fig 3B). On the basis of this observation, this group89 recently demonstrated that both fluticasone furoate/vilanterol (another LABA/ICS combination) and tiotropium (a long-acting anticholinergic bronchodilator) produced a clinically relevant decrease in PWV (21 m/s)17 in patients with COPD with an aortic PWV . 11 m/s at baseline. The putative targets of reduction in arterial stiffness after drug treatment (FSC) are denoted by green arrows in Figure 4. b-agonists have previously been reported to reduce arterial stiffness through a systemic stimulation of endothelial NO synthase that improves vascular tone,92 whereas corticosteroids are known to inhibit multiple cell types and mediator production or secretion involved in low-grade inflammation that contributes to both atherosclerosis and arterial stiffness. However, the impact of ICS and LABA/ICS combinations on markers of systemic inflammation is subject to controversy,93 and their role in improving cardiovascular risk after therapeutic intervention in COPD deserves further investigation. Finally, one could suspect that an improvement in FEV1 may reduce the effect of lung hyperinflation, hypoxia, or both on arterial stiffness, although it has never been firmly established. Oxygen Supplementation The study of Bartels et al90 demonstrated acute changes in peripheral arterial stiffness after oxygen supplementation compared with room air in severe

COPD (Table 2). This result was found in parallel with greater baroreflex sensitivity following oxygen supplementation. The findings of this study suggest a protective effect of oxygen supplementation on vasomotor activity in severe and hypoxemic COPD, although this should be investigated further. Exercise Training and Rehabilitation We have previously demonstrated that arterial stiffness in patients with COPD could significantly improve after a short endurance training program 20 (Fig 5A, Table 2). Improvements in arterial stiffness were proportional to those in exercise capacity after training and were significantly related to changes in fasting glucose and BP. The magnitude of reduction in arterial stiffness was about 10%, which is comparable to the effects of classic cardiovascular medications, such as statins or anti-TNF-a treatment.94 In another study, aortic stiffness was improved following a 7-week standard multidisciplinary pulmonary rehabilitation program for patients with COPD21 (Fig 5B). The reduction in PWV was lower than in our study (9.3 ⫾ 2.7 m/s vs 9.8 ⫾ 3.0 m/s after vs before rehabilitation, respectively), but this could be explained by the level of PWV at baseline and by the intensity of training.95 In concordance with our study, the authors demonstrated that the reduction in systolic BP accounted for improvement in arterial stiffness. Finally, two studies suggested a significant link between functional capacity or physical activity and endothelial function.31,32 The small sample size is a limitation for these studies. Large randomized controlled trials should address

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COPD (n 5 70) Age: 63 ⫾ 9 y FEV1: 0.78 ⫾ 0.37 L BMI: 24 ⫾ 4 kg/m2

COPD (n 5 17) Age: 62 ⫾ 7 y FEV1: 1.32 ⫾ 0.48 L BMI: 23 ⫾ 5 kg/m2 COPD (n 5 32) Age: 65 (49-80) y FEV1: 0.99 ⫾ 0.39 L BMI: 25 ⫾ 6 kg/m2

COPD (n 5 260) with aPWV . 11 m/s Age: 64 y Postbronchodilator FEV1: 46% predicteda

COPD (n 5 14) free of overt CV disease Age: 66 ⫾ 8 y FEV1: 1.01 ⫾ 0.29 L COPD (n 5 249) Age: 56 ⫾ 15 y FEV1: 1.64 ⫾ 0.58 L BMI: 27 ⫾ 5 kg/m2

Population

Oxygen supplementation 31% vs CA crossover study

Rehabilitation outpatient based vs healthy subjects (n 5 20) 3 times/wk for 7 wk

Rehabilitation inpatient based (n 5 10) vs untrained COPD (n 5 7) 4 times/wk for 4 wk

FF/VI 100/25 mg vs TIO 18 mg for 12 wk

FSC vs placebo 250 mg bid for 12 wk

FSC vs placebo 500 mg/d for 4 and 8 wk

Intervention

AIx; BRS by R-R intervals

aPWV bPWV AIx

cbPWV

AIx aPWV

aPWV

aPWV; AIx

Markers

O2 vs CA: 13% ⫾ 6% vs 11% ⫾ 5% (P . .001) O2 vs CA: 3.5 ⫾ 2.3 ms/mm Hg vs 3.1 ⫾ 2.1 ms/mm Hg (P , .03)

20.5 m/s (25.3%) (P , .05) No effect

21.1 m/s (210%) (P 5 .001)

ITT: 20.42 m/s (P 5 .065) PP: 20.49 m/s (P 5 .045) In tertile 3 (PWV . 10.9 m/s): 21.1 m/s (P 5 .05) No effect FF/VI: 20.9 m/s (P 5 .0024) TIO: 21.1 m/s (P 5 .0006) No significant difference between the two treatments

22.2 m/s (P , .01); no effect

Main Resulta

Oxygen supplementation may modulate arterial stiffness.

Reduction in SBP and fasting glucose levels correlated to changes in PWV. Reduction in PWV proportional to the gain in exercise capacity. Reduction concomitant in SBP and in PWV.

Both classes of inhaled therapies were associated with clinically relevant decrease in PWV.

Greater effect seen in patients with higher aPWV at baseline.

Reduction in MAP and increase in FEV1 Time-dependent effect: results at 8 wk . 4 wk

Comments

Data are presented as mean ⫾ SD unless otherwise indicated. bPWV 5 brachial pulse wave velocity; BRS 5 baroreflex sensitivity, CA 5 compressed air; cbPWV 5 carotid-brachial pulse wave velocity; CV 5 cardiovascular; FF/VI 5 fluticasone furoate/vilanterol; FSC 5 fluticasone propionate/salmeterol combination; ITT 5 intention to treat; PP 5 per protocol analysis; TIO 5 tiotropium. See Table 1 legend for expansion of other abbreviations. aA reduction of 1 m/s in PWV is clinically significant.15

Oxygen therapy (acute effect, n 5 1) Bartels et al90/2004

Gale et al21/2011

Rehabilitation (n 5 2) Vivodtzev et al20/2010

Rubin et al89/2013

Dransfield et al22/2011

Inhaled therapies (n 5 3) Sabit et al19/2007

Study/Year

Table 2—Studies Investigating the Impact of Therapeutic Interventions on Arterial Stiffness in COPD

Figure 4. Putative targets of reduction in arterial stiffness after therapeutic interventions in COPD. Green arrows show published data available in the COPD population on the effect of inhaled therapies (fluticasone propionate/salmeterol, fluticasone furoate/vilanterol, and tiotropium), rehabilitation, and oxygen supplementation. See Figure 2 legend for expansion of abbreviations. (Adapted with permission from Zieman et al.65)

the effect of rehabilitation programs in COPD in terms of cardiovascular outcomes and impact on arterial stiffness. Mechanisms for the reduction in arterial stiffness after rehabilitation programs have been suggested in pilot studies (Fig 4, green arrows). The role of physical activity in improving arterial compliance has been demonstrated in healthy men.96 Exercise training, by

reducing basal sympathetic activity, enhancing vagal activity, and restoring baroreflex sensitivity,87 might decrease BP. Furthermore, shear stress during or immediately after bouts of exercise may stimulate NO production, leading to vasodilatation and reductions in BP and sympathetic drive.97 Finally, the positive effect of exercise on glucose regulation would reduce activation of the RAAS and prevent AGE formation,

Figure 5. Effect of rehabilitation on arterial stiffness in COPD. A, Respective effects of a 4-wk rehabilitation program () and control period () on carotid-brachial PWV in COPD. PWV was significantly reduced by 2 1.1 m/s ( 2 10%) in trained patients compared with untrained patients ( P 5 .001). (Reproduced with permission from Vivodtzev et al.20) B, Effect of a 7-wk rehabilitation program on aortic PWV and in BP in COPD. Both were significantly reduced after training (aortic PWV, P , .05; BP, P , .01). See Figure 1 legend for expansion of abbreviation. (Adapted with permission from Gale et al.21) 872

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Recent Advances in Chest Medicine

thus, limiting the alteration of arterial wall properties in COPD. Clinical Impact and Perspectives A large number of studies addressing arterial stiffness in COPD support the use of PWV for arterial stiffness measurements in clinical practice and as an objective and reproducible outcome for clinical trials. The recent consensus document published by the cardiology community on PWV measurements and reference values may help clinicians to standardize measurements and detect patients with abnormal values. Smoking and airflow limitation; systemic inflammation and hypoxia (that are amplified in COPD); premature comorbidities; and a systemic susceptibility to lung, skin, and arterial connective tissue damage all contribute to elevated arterial stiffness in COPD. The main message of this review is that we should consider the measurement of arterial stiffness during routine evaluations of patients with COPD with the goal of better risk stratification of multimorbidity in COPD. Nevertheless, additional studies are needed to establish the clinical impact of PWV measurement in patients with COPD. Moreover, PWV may be a useful and sensitive tool for assessing the impact of different types of therapeutic interventions in COPD. Combined therapeutic strategies associating exercise, antiinflammatory medications, and destiffening drugs need to be investigated in terms of their synergistic effects in reducing cardiovascular risk in patients with COPD. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Other contributions: The manuscript was critically edited by Alison Foote, PhD, with particular attention to English usage.

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91.

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Arterial stiffness in COPD.

In patients with COPD, cardiovascular diseases are the most common concomitant chronic diseases, a leading cause of hospitalization, and one of the ma...
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