Atherosclerosis 237 (2014) 381e390

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Review

“Inflammation and arterial stiffness in humans” Snigdha Jain a, Rohan Khera a, Vicente F. CorraleseMedina b, Raymond R. Townsend c, Julio A. Chirinos c, * a

University of Iowa Hospitals and Clinics, Iowa City, IA, USA University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada c University of Pennsylvania and Philadelphia VA Medical Center, Philadelphia, PA 19060, USA b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 July 2014 Received in revised form 15 September 2014 Accepted 16 September 2014 Available online 28 September 2014

Arterial stiffness is an established marker of cardiovascular morbidity and mortality and a potential therapeutic target. While hypertension and aging are established factors contributing to arterial stiffness, the role of inflammation in stiffening of the arteries is less well understood. We summarize existing literature regarding inflammation and arterial stiffness, including a discussion of the potential mechanisms by which inflammation may lead to arterial stiffening and studies assessing: (1) The association between subclinical inflammation and arterial stiffness in the general population; (2) The presence of increased arterial stiffness in primary inflammatory diseases; (3) The effect of anti-inflammatory therapy on arterial stiffness in primary inflammatory disease including the effect of statins; (4) Experimental evidence of immunization-induced arterial stiffening in normal adults. We discuss potential opportunities to assess the impact of anti-inflammatory interventions on arterial stiffness in subjects without primary inflammatory conditions. We also review the effect of inflammation on wave reflections. Published by Elsevier Ireland Ltd.

Keywords: Arterial stiffness Inflammation Pulse wave velocity Cardiovascular risk

Contents 1. 2. 3.

4. 5. 6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Potential mechanisms of inflammation-induced arterial stiffening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Association between inflammation and arterial stiffness in subjects with hypertension and in the general population . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.1. Cross sectional studies (Table S5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.2. Prospective studies (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Studies evaluating arterial stiffness in patients with primary inflammatory disorders (Table S6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Effect of anti-inflammatory treatment on arterial stiffness in patients with primary inflammatory disorders (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Effect of statins on arterial stiffness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Experimental studies in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Source of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conflict(s) of interest/disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1. Introduction

* Corresponding author. E-mail address: [email protected] (J.A. Chirinos). http://dx.doi.org/10.1016/j.atherosclerosis.2014.09.011 0021-9150/Published by Elsevier Ireland Ltd.

Arterial stiffness is an important arterial phenotype and an independent predictor of cardiovascular disease [1]. Arterial stiffness impairs the ability of arteries to accommodate the blood ejected by the left ventricle, resulting in excessive pulsatile afterload that may promote left ventricular remodeling, dysfunction and failure [2]. By

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virtue of its effect on pressure and flow pulsatility, large artery stiffening appears to promote target organ damage through penetration of pulsatile energy into peripheral target organs such as the kidney and brain [3]. Arterial stiffness is therefore important not only as a surrogate marker of cardiovascular risk, but also because of its pathophysiological consequences. Carotid-femoral pulse wave velocity (cfPWV), the established gold-standard measure of aortic stiffness, predicts cardiovascular outcomes in the general population and in patients with kidney disease, hypertension and diabetes mellitus [4e8]. Augmentation index (AIx), often reported along with indices of arterial stiffness, is a measure of the contribution of wave reflections to the rise in central systolic and pulse pressure. AIx and cfPWV can demonstrate divergent trends with aging and

inflammation (as discussed later in this article) [9] and should not be considered interchangeable. The pathophysiological implications of arterial stiffness on cardiovascular disease have led to its emergence as a potential target for therapeutic interventions. However, the design of effective interventions to reduce large artery stiffness requires a clearer understanding of the mechanisms that lead to arterial remodeling and stiffening. In this context, chronic subclinical inflammation is an important and potentially treatable process that may contribute to arterial stiffening. The role of inflammation in the pathogenesis of atherosclerosis is well known [10]. However, by virtue of its effect on the arterial medial layer, inflammation can also contribute to increased arterial wall stiffness. Herein, we aimed at building on

Fig. 1. Possible mechanisms by which inflammation may induce short-term functional effects influencing arterial stiffness. NO e Nitric oxide, iNOS e Inducible nitric oxide synthase, eNOS e Endothelial nitric oxide synthase, NADPH e Nicotinamide adenine dinucleotide phosphate, BH4 e Tetrahydrobiopterin, an essential cofactor the eNOS enzyme, O2 e Superoxide ion, O2 e Oxygen, H2O2 e Hydrogen peroxide, MPO e Myeloperoxidase, TNF-a-Tumor necrosis factor a, IL-1- Interleukin 1, IL-6-Interleukin 6, ROS e Reactive oxygen species.

S. Jain et al. / Atherosclerosis 237 (2014) 381e390

previews reviews [4,11,12] regarding the association between inflammation and arterial stiffness and addressing the following specific issues: (1) Potential mechanisms of inflammation-induced arterial stiffening; (2) The association between inflammation and arterial stiffness in subjects with and without primary inflammatory conditions, including prospective studies in the general population; (3) The effect of anti-inflammatory therapy on arterial stiffness in patients with primary inflammatory disorders and the effects of statins on arterial stiffness; (4) Experimental studies in humans. Our methodology and comprehensive literature search strategy are summarized in the Supplemental Online Section. 2. Potential mechanisms of inflammation-induced arterial stiffening Multiple potential mechanisms have been suggested by which inflammation could have an effect on arterial stiffness. Some of these mechanisms could induce rapid changes in the stiffness of large arteries through functional effects on the arterial endothelium or smooth muscle cells (Fig. 1), thus explaining the effect of acute inflammation on large artery stiffness [13]. However, a variety of mechanisms can also link chronic low-grade inflammation with structural changes in the arterial wall (Fig. 2). Although the latter

383

mechanisms are likely more relevant to the structural degeneration that characterizes large artery stiffening in aging and disease, this is not an absolute distinction, as acute and chronic inflammatory pathways are likely interconnected in their effects on the arterial wall. A key molecule responsible for endothelial dysfunction is nitric oxide (NO). This has been shown to increase distensibility of not only muscular arteries but also large vessels in vivo [14] and inhibition of basal NO synthesis has been shown to increase cfPWV and AIx suggesting an influence on both arterial stiffness and wave reflections [15,16]. Inflammatory cytokines impair vasodilatory responses by affecting NO production, while the reactive oxygen species generated in the inflammatory process further consume existing NO [17]. Cytokines, including TNF-a and IL-1, decrease the half-life of mRNA coding the constitutive endothelial NO synthase [18] (eNOS, mainly involved in regulating vascular tone), inhibit eNOS activation in response to receptor dependent agonists, and increase the expression of inducible NO synthase (iNOS, mainly involved in the oxidative burst in macrophages), which further inhibits eNOS activity [17]. These inflammatory cytokines also drive the production of arginase, which diverts arginine, the substrate for eNOS, to a different pathway. Moreover, they activate NADPH oxidase, promoting oxidization of tetrahydrobiopterin (BH4), a key co-

Fig. 2. Potential mechanisms by which inflammation can induce structural changes in the vessel wall contributing to increased vascular stiffness. Mf e Macrophage, CRP: C reactive protein, ROS: Reactive oxygen species, O2
: Superoxide, H2O2: Hydrogen peroxide, Akt/PKB: Serine threonine kinase/Protein kinase B SMC: Smooth muscle cell, MMP: Matrix metalloproteinases, TIMP: Tissue inhibitor of matrix metalloproteinases, BM: Basement membrane, ECM: Extracellular matrix, PO3
4 : Phosphate, GAG: Glycosaminoglycan, TNF-a: Tumor necrosis factor a, IL-1: Interleukin-1.

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factor for eNOS [19]. In the absence of its substrate and cofactor, eNOS is uncoupled. Hypochlorous acid generated by the catalytic enzyme myeloperoxidase, released by activated neutrophils, further contributes to this uncoupling by combining with NO to generate reactive nitrogen species that oxidize the zinc thiolate center of eNOS [19,20]. C-reactive protein has also been shown to directly decrease eNOS expression, thus decreasing NO production [21]. The activation of NADPH oxidase by inflammatory cytokines as previously mentioned, also creates a milieu of increased oxidative stress that influences endothelial function through mechanisms other than NO. Superoxide and hydrogen peroxide stimulate mitogen activated protein kinases, specifically, serine threonine kinase/protein kinase B (Akt/PKB), leading to hypertrophy and increased survival of vascular smooth muscle cells [22] and trigger matrix metalloproteinases (MMP), the effects of which are discussed below [23]. Vascular superoxide production has been shown to correlate with aortic compliance [24], augmentation index [13] and endothelial reactivity [25,26]. Vascular NADPH oxidase activity has also been shown to negatively impact vasomotor response to endothelium-dependent agonists [26]. Inflammation may induce structural changes in arterial wall through the breakdown of elastin, proliferation of smooth muscle cells, and changes in the composition of the extracellular matrix [27e30]. Fragmentation of elastin in the lamellae of the medial arterial layer is characteristic of arterial aging and leads to greater transfer of load to the less compliant collagen fibers. Although elastin fracture has long been regarded as a passive phenomenon from repeated pulsations, it can also result from the action of proteolytic enzymes with “elastase-like” activity, some of which are released and activated during inflammatory responses. Some matrix metalloproteinases (MMPs), like MMP-2, are produced constitutively by endothelial cells and smooth muscle cells but their enzymatic activity is not significant, due to the counterbalance of tissue inhibitors of metalloproteinases (TIMPs). Inflammation alters this equilibrium by a few mechanisms. Reactive oxygen species activate latent MMPs and degrade TIMPs. Macrophages and neutrophils, under the influence of inflammatory cytokines, produce MMP- 1 (collagenase), MMP-9 (gelatinase), MMP-7 (matrilysin) and MMP-7 (elastase) [31,32] and these enzymes disrupt the cross linking of collagen and elastin and result in the accumulation of stiffer, uncoiled collagen. MMP-9 levels have been shown to increase in association with PWV in acute inflammation induced by vaccination with Salmonella typhi antigen [13]. MMP 2, 9 and serum elastase were also found to correlate positively with aortic PWV in high-risk hypertensive individuals [33]. However, MMP-2 and MMP-9 were shown to be inversely associated with PWV in a healthy low-risk population with low inflammatory burden (as evidenced by serum hsCRP) [34]. Lysyl oxidase (LOX) is another enzyme that is essential to maintain the tensile and elastic features of blood vessels and its deficiency has been implicated in atherosclerosis, fragmentation of elastic fibers and alterations in endothelial cell characteristics [35]. Rodriguez et al. recently demonstrated that TNF-a down-regulates LOX levels providing another possible mechanism by which inflammatory cells can alter structural composition of the vessel wall [36]. Inflammatory processes can also induce changes in the structure of proteoglycans and up-regulate the synthesis of glycosaminoglycans such as versican and hyaluronan. Hyaluronan traps water and swells, forming a gel that allows ECM to resist compression forces, thus making the arterial wall stiffer [4]. There is also evidence that inflammation promotes calcification of the vessel wall by inducing an osteogenic phenotype in smooth muscle cells (SMCs), increasing expression of osteoblast markers and downregulating fetuin-A, an inhibitor of vascular calcification [37].

3. Association between inflammation and arterial stiffness in subjects with hypertension and in the general population 3.1. Cross sectional studies (Table S5) Several studies have assessed the association between cfPWV and various inflammatory markers. Table S5 summarizes 30 studies that have addressed this issue. In the largest available study assessing cfPWV, Schnabel et al. reported an association between interleukin-6 (IL-6) and cfPWV in the Framingham Offspring cohort [38]. An association between CRP and cfPWV was observed in studies on Caucasian middle-aged [39] and older individuals [40] with low burden of cardiovascular risk factors as well as hypertensive adults. Interestingly, large studies in Chinese and black South-African populations have failed to show an association between CRP and cfPWV, suggesting that race/ethnicity may modulate this relationship. Studies assessing the brachial-ankle PWV (baPWV), on the other hand, have been more consistently positive in describing an association with CRP and white blood cell count, although most data to date derives from Asian populations. A significant association between CRP with peripheral pulse pressure has also been described in both Caucasian and African-American adults. CRP was also found to be associated with central pulse pressure in healthy European but not in South African blacks. Evidence regarding the association of inflammatory markers with augmentation index is more conflicting. While two studies on the Framingham Offspring cohort by Schnabel et al. [38] and Lieb et al. [41] found CRP to be associated with reflected pressure wave and augmented pressure respectively, they did not study AIx as a parameter. In the subgroup of hypertensives, Yasmin et al. [39] and Pietri et al. [23] found no correlation of CRP with AIx despite showing an association with cfPWV. Multiple studies, however, described a significant association of CRP with augmentation index even after adjustment for mean arterial pressure (MAP). IL-12 and IL-18 have also been associated with arterial stiffness in adults with low cardiovascular risk.

3.2. Prospective studies (Table 1) While cross sectional studies generally support an association between inflammatory biomarkers and arterial stiffness, they cannot be used to assess whether inflammation precedes arterial stiffening, as would be expected if a causeeeffect relationship exists between inflammation and arterial stiffness. Five prospective studies assessing the association between inflammatory markers and arterial stiffness have been reported so far and their results have been conflicting. The Whitehall study found baseline CRP, IL-6, IL-1Ra and fibrinogen to be significantly associated with cfPWV measured 10 years later [42]. Similarly, the Caerphilly study demonstrated a significant relationship between baseline CRP values and cfPWV measured 20 years later [43]. However, three other prospective studies over shorter follow up periods, ranging from 1 to 6 years, did not find inflammatory markers at baseline to be associated with stiffness measures [44e46]. All five studies performed adequate adjustments for cardiovascular risk factors and mean arterial pressure. One possible explanation for this discrepancy is that the effect of inflammation in arterial stiffness requires long exposure intervals and thus, only the Caerphilly and Whitehall studies had follow-up periods long enough to detect it. However, both of these large studies lacked baseline cfPWV values, precluding an assessment of whether the change in cfPWV over time is related to ongoing inflammation.

Table 1 Prospective studies evaluating the correlation of inflammatory markers with arterial stiffness and wave reflections in subjects without primary inflammatory diseases. Biomarkers

Disease status and ethnicity

Mean age

N (% males)

cfPWV

AIx

Other indices

Variables adjusted for

Johansen et al. (2012) [42] 10 year follow up

CRP IL-6

Occupational cohort excluding subjects with coronary heart disease and known diabetes. Caucasian

48

3769 (76)

Men CRP: b ¼ 0.13, 95% CI ¼ 0.07 e0.19, P < 0.0001 IL-6: b ¼ 0.28, 95% CI e 0.15 e0.40; P < 0.0001 IL-1Ra: b ¼ 0.46, 95% CI e 0.22e0.70, P < 0.01 Fibrinogen: b ¼ 0.33, 95% CI ¼ 0.19e0.48, P < 0.0001 Women CRP: b ¼ 0.14, 95% CI ¼ 0.04 e0.25, P < 0.01 IL-6: b ¼ 0.23, 95% CI
0.03 e 0.43, P > 0.05 IL-1Ra:b ¼ 0.42, 95% CI
0.08e 0.75, P < 0.01 Fibrinogen: b ¼ 95% CI ¼ 0.04e0.44, NS CRP:b ¼ 0.021, P ¼ 0.170

e

e

Age, quadratic age, BMI, MAP, diabetes, cholesterol, antihypertensive use, lipid lowering treatment, coronary heart disease events

e

e

CRP:b ¼ 0.35, CI ¼ 0.12 e0.57, P ¼ 0.002 Fibrinogen: b ¼ 0.07, CI ¼
0.16e0.30, P ¼ 0.53(NS) CRP: b ¼
0.074, CI ¼
0.37 e0.24, P ¼ 0.626 (NS)

CRP: b ¼ 0.29, CI ¼
0.39 e0.96, P ¼ 0.41(NS) Fibrinogen: b ¼ 0.78, CI ¼ 0.08e1.47, P ¼ 0.03

e

Age, sex, BMI, mean BP, heart rate, cholesterol, glucose, medication use for cardiovascular disease, change in all these factors over follow up period Age, MAP, heart rate, vasoactive drug use

e

Distensibility coefficient (carotid artery)

IL-1Ra

Tomiyama et al. (2010) [46] 5e6 years

CRP

Occupational cohort (asymptomatic) of smokers in Japan

41

2054 (80)

McEniery et al. (2010) [43]

CRP

Population based cohort, Caucasian

56

825 (46)

20 year follow up

Fibrinogen

Van Bussel et al. (2011) [44] 6 year follow up

Healthy adults. Ethnicity not reported

37

293 (47)

Jae et al. (2012) [45]

CRP SAA IL-6 IL-8 TNF-a sICAM-1 WBC

1-year follow up

CRP

Fibrinogen

Age, sex, height, MAP

b ¼
0.91, CI ¼
1.81 to
0.008, P ¼ 0.048 Healthy Koreans

53

107 (100)

e

e

baPWV Baseline: WBC: R ¼ 0.19, P < 0.05 CRP: R ¼ 0.06, P ¼ 0.56 Fibrinogen: R ¼ 0.12, P ¼ 0.21 Follow up: WBC: R ¼ 0.18, P ¼ 0.06 CRP: R ¼ 0.05, P ¼ 0.62 Fibrinogen: R ¼ 0.07, P ¼ 0.46 Multivariate analysis: none were associated with change in cfPWV

S. Jain et al. / Atherosclerosis 237 (2014) 381e390

Study

BMI, HbA1C, product of heart rate and pulse pressure, MAP

Studies have been arranged in the descending order of sample size. PWV- Pulse Wave Velocity, cfPWV eCarotid-Femoral Pulse Wave Velocity, baPWV- Brachial ankle Pulse Wave Velocity, AIx- Augmentation Index, MAP- Mean Arterial Pressure, SBP- Systolic blood pressure, DBP-Diastolic blood pressure, BMI e Body mass index, CRP- C-Reactive Protein, IL-1 e Interleukin-1 receptor a, IL-6-Interleukin-6, IL-8 e Interleukin 8, IL-12-Interleukin 12, IL-18Interleukin 18, TNF-a-Tumor Necrosis Factor- a, TNF- R II-Tumor Necrosis Factor Receptor II, WBC e White blood cell count, MMP-2-Matrix Metalloproteinase 2, SAA e Serum amyloid A, sICAM-1-Soluble Intercellular Adhesion molecule.

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4. Studies evaluating arterial stiffness in patients with primary inflammatory disorders (Table S6) A causeeeffect relationship between inflammation and arterial stiffness would be expected to cause increased stiffness in patients with primary inflammatory diseases. Several small cross-sectional studies have compared arterial stiffness indices in patients with inflammatory disorders against normal controls. We reviewed 36 such studies, including patients with various inflammatory conditions such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus, systemic sclerosis, polymyalgia rheumatica, sarcoidosis, psoriasis, inflammatory bowel disease, autoimmune gastritis and familial Mediterranean fever. As shown in Table S6, cfPWV was found to be significantly greater in these patients in most studies, even after adjustment for mean arterial pressure and other cardiovascular risk factors [47e49], or after exclusion of patients with traditional cardiovascular risk factors [50,51]. A similar situation was found for augmentation index, with most studies reporting a significantly higher AIx in patients with inflammatory conditions as compared to controls, with or without adjustment for MAP and cardiovascular risk factors [49]. Only 3 studies [47,52,53] found AIx not to be associated with disease status. Interestingly in 2 of these studies cfPWV [47] and carotid stiffness [53] was associated with disease status. A possible explanation for this observation is that the concomitant stiffening of large and medium sized arteries in these patients causes minimal changes in wave reflections (which depend on impedance mismatch between proximal and distal arterial segments), leading to the absence of changes in AIx despite significant changes in cfPWV. Studies reporting other measures such as arterial stiffness index, distensibility, carotid artery compliance and baPWV also found increased stiffness in patients with inflammatory disease with the exception of two small studies. Therefore, overall, the weight of the evidence is heavily in favor of increased arterial stiffness in patients with primary inflammatory diseases.

Mathieu et al. (other studies in RA patients were between 6 and 24 weeks). In patients with polymyalgia rheumatica, reduction in cfPWV [67] and AIx [68] has been reported after treatment with prednisone. This is notable given the contrary influence of steroids on other cardiovascular risk factors such as glycemic control and blood pressure and suggests that the influence of inflammation may actually be stronger than these factors on arterial stiffness. Improvement in both these parameters has also been reported in RA patients treated with anti-TNFs in combination with prednisone; however, the independent effect of steroid treatment in this disorder has not been studied [58,61]. Therefore, as shown in Table 2, currently available evidence support a beneficial effect of anti-inflammatory therapy (especially with anti-TNF agents), on arterial stiffness in patients with primary inflammatory diseases, although some data from smaller studies is conflicting.

6. Effect of statins on arterial stiffness Several studies have reported a beneficial effect of statins in reducing arterial stiffness. Five randomized, controlled trials in patients with hyperlipidemia [69e73] and one in stable coronary heart disease patients [74] reported a significant reduction in cfPWV [69,71,74] and baPWV [70,72,73] after treatment with statins for periods between one month to 5 years after statin therapy, compared to placebo, low-fat diet or other cholesterol-lowering agents. Three other trials in obese adults [75], hypertensive adults [76] and patients with RA [77] also reported a significant reduction in cfPWV [75,77] or systemic arterial compliance [76]. One small (n ¼ 23) trial that followed hypertensive patients for 12 weeks reported a slight increase in cfPWV and this was attributed to initial changes in stiffness after inducing reductions in lipid levels [78]. Trials in chronic kidney disease patients have been less conclusive, although they describe a trend in the same direction [79,80]. Other prospective studies with [81e84] or without [85e89] a control group also support an effect of statins on arterial stiffness.

5. Effect of anti-inflammatory treatment on arterial stiffness in patients with primary inflammatory disorders (Table 2) Three randomized, placebo-controlled trials evaluated the effect of biologic anti-inflammatory agents on arterial stiffness in patients with rheumatoid arthritis (RA). Tam et al. [54] and Wong et al. [55] both reported significant reduction in PWV after 6 months and about 1 year of treatment, respectively, with anti-TNFa agents in combination with methotrexate but not with methotrexate alone. Kume et al. found both tocilizumab (an IL-6 receptor antagonist) and anti-TNF agents to be equally effective in reducing cardiac ankle-vascular index after 24 weeks of therapy [56] while McInnes et al. found tocilizumab to not reduce PWV significantly after 12 weeks [57]. Among other prospective studies evaluating the effect of antiinflammatory agents, many studies reported a significant improvement in either PWV [58,59] or AIx [56,60,61] after treatment with TNF-a antagonists with or without other agents. However, therapy with abatacept, an immunoregulatory fusion protein, in patients with RA was associated with an increase in cfPWV although in this study an objective decrease in inflammation was not noted [62]. Moreover, two small, uncontrolled studies in RA patients [63,64] and two studies done in AS patients [65,66] did not find a significant improvement in cfPWV or AIx with use anti-TNF agents for 6e52 weeks. Possible explanation include insufficient power to detect a difference (sample sizes 14 and 49 respectively) or the relatively short duration of therapy except for the study by

7. Experimental studies in humans A few experimental studies have been conducted so far to allow assessment of the direct cause and effect relationship between inflammation and arterial stiffness. Vlachopoulos et al., in a randomized, sham-controlled study on healthy humans, found a significant increase in cfPWV (by 0.43 m/sec) after vaccination with S. typhi [13]. This was accompanied by an increase in inflammatory markers (CRP and IL-6) and interestingly, a reduction in AIx (which may suggest changes in wave reflections or ventricular contraction). Jae et al. reported similar results in older adults after influenza vaccination with an increase in cfPWV but no change in AIx [90]. Attenuation of this effect was also observed after pretreatment with statins, with no observable rise in cfPWV after S. typhi vaccination in such subjects in contrast to a significant rise in cfPWV in the placebo group [91]. Therefore, while studies on subjects with chronic inflammation have mostly reported either an increase or no change in AIx despite an increase in PWV, acute inflammation seems to be associated with a fall in AIx, despite an increase in large artery stiffness. A possible explanation for this finding is that AIx is mostly a marker of wave reflections. Selective stiffening of large arteries may result in reductions in the impedance mismatch with more distal arterial segments, which may reduce wave reflections, and therefore, AIx.

Table 2 Studies assessing the effect of anti-inflammatory treatment on arterial stiffness and wave reflections in patients with primary inflammatory disorders. Study (year)

McInnes et al. (2013) [57]

Type of study

Auto immune Anti e disease Inflammatory agent(s) studied

Treatment group n

Treatment received

Control group Change in index of arterial stiffness

n

Treatment duration Statistical significance

Treatment received Change in index of arterial stiffness

RA

Tocilizumab

69 Tocilizumab þ Methotrexate

cfPWV:
0.17

59 Placebo þ Methotrexate

cfPWV:
0.47

24 weeks

PWV:P ¼ 0.3042

AS

Infliximab, Etanercept, Adalimumab

cfPWV: þ0.04 AIx:
0.8%

e

Not present

12 months

PWV: P ¼ 0.64 AIx: P ¼ 0.87

cfPWV:
0.54 ± 0.79 (P < 0.001)

19 No anti-TNF drugs. cfPWV:
0.06 ± 0.61 prednisolone/ (P ¼ 0.66) methotrexate/ sulfasalazine

12 months

PWV: P ¼ 0.004

AIx@75: þ2.6%

e

Not present

Not present

7 weeks

AIx@75: P ¼ 0.03

Angel et al. (2012) [59]

Prospective, controlled

RA, AS, PsA

Infliximab, Etanercept, Adalimumab

Pieringer et al. (2010) [60] Mathieu et al. (2013) [62] Schillaci et al. (2012) [67] Capkin et al. (2012) [66]

Prospective, uncontrolled Prospective, uncontrolled Prospective, uncontrolled Prospective, uncontrolled

RA, AS

Infliximab

49 Infliximab (6), Etanercept (26), Adalimumab (17) 36 Infliximab (9), Etanercept (17), Adalimumab (10) 30 Infliximab

RA

Abatacept

21 Not present

cfPWV: þ1.3

e

Not present

Not present

24 weeks

CFPWV: P ¼ 0.02

PMR

Prednisone

29 Prednisone

e

Not present

Not present

4 weeks

AS

Infliximab, Etanercept, Adalimumab

cfPWV:
1.3 AIx @75:
5% cfPWV:
0.2 AIx @75:
10%

e

Not present

Not present

24 weeks

Galarraga et al. (2009) [61]

Prospective, uncontrolled

RA

Etanercept

21 Methotrexate

AIx@75:0 (P ¼ 0.971)

4 months

Ikonomidis et al. (2008) [93]

Prospective, controlled

RA

Anakinra

28 Infliximab (8), Etanercept (13), Adalimumab (7) AIx@75:
2.5% 26 Etanercept ± other DMARDs/ (P ¼ 0.025) prednisone 23 Anakinra cfPWV ¼ þ0.1 (P ¼ 0.7)

PWV: P ¼ 0.015 AIx@75: P ¼ 0.012 PWV: P ¼ 0.412 AIx: P ¼ 0.177

19 Prednisolone

cfPWV ¼
0.2 (P ¼ 0.7)

Kume et al. (2011) [56]

Open label, RCT RA

Tocilizumab

22 Tocilizumab

CAVI:
0.85 (P ¼ 0.02) AIx@75:
3.59% (P ¼ 0.03)

Not present

42 Etanercept (21)

Adalimumab (21)

Tam et al. (2012) Randomized, [54] prospective, open-label Maki-Petaja et al. Non(2012) [58] randomized, prospective, open-label

RA

Infliximab

20 Infliximab þ Methotrexate

baPWV:
0.78 ± 1.13 20 Methotrexate

RA

Etanercept, Adalimumab

cfPWV:
0.46 AIx:
2%

Wong et al. (2009) [55]

RA

Infliximab

17 Etanercept (5) Adalimumab (12) þ DMARDs ± Prednisolone 17 Infliximab þ Methotrexate

RA

Infliximab

Komai et al. (2007) [64]

Randomized, placebocontrolled, double blind Prospective, uncontrolled

15 Infliximab

cfPWV: P ¼ 0.004 AIx@75: P ¼ 0.267 cfPWV: NS P value not quoted

e

Not present

9 Methotrexate

e

Not present

30 days of prednisone vs single shot of anakinra CAVI:
0.81 ± 0.18 (P ¼ 0.03) 24 weeks AIx@75:
1.03%±0.44% (P ¼ 0.03) CAVI:
0.90 ± 0.21 (P ¼ 0.02) AIx@75:
3.54% ± 0.52% (P ¼ 0.02) baPWV: 0.18 ± 1.59 6 months

Not specified

P not specified

S. Jain et al. / Atherosclerosis 237 (2014) 381e390

Mathieu et al. (2013) [65]

Randomized, double-blind, placebo controlled trial Prospective, uncontrolled

CAVI: P > 0.05 AIx@75: P > 0.05

BaPWV: P ¼ 0.044

Not present

8 weeks

CFPWV: P ¼ 0.04 AIx: P ¼ 0.4

All subjects entered treatment arm after 14 weeks (P n/a)

54 weeks

Multivariate analysis: Coefficient for CFPWV ¼
0.03 ± 0.01, P < 0.001

Not present

6 weeks

NS 387

(continued on next page)

Studies have been arranged in descending order of sample size of patients in the intervention group. RA- Rheumatoid arthritis, PsA- Psoriatic arthritis, AS- Ankylosing spondylitis, PMR e Polymyalgia rheumatic, DMARDs e Disease modifying anti-rheumatic drugs, PWV- Pulse Wave Velocity, cfPWV- Carotid-femoral pulse wave velocity, CAVI: Carotid Ankle Vascular Index, AIx@75 e Augmentation Index at heart rate 75 beats per minute, AIx e Augmentation index.

PWV: P < 0.001 6 months RA

Tocilizumab

PMR

Prospective, uncontrolled Nonrandomized, prospective, controlled.

Infliximab Etanercept Adalimumab Prednisone RA Prospective, uncontrolled

Van Doornum et al. (2005) [63] Pieringer et al. (2008) [68] Protogerou et al. (2011) [94]

Not present e cfPWV:
1.2 11 Tocilizumab

Not present

4 weeks Not present e AIx:e3.2%

Not present

AIx: P ¼ 0.504 6 weeks Not present Not present e AIx:
1%

14 Infliximab Etanercept Adalimumab 13 Prednisone

Treatment received Change in index of arterial stiffness n Change in index of arterial stiffness n

Treatment received

Control group Treatment group

Auto immune Anti e disease Inflammatory agent(s) studied Type of study Study (year)

Table 2 (continued )

AIx: P ¼ 0.006

S. Jain et al. / Atherosclerosis 237 (2014) 381e390

Treatment duration Statistical significance

388

8. Conclusions and future directions There are multiple potential mechanisms by which inflammation can influence arterial stiffness. Several studies in the general population reveal an association between inflammatory biomarkers and arterial stiffness. Although the results of crosssectional studies have been inconsistent, two recent large prospective studies support an association between baseline inflammation and cfPWV measured several years later. However, these studies did not repeated measurements of PWV to assess its rate of change. Clearly, more studies are needed to assess the association between ongoing inflammation and increase in PWV over time, and whether this association is independent of other cardiovascular risk factors or restricted to specific subpopulations. In addition, studies including younger populations and those specifically assessing the ascending aorta may be informative regarding the role of inflammation earlier in life, since ascending aortic stiffening appears to precede stiffening or other arteries during aging [92]. However, given the relatively slow and variable changes in the stiffness of large arteries over time, large population studies with repeated measures and relatively long follow-up periods will be required to better address this issue. Multiple studies have shown elevated indices of arterial stiffness in subjects with primary inflammatory disorders and prospective studies (including 2 RCTs) [13] have generally demonstrated reductions in arterial stiffness following treatment with anti-TNF and other anti-inflammatory agents. However, at this time, there is not enough evidence to support the use of immunosuppressive agents for the purpose of cfPWV reduction. It is noteworthy that the association of wave reflection measures with inflammation has not been as consistent as aortic stiffness in the general population or in subjects with primary inflammatory diseases. As discussed previously, this could be due to a more selective impact of inflammation on large arteries, resulting in decreased impedance mismatch and reduced peripheral wave reflection. An important question to address is whether low-grade subclinical inflammation can be targeted in adults without primary inflammatory conditions to reduce arterial stiffening. Although RCTs designed specifically for this purpose are unlikely to take place in the foreseeable future, ongoing RCTs of anti-inflammatory therapy for the secondary prevention of cardiovascular events (such as the Cardiovascular Inflammation Reduction Trial, CIRT), may offer unique opportunities to assess the effect of randomized anti-inflammatory therapy on arterial stiffness in adults without inflammatory disease. Source of funding This work was supported by NIH grant 1R21AG043802 (JAC). Conflict(s) of interest/disclosures None. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2014.09.011. References [1] Laurent S, Boutouyrie P, Asmar R, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37(5):1236e41. [2] Kelly RP, Tunin R, Kass DA. Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ. Res. 1992;71(3):490e502.

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