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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 17  |  Issue : 2  |  Page : 157-165

Arterial stiffness in rheumatoid arthritis: Current knowledge and future perspectivess


1 Second Medical Department, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
2 Fourth Department of Internal Medicine, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
3 Department of Rheumatology, Russells Hall Hospital, Dudley Group NHS Foundation Trust, Dudley; School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK

Date of Submission01-Nov-2021
Date of Acceptance12-Nov-2021
Date of Web Publication21-Apr-2022

Correspondence Address:
Dr. Theodoros Dimitroulas
Fourth Department of Internal Medicine, Hippokratio Hospital, 49 Konstantinoupoleos Street, 54642 Thessaloniki
Greece
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_254_21

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  Abstract 


Rheumatoid arthritis (RA) is characterized by the excess cardiovascular risk that remains essentially unaltered despite current medical advances. The introduction of reliable markers towards early identification and subsequently effective management of high-risk patients with RA are urgently needed. Arterial stiffness represents an early indicator of cardiovascular morbidity and mortality and has emerged as a surrogate marker of cardiovascular disease. From a pathophysiological perspective, it is significantly accelerated by the accumulation of cardiovascular risk factors and is considered an intermediate process towards the development and progression of atherosclerotic cardiovascular disease. The aim of this review is to critically upraise current knowledge on arterial stiffness in patients with RA. Although not all studies concur, increased Pulse Wave Velocity (PWV) has been repeatedly reported in patients with RA. However, results need to be interpreted with caution as most studies enrolled patients with multiple cardiovascular risk factors and/or established cardiovascular disease, or with uncontrolled RA with high levels of systemic inflammation. Whether and to which extent increased arterial stiffness among patients with RA is associated with the disease per se, or rather represents the composite effect of hypertension and other classical cardiovascular risk factors, warrants further investigation. The impact of antirheumatic drugs on arterial stiffness is also discussed. Considering the well-established predictive value of increased PWV both in the general population and patients at high cardiovascular risk, future studies need to focus on the clinical utility of this surrogate risk marker specifically in patients with RA.

Keywords: Arterial stiffness, cardiovascular risk, pulse wave velocity, rheumatoid arthritis


How to cite this article:
Anyfanti P, Bekiari E, Angeloudi E, Pagkopoulou E, Kitas GD, Dimitroulas T. Arterial stiffness in rheumatoid arthritis: Current knowledge and future perspectivess. Indian J Rheumatol 2022;17:157-65

How to cite this URL:
Anyfanti P, Bekiari E, Angeloudi E, Pagkopoulou E, Kitas GD, Dimitroulas T. Arterial stiffness in rheumatoid arthritis: Current knowledge and future perspectivess. Indian J Rheumatol [serial online] 2022 [cited 2022 Jul 4];17:157-65. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/157/343638




  Introduction Top


Since the first observations of excess cardiovascular risk in rheumatoid arthritis (RA) in 1953,[1] the link between RA and premature or accelerated atherosclerosis has been unequivocally established from observational, epidemiological, and mechanistic studies.[2] Cardiovascular mortality in patients with RA is increased by approximately 50% compared to the general population,[3] and the incidence of heart failure (ischemic or nonischemic) by as much as 72%.[4] Even though RA patients are less likely to exhibit typical signs and symptoms of cardiac disease,[5] cardiac tissue characterization with techniques such as cardiovascular magnetic resonance has enabled early identification of pathophysiologic phenomena that occur before the clinically overt cardiac disease.[6] RA triggers complex immune responses along with systemic inflammatory cascades which are considered to substantially aggravate the cardiovascular risk associated with the disease.[7] On the other hand, increased prevalence of conventional cardiovascular risk factors has been consistently reported in RA patients and is considered to contribute, at least partially, to their excess cardiovascular risk.[8],[9] Vascular function and morphology are impaired early on in RA,[10] with subclinical vascular alterations evident even among RA patients without overt cardiovascular disease.[11],[12],[13] It is critical that novel biomarkers, as well as surrogate markers of cardiovascular risk, are evaluated in patients with RA for better risk stratification and earlier management.[14],[15]

Cardiovascular disease is induced by the major pathophysiological processes of arteriosclerosis and atherosclerosis, which are largely driven by the accumulation of conventional cardiovascular risk factors. The most clinically relevant manifestations include ischemic heart disease, stroke, and peripheral artery disease, but may remain clinically silent for years before the establishment of overt cardiovascular manifestations.[16] To this end, markers of subclinical cardiovascular disease have been assessed. In particular, arterial stiffness is a powerful predictor of cardiovascular morbidity and mortality and has been acknowledged as a surrogate marker of cardiovascular disease both in the general population and in high-risk patient populations, such as people with diabetes. In this light, evaluation of arterial stiffness in patients with RA might contribute to more effective stratification and management.

Considering that the cardiovascular mortality rate in RA remains essentially unchanged over the past 50 years despite rapid medical advances,[17] incorporation of surrogate markers in routine cardiovascular risk assessment might be an appealing approach towards reducing the cardiovascular burden of RA patients. Realizing the complex interactions between autoimmune dysregulation, chronic inflammation, and subclinical vascular injury, this narrative review focuses on critically reappraising current evidence about the presence of arterial stiffness in RA and underlying pathophysiological mechanisms. We specifically focus on highlighting existing controversies about the impact of traditional cardiovascular risk factors or the disease per se on the development and progression of arterial stiffness. In addition, current knowledge and future perspectives on the clinical importance of arterial stiffness in patients with RA are discussed, and the impact of antirheumatic drugs is summarized. For this purpose, a PubMed search was performed up to June 2021 using the following keywords: RA; arterial stiffness; pulse wave velocity (PWV); cardiovascular risk.[18]


  Arterial Stiffness: Pathophysiological Principles and Links to Inflammation Top


According to their anatomic features, arteries within the human body are separated into large elastic arteries (e. g. aorta, carotid, iliac), and the smaller muscular arteries expanding toward the lower body and contributing to systemic peripheral resistance. Large elastic arteries store blood through systole and expel it during diastole toward the peripheral circulation, to maintain steady capillary blood flow throughout the whole cardiac cycle.[19] The normal function of large elastic arteries is mainly driven by their anatomical properties. The high elastin to collagen ratio within the walls of the large arteries, which progressively declines towards the periphery of the arterial tree, is the main determinant of their elasticity. Aging and high blood pressure induce structural changes in the medial layer of the aorta and major arterial conduits and exert a major impact on arterial stiffness.[20] Furthermore, increasing distending pressure results in reduced elasticity through the recruitment of inelastic fibers. Increasing age and the cumulative effect of traditional cardiovascular risk factors, predominantly hypertension, result in progressive elastic fiber degeneration, accumulation of abnormal collagen, and hypertrophy of vascular smooth muscle cells.[20] The subsequent stiffening of large arteries increases left ventricular afterload and obscures the perfusion of coronary and peripheral vessels.[21]

A strong theoretical background supports the observed association between chronic inflammatory diseases and exaggerated cardiovascular risk. [Figure 1] summarizes driving mechanisms and risk factors implicated in the pathophysiology of arterial stiffness in RA. Chronic low-grade inflammation has been linked with the accelerated progression of atherosclerosis.[22] Atherosclerosis is a major precursor of cardiovascular diseases implicating both humoral and cellular compartments of innate and adaptive immunity. An apparent “synergism” exists between autoimmune-mediated chronic inflammation and endothelial dysfunction and has been described in detail elsewhere.[23] Mutual pathophysiological pathways include aggregation of inflammatory cells, proliferation and migration of endothelial and smooth muscle cells, disintegration of collagen fibers, platelet activation, and generation of reactive oxygen species.[23],[24] Based on the pathophysiology of atherosclerosis which shares remarkable similarities with the underlying mechanisms of RA, it can be hypothesized that RA per se predisposes to chronic inflammation-mediated arterial disorders such as arterial stiffness.
Figure 1: Major pathophysiological mechanisms and risk factors implicated in the development and progression of arterial stiffness in rheumatoid arthritis

Click here to view



  Evaluation of Arterial Stiffness Top


Of all direct and indirect measures of arterial stiffness, PWV represents the most reliable marker. PWV corresponds to the rate at which pressure waves travel downstream through the arterial wall. Increased PWV denotes increased pulse pressure wave, which is generated by the left ventricle during systole and is formed by the combination of the incident wave and waves reflected from the periphery.[25] The most clinically relevant consequences of increased arterial stiffness are increased pulse pressure, corresponding to the difference between systolic and diastolic blood pressure, increased left ventricular afterload, and decreased coronary perfusion.[26] Indirect measures of arterial stiffness are obtained from the analysis of wave reflections. Augmentation index (AIx) is calculated as the increment in pressure from the first shoulder in the ascending aortic pressure wave to the peak of this wave, expressed as a percentage of the peak ascending aortic pressure wave.[21] AIx offers further information on wave reflections but is limited from its interdependence of several parameters including the duration of the cardiac cycle and subsequently heart rate, and the amplitude of the reflected pulse wave, hence diastolic blood pressure and the individual's height. For this purpose, the heart rate-corrected ([email protected]) is being widely used.[27] Analysis of 4001 healthy subjects has shown that AIx might represent a more sensitive marker of arterial stiffness in the young and PWV in the older individuals, as both AIx and PWV increase with age but AIx increases more in young individuals and PWV increases more in older ones.[28]

The prognostic value of arterial stiffness in terms of cardiovascular risk prediction is indisputable and has been verified from data in tenths of thousands of individuals.[29] Arterial stiffness accelerates the clinical manifestation of cardiovascular disease and is associated with established cardiovascular risk factors including age,[28] hypertension,[30] smoking,[31] obesity, metabolic syndrome and diabetes mellitus,[32] inflammation,[27] hypercholesterolemia,[33] left ventricular hypertrophy,[34] and renal dysfunction.[35] Arterial stiffness is an independent predictor of total and cardiovascular mortality, fatal and nonfatal coronary events in the general population, and high-risk patients including those with uncomplicated hypertension, type 2 diabetes mellitus, end-stage renal disease, and elderly individuals.[27],[29] It remains an independent predictor of coronary events even after adjustment for the estimated Framingham risk score,[36] while its added on top of classical cardiovascular risk factors in risk prediction models has been found to improve their predictive value.[37] Similarly, AIx and central pulse pressure have been associated with total mortality in patients with hypertension,[38] end-stage renal disease,[35] and acute coronary syndromes undergoing coronary interventions.[39] Hence, evaluation of arterial stiffness translates into a reliable marker of biological age and reflects the structural and functional alterations in the microvasculature associated with the long-term consequences of chronic diseases.


  Arterial Stiffness in Patients with Rheumatoid Arthritis Top


Several studies have addressed arterial stiffness in patients with RA. Increased markers of arterial stiffness have been repeatedly found in patients with RA, compared to non-RA individuals.[40],[41],[42] In one of the first relevant studies with a relatively large sample size, increased PWV was reported not only among 80 patients with RA but also in 101 patients with systemic lupus erythematosus, compared to 105 healthy volunteers. PWV was significantly associated with disease-related parameters including the age of rheumatological diagnosis, disease duration, C-reactive protein, and interleukin-6.[40] Such results appeared to confirm previous hypotheses on the association between RA and arterial stiffness. However, not all studies concur, with some presenting nonsignificant differences in measures of arterial stiffness between patients and controls.[43],[44] In 2015, Ambrosino et al. published a meta-analysis of 25 studies with 1472 patients with RA and 1583 controls. PWV was increased in patients with RA by 1.32 m/s (P < 0.00001).[45] Likewise, both AIx and [email protected] were elevated compared to controls. However, results need to be interpreted in light of some limitations. Studies were highly heterogenous (I2 = 89%, P < 0.00001) with significant publication bias, while the majority of participants had multiple traditional cardiovascular risk factors (hypertension, diabetes, smoking, dyslipidemia) and varying disease activity, as admitted by the authors. In an updated meta-analysis published in 2019 of 38 studies with 2733 RA patients and 2416 controls, patients with RA presented likewise significantly increased levels of carotid-femoral PWV, brachial-ankle PWV, carotid-radial PWV, and AIx.[46] However, similar limitations apply as with the previous meta-analysis.

More specifically, inadequate matching for cardiovascular risk factors in several studies might account for the observed differences in arterial stiffness between patients and controls.[47] In addition, it seems that patients with high disease activity and increased levels of systemic inflammation present the highest values of arterial stiffness, whereas well-controlled disease does not seem to exert the same negative impact on arterial stiffness. Indeed, arterial stiffness correlates with the levels of inflammatory markers and proinflammatory cytokines.[48] In the previously mentioned meta-analysis by Ambrosino et al., DAS28 (Disease Activity Score in 28 joints), erythrocyte sedimentation rate and CRP were associated with PWV and AIx.[45] In addition, AIx has been associated with disability levels as assessed with the HAQ-DI (Health Assessment Questionnaire-Disability Index).[49] In the updated metanalysis by Wang et al., increased PWV was associated with age, disease duration, and erythrocyte sedimentation rate.[46] On the other hand, increased arterial stiffness has been documented in early disease,[45] before adequate control of systemic inflammation. In a well-designed study, Provan et al. showed that patients with active RA presented significantly higher PWV in comparison to patients in remission. The latter presented similar levels of PWV compared to the control group.[50]

Other studies have emphasized the role of conventional cardiovascular risk factors, rather than disease-related parameters, as independent predictors of arterial stiffness in RA.[43],[51] It has been argued that arterial stiffness seems to be primarily affected by the presence of traditional cardiovascular risk factors among well-controlled RA patients without pronounced levels of systemic inflammation. In a recent study of 267 patients with RA, those free from traditional cardiovascular risk factors including hypertension, diabetes, cardiovascular events, dyslipidemia, and smoking, were separately analyzed (n = 41) had similar PWV to healthy volunteers, even if they had the long-standing disease.[52] A recent study with a follow-up period that exceeded 3 years included 139 RA patients, who were in remission for more than — of the time, and a similar number of control individuals matched for cardiovascular risk factors. The rates of increase in both PWV and IMT, as well as the development of atherosclerotic plaques, did not differ between patients and controls. These findings were attributed to the low levels of systemic inflammation and effective disease control.[53] The prospective design of the study further reinforces the hypothesis that effective control of inflammation in patients with RA appears to negate the adverse impact of the disease on macrovascular function.

In any case, the role of traditional cardiovascular risk factors in the development and progression of arterial stiffness in RA is indisputable, in accordance with their well-acknowledged detrimental effects on the macrovascular function that has been consistently described in other high cardiovascular risk patients and the general population. Indeed, increased prevalence of traditional cardiovascular risk factors has been repeatedly reported in patients with chronic rheumatic diseases including RA.[54],[55],[56],[57] Most studies concur that insulin resistance, abnormal distribution of body fat, and lack of physical activity are highly prevalent among patients with RA. Although data are not always consistent regarding hypertension, diabetes, and dyslipidemia, several epidemiological studies have reported increased prevalence of these comorbidities.[58],[59] In particular, hypertension, the major determinant of arterial stiffness, is highly prevalent in RA but remains largely underdiagnosed and undertreated.[60] Remarkably, hypertension has been recently reported as the most prevalent cardiovascular risk factor in a large cohort of patients attending a Rheumatology Outpatient Department, affecting 54.5% of the total population and as many as 60.9% of patients with RA. Of note, as many as 21.7% of the study population were unaware that they had hypertension, 32.8% were untreated, while less than half of treated patients reached the treatment blood pressure goals.[8] Systemic inflammation, environmental lifestyle factors, drug therapy, and several genetic factors affect lipid metabolism in RA,[61] and although a substantial portion of RA patients are eligible to statin treatment, many remain untreated.[62] Obesity affects several aspects of life in patients with RA, but available literature is more limited and uncertainties in this area have been previously highlighted.[63] Finally, physical inactivity is highly pervasive in RA, most likely as a result of physical disability and persistent fatigue.[64] Considering the indisputable adverse impact of traditional cardiovascular risk factors, especially hypertension, on large artery stiffening, it can be reasonably hypothesized that their increased prevalence in RA accounts, at least partially, for the elevated levels of arterial stiffness. As has been highlighted elsewhere, classical cardiovascular risk factors are the most powerful determinants of adverse vascular outcomes directly and via subtle interactions with RA-related inflammation.[65] Toward this direction, classical cardiovascular risk factors, but not RA-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function, and carotid atherosclerosis in a cohort of 201 RA individuals over a 6-year follow-up period,[66] although studies specifically addressing arterial stiffness are warranted.


  Association of Arterial Stiffness with Clinical Outcomes in Rheumatoid Arthritis Top


sA plethora of studies in the general population and in high-risk patients have demonstrated the association of arterial stiffness with hard cardiovascular end-points and subclinical alterations in the vasculature, including functional and morphological alterations of the coronary, retinal and renal microcirculation.[29],[67],[68],[69] By contrast, data remain far too limited when it comes to the specific population of patients with RA. In a cohort of 138 patients with RA who underwent baseline assessment of vascular biomarkers, PWV was predictive of cardiovascular events during a median follow-up period of 5.4 years, even after adjustment for demographic variables, traditional cardiovascular risk factors, RA disease-related variables, or medication.[70] Still, most relevant data are indirect and derived from cross-sectional studies. In a study of 40 patients with RA, PWV was associated with left ventricular dysfunction assessed with tissue Doppler techniques.[71] In a larger study of 104 patients with RA, PWV correlated with markers of myocardial blood flow, myocardial contractility, preload and afterload, noninvasively assessed with impedance cardiography. However, these associations were no longer significant after adjustment for cardiovascular risk factors and systemic inflammation.[47] Urinary albumin excretion, a powerful cardiovascular risk marker, correlated with AIx in a population of 136 RA individuals,[72] although the association between arterial stiffness and microalbuminuria was not reproduced elsewhere.[73] PWV was not associated with microcirculatory disorders, specifically dermal capillary density, among 99 patients with RA, after adjustment for cardiovascular risk factors and systemic inflammation.[12]


  The Impact of Medication on Arterial Stiffness in Patients with Rheumatoid Arthritis Top


Cardiovascular effects of antirheumatic drugs remain a field of ongoing research. Modern treatment strategies with biologic disease-modifying antirheumatic drugs (bDMARDs) seem to have a positive impact on cardiovascular mortality, potentially mediated by effective control of inflammation or direct vascular effects.[74] Several studies have assessed the impact of bDMARDs on arterial stiffness. Some of the earliest studies showed significant improvement in PWV in RA patients treated with infliximab[75],[76] or etanercept.[41] The favorable effects of tumor necrosis factor-a (TNF-a) antagonists on aortic stiffness in patients with RA were summarized in a recent meta-analysis that incorporated both short-and medium-term studies.[77] However, this has not been unanimously observed with biologics as a class effect and available data are often conflicting. Treatment with tocilizumab and rituximab, but not abatacept, reduced PWV in patients with RA at 3 and 12 months, respectively.[78] In fact, PWV worsened after 6 months of abatacept therapy according to another study, which was likely attributed to an insufficient decrease in systemic inflammation.[79] Remarkably, in another study, arterial stiffness did not improve after 6 and 12 months of rituximab therapy, even though a beneficial effect on biologic inflammation and disease activity was observed.[80] A nonrandomized prospective pilot study showed decreased PWV after 3 and 6 months of treatment with tocilizumab.[81] On the other hand, PWV decreases were greater with placebo than tocilizumab at 12 weeks of treatment, according to a randomized, placebo-controlled study.[82]

On the other hand, the impact of other antirheumatic drugs on arterial stiffness has not been extensively explored. An association between PWV and corticosteroid use has been previously described.[47] In an Asian population of 262 relatively well-controlled patients with RA, corticosteroid use was identified to be a major determinant of PWV, along with increasing age and high systolic blood pressure.[51] Experimental data have shown that corticosteroids decrease nitric oxide bioavailability, inhibit the expression and activity of endothelial nitric oxide synthase, and accelerate the production of oxidative stress and free radical species within the vessels.[83] On the other hand, acute corticosteroid administration might actually downregulate inflammation and inhibit the detrimental effects of inflammatory cytokines on the vascular wall. Indeed, postprandial AIx was actually lower after acute prednisolone, but not chronic prednisolone administration in patients with RA.[84] The same group showed that PWV was unaltered after acute (7–10 days) prednisolone administration.[85] However, further, prospectively designed studies with adequate numbers of participants are warranted to clarify the acute and chronic effects of glucocorticoids on arterial stiffness among patients with RA.

Collectively, it seems that treatment with biologics may lead to improvement in arterial stiffness, but relevant studies have often produced inconclusive results. At the same time, the effect of other antirheumatic drugs including the newest bDMARDs remains substantially understudied. It is speculated that the down-regulation of systemic inflammation may induce significant decreases in arterial stiffness. Toward this direction, PWV was significantly decreased in RA patients after 6 weeks of treatment with simvastatin, and the reduction was attributed to the anti-inflammatory effects of statins.[86] Whether potential favorable effects of biologics are inherent to their mechanism of action or relate to better control of inflammation warrants further investigation.


  Summary and Conclusions Top


RA is the most common chronic autoimmune rheumatic disease[87] characterized by excess cardiovascular risk, which remains unaltered despite current medical advances.[17] The introduction of reliable markers that would lead to early identification and subsequently effective treatment of individuals at risk before the establishment of overt cardiovascular complications are urgently needed. Arterial stiffness represents an early indicator of cardiovascular morbidity and mortality in both hypertension and normotension and has emerged as a surrogate marker of cardiovascular disease.[88] Arterial stiffness provokes the development of structural and functional alterations in the vasculature of the heart, the brain, the aorta, and the larger peripheral vessels. Pathophysiologically, it is perceived as an intermediate clinical outcome that precedes the establishment of cardiovascular disease. From a clinical point of view, early intervention after assessment of PWV improves cardiovascular prognosis and is being recommended from international guidelines in the field of cardiology towards more effective cardiovascular risk stratification.[89]

Although not all studies concur, increased PWV has been repeatedly reported in patients with RA. However, the majority of studies enrolled patients with multiple cardiovascular risk factors and/or established cardiovascular disease, or with uncontrolled disease and increased levels of systemic inflammation. Hence, it remains unclear whether and to which extent increased arterial stiffness among patients with RA is associated with the disease per se, or rather represents the composite of hypertension and classical cardiovascular risk factors. Studies with well-controlled patients carefully matched with control individuals suggest that effective control of RA does not provoke accelerated arterial stiffness. Towards this direction, biologics seem to exert in general a favorable effect on arterial stiffness in patients with RA, although this effect has not been universally observed and data on the newest bDMARDs remain scarce. There is some evidence that arterial stiffness may predict cardiovascular events in RA individuals. However, there are at present not enough data from appropriately designed studies to support the incorporation of PWV in RA-specific cardiovascular risk prediction models. Considering the well-established predictive value of increased PWV both in the general population and in high cardiovascular risk patients, future studies need to focus on the clinical utility of this surrogate cardiovascular risk marker in this specific high-risk group of patients with RA.

Financial support and sponsorship

PA has received funding by Greece and the European Union (European Social Fund-ESF) through the Operational Programme “Human Resources Development, Education and Lifelong Learning 2014-2020” in the context of the project “Evaluation of novel markers of endothelial dysfunction and thrombotic microenvironment in patients with RA: Association with markers of subclinical inflammation and cardiovascular damage (MIS 5047870).”

Conflicts of interest

There are no conflicts of interest.



 
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