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12of rheumatology
EAAHNIKH PEYMATQAOriA
ANAXKOnHXH REViEW
H ouMMeipiKn Kai aoupperpn Sipe9uAapYivivn wq PioxnpiKoi SeiKreQ rnQ evSo9nAiaKHQ SuoAeiroupYiaQ Kai thq a9npooKAHpwonQ oth PeuMaToeiSn Ap9piTi6a.
QeoSwpoq AnMnTpouXaq1'2, Aamer Sandoo13, Karen Douglas1, rewpYiOQ Kr)Taq14
1Department of Rheumatology, Russels Hall Hospital, DudleyNHS FT, United Kingdom, 2A" naBoAoYiKr] KAiviKr] AnQ, InnoKpareio reviKo NoooKopelo QeooaAoviKn, 3School of Sport, Health and Exercise Sciences, Bangor University, Gwynedd, Wales, United Kingdom, 4Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom
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H PeuparoeiSnQ ap9piriSa (PA) xapaKrnpiZerai ano auEinpevn KapSiaYYeiaKH voonpornra Kai 9vnTOTnTa nou anoreAei Tnv Kupia aiTia tou peiwpevou npooSoKipou eniPiwonQ nou napaTnpeiTai otouq ao9eveiQ nou naoxouv ano Tn vooo. KapSiaYYeiaKa oupPapara onwQ eYKe^aAiKa eneiooSia Kai ep^paYMaTa tou puoKapSiou eivai ouxva Kai ¿xouv xeiporepn ¿KPaon otouq ao9eveiQ pe PA oe oxeon Me to YeviKo nAn9uopo YeYovoQ nou o^eiAerai oe npwipn unoKAiviKH a9npwpaTiKn vooo twv eYKe0aAiKwv Kai ore0aviaiwv aYYeiwv. H SuoAeiroupYia tou evSo9nAiaKou Kurrapou anoTeAei to npoSpopo oraSio TnQ SnpioupYia a9npwpaTiKnQ nAaKaQ Kai oHpepa YvwpiZoupe ori aYYeiaKeQ PAaPeQ otouq ao9eveiQ pe PA epQaviZovrai npiv Tnv kAivikh eKSHAwon twv ouмптwмaтwv. To evSo9HAio anoTeAei to onpavTiKoTepo opYavo-oroxo twv na9oAoYiKwv Karaoraoewv nou anoreAouv napaYovreQ KivSuvou Yia Tnv ep0avion KapSiaYYeiaKwv voonparwv (uпepxoAnoтeplvalмía, oaKxapwSnQ SiaPHrnQ, Kanviopa ktA.), evw oi ao9eveiQ pe PA ep^aviZouv SiarapaxH TnQ evSo9nAiaKHQ AeiToupYiaQ oe oxeon pe paprupeQ TnQ iSiaQ nAiKiaQ Kai 0uAou. To o^eiSio tou aZwrou (NO) anoTeAei pia ano tiq PaoiKeQ aYYeioSpaoriKeQ ouoieQ Kai SiaSpapariZei npwrapxiKo poAo otov ¿Aeyxo TnQ aYYeiaKHQ AeiToupYiaQ. Aiarapaxn TnQ anpooKonrnQ napaY^YHQ Kai eAeu9epwonQ tou NO ano Ta evSo9nAiaKa Kurrapa eivai ni9avov va anoTeAei PaoiKo na9o0uoioAoYiKo pnxaviopo TnQ evSo9nAiaKHQ PAaPnQ, oTnv onoia cpaiverai va epnAeKovrai oi Sipe9uAapYiviveQ nou eivai evSoYeveiQ avaaroAeiQ TnQ ouv9eraonQ tou NO - tou evZupou nou eivai uneU9uvo Yia Tnv napaYWYH tou NO. H aoupperpn (ADMA) Kai n ouppeTpiKH (SDMA) Sipe9uAapYivivn ¿xouv nAeov Ka9iepw9ei wq PioxnpiKoi SeiKTeQ TnQ evSo9nAiaKHQ SuoAeiToupYiaQ aAAa Kai wq veorepoi napaYovreQ au^npevou KapSiaYYeiaKou KivSuvou YeviKorepa, Ka9wQ au^npeva enineSa ADMA Kai SDMA ¿xouv ouoxeTio9ei pe nAH9oQ voooAoyikwv ovtothtwv onwQ oaKxapwSnQ SiaPHrnQ, unepraon, ve0piKq avenapKeia ktA., nou oSnYouv oe a9npooKAHpuvon Kai ore^aviaia vooo.
Irn PA n au^npevn eninTwon KapSiaYYeiaKwv voonparwv ¿xei oSnYHoei arnv avaYKn eupeonQ anAwv, pn enepPaTiKwv pioSeiKTwv nou 9a oupPaAAouv arnv Karavonon twv noAunAoKwv na9o0uoioAoYiKwv мnxavloмwv rnQ aYYeiaKHQ PAaPnQ Kai rnv avaYvwpion twv ao9evwv nou PpioKovrai oe peYaAurepo KivSuvo Yia rnv avanru^n a9npwpaTiKnQ vooou. MeAereQ ¿xouv
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EAAHNIKH PEYMATQAOriA
Sei^ei au^HM^va enineöa ADMA irq evSoBqAiaKHQ öuGÄeiioupYiaQ MeyaAeq avaöpoMiK£Q MeAeieq Sev
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KuvCTTavTivounöAeuQ 49, QeaaaAoviKn 546 42 E-mail: [email protected], [email protected] TnA. +302310992811 Corresponding author; Theodoras Dimitroulas, MD, MSc, PhD 4th Department of Internal Medicine, Ippokrateion Hospital, Thessaloniki, Greece E-mail: [email protected], [email protected] Tel. No.: +302310992811
Ge aG0eveiQ Me PA Kai gugxstigh Me aAAeq napaMSipouQ onwQ Me to naxoQ iou lOix^MaiOQ iwv Kapwiiöwv. Av Kai ¿xouv npaYMaionoir|6ei Ge nÄn6uGM0ÜQ PA niGieueiai on oi SiMeBuXapYiviveQ Mnopouv va anoieXeGOuv Mia evaAAaKiiKn oSo npoGSYYiGHQ Kai SiepeuvnGnQ iwv aYYeiaKÜv öiaiapaxwv gtouq aG0eveiQ auiouQ. H napouGa avaGKonnGn Guvo^iZei na SeSoMsva Yia in xPHGiMonnia IRQ ADMA Kai IRQ SDMA Ginv eKiiMlGn i|Q evSoGnXoKHQ SuGXenoupYiaQ Kai iou KapöiaYYeiaKOü Kivöuvou gtouq aG0eveiQ Me PA.
Mediterr J Rheumatol 2015; 26(2): 62-76
Ae^eiQ-KAeiöiä: aGUMMeipn öiMeGuAapYivivn, GUMMeip^n SiMeGuAapYivivn, PeuMaioeiönQ ApGpinöa, Q0npoGKÄnpwGn
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Symmetric and asymmetric dimethylarginines as biochemical markers of endothelial dysfunction and atherosclerosis in Rheumatoid Arthritis.
Theodoros Dimitroulas1,2, Aamer Sandoo1'3, Karen Douglas1, George Kitas1-4
1Department of Rheumatology, Russels Hall Hospital, DudleyNHS FT, United Kingdom, 24th Department of Internal Medicine, Ippokrateion Hospital, Thessaloniki, Greece, 3School of Sport, Health and Exercise Sciences, Bangor University, Gwynedd, Wales, United Kingdom, 4Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom
ABSTRACT
Rheumatoid arthritis (RA) is associated with reduced life expectancy due to excess cardiovascular (CV) disease. Endothelial dysfunction is common in patients with RA, and accelerated coronary and cerebrovascular atherosclerosis are the major contributors to higher rates of CV events in RA compared to the general population. Nitric oxide (NO) produced by L-arginine is an important vasoactive agent for the maintenance of vascular health. The derangement of the NO/L-arginine pathway leads to vascular changes, predisposing to atherosclerosis. Nitric oxide metabolism is disrupted in RA, with a growing body of evidence suggesting that circulating inhibitors of NO synthase play a crucial role. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines have been recognized as emerging novel markers of endothelial dysfunction and CV morbidity and mortality in several CV disease settings; for example, coronary artery disease, stroke, lipids disorders, etc., as well as in the general population. Thus, it not surprising that they have been evaluated as indicators of vascular disease in RA. This paper provides an overview of the potential role and utility of these molecules in the pathophysiology of CV disease and the evaluation of endothelial function with a specific focus on RA patients.
Mediterr J Rheumatol 2015; 26(2): 62-76
Keywords: Asymmetric dimethylarginines, symmetric dimethylarginines, Rheumatoid Arthritis, atherosclerosis
H IYMMETPIKH KAI AIYMMETPH AIMESYAARHNINH QI BIOXHMIKOI AEIKTEI THI ENAO0HAIAKHI AYIAEITOYPRAI KAI THI A0HPOIKAHPQIHI ITH PEYMATOEIAH APQPITIAA SYMMETRiC AND ASYMMETRiC DiMETHYLARGiNiNES AS BiOCHEMiCAL MARKERS Of ENDOTHELiAL DYSfUNCTiON AND ATHEROSCLEROSiSiN RHEUMATOiD ARTHRiTiS
INTRODUCTION
Rheumatoid arthritis (RA) is a chronic progressive inflammatory disease affecting the joints and other parts of the body. In addition to physical disability, patients suffering from RA die earlier than the general population with life expectancy being reduced by 1015 years1 despite the dramatic advances observed in this field in general population since the 1960s.2 It is now well recognized that cardiovascular (CV) disease is the biggest contributor to premature mortality, accounting for up to 50% of deaths in RA individuals.3 Although classical CV disease risk factors such as hypertension,4 dyslipidaemia,5 physical inactivity and obesity6 are more prominent in RA, they are not sufficient on their own to explain the higher rates and worse outcomes of CV events amongst RA individuals compared to the general population.7 It has been suggested that disease-specific factors, including systemic inflammation and autoimmune activation, trigger pathways of atherosclerosis and/or thrombosis, and, combined with traditional risk factors, lead to increased CV morbidity and mortality.8,9 Increased CV burden in RA is mainly associated with accelerated atherosclerosis, resulting in coronary artery disease. High intensity of systemic inflammation underlies structural and morphological changes in vasculature which can exacerbate or accelerate atherosclerosis.10 Indeed, the inflammatory process in rheumatoid synovium and atherosclerotic vascular wall share several similarities in terms of inflammatory cell migration and activation, the production of proinflammatory cytokines and the expression of adhesion molecules. Endothelial dysfunction - the initial step to atherogenesis - has been reported in several studies, assessing vascular morphology in RA,11 and it appears that the pathophysiological process may actually precede the clinical appearance of the disease.12 Thus, the prompt recognition of early, pre-atherogenic changes may contribute to the introduction of protection measures and more effective CV risk management in RA individuals.
In that respect, a European League Against Rheumatism (EULAR) task force made a commendable effort in producing recommendations for CV risk management in patients with inflammatory arthritis;13 however, the performance of risk factor assessment algorithms for predicting CV risk in RA is suboptimal, as they seem to underestimate CV risk in this population.14 Consequently, other approaches including validated biomarkers routinely used in the management of RA such as C-reactive protein (CRP) have been suggested in the assessment of CV risk.15 While CRP indicates systemic inflammatory load and in parallel is associated with accelerated atherosclerosis16 and CV events,17
the search for novel, sensitive, surrogate markers of endothelial dysfunction continues. Dimethylarginines are formed during endogenous protein turnover as guanidino-substituted analogues of L-arginine and interfere with numerous metabolic and signaling pathways. Asymmetric dimethylarginine (ADMA) is the most potent endogenous nitric oxide (NO) synthase inhibitor whilst its structural isomer symmetric dimethylarginine (SDMA) reduces NO synthesis indirectly by enhancing formation of reactive oxygen species18 and/or by inhibiting cellular transport of L-arginine and other amino acid.19 Both molecules have emerged as potential new markers of endothelial dysfunction with independent roles in CV disease20 and predictions of CV events.21 In fact, ADMA correlates with traditional and non-traditional CV disease risk factors22 and it is associated with CV mortality and morbidity in various conditions such as coronary artery disease,23 peripheral vascular disease,24 chronic renal failure25 as well as in general population.26 Although SDMA has not been studied to a similar extent, recent data demonstrates that elevated circulating SDMA levels are associated with worse prognosis in patients suffering from stroke27 and increased risk of cardiac death in individuals referred for coronary angiography28 and diagnosed with myocardial infraction.29 It is worth noting that ADMA and SDMA have been found to have the same prognostic significance for CV risk in the general population.30 Finally, recent insights indicate ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction, suggesting that endogenous NO synthase inhibitors have an important role in the adverse CV events and outcomes reported with nonsteroidal anti-inflammatory drug usage.31
As CV disease is one of the major and most important co-morbidities in RA, dimethylarginines have attracted interest as potential sensitive laboratory markers of endothelial impairment and atherosclerosis in this population. Specifically, the role of ADMA has been investigated not only in RA, but also in other cardiovascular complications of immunologic abnormalities.32 The aim of the current review is to summarize the available amount of data and evidence regarding the utility of ADMA and SDMA in assessing CV risk in RA.
NO as a regulator of vascular function
The vascular endothelium forms the innermost lining of the vasculature and represents one of the largest endocrine organs in the human body. The endothelium performs vital tasks crucial for several physiological functions, including tissue fluid balance, angiogenesis, vessel tone, and host defense.33 Amongst others,
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endothelial cells control vascular function and structure by secreting various hormones and vasoactive substances which are involved in a broad variety of regulatory mechanisms of CV system by affecting vasomotion, coagulation, vessel wall growth and inflammation.34 Nitric oxide (NO) is an endothelium-derived vasodilator of particular importance with inhibitory effects on vascular muscle cell proliferation and constriction, and cell-to-cell interactions in blood vessels, such as platelet aggregation and leucocyte adhesion. Nitric oxide regulates blood flow by maintaining basal vasodilator tone and protects vasculature from multiple atherothrombotic biological processes, representing a significant regulator of vascular function and health.
The production of NO is catalyzed by the enzyme NO synthase which converts L-arginine to NO. Three isoforms of NO synthase have been identified; classified by the cells they were originally found in: neuronal isoform, which functions as a retrograde neurotransmitter; inducible or macrophage isoform, which is upregulated in an oxidative environment after activation of macrophages; and endothelial isoform, which is responsible for the constitutional production and release of NO in the vasculature.35 The later physiological function of endothelial isoform requires dimerization of the enzyme, the presence of the substrate l-arginine, and the essential cofactor (6fi)-5,6,7,8-tetrahydro-l-biopterin (BH4); one of the most potent naturally occurring reducing agents.36 Physiologically, NO diffuses from endothelial cells to subendothelial layers of the vascular wall or to the cells of flowing blood to induce vascular dilatation and other atheroprotective properties, mainly by increasing production of the second messenger cyclic guanosine monophosphate via activation of soluble guanylate. As L-arginine/NO pathway is thought to be the major effector of endothelial control of vascular homeostasis, alterations in endothelial biology due to impaired NO synthesis and particularly the imbalance between the secretion of vasodilators and endothelium-derived contracting factors result in endothelial dysfunction, which represents a key early event in the long road towards atherosclerotic vascular disease.37 Reduction of endothelial NO synthase activity and the consequent reduction in NO bioavailability lead to abnormal vasoreactivity and endothelial cell activation accompanied by derangement of fibrinolysis and prothrombotic status; abnormalities which characterize atherosclerotic plaque formation, progression and rupture.38
Dimethylarginines, endothelial dysfunction and CV disease
Synthesis and Metabolism
Dimethylarginines are naturally occurring components of human plasma derived from the proteolysis of proteins with methylated arginine residues. The methylation is catalyzed by arginine methyltransferases and gives rise to three types of compounds: ADMA, SDMA and L-NG-monomethylarginine (L-NMMA).39 According to their specific catalytic activity, protein arginine methyltransferases (PRMT) are classified into two types: Type I catalyzes the formation of ADMA and L-NMMA, while Type II catalyzes the formation of SDMA and L-NMMA.40 After proteolysis, free dimethylarginines are released by the cells. As the structure of ADMA is similar to L-arginine, it competes with L-arginine for NO synthase binding; thereby inhibiting NO formation whilst SDMA is a weaker indirect inhibitor of NO synthase activity.41 Despite common synthetic pathways, clearance of ADMA and SDMA occurs through different mechanisms. ADMA is predominantly metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citrulline and dimethylamine, with other pathways such as liver degradation and renal excretion having a minor contribution.42 Dimethylarginine dimethylaminohydrolase has two isoforms (DDAH-1 and DDAH-2) which are distributed differently across tissues, with DDAH-1 being primarily an enzyme of epithelial cells, whereas DDAH-2 is present in the vasculature.43 On the other hand, SDMA seems to be strictly eliminated by renal excretion and it is considered as a very reliable marker of renal function.44 Recently, it has been suggested that enzymatic activity of alanine-glyoxylate aminotransferase 2 represents an alternative cleavage route for SDMA degradation in different population settings (Figure 1).45,46
The role of dimethylarginines in atherosclerosis Impairment of endothelial function represents the most common process through which several CV risk factors such as hypertension, smoking, obesity, etc., exert adverse effects on vascular architecture and function. There is evidence that a number of vascular conditions are characterized by reduced NO generation, suggesting that endogenous control mechanisms of L-arginine/NO pathway underlie pathogenesis of CV disease.39 Such observations have provided the rationale for in vitro and in vivo studies exploring the possible role of dimethylarginines in aberrant regulation of NO metabolism. Particularly, the role of ADMA has been an area of intense research in recent years. Experimental evidence suggests that even small changes of circulating ADMA levels affect endothelial homeostasis and modulate vascular function. For example, in a mouse model, overexpression
H IYMMETPIKH KAIAIYMMETPH AIMEQYAAPHNINH QI BIOXHMIKOI AEIKTEI THI ENAO0HAIAKHI AYIAETOYPHAX KAI THI A0HPOIKAHPQIHI ITH PEYMATOEIAH AP0PITIAA SYMMETRiC AND ASYMMETRiC DiMETHYLARGiNiNES AS BiOCHEMiCAL MARKERS Of ENDOTHELiAL DYSfUNCTiON AND ATHEROSCLEROSiS iN RHEUMATOiD ARTHRiTiS
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ADMA: Asymmetric dimethylarginie AGTX2: Alanine:glyoxylate aminotransferase 2 DDAH: Dimethylarginine dimethylaminohydrolase SDMA: Symmetric dimethylarginine PRMTs: Protein arginine methyltransferases
Figure 1. Metabolic pathway of dimethylarginines. Arginine residues that lie within appropriate consensus sequences in proteins can be post-translationally methylated by the action of PRMTs. PRMT I catalyzes asymmetrical dimethylation and monomethylation of arginine residues and produces ADMA, whereas 32 type II catalyzes symmetrical dimethylation and monomrthylasion and forms symmetric dimethylarginine - the biologically inactive stereoisomer of ADMA. The former is degraded via DDAH action to citrulline plus dimethylarginine and the latter is predominantly eliminated through kidneys. Although there is data in mice for contribution of AGXT2 to ADMA degradation, these findings have not been confirmed in humans.
of the DDAH-1 gene improved blood pressure and vascular resistance through enhanced NO production.47 Furthermore, overexpression of DDAH-1 in apolipoprotein E-deficient mice reduced plaque formation in the aorta and improved endothelial function as assessed by endothelium-dependent vasodilatation.48 In contrast, exogenous ADMA treatment in cell culture models of human umbilical vein endothelial cells blocks endothelial cells differentiation and senescence, induces monocytoid cells adhesion, smooth muscle cell migration and foam cell formation; processes involved in the initial steps of atherosclerosis.49,50 In addition, ADMA inversely interferes with differentiation and mobilization of endothelial progenitor cells in patients with coronary artery disease.51
In the context of clinical data in humans, Miyazaki et al. demonstrated that ADMA levels were correlated with age, mean blood pressure, glucose tolerance and carotid artery intima media thickness in 116 healthy
individuals without apparent CV disease;52 suggesting that ADMA may have a prognostic significance in the development of vascular disease before it manifests clinically. Plasma ADMA levels were also significantly correlated with carotid artery intima thickness in patients with subclinical carotid atherosclerosis, even in those who were not taking any medication.53 Elevated ADMA levels have been reported in several conditions associated with vascular pathology and excess CV risk, such as hypertension,54 hypercholesterolemia,55 hyperhomocysteinemia,56 peripheral vascular disease,57 renal failure,58 and heart failure of various etiologies.59,60 Thus, it is not surprising that ADMA has been evaluated as a novel surrogate marker of endothelial dysfunction and CV risk in different disease settings and general population, with outcomes indicating its prognostic value for both occurrence and outcomes of CV events, as well as overall CV morbidity and mortality.61 The appreciation that the - originally considered biologically inert - SDMA affects vascular homeostasis
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through NO-dependent but also through NO-independent mechanisms19,20 has led to studies assessing its clinical significance in populations with high CV risk. Although the amount of data is limited, the current level of evidence suggests that elevated SDMA levels are linked with increased CV risk in conditions such as coronary and peripheral artery disease62 with the prognostic impact of SDMA in some populations - stroke,63 for example - being reported superior to that of ADMA. The interrelationship between the two molecules has not been fully understood today; however, they modulate NO metabolism, and potentially hold an important role in the development and progression of CV disease.
Atherosclerosis and CV risk in RA
Rheumatoid arthritis patients are more susceptible to developing CV disease, which accounts for the excess morbidity and mortality. Although cardiac disease in RA is heterogeneous including a wide spectrum of clinical manifestations such as systolic and diastolic heart failure, (myo)pericarditis, valvular disease and pulmonary hypertension, it appears that heightened CV risk and reduced life expectancy in this population are specifically attributable to accelerated coronary artery and cerebrovascular atherosclerosis.64 Rheumatoid arthritis patients are at higher risk of myocardial infractions and cerebrovascular events compared to the general population65 that are characterized by higher rates of re-occurrence and worse long-term outcomes.66 Rheumatoid arthritis is now considered a novel risk factor for CV disease67 and a coronary artery disease equivalent.68
Appreciation has increased that upregulation of proinflammatory cytokines such as tumor necrosis factor-alpha and IL-6 which are abundantly present in the inflamed synovium and the systemic circulation leads to endothelial dysfunction and contributes to the development of atherosclerosis in RA.69 Systemic inflammation can cause vascular damage through several mechanisms, including promotion of oxidative stress via uncoupling of endothelial NO synthase and reduced NO bioavailability, increased extent of coronary artery calcification, induction of secondary dyslipidemia, abnormal fibrinolytic activity and enhancement of prothrombotic propensity.70 In addition, the intensity of vascular inflammation in RA not only drives the formation and progression of atherosclerotic plaque, but more importantly, contributes to greater plaque instability and subsequently clot formation that causes acute events.71 Last but not least, chronic high-grade systemic inflammation precipitates the adverse effects of traditional CV risk factors on vascular wall underlying the complexity of the links between RA-related factors and impairment of endothelial function.72
The central role of inflammation in CV risk is further supported by clinical observations suggesting that high sensitive C-reactive protein (CRP) has been described as a predictor of future coronary heart disease in general population.73 In RA higher CRP levels are associated with subclinical atherosclerosis assessed by carotid-artery intima thickness - a validated morphological marker of CV disease.74 High erythrocyte sedimentation rate (ESR) values and severe, active RA defined by erosive bone disease, extraarticular involvement and serological abnormalities are significantly associated with increased CV morbidity and mortality.75,76 The observations that rheumatoid factor and antinuclear antibodies positive individuals are in higher risk of CV events and death77 and anti-cyclic citrullinated peptide (anti-CCP) antibodies in patients with RA are independently associated with the development of ischemic heart disease78 indicate that the systemic autoimmune process may play a role to the genesis of endothelial damage and atherosclerosis in RA patients.
Dimethylarginines, endothelial dysfunction and inflammation in RA
Growing amount of evidence demonstrates that ADMA levels are raised in RA individuals, even in the absence of atherosclerotic disease or conventional CV risk factors (Table 1).79-82 Although several mechanisms have been proposed to explain elevated ADMA such as inflammation-induced upregulation of PRMTs and increased endothelial cell turnover in the inflamed synovium with liberation of ADMA during cell catabolism,83 it appears that the most important parameter is DDAH dysfunction.84 Inflammatory mediators, oxidative stress and high levels of NO production following overexpression of inducible NO synthase inhibit DDAH activity leading to ADMA accumulation. In this way, ADMA acts in a multiplicative manner in promoting endothelial dysfunction, not only by reducing NO synthesis, but also by evoking endothelial NO synthase uncoupling; switching it to a superoxide synthase.85 Thus, ADMA may represent a novel link between endothelial dysfunction and vascular inflammation: this relationship may be of high importance in chronic, systemic inflammatory conditions such as RA. To lend more support to the former, higher ADMA levels in RA patients do not seem to have a genetic background, as they were not associated with DDAH gene variants in a recent study.86 However, the association between ADMA and systemic inflammation remains controversial. Although Surdacki et al. described positive associations between ADMA and RA-specific autoantibodies,87 preliminary reports failed to establish a direct relationship between inflammatory markers and ADMA79,80,88 whilst others89 demonstrated positive correlations between oxidative
H IYMMETPIKH KAI AIYMMETPH AIMEQYAAPriNINH OI BIOXHMIKOI AEIKTEI THI ENAO0HAIAKHIAYIAEITOYPRIAI KAI THI A0HPOIKAHPOIHI ITH PEYMATOEIAH AP0PTIAA SYMMETRiC AND ASYMMETRiC DiMETHYLARGiNiNES AS BiOCHEMiCAL MARKERS OF ENDOTHELiAL DYSFUNCTiON AND ATHEROSCLEROSiS iN RHEUMATOiD ARTHRiTiS
Table 1. Overview of the studies assessing ADMA and SDMA in RA patients.
Authors Patients Parameters assessed Assessment ADMA SDMA Associations
tools
Surdacki et al.79 30 RA/20 controls Atherosclerosis Carotid U/S |RA Not assessed IMT, endothelial progenitor cells count
Sandoo et al.80 67 RA/29 controls Microvascular / macrovascular function Arterial stiffness LDI with iontophoresis of ACh and SNP FMD with highresolution U/S of the brachial artery Augmentation index |RA Not assessed No associations
Klimek et al.81 29 RA/29 controls Disease activity DAS28 |RA with high DAS28 No difference
Surdacki et al.87 20 RA Autoimmunity APCA Not assessed APCA
Korkosz et al.88 29RA/23 controls Disease activity |RA No difference
Kwasny-Krochin et al.89 46 RA/50 controls Disease activity Inflammatory markers Disease activity and disability scores |RA |RA CRP, DAS28, HAQ
Sandoo et al.91 201 RA Cumulative inflammation Quarterly measurement of CRP and ESR / year Not assessed Cumulative inflammatory load
Dimitroulas et al.92 197 RA Cumulative inflammation Quarterly measurement of CRP and ESR / year Not assessed No associations
Turiel et al.93 25 RA/25 controls Coronary circulation Dipyridamole trans-thoracic stress U/S |RA Not assessed Coronary flow reserve
Sandoo et al.96 35 RA Response to biologics (-) after Not
Turiel et al.97 10 RA treatment assessed
Di Franco et al.82 20 RA/20 controls Response to DMARDS i ADMA after treatment Not assessed
Dimitroulas et al.103 67 RA Classic CVD risk factors HOMA, QUICKI, BMI, Reynolds score Not assessed HOMA
Dimitroulas et al.105 197 RA/ 82 controls Disease activity Classic CVD risk factors CRP, ESR,HOMA, QUICKI, BMI, Reynolds score, DAS28 Not assessed i RA QUICKI, DAS28
Dimitroulas et al.108 201 RA Coronary microvascular perfusion Subendocardial viability ratio Not assessed No associations
ACh: acetylcholine, ADMA: asymmetric dimethylarginine, APCA: anti-citrullinated protein antibodies, BMI: body mass index, CFR: coronary flow reserve, CRP: C-reactive protein, CVD: cardiovascular disease, DAS28: disease activity score, ED: endothelial dysfunction, ESR: erythrocyte sedimentation rate, HOMA: haemostatic model assessment, FMD: flow mediated dilatation, HAQ: health assessment questionnaire, IMT: intima-media thickness, LDI: laser Doppler imaging, QUICKI: quantitative insulin sensitivity check index, RA: rheumatoid arthritis, SDMA: symmetric dimethylarginine, U/S: ultrasound
stress and CRP in 46 RA patients with active disease. These cross-sectional studies included only one single measurement of ESR and/or CRP and subsequently did not accurately reflect cumulative inflammatory load over a longer period of time, which is considered
to have a larger impact on endothelial injury and the development of atherosclerosis in chronic conditions such as RA.90 A recent publication shed more light on this unresolved issue as ADMA was found to be associated with cumulative inflammatory load in a
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Figure 2. Schematic overview of NO synthase inhibition in RA. Increased production and release of various proinflammatory cytokines and mediators by activated immune cells in rheumatoid synovium has a dual role in mediating vascular injury: a potential direct inhibitory effect on NO synthase activity, and a significant input on ADMA synthesis upregulation through various mechanisms. ADMA inhibits NO synthase and the ensuing disruption in endothelial hemostasis results in vascular damage and promotion of various stages of atherosclerosis.
well-characterized cohort of RA patients in a 6-year follow-up study; suggesting a further mechanistic link between chronic inflammation and vascular injury, and an additional pathway for excessive CV morbidity in RA.91 It is worth noting that a similar study investigating the relationship between SDMA and cumulative inflammation in the same RA population yielded negative results,92 indicating that SDMA may have less proinflammatory properties compared to ADMA, and that NO synthase inhibitors may promote endothelial insult via different pathways20. With regards to other surrogate markers of atherosclerosis and vascular abnormalities, ADMA has been associated with morphological and functional parameters of endothelial dysfunction in some, but not all, studies. Significant correlations have been established between ADMA and carotid artery intima-media thickness79 as well as coronary flow reserve in patients with early RA.93 In contrast, no significant relationship between ADMA and assessments of in vivo endothelium-dependent and
-independent microvascular and microvascular function was established in 67 RA patients with moderate disease activity.80 These inconsistent reports emphasize the complexity of vascular pathology in RA, indicating that assessments of vascular function and morphology cannot be used interchangeably to assess vascular health, as previous studies have found that microvascular and macrovascular endothelial function are independent of each other in this population.94 Asymmetric dimethylarginines - a biochemical marker with no known specificity for the microvasculature or microvasculature - can be a useful, additional tool in the global evaluation of endothelial function and vascular health complementing information providing by clinical examination and other assessments of vascular function.
Whether clinical remission following treatment with antiinflammatory drugs improves CV risk in RA remains to be determined as observational studies and data from registries did not always demonstrate a decrease in CV events.95
H IYMMETPIKH KAI AIYMMETPH AIMEQYAAPPNINH 01 BIOXHMIKOI AEIKTEI THI ENAO0HAIAKHIAYIAEITOYPPAI KAI THI A0HPOIKAHPOIHI ITH PEYMATOEIAH AP0PITIAA SYMMETRiC AND ASYMMETRiC DiMETHYLARGiNiNES AS BiOCHEMiCAL MARKERS OF ENDOTHELiAL DYSFUNCTiON AND ATHEROSCLEROSiS iN RHEUMATOiD ARTHRiTiS
As ADMA is high in RA patients, the effects of treatment with conventional and biologic disease-modifying drugs on ADMA have been investigated in longitudinal studies. Most of the studies in patients with longstanding disease have not demonstrated any statistically significant difference in ADMA levels prior and after treatment with tumor necrosis-alpha inhibitors and/or synthetic anti-rheumatic drugs;96-98 suggesting that mechanisms of ADMA accumulation in RA may be independent of tumor necrosis factor-alpha mediated pathways. On the other hand, a small study including 20 disease modifying drugs-naive patients with early RA showed reduction of ADMA levels after 12 months of treatment with conventional and biologic agents.81 This finding may imply that early intervention may be helpful in restoring endothelial function in RA but further studies are required.
The role of dimethylarginines in insulin resistance
Rheumatoid arthritis shares numerous pathophysiological processes with metabolic syndrome, such as acute phase response and vascular injury along with potential prognostic implications.99 Insulin resistance is one of the main components of metabolic syndrome, and it is an important contributor to the CV risk associated with it. The chronic state of low-grade inflammation present in the metabolic syndrome and the multiple pleiotropic effects of adipokines on the vasculature have been implicated in the pathogenesis of vascular injury in RA, further augmented by high levels of systemic inflammation and immune activation.100 It is now well-recognized and accepted that the magnitude of CV risk in RA is comparable to that of diabetes mellitus; the prototypic disease carrying increasing risk for atherosclerotic CV events.101,102
Nitric oxide production and vascular homeostasis are disrupted in RA and insulin resistance and dimethylarginines have been proposed as significant regulators of endothelial dysfunction in both conditions. For example, Homeostasis Model Assessment, a strong indicator of insulin resistance, has been established as an independent predictor of high ADMA levels in RA individuals.103 Other studies have confirmed a strong relationship between insulin resistance and ADMA104 reinforcing the hypothesis that a bidirectional influence between ADMA and insulin resistance might exist, and it is possible that the coexistence of high ADMA and abnormal insulin metabolism in RA act together in inducing and promoting inflammatory vascular reaction leading to atherosclerosis.
Similarities between RA and insulin resistance have been also described with other dimethylarginines. In contrast to ADMA, SDMA values are lower in RA patients and are correlated with insulin sensitivity105in
line with observations in insulin resistant patients106. These findings may reflect a mechanism associated specifically with RA; similarly to what occurs in diabetes mellitus, where intriguing interactions between ADMA and CV events have been described.107
Conclusions and clinical implications
There is well-established evidence for considerable overlap between pathogenetic processes characterizing RA and atherosclerosis, resulting in high CV mortality and morbidity in these individuals. Cardiovascular risk management is an integral part of the care of RA patients, requiring - besides tight control of systemic inflammatory disease - modification of traditional CV risk factors. Complex interactions between environmental and genetic indices affect the immune system and vasculature, contributing to the disruption of endothelial function, and the initiation, development and destabilization of atherosclerotic lesions. Abnormal NO metabolism is considered to be the most important pathway through which systemic inflammation exerts deleterious effects on vascular wall, although NO-independent mechanisms have also been suggested to participate in accelerated atherosclerosis in RA. Dimethylarginines which have been recognized as regulators of NO/L-arginine pathway as well as mediators of inflammatory vascular disease encompass different aspects of pathogenesis of vascular disease in RA. The current level of evidence indicates that these molecules may be useful tools in the assessment of endothelial dysfunction in RA but large prospective studies are lacking. The role of ADMA and SDMA as biomarkers for CV stratification and earlier therapeutic intervention as part of a multilevel risk assessment tool needs to be examined in long term trials with specific hard endpoints.
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References
1. Van Doornum S, Jennings GL, Wicks IP. Reducing the cardiovascular disease burden in rheumatoid arthritis. Med J Aust 2006; 184:287-90.
2. Gonzalez A, Maradit-Kremers H, Crowson CS, Nicola PJ, Davis JM 3rd, Therneau TM, et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum 2007; 56:3583-7.
3. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690-7.
4. Panoulas VF, Metsios GS, Pace AV, John H, Treharne GJ, Banks MJ, et al. Hypertension in rheumatoid arthritis. Rheumatology (Oxford) 2008; 47:1286-98.
5. Toms TE, Symmons DP, Kitas GD. Dyslipidaemia in rheumatoid arthritis: the role of inflammation, drugs, lifestyle and genetic factors. Curr Vasc Pharmacol 2010; 8:301-26.
6. Metsios GS, Stavropoulos-Kalinoglou A, Panoulas VF, Sandoo A, Toms TE, Nevill AM, et al. Rheumatoid cachexia and cardiovascular disease. Clin Exp Rheumatol 2009; 27:985-8.
7. Douglas KM, Pace AV, Treharne GJ, Saratzis A, Nightingale P, Erb N, et al. Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome. Ann Rheum Dis 2006; 65:348-53.
8. Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann Rheum Dis 2011; 70:8-14.
9. Gasparyan AY. Cardiovascular risk and inflammation: pathophysiological mechanisms, drug design, and targets. Curr Pharm Des 2012; 18:1447-9.
10. Mason JC, Libby P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J 2015; 36:482-9c.
11. Sandoo A, Veldhuijzen van Zanten JJ, Metsios GS, Carroll D, Kitas GD. Vascular function and morphology in rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 2011; 50:2125-39.
12. Nurmohamed MT, Kitas G. Cardiovascular risk in rheumatoid arthritis and diabetes: how does it compare and when does it start? Ann Rheum Dis 2011; 70:881-3.
13. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69:325-31.
14. Arts EE, Popa CD, Den Broeder AA, Donders R, Sandoo A, Toms T, et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms. Ann Rheum Dis. 2015 Feb 17
15. Dessein PH, Semb AG. Could cardiovascular disease risk stratification and management in rheumatoid arthritis be enhanced? Ann Rheum Dis. 2013; 72:1743-6.
16. Gonzalez-Gay MA, Gonzalez-Juanatey C, Pineiro A, Garcia-Porrua C, Testa A, Llorca J. High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol.2005; 32:1219-23.
17. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499-511.
18. Schepers E, Glorieux G, Dhondt A, Leybaert L, Vanholder R. Role of symmetric dimethylarginine in vascular damage by
increasing ROS via store-operated calcium influx in monocytes. Nephrol Dial Transplant 2009; 24:1429-35.
19. Strobel J, Mieth M, Endress B, Auge D, König J, Fromm MF, Maas R. Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1). J Mol Cell Cardiol 2012; 53:392-400.
20. Wang Z, Tang WH, Cho L, Brennan DM, Hazen SL. Targeted metabolomic evaluation of arginine methylation and cardiovascular risks: potential mechanisms beyond nitric oxide synthase inhibition. Arterioscler Thromb Vasc Biol 2009; 29:1383-91.
21. Siegerink B, Maas R, Vossen CY, Schwedhelm E, Koenig W, Böger R, et al. Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study. Clin Res Cardiol 2013; 102:193-202.
22. Böger RH, Maas R, Schulze F, Schwedhelm E. Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality--an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res 2009; 60:481-7.
23. Gürel E, Tigen K, Karaahmet T, Gegmen C, MutluB, Ba§aran Y. Predictive value of plasma asymmetric dimethylarginine, homocysteine, and high-sensitive CRP levels in occult coronary artery disease: A multidetector-row computed tomography study. Herz 2013; 40:495-501.
24. Hafner F, Kieninger A, Meinitzer A, Gary T, Froehlich H, Haas E, et al. Endothelial dysfunction and brachial intima-media thickness: long term cardiovascular risk with claudication related to peripheral arterial disease: a prospective analysis. PLoS One 2014; 9:e93357.
25. Levin A, Rigatto C, Brendan B, Madore F, Muirhead N, Holmes D, et al. CanPREDDICT investigators. Cohort profile: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT). BMC Nephrol 2013; 14:121.
26. Böger RH, Sullivan LM, Schwedhelm E, et al. Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation 2009; 119:1592-600.
27. Schulze F, Carter AM, Schwedhelm E, Ajjan R, Maas R, von Holten RA, et al. Symmetric dimethylarginine predicts all-cause mortality following ischemic stroke. Atherosclerosis 2010; 208:518-23.
28. Meinitzer A, Kielstein JT, Pilz S, Drechsler C, Ritz E, Boehm BO, Winkelmann BR, März W. Symmetrical and asymmetrical dimethylarginine as predictors for mortality in patients referred for coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study. Clin Chem 2011; 57:112-21.
29. Cavalca V, Veglia F, Squellerio I, De Metrio M, Rubino M, Porro B, et al. Circulating levels of dimethylarginines, chronic kidney disease and long-term clinical outcome in non-ST-elevation myocardial infarction. PLoS One 2012; 7:e48499.
30. Kiechl S, Lee T, Santer P, Thompson G, Tsimikas S, Egger G, et al. Asymmetric and symmetric dimethylarginines are of similar predictive value for cardiovascular risk in the general population. Atherosclerosis 2009; 205:261-5.
31. Ahmetaj-Shala B, Kirkby NS, Knowles R, Al'Yamani M, Mazi S, Wang Z, et al. Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associate with anti-inflammatory drugs. Circulation 2015; 131:633-42.
32. Dimitroulas T, Sandoo A, Kitas GD. Asymmetric dimethylarginine as a surrogate marker of endothelial dysfunction and cardiovascular risk in patients with systemic rheumatic diseases. Int J Mol Sci 2012; 13:12315-35.
33. Sukriti S, Tauseef M, Yazbeck P, Mehta D. Mechanisms regulating endothelial permeability. Pulm Circ 2014; 4:535-51.
H IYMMETPIKH KAI AIYMMETPH AIMEQYAAPPNINH Ol BIÜXHMIKÜI AEIKTEI THI ENAÜQHAAKHI AYIAEITOYPPAI KAI THI A0HPOIKAHPOIHI ITH PEYMATOEIAH AP0PITIAA SYMMETRiC AND ASYMMETRiC DiMETHYLARGiNiNES AS BiOCHEMiCAL MARKERS OF ENDOTHELiAL DYSFUNCTiON AND ATHEROSCLEROSiS iN RHEUMATOiD ARTHRiTiS
34. Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 2010; 4:302-12.
35. Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci 1999; 55:1078-87.
36. Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 2006; 113:1708-14.
37. Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag 2005; 1:183-98.
38. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105:1135-43.
39. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004; 24:1023-30.
40. Anthony S, Leiper J, Vallance P. Endogenous production of nitric oxide synthase inhibitors. Vasc Med. 2005; Suppl 1:S3-9.
41. Tsikas D, Sandmann J, Savva A, Luessen P, Böger RH, Gutzki FM, et al. Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography-mass spectrometry. J Chromatogr B Biomed Sci Appl 2000; 742:143-53.
42. Leiper JM. The DDAH-ADMA-NOS pathway. Ther Drug Monit 2005; 27:744-6.
43. Arrigoni F, Ahmetaj B, Leiper J. The biology and therapeutic potential of the DDAH/ADMA pathway. Curr Pharm Des 2010; 16:4089-102.
44. Kielstein JT, Salpeter SR, Bode-Boeger SM, Cooke JP, Fliser D. Symmetric dimethylarginine (SDMA) as endogenous marker of renal function-- a meta-analysis. Nephrol Dial Transplant 2006; 21:2446-51.
45. Anderssohn M, McLachlan S, Lüneburg N, Robertson C, Schwedhelm E, Williamson RM, Strachan MW, Ajjan R, Grant PJ, Böger RH, Price JF. Genetic and environmental determinants of dimethylarginines and association with cardiovascular disease in patients with type 2 diabetes. Diabetes Care 2014; 37:846-54.
46. Seppälä I, Kleber ME, Lyytikäinen LP, Hernesniemi JA, Mäkelä KM, Oksala N, et al. Athero Remo Consortium. Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality. Eur Heart J 2014; 35:524-31.
47. Ogawa T, Kimoto M, Sasaoka K. Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Commun 1987;148:671-7.
48. Jacobi J, Maas R, Cardounel AJ, Arend M, Pope AJ, Cordasic N, et al. Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine. Am J Pathol 2010; 176:2559-70.
49. Smirnova IV, Kajstura M, Sawamura T, Goligorsky MS. Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation. Am J Physiol Heart Circ Physiol 2004; 287:H782-90.
50. Chen M, Li Y, Yang T, Wang Y, Bai Y, Xie X. ADMA induces monocyte adhesion via activation of chemokine receptors in cultured THP-1 cells. Cytokine 2008; 43:149-59.
51. Thum T, Tsikas D, Stein S, Schultheiss M, Eigenthaler M, Anker SD, et al. Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol 2005; 46:1693-701.
52. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999; 99:1141-6.
53. Riccioni G, Scotti L, D'Orazio N, Gallina S, Speziale G,
Speranza L, Bucciarelli T. ADMA/SDMA in elderly subjects with asymptomatic carotid atherosclerosis: values and site-specific association. Int J Mol Sci 2014; 15:6391-8.
54. Kielstein JT, Bode-Böger SM, Frölich JC, Ritz E, Haller H, Fliser D. Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation 2003; 107:1891-5.
55. Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98:1842-7.
56. Stühlinger MC, Stanger O. Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocysteine and endothelial dysfunction. Curr Drug Metab 2005; 6:3-14.
57. Wilson AM, Shin DS, Weatherby C, Harada RK, Ng MK, Nair N, et al. Asymmetric dimethylarginine correlates with measures of disease severity, major adverse cardiovascular events and all-cause mortality in patients with peripheral arterial disease. Vasc Med 2010; 15:267-74.
58. Zoccali C, Mallamaci F, Maas R, Benedetto FA, Tripepi G, Malatino LS, et al.; CREED Investigators. Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int 2002; 62:339-45.
59. Zairis MN, Patsourakos NG, Tsiaousis GZ, Theodossis Georgilas A, Melidonis A, et al. Plasma asymmetric dimethylarginine and mortality in patients with acute decompensation of chronic heart failure. Heart 2012; 98:860-4.
60. Napora M, Graczykowska A, Pröchniewska K, Zdrojewski Z, Catka A, Görny J, et al. Relationship between serum asymmetric dimethylarginine and left ventricular structure and function in patients with end-stage renal disease treated with hemodialysis. Pol Arch Med Wewn 2012; 122:226-34.
61. Szuba A, Podgörski M. Asymmetric dimethylarginine (ADMA) a novel cardiovascular risk factor-evidence from epidemiological and prospective clinical trials. Pharmacol Rep 2006; Suppl:16-20.
62. Staniszewska A, Rajagopalan S, Al-Shaheen A, Thies F, Brittenden J. Increased levels of symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease. J VascSurg 2015; 61:1292-8.
63. Chen S, Li N, Deb-Chatterji M, Dong Q, Kielstein JT, Weissenborn K, Worthmann et al. Asymmetric dimethylarginine as marker and mediator in ischemic stroke. Int J MolSci 2012; 13:15983-6004.
64. Sen D, Gonzalez-Mayda M, Brasington RD Jr. Cardiovascular disease in rheumatoid arthritis. Rheum Dis Clin North Am 2014; 40:27-49.
65. Avina-Zubieta J, Thomas J, Sadatsafavi M, et al. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2012; 71:1524-9.
66. Douglas KM, Pace AV, Treharne GJ, et al. Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome. Ann Rheum Dis 2006; 65:348-53.
67. John H, Kitas GD. Inflammatory arthritis as a novel risk factor for cardiovascular disease. Eur J Intern Med 2012; 23:575-9.
68. John H, Toms TE, Kitas GD. Rheumatoid arthritis: is it a coronary heart disease equivalent? Curr Opin Cardiol 2011; 26:327-33.
69. Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med. 2008; 121(10 Suppl 1):S21-31.
70. John H, Kitas G, Toms T, Goodson N. Cardiovascular co-morbidity in early rheumatoid arthritis. Best Pract Res Clin Rheumatol 2009; 23:71-82.
71. Stevens RJ, Douglas KM, Saratzis AN, Kitas GD. Inflammation
of rheumatology
E ЛЛ H N I К H PEYMATOЛOПA
and atherosclerosis in rheumatoid arthritis. Expert Rev Mol Med 2005; 7:1-24.
72. Prati C, Demougeot C, Guillot X, Godfrin-Valnet M, Wendling D. Endothelial dysfunction in joint disease. Joint Bone Spine 2014; 81:386-91.
73. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375:132-40.
74. MA Gonzalez-Gay, C Gonzalez-Juanatey, A Piñeiro, C Garcia-Porrua, A Testa, J Llorca. High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol 2005; 32:1219-1223.
75. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Jacobsen SJ, Roger VL, et al. Raised erythrocyte sedimentation rate signals heart failure in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:76-80.
76. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005; 52:722-32.
77. Maradit-Kremers H, Nicola PJ, Crowson CS, O'Fallon WM, Gabriel SE. Patient, disease, and therapy-related factors that influence discontinuation of disease-modifying antirheumatic drugs: a population-based incidence cohort of patients with rheumatoid arthritis. J Rheumatol 2006; 33:248-55.
78. López-Longo FJ, Oliver-Miñarro D, de la Torre I, González-Díaz de Rábago E, Sánchez-Ramón S, Rodríguez-Mahou M, et al. Association between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis. Arthritis Rheum 2009; 61:419-24.
79. Surdacki A, Martens-Lobenhoffer J, Wloch A, Marewicz E, Rakowski T, Wieczorek-Surdacka E, et al. Elevated plasma asymmetric dimethyl-L-arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum 2007; 56:809-19.
80. Sandoo A, Dimitroulas T, Veldhuijzen van Zanten JJ, Smith JP, Metsios GS, Nightingale P, et al. Lack of association between asymmetric dimethylarginine and in vivo microvascular and macrovascular endothelial function in patients with rheumatoid arthritis. Clin Exp Rheumatol 2012; 30:388-96.
81. Klimek E, Skalska A, Kwasny-Krochin B, Surdacki A, Sulicka J, Korkosz M, et al. Differential associations of inflammatory and endothelial biomarkers with disease activity in rheumatoid arthritis of short duration. Mediators Inflamm 2014; 2014:681635.
82. Di Franco M, Spinelli FR, Metere A, Gerardi MC, Conti V, Boccalini F, et al. Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis. Mediators Inflamm.2012; 2012:347268.
83. Wtoch A, Wieczorek-Surdacka E, Sulicka-Grodzicka J, Kruszelnicka O, Surdacki A. Asymmetric dimethylarginine reflects cumulative inflammatory burden in rheumatoid arthritis. Rheumatology (Oxford) 2015; 54:1135-6.
84. Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci U S A. 2002; 99:13527-32.
85. Karbach S, Wenzel P, Waisman A, Munzel T, Daiber A. eNOS uncoupling in cardiovascular diseases--the role of oxidative stress and inflammation. Curr Pharm Des 2014; 20:3579-94.
86. Dimitroulas T, Sandoo A, Hodson J, Smith J, Panoulas VF, Kitas GD. Relationship between dimethylarginine dimethylaminohydrolase gene variants and asymmetric dimethylarginine in patients with rheumatoid arthritis. Atherosclerosis 2014; 237:38-44.
87. Surdacki A, Martens-Lobenhoffer J, Wloch A, Gluszko
P, Rakowski T, Dubiel JS, et al. Plasma asymmetric dimethylarginine is related to anticitrullinated protein antibodies in rheumatoid arthritis of short duration. Metabolism 2009; 58:316-8.
88. Korkosz M, Sulicka J, Surdacki A. Dimethylated L-arginine analogues versus autoantibodies in early rheumatoid arthritis. Scand J Rheumatol 2012; 41:82-3.
89. Kwasny-Krochin B, Gtuszko P, Undas A. Plasma asymmetric dimethylarginine in active rheumatoid arthritis: links with oxidative stress and inflammation. Pol Arch Med Wewn2012; 122:270-6.
90. Sandoo A, Kitas GD. Current perspectives on the assessment of vascular function and morphology in rheumatoid arthritis. Int J Clin Rheumatol 2013;8:1-3.
91. Sandoo A, Dimitroulas T, Hodson J, Smith JP, Douglas KM, Kitas GD. Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study. Rheumatology (Oxford) 2015; 54:1145-52.
92. Dimitroulas T, Hodson J, Sandoo A, Smith JP, Douglas KM et al. Symmetric Dimethylarginine Is Not Associated with Cumulative Inflammatory Load or Classical Cardiovascular Risk Factors in Rheumatoid Arthritis: A 6-Year Follow-Up Study. Mediators of Inflammation 2015 Article ID 796562, In press.
93. Turiel M, Atzeni F, Tomasoni L, de Portu S, Delfino L, Bodini BD, et al. Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients. Rheumatology (Oxford) 2009; 48:834-9.
94. Sandoo A, Hodson J, Douglas KM, Smith JP, Kitas GD: The association between functional and morphological assessments of endothelial function in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther 2013; 15:R107.
95. Barbhaiya M, Solomon DH. Rheumatoid arthritis and cardiovascular disease: an update on treatment issues. Curr Opin Rheumatol.2013; 25:317-24.
96. Sandoo A, Dimitroulas T, Toms TE, Hodson J, Veldhuijzen van Zanten JJ, Smith JP, et al. Clinical remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis. Clin Biochem 2012; 45:1399-403.
97. Turiel M, Tomasoni L, Sitia S, Cicala S, Gianturco L, Ricci C, et al. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovasc Ther 2010; 28:e53-64.
98. Angel K, Provan SA, Mowinckel P, Seljeflot I, Kvien TK, Atar D. The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor-a therapy in inflammatory arthropathies. Associations with aortic stiffness. Atherosclerosis 2012; 225:160-5.
99. Bilecik NA, Tuna S, Samanci N, Balci N, Akbaç H. Prevalence of metabolic syndrome in women with rheumatoid arthritis and effective factors. Int J Clin Exp Med 2014; 7:2258-65.
100. Ferraccioli G, Gremese E. Adiposity, joint and systemic inflammation: the additional risk of having a metabolic syndrome in rheumatoid arthritis. Swiss Med Wkly 2011; 141:w13211.
101. Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis 2011; 70:929-34.
102. Stamatelopoulos KS, Kitas GD, Papamichael CM, Chryssohoou E, Kyrkou K, Georgiopoulos G, et al. Atherosclerosis in rheumatoid arthritis versus diabetes: a comparative study. Arterioscler Thromb Vasc Biol 2009; 29:1702-8.
103. Dimitroulas T, Sandoo A, Veldhuijzen van Zanten JJ, Smith JP, Hodson J, Metsios GS, et al. Predictors of asymmetric dimethylarginine levels in patients with rheumatoid arthritis: the role of insulin resistance. Scand J Rheumatol.2013; 42:176-81.
104. Surdacki A, Kruszelnicka O, Rakowski T, Jazwinska-Kozuba
H IYMMETPIKH KAI AIYMMETPH AIME0YAAPHNINH OI BIOXHMIKOI AEIKTEI THI ENAO0HAIAKHIAYIAETOYPHAI KAI THI A0HPOIKAHPOIHI ITH PEYMATOEIAH AP0PITIAA SYMMETRiC AND ASYMMETRiC DiMETHYLARGiNiNES AS BiOCHEMiCAL MARKERS OF ENDOTHELiAL DYSFuNCTiON AND ATHEROSCLEROSiS iN RHEuMATOiD ARTHRiTiS
A, Dubiel JS. Asymmetric dimethylarginine predicts decline of glucose tolerance in men with stable coronary artery disease: a 4.5-year follow-up study. Cardiovasc Diabetol 2013; 12:64.
105. Dimitroulas T, Hodson J, Sandoo A, Smith J, Kitas GD. Symmetric dimethylarginine (SDMA) serum levels in rheumatoid arthritis: correlations with insulin resistance and disease activity scores. Amino Acids. 2015 Mar 13. [Epub ahead of print]
106. Zsuga J, Török J, Magyar MT, Valikovics A, Gesztelyi R, Lenkei A, et al. Dimethylarginines at the crossroad of insulin resistance and atherosclerosis. Metabolism 2007; 56:394-9.
107. Anderssohn M, Schwedhelm E, Lüneburg N, Vasan RS, Böger RH. Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus. DiabVasc Dis Res 2010; 7:105-18.
108. Dimitroulas T, Sandoo A, Smith JP, Kitas GD. Asymmetric dimethylarginine is not associated with subendocardial viability ratio in Rheumatoid Arthritis. Int J Cardiol 2014; 172:285-6.
