European Heart Journal Advance Access published February 23, 2016

REVIEW

European Heart Journal doi:10.1093/eurheartj/ehw018

Frontiers in cardiovascular medicine

Coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases Alessia Faccini 1, Juan Carlos Kaski 2†, and Paolo G. Camici 1*† 1 Vita-Salute University and San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy; and 2Cardiovascular and Cell Sciences Research Institute, St George’s, University of London, London, UK

Received 17 September 2015; revised 31 December 2015; accepted 19 January 2016

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Inflammation † Rheumatic diseases † Coronary microvascular dysfunction † Rheumatoid arthritis † Systemic lupus erythematosus † Systemic sclerosis † Microvascular angina

Introduction Chronic inflammatory rheumatoid diseases (CIRD) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) have a wide spectrum of cardiovascular (CV) manifestations. They can affect the myocardium, the cardiac valves, the pericardium, the conduction system, and both the large and small coronary vessels.1 Importantly, these conditions have been shown to be associated with a heightened risk of premature coronary artery disease (CAD) and stroke (Figure 1A).2 Studies suggest a direct link between the degree of inflammation present in individuals affected by chronic inflammatory diseases and the risk of developing CV events.3 The complex role that inflammation plays in the pathogenesis of atherosclerosis and rapid CAD progression has been highlighted by many experimental and clinical studies over the past 20 years.4 – 6 Inflammatory mechanisms can affect coronary microvascular function and myocardial blood flow (MBF) regulatory mechanisms, which can, in turn, contribute to the development of myocardial ischaemia and CV events. Indeed, inflammation-related coronary

microvascular dysfunction (CMD), expressed as either an inability of the microcirculation to dilate appropriately to meet myocardial oxygen demand or as coronary microvascular spasm, is known to play an important pathogenic role in CV morbidity and mortality in patients affected by CIRD. To carry out this investigation, we searched PubMed for original articles and reviews using the following keywords: coronary microvascular dysfunction, coronary artery disease, cardiac ischaemia, oxidative stress, T cells, NK cells, monocytes, inflammatory mechanisms, cardiovascular risk, cardiac manifestations, anti-inflammatory therapies, and therapeutic targets, in association with ‘systemic inflammatory diseases OR rheumatoid arthritis OR systemic lupus erythematosus OR systemic sclerosis’. We also assessed relevant papers contained in the ‘references’ section of articles identified as suitable by our search strategy. This review focuses on the mechanisms leading to CMD and myocardial ischaemia—in the absence of obstructive epicardial disease—in patients suffering from CIRD. We have also summarized relevant molecular aspects and proposed both practical diagnostic algorithms and possible therapeutic targets that may benefit patients affected by CIRD.

* Corresponding author. Tel: +39 2 26436206, Fax: +39 2 26436218, Email: [email protected]

These two authors contributed equally to the study.

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].

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Chronic inflammatory rheumatoid diseases (CIRD) such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis are an important risk factor for the development of ischaemic heart disease and a source of high cardiovascular morbidity and mortality. In patients affected by CIRD, inflammation can affect coronary microvascular function and contribute to the development of myocardial ischemia and cardiovascular events, even in the absence of obstructive epicardial coronary artery disease. Understanding the molecular aspects that underlie the development of coronary microvascular dysfunction (CMD) in CIRD is of fundamental importance to identify specific therapeutic targets. In this article, we review the pathogenic mechanisms leading to CMD in CIRD, including the controversial results obtained with the use of different therapeutic strategies. We also propose that a practical diagnostic algorithm as the identification of CMD in patients with CIRD may lead to effective measures to prevent the development of angina pectoris and reduce the risk of rapid disease progression.

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The coronary microcirculation The coronary arterial system can be considered to comprise three compartments that have different functions: (i) the large epicardial coronary arteries (vessel diameter 500 mm to 5 mm) have a capacitance function and offer little resistance to blood flow; (ii) the pre-arterioles (diameter 100– 500 mm); and (iii) the arterioles (diameter ,100 mm). Compartments (ii) and (iii) represent what is known as the ‘coronary microvasculature’. Pre-arterioles are specifically responsible for the modulation of pressure within the system in response to changes in coronary perfusion pressure and/or blood flow; ‘proximal’ pre-arterioles are mainly responsive to changes in MBF whereas ‘distal’ pre-arterioles are more responsive to changes in pressure. Arterioles are characterized by generating a very large pressure drop along their length and are mainly responsive to metabolic factors (metabolic regulation of MBF), as their tone is influenced by substances such as hydrogen peroxide and adenosine, produced during myocardial metabolism. The specific function of the arterioles is ensuring a good matching between myocardial blood supply and myocardial oxygen demand. Non-invasive methods such as gated single-photon emission computed tomography (SPECT), cardiac magnetic resonance (CMR), and echocardiography can be used to detect the presence of inducible myocardial ischaemia by demonstrating myocardial perfusion defects or regional wall motion abnormalities (RWMA) during stress.7 However, the coronary microcirculation is beyond the resolution of coronary angiography and cannot be directly imaged in vivo. In clinical practice, it is possible to assess coronary

microvascular function using non-invasive and invasive techniques for the assessment of blood flow and coronary flow reserve (CFR), the ratio of hyperaemic to baseline blood flow.8 Transthoracic Doppler echocardiography and CMR can be used for the semiquantitative measurement of CFR.9 Positron emission tomography (PET) is the only technique that allows accurate and reproducible non-invasive quantification of regional MBF (in units of millilitre per minute per gram) and CFR.10 Invasive methods, i.e. Doppler flow wires and thermodilution, allow measurement of coronary flow velocity (centimetre per second) or volumetric flow (millilitre per minute).11 Coronary microvascular dysfunction can be responsible for myocardial ischaemia in patients without obstructive CAD and can also act as an adjunctive mechanism of ischaemia in patients with obstructive, atherosclerotic, epicardial CAD.12 – 14 Of importance, it has been demonstrated that patients with CAD have an increased coronary microvascular resistance due to an impairment of both endotheliumdependent and -independent vasodilator responses.15,16 Coronary microvascular dysfunction can explain the persistence of anginal symptoms, despite successful myocardial revascularization by stenting or bypass surgery, in .20% of patients 12 months after revascularization.17 Moreover, it has been shown that microvascular resistance can increase as a result of ischaemia per se due to microvascular vasoconstriction elicited by vasoactive signals either linked or independent from coronary thrombosis (i.e. serotonin in the presence of atherosclerotic endothelial damage, neuropeptide-Y and endothelin-1, mechanisms mediated by a1-adrenergic receptors).18 In addition, myocardial ischaemia can lead to a rise in left ventricular end-diastolic

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Figure 1 (A) Clinical vascular manifestations in rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. (B) Mechanisms of microvascular dysfunction identified as triggers of cardiovascular events in chronic inflammatory rheumatoid diseases (adapted from Camici et al.8).

Coronary microvascular dysfunction in CIRD

Ischaemia and coronary artery disease in patients with chronic inflammatory rheumatoid diseases Evidence for an increased incidence of CMD, CAD, and elevated CV morbidity and mortality has been gathered over the past two decades in subjects affected by CIRD.25 In particular, RA is associated with a two- to three-fold higher risk of myocardial infarction (MI)26 and, according to a meta-analysis conducted on 111 758 subjects, RA patients have a standardized cardiovascular mortality ratio (SCMR) of 1.5 (95% CI 1.4 –1.6) compared with the general population.27 As shown in another meta-analysis that included 27 210 patients, SLE had a SCMR of 2.72 (95% CI 1.83 – 4.04)28 with a five- to six-fold increased risk of CV events compared with that in the general population29 and a reported 50-fold increased risk of MI among women aged 35 – 44 years.30 Moreover, a more recent meta-analysis demonstrated a statistically significant increase in CAD risk among SSc patients with a pooled risk ratio for CAD—defined as acute MI, old MI, angina, or coronary revascularization—of 1.8231 while another study reported a three-fold higher occurrence of ischaemic heart disease in these patients.32 The presence of conventional risk factors cannot fully explain the increased risk of CAD in patients with CIRD and therefore high concentrations of pro-inflammatory molecules such as tumour necrosis factor-a (TNF-a) and interleukin-6 (IL-6) have been suggested to contribute to the development of accelerated atherosclerosis and CV events both in RA33 and SLE patients.34

Coronary microvascular dysfunction leading to myocardial ischaemia has been shown to be associated with chronic inflammation in CIRD patients without evidence of obstructive CAD (Figure 1B).35 – 38 In the early stages of CIRD, pro-inflammatory molecules promote endothelial dysfunction by reducing the synthesis and bioavailability of nitric oxide (NO) and exerting metabolic effects on the adipose tissue, skeletal muscle, and liver, as well as increasing the incidence of traditional CV risk factors such as dyslipidaemia, insulin resistance, and obesity.34,39 Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and is characterized by reduced vasodilator function, increased vascular adhesion of circulating inflammatory cells and platelets, and heightened pro-coagulant activity.40 Decreased NO bioavailability appears to be a common and critical step linking TNF-a to endothelial dysfunction, and it has been demonstrated in vivo both in animal experimental models and in humans. Nitric oxide bioavailability is impaired in the presence of inflammation due to a reduction in the expression of endothelial NO synthase (eNOS) via a TNF-a-induced inhibition of eNOS promoter activity and mRNA destabilization as well as an impaired degradation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. Inflammatory cytokines are also responsible for the increased production of reactive oxygen species (ROS), which contribute to modulate NO availability. For instance, the rapid reaction of superoxide anion with NO leads to production of peroxynitrite, which, in turn, decreases NO availability. Moreover, it has been demonstrated that chronic inflammation can alter the molecular structure of lipoproteins inducing the formation of small, dense, pro-atherogenic low-density lipoprotein (LDL), which can modulate NO and ROS production contributing to endothelial dysfunction. Of importance, an association between high concentrations of C-reactive protein and low levels of high-density lipoprotein (HDL) has been shown to exist in RA patients.41,42 Different mechanisms have been proposed to be responsible for endothelial dysfunction in patients with scleroderma, including an imbalance between vasoconstrictor and vasodilator mediators, defective angiogenesis, endothelial injury and activation elicited by the stimulation of the innate and adaptive immune responses, and functional defects of progenitor endothelial cells.43 In patients with cutaneous psoriasis, another systemic inflammatory disease, current data suggest a relation between impaired endothelial-dependent relaxation and the development of atherosclerosis and CV events.41

Molecular mechanism of coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases Despite a link between atherosclerosis and inflammation has been clearly established over the past years,44 the true role of CMD in the pathogenesis of myocardial ischaemia and CAD in patients with CIRD remains incompletely understood. Vaccarino et al.45 assessed 268 asymptomatic monozygotic males and dizygotic twins in whom PET-CFR and plasma biomarkers of inflammation and endothelial cell activation were measured. Independently of CAD risk factors, twins with lower CFR had higher white blood cell count,

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pressure, thus increasing extravascular compressing force and further aggravating microvascular dysfunction.19 In this scenario, a prolonged late INa may impair the overall capacity of the cell to eliminate Ca2+ from the cytosol, which leads to intracellular Ca2+ overload and subsequent diastolic dysfunction. The latter, in turn, increases microvascular resistance and further impairs the energy balance in the ischaemic myocardium.20 Coronary microvascular dysfunction can also influence myocardial perfusion, ventricular function, and clinical outcome following myocardial reperfusion therapies in the acute clinical setting, by causing both the no-reflow phenomenon and reperfusion-injury, resulting in endothelial and myocardial cell damage.21 In this context, an interesting study by Agullo` et al., conducted on cultured endothelial cells from adult rat hearts, showed that acidosis can negatively affect cyclic guanosine monophosphate (cGMP) synthesis without intrinsic protein alteration, with a possible role in the ischaemiareperfusion damage.22 Coronary microvascular dysfunction has also been demonstrated to be an independent predictor of longterm CV events.13,23 Camici and Crea classified CMD into four types according to the clinical setting in which it occurs: dysfunction occurring in the absence of CAD and myocardial diseases; dysfunction in the absence of CAD, but in the presence of myocardial diseases; dysfunction in the presence of obstructive epicardial CAD; and iatrogenic dysfunction, sustained by different structural, functional, and extravascular alterations.24 Recently, Hermann et al. added to this classification a fifth category, i.e. post-cardiac transplant CMD.21

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and increased concentrations of C-reactive protein, IL-6, and intercellular adhesion molecule-1, but not increased vascular cell adhesion molecule-1 levels. Their study indicates that even in asymptomatic subjects, CMD, defined as reduced (,2.5) CFR, is associated with a systemic inflammatory response. Currently, it is difficult to identify a single main pathogenic mechanism that can fully explain the relationship between CIRD and CAD and CMD as different mechanisms/molecular pathways are likely to operate in different patients and in different CIRD. We discuss in the following sections the processes we believe are more likely to explain the relationship (Table 1, Figure 2).

Proved association

Argued association

ROS production

Increased T, B, and NK cells levels

CD4+CD28null T cells Monocytes dysregulation

suPAR activity

................................................................................

ROS, reactive oxygen species; suPAR, soluble urokinase-type plasminogen activator receptor.

Oxidative stress has been shown to play a key role in inflammation and tissue damage in different clinical conditions, including CIRD.46 Indeed, ROS production directly correlates with CMD in patients with SLE, as shown by Yilmaz et al.47 It has also been recently demonstrated that endothelial tissue hypoxia leads to ROS formation through the FoxO3a and HIF 1-a pathway. In parallel, increased ROS promotes the activity of FoxO3a, which, in turn, increases the production of pro-apoptotic proteins such as Bim and Bax and reduces the production of anti-apoptotic proteins, i.e. Bcl-xL and Bcl-2, thus favouring apoptotic mechanisms affecting coronary microvascular endothelial cells.48

T and natural killer cells T cells play an important role in atherosclerotic disease progression and are also involved in the pathogenesis of CIRD. Leonard et al. demonstrated that T cells and natural killer (NK) cells or their products have physiological influences on microvascular arteriolar reactivity in murine cremaster arterioles.49 Testing the microvascular response to vasoconstrictor and vasodilator stimuli in normal mice and in mice genetically deleted in T and B cells or T, B, and NK cells, they showed that compared with wild types, immunodeficient mice have smaller diameters (both at baseline and during maximal vasodilatation) of third-order cremaster arterioles. Natural killer cells, in particular, seem to promote vasoconstriction and to

Figure 2 Molecular and cellular mechanisms involved in the development of microvascular dysfunction in chronic inflammatory rheumatoid diseases. ROS, reactive oxygen species; Ado, adenosine; Ach, acetylcholine; Ang-II, angiotensine-II; IFN-g, interferon-g; TNF-a, tumour necrosis factor-a; IL, interleukin; suPAR, soluble urokinase-type plasminogen activator receptor.

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Table 1 Molecular mechanisms of coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases

Oxidative stress

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suppress adenosine (Ado) and acetylcholine (Ach) induced dilatation. T and B cells, on the other hand, appear to have more complex actions, as they can promote vasodilator responses to Ado, but can also attenuate dilatory responses in the presence of low concentrations of Ach, and exaggerate constrictor responses to angiotensin II (Ang-II).49 Jurewicz et al.50 argued that T and NK cells are fully equipped with renin–angiotensin elements and are potentially capable of producing and delivering Ang-II to sites of inflammation, which, in turn, enhances their chemotaxis, creating a potential inflammatory amplification system that may worsen the immunological response in this environment. They demonstrated that Ang-II causes an augmentation of T and NK cell proliferation through a co-stimulatory effect and that the same result is reached by angiotensinogen and angiotensin I suggesting, in this last setting, that NK and T cells have functional renin and angiotensin-converting enzyme activity. Indeed, they detected the expression of renin, renin receptor, angiotensinogen, and angiotensin-converting enzyme by mRNA analysis, further confirming this hypothesis. They also characterized the T and NK cells expression of angiotensin receptors 1 (AT1) and 2 (AT2) and showed that AT1 and AT2 antagonists, alone or in combination, were unable to abrogate completely the effects of Ang-II. This suggests that another Ang-II receptor may also be functional in leukocytes.50

subpopulation, i.e. CD14dimCD16+, and subclinical atherosclerosis was reported in SLE patients.64

CD41CD28null T cells

Rheumatoid arthritis

Monocytes Monocytes are involved in atherogenesis since the initial phases of the disease.57 It has been demonstrated that their chemotactic response is impaired in smokers and in patients with diabetes mellitus (DM) and/or hypercholesterolaemia, which are established risk factors for both CMD and CAD. This seems to be due to an oxidative stress-mediated desensitization, leading to impaired vasomotion.58 – 61 Interestingly, an increased production of IL-1b has been found in monocytes ex vivo in patients with DM or RA, due to inflammasome activation, suggesting an alternative role for monocytes in the pathogenesis of these conditions.62 Moreover, a positive correlation has been recently demonstrated in RA between the number of a specific inflammatory monocyte subtype (CD14hiCD16+) and subclinical atherosclerosis.63 Similarly, a correlation between the concentration of a slightly different pro-inflammatory monocyte

Soluble urokinase-type plasminogen activator receptor (suPAR) has been recently proposed as a possible biomarker for both CMD65 and SLE.66 Soluble urokinase-type plasminogen activator receptor is the soluble form that originates from cleavage and release of the membrane-bound suPAR, and is present in various concentrations depending on the activation level of the immune system.67 Even though suPAR activity appears to be non-specific, as it is also advocated in many conditions such as sepsis, 68 its role as a biomarker in this setting supports the strong, albeit elusive, bond that exists between systemic inflammation and microvascular dysfunction.

Clinical manifestations of coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases Rheumatoid arthritis is a chronic autoimmune inflammatory disease characterized by increased CV morbidity and mortality and is considered as an independent risk factor for early and accelerated atherosclerosis. Beyond traditional CV risk factors, several pathogenetic mechanisms have been proposed, including inflammatory and autoimmune mechanisms.69 Endothelial dysfunction is believed to be a contributor to the increased CV risk reported in RA patients. The assessment of both microvascular and epicardial function may provide meaningful clinical information regarding CV risk in RA.70,71 Anti-inflammatory treatment for RA has been shown to improve microvascular endothelial function thus reinforcing the pathogenic link between inflammation and microvascular dysfunction in RA patients.72 Recio-Mayoral et al. demonstrated the presence of CMD using PET in RA patients who did not have any of the common CV risk factors or epicardial CAD, as assessed angiographically37 (Figure 3A). In patients with RA, Ciftci et al. showed impaired CFR, as assessed by transthoracic Doppler echocardiography, and increased carotid intima media thickness35 while Turiel et al. reported a negative effect of ADMA, an inhibitor of NO production by NO synthase, on CFR as assessed by transthoracic Doppler echocardiography following dipyridamole stress.73

Systemic lupus erythematosus Systemic lupus erythematosus is a multisystem, autoimmune, connective tissue disorder and one of the strongest risk factors for atherosclerosis and CAD.74 Patients with SLE frequently report chest pain, which, in the presence of a normal coronary angiogram, is most likely due to CMD, as demonstrated in different studies using diagnostic techniques such as transthoracic Doppler echocardiography,36 SPECT,75 PET37 (Figure 3A), and CMR during adenosine stress.76 As in RA patients, CMD in SLE patients seems to be related to both endothelial dysfunction77 and inflammatory status.47

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A particular subset of CD4+ lymphocytes, characterized by the lack of the CD28 co-stimulatory receptor (CD4+CD28null T cells) and their intense cytolytic action,51 release inflammatory cytokines, due to constitutive transcription of cytokine genes, and produce interferon-g, TNF-a, and IL-2.52 They also exert cytotoxic activity through perforin and granzyme B, similarly to NK cells, and have a reduced sensitivity to apoptosis induction, becoming resistant to regulatory T cells.53,54 CD4+CD28null T cells expand in several diseases associated with chronic inflammation, including RA, where they were found to be increased in almost one-third of the patients, correlating directly with the severity of the disease. However, conflicting results are present in the literature regarding this issue.55,56 Finally, it has also been suggested that these cells have a role in atherosclerosis and in the acute coronary syndrome.55

Soluble urokinase-type plasminogen activator receptor

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values of myocardial blood flow during hyperaemia induced by adenosine in rheumatoid arthritis and systemic lupus erythematosus patients without significant epicardial coronary artery disease and with no traditional cardiovascular risk factors (from Recio-Mayoral et al. 37). (B) Inverse correlation between coronary flow reserve values and duration of disease in patients affected by the limited form of systemic sclerosis, suggesting that in this subgroup coronary microvasculature is affected in a more indolent manner, leading to coronary flow reserve reduction later in the course of the disease (from Faccini et al. 38).

Systemic sclerosis Systemic sclerosis is a connective tissue disease characterized by vascular dysfunction and excessive fibrosis. It has been suggested that endothelial damage occurs early in the disease process leading to endothelial dysfunction.78 A severe blunting of CFR, measured invasively during cardiac catheterization, has been demonstrated in patients with diffuse cutaneous SSc with established myocardial involvement and normal coronary angiograms.79 Studies have demonstrated the presence of CMD in SSc patients assessed with non-invasive tests such as adenosine- or dobutamine-stress echocardiography.80,81 Asymptomatic scleroderma patients have been shown to have a higher prevalence of reduced CFR. In patients affected by the limited form of the disease, an inverse correlation between CFR values and the duration of the disease was observed with dipyridamole stress echocardiography38 (Figure 3B). An early (even ‘clinically silent’) coronary microvascular involvement in SSc patients has been linked to impaired prognosis.82

pattern similar to that detected in systemic inflammatory diseases have been identified in an in vivo study by Pasqui et al.86 An interesting study by Recio-Mayoral et al.,85 in patients with chest pain and angiographically normal coronary arteries, but without risk factors for CV disease, showed that patients with high levels of C-reactive protein had more severe impairment of CFR and more ischaemic electrocardiographic (ECG) changes during adenosine administration than patients with lower C-reactive protein, suggesting that inflammation could play a role in the modulation of coronary microvascular responses. Furthermore, in a population similar to that of the above study, Tondi et al. demonstrated an inverse relationship between impaired flow-mediated dilatation (FMD) and C-reactive protein plasma concentration, suggesting that subclinical inflammation may play a significant role in the impairment of endothelium-dependent vasodilator function in these patients.87

Possible therapeutic targets Patients with chest pain, normal arteries, and elevated C-reactive protein In patients with angina and angiographically normal coronary arteries, myocardial ischaemia can result from CMD due to several mechanisms, including endothelial dysfunction, with reduced bioavailability of endogenous NO and increased plasma levels of endothelin-1.83,84 Traditional CV risk factors, insulin resistance, and oestrogen deficiency (in women) that are known to be associated with reduced CFR and the impairment of endotheliumdependent vasodilation and release of endogenous vasoconstrictor substances such as endothelin-1 have been identified as contributors to CMD in these patients.85 Systemic inflammation has also been proposed as a pathogenic mechanism in this setting. Structural and functional alterations of systemic microvasculature with a

Inflammation, an intrinsic component of CIRD, represents the basis for increased CV risk in these patients, and it is conceivable that the earlier the initiation of anti-inflammatory treatment, the lower the risk of CV disease progression. As many patients affected by CIRD exhibit both micro- and macrovascular disease,35 it is extremely difficult to ascertain whether any clinical benefits that may derive from treatment, i.e. reduced incidence of major CV events, result from a beneficial effect on the epicardial coronary vessels, the coronary microcirculation, or both. A recent review by Ridker et al. addressed the potential usefulness of anti-inflammatory treatments in ischaemic heart disease. 88 The authors highlight how emerging anti-inflammatory approaches to vascular protection can be categorized into two broad groups: i.e. (i) those that target the central IL-6 inflammatory signalling pathway (including IL-1 and

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Figure 3 Published data about reduced coronary flow reserve in patients affected by chronic inflammatory rheumatoid diseases. (A) Lower

Coronary microvascular dysfunction in CIRD

the plaque’s necrotic core.95 All three studies provided negative results. The VISTA-16 was stopped prematurely because of a significant increase in the rate of MI by varespladib.96 The STABILITY trial demonstrated a non-significant reduction in the risk of CV events in patients with stable atherosclerosis treated with darapladib.97 Finally, the SOLID-TIMI-52 showed that darapladib did not reduce the risk of major coronary events in patients with acute coronary syndromes.98 Thus, conflictive results in different trials represent a challenge to the inflammatory hypothesis and therefore the results of ongoing large studies are eagerly awaited. Statins are widely used in atherosclerotic disease prevention due to their beneficial effects on LDL cholesterol. These agents have also been shown to have anti-inflammatory, anti-oxidant, and endothelial repairing properties.99 Clinical trials investigating the role of statins in the treatment and prevention of atherosclerosis have demonstrated that the reduction in the absolute risk of CV events seen with the use of statins was related to a parallel reduction of LDL cholesterol and C-reactive protein levels; these findings suggest that the anti-inflammatory effect of statins was dependent on LDL cholesterol levels.100 – 102 Statins have been tested in patients with CIRD. The TARA study, the first clinical trial that supported an anti-inflammatory effect of statins in RA, demonstrated that after 6 months of therapy with atorvastatin, there was a more rapid reduction in C-reactive protein concentrations and a reduction in the number of swollen joints compared with subjects on placebo.103 These results were also confirmed by a recent meta-analysis of 15 studies with a total of 992 RA

Figure 4 Proposal of diagnostic algorithm applicable to patients with chronic inflammatory conditions to identify those with coronary microvascular dysfunction and/or coronary artery disease. See text for more details. CIRD, chronic inflammatory rheumatoid diseases; RWM, regional wall motion; CMR, cardiac magnetic resonance; SPECT, single-photon emission computed tomography; CFR, coronary flow reserve; PET, positron emission tomography; ECG, electrocardiogram; RWMA, regional wall motion abnormalities; CMD, coronary microvascular dysfunction; CAD, coronary artery disease.

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TNF-a) and (ii) those that target alternative pathways such as secretory phospolipases, oxidative molecules, and adhesion molecules. The ‘inflammatory’ hypothesis of atherothrombosis is currently being tested by two large studies. The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) is a phase III trial, in patients with stable CAD and persistent elevation of C-reactive protein despite standard treatment. Canakinumab is a human monoclonal anti-human IL-1b antibody producing a reduction in C-reactive protein and IL-6 levels without influencing lipid levels and platelet function.89,90 The other study is CIRT (Cardiovascular Inflammation Reduction Trial), in patients with chronic atherosclerosis and either DM or metabolic syndrome who are being randomized to usual care plus placebo or to usual care plus low dose of methotrexate, one of the treatments of choice for RA. Methotrexate reduces IL-6 and C-reactive protein through a direct effect on the central IL-6 signalling pathway, with no substantial effect on lipid levels, haemostasis, or platelet function.90,91 Of interest, systematic reviews92 and meta-analyses93 have shown that methotrexate, a widely used disease-modifying anti-rheumatic drug with anti-inflammatory effects, is associated with reduced CV risk in RA patients, i.e. up to 21% reduction in risk for total CV events. Similar data have been presented for RA patients receiving treatment with TNF-a inhibitors such as etanercept and infliximab or the IL-6 inhibitor tocilizumab.94 Furthermore, three large phase III trials have been conducted to test the role of secretory phospholipase inhibitors varespladib or darapladib on recurrent vascular events. These two drugs do not influence IL-6 or C-reactive protein levels, but can improve the progression of

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Diagnostic algorithm: a proposal Given the likely contribution of CMD to the development of myocardial ischaemia and increased CV morbidity in CIRD, we believe that it would be logical to proactively search for the presence of CMD in these patients. Figure 4 shows our proposed diagnostic algorithm. Briefly, if RWMA or perfusion defects are identified together with ischaemic ECG signs and/or angina, the presence of obstructive CAD is confirmed. If no RWMA and/or perfusion defects are detected, despite development of ischaemic ECG changes and/or angina, then CMD is diagnosed if CFR is reduced. Finally, in patients who develop ischaemic ECG changes and/or angina during stress, but have normal CFR, invasive acetylcholine testing should be carried out to rule out macro- or microvascular spasm.114 The diagnostic algorithm proposed herein represents the authors’ opinion regarding possible strategies that could be implemented for the characterization of CIRD patients whose symptoms are suggestive of CMD. The proposed algorithm is not, as yet, backed up by specific data regarding the clinical benefit and costeffectiveness of the strategic approach that we advocate. We are aware of the many implications of implementing such an approach, including cost-efficacy considerations, diagnostic accuracy issues, and therapeutic strategies that may be derived from potential findings with this approach and that may not be effective. However, we believe that this algorithm may represent a useful initial effort aimed at both investigating—in the clinical setting—CMD as a pathogenic

mechanism underlying angina symptoms and creating the basis for the development of meaningful clinical research protocols. We have chosen to evaluate CFR by transthoracic echo-Doppler because of its non-invasive nature, widespread availability, and relatively low cost. Furthermore, previous studies have demonstrated that this technique allows reliable measurements of CFR, which are correlated with invasive Doppler guide wire measurements.115 – 117

Conclusion Coronary microvascular dysfunction has been demonstrated to play an important role in the development of CV manifestation in CIRD and worsening morbidity and mortality in these patients. The possible link between systemic inflammation and CMD may lead to an improvement in the treatment of CV involvement in CIRD although specific, ad hoc randomized trials are needed to prove it.

Authors’ contributions A.F., J.C.K., and P.G.C. acquired the data. J.C.K. and P.G.C. conceived and designed the research. A.F. drafted the manuscript. J.C.K. and P.G.C. made critical revision of the manuscript for key intellectual content. Conflict of interest: P.G. C. is consultant for Servier. J.C.K. has received small honoraria re speaking at scientific meetings—from Servier UK and Menarini UK.

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patients.104 A recent review regarding the impact of statin treatment on CV events in RA patients showed that statins were associated with reduced CV events and mortality when used for primary prevention but not in secondary prevention.105 In SLE, treatment with atorvastatin resulted in a higher reduction in atherosclerosis progression in patients with higher levels of C-reactive protein. 106 Moreover, a reduction of inflammatory biomarkers has been observed in antiphospholipid antibody-positive patients treated with fluvastatin.107 Unfortunately, conflicting results exist in the literature regarding the true role of statins in CIRD. Rosuvastatin has been shown to improve brachial artery flow- FMD, correct dyslipidaemia and decrease C-reactive protein and immune complex levels.108 Short term atorvastatin treatment, on the contrary, has been shown not to affect microvascular function or structure.109 Finally, treatment with pravastatin for 3 months has been reported to improve FMD and myocardial ischaemia in patients with microvascular angina.110 Given the importance of leucocytes in atherogenesis and disease progression, the SELECT-ACS trial has been conducted to test the effect of inclacumab, a recombinant monoclonal antibody against P-selectin. P-selectin is a cell surface glycoprotein involved in the initiation and progression of the atherosclerotic plaque mediating leucocyte tethering and rolling along the vascular endothelium. This phase II trial showed a moderate reduction of myocardial damage in patients with non-ST-segment elevation MI treated with inclacumab.111 Being RA a T-cell mediated disease, several drugs targeting T-lymphocytes have been tested and new ones are currently under investigation (i.e. the recombinant human protein abatacept and T cell vaccine), but no data are currently available regarding their role in preventing CV events.112,113

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Coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases.

Chronic inflammatory rheumatoid diseases (CIRD) such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis are an important ri...
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