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Rheumatology 2006 45(Supplement 4):iv4-iv7; doi:10.1093/rheumatology/kel313
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The heart and cardiovascular manifestations in rheumatoid arthritis

A. E. Voskuyl

Department of Rheumatology, 4-A-42, VU University Medical Center, POB 9057, 1007 MB, Amsterdam, The Netherlands.

Correspondence to: Alexandre E. Voskuyl, MD, PhD, Department of Rheumatology, 4-A-42, VU University Medical Center, POB 9057, 1007 MB Amsterdam, The Netherlands. E-mail: ae.voskuyl{at}vumc.nl


   Abstract
Top
 Abstract
Introduction
 References
 
Cardiovascular features in rheumatoid arthritis (RA) are common. Among those are the classical extra-articular features that not only include pericarditis, cardiomyopathy/myocarditis, cardiac amyloidosis, coronary vasculitis, arrythmia and valve diseases, but also congestive heart failure and ischaemic heart disease which are found more frequently and are associated with an increased mortality compared with the general population. This overview discusses the epidemiological aspects of these cardiovascular diseases and their relevance for diagnosis and treatment of RA.


   Introduction
Top
 Abstract
 Introduction
References
 
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, and extra-articular features may also develop. Joint pain, swelling and limited mobility of the joint are the most prominent features. The disease course varies greatly between patients. Some patients have a mild disease course although in the majority of patients, the disease leads to progressive joint destruction and disability. Besides articular symptoms, RA can be associated with extra-articular features. Extra-articular features, some associated with histological vasculitis, are considered to be one of the prognostic severe signs of RA [1, 2]. Among those extra-articular features are cardiovascular diseases, including pericarditis, cardiomyopathy/myocarditis, cardiac amyloidosis, coronary vasculitis, arrythmia, valve diseases and, most importantly, congestive heart failure and ischaemic heart disease. When compared with the general population, RA is associated with an increased mortality the majority of which is originating from cardiovascular diseases [3].

In this overview on cardiac involvement in RA, epidemiological aspects and their relevance for diagnosis and treatment of RA patients will be discussed.

Pericarditis
The most common cardiac involvement in RA is pericarditis. Varying the method of assessment (echographic or postmortem studies), pericarditis occurs in 30–50% of the patients [4]. While high incidences are found by echographic or postmortem studies, clinical evidence of pericarditis is much lower, i.e. <10% in patients with severe RA [4–7]. Classically, pericarditis occurs predominantly in male patients with severely destructive and nodular RA, as is the case with other extra-articular features of RA [7]. The prognosis of RA patients with clinical pericarditis appears to be impaired, in particular in the first year after diagnosis, and the age and cardiac status best predict survival [8]. Whether pericarditis itself contributes significantly to the overall mortality is unknown, except perhaps in the few patients with constrictive pericarditis or rapidly progressive effusive pericarditis that are known to be associated with a high morbidity and mortality. Treatment with non-steroidal anti-inflammatory drugs, corticosteroids and/or other immunosuppressive drugs seems appropriate in the majority of patients with a definite diagnosis of RA-associated pericarditis, and in severe cases, pericardiectomy is warranted.

The majority of patients develop pericarditis after the onset of arthritis; however, pericarditis may precede the diagnosis of RA in some patients. The use of an aetiological evaluation strategy in patients with pericardial effusion may help in diagnosing RA early, including a thorough physical examination and antibody screening [i.e. anti-nuclear antibodies, IgM-rheumatoid factor and anti-citrullinated peptide (anti-CCP)] [9]. The early diagnosis of RA is relevant, and effective treatment improves the outcome of patients with RA [10].

Cardiomyopathy
Cardiomyopathy consists of a group of diseases, often of unknown aetiology, involving the heart muscle itself and are not a result of ischaemic, hypertensive, congenital, valvular or pericardial diseases. Two classification schemes are frequently used. First, the functional classification includes dilated or congestive cardiomyopathy, hypertrophic cardiomyopathy and restrictive cardiomyopathy. These distinctions are not absolute as overlaps can occur. Second, the primary and the secondary cardiomyopathies, the latter includes RA amongst other aetiologies. The RA-associated cardiomyopathy may be the result of focal non-specific, diffuse necrotizing or granulomatous myocarditis. These entities are histological diagnoses, which may be found in 3–30% of RA patients in postmortem studies [4]. Furthermore, some drugs used in the treatment of RA have also been associated with cardiomyopathy, for instance, corticosteroids and anti-malarials, and the aetiology of cardiomyopathies in RA may therefore be difficult to determine [11].

Little is known on the epidemiology of RA-associated cardiomyopathy. For instance, in one small case-series of 30 RA patients, cardiomyopathy was found by echography in 37% [12]. The recent introduction of cardiovascular MRI (CMR) gives the opportunity to evaluate cardiac morphology and function by cineCMR, assess myocardial perfusion reserve by perfusion CMR and differentiate ischaemic cardiomyopathy more clearly from non-ischaemic cardiomyopathy by delayed enhancement CMI [13, 14]. To date, no large-scale studies with CMI have been performed in RA, but it should be envisaged to do so in order to determine the frequency and the possible aetiology of non-ischaemic cardiomyopathy in this disease.

Amyloidosis
Cardiac amyloidosis is one of the causes of restrictive cardiomyopathy, and the infiltration with fibrillar proteins can cause a loss of compliance and impairs diastolic function as well as systolic function. Although a definite diagnosis of cardiac amyloidosis is made histologically, a ‘sparkling’ pattern on echography of the heart may suggest its presence. Furthermore, on echography and with MRI, functional impairment and biventricular hypertrophy can be observed [13]. Systematic prospective studies on the prevalence and incidence of (cardiac) amyloidosis in RA are lacking, although it is considered to be rare. Amyloidosis in RA has been reported in numerous case-series studies to be present in a high variation of frequency, probably due to patients’ selection [4, 15]. Amyloidosis occurs preferentially in male patients with a longer disease duration. The relevance of cardiac involvement including cardiac amyloidosis is illustrated by the high frequency of cardiac failure as a cause of mortality in RA patients treated with haemodialysis [16]. Intensified immunosuppressive treatment should be considered if a RA patient is diagnosed with amyloidosis.

Coronary vasculitis
Vasculitis of the coronary arteries has been observed in RA patients, up to 20% in postmortem studies published in the early 1960s [17, 18], although it is diagnosed rarely during life [19, 20]. As in the general population, abnormalities of the coronary arteries are mainly due to atherosclerosis. Differentiation between atherosclerosis and diffuse cardiac vasculitis may be obtained by electro beam CT for the detection of coronary artery calcification or endomyocardial biopsy for the diagnosis of vasculitis [21]. A rapid and correct diagnosis is relevant, as RA patients with life-threatening vasculitis should be treated promptly with immunosuppressive drugs [22, 23].

Rheumatoid nodules or granuloma
Rheumatoid nodules (also called rheumatoid granuloma) may occur in all organs and also in the epicardial fat, epicardium, myocardium, interventricular septum, chordae tendinae, aorta and valves. These nodules may cause functional impairment such as arrhythmias and valve disease. There is no evidence that immunosuppressive treatment may resolve these cardiac nodules, and if functional cardiac impairment occurs, symptom-reducing drugs or surgical treatment should be considered.

Arrhythmia
Arrhythmia is an important cause of mortality in RA and may be secondary to ischaemia, conduction abnormalities due to rheumatoid nodules, amyloidosis or congestive heart failure. Also, it seems that RA patients may have an increased sympathetic activity, which may play a role in the development of ventricular tachy-arrhythmias [24]. Furthermore, it has been shown that QT-dispersion and corrected QT-dispersion intervals were significantly longer in RA compared with healthy controls, and it was suggested that QT-dispersion may be a useful marker of cardiovascular morbidity and mortality due to complex ventricular arrhythmias in RA [25]. Also, QT-dispersion seems to be related to disease duration [26]. However, whether these QT-dispersions are disease related or should be related to drugs used in the treatment of RA remains to be determined.

Valve disease
The most prevalent valve disease in RA is mitral valve insufficiency, varying from 30 to 80% in small case series followed by aortic valve insufficiency varying from 9 to 33% [11, 27]. From these studies, it appears that mitral valve insufficiency is found more frequently in RA patients compared with the general population and is associated with nodular RA.

Congestive heart failure, ischaemic heart disease and risk factors
Mounting evidence has been obtained in the past years about cardiovascular mortality in RA, as reviewed by Van Doornum et al. [3]. More recently, congestive heart failure, more than ischaemic heart diseases, appears to be an important contributor to the excess overall mortality among RA patients. CHF contributes to this excess mortality primarily through the increased incidence of CHF in RA, rather than increased mortality associated with CHF in patients compared with non-RA patients [28]. The risk of developing CHF in RA is twice the risk of developing CHF in persons without RA, and this excess is not explained by traditional cardiovascular risk factors and/or clinical ischaemic heart disease [29, 30]. Recurrence of cardiac events appears to be higher among RA patients compared with matched controls [31]. Cardiovascular death seems to be associated with markers of systemic inflammation in RA, i.e. increased sedimentation rate, RA vasculitis and RA lung disease [32]. Most importantly, RA patients are less likely to report symptoms of angina and are more likely to experience unrecognized myocardial infarction and sudden death [33]. Interestingly, RA patients were more likely to be hospitalized for acute myocardial infarction or to have experienced unrecognized myocardial infarctions prior to their diagnosis of RA [33]. In addition, rheumatoid factor positive patients with a relatively short-disease duration have increased cardiovascular mortality risk [34]. These observations extend the finding in pre-clinical RA patients that serum lipid levels are increased independently of inflammatory parameters [35].

Several reports showed that the increased incidence of cardiovascular disease, including ischaemic heart diseases, or the presence of carotid atherosclerosis is not explained by traditional cardiovascular risk factors (smoking, lipid levels, diabetes, hypertension and body mass index), suggesting that RA-related factors might influence the risk of cardiovascular disease [36–38].

The hypothesis that RA-related factors might influence the risk of cardiovascular disease is supported by several observations. Coronary calcification, a marker of ischaemic heart disease, as detected with electron-beam CT-scan, was found more frequently and was more severe in patients with established RA than in early RA patients and controls [38], which is in line with observations made by del Rincon et al. [37] using carotid ultrasound as marker of cardiovascular disease. Interestingly, a significant interaction between cardiovascular risk factors and sedimentation rate was found, suggesting that the effect of inflammation on intima-media thickness varied according to the number of risk factors. Additional support for the hypothesis that RA-severity and atherosclerosis are associated is shown in an unique small case control study in patients with RA without cardiovascular risk factors. In that study, an association between carotid plaques and the presence of extra-articular features was found. Other evidence is coming from a study that found an association between the presence of extra-articular features in RA and non-cardiac vascular events, i.e. cerebrovascular disease and peripheral vascular disease [39]. Further support for this hypothesis is coming from a study showing an association between the severity of joint damage as determined by the Larsen score and intima-media thickness, although the latter has not been confirmed by others [40, 41]. Finally, in patients with RA who developed congestive heart failure, the proportion of patients with an increased erythrocyte sedimentation rate >40 mm/h was highest during the 6-month period immediately preceding the new onset of heart failure, as compared with the average sedimentation rate during the entire remaining follow-up, both before and after heart failure, again suggesting that inflammatory stimuli may be involved in initiation of heart failure among patients with RA [42].

The increased prevalence of congestive heart failure found in RA patients is underlined by recent echocardiographic studies. Left ventricular systolic dysfunction has been found to be three times more common than in the general population and was associated with abnormal electrocardiography, suggesting that screening of RA patients with abnormal electrocardiography may be worthwhile [43]. Also, right and left ventricular diastolic dysfunction are found more frequently in RA patients without evident cardiovascular disease [44].

Whether RA itself or other factors in RA may have deleterious effect on the heart and the cardiovascular system is not clear, but there is some evidence that drugs used in RA may be the cause. For instance, the use of corticosteroids decreases inflammation and has lipid lowering effects, thereby reducing the pro-atherogenic effect of inflammation [45]. Contrary to these observations is the association found between carotid plaques and high exposure of corticosteroids (>16 gm lifetime), independently of cardiovascular risk factors and RA clinical manifestations [46]. However, in that study, no association was found with intima-media thickness and lower-limb arterial obstruction and, therefore, it remains unclear whether there is a clear deleterious effect of corticosteroids on the cardiovascular system. Another drug implicated in cardiovascular disease is methotrexate [47], although others showed the contrary in large-scale studies, i.e. the use of methotrexate is associated with a reduced cardiovascular mortality and morbidity [48, 49]. Recently, the use of anti-TNF in RA patients with cardiovascular disease has been debated due to the observation of an increased mortality of non-RA patients with congestive heart failure who were treated with anti-TNF agents compared with placebo-treated patients. Although a variety of possible explanations are brought up and none are elucidated yet, recommendations have been proposed on the use of anti-TNF in patients with a history of congestive heart failure [50, 51]. Most recently, the use of paracetamol and NSAIDs at high frequency or dose has been associated with an increased risk of cardiovascular events in the general population, and it was suggested that this association remained after controlling for diseases such as RA [52]. Also, the use of COX-2 inhibitors has been associated with an increased risk of cardiovascular events [53–55]. Although such association studies do not prove any causality, it put forward the need of guidelines on how NSAIDs and COX-2 inhibitors should be used in RA.

As the use of several drugs in RA, including corticosteroids and biological therapy, have such an important positive effect in the reduction of arthritis activity and improvement of functional capacity, it is important to have more knowledge on possible deleterious effects on the function of the heart due to these drugs.

How to reduce cardiovascular morbidity and mortality in RA?
Much has to be learned from future studies on cardiovascular diseases, i.e. to determine the prevalence and incidence of cardiomyopathy and valve disease that may be detected more easily with new imaging techniques like echocardiography and cardiovascular MRI, and may explain why congestive heart failure is more important than ischaemic heart disease in the mortality of RA. In the mean time, strategies to reduce cardiovascular disease implied in the general population should be used extensively in RA. Also, more RA oriented strategies will be needed as RA-specific factors are important as well [56], and, therefore, more knowledge is needed on these factors and among those drugs used in RA. Finally, it has been shown that untreated comorbidity in patients with RA is an important problem and joint efforts of rheumatologists and cardiologists may help to improve the cardiovascular morbidity and mortality in RA [57, 58].

The authors have declared no conflicts of interest.


   References
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 Introduction
 References
 

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