The heart in rheumatoid arthritis
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Overview
Cardiac disease in rheumatoid arthritis can take on many forms related to either granulomatous proliferation or vasculitis. Advances in echocardiography have made the diagnosis of pericarditis and endocardial inflammyouration easier and more specific. Endomyocardial biopsy has further facilitated diagnosis and classification of myocarditis. In a detailed study of rheumatoid patients using echocardiography, Holter monitors, and electrocardiogram (ECG), it is reported that 70% of patients with nodular disease and 40% of those with non nodular rheumatoid arthritis have some form of cardiac involvement, including valve thickening or incompetence[1]
Rheumatoid arthritis (RA), by itself, may represent a significant independent risk factor for early atherosclerosis and development of cardiovascular disease [1] and many epidemiologic, clinical and laboratory investigations have suggested that the chronic inflammation and immune dysregulation that characterize rheumatoid arthritis may play a role in accelerating atherosclerosis.[1] [1] As also found in the RA joint, atherosclerotic plaques are characterized by enhanced expression of adhesion molecules and by abundant proinflammatory cytokine secreting cells, which are attracted by chemokines and locally activated endothelium.
The release of collagen-breaking mediators, such as matrix metalloproteinases, may play a role in the destabilization of atherosclerotic plaques, as well as in the erosion of cartilage and bone in the joint in rheumatoid arthritis. Thus, it is conceivable that the chronic systemic inflammation that characterizes RA might trigger early events that accelerate the development of diffuse atherosclerosis. It has been shown that the CVD mortality rate is higher in patients with RA who have more systemic manifestations of RA (i.e. those with lung involvement and vasculitis) and elevated markers of systemic inflammation.[1]
Functional abnormalities of the endothelium have been found in cohorts of patients with rheumatoid arthritis, independent of their age, duration of disease, degree of disease activity or seropositivity. Persistent endothelial dysfunction predisposes vascular walls to damage that can be detected at a preclinical stage by ultrasonographic measurement of carotid intimal medial thickness (IMT). Several studies have demonstrated increased carotid IMT in patients with RA.[1] [1] [1]
This finding could not be explained by corticosteroid treatment, but instead seems to be associated with disease duration and elevated markers of systemic inflammation, thereby emphasizing the importance of rheumatoid arthritis as a risk factor for atherosclerosis. Among the immunologic factors that are shared by the pathogenic processes of atherosclerosis and RA, a particular subset of CD4+ T cells that lack surface expression of CD28 (CD4+CD28–T) have caused concern in recent years. These CD4+CD28–T cells are probably stimulated to expand by endothelial autoantigens, and are found in increased numbers in the peripheral blood of patients with unstable angina pectoris and a subgroup of patients with RA.[1] Furthermore, they infiltrate atherosclerotic plaques and display pro inflammatory and tissue-damaging effects that promote vascular injury.
The role of these cells in the early development of atherosclerosis in rheumatoid arthritis was confirmed in a study showing that patients with rheumatoid arthritis and an expanded population of CD4+CD28–T cells have a higher degree of endothelial dysfunction and a higher carotid IMT than patients with normal levels of these cells.[1] In addition, the MHC II transactivator gene was recently found to be associated with differential expression of major histocompatibility complex molecules and susceptibility to RA and MI.[1]
Cardiac arrhythmias in rheumatoid arthritis
Coronary artery disease (CAD) is a major contributor to the increased risk of Sudden Cardiac Death in rheumatoid arthritis (RA), leading to acute coronary syndrome and ventricular arrhythmias [1] Accelerated coronary atherosclerosis, coronary vasculitis, superimposed coronary thrombosis, myocarditis and pulmonary hypertension also contribute to the rhythm disturbances.
Heart rate variability measurement is useful for the risk assessment for ventricular arrhythmias. Significant correlation was observed between Rheumatoid Arthritis activity and heart rate variability [1] In patients with high activity of RA, the decrease of heart rate variability reflects severity of inflammation. Decreased heart rate variability in degree I-II Rheumatoid Arthritis activity, is predictor for ventricular arrhythmias, Sudden Cardiac Death (SCD) and acute myocardial infarction (AMI).
Management of cardiac arrhythmias in rheumatic diseases
In the management of arrhythmias, the understanding of the aetiopathogenesis of Autoimmun Rheumatoid Disorders (ARD) is very important. In patients with a chronic disease, often related to significant disabilities, arrhythmias may cause anxiety despite its clinical irrelevance and reassurance is very important. Anti-arrhythmic drug therapy is the mainstay of management. Drug selection is based upon their electrophysiological effects and the type of arrhythmia. No randomized controlled trials have evaluated any of these therapies specifically for use in patients with rheumatological disease, and therefore, therapy should be tailored to the individual patient. Verapamil type calcium channel blockers are preferred for the treatment of supraventricular arrhythmias. Digoxin can be used to decrease ventricular response in atrial fibrillation and in end-stage heart failure. The treatment of sinus tachycardia in SLE is generally carried out by beta blockers. Classic beta blockers are contraindicated in patients with Progressive Systemic Sclerosis and conditions with vasculitis and pulmonary hypertension.
Ventricular fibrillation (except in the first few hours of acute MI) and medically intractable life-threatening VT are indications for treatment with implantable cardioverter defibrillators (ICDs) [1] Preventive ICD implantation was proven to decrease mortality of patients with dilated cardiomyopathy and in combination with resynchronization pacing is nowadays regarded as a treatment of choice for patients with heart failure and advanced left ventricular dysfunction. Importantly, defibrillators do not prevent symptomatic arrhythmias and should be combined with suppressive anti arrhythmic therapy. Radiofrequency (RF) ablation has revolutionized the approach to many types of arrhythmias.
Patients considered for RF catheter ablation of VT are those with symptomatic, sustained, monomorphic VT when the tachycardia is drug resistant, when the patient is drug intolerant or when the patient does not desire long term drug therapy; patients with bundle branch re-entrant VT; and patients with sustained monomorphic VT and an ICD who are receiving multiple shocks not manageable by re-programming or concomitant drug therapy.
Occasionally, non-sustained VT or even severely symptomatic PVCs require radio frequency (RF) catheter ablation. Success rates >90% are expected for accessory pathway tachycardias, para atrioventricular (AV) nodal re-entry tachycardia, atrial tachycardia and right ventricular outflow tract tachycardia. AV node ablation (used for ventricular rate control in atrial fibrillation) is possible in >99% of patients. Success rates of 85% are reported for the cure of atrial flutter [1]
Conduction disorders in rheumatoid arthritis
Atrioventricular block is unusual in RA but is probably related to direct granulomatous involvement. Primary infiltration of the AV node or other conducting tissue by mononuclear cells or rheumatoid granulomas can be revealed in patients with conduction disorders and RA. Pathologic examination may reveal proliferative lesions or healed scars. Complete heart block has been described in more than 30 patients with RA. It generally occurs in patients with established erosive nodular disease. [1] It usually is permanent and is caused by rheumatoid granulomas in or near the atrioventricular node or bundle of His. Rarely, amyloidosis is responsible for heart block.
Other potential mechanisms are vasculitis of the arterial supply to conductive tissue, haemorrhage into a rheumatoid nodule or extension of an inflammatory lesion from the aortic or mitral valve. Rarely, these lesions may be due to amyloid deposition. Villecco et al. [1] described right bundle branch block in 35% of 60 patients with RA. Antibodies to cardiac conducting tissue were found significantly more often in these patients than in those without conduction abnormalities (76 vs 21%). AV block is rare in RA usually complete, and does not respond to anti-inflammatory and immunosuppressive therapy. Ahern et al. [1] described congenital complete heart block (CHB) in 0.1% of patients with RA, mainly in females, with sudden onset, and more prevalent in patients with subcutaneous nodules. However, no major conduction disorders were noted in anti-Ro/SSA positive RA patients [1]
Management of conduction disturbances in rheumatic diseases
Pacemaker implantation is the method of choice for the treatment of complete heart block and other serious conduction abnormalities. Sophisticated pacing modalities and programmability as well as low-energy circuitry and new battery designs have increased device longevity and enabled wide clinical application. A simple VVI pacemaker (paces and senses the ventricle and is inhibited by a sensed ventricular event) may be adequate for transient or infrequent bradyarrhythmia. For frequent or persistent bradyarrhythmia, prolonged dependence on ventricular pacing may warrant use of a rate-responsive demand unit or, if no atrial or sinus node abnormalities are present, a dual-chamber system (DDD—both chambers are capable of being sensed and paced). New devices enable resynchronization therapy in patients with dilated cardiomyopathy and severely impaired contractility, with beneficial effect on haemodynamics and long-term survival.
Pericarditis
Infrequently diagnosed on the basis of history and physical examination in RA, pericarditis is present in up to 50% of patients at autopsy. In one study, 31% of patients with RA had echocardiographic evidence of [[pericardial effusion]. The same study revealed only rare evidence of impaired left ventricular function in prospectively studied outpatients with RA. [1]Although unusual, cardiac tamponade with constrictive pericarditis develops in RA and may require pericardectomy. Almost all patients have a positive test for RF, and half have nodules. The preservation of good ventricular function on echocardiography in the face of deteriorating clinical myocardial function should raise a high index of suspicion of constrictive pericarditis. [1]
Myocarditis
Myocarditis can take the form of either granulomatous disease or interstitial myocarditis. The granulomatous process resembles subcutaneous nodules and could be considered specific for the disease. Diffuse infiltration of the myocardium by mononuclear cells, on the other hand, may involve the entire myocardium and yet have no clinical manifestations, but it could possibly be suggested by echocardiography.
Cardiomyopathy
The RA-associated cardiomyopathy may be the result of focal non-specific, diffuse necrotizing or granulomatous myocarditis. These entities are histological diagnoses, which may befound in 3–30% of RA patients in postmortem studies. [1]
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. 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% [1]. The introduction of cardiovascular MRI (CMR) gives the opportunity to evaluate cardiac morphology and function by cineCMR, assess myocardialperfusion reserve by perfusion CMR and differentiate ischaemic cardiomyopathy more clearly from non ischaemic cardiomyopathy by delayed enhancement CMI. 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 andthe possible aetiology of non-ischaemic cardiomyopathy in this disease. [1]
Amyloidosis
Amyloidosis in RA has been reported in numerous caseseries studies to be present in a high variation of frequency, probably due to patients’ selection. [1] 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 [1]. Intensified immunosuppressive treatment should be considered if a RA patient is diagnosed with amyloidosis.
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. [1]
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.
Valve Disease
The most prevalent valve disease in Rheumatoid Arthritis is mitral valve insufficiency, varying from 30 to 80% in small case series followed by aortic valve insufficiency varying from 9 to 33% [1] From these studies, it appears that mitral valve insufficiency is found more frequently in Rheumatoid Arthritis patients compared with the general population and is associated with nodular Rheumatoid Arthritis.
Endocardial Inflammation
Echocardiographic studies have reported evidence of previously unrecognized mitral valve disease diagnosed by a reduced E-F slope of the anterior leaflet of the mitral valve. Although aortic valve disease and arthritis are generally associated through ankylosing spondylitis, a number of patients with granulomatous nodules on the valve have been reported [1]
Coronary Arteritis
Vasculitis of the coronary arteries has been observed in RA patients, up to 20% in postmortem studies published in the early 1960s, although it is diagnosed rarely during life. 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. A rapid and correct diagnosis is relevant, as RA patients with life-threatening vasculitis should be treated promptly with immunosuppressive drugs. [1]
Patients with severe Rheumatoid Arthritis and active vasculitis who develop a myocardial infarction are likely to have coronary arteritis as a basis for the process.
Congestive Heart Failure, Ischemic Heart Disease and Risk Factors
Congestive heart failure, more than ischemic heart diseases, appears to be an important contributor to the excess overall mortality among Rheumatoid Arthritis patients. Congestive Heart Failure contributes to this excess mortality primarily through the increased incidence of Congestive Heart Failure in Rheumatoid Arthritis, rather than increased mortality associated with Congestive Heart Failure in patients compared with non-Rheumatoid Arthritis patients [1]. The risk of developing Congestive Heart Failure in Rheumatoid Arthritis is twice the risk of developing CHF in persons without Rheumatoid Arthritis, and this excess is not explained by traditional cardiovascular risk factors and/or clinical ischaemic heart disease [1], [1]. Recurrence of cardiac events appears to be higher among RA patients compared with matched controls [1]
Cardiovascular death seems to be associated with markers of systemic inflammation in Rheumatoid Arthritis, i.e. increased sedimentation rate, Rheumatoid Arthritis vasculitis and Rheumatoid Arthritis lung disease [1]. Most importantly, RA patients are less likely to report symptoms of angina and are more likely to experience unrecognized myocardial infarction and sudden death [1]
Interestingly, Rheumatoid Arthritis patients were more likely to be hospitalized for acute myocardial infarction or to have experienced unrecognized myocardial infarctions prior to their diagnosis of Rheumatoid Arthritis.
Rheumatoid factor positive patients with a relatively short disease duration have increased cardiovascular mortality risk [1]. These observations extend the finding in pre-clinical RA patients that serum lipid levels are increased independently of inflammatory parameters [1]
Several reports showed that the increased incidence of cardiovascular disease, including ischemic heart disease, 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 [1] [1] [1]
References
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
