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1007/s11936-012-0208-3
Sarcoidosis
Granulomatous
Granuloma
Opinion statement
Cardiac sarcoidosis can be life threatening if not promptly diagnosed and treated appropriately and aggressively. The diagnosis of myocardial disease is often difficult and circumstantial because there are no reliable diagnostic tests. Except for the finding of noncaseating granulomas on endomyocardial biopsy, most tests are limited and nonspecific. Therefore, the decision of initiating treatment is based on the patients symptoms and the course of the disease, rather than on the presence of histologic confirmation. The goal of therapy is to prevent irreversible cardiomyopathy and to thwart the progression to heart transplantation. The mainstay of treatment is corticosteroids, although there are no large randomized trials analyzing corticosteroid use. The combination with other immunosuppressant agents, such as Methotrexate and Azathioprine, is initiated on the patients failing or experiencing severe side effects from corticosteroids. While there are small studies proving the efficacy of tumor necrosis factor-inhibitors in cardiac sarcoidosis, more experience with these agents is needed. Catheter ablation or placement of implantable devices is indicated prophylactically in patients with severe ventricular tachyarrhythmias. Heart transplantation should be considered in patients with severe heart failure refractory to medical therapy. This article focuses on the current diagnostic tests and treatment recommendations for cardiac sarcoidosis.
Introduction
Sarcoidosis is a multisystemic disease characterized by the presence of noncaseating granulomas in the affected organs. Lung involvement is the most common presentation in 90 % of the cases, manifested by bilateral hilar lymphadenopathy. Approximately 30 % of these patients have extrapulmonary involvement. The following extrapulmonary sites are affected in decreasing frequency: skin, endocrine organs, extra-thoracic lymph nodes, neurologic sites, eyes, liver, spleen, bone marrow, cardiac,
Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors) ear/nose/throat, parotid/salivary, muscles, bones/ joint, and kidney [1]. The clinical involvement of heart occurs in about 5 % of patients. However, autopsy studies indicate that subclinical cardiac involvement is present in 2030 % of cases [2, 3, 4]. In a retrospective autopsy review at the Los Angeles CountyUniversity of California Medical Center, cardiac involvement was found in 24 of 123 sarcoid patients (19.5 %) [5]. Cardiac involvement may occur at any time during the course of the disease, and can be considered a poor prognostic factor. In a study by Iwai et al., Japanese patients showed the highest rate of cardiac sarcoid-attributed death, either from sudden death or heart failure [6, 7]. It may precede, follow or occur concurrently with pulmonary manifestations. Asymptomatic heart involvement is also common. For this reason, cardiac sarcoidosis is frequently first diagnosed postmortem, and is a more common cause of death than previously reported. In a review of autopsy cases to evaluate the contribution of sarcoidosis to death, 50 % resulted from cardiac involvement and 43 % from pulmonary disease. Antemortem diagnosis was made in only 29 % of the fatal cardiac cases, versus 75 % of the pulmonary cases [8]. which could be either systolic or diastolic in nature. It is difficult to distinguish this diagnosis from idiopathic dilated cardiomyopathy, especially in patients without evidence of sarcoidoisis in other organs. Direct valvular involvement is uncommon in sarcoidosis. While infiltration of the pericardium may lead to pericardial effusions and fibrosis [10, 11], clinical pericarditis is rare. Constrictive pericarditis and pericardial tamponade have also been described [12 14]. Pulmonary hypertension is well described in sar-
Table 1. Revised guidelines for diagnosing cardiac sarcoidosis 2006 (Japan Society of Sarcoidosis and Other Granulomatous Disorders)
1. Histologic diagnosis group Cardiac sarcoidosis is confirmed when myocardial biopsy specimens demonstrate noncaseating epithelioid cell granuloma with histological or clinical diagnosis of extracardiac sarcoidosis. 2. Clinical diagnosis group Cardiac sarcoidosis is diagnosed in the absence of a cardiac biopsy when extracardiac sarcoidosis is diagnosed histologically or clinically and satisfies the following conditions and more than one in six basic diagnostic criteria. (1) More than two of four major criteria are satisfied, OR (2) One in four major criteria and more than two in five minor criteria are satisfied. Major Criteria (a) Advanced AV block (b) Basal thinning of the interventricular septum (c) Positive cardiac gallium uptake (d) Left ventricle ejection fraction less than 50 % Minor Criteria (a) Abnormal ECG findings: Ventricular arrhythmias (VT, multifocal or frequent PVCs), CRBBB, axis deviation or abnormal Q-wave (b) Abnormal echocardiography: Regional abnormal wall motion or morphological abnormality (ventricular aneurysm, wall thickening) (c) Perfusion defect detected by 201Tl myocardial scintigraphy or 99Tc myocardial scintigraphy (d) Gd-enhanced MRI: Delayed enhancement of myocardium. (e) Endomyocardial biopsy: Interstitial fibrosis or monocyte infiltration over moderate grade
AV: atrioventricular; ECG: electrocardiogram; VT: ventricular tachycardia; PVCs: premature ventricular contractions; MRI: magnetic resonance imaging; CRBBB: Complete right bundle branch block
Clinical manifestations Any part of the heart can be involved, but the granulomatous inflammation has a predilection for the conduction system. Complete heart block is the most common finding in patients with clinical evidence of sarcoidosis [9]. This is due to the involvement of the basal septum by scar tissue, granuloma formation, or the involvement of the atrioventricular (AV) nodal artery, leading to ischemia in the conduction system [6]. Sustained or nonsustained ventricular tachycardia (VT) and ventricular premature beats are the second most common presentation of cardiac sarcoidosis. A necropsy series by Roberts et al. reported the following electrocardiogram (ECG) abnormalities: complete heart block (22 %); complete bundle branch block (22 %); VT (17 %); premature ventricular contractions (PVCs) (29 %); and atrial arrhythmias (16 %) [10]. If syncope occurs in a younger patient, the diagnosis of sarcoidosis should be entertained. Extensive myocardial granulomatous infiltration results in dilated cardiomyopathy and heart failure,
Cardiac Sarcoidosis: Diagnosis and Management coidosis. Its prevalence ranges from 5.7 % to 73.8 % in patients listed for lung transplantation [1517]. Cor pul-
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Diagnosis
The diagnosis of cardiac sarcoidosis is challenging because the clinical manifestations are nonspecific and there is no gold standard diagnostic test. In 2006, the original Japanese Ministry of Health and Welfare guidelines for the diagnosis of cardiac sarcoidosis were revised (Table 1)[18]. However, most diagnostic tests have low sensitivity and/or specificity, and the optimal strategy is unknown [19].
Endomyocardial biopsy
Transvenous right ventricular (RV) endomyocardial biopsy was introduced in 1962. It has a limited yield of 19 % [20], due to the patchy involvement of the myocardium, particularly in early or mild disease. Also, the biopsies are obtained mostly from the RV free wall and apex of the interventricular septum, whereas granulomas more commonly are found in the left ventricular (LV) free wall or base of the septum [10]. Therefore, there is a need to obtain multiple specimens with each procedure, due to increased sampling error [21]. Because of the low yield and potential morbidity associated with endomyocardial biopsies, we currently do not recommend routine use of biopsy techniques to confirm cardiac sarcoidosis. However, biopsy should be considered if there is no evidence of heart involvement by other diagnostic tests or no histological confirmation of sarcoidosis in any other tissue.
Eletrocardiography
There is evidence that the prevalence of ECG abnormalities is related to the severity of the disease. A study done by Silverman et al. [22] reported that 15 % of the patients without cardiac involvement at autopsy had ECG abnormalities, versus 42 % in patients with mild cardiac involvement (visible only on microscopy), and 75 % in patients with severe involvement (gross evidence of granulomas or infiltration). A resting ECG should be ordered as a screening test in every patient with sarcoidosis.
Echocardiography
Echocardiographic abnormalities have been detected in 1441 % of patients with sarcoidosis, even in the absence of ECG changes and clinical
Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors) symptoms [2426]. Echocardiography may document abnormalities such as pericardial effusions, depressed ejection fraction, ventricular aneurysms, valvular regurgitation, mitral valve prolapse due to papillary muscle dysfunction, left ventricular dilatation or hyperthrophy, diastolic dysfunction, chamber enlargement, segmental or global hypokinesis or dyskinesis [5, 27]. Cardiac tissue, particularly the ventricular septum or the left ventricular free wall, appears hyperechogenic when there is granulomatous involvement and scar formation [25]. Echocardiography cannot identify microscopic granulomas, and the test cannot definitively establish or exclude the presence of cardiac sarcoidosis.
Radionuclide imaging
Myocardial imaging with thallium-201 in patients with suspected cardiac sarcoidosis is useful to suggest myocardial involvement, and to exclude cardiac dysfunction secondary to coronary artery disease. This radionuclide is absorbed by living heart muscle cells. Areas with scars, necrosis, ischemia or inflammation accumulate less thallium-201 and appear as cold spots [28]. Thus, segmental areas of decreased thallium-201 uptake in the ventricular myocardium correspond to areas of fibro-granulomatous replacement [5, 28]. Rest imaging may mimic patterns seen with coronary artery disease, although the distribution of defects may not be typical for coronary disease. On delayed scans or with exercise, dipyridamole or adenosine, the perfusion defects decrease in size in patients with sarcoidosis, in contrast to the increase seen in patients with coronary artery disease [29]. This phenomenon, known as reverse distribution [30], is not specific for cardiac sarcoidosis, as it may also occur in other cardiomyopathies. Progression or regression of thallium perfusion defects is useful in monitoring the response to treatment [31]. The Technetium-99 sesta-methoxy-isobutyl-isonitrile (sestamibi) has higher radioactivity than thallium-201 or gallium-67, and may be more sensitive for evaluating myocardial involvement [32, 33]. The combined use of thallium-201 and gallium-67 (which concentrates in areas of active inflammation) may improve the detection of cardiac sarcoidosis. In addition, small series suggest that the presence of gallium-avid lesions may predict a greater response to glucocorticoid treatment [34]. Radionuclide studies may be useful in patients in whom cardiac sarcoidosis is suspected because of clinical or electrocardiographic findings. These tests are not recommended as screening tests in individuals with sarcoidosis involving other organs, because nonspecific results can also occur [35].
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sequence for evaluation of cardiac sarcoidosis [19, 3741]. Preliminary observations suggest that monitoring gadolinium enhancement may also be helpful in the assessment of the efficacy of steroid therapy [3739].
Coronary angiography
Cardiac catheterization with coronary angiography is useful in excluding atherosclerotic coronary artery disease. Vascular filling defects may be seen due to granulomas in the myocardium, and wall motion abnormalities may be seen on the ventriculogram. Perfusion defects on thallium-201 imaging in patients with known systemic sarcoidosis strongly suggest cardiac involvement if coronary angiography has excluded significant atherosclerosis. Primary sarcoidosis rarely involves the coronary arteries [43].
Treatment
The evidence of active cardiac sarcoidosis is an indication for treatment, due to the poor prognosis of the disease and the increased risk of sudden death. The treatment of cardiac sarcoidosis is aimed at controlling the inflammation and fibrosis, which characterize the disease, and at preventing compromise of cardiac structure or function. Corticosteroids are the mainstay for treatment, even though there are no large randomized controlled trials to support their efficacy. Recommendations are based on case reports and retrospective studies. If congestive heart failure is present, it should be managed similarly to the other forms of dilated cardiomyopathy. Angiotensin-converting-enzyme (ACE) inhibitors, diuretics and betablocking agents should be given in addition to the immunosuppressive therapy. The indication for antiarrhythmic therapy and implantable devices are also similar to those in patients without cardiac sarcoidosis.
Pharmacological treatment
Glucocorticoids
Because of their ability to attenuate the inflammatory response, glucocorticoids are believed to be capable of halting or slowing the progression of inflammation and fibrosis in sarcoidosis. However, the data that support efficacy are largely anecdotal. In a retrospective, survey-based study of 104 cases of cardiac sarcoidosis, survival was better with glucocorticoids than with usual care (64 % versus 40 %) [44]. In another report, 75 patients with cardiac sarcoidosis treated with glucocorticoids were compared to 20 patients not treated with glucocorticoids, in whom the diagnosis of cardiac sarcoidosis was proven at autopsy [45]. Five-year survival was much higher in the steroid-treated patients (75 % versus 10 %). Among the treated patients, the outcome was best (89 % five-year survival) when steroids were begun when the left ventricular ejection fraction was 50 %. This observation suggests that early initiation of therapy is important to prevent deterioration of cardiac function. Therefore, we recommend immunosuppression for documented or suspected cardiac sarcoidosis, particularly when cardiac symptoms, ECG abnormalities, or thallium-201 imaging defects are present. The optimal dose of glucocorticoids is not known, and choosing a dose requires balancing the risk of side effects with the likelihood of response [46]. Doses of 6080 mg of prednisone daily are generally needed initially [2]. We recommend reducing the dose gradually to a maintenance level of 1015 mg per day over a period of 6 months.
Hypersensitivity to any component of the formulation; systemic fungal infections; administration of live or live attenuated vaccines with immunosuppressive doses of prednisone; active or recent varicella infection; active or recent measles infection. Warfarinmay enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy. Wound healing impaired, osteoporosis, bruising, hypertension, glaucoma, insomnia, cataracts, avascular necrosis, peptic ulcer disease, weight gain, hyperglycemia, Cushing syndrome, psychosis, steroid myopathy. Relapses are common after tapering of steroid therapy, as evidenced by clinical deterioration or worsening of electrocardiographic, echocardiographic, or thallium studies. If serial evaluations reveal that the disease is stable or dormant, glucocorticoids may be tapered further and eventually discontinued. Vigilance must continue, however, for the rest of the patient's life. Any evidence of recurrence should be handled by reinstituting or increasing prednisone to 60 mg/day. Available in the generic form. 10 mg (21 ea): $24.80.
Standard dosage
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Other immunosuppressants
Treatment with alternative agents such as methotrexate, azathioprine, chloroquine, hydroxychloroquine and cyclosporine can be used as a steroid-sparing agent, or in patients who do not respond to glucocorticoids or who cannot tolerate their side effects. There are several case reports and
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small studies done on patients with pulmonary sarcoidosis using these agents [47, 48, 49, 50]. However, the experience with myocardial sarcoidosis is limited. Therefore, there are insufficient data to recommend a specific treatment algorithm for the use of these alternative medications for cardiac sarcoidosis. Methotrexate is the most commonly used steroid-sparing agent for sarcoidosis. The typical dose for this agent is 1020 mg/week, and it can be administered orally or intramuscularly. Due to the greater clinical experience with methotrexate, azathioprine is usually used in patients who have failed methotrexate, due to side effects or lack of benefit. Azathioprine can be also used as a supplement to glucocorticoids rather than as a single drug [51, 52]. The usual starting dose of Azathioprine is 50 mg/day, to a target dose of 2 mg/ kg/d orally. Infliximab is a monoclonal antibody that specifically inhibits tumor necrosis factor-alpha (TNF-alpha), a cytokine that plays a role in the inflammation of sarcoidosis. This agent has been used in pulmonary sarcoidosis for patients who have persistent disease despite treatment with glucocorticoids and at least one second-line immunosuppressive agent [53 55]. The dose of Infliximab is 35 mg/kg intravenously at weeks 0, 2, 6, and 12. The optimal frequency for subsequent dosing is not known. There are some small studies proving the efficacy of this drug in cardiac sarcoidosis, but larger trials are necessary [5658].
Interventional procedures
Sustained or nonsustained VT and ventricular premature beats are the second most common presentation of cardiac sarcoidosis. Sarcoid granulomas in the ventricular myocardium can become foci for abnormal automaticity, or may disrupt ventricular activation and recovery, causing reentrant arrhythmias. Sudden death due to VTs or conduction block accounts for 2565 % of deaths due to cardiac sarcoidosis [10, 45]. Atrial arrhythmias, however, likely reflect atrial dilatation secondary to ventricular dysfunction or pulmonary involvement, rather than direct atrial involvement from granulomas or scar tissue [10, 59]. They are less common than ventricular arrhythmias, occurring in 1517 % of cases. Described presentations are paroxysmal atrial tachycardia, atrial flutter, atrial fibrillation, and sinus arrest secondary to granulomatous involvement of the sinus node [59].
Catheter ablation
In addition to device implantation, catheter ablation or antiarrhythmic agents may be effective in eliminating or reducing recurrent uncontrollable VTs [60] and preventing electrical storm. It may also benefit cardiac sarcoidosis patients who suffer from spontaneous VT to have catheter ablation prior to device implantation. Recently, prophylactic catheter ablation has been demonstrated to have a benefit in patients who will have implantable cardioverter defibrillator (ICD) implantation for sustained VT associated with ischemic cardiomyopathy [61].
Contraindications Few absolute contraindications exist. Radiofrequency ablation should not be performed in the presence of a known atrial or ventricular thrombus due to
Complications
Special points
Cost/cost-effectiveness
Assist devices
There is a high recurrence rate of VT or sudden death with antiarrhythmic drug therapy, even when guided by electrophysiologic testing [68]. In addition, antiarrhythmic agents may increase the risk of heart block in these patients. For these reasons, we recommend the use of pacemakers and ICDs in cardiac sarcoidosis, in combination with aggressive medical therapy.
Contraindications Complications
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related, lead-related, pacemaker generator or device-related: bleeding, infection, hematoma, phlebitis or thrombophlebitis of vein, air or pulmonary embolism, dysrhythmias, chylothorax, tricuspid valve laceration, pneumothorax, hemothorax, cardiac tamponade, lead dislodgement, lead malfunction or fracture, Twiddler syndrome, and pacemaker malfunction. Cost/cost-effectiveness Generally accepted as cost effective, based on quality-adjusted life years for each patient and their associated costs.
Surgery
Heart transplantation
The diagnosis of sarcoidosis should not bar consideration of potential transplantation [73, 74]. Heart transplantation should be considered in patients with severe heart failure refractory to medical therapy, especially in younger patients. The largest published experience comes from a retrospective review from the United Network for Organ Sharing (UNOS) database of 65 patients (mean age 46) with sarcoidosis who underwent cardiac transplantation [73]. This represents less than 0.2 % of all transplants. One-year post-transplant survival was better for sarcoid patients than for patients receiving transplantation for all other diagnoses (87.7 % versus 84.5 %). Estimated post-transplant survival at five years was 80 % for patients with sarcoidosis. Cardiac transplantation can be avoided if corticosteroid treatment is started before the occurrence of severe systolic dysfunction. Recurrent sarcoidosis can occur in the transplant, and has been documented to recur 24 weeks to 19 months after transplantation [75]. Absolute contraindications include current malignancy, fixed pulmonary hypertension, HIV/AIDS, any systemic process with a high probability of recurring in the transplanted heart, and systemic illness that would limit survival despite heart transplantation. Relative contraindications include advanced age, diabetes mellitus with end organ damage, severe lung disease, active systemic infection, psychosocial impairment that would jeopardize post-transplant survival, uncorrected abdominal aneurysms greater than 4 6 cm, asymptomatic carotid stenosis greater than 75 %, or symptomatic less severe carotid artery stenosis, and peripheral vascular disease not amenable to revascularization.
Acute cellular rejection, acute antibody mediated rejection, infection, chronic rejection, phrenic nerve dysfunction, gastroparesis, chylothorax, malignancies, hypertension, diabetes mellitus, osteoporosis, dyslipidemia, kidney disease, allograft coronary artery disease, arrhythmias, death. Data from the International Society for Heart and Lung Transplantation indicate a generally excellent functional capacity after cardiac transplantation. Data show that about 90 % of surviving patients have no limitation of activity at 1 year and 5 years post-transplantation [76]. According to Transplant Living, the average total cost of a single heart transplant in 2011 was $997,700, including hospital stay and anti-rejection drugs
Contraindications
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Disclosure
No potential conflicts of interest relevant to this article were reported.
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