Cardiac Sarcoidosis

Current Treatment Options in Cardiovascular MedicineDOI 10.1007/s11936-012-0208-3

Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

Cardiac Sarcoidosis: Diagnosisand ManagementMichelle Bussinguer, MD1,*

Alfred Danielian, MD2

Om P. Sharma, MD, FRCP, Master FCCP, FACP1

Address*,1Division of Pulmonary and Critical medicine, Keck School of Medicine of USC,Los Angeles, CA, USAEmail: [email protected] of Cardiology, University of Connecticut Health Center, Farmington,CT, USA

* Springer Science+Business Media, LLC 2012

Keywords Cardiac sarcoidosis I Sarcoidosis I Granulomatous I Granuloma

Opinion statement

Cardiac sarcoidosis can be life threatening if not promptly diagnosed and treated appropri-ately and aggressively. The diagnosis of myocardial disease is often difficult and circum-stantial because there are no reliable diagnostic tests. Except for the finding ofnoncaseating granulomas on endomyocardial biopsy, most tests are limited and nonspe-cific. Therefore, the decision of initiating treatment is based on the patient’s symptomsand 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 progressionto heart transplantation. The mainstay of treatment is corticosteroids, although there areno large randomized trials analyzing corticosteroid use. The combination with other immu-nosuppressant agents, such as Methotrexate and Azathioprine, is initiated on the patient’sfailing or experiencing severe side effects from corticosteroids. While there are small stud-ies proving the efficacy of tumor necrosis factor-inhibitors in cardiac sarcoidosis, more ex-perience with these agents is needed. Catheter ablation or placement of implantabledevices is indicated prophylactically in patients with severe ventricular tachyarrhythmias.Heart transplantation should be considered in patients with severe heart failure refractoryto medical therapy. This article focuses on the current diagnostic tests and treatment rec-ommendations for cardiac sarcoidosis.

IntroductionSarcoidosis is a multisystemic disease characterizedby the presence of noncaseating granulomas inthe affected organs. Lung involvement is the mostcommon presentation in 90 % of the cases, mani-fested by bilateral hilar lymphadenopathy. Approx-

imately 30 % of these patients have extrapulmonaryinvolvement. The following extrapulmonary sitesare affected in decreasing frequency: skin, endocrineorgans, extra-thoracic lymph nodes, neurologicsites, eyes, liver, spleen, bone marrow, cardiac,

ear/nose/throat, parotid/salivary, muscles, bones/joint, and kidney [1]. The clinical involvement ofheart occurs in about 5 % of patients. However, au-topsy studies indicate that subclinical cardiac in-volvement is present in 20–30 % of cases [2••, 3,4]. In a retrospective autopsy review at the LosAngeles County–University of California MedicalCenter, cardiac involvement was found in 24 of123 sarcoid patients (19.5 %) [5]. Cardiac involve-ment may occur at any time during the course ofthe disease, and can be considered a poor prognos-tic factor. In a study by Iwai et al., Japanesepatients showed the highest rate of cardiac sar-coid-attributed death, either from sudden death orheart failure [6, 7]. It may precede, follow or occurconcurrently with pulmonary manifestations.Asymptomatic heart involvement is also common.For this reason, cardiac sarcoidosis is frequentlyfirst diagnosed postmortem, and is a more com-mon cause of death than previously reported. In areview of autopsy cases to evaluate the contributionof sarcoidosis to death, 50 % resulted from cardiacinvolvement and 43 % from pulmonary disease.Antemortem diagnosis was made in only 29 % ofthe fatal cardiac cases, versus 75 % of the pulmo-nary cases [8].

Clinical manifestationsAny part of the heart can be involved, but the gran-ulomatous inflammation has a predilection for theconduction system. Complete heart block is themost common finding in patients with clinical evi-dence of sarcoidosis [9]. This is due to the involve-ment of the basal septum by scar tissue, granulomaformation, or the involvement of the atrioventricu-lar (AV) nodal artery, leading to ischemia in theconduction system [6]. Sustained or nonsustainedventricular tachycardia (VT) and ventricular prema-ture beats are the second most common presenta-tion of cardiac sarcoidosis. A necropsy series byRoberts 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 syncopeoccurs in a younger patient, the diagnosis of sar-coidosis should be entertained.

Extensive myocardial granulomatous infiltrationresults in dilated cardiomyopathy and heart failure,

which could be either systolic or diastolic in nature.It is difficult to distinguish this diagnosis from idi-opathic dilated cardiomyopathy, especially inpatients without evidence of sarcoidoisis in otherorgans.

Direct valvular involvement is uncommon insarcoidosis. While infiltration of the pericardiummay lead to pericardial effusions and fibrosis [10, 11],clinical pericarditis is rare. Constrictive pericarditis andpericardial tamponade have also been described [12–14]. Pulmonary hypertension is well described in sar-

Table 1. Revised guidelines for diagnosing cardiacsarcoidosis 2006 (Japan Society of Sarcoidosis andOther Granulomatous Disorders)

1. Histologic diagnosis groupCardiac sarcoidosis is confirmed when myocardial biopsyspecimens demonstrate noncaseating epithelioid cellgranuloma with histological or clinical diagnosis ofextracardiac sarcoidosis.

2. Clinical diagnosis groupCardiac sarcoidosis is diagnosed in the absence of acardiac biopsy when extracardiac sarcoidosis is diagnosedhistologically or clinically and satisfies the followingconditions and more than one in six basic diagnosticcriteria.(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 orabnormal Q-wave

(b) Abnormal echocardiography: Regional abnormal wallmotion or morphological abnormality (ventricularaneurysm, wall thickening)

(c) Perfusion defect detected by 201Tl myocardial scintig-raphy or 99Tc myocardial scintigraphy

(d) Gd-enhanced MRI: Delayed enhancement of myocardium.(e) Endomyocardial biopsy: Interstitial fibrosis or mono-

cyte infiltration over moderate grade

AV: atrioventricular; ECG: electrocardiogram; VT: ventriculartachycardia; PVCs: premature ventricular contractions; MRI: mag-netic resonance imaging; CRBBB: Complete right bundle branchblock


coidosis. Its prevalence ranges from 5.7 % to 73.8 % inpatients listed for lung transplantation [15–17]. Cor pul-

monale may develop in patients with advanced fibroticpulmonary sarcoidosis.

Diagnosis

The diagnosis of cardiac sarcoidosis is challenging because the clinicalmanifestations are nonspecific and there is no gold standard diagnostic test. In2006, the original Japanese Ministry of Health and Welfare guidelines for thediagnosis of cardiac sarcoidosis were revised (Table 1)[18]. However, most di-agnostic tests have low sensitivity and/or specificity, and the optimal strategy isunknown [19].

Endomyocardial biopsyTransvenous right ventricular (RV) endomyocardial biopsy was introducedin 1962. It has a limited yield of 19 % [20••], due to the patchy involvementof the myocardium, particularly in early or mild disease. Also, thebiopsies are obtained mostly from the RV free wall and apex of theinterventricular septum, whereas granulomas more commonly are foundin the left ventricular (LV) freewall or base of the septum [10]. Therefore, there isa need to obtain multiple specimens with each procedure, due to increasedsampling error [21].

Because of the low yield and potential morbidity associated with endomyo-cardial biopsies, we currently do not recommend routine use of biopsytechniques to confirm cardiac sarcoidosis. However, biopsy should be consid-ered if there is no evidence of heart involvement by other diagnostic testsor no histological confirmation of sarcoidosis in any other tissue.

EletrocardiographyThere is evidence that the prevalence of ECG abnormalities is related to the se-verity of the disease. A study done by Silverman et al. [22] reported that 15% ofthe patients without cardiac involvement at autopsy had ECG abnormalities,versus 42 % in patients with mild cardiac involvement (visible only on mi-croscopy), and 75 % in patients with severe involvement (gross evidence ofgranulomas or infiltration). A resting ECG should be ordered as a screening testin every patient with sarcoidosis.

Holter monitoring and exercise ECGTwenty-four-hour Holter monitoring and exercise electrocardiographyshould be routinely performed in patients with suspected or knowncardiac sarcoidosis. These studies can document and define subclinicalrhythm disturbances that are missed on ECG [23]. Moreover, Holtermonitoring may identify severe tachyarrhythmias or heart block, even inasymptomatic patients [5, 23].

EchocardiographyEchocardiographic abnormalities have been detected in 14–41 % ofpatients with sarcoidosis, even in the absence of ECG changes and clinical

Cardiac Sarcoidosis: Diagnosis and Management Bussinguer et al.

symptoms [24–26]. Echocardiography may document abnormalities such aspericardial effusions, depressed ejection fraction, ventricular aneurysms,valvular regurgitation, mitral valve prolapse due to papillary muscle dysfunc-tion, 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 freewall, appears hyperechogenic when there is granulomatous involvementand scar formation [25]. Echocardiography cannot identify microscopic granu-lomas, and the test cannot definitively establish or exclude the presence ofcardiac sarcoidosis.

Radionuclide imagingMyocardial imaging with thallium-201 in patients with suspected cardiacsarcoidosis is useful to suggest myocardial involvement, and to excludecardiac dysfunction secondary to coronary artery disease. This radionuclide isabsorbed by living heart muscle cells. Areas with scars, necrosis, ischemiaor inflammation accumulate less thallium-201 and appear as “ cold spots”[28]. Thus, segmental areas of decreased thallium-201 uptake in the ventric-ular 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 perfusiondefects decrease in size in patients with sarcoidosis, in contrast to the increaseseen in patients with coronary artery disease [29•]. This phenomenon,known as “reverse distribution” [30], is not specific for cardiac sarcoidosis, as itmay also occur in other cardiomyopathies. Progression or regression of thalliumperfusion defects is useful in monitoring the response to treatment [31].

The Technetium-99 sesta-methoxy-isobutyl-isonitrile (sestamibi) hashigher radioactivity than thallium-201 or gallium-67, and may be moresensitive for evaluating myocardial involvement [32, 33]. The combined useof thallium-201 and gallium-67 (which concentrates in areas of active in-flammation) may improve the detection of cardiac sarcoidosis. In addition,small series suggest that the presence of gallium-avid lesions may predict agreater response to glucocorticoid treatment [34].

Radionuclide studies may be useful in patients in whom cardiacsarcoidosis is suspected because of clinical or electrocardiographic find-ings. These tests are not recommended as screening tests in individualswith sarcoidosis involving other organs, because nonspecific resultscan also occur [35].

Magnetic resonance imaging (MRI)Magnetic resonance imaging (MRI) may improve the sensitivity of diagnosisof myocardial sarcoidosis. MRI findings include localized high intensityregions on T2-weighted images and early gadolinium-enhanced lesions,caused by the edema associated with inflammation and granuloma forma-tion. Delayed gadolinium enhancement represents myocardium that hasbeen replaced by the fibro-granulomatous tissue of sarcoidosis, resulting indecreased wall motion [36]. This test has emerged as the dominant MRI


sequence for evaluation of cardiac sarcoidosis [19, 37–41]. Preliminaryobservations suggest that monitoring gadolinium enhancement may also behelpful in the assessment of the efficacy of steroid therapy [37–39].

Positron emission tomography (PET)Cardiac involvement can be clearly diagnosed by fluorodeoxyglucose(FDG)-PET technique, but data are based on small studies only. Yami-gishi et al. performed FDG- PET in 17 patients with cardiac sarcoidosis[42]. FDG-PET was positive in 14 (82 %) of these patients, versus sixpatients (35 %) with thallium-201 defects, and only three patients(18 %) with abnormal gallium-67 accumulation. In addition, thepatients who were treated with steroids showed a decrease in uptake andhence improvement on FDG-PET. This imaging study seems promisingfor both diagnosis and monitoring of disease activity. Appropriate pa-tient preparation is key to maximize study results, and specific protocolsshould be followed. Carbohydrate load prior to the test will result inelevated insulin levels, which will drive glucose into the muscle cells,causing increase FDG uptake by the myocardium. High protein dietcauses reduction of cardiac uptake normally seen on a scan. Therefore,patients should be instructed to follow a high protein/low carbohydratediet for 12 hours and fast for at least 6 hours prior to the exam. Exerciseshould also be avoided for a minimum of 24 hours prior to FDG-PET,since it will cause hypermetabolism, leading to increased activity of FDGin muscle groups that have recently undergone contraction.

Coronary angiographyCardiac catheterization with coronary angiography is useful in excluding ath-erosclerotic coronary artery disease. Vascular filling defects may be seen due togranulomas in themyocardium, andwallmotion abnormalitiesmay be seen onthe ventriculogram. Perfusion defects on thallium-201 imaging in patients withknown systemic sarcoidosis strongly suggest cardiac involvement if coronaryangiography has excluded significant atherosclerosis. Primary sarcoidosis rarelyinvolves the coronary arteries [43].

Treatment

The evidence of active cardiac sarcoidosis is an indication for treatment, due to thepoor prognosis of the disease and the increased risk of sudden death. The treat-ment of cardiac sarcoidosis is aimed at controlling the inflammation and fibrosis,which characterize the disease, and at preventing compromise of cardiac structureor function. Corticosteroids are themainstay for treatment, even though there areno large randomized controlled trials to support their efficacy. Recommendationsare based on case reports and retrospective studies. If congestive heart failure ispresent, it should be managed similarly to the other forms of dilated cardiomy-opathy. Angiotensin-converting-enzyme (ACE) inhibitors, diuretics and beta-blocking agents should be given in addition to the immunosuppressive therapy.The indication for antiarrhythmic therapy and implantable devices are alsosimilar to those in patients without cardiac sarcoidosis.


Pharmacological treatment

Glucocorticoids

Because of their ability to attenuate the inflammatory response, glucocor-ticoids are believed to be capable of halting or slowing the progression ofinflammation and fibrosis in sarcoidosis. However, the data that supportefficacy are largely anecdotal. In a retrospective, survey-based study of 104cases of cardiac sarcoidosis, survival was better with glucocorticoids thanwith usual care (64% versus 40%) [44]. In another report, 75 patients withcardiac sarcoidosis treated with glucocorticoids were compared to 20patients not treated with glucocorticoids, in whom the diagnosis of cardiacsarcoidosis was proven at autopsy [45]. Five-year survival was muchhigher in the steroid-treated patients (75 % versus 10 %). Among thetreated patients, the outcome was best (89 % five-year survival)when steroids were begun when the left ventricular ejection fractionwas ≥50 %. This observation suggests that early initiation of therapyis important to prevent deterioration of cardiac function. Therefore,we recommend immunosuppression for documented or suspectedcardiac sarcoidosis, particularly when cardiac symptoms, ECG ab-normalities, or thallium-201 imaging defects are present.

Standard dosage The optimal dose of glucocorticoids is not known, and choosing a doserequires balancing the risk of side effects with the likelihood of response[46]. Doses of 60–80 mg of prednisone daily are generally needed initially[2••]. We recommend reducing the dose gradually to a maintenance level of10–15 mg per day over a period of 6 months.

Contraindications Hypersensitivity to any component of the formulation; systemic fungalinfections; administration of live or live attenuated vaccines with immuno-suppressive doses of prednisone; active or recent varicella infection; active orrecent measles infection.

Main drug interactions Warfarin—may enhance the anticoagulant effect of Warfarin. Risk C: Monitortherapy.

Main side effects Wound healing impaired, osteoporosis, bruising, hypertension, glauco-ma, insomnia, cataracts, avascular necrosis, peptic ulcer disease, weightgain, hyperglycemia, Cushing syndrome, psychosis, steroid myopathy.

Special points Relapses are common after tapering of steroid therapy, as evidenced by clinicaldeterioration or worsening of electrocardiographic, echocardiographic, or thalli-um studies. If serial evaluations reveal that the disease is stable or dormant, glu-cocorticoids may be tapered further and eventually discontinued. Vigilance mustcontinue, however, for the rest of the patient's life. Any evidence of recurrenceshould be handled by reinstituting or increasing prednisone to 60 mg/day.

Cost/cost-effectiveness Available in the generic form. 10 mg (21 ea): $24.80.

Other immunosuppressants

Treatment with alternative agents such as methotrexate, azathioprine,chloroquine, hydroxychloroquine and cyclosporine can be used as asteroid-sparing agent, or in patients who do not respond to glucocorticoidsor who cannot tolerate their side effects. There are several case reports and


small studies done onpatientswithpulmonary sarcoidosis using these agents[47, 48•, 49, 50]. However, the experience with myocardial sarcoidosis islimited. Therefore, there are insufficient data to recommend a specific treat-ment algorithm for the use of these alternative medications for cardiac sar-coidosis. Methotrexate is the most commonly used steroid-sparing agent forsarcoidosis. The typical dose for this agent is 10–20 mg/week, and it can beadministered orally or intramuscularly. Due to the greater clinical experiencewith methotrexate, azathioprine is usually used in patients who have failedmethotrexate, due to side effects or lack of benefit. Azathioprine can be alsoused as a supplement to glucocorticoids rather than as a single drug [51, 52].The usual starting dose of Azathioprine is 50mg/day, to a target dose of 2mg/kg/d orally. Infliximab is a monoclonal antibody that specifically inhibitstumor necrosis factor-alpha (TNF-alpha), a cytokine that plays a role in theinflammation of sarcoidosis. This agent has been used in pulmonary sar-coidosis for patients who have persistent disease despite treatment withglucocorticoids and at least one second-line immunosuppressive agent [53–55]. The dose of Infliximab is 3–5 mg/kg intravenously at weeks 0, 2, 6, and12. The optimal frequency for subsequent dosing is not known. There aresome small studies proving the efficacy of this drug in cardiac sarcoidosis, butlarger trials are necessary [56–58].

Interventional procedures

Sustained or nonsustained VT and ventricular premature beats are thesecond most common presentation of cardiac sarcoidosis. Sarcoid gran-ulomas in the ventricular myocardium can become foci for abnormalautomaticity, or may disrupt ventricular activation and recovery, causingreentrant arrhythmias. Sudden death due to VTs or conduction blockaccounts for 25–65 % of deaths due to cardiac sarcoidosis [10, 45].Atrial arrhythmias, however, likely reflect atrial dilatation secondary toventricular dysfunction or pulmonary involvement, rather than directatrial involvement from granulomas or scar tissue [10, 59]. They are lesscommon than ventricular arrhythmias, occurring in 15–17% of cases. Describedpresentations are paroxysmal atrial tachycardia, atrial flutter, atrial fibrillation,and sinus arrest secondary to granulomatous involvement of the sinus node [59].

Catheter ablationIn addition to device implantation, catheter ablation or antiarrhythmic agentsmay be effective in eliminating or reducing recurrent uncontrollable VTs [60] andpreventing electrical storm. It may also benefit cardiac sarcoidosis patients whosuffer from spontaneous VT to have catheter ablation prior to device implanta-tion. Recently, prophylactic catheter ablation has been demonstrated tohave a benefit in patients who will have implantable cardioverter defi-brillator (ICD) implantation for sustained VT associated with ischemiccardiomyopathy [61].

Contraindications Few absolute contraindications exist. Radiofrequency ablation should not beperformed in the presence of a known atrial or ventricular thrombus due to


concern for thromboembolism. Also,mechanical prosthetic valves are generallynot crossed with ablation catheters.

Complications Major complication rates are rare and range from 0.8–6 %, depending on theablation procedure [62]. The incidences of complications are similar inyounger and older patients and include [63–65]: radiation exposure,arrhythmias, death (0.1–0.3 %); heart block requiring permanent pacemaker(1–2 %); thromboembolism (G 1 %), including pulmonary embolism, sys-temic embolism, and stroke; complications stemming from vascular access(2–4 %); cardiac trauma, including tamponade, myocardial infarction andperforation, valvular damage (1–2 %), rare reports of coronary artery dis-section and embolism, esophagoatrial fistula formation (0.01–0.2 %) andpulmonary hypertension due to pulmonary vein stenosis after atrial fibril-lation ablation.

Special points Even tough most arrhythmias that are treated with ablation are not life-threatening, they often impair the patient’s functional capacity and senseof well-being [66]. Radiofrequency ablation of supraventricular andventricular arrhythmias has been demonstrated to improve the patient’shealth-related quality of life and functional capacity [66, 67].

Cost/cost-effectiveness In the United States, catheter ablation costs between $17,000 and $21,000initially, with an ongoing cost of $1,500 to $2,000 per year. In comparison,medical therapy costs $4,000 to $5,000 per year.

Assist devicesThere is a high recurrence rate of VT or sudden death with antiarrhythmicdrug therapy, even when guided by electrophysiologic testing [68]. In addi-tion, antiarrhythmic agents may increase the risk of heart block in thesepatients. For these reasons, we recommend the use of pacemakers and ICDsin cardiac sarcoidosis, in combination with aggressive medical therapy.

Pacemakers and automatic implantable cardioverter-defibrillator (ICD)

Most pacemakers are inserted to treat bradycardia. Indications for pace-maker insertion include sinus node dysfunction, atrioventricular block,chronic bifascicular block, after the acute phase of a myocardial infarction,hypersensitive carotid sinus syndrome and neurocardiogenic syncope, aswell as other special situations. Glucocorticoids or other forms of anti-in-flammatory therapy should be continued on an individual basis (as toler-ated and as needed clinically) in patients who have pacemakers.There is limited experience with ICDs in patients with cardiac sarcoidosis[68, 69••, 70]. The 2008 American College of Cardiology/AmericanHeart Association/Heart Rhythm Society guidelines for device-basedtherapy offer clinical considerations for patients with cardiac sarcoidosisbut no specific recommendations for ICD therapy [71]. For this reason,the indications for ICDs are similar to those in patients with other causesof cardiomyopathies, such as primary and secondary prevention ofsudden cardiac death.

Contraindications Local infection at the device implantation site and active infection withbacteremia.

Complications The rate of complications during or shortly after device implantationranges from 1–5 % [72]. Complications can be access-related, pocket-


related, lead-related, pacemaker generator or device-related: bleeding,infection, hematoma, phlebitis or thrombophlebitis of vein, air orpulmonary embolism, dysrhythmias, chylothorax, tricuspid valve lac-eration, pneumothorax, hemothorax, cardiac tamponade, lead dis-lodgement, lead malfunction or fracture, Twiddler syndrome, andpacemaker malfunction.

Cost/cost-effectiveness Generally accepted as cost effective, based on quality-adjusted life yearsfor each patient and their associated costs.

Surgery

Heart transplantation

The diagnosis of sarcoidosis should not bar consideration of poten-tial transplantation [73, 74]. Heart transplantation should be con-sidered in patients with severe heart failure refractory to medicaltherapy, especially in younger patients. The largest published expe-rience comes from a retrospective review from the United Networkfor Organ Sharing (UNOS) database of 65 patients (mean age 46)with sarcoidosis who underwent cardiac transplantation [73]. Thisrepresents less than 0.2 % of all transplants. One-year post-transplantsurvival was better for sarcoid patients than for patients receivingtransplantation for all other diagnoses (87.7 % versus 84.5 %). Es-timated post-transplant survival at five years was 80 % for patientswith sarcoidosis. Cardiac transplantation can be avoided if cortico-steroid treatment is started before the occurrence of severe systolicdysfunction. Recurrent sarcoidosis can occur in the transplant, andhas been documented to recur 24 weeks to 19 months after trans-plantation [75].

Contraindications Absolute contraindications include current malignancy, fixed pulmonaryhypertension, HIV/AIDS, any systemic process with a high probability ofrecurring in the transplanted heart, and systemic illness that would limitsurvival despite heart transplantation. Relative contraindications includeadvanced age, diabetes mellitus with end organ damage, severe lung disease,active systemic infection, psychosocial impairment that would jeopardizepost-transplant survival, uncorrected abdominal aneurysms greater than 4–6 cm, asymptomatic carotid stenosis greater than 75 %, or symptomatic lesssevere carotid artery stenosis, and peripheral vascular disease not amenableto revascularization.

Complications Acute cellular rejection, acute antibody mediated rejection, infection, chronicrejection, phrenic nerve dysfunction, gastroparesis, chylothorax, malignan-cies, hypertension, diabetes mellitus, osteoporosis, dyslipidemia, kidneydisease, allograft coronary artery disease, arrhythmias, death.

Special points Data from the International Society for Heart and Lung Transplantationindicate a generally excellent functional capacity after cardiac trans-plantation. Data show that about 90 % of surviving patients have nolimitation of activity at 1 year and 5 years post-transplantation [76].

Cost/cost effectiveness According to Transplant Living, the average total cost of a single hearttransplant in 2011 was $997,700, including hospital stay and anti-rejectiondrugs


Disclosure

No potential conflicts of interest relevant to this article were reported.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. The pathology of pulmonary sarcoidosis: update.Ma Y, Gal A, Koss MN. Semin Diagn Pathol. 2007Aug;24(3):150–61. Review. PMID: 17882899[PubMed - indexed for MEDLINE]

2.•• Chapelon-Abric C, de Zuttere D, Duhaut P, et al.Cardiac sarcoidosis: a retrospective study of 41cases. Medicine (Baltimore). 2004;83:315–34.

In this retrospective study, 39 patients received steroidtherapy (initial dose mostly equal to 1 mg/kg per day),associated in 13 cases with another immunosuppressivetreatment. In 26% of cases the immunosuppressivetreatment was associated with a specific cardiac treat-ment. In the long-term follow-up, 87% of the casesshowed an improvement, and 54% were cured from aclinical and laboratory point of view. In conclusion, theauthors recommend treatment of cardiac sarcoidosis withcorticosteroids as soon as possible and to use anotherimmunosuppressive treatment where there is an insuffi-cient therapeutic response or where there are contraindi-cations to corticosteroids.3. Kim JS, Judson MA, Donnino R, et al. Cardiac sar-

coidosis. Am Heart J. 2009;157:9.4. Thomsen TK, Eriksson T. Myocardial sarcoidosis in fo-

rensic medicine. Am J Forensic Med Pathol. 1999;20:52.5. Sharma OP, Maheshwari A, Thaker K. Myocardial

sarcoidosis. Chest. 1993;103:253–8.6. Matsui Y, Iwai K, Tachibana T, et al. Clinicopatho-

logical study on fatal myocardial sarcoidosis. Ann NY Acad Sci. 1976;278:455–69.

7. Iwai K, Sekiguti M, Hosoda Y, et al. Racial differencein cardiac sarcoidosis incidence observed at autopsy.Sarcoidosis. 1994;11:26–31.

8. Perry A, Vuitch F. Causes of death in patients withsarcoidosis: a morphologic study of 38 autopsieswith clinicopathologic correlations. Arch Pathol LabMed. 1995;119:167–72.

9. Fleming HA. Sarcoid heart disease. Br Heart J1974;36:54–68.

10. Roberts WC, McAllister Jr HA, Ferrans VJ. Sarcoidosisof the heart. A clinicopathologic study of 35 necropsypatients (group 1) and review of 78 previously de-scribed necropsy patients (group 11). Am J Med.1977;63:86–108.

11. Angomachalelis N, Hourzamanis A, Salem N, et al.Pericardial effusion concomitant with specific heartmusle disease in systemic sarcoidosis. Postgrad MedJ. 1994;70 Suppl 1:S8–S12.

12. Garret J, O’Neill H, Blake S. Constrictive pericarditisassociated with sarcoidosis. Am Heart J.1984;107:394.

13. Israel RH, Poe RH. Massive pericardial effusion insarcoidosis. Respiration. 1994;61:176–80.

14. Verkleeren JL, Glover MU, Bloor C, et al. Cardiactamponade secondary to sarcoidosis. Am Heart J.1983;106:601–3.

15. Shorr AF, Helman DL, Davies DB, Nathan SD. Pul-monary hypertension in advanced sarcoidosis: epi-demiology and clinical characteristics. Eur Respir J.2005;25:783–8.

16. Handa T, Uozato H, Higa R, et al. Incidence of pul-monary hypertension and its clinical relevance inpatients with sarcoidosis. Chest. 2006;129:1246–52.

17. Nunes H, Humbert M, Capron F, et al. Pulmonaryhypertension associated with sarcoidosis: mecha-nisms, haemodynamics and prognosis. Thorax.2006;61:68–74.

18. Hiraga, H, Yuwai, K, Hiroe, M, et al. Guidelines for thediagnosis of cardiac sarcoidosis: Study Report of DiffusePulmonary Diseases. The Japanese Ministry of Healthand Welfare 1993; pp. 23–24

19. Smedema JP, Snoep G, van Kroonenburgh MP, et al.Evaluation of the accuracy of gadolinium-enhancedcardiovascular magnetic resonance in the diagnosis ofcardiac sarcoidosis. J Am Coll Cardiol. 2005;45:1683.

20.•• Uemura A, Morimoto S, Hiramitsu S, et al. Histologicdiagnostic rate of cardiac sarcoidosis: evaluation ofendomyocardial biopsies. Am Heart J.1999;138:299–302.

This study investigated the diagnostic success rate of histo-logic evaluation of endomyocardial biopsy specimens inpatients with this disease. Noncaseating granulomas werefound in only 5 (19.2 %) of the 26 cases, thus permitting ahistologic diagnosis of cardiac sarcoidosis. The diagnosticrate achieved with biopsy in cardiac sarcoidosis was low. Inconclusion, the authors recommend that patients with sar-coidosis and evidence of significant cardiac involvement


should be treated for cardiac sarcoidosis despite negativemyocardial biopsies for this disease.21. Ratner SJ, Fenoglio JJ, Ursell P. Utility of endomyo-

cardial biopsy in the diagnosis of cardiac sarcoidosis.Chest. 1986;90:528–33.

22. Silverman KJ, Hutchins GM, Buckley BH. CardiacSarcoid: a clinicopathologic study of 84 unselectedpatients with systemic sarcoidosis. Circulation.1978;58:1204–11.

23. Suzuki T, Kanda T, Kubota S, et al. Holter monitoringas a noninvasive indicator of cardiac involvement insarcoidosis. Chest. 1994;106:1021.

24. Kinney EL, Jackson GL, Reeves WC, et al. Thallium-scan myocardial defects and echocardiographic ab-normalities in patients with sarcoidosis withoutclinical cardiac dysfunction: an analysis of 44patients. Am J Med. 1980;68:497–503.

25. Fahy GJ, Marwick T, McCreery CJ, et al. Dopplerechocardiographic detection of left ventricular dia-stolic dysfunction in patients with pulmonary sar-coidosis. Chest. 1996;109:62–6.

26. Burstow DJ, Tajik AJ, Bailey KR, et al. Two-dimen-sional echocardiographic findings in systemic sar-coidosis. Am J Cardiol. 1989;63:478–82.

27. Lewin RF, Mor R, Spitzer S, et al. Echocardiographicevaluation of patients with systemic sarcoidosis. AmHeart J. 1985;110:116–22.

28. Bulkley BH, Rouleau JR, Whitaker JQ, et al. Theuse of 201thallium for myocardial perfusion im-aging in sarcoid heart disease. Chest. 1977;72:27–32.

29.• Haywood LJ, Sharma OP, Siegel ME, et al. Detectionof myocardial sarcoidosis by thallium-201 imaging. JNatl Med Assoc. 1982;74:959.

In this study, Thallium-201 myocardial perfusion scanningrevealed focal left ventricular defects at rest in 13 % of pa-tient with systemic sarcoidosis. All the defects decreased insize during thallium stress imaging, a finding opposite ofthat usually seen in myocardial ischemia. Right ventricularuptake generally appears to correlate with the severity ofpulmonary involvement by sarcoidosis, yet does not appearto be a specific finding.30. Tellier P, Paycha F, Antony I, et al. Reversibility by

dipyridamole of thallium-201 myocardial defectsin patients with sarcoidosis. Am J Med.1988;85:189–93.

31. Mañá J. Nuclear imaging. 67Gallium, 201thallium,18F-labeled fluoro-2-deoxy-D-glucose positronemission tomography. Clin Chest Med. 1997;18:799.

32. Le Guludec D, Menad F, Faraggi M, et al. Myo-cardial sarcoidosis: clinical value of technetium-99m sestamibi tomoscintigraphy. Chest.1994;106:1675–168.

33. Eguchi M, Tsuchihashi K, Hotta D, et al. Technetium99m sestamibi/tetrofosmin myocardial perfusionscanning in cardiac and noncardiac sarcoidosis. Car-diology. 2000;94:193–9.

34. Okayama K, Kurata C, Tawarahara K, et al. Diag-nostic and prognostic value of myocardial scintigra-phy with thallium-201 and gallium-67 in cardiacsarcoidosis. Chest. 1995;107:330.

35. Kiuchi S, Teraoka K, Koizumi K, et al. Usefulness oflate gadolinium enhancement combined with MRIand 67-Ga scintigraphy in the diagnosis of cardiacsarcoidosis and disease activity evaluation. Int JCardiovasc Imaging. 2007;23:237.

36. Tadamura E, Yamamuro M, Kubo S, et al. Effec-tiveness of delayed enhanced MRI for identifica-tion of cardiac sarcoidosis: comparison withradionuclide imaging. AJR Am J Roentgenol.2005;185:110–5.

37. Shimada T, Shimada K, Sakane T, et al. Diagnosis ofcardiac sarcoidosis and evaluation of the effects of ste-roid therapy by gadolinium-DTPA-enhanced magneticresonance imaging. Am J Med. 2001;110:520.

38. Matsuki M, Matsuo M. MR findings of myocardialsarcoidosis. Clin Radiol 2000;55:323–5.

39. Smedema JP, Snoep G, van Kroonenburgh MP, et al.The additional value of gadolinium-enhanced MRI tostandard assessment for cardiac involvement inpatients with pulmonary sarcoidosis. Chest.2005;128:1629.

40. Vignaux O, Dhote R, Duboc D, et al. Clinical signif-icance of myocardial magnetic resonance abnormal-ities in patients with sarcoidosis: a 1-year follow-upstudy. Chest. 2002;122:1895.

41. Patel MR, Cawley PJ, Heitner JF, et al. Detection ofmyocardial damage in patients with sarcoidosis.Circulation. 2009;120:1969.

42. Yamagishi H, Shirai N, Takagi M, et al. Identificationof cardiac sarcoidosis with (13)N-NH(3)/(18)F-FDGPET. J Nucl Med. 2003;44:1030–6.

43. Butany J, Bahl NE, Morales K, et al. The intricacies ofcardiac sarcoidosis: a case report involving the coro-nary arteries and a review of the literature. Cardio-vasc Pathol. 2006;15:222.

44. Takada K, Ina Y, Yamamoto M, et al. Prognosis afterpacemaker implantation in cardiac sarcoidosis in Ja-pan. Clinical evaluation of corticosteroid therapy.Sarcoidosis. 1994;11:113.

45. Yazaki Y, Isobe M, Hiroe M, et al. Prognostic deter-minants of long-term survival in Japanese patientswith cardiac sarcoidosis treated with prednisone. AmJ Cardiol. 2001;88:1006.

46. du Bois RM. Corticosteroids in sarcoidosis: friend orfoe? Eur Respir J. 1994;7:1203.

47. Baughman RP, Sharma OP, Lynch III JP. Sarcoidosis:is therapy effective? Semin Respir Infect.1998;13:255–73.x

48.• Lower EE, Baughman RP. Prolonged use of metho-trexate for sarcoidosis. Arch Intern Med.1995;155:846–51. doi:10.1001/archinte.155.8.846.

This is a nonrandomized interventional study to determinethe safety and efficacy of methotrexate as a steroid-sparing


http://dx.doi.org/10.1001/archinte.155.8.846

agent in patients with symptomatic sarcoidosis. Efficacy wasassessed for all patients after 2 years of treatment. There wasimprovement in vital capacity or other affected symptomaticorgan noted in 33 of 50 treated patients. Corticosteroidswere discontinued in an additional six patients whoremained stable with clinical or symptomatic improvement.Methotrexate was a well-tolerated therapeutic agent withsignificant steroid sparing and efficacy for the treatment ofchronic symptomatic sarcoidosis.49. Webster GF, Razsi LK, Sanchez M, et al. Weekly low-

dose methotrexate therapy for cutaneous sarcoidosis.J Am Acad Dermatol. 1991;24:451–4.

50. Baughman RP, Lower EE. A clinical approach to theuse of methotrexate for sarcoidosis. Thorax.1999;54:742–6.

51. Pacheco Y, Marechal C, Marechal F, et al. Azathio-prine treatment of chronic pulmonary sarcoidosis.Sarcoidosis. 1985;2:107.

52. Müller-Quernheim J, Kienast K, Held M, et al.Treatment of chronic sarcoidosis with an azathio-prine/prednisolone regimen. Eur Respir J.1999;14:1117.

53. Baughman RP, Lower EE. Infliximab for refractory sar-coidosis. Sarcoidosis Vasc Diffuse LungDis. 2001;18:70.

54. Baughman RP, Drent M, Kavuru M, et al. Infliximabtherapy in patients with chronic sarcoidosis andpulmonary involvement. Am J Respir Crit Care Med.2006;174:795.

55. Rossman MD, Newman LS, Baughman RP, et al. Adouble-blinded, randomized, placebo-controlled trial ofinfliximab in subjects with active pulmonary sarcoido-sis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23:201.

56. Doty JD, Mazure JE, Judson MA. Treatment of sar-coidosis with infliximab. Chest. 2005;127:1064–71.

57. Roberts SD, Wilkes DS, Burgett RA, Knox KS. Re-fractory sarcoidosis responding to infliximab. Chest.2003;124:2028–31.

58. Uthman I, Touma Z, Khoury M. Cardiac sarcoidosisresponding to monotherapy with infliximab. ClinRheumatol. 2007;26:2001–3.

59. Shammas RL, Movahed A. Sarcoidosis of the heart.Clin Cardiol. 1993;16:462–72.

60. Ahmad K, Kim YH, Spitzer AR, et al. Total nodal ra-diation in progressive sarcoidosis. Case report Am JClin Oncol. 1992;15:311.

61. Jefic D, Joel B, Good E, et al. Role of radiofrequencycatheter ablation of ventricular tachycardia in cardiacsarcoidosis: report from a multicenter registry. HeartRhythm. 2009;6:189.

62. Bohnen M, Stevenson WG, Tedrow UB, et al. In-cidence and predictors of major complicationsfrom contemporary catheter ablation to treat car-diac arrhythmias. Heart Rhythm. 2011;8(11):1661.

63. Kay GN, Epstein AE, Dailey SM, Plumb VJ. Role ofradiofrequency ablation in the management of sup-raventricular arrhythmias: experience in 760 consec-

utive patients. J Cardiovasc Electrophysiol. 1993;4(4):371.

64. Chen SA, Chiang CE, Tai CT, et al. Complications ofdiagnostic electrophysiologic studies and radiofre-quency catheter ablation in patients with tachyar-rhythmias: an eight-year survey of 3,966 consecutiveprocedures in a tertiary referral center. Am J Cardiol.1996;77(1):41.

65. Scheinman MM, Huang S. The 1998 NASPE pro-spective catheter ablation registry. Pacing Clin Elec-trophysiol. 2000;23(6):1020.

66. Bubien RS, Knotts-Dolson SM, Plumb VJ, Kay GN.Effect of radiofrequency catheter ablation on health-related quality of life and activities of daily living inpatients with recurrent arrhythmias. Circulation.1996;94:1585–91.

67. Strickberger SA, Man KC, Daoud EG, et al. A pro-spective evaluation of catheter ablation of ventriculartachycardia as adjuvant therapy in patients withcoronary artery disease and an implantable cardi-overter-defibrillator. Circulation. 1997;96:1525–31.

68. Crandall MA, Bradley DJ, Packer DL, Asirvatham SJ.Contemporary management of atrial fibrillation:update on anticoagulation and invasive managementstrategies. Mayo Clin Proc. 2009;84:643–62.

69.•• Winters SL, Cohen M, Greenberg S, et al. Sustainedventricular tachycardia associated with sarcoidosis:assessment of the underlying cardiac anatomy andthe prospective utility of programmed ventricularstimulation, drug therapy and an implantable anti-tachycardia device. J Am Coll Cardiol. 1991;18:937.

This report represents the largest descriptive series of con-secutive patients with sustained ventricular tachycardia as-sociated with sarcoidosis. Antiarrhythmic drug therapy ofventricular tachycardia in patients with sarcoidosis, evenwhen guided with programmed ventricular stimulation, wasassociated with a high rate of arrhythmia recurrence orsudden death, or both. Thus, implantation of an automaticantitachycardia device (cardioverter-defibrillator) should beconsidered as primary therapy in such patients. Furthermore,sarcoidosis should be excluded in any patient with sustainedventricular tachycardia of unknown origin.70. Bajaj AK, Kopelman HA, Echt DS. Cardiac sarcoidosis

with sudden death: treatment with the automaticimplantable cardioverter defibrillator. Am Heart J.1988;116:557.

71. Epstein AE, DiMarco JP, Ellenbogen KA, et al.ACC/AHA/HRS 2008 Guidelines for Device-BasedTherapy of Cardiac Rhythm Abnormalities: a re-port of the American College of Cardiology/American Heart Association Task Force on PracticeGuidelines (Writing Committee to Revise theACC/AHA/NASPE 2002 Guideline Update for Im-plantation of Cardiac Pacemakers and Antiar-rhythmia Devices) developed in collaborationwith the American Association for Thoracic Sur-gery and Society of Thoracic Surgeons. J Am CollCardiol. 2008;51:e1.


72. Wood MA, Ellenbogen KA. Cardiology patient pages.Cardiac pacemakers from the patient’s perspective.Circulation. 2002;105(18):2136.

73. Zaidi AR, Zaidi A, Vaitkus PT. Outcome of hearttransplantation in patients with sarcoid cardiomy-opathy. J Heart Lung Transplant. 2007;26:714.

74. Valantine HA, Tazelaar HD, Macoviak J, et al. Cardiacsarcoidosis: response to steroids and transplantation.J Heart Transplant. 1987;6:244–50.

75. Oni AA, Hershberger RE, Norman DJ, et al. Recur-rence of sarcoidosis in a cardiac allograft: controlwith augmented corticosteroids. J Heart Lung Trans-plant. 1992;11:367.

76. Taylor DO, Stehlik J, Edwards LB, et al. Registry of theInternational Society for Heart and Lung Transplan-tation: Twenty-sixth Official Adult Heart TransplantReport-2009. J Heart Lung Transplant. 2009;28(10):1007.


Documents

Cardiac Sarcoidosis