Abbreviations: 18F-FDG (18-F-fluorodeoxyglucose), ARVC (arrhythmogenic right ventricular cardiomyopathy), CS (cardiac sarcoidosis), EMB (endomyocardial biopsy)

Helsinki, Finland

Cardiac sarcoidosis (CS) is a rare butrious form of granulomatous myocarditis afflicting mainly middle-aged individuals. Despite a 90-year history, it remains an enigmatic entity, and even the most astute cardiologist often feels to be in a puzzle about its diagnosis and treatment. Although clinical guidelines exist,1Birnie D.H. Sauer W.H. Bogun F. et al.HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.,2Terasaki F. Azuma A. Anzai T. et al.on behalf of the Japanese Circulation Society Joint Working Group. JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis. their evidence level is low because most research is empirical, retrospective, and based on small groups of patients with variably diagnosed or suspected CS. No high-quality clinical trials have been published hitherto.CS has a spectrum of appearances that extends from a patient with extracardiac sarcoidosis and silent myocardial involvement detectable only by modern cardiac imaging to another having fulminant myocarditis and facing imminent death without rescue therapy. Between these extremes are the most common presenting manifestations, including high-grade atrioventricular block, heart failure, and sustained ventricular tachycardia with frequencies on admission, by our experience in 351 patients,3Ekström K. Lehtonen J. Nordenswan H.-K. et al.Sudden death in cardiac sarcoidosis: an analysis of clinical and cause-of-death registries. of 42%, 17%, and 14%, respectively. Other forms of presentation, much rarer, are atrial tachyarrhythmias, mimics of chronic or acute myocardial ischemia, mitral regurgitation, and pericarditis. For its many phenotypes, CS has been called “the chameleon” or “the great masquer” of cardiology. It also might be called “an assassin in the heart,” because an unexpected sudden death was its only manifestation in 11% of all cases diagnosed in our country over the last two to three decades.3Ekström K. Lehtonen J. Nordenswan H.-K. et al.Sudden death in cardiac sarcoidosis: an analysis of clinical and cause-of-death registries.As many as 57% to 65% of patients presenting with these cardiac manifestations have neither history nor signs of extracardiac sarcoidosis according to routine clinical, laboratory, and imaging studies on admission.4Okura Y. Dec G.W. Hare J.M. et al.A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis.,5Kandolin R. Lehtonen J. Airaksinen J. et al.Cardiac sarcoidosis: epidemiology, characteristics and outcome over 25 years in a nationwide study. These cases represent clinically isolated CS. Subsequent studies with CT of the chest, MRI, or 18F-fluorodeoxyglucose PET (18F-FDG PET) scan expose signs of extracardiac sarcoidosis in many of them, however. In this respect, whole-body 18F-FDG PET scan is particularly revealing. In our analysis of 57 CS patients undergoing whole-body PET scan during their early diagnostic assessment,6Simonen P. Lehtonen J. Kandolin R. et al.F-18-fluorodeoxyglucose positron emission tomography-guided mediastinal lymph node sampling in the diagnosis of cardiac sarcoidosis. 18 individuals (32%) had no extracardiac FDG uptake. In 14 of them, the diagnosis of CS was made by endomyocardial biopsy (EMB). Excluding one steroid-treated patient, 23% of the CS population under study had isolated cardiac involvement clinically, histologically, and by PET scan. In sharp contrast to our experience, a prospective Canadian study using whole-body PET scan and careful clinical assessment found isolated cardiac involvement in only one of 31 (3.2%) consecutive patients with CS.7Juneau D. Nery P. Russo J. et al.How common is isolated cardiac sarcoidosis? Extra-cardiac and cardiac findings on clinical examination and whole-body 18F–fuorodeoxyglucose positron emission tomography. A comparable but retrospective Australian PET study,8Giudicatti L. Marangou J. Nolan D. et al.The utility of whole body 18-F-FDG PET-CT in diagnosing isolated cardiac sarcoidosis: The Western Australian Cardiac Sarcoid Study. in turn, found isolated CS in three of 32 patients (9.6%). In the most recent study, seven of 34 CS patients fulfilling the current Japanese diagnostic criteria2Terasaki F. Azuma A. Anzai T. et al.on behalf of the Japanese Circulation Society Joint Working Group. JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis. had definitive isolated CS (21%), and four had suspected isolated CS (12%), by whole-body PET scan and a comprehensive clinical assessment.9Kawai H. Sarai M. Kato Y. et al.Diagnosis of isolated cardiac sarcoidosis by new guidelines..In certain clinical scenarios, cardiologists should be particularly alert to the possibility of isolated CS. One is the phenotype of severe chronic heart failure akin to nonischemic dilated cardiomyopathy. Sperry et al10Sperry B.W. Oldan J. Hachamovitz R. Tamarappoo B.K. Insights into biopsy-proven cardiac sarcoidosis in patients with heart failure. analyzed 27 consecutive patients with CS having diagnostic myocardial histology, impaired ejection fraction (mean, 27%), and moderate to severe symptoms. Fourteen of them (52%) had isolated CS, defined as lack of symptoms, histology, and PET scan findings indicative of extracardiac disease, although PET scan was not available in each case. The reports on cardiac transplantations for CS, reviewed and compiled recently by Chazal et al,11Chazal T. Varnous S. Guihaire J. et al.Sarcoidosis diagnosed on granulomas in the explanted heart after transplantation: results of a French nationwide study. show that of 69 detailed patients, 65% were diagnosed with CS only at the study of the explanted heart, and 58% very likely had isolated CS, because signs of extracardiac sarcoidosis were absent both before and at transplantation. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is another disguise of CS. In a prospective study of patients referred for ARVC, Vasaiwala et al12Vasaiwala S.C. Finn C. Delpriore J. et al.Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia. found that three of 20 patients (15%) fulfilling the ARVC criteria had CS by right ventricular biopsy without signs of extracardiac sarcoidosis. Vakil et al13Vakil K. Minami E. Fishbein D.B. Right ventricular sarcoidosis: is it time for updated diagnostic criteria?. identified from the literature 15 cases of CS mimicking ARVC, of whom seven (47%) were free of extracardiac sarcoidosis and thus probably had isolated CS. Philips et al,14Philips B. Madhavan S. James C.A. et al.Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. by contrast, found signs of extracardiac sarcoidosis in each of their 15 patients with CS masquerading as ARVC.Given the systemic nature of sarcoidosis, whether true isolated CS exists can be questioned because extracardiac tissues may harbor granulomas escaping detection by any diagnostic method aside from biopsy and microscopy.15Petek B.J. Rosenthal D.G. Patton K.K. et al.Cardiac sarcoidosis: diagnosis confirmation by bronchoalveolar lavage and lung biopsy. This may be of scientific interest, yet it is not a major clinical issue because such invisible and silent microgranulomas have no relevance to the treatment or prognosis of manifest CS. At our institution, isolated CS is currently defined as (1) myocardial histology showing sarcoid granulomas and (2) absence of extracardiac sarcoidosis by history, physical examination, CT, and whole-body PET scan. A case example is shown in Figure 1. We have not asked for ophthalmologic or dermatologic studies in asymptomatic patients. Although a routine ophthalmologic examination was recommended in a recent practice guideline,16Crouser E.D. Maier L.A. Wilson K.C. et al.Diagnosis and detection of sarcoidosis: an official American Thoracic Society clinical practice guideline. the quality of evidence was considered “very low,” and the prevalence of asymptomatic eye involvement unknown. The Japanese guideline2Terasaki F. Azuma A. Anzai T. et al.on behalf of the Japanese Circulation Society Joint Working Group. JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis. for diagnosis of isolated CS does not require positive myocardial histology but appears to allow substitution of cardiac uptake of 18F-FDG, nonspecific as it is,17Divakaran S. Stewart G.C. Lakdawala N.K. et al.Diagnostic accuracy of advanced imaging in cardiac sarcoidosis. for the presence of granulomas in the heart. This is something we cannot fully subscribe to. Manifest CS has 5-year survival rates from 60%18Yazaki Y. Isobe M. Hiroe M. et al.Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. to 85%,3Ekström K. Lehtonen J. Nordenswan H.-K. et al.Sudden death in cardiac sarcoidosis: an analysis of clinical and cause-of-death registries. indicating that mortality is similar to or worse than in some common cancers. Given the implications of diagnosis, histologic confirmation should be considered important also in CS. We think that EMB is currently underused in suspected CS and that its sensitivity, although not optimal, is significantly better than the continually quoted figure of 20% based on reports of nontargeted right ventricular biopsies,19Uemura A. Morimoto S. Hiramitsu S. Kato Y. Ito T. Hishida H. Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.,20Ardehali H. Howard D.L. Hariri A. et al.A positive endomyocardial biopsy results for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. an outdated procedure today. Aiming the bioptome at the most diseased area in the right or left ventricle with help of findings on MRI or PET scan (Fig 1),21Kandolin R. Lehtonen J. Graner M. et al.Diagnosing isolated cardiac sarcoidosis. fine-tuning the sampling procedure with endocardial voltage mapping,22Nery P.B. Keren A. Healey J. Leug E. Beanlands R.S. Birnie D.H. Isolated cardiac sarcoidosis: establishing the diagnosis with electroanatomic mapping-guided endomyocardial biopsy. and being ready for repeat biopsies21Kandolin R. Lehtonen J. Graner M. et al.Diagnosing isolated cardiac sarcoidosis. can significantly improve the sensitivity. The risk of serious complications is 23Contribution and risk of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period. In case EMBs remain nondiagnostic, we follow the patient under the diagnosis “suspected isolated CS,” or, if an absolute diagnosis is considered essential, we recommend open-chest myocardial biopsy.24Lehtonen J.Y.A. Jokinen J.J. Holmström M. Kupari M. Open chest core needle biopsy of the left ventricle in the evaluation of suspected focal myocardial inflammation. The whys and wherefores for our active biopsy policy relate to the seriousness of CS and to the potentially grave complications its treatment may cause. The diagnosis should leave as little room for doubt as possible.

Figure 1Example of isolated CS. A 54-year-old woman presented with ventricular tachyarrhythmias and elevated troponin T. Her medical history and physical examination were nonrevealing. A, Cardiac MRI showed late contrast enhancement in the lateral wall of the left ventricle (arrow) with B, whole-body PET scan showing abnormal 18FDG uptake in the heart only (arrow). C, EMB from left ventricle exposed granulomatous myocarditis with Langhans-type giant cells consistent with sarcoidosis. She received an implantable cardioverter-defibrillator and prednisone, combined later with azathioprine, for a total duration of 1 year. After early recurrences of ventricular tachycardia, her condition has been stable, and, 3.5 years since diagnosis, she remains free of signs of systemic sarcoidosis. 18F-FDG = 18-F-fluorodeoxyglucose; CS = cardiac sarcoidosis; EMB = endomyocardial biopsy.

Sarcoidosis confined to the heart by clinical and imaging examinations has practical importance mainly for the diagnostic challenges it creates. It may delay the detection of CS to a more advanced and prognostically worse stage of myocardial involvement, at the utmost to transplantation or autopsy.3Ekström K. Lehtonen J. Nordenswan H.-K. et al.Sudden death in cardiac sarcoidosis: an analysis of clinical and cause-of-death registries.,5Kandolin R. Lehtonen J. Airaksinen J. et al.Cardiac sarcoidosis: epidemiology, characteristics and outcome over 25 years in a nationwide study. Isolated CS is not a curiosity to be dismissed as an exception to the rule but a manifestation that covers a significant, though debated, segment of CS and has a wide variety of clinical appearances. Its undelayed detection rests on a high index of suspicion and, at times, on perseverance in diagnostic examinations.ReferencesBirnie D.H. Sauer W.H. Bogun F. et al.

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Sudden death in cardiac sarcoidosis: an analysis of clinical and cause-of-death registries.

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Cardiac sarcoidosis: epidemiology, characteristics and outcome over 25 years in a nationwide study.

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Am J Cardiol. 116: 1581-1585Juneau D. Nery P. Russo J. et al.

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J Cardiovasc Electrophysiol. 20: 473-476Vakil K. Minami E. Fishbein D.B.

Right ventricular sarcoidosis: is it time for updated diagnostic criteria?.

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Respir Med. 144S: S13-S19Crouser E.D. Maier L.A. Wilson K.C. et al.

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Am J Respir Crit Care Med. 201: e26-e51Divakaran S. Stewart G.C. Lakdawala N.K. et al.

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Circ Cardiovasc Imaging. 12e008975Yazaki Y. Isobe M. Hiroe M. et al.

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J Thorac Cardiovasc Surg. 149: e99-e102Article InfoFootnotes

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

Identification

DOI: https://doi.org/10.1016/j.chest.2020.12.037

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© 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

ScienceDirectAccess this article on ScienceDirect Linked ArticleRebuttal From Drs Kupari and Lehtonen

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Although sarcoidosis is considered a systemic disease, the details of its pathobiology remain obscure. The lungs are involved most often, usually as part of multi-organ disease but also as isolated pulmonary sarcoidosis.1,2 Extrapulmonary single-organ involvement is also a possible though much rarer manifestation, with isolated cutaneous sarcoidosis topping the respective statistics.3 In countering the significance of isolated cardiac sarcoidosis (CS), Birnie et al4 emphasize the nonexistence of “truly isolated CS.” However, as we pointed out in our initial editorial, this is a theoretical issue only, because the co-existence with myocardial involvement of invisible extracardiac granulomas is clinically irrelevant and impossible to prove or disprove with certainty.

Full-Text PDF Rebuttal From Drs Birnie, Nery, and Beanlands

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We greatly enjoyed reading the counterpoint from our esteemed colleagues. It certainly seems that there is much we agree on but still some points of contention.

Full-Text PDF COUNTERPOINT: Should Isolated Cardiac Sarcoidosis Be Considered a Significant Manifestation of Sarcoidosis? No

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Sarcoidosis is, by definition1 and biology, a systemic disease, so really the debate is whether there is “a sarcoidosis-like disease” that only involves the heart. The reported prevalence of isolated cardiac sarcoidosis (CS) varies widely, from 3.2% to 54%,2-4 and there is one primary reason for this variability—the lack of an agreed definition of isolated CS. Hence, it follows that there are two levels of debate; the first point is to discuss what a reasonable definition might be, and once that is agreed, the second is whether the entity exists.

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