Cardiac Sarcoidosis: There Is No Instant Replay

Abstract

Several years ago near my hospital, a 36-year-old African-American man without any previous medical problems walked out of a movie theater and suddenly collapsed and died. An autopsy revealed that his entire myocardium had been replaced by noncaseating granulomas. Recently, a similar but higher profile incident shocked the nation when Reggie White, a former National Football League player, died suddenly of cardiac sarcoidosis. Both of these events underscore a truism about cardiac sarcoidosis: it is underdiagnosed and can be fatal.The failure to diagnose cardiac sarcoidosis is partly attributable to the relative rarity of clinically apparent forms of the disease. Only 5% of patients with sarcoidosis have signs or symptoms of cardiac involvement,1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar even though 25% of patients have autopsy evidence of granulomatous inflammation affecting the heart.2Silverman KJ Hutchins GM Bulkley BH Cardiac sarcoid: a clinicopathological study of 84 unselected patients with systemic sarcoidosis.Circulation. 1978; 58: 1204-1211Crossref PubMed Scopus (755) Google Scholar Sarcoidosis also defies early diagnosis because it can affect any portion of the heart and produce a myriad of perplexing clinical problems that may simulate other more common disorders. Granulomas may massively infiltrate the myocardium and cause congestive heart failure1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar3Yazaki Y, Osobe M, Hiroe M, et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 1001; 88: 1006-1010Google Scholar4Fasano R Rimmerman CM Jaber WA Cardiac sarcoidosis: a cause of infiltrative cardiomyopathy.Cleve Clin J Med. 2004; 71: 483-488Crossref Scopus (7) Google Scholar or deposit in papillary muscles and set the stage for mitral regurgitation or, rarely, pulmonary hypertension.5Desai MY Fallert MA Rapidly progressing congestive heart failure due to cardiac sarcoidosis involving papillary muscles: a case report and brief review of the literature.Cardiol Rev. 2003; 11: 163-168Crossref PubMed Scopus (19) Google Scholar Sarcoidosis may cause granulomatous pericarditis with or without pericardial effusion.6Sekiguchi M Yazaki Y Isobe M et al.Cardiac sarcoidosis: diagnostic, prognostic, and therapeutic considerations.Cardiovasc Drugs Ther. 1996; 10: 495-510Crossref PubMed Scopus (142) Google Scholar7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar Granulomas may entangle small coronary arteries in a web of fibrosis while leaving larger coronary arteries unaffected.1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar8Morales AR Levy S Davis J et al.Sarcoidosis and the heart.Pathol Annu. 1974; 9: 139-155PubMed Google Scholar Long-term granulomatous inflammation may generate myocardial scarring with the formation of ventricular aneurysms.9Haraki T Ueda K Shintani H et al.Spontaneous development of left ventricular aneurysm in a patient with untreated sarcoidosis.Circ J. 2002; 66: 519-521Crossref PubMed Scopus (14) Google Scholar The diagnosis is also problematic because cardiac sarcoidosis may become manifest several years after the initial diagnosis of sarcoidosis is established.10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google ScholarThe myocardial conducting system is especially vulnerable to sarcoid granulomas, which may result in serious consequences that include complete atrioventricular block, premature ventricular contractions, ventricular arrhythmias, and sudden death.1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar3Yazaki Y, Osobe M, Hiroe M, et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 1001; 88: 1006-1010Google Scholar6Sekiguchi M Yazaki Y Isobe M et al.Cardiac sarcoidosis: diagnostic, prognostic, and therapeutic considerations.Cardiovasc Drugs Ther. 1996; 10: 495-510Crossref PubMed Scopus (142) Google Scholar7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar11Kato Y Morimoto S Uemura A et al.Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block.Sarcoid Vasc Diff Lung Dis. 2003; 20: 133-137PubMed Google Scholar12Larsen F Pehrsson SK Hammar N et al.ECG abnormalities in Japanese and Swedish patients with sarcoidosis: a comparison.Sarcoid Vasc Diff Lung Dis. 2001; 18: 284-288PubMed Google Scholar13Boglioli LR Taff ML Funke S et al.Sudden death due to sarcoid heart disease.J Forensic Sci. 1998; 43: 1072-1073Crossref PubMed Google Scholar The risks of sudden death and progressive congestive heart failure are the most feared complications of cardiac sarcoidosis and underscore why this disease must be diagnosed early and followed up with extreme vigilance.Fortunately, sarcoidosis in general is rarely a lethal condition. In one US study14Huang CT Heurich AE Sutton AL et al.Mortality in sarcoidosis: a changing pattern of the causes of death.Eur J Respir Dis. 1981; 62: 231-238PubMed Google Scholar of 1,090 patients with sarcoidosis who were hospitalized over a 17-year period, only 28 patients (2.5%) died as a direct result of sarcoidosis. Twenty-two of the 28 deaths (79%) occurred as a result of advanced pulmonary sarcoidosis that had slowly progressed over many years. These deaths were distinctly “nonsudden” and occurred on average 10 years after disease onset and 4 years after the development of respiratory insufficiency. In contrast, the remaining patients experienced sudden death attributable to neurosarcoidosis (4 of 28 patients, 14%) and cardiac sarcoidosis (2 of 28 patients, 7%).Even when clinically suspected, confirmation of a diagnosis of cardiac sarcoidosis presents considerable challenges. Endomyocardial biopsy reveals noncaseating granulomas in less than one fourth of cases because of the patchy distribution of the disease.15Uemura A Morimoto S Hiramitsu S et al.Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.Am Heart J. 1999; 138: 299-302Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar When cardiac sarcoidosis causes conduction disturbances, the diagnostic yield of endomyocardial biopsy is particularly low at < 10%.15Uemura A Morimoto S Hiramitsu S et al.Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.Am Heart J. 1999; 138: 299-302Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar Even in the case of dilated cardiomyopathy from sarcoidosis, the yield from endomyocardial biopsy is approximately one third.15Uemura A Morimoto S Hiramitsu S et al.Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.Am Heart J. 1999; 138: 299-302Abstract Full Text Full Text PDF PubMed Scopus (337) Google ScholarMost clinicians consequently rely on noninvasive tests to establish the diagnosis of cardiac involvement with sarcoidosis. Available tests include ECG,7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google Scholar11Kato Y Morimoto S Uemura A et al.Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block.Sarcoid Vasc Diff Lung Dis. 2003; 20: 133-137PubMed Google Scholar echocardiography,7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google Scholar201Tl perfusion scan,16Umetani K Ishihara T Sawanobori T et al.Successfully treated complete atrioventricular block with corticosteroid in a patient with cardiac sarcoidosis: usefulness of gallium-67 and thallium-201 scintigraphy.Intern Med. 2000; 39: 245-248Crossref PubMed Scopus (22) Google Scholar17Resting Tl-201 scintigraphy in the evaluation of myocardial sarcoidosis.J Nucl Med. 1997; 22: 475-478Google Scholar67Ga scan,16Umetani K Ishihara T Sawanobori T et al.Successfully treated complete atrioventricular block with corticosteroid in a patient with cardiac sarcoidosis: usefulness of gallium-67 and thallium-201 scintigraphy.Intern Med. 2000; 39: 245-248Crossref PubMed Scopus (22) Google Scholar18Barneveld PC van Leeuwen C van Isselt JW Scintigraphic demonstration of myocardial sarcoidosis: the added value of single photon emission computed tomography.J Nucl Cardiol. 1997; 4: 256-257Crossref PubMed Scopus (7) Google Scholar19Nakazawa A Ikeda K Ito Y et al.Usefulness of dual67Ga and99mTc-sestamibi single-photon-emission scanning in the diagnosis of cardiac sarcoidosis.Chest. 2004; 126: 1372-1376Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and gadolinium-enhanced magnetic resonance (MR) scan,20Doherty MJ Kumar K Nicholson AA et al.Cardiac sarcoidosis: the value of magnetic resonance imagine in diagnosis and assessment of response to treatment.Respir Med. 1998; 92: 697-699Abstract Full Text PDF PubMed Scopus (36) Google Scholar21Shimada T Shimada K Sakane T et al.Diagnosis of cardiac sarcoidosis and evaluation of the effects of steroid therapy by gadolinium-DPTA-enhanced magnetic resonance imaging.Am J Med. 2001; 110: 520-527Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar22Vignaux O Dhote R Duboe D et al.Clinical significance of myocardial magnetic resonance abnormalities in patients with sarcoidosis.Chest. 2002; 122: 1895-1901Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar and positron emission tomography.23Okumura W Iwasaki T Toyama T et al.Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis.J Nucl Med. 2004; 45: 1989-1998PubMed Google Scholar The accuracy of thallium and gallium scans is enhanced by using a single-photon emission CT (SPECT) technique.18Barneveld PC van Leeuwen C van Isselt JW Scintigraphic demonstration of myocardial sarcoidosis: the added value of single photon emission computed tomography.J Nucl Cardiol. 1997; 4: 256-257Crossref PubMed Scopus (7) Google Scholar19Nakazawa A Ikeda K Ito Y et al.Usefulness of dual67Ga and99mTc-sestamibi single-photon-emission scanning in the diagnosis of cardiac sarcoidosis.Chest. 2004; 126: 1372-1376Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Thallium defects from ischemic heart disease can often be differentiated from sarcoid heart disease, in that the latter may decrease in size with exercise (reverse distribution).1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar New, promising tests include 123I-labeled 15-(p-iodophenyl)-3R, S-methylpentadeconanoic acid scintigraphy,24Kaminaga T Takeshita T Yamauchi T et al.The role of iodine-123-labeled 15-(p-iodophenyl)-3R,S-methylpentadeconanoic acid scintigraphy in the detection of local myocardial involvement of sarcoidosis.Int J Cardiol. 2004; 94: 99-103Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar and ultrasonic tissue characterization.25Hyodo E Hozumi T Takemoto Y et al.Early detection of cardiac involvement in patients with sarcoidosis by a non-invasive method with ultrasonic tissue characterization.Heart. 2004; 90: 1275-1280Crossref PubMed Scopus (33) Google ScholarEach of these noninvasive tests has a different sensitivity and specificity. Unfortunately, an idealized algorithm for the diagnosis of cardiac sarcoidosis has not been established because of the diagnostic shortcomings of the only available “gold standard,” which is endomyocardial biopsy. Moreover, existing noninvasive tests have rarely been compared with each other within the same clinical trials. When such comparisons are made, there is a poor concordance of the tests, such that a negative result on any one test does not ensure the possibility of another test result being positive.7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google Scholar22Vignaux O Dhote R Duboe D et al.Clinical significance of myocardial magnetic resonance abnormalities in patients with sarcoidosis.Chest. 2002; 122: 1895-1901Abstract Full Text Full Text PDF PubMed Scopus (212) Google ScholarNevertheless, guidelines for the application of noninvasive tests to the diagnosis of cardiac sarcoidosis have been developed by the Japanese Ministry of Health and Welfare26Hiraga H Yuwai K Hiroe M et al.Guideline for the diagnosis of cardiac sarcoidosis: study report on diffuse pulmonary diseases [in Japanese]. Ministry of Health and Welfare, Tokyo, Japan1993: 23-24Google Scholar and the research group conducting A Case Control Etiology of Sarcoidosis Study.27Judson MA Baughman RP Teirstein AS et al.Defining organ involvement in sarcoidosis: the ACCESS proposed instrument.Sarcoid Vasc Diffuse Lung Dis. 1999; 16: 75-86PubMed Google Scholar Both of these guidelines combine the results of noninvasive tests with histologic confirmation of noncaseating granulomatous inflammation in an extracardiac organ and evidence of unexplained arrhythmias, conduction system abnormalities, or ventricular dysfunction.Although these guidelines assist diagnosis in patients suspected of having the disease, the common occurrence of asymptomatic cardiac sarcoidosis poses the question as to the threshold of suspicion that warrants application of noninvasive cardiac testing in patients with underlying sarcoidosis. Furthermore, the clinical significance of asymptomatic cardiac sarcoidosis detected by noninvasive testing or need for therapy is unknown. These are the questions addressed by Smedema and coworkers in their study published in this issue of CHEST (see page 30).Smedema and coworkers classified 101 consecutive patients with biopsy-proven sarcoidosis into two groups: those who presented with symptoms of cardiac sarcoidosis (group A), and those who were screened for the condition (group B). Sixteen of 19 patients (84%) in group A received a diagnosis of cardiac sarcoidosis, compared to 3 of 82 patients (4%) in group B (p < 0.0001). During a mean follow-up of 1.7 years, there were four deaths in group A patients (20%) and nine pacemaker or internal cardiac defibrillator placements (47%), compared to an uncomplicated course in group B patients. These results indicate that cardiac sarcoidosis is common in those with cardiac symptoms and rare in those without such symptoms. More importantly, patients with asymptomatic cardiac sarcoidosis have a benign clinical course so that an aggressive search for the diagnosis is not warranted.This study has several limitations. First, the noninvasive screening tests used for diagnosis were not standardized. These authors used a battery of tests including ECG, echocardiography, 201Tl SPECT, gadolinium-enhanced MR scan, and endomyocardial biopsy. However, not all patients underwent all tests, making it unclear if cases of cardiac sarcoidosis were missed. Second, the study was retrospective, and it is unclear how aggressive the clinicians were in searching for symptoms of cardiac sarcoidosis in these patients. Third, it is problematic to use the criteria of The Japanese Ministry of Health and Welfare for the diagnosis of cardiac sarcoidosis26Hiraga H Yuwai K Hiroe M et al.Guideline for the diagnosis of cardiac sarcoidosis: study report on diffuse pulmonary diseases [in Japanese]. Ministry of Health and Welfare, Tokyo, Japan1993: 23-24Google Scholar in this study because those criteria predated the use of SPECT and cardiac MR scanning. For example, only three patients in group B received a diagnosis of cardiac sarcoidosis, and an additional three patients in this group received a diagnosis of another heart disease. However, a total of 12 patients in group B had abnormal cardiac MR scan results. Therefore, six patients with abnormal cardiac MR scans had no cardiac diagnosis. It is possible that these patients also had cardiac sarcoidosis. Nonetheless, the authors have provided ample evidence to support the premise that patients with symptomatic cardiac sarcoidosis have a poor prognosis and require detection and therapy.The treatment of cardiac sarcoidosis begins with an alert clinician. Every patient with a diagnosis of sarcoidosis should be asked about symptoms of palpitations, “skipped” heartbeats, orthopnea, and syncope. Patients should also be asked about chest pain that is different from the typical chest pain of sarcoidosis, which is pleuritic and substernal or infrascapular in location.28Highland KB Retalis P Coppage L et al.Is there an anatomical explanation for chest pain in patients with pulmonary sarcoidosis?.South Med J. 1997; 90: 911-914Crossref PubMed Scopus (22) Google Scholar A 12-lead ECG should be performed for all patients with newly diagnosed disease.29Hunninghake GW Costabel U Ando M et al.Statement on sarcoidosis.Am J Respir Crit Care Med. 1999; 160: 736-755Crossref PubMed Scopus (2163) Google Scholar On the basis of the findings by Smedema and colleagues, the absence of cardiac signs or symptoms suggests a benign course even if occult sarcoidosis is present. The presence of clinical evidence of cardiac sarcoidosis, however, requires prompt evaluation to identify those patients at risk for sudden death who may benefit from directed therapy.Given the serious potential complications of symptomatic cardiac sarcoidosis, it is disheartening that this condition is often not searched for or appropriately treated. As the director of a large sarcoidosis center, most patients referred for sarcoidosis have not had a previous ECG. I am often the first physician who has elicited a history of palpitations or skipped heartbeats.Although cardiac sarcoidosis is rare, it can be lethal, but death can often be prevented if the clinician is armed with adequate knowledge. Eleven years ago in CHEST, a warning was issued concerning the danger of cardiac sarcoidosis.30Sharma OP Myocardial sarcoidosis: a wolf in sheep's clothing.Chest. 1994; 106: 988-990Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar I believe that this warning has largely been unheeded. Let me try another warning with a National Football League flavor: in terms of detecting cardiac sarcoidosis, there is no instant replay.Author's DisclaimerThe author has no first-hand knowledge about the medical case of Mr. Reggie White. He only knows, via the lay media, that Mr. White had received a diagnosis of cardiac sarcoidosis and obstructive sleep apnea and had sudden death. Several years ago near my hospital, a 36-year-old African-American man without any previous medical problems walked out of a movie theater and suddenly collapsed and died. An autopsy revealed that his entire myocardium had been replaced by noncaseating granulomas. Recently, a similar but higher profile incident shocked the nation when Reggie White, a former National Football League player, died suddenly of cardiac sarcoidosis. Both of these events underscore a truism about cardiac sarcoidosis: it is underdiagnosed and can be fatal. The failure to diagnose cardiac sarcoidosis is partly attributable to the relative rarity of clinically apparent forms of the disease. Only 5% of patients with sarcoidosis have signs or symptoms of cardiac involvement,1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar even though 25% of patients have autopsy evidence of granulomatous inflammation affecting the heart.2Silverman KJ Hutchins GM Bulkley BH Cardiac sarcoid: a clinicopathological study of 84 unselected patients with systemic sarcoidosis.Circulation. 1978; 58: 1204-1211Crossref PubMed Scopus (755) Google Scholar Sarcoidosis also defies early diagnosis because it can affect any portion of the heart and produce a myriad of perplexing clinical problems that may simulate other more common disorders. Granulomas may massively infiltrate the myocardium and cause congestive heart failure1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar3Yazaki Y, Osobe M, Hiroe M, et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 1001; 88: 1006-1010Google Scholar4Fasano R Rimmerman CM Jaber WA Cardiac sarcoidosis: a cause of infiltrative cardiomyopathy.Cleve Clin J Med. 2004; 71: 483-488Crossref Scopus (7) Google Scholar or deposit in papillary muscles and set the stage for mitral regurgitation or, rarely, pulmonary hypertension.5Desai MY Fallert MA Rapidly progressing congestive heart failure due to cardiac sarcoidosis involving papillary muscles: a case report and brief review of the literature.Cardiol Rev. 2003; 11: 163-168Crossref PubMed Scopus (19) Google Scholar Sarcoidosis may cause granulomatous pericarditis with or without pericardial effusion.6Sekiguchi M Yazaki Y Isobe M et al.Cardiac sarcoidosis: diagnostic, prognostic, and therapeutic considerations.Cardiovasc Drugs Ther. 1996; 10: 495-510Crossref PubMed Scopus (142) Google Scholar7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar Granulomas may entangle small coronary arteries in a web of fibrosis while leaving larger coronary arteries unaffected.1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar8Morales AR Levy S Davis J et al.Sarcoidosis and the heart.Pathol Annu. 1974; 9: 139-155PubMed Google Scholar Long-term granulomatous inflammation may generate myocardial scarring with the formation of ventricular aneurysms.9Haraki T Ueda K Shintani H et al.Spontaneous development of left ventricular aneurysm in a patient with untreated sarcoidosis.Circ J. 2002; 66: 519-521Crossref PubMed Scopus (14) Google Scholar The diagnosis is also problematic because cardiac sarcoidosis may become manifest several years after the initial diagnosis of sarcoidosis is established.10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google Scholar The myocardial conducting system is especially vulnerable to sarcoid granulomas, which may result in serious consequences that include complete atrioventricular block, premature ventricular contractions, ventricular arrhythmias, and sudden death.1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar3Yazaki Y, Osobe M, Hiroe M, et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 1001; 88: 1006-1010Google Scholar6Sekiguchi M Yazaki Y Isobe M et al.Cardiac sarcoidosis: diagnostic, prognostic, and therapeutic considerations.Cardiovasc Drugs Ther. 1996; 10: 495-510Crossref PubMed Scopus (142) Google Scholar7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar11Kato Y Morimoto S Uemura A et al.Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block.Sarcoid Vasc Diff Lung Dis. 2003; 20: 133-137PubMed Google Scholar12Larsen F Pehrsson SK Hammar N et al.ECG abnormalities in Japanese and Swedish patients with sarcoidosis: a comparison.Sarcoid Vasc Diff Lung Dis. 2001; 18: 284-288PubMed Google Scholar13Boglioli LR Taff ML Funke S et al.Sudden death due to sarcoid heart disease.J Forensic Sci. 1998; 43: 1072-1073Crossref PubMed Google Scholar The risks of sudden death and progressive congestive heart failure are the most feared complications of cardiac sarcoidosis and underscore why this disease must be diagnosed early and followed up with extreme vigilance. Fortunately, sarcoidosis in general is rarely a lethal condition. In one US study14Huang CT Heurich AE Sutton AL et al.Mortality in sarcoidosis: a changing pattern of the causes of death.Eur J Respir Dis. 1981; 62: 231-238PubMed Google Scholar of 1,090 patients with sarcoidosis who were hospitalized over a 17-year period, only 28 patients (2.5%) died as a direct result of sarcoidosis. Twenty-two of the 28 deaths (79%) occurred as a result of advanced pulmonary sarcoidosis that had slowly progressed over many years. These deaths were distinctly “nonsudden” and occurred on average 10 years after disease onset and 4 years after the development of respiratory insufficiency. In contrast, the remaining patients experienced sudden death attributable to neurosarcoidosis (4 of 28 patients, 14%) and cardiac sarcoidosis (2 of 28 patients, 7%). Even when clinically suspected, confirmation of a diagnosis of cardiac sarcoidosis presents considerable challenges. Endomyocardial biopsy reveals noncaseating granulomas in less than one fourth of cases because of the patchy distribution of the disease.15Uemura A Morimoto S Hiramitsu S et al.Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.Am Heart J. 1999; 138: 299-302Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar When cardiac sarcoidosis causes conduction disturbances, the diagnostic yield of endomyocardial biopsy is particularly low at < 10%.15Uemura A Morimoto S Hiramitsu S et al.Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.Am Heart J. 1999; 138: 299-302Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar Even in the case of dilated cardiomyopathy from sarcoidosis, the yield from endomyocardial biopsy is approximately one third.15Uemura A Morimoto S Hiramitsu S et al.Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.Am Heart J. 1999; 138: 299-302Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar Most clinicians consequently rely on noninvasive tests to establish the diagnosis of cardiac involvement with sarcoidosis. Available tests include ECG,7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google Scholar11Kato Y Morimoto S Uemura A et al.Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block.Sarcoid Vasc Diff Lung Dis. 2003; 20: 133-137PubMed Google Scholar echocardiography,7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google Scholar201Tl perfusion scan,16Umetani K Ishihara T Sawanobori T et al.Successfully treated complete atrioventricular block with corticosteroid in a patient with cardiac sarcoidosis: usefulness of gallium-67 and thallium-201 scintigraphy.Intern Med. 2000; 39: 245-248Crossref PubMed Scopus (22) Google Scholar17Resting Tl-201 scintigraphy in the evaluation of myocardial sarcoidosis.J Nucl Med. 1997; 22: 475-478Google Scholar67Ga scan,16Umetani K Ishihara T Sawanobori T et al.Successfully treated complete atrioventricular block with corticosteroid in a patient with cardiac sarcoidosis: usefulness of gallium-67 and thallium-201 scintigraphy.Intern Med. 2000; 39: 245-248Crossref PubMed Scopus (22) Google Scholar18Barneveld PC van Leeuwen C van Isselt JW Scintigraphic demonstration of myocardial sarcoidosis: the added value of single photon emission computed tomography.J Nucl Cardiol. 1997; 4: 256-257Crossref PubMed Scopus (7) Google Scholar19Nakazawa A Ikeda K Ito Y et al.Usefulness of dual67Ga and99mTc-sestamibi single-photon-emission scanning in the diagnosis of cardiac sarcoidosis.Chest. 2004; 126: 1372-1376Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and gadolinium-enhanced magnetic resonance (MR) scan,20Doherty MJ Kumar K Nicholson AA et al.Cardiac sarcoidosis: the value of magnetic resonance imagine in diagnosis and assessment of response to treatment.Respir Med. 1998; 92: 697-699Abstract Full Text PDF PubMed Scopus (36) Google Scholar21Shimada T Shimada K Sakane T et al.Diagnosis of cardiac sarcoidosis and evaluation of the effects of steroid therapy by gadolinium-DPTA-enhanced magnetic resonance imaging.Am J Med. 2001; 110: 520-527Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar22Vignaux O Dhote R Duboe D et al.Clinical significance of myocardial magnetic resonance abnormalities in patients with sarcoidosis.Chest. 2002; 122: 1895-1901Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar and positron emission tomography.23Okumura W Iwasaki T Toyama T et al.Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis.J Nucl Med. 2004; 45: 1989-1998PubMed Google Scholar The accuracy of thallium and gallium scans is enhanced by using a single-photon emission CT (SPECT) technique.18Barneveld PC van Leeuwen C van Isselt JW Scintigraphic demonstration of myocardial sarcoidosis: the added value of single photon emission computed tomography.J Nucl Cardiol. 1997; 4: 256-257Crossref PubMed Scopus (7) Google Scholar19Nakazawa A Ikeda K Ito Y et al.Usefulness of dual67Ga and99mTc-sestamibi single-photon-emission scanning in the diagnosis of cardiac sarcoidosis.Chest. 2004; 126: 1372-1376Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Thallium defects from ischemic heart disease can often be differentiated from sarcoid heart disease, in that the latter may decrease in size with exercise (reverse distribution).1Sharma OP Maheshwari A Thaker K Myocardial sarcoidosis.Chest. 1993; 103: 253-288Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar New, promising tests include 123I-labeled 15-(p-iodophenyl)-3R, S-methylpentadeconanoic acid scintigraphy,24Kaminaga T Takeshita T Yamauchi T et al.The role of iodine-123-labeled 15-(p-iodophenyl)-3R,S-methylpentadeconanoic acid scintigraphy in the detection of local myocardial involvement of sarcoidosis.Int J Cardiol. 2004; 94: 99-103Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar and ultrasonic tissue characterization.25Hyodo E Hozumi T Takemoto Y et al.Early detection of cardiac involvement in patients with sarcoidosis by a non-invasive method with ultrasonic tissue characterization.Heart. 2004; 90: 1275-1280Crossref PubMed Scopus (33) Google Scholar Each of these noninvasive tests has a different sensitivity and specificity. Unfortunately, an idealized algorithm for the diagnosis of cardiac sarcoidosis has not been established because of the diagnostic shortcomings of the only available “gold standard,” which is endomyocardial biopsy. Moreover, existing noninvasive tests have rarely been compared with each other within the same clinical trials. When such comparisons are made, there is a poor concordance of the tests, such that a negative result on any one test does not ensure the possibility of another test result being positive.7Chapelon-Abric C de Zuttere D DuHaut P et al.Cardiac sarcoidosis: a retrospective study of 41 cases.Medicine (Baltimore). 2004; 83: 315-334Crossref PubMed Scopus (231) Google Scholar10Bagg SA Gordon LL Judson MA Diagnostic yield of noninvasive tests for cardiac sarcoidosis [abstract].Am J Respir Crit Care Med. 2005; 171: A864Google Scholar22Vignaux O Dhote R Duboe D et al.Clinical significance of myocardial magnetic resonance abnormalities in patients with sarcoidosis.Chest. 2002; 122: 1895-1901Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Nevertheless, guidelines for the application of noninvasive tests to the diagnosis of cardiac sarcoidosis have been developed by the Japanese Ministry of Health and Welfare26Hiraga H Yuwai K Hiroe M et al.Guideline for the diagnosis of cardiac sarcoidosis: study report on diffuse pulmonary diseases [in Japanese]. Ministry of Health and Welfare, Tokyo, Japan1993: 23-24Google Scholar and the research group conducting A Case Control Etiology of Sarcoidosis Study.27Judson MA Baughman RP Teirstein AS et al.Defining organ involvement in sarcoidosis: the ACCESS proposed instrument.Sarcoid Vasc Diffuse Lung Dis. 1999; 16: 75-86PubMed Google Scholar Both of these guidelines combine the results of noninvasive tests with histologic confirmation of noncaseating granulomatous inflammation in an extracardiac organ and evidence of unexplained arrhythmias, conduction system abnormalities, or ventricular dysfunction. Although these guidelines assist diagnosis in patients suspected of having the disease, the common occurrence of asymptomatic cardiac sarcoidosis poses the question as to the threshold of suspicion that warrants application of noninvasive cardiac testing in patients with underlying sarcoidosis. Furthermore, the clinical significance of asymptomatic cardiac sarcoidosis detected by noninvasive testing or need for therapy is unknown. These are the questions addressed by Smedema and coworkers in their study published in this issue of CHEST (see page 30). Smedema and coworkers classified 101 consecutive patients with biopsy-proven sarcoidosis into two groups: those who presented with symptoms of cardiac sarcoidosis (group A), and those who were screened for the condition (group B). Sixteen of 19 patients (84%) in group A received a diagnosis of cardiac sarcoidosis, compared to 3 of 82 patients (4%) in group B (p < 0.0001). During a mean follow-up of 1.7 years, there were four deaths in group A patients (20%) and nine pacemaker or internal cardiac defibrillator placements (47%), compared to an uncomplicated course in group B patients. These results indicate that cardiac sarcoidosis is common in those with cardiac symptoms and rare in those without such symptoms. More importantly, patients with asymptomatic cardiac sarcoidosis have a benign clinical course so that an aggressive search for the diagnosis is not warranted. This study has several limitations. First, the noninvasive screening tests used for diagnosis were not standardized. These authors used a battery of tests including ECG, echocardiography, 201Tl SPECT, gadolinium-enhanced MR scan, and endomyocardial biopsy. However, not all patients underwent all tests, making it unclear if cases of cardiac sarcoidosis were missed. Second, the study was retrospective, and it is unclear how aggressive the clinicians were in searching for symptoms of cardiac sarcoidosis in these patients. Third, it is problematic to use the criteria of The Japanese Ministry of Health and Welfare for the diagnosis of cardiac sarcoidosis26Hiraga H Yuwai K Hiroe M et al.Guideline for the diagnosis of cardiac sarcoidosis: study report on diffuse pulmonary diseases [in Japanese]. Ministry of Health and Welfare, Tokyo, Japan1993: 23-24Google Scholar in this study because those criteria predated the use of SPECT and cardiac MR scanning. For example, only three patients in group B received a diagnosis of cardiac sarcoidosis, and an additional three patients in this group received a diagnosis of another heart disease. However, a total of 12 patients in group B had abnormal cardiac MR scan results. Therefore, six patients with abnormal cardiac MR scans had no cardiac diagnosis. It is possible that these patients also had cardiac sarcoidosis. Nonetheless, the authors have provided ample evidence to support the premise that patients with symptomatic cardiac sarcoidosis have a poor prognosis and require detection and therapy. The treatment of cardiac sarcoidosis begins with an alert clinician. Every patient with a diagnosis of sarcoidosis should be asked about symptoms of palpitations, “skipped” heartbeats, orthopnea, and syncope. Patients should also be asked about chest pain that is different from the typical chest pain of sarcoidosis, which is pleuritic and substernal or infrascapular in location.28Highland KB Retalis P Coppage L et al.Is there an anatomical explanation for chest pain in patients with pulmonary sarcoidosis?.South Med J. 1997; 90: 911-914Crossref PubMed Scopus (22) Google Scholar A 12-lead ECG should be performed for all patients with newly diagnosed disease.29Hunninghake GW Costabel U Ando M et al.Statement on sarcoidosis.Am J Respir Crit Care Med. 1999; 160: 736-755Crossref PubMed Scopus (2163) Google Scholar On the basis of the findings by Smedema and colleagues, the absence of cardiac signs or symptoms suggests a benign course even if occult sarcoidosis is present. The presence of clinical evidence of cardiac sarcoidosis, however, requires prompt evaluation to identify those patients at risk for sudden death who may benefit from directed therapy. Given the serious potential complications of symptomatic cardiac sarcoidosis, it is disheartening that this condition is often not searched for or appropriately treated. As the director of a large sarcoidosis center, most patients referred for sarcoidosis have not had a previous ECG. I am often the first physician who has elicited a history of palpitations or skipped heartbeats. Although cardiac sarcoidosis is rare, it can be lethal, but death can often be prevented if the clinician is armed with adequate knowledge. Eleven years ago in CHEST, a warning was issued concerning the danger of cardiac sarcoidosis.30Sharma OP Myocardial sarcoidosis: a wolf in sheep's clothing.Chest. 1994; 106: 988-990Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar I believe that this warning has largely been unheeded. Let me try another warning with a National Football League flavor: in terms of detecting cardiac sarcoidosis, there is no instant replay. Author's DisclaimerThe author has no first-hand knowledge about the medical case of Mr. Reggie White. He only knows, via the lay media, that Mr. White had received a diagnosis of cardiac sarcoidosis and obstructive sleep apnea and had sudden death. The author has no first-hand knowledge about the medical case of Mr. Reggie White. He only knows, via the lay media, that Mr. White had received a diagnosis of cardiac sarcoidosis and obstructive sleep apnea and had sudden death. Dr. John Heffner is thanked for his thoughtful review of this manuscript.