Endomyocardial fibrosis

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 An autopsy revealed that his entire myocardium had been replaced by noncaseating granulomas.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 underdiaguosed 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, (1) even though 25% of patients have autopsy evidence of granulomatous inflammation affecting the heart. (2) 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 failure (1,3,4) or deposit in papillary muscles and set the stage for mitral regurgitation or, rarely, pulmonary hypertension. (5) Sarcoidosis may cause granulomatous pericarditis with or without pericardial effusion. (6,7) Granulomas may entangle small coronary arteries in a web of fibrosis while leaving larger coronary arteries unaffected. (1,8) Long-term granulomatous inflammation may generate myocardial scarring with the formation of ventricular aneurysms. (9) The diagnosis is also problematic because cardiac sarcoidosis may become manifest several years after the initial diagnosis of sarcoidosis is established. (10)

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. (1,3,6,7,11-13) 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 study (14) 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 "nonsndden" and occurred on average 10 years after disease onset and 4 vears after the development of respiratory insufficiency. In contrast, the remaining patients experienced sudden death attributable to neurosareoidosis (4 of 28 patients, 14%) and cardiac sareoidosis (2 of 28 patients, 7%).

Even when clinically suspected, confirmation of a diagnosis of cardiac sareoidosis presents considerable challenges. Endomyocardial biopsy reveals noncaseating granulomas in less than one fourth of cases because of the patchy distribution of the disease. (15) When cardiac sarcoidosis causes conduction disturbances, the diagnostic yield of endomyocardial biopsy is particularly low at < 10%. (15) Even in the case of dilated cardiomyopathy from sarcoidosis, the yield from endomyocardial biopsy is approximately one third. (15)

Most clinicians consequently rely on noninvasive tests to establish the diagnosis of cardiac involvement with sareoidosis. Available tests include ECG, (7,10,11) echocardiography, (7,10) [sup.201]Tl perfusion scan, (16,17) [sup.67]Ga scan, (16,18,19) and gadolinium-enhanced magnetic resonance (MR) scan, (20-22) and positron emission tomography. (23) The accuracy of thallium and gallium scans is enhanced by using a single-photon emission CT (SPECT) technique. (18,19) 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). (1) New, promising tests include [sup.123]-labeled 15-(piodophenyl)-3R, S-methylpentadeeonanoic acid scintigraphy, (24) and ultrasonic tissue characterization. (25)

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. (7,10,22)

Nevertheless, guidelines for the application of noninvasive tests to the diagnosis of cardiac sarcoidosis have been developed by the Japanese Ministry of Health and Welfare (26) and the research group conducting A Case Control Etiology of Sarcoidosis Study. (27) Both of these guidelines combine the results of noninvasive tests with histologic confirmation of noneaseating 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 cardiae 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 seareh 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, [sup.201]Tl 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 sarcoidosis (26) 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. (28) A 12-lead ECG should be performed for all patients with newly diagnosed disease. (29) 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. (30) 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 Disclaimer: The author has no first-hand knowledge about the medical case of Mr. Beggie 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.

ACKNOWLEDGMENT: Dr. John Heffner is thanked for his thoughtful review of this manuscript.

Marc A. Judson, MD, FCCP Charleston, SC

Dr. Judson is Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Medical University of South Carolina.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Marc A. Judson, MD, FCCP, Department of Pulmonary and Critical Care Medicine, Medical University of South Carolina, 96 Jonathan Lucas St, PO Box 250623, Charleston, SC 29425; e-email: judsonma@musc.edu

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