Endomyocardial fibrosis

Study objectives: We aimed to determine cardiac involvement in patients with pulmonary sarcoidosis (PS) followed up at two university medical centers in the Netherlands.

Design: We reviewed the findings in consecutive patients assessed by our departments during 1998 to 2004, and classified them as patients who had presented with symptoms of cardiac sarcoidosis (CS) [group A], and those who had been screened for this condition (group B).

Setting: Two university medical centers in the Netherlands.

Patients: One hundred one patients (69 men [mean age, 47.6 years] and 32 women [mean age, 47.3 years]) with biopsy-proven PS.

Interventions: Twelve-lead ECG (n = 101), ambulatory ECG (n = 74), echocardiography (n = 80), [sup.201]Tl single-photon emission CT (n = 61), cardiac MRI (n = 87), coronary angiography to exclude coronary artery disease (n = 17), and endomyocardial biopsy (n = 9).

Measurements: ECG, structural, and functional cardiac abnormalities according to the modified guidelines of the Japanese Ministry of Health and Welfare (1993).

Results: Sixteen of 19 patients in group A and 3 of 82 patients in group B received a diagnosis of CS. During a mean follow-up of 1.7 years (range, 3 months to 4 years), four patients in group A died (20%) and nine patients received a pacemaker and/or an implantable cardioverter-defibrillator (47%), while the patients in group B had an uncomplicated course.

Conclusions: Once symptomatic CS develops in PS patients, the prognosis becomes very grim. In contrast, the prognosis in asymptomatic cardiac involvement in PS patients is good. Considering the poor prognosis of symptomatic CS, pulmonologists should consider regular screening of their PS patients for cardiac involvement with straightforward detection methods. (CHEST 2005; 128:30-35)

Key words: cardiac sarcoidosis; heart failure; MRI; myocardial fibrosis; sudden death; ventricular tachycardia

Abbreviations: CAD = coronary artely disease; CMR = cardiac MRI; CS = cardiac sarcoidosis; DTPA = diethylenetriamine pentaacetic acid; ICD = implantable cardioverter-defibrillator; LV= left ventricular; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; PS = pulmonary sarcoidosis; PVC = premature ventricular complex; SPECT = single-photon emission CT; VT = ventricular tachycardia

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Sarcoidosis is a multisystem granulomatous disorder of unknown etiology with symptomatic cardiac involvement in approximately 5% of patients. (1,2) The clinical features of cardiac sarcoidosis (CS) include congestive heart failure, cor pulmonale, supraventricular and ventricular arrhythmias, conduction disturbances, ventricular aneurysms, pericardial effusion, and sudden death. (3)

The diagnosis of CS is made in the coexistence of noncaseating granulolnas on myocardial biopsy or biopsies of any extracardiac tissue (with the exclusion of other causes for granulomatous inflammation such as mycobacterial or fungal infection) and cardiovascular abnormalities for which other possible causes have been excluded. The guidelines from the Japanese Ministry of Health and Welfare provides an excellent diagnostic framework (Table 1). (4) The prevalence of sarcoidosis in the Netherlands is estimated to be 20 to 30 per 100,000, while the prevalence of cardiac involvement is unknown.

Postmortem studies 5,6 revealed cardiac involvement in 20 to 30% of patients with sarcoidosis in the United States. In Japan, cardiac involvement is reported to be present in as many as 58% of patients, and is responsible for as many as 85% of deaths from sarcoidosis. (7,8) We aimed to determine cardiac involvement in sarcoidosis patients followed up at two university medical centers in the Netherlands, and reviewed the findings in consecutive patients who had presented with symptoms of CS, and in those who had been screened for this condition.

MATERIALS AND METHODS

Study Population

Between July 2000 and May 2004, 101 patients (69 men [age range, 33 to 71 years; mean age, 47.6 years] and 32 women [age range, 29 to 72 years; mean age, 47.3 years]; white race [n = 87; 85%]; African [n = 4]; Asian [n = 9]; and Middle Eastern [n = 1]) with histologically proven pulmonary sarcoidosis (PS) underwent cardiac assessment in the cardiology departments of, the Erasmus Medical Centre (n = 16) and University Hospital Maastricht (n = 85). The diagnosis of sarcoidosis was confirmed if the clinical presentation and chest radiogragraphic finding were supported by histologic evidence of noncaseating granulomas by transbronchial biopsy, and the possibility of infection, environmental factors, or hypersensitivity reaction to medication causing granulomatous inflammation had been eliminated. Patients presented with symptoms suggestive of CS (n = 19) or had been screened for cardiac involvement (n = 82). Patients underwent clinical assessment, including determination of highest serum levels of angiotensin-converting enzyme (n = 64), 12-lead ECGs (n = 101), ambulatory ECG monitoring (n = 74), radiologic chest stage by radiography and/or high-resolution CT (n = 101), transthoracic echocardiograms (n = 80), [sup.201]T1 single-photon emission CT (SPECT) [n = 61], and gadolinimn-diethylenetriamine pentaacetic acid (DTPA) cardiac MRI (CMR) [n = 87]. Of the 88 CMR studies, 5 were discarded because of insufficient image quality. Seventeen patients underwent diagnostic coronary angiography to exclude coronary artery disease (CAD), endomyocardial biopsies were performed in 6 patients, and 3 patients underwent postmortem examinations. Because of the limited diagnostic yield of endomyocardial biopsies, and the invasive nature with an associated risk of morbidity, we were not justified in systematically subjecting patients who were screened for CS to this procedure. For the purpose of the present study, the Japanese guidelines were modified by excluding endomyocardial biopsy as a diagnostic parameter. Since the guidelines were compiled before CMR had become integral part of cardiac assessment, we further modified our diagnostic scheme by incorporating CMR assessment of wall thickness and motion. The diagnosis of CS, according to the modified guidelines (Table 1), was made in 19 of 101 patients included in the study.

ECG and Ambulatory ECG

A 12-lead surface ECG was performed (MAC; Marquette; Milwaukee, WI; paper speed 25 mm/s), and the findings were classified as abnormal, ie, in keeping with the ECG criteria of the guidelines (Table 1). Ambulatory ECGs (n = 74) were performed for 24 to 72 h, and results were considered abnormal when evidence of intermittent atrioventricular conduction delay or block; intermittent bundle-branch blocks or ventricular arrtaythmias, such as frequent monomorphic and/or polymorphic premature ventricular complexes (PVCs) > 100 per 24 h; nonsustained ventricular tachycardias (VTs); and/or sustained VTs were found.

Echocardiography

Studies were performed with a phased-array imaging system (Sonos 5500; Hewlett Packard; Andover, MA) and considered abnormal when regional or global systolic dysfunction, wall thickening, or thinning was found.

Thallium Myocardial Scintigraphy

After treadmill peak exercise, or during IV infusion of dipyridamol, [sup.201]Tl was administered and SPECT was performed on a triple-detector gamma camera (MultiSPECT-3; Siemens; Erlangen, Germany) equipped with low-energy, high-resolution collimators. The images were made in a 64 X 64 matrix (60 frames per 45 s). The thallium scan was considered suggestive of CS when areas with reversed uptake and/or irreversible perfusion defects were present, and/or reversible perfusion defects were found in patients with normal coronary arteries at angiography. Regional defects were localized according to the 17-segment model. (9)

CMR

Studies were performed using a 1.5-T MRI scanner (Philips; Best, the Netherlands; and General Electric; Milwaukee, WI) with a cardiac-dedicated, phased-array coil. The CMR studies were ECG triggered by standard software, and obtained in diastole to minimize artifact due to cardiac motion. Studies consisted of multislice/ multiphase steady-state-free precession, spin echo, and fat-saturated, [T.sub.2]-weighted, breath-hold sequences of the short axis, vertical long axis, and four-chamber views. Steady-state-free precession sequences were performed to assess regional wall-motion abnormalities. T2-weighted studies were performed to assess the presence of myocardial inflammation. Ten minutes 'after the additional administration of 0.1 to 0.2 mmol/kg gadolinium-DTPA (Schering; Berlin, Germany), a spin echo (slice thickness, 8 mm; gap, 0.8 mm; matrix, 512 x 512; field of view, 360 mm) and/or three-dimensional inversion recovery-gradient echo breath-hold sequence (short axis, vertical long axis, and four-chamber views) [slice thickness, 10 mm; no gap; matrix, 256 x 256; field of view, 400 mm] were used to assess for the presence of contrast-enhancing lesions. The inversion time (250 to 400 ms) was determined on an individual basis to obtain optimal nulling of the unenhanced myocardial signal. Regional differences in left ventricular (LV) wall enhancement were measured and localized according to the 17-segment model (9) (MASS Suite Postprocessing Software; MEDIS; Leiden, the Netherlands). The total time required for the investigation was 30 to 45 min. The study findings were independently evaluated by four blinded observers, three cardiologists, and one radiologist, with experience in CMR. The study findings were considered to be abnormal when at least two observers described identical abnormalities.

Coronary Angiography

Diagnostic coronary angiography was performed when considered indicated by the managing physician, and was generally done in patients with symptoms and findings suggestive of significant CAD. One patient underwent diagnostic coronary angiography as part of the diagnostic workup before cardiac transplantation.

Statistical Analysis

All statistical analyses were performed using statistical software (Version 11.5; SPSS; Chicago, IL). Group data are expressed as mean [+ or -] SD. Continuous variables were assessed using the parametric t test for independent samples or Mann-Whitney test when appropriate, and all categorical variables were assessed using the [chi square] test. Statistical significance was defined at p < 0.05.

RESULTS

Patient Characteristics

The demographic and clinical characteristics of group A and group B are presented in Table 2. Significantly more patients in group A had CS compared to group B. Pulmonary involvement based on radiologic chest stage was significantly more extensive in group B, while the degree of functional impairment was significantly higher in group A.

Findings at Cardiac Assessment

The findings at cardiac assessment are presented in Table 2, with Tables 3, 4 presenting more detailed information on the findings in all patients with CS. The ECG, ambulatory ECG, echocardiogram, and CMR studies revealed significantly more conduction abnormalities, ventricular arrhythmias, and regional loss of LV wall thickness and function in group A. Of the diagnostic techniques, ECG and CMR showed the most abnormalities.

The ECG demonstrated conduction abnormalities in 10 of the 16 patients (63%) with CS. In four patients in group B, ECG signs of right ventricular hypertrophy were present.

CMR and/or echocardiography diagnosed decreased systolic left ventricular function (mean, 35%; range, 20 to 56%) with global or regional wall motion abnormalities in 12 CS patients (75%). In 10 of the 16 CS patients, CMR and SPECT were available. In four patients, CMR and SPECT diagnosed defects, while CMR revealed small defects in four patients with normal SPECT study findings. The findings with SPECT were not significantly different between groups A and B. In eight patients in group B, small, irreversible perfusion defects were detected that were mainly located in the inferior LV wall. SPECT demonstrated reversible perfusion defects in the anterior wall in two patients with CAD in group B and an irreversible perfusion defect in this region in one patient with CAD in group A. Coronary angiography was performed in 17 patients, and revealed significant CAD in 2 patients in group A. Hypertrophic cardiomyopathy was diagnosed in two patients, one of whom also had CS.

Clinical Data at Follow-up

The management, duration of follow-up, and outcome during follow-up are presented in Tables 3, 4. Of the 16 patients with CS in group A, 9 patients received a pacemaker and/or implantable cardioverter/defibrillator (ICD). Three patients died of ventricular arrhythmias, one of treatment-resistant VTs after implantation of an ICD, and one patient died of complications after cardiac transplantation. Nine patients were treated with immune-suppressive drugs, corticosteroids, with methotrexate or azathioprine. None of the patients in group B had significant cardiovascular complications or died during follow-up.

DISCUSSION

Our study is the first to systematically evaluate cardiac involvement in patients with sarcoidosis in the Netherlands, and the largest to employ CMR. Earlier studies in the Sweden (86 patients), Ireland (50 patients), Israel (42 patients), the United States (88 patients), Japan (41 patients), and France (50 patients) used ECG, echocardiography, [sup.201]Tl SPECT, and CMR in prospective studies (10-18) evaluating the prevalence of cardiac involvement in referred patients with sarcoidosis.

Abnormalities were found in up to 23% of European and 63.4% of Japanese patients. In our study, depending on the technique used, abnormalities were found in 10 to 26% of patients without cardiac symptoms. SPECT detected small, irreversible perfusion defects in 13 patients, while gadolinium-enhancing lesions were present in 12 patients. Both SPECT and CMR demonstrated lesions in four patients. Wagner et al (19) previously demonstrated the ability of gadolinium-enhanced CMR to diagnose even small amounts of myocardial scar tissue not detected by SPECT in patients with CAD.

Histologic assessment of gadolinium-DTPA-enhanced myocardium has been correlated with fibrosis and active myocarditis. (20-22) Since [T.sub.2]-weighted studies revealed increased signal, signifying inflammation in only one patient, delayed enhancement in our patients suggest the presence of myocardial scar tissue. The favorable prognosis of abnormal SPECT findings in asymptomatic sarcoidosis patients was demonstrated by Kinney and Caldwell (23) in 52 similar patients in whom the presence of perfusion defects diagnosed with SPECT did not predict survival during a mean follow-up of 89 months. Since CMR is a relatively new diagnostic technique, and experience in evaluating patients with sarcoidosis is limited, long-term follow-up will have to determine the significance of small gadolinium-enhancing lesions in asymptomatic patients.

The significantly poorer New York Heart Association (NYHA) functional class in patients in group A, despite less radiologic pulmonary involvement, is explained by more extensive LV involvement, resulting in a lower LV ejection fraction (LVEF), heart failure, and ventricular arrhythmias. When considering the study of Yazaki et al, (24) who determined with multivariate analysis that the presence of higher NYHA functional class increased LV end-diastolic diameter and sustained VTs were independent predictors of death, we anticipated poorer outcome in group A. Although the introduction of the ICD is expected to improve outcome in patients with CS, during a mean follow-up of 15 months (3 to 54 months) in our population it delivered therapy in only one of six patients who received the device. (25)

Study Limitations

Theoretically, bias was introduced by evaluating a preselected patient population that had been referred to tertiary centers. This, however, seems unlikely when considering the fact that only a few of the patients who were screened for CS actually had this condition. It seems more likely that cardiac involvement may have been underestimated, since the diagnosis was based on the modified guideline of the Japanese Ministry of Health and Welfare. In the absence of diagnostic cardiac histology, CS could only be diagnosed in the presence of ECG abnormalities. As previously published by Silverman et al, (5) and demonstrated by patients 1 and 3 (Table 3), cardiac involvement may well be present in the absence of diagnostic ECG abnormalities.

CONCLUSION

In our cohort of 101 PS patients, the rate of cardiac involvement in those screened for this condition was low (4%) and the prognosis was good. The CS patients who presented with cardiac failure or ventricular arrhythmias had significant morbidity and a mortality rate of 25% during a mean follow-up of 15 months. Based on the findings of our current study, we recommend regular ECG evaluation in patients with PS and early referral for additional cardiac assessment with echocardiography or CMR in patients with unexplained fatigue, dyspnea, or palpitations.

ACKNOWLEDGMENT: The authors thank Dr. H. Kuehl, MD, PhD, Aachen University Medical Centre, and Dr. A. M. Beck, MD, Free University Medical Centre, Amsterdam, for assessing the CMR studies.

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* From the Departments of Cardiology (Drs. Smedema, Dassen, Crijns, and Gorgels), Radiology (Dr. Snoep), and Nuclear Medicine (Dr. van Kroonenburgh), University Hospital Maastricht, Maastricht; and Department of Cardiology and Radiology (Dr. van Geuns), Erasmus Medical Centre, Rotterdam, the Netherlands.

Manuscript received August 11, 2004; revision accepted January 19, 2005.

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

Correspondence to: J. P. Smedema, MD, MMed(Int), Department of Cardiology, University Hospital Maastricht, Dr Debyelaan 25, 6202 AZ Maastricht, the Netherlands; e-mail: j.smedema@cardio.azm.nl

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