Author + information
- Received July 27, 2004
- Revision received January 13, 2005
- Accepted January 25, 2005
- Published online May 17, 2005.
- Jan-Peter Smedema, MD, MMed(Int), FCP(SA)⁎,⁎ (, )
- Gabriel Snoep, MD†,
- Marinus P.G. van Kroonenburgh, MD, PhD‡,
- Robert-Jan van Geuns, MD, PhD§,
- Willem R.M. Dassen, PhD⁎,
- Anton P.M. Gorgels, MD, PhD, FACC⁎ and
- Harry J.G.M. Crijns, MD, PhD, FESC⁎
- ↵⁎Reprint requests and correspondence:
Dr. Jan-Peter Smedema, Department of Cardiology, University Hospital Maastricht, Dr. Debyelaan 25, 6202 AZ Maastricht, the Netherlands
Objectives This study analyzed the accuracy of gadolinium-enhanced cardiovascular magnetic resonance (CMR) for the diagnosis of cardiac sarcoidosis (CS).
Background The diagnosis of CS was made according to the guidelines of the Japanese Ministry of Health and Welfare (1993); CMR has not been incorporated into the guidelines, and the diagnostic accuracy of CMR for the diagnosis of CS has not yet been evaluated.
Methods We performed an analysis of 12-lead electrocardiograms (ECGs), 24-h ambulatory ECGs, echocardiograms, thallium scintigrams, and gadolinium-enhanced CMR studies in 58 biopsy-proven pulmonary sarcoidosis patients assessed for CS. The diagnostic accuracy of CMR for CS was determined using modified Japanese guidelines as the gold standard.
Results The diagnosis of CS was made in 12 of 58 patients (21%); CMR revealed late gadolinium enhancement (LGE), mostly involving basal and lateral segments (73%), in 19 patients. In 8 of the 19 patients, scintigraphy was normal, while patchy LGE was present. The sensitivity and specificity of CMR were 100% (95% confidence interval, 78% to 100%) and 78% (95% confidence interval, 64% to 89%), and the positive and negative predictive values were 55% and 100%, respectively, with an overall accuracy of 83%.
Conclusions In patients with sarcoidosis, CMR is a useful diagnostic tool to determine cardiac involvement. New diagnostic guidelines should include CMR.
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology with symptomatic cardiac involvement in up to 7% of patients (1–3).
Postmortem studies reveal cardiac involvement in 20% to 30% of patients with sarcoidosis in the U.S. (4,5). In Japan, cardiac involvement is present in as many as 58% of patients, and is responsible for as many as 85% of deaths from sarcoidosis (6,7). The clinical features of sarcoid heart disease include congestive heart failure, cor pulmonale, supraventricular and ventricular arrhythmias, conduction disturbances, ventricular aneurysms, pericardial effusion, and sudden death (8). The diagnosis of cardiac sarcoidosis (CS) is made in the co-existence of non-caseating granulomas on myocardial biopsy and/or biopsies of any extracardiac tissue (with the exclusion of other causes of granulomatous inflammation such as mycobacterial or fungal infection) and cardiovascular abnormalities for which other possible causes have been excluded. The guideline from the Japanese Ministry of Health and Welfare provide an excellent framework (9) (Table 1).
The guideline combines the results of various diagnostic tests such as tissue biopsy, electrocardiography, echocardiography, and myocardial scintigraphy to either exclude or diagnose CS. Most diagnostic tests, including endomyocardial biopsy, suffer of low sensitivity, low specificity, or both. The most accurate diagnostic strategy for this condition is currently unknown. We aimed to assess the accuracy of gadolinium-enhanced cardiovascular magnetic resonance (CMR) in the diagnosis of CS with a modified guideline of the Japanese Ministry of Health and Welfare (1993) as the gold standard.
Because of the limited diagnostic yield and invasive nature of the procedure with an associated risk of morbidity, we did not feel justified to systematically subject patients who were screened for CS to endomyocardial biopsy (10). For the purpose of the present study, the Japanese guideline was modified by excluding endomyocardial biopsy as a diagnostic parameter (Table 1).
Between July 1998 and May 2004, 58 patients with histologically proven pulmonary sarcoidosis underwent cardiac assessment in the cardiology departments of Tygerberg Hospital (1 patient), Medical Centre Haaglanden (1 patient), the Erasmus University Medical Centre (3 patients), and the University Hospital Maastricht (53 patients). The diagnosis of sarcoidosis was confirmed if the clinical presentation and chest radiographic finding were supported by histological evidence of noncaseating granulomas by transbronchial biopsy, and if the possibility of infection, environmental factors, or hypersensitivity reaction to medication causing granulomatous inflammation had been eliminated. The patients had either cardiac symptoms (16 patients) or were screened for cardiac involvement in the absence of cardiac symptoms (42 patients). All patients underwent clinical assessment, 12-lead electrocardiography (ECG), ambulatory ECG monitoring, transthoracic echocardiography, 201thallium single-photon emission computed tomography (SPECT), and CMR. Patients underwent diagnostic coronary angiography to exclude coronary artery disease when a (partially) reversible perfusion defect on SPECT, decreased left ventricular ejection fraction, or regional wall motion abnormalities were present.
Cardiac histology was obtained in five patients by cardiac biopsy, and in three patients who had a postmortem examination. The diagnosis of CS, according to the modified guideline of the Japanese Ministry of Health and Welfare (Table 1), was made in 12 of 58 patients included in the study.
ECG and ambulatory ECG
A 12-lead surface ECG was recorded (MAC, Marquette, Milwaukee, Wisconsin; paper speed 25 mm/s), and the findings were interpreted by two experienced cardiologists and classified as abnormal (i.e., in keeping with the ECG criteria of the Japanese guideline [complete right bundle branch block or left bundle branch block, bifascicular block, third-degree atrioventricular block, ventricular tachycardia [VT], or pathological Q or ST-T abnormalities]) or normal.
Ambulatory ECGs were performed for 24 to 72 h, and they were considered abnormal when intermittent atrioventricular conduction delay or block, intermittent bundle branch blocks, or ventricular arrhythmias such as frequent monomorphic and/or polymorphic premature ventricular contractions >100 per 24 h, nonsustained VTs, and/or sustained VTs were found.
Studies were performed with a Sonos 5500 phased-array imaging system (Hewlett Packard, California) and considered abnormal when regional or global systolic dysfunction, wall thickening, or thinning was found. Regional differences in left ventricular wall enhancement were measured and localized according to the 17-segment model (11).
Thallium myocardial scintigraphy
After treadmill peak exercise, or during intravenous infusion of dipyridamol, 201thallium was administered and SPECT performed on a Siemens triple-detector gamma camera (MultiSPECT-3, Siemens, Erlangen, Germany), equipped with low-energy, high-resolution collimators. The images were made in a 64 × 64 matrix (60 frames/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 (11).
Studies were performed using a 1.5-T magnetic resonance imaging scanner (Philips, Best, the Netherlands, and General Electric, Milwaukee, Wisconsin) 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 steady-state-free precession in 58 patients, spin echo in 57 patients, and fat-saturated T2-weighted breath hold sequences in 58 patients. Short-axis, vertical long-axis, and four-chamber views were obtained. 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 mmol/kg gadolinium-DTPA (Schering, Berlin, Germany), short-axis and four-chamber images were obtained with spin echo in 57 patients (slice thickness 8 mm, gap 0.8 mm, matrix 512 × 512, field of vision 380 mm, voxel size 0.7 mm × 0.7 mm × 8 mm) and three-dimensional breath hold inversion recovery-gradient echo sequences (short-axis, vertical long-axis, four-chamber) in 16 patients (slice thickness 10 mm, no gap, matrix 256 × 256, field of vision 400 mm, voxel size 1.6 mm × 1.6 mm × 10 mm) to assess for the presence of gadolinium-enhancing lesions (LGE). Fifteen patients had both spin echo and inversion recovery-gradient echo studies. 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 wall enhancement were measured and localized according to the 17-segment model (11) (MASS suite post-processing software, MEDIS, Leiden, the Netherlands). The total time required for the investigation was 30 to 45 min.
The studies were independently evaluated by four blinded observers, three cardiologists, and one radiologist with experience in contrast-enhanced CMR. The studies were considered to be abnormal when at least two independent observers described identical abnormalities.
All statistical analyses were performed using the statistical software package SSPS version 11.5 (SPSS Inc., Chicago, Illinois). Group data are expressed as mean values ± SD. Continuous variables were assessed using the parametric ttest for independent samples or Mann-Whitney test where appropriate, and all categorical variables were assessed using the chi-square test. Statistical significance was defined as a p value <0.05.
A total of 58 patients were assessed. Twelve of the patients were diagnosed with CS according to the modified guidelines. The demographic, clinical, and diagnostic findings for the groups with CS and without CS are shown in Tables 2 and 3.⇓The ages, gender, race, the time between cardiac evaluation and the diagnosis of sarcoidosis, and pulmonary stage did not differ significantly between the groups. Functional class was significantly poorer in the patient group with CS compared to the group without CS due to heart failure.
Table 4summarizes the findings of the CMR studies. In 40 (69%) studies 4 out of 4 observers, in 13 (22%) studies 3 out of 4 observers, and in 5 (9%) studies 2 out of 4 observers agreed on the absence or the presence and localization of LGE. Late gadolinium-enhancing lesions were present in 19 patients (mean 3.6 segments per patient, range 1 to 12 segments). Nine of 19 patients had evaluation with spin echo, 9 patients with spin echo and inversion recovery-gradient echo, and 1 patient had only inversion recovery-gradient echo. In 5 of the spin echo patients, two observers, and in 3 of the spin echo patients 3 observers agreed on the presence and localization of LGE, whereas in 9 of the 10 patients who had both spin echo and inversion recovery-gradient echo or only inversion recovery-gradient echo all observers agreed on the presence and localization of LGE.
Most enhancing lesions were located in the basal and lateral left ventricular segments (segments 1 to 7, 11, 12, 16; 60 of 71 enhancing segments [73%]) (Fig. 1).In 10 patients, a significantly reduced left ventricular systolic function (left ventricular ejection fraction 20% to 51%, mean 36%) was reported, 7(54%) with CS, 1 patient with dilated cardiomyopathy, 1with valvular heart disease, and 1 with coronary artery disease (Figs. 2A, 2B, 3, and 4).In three patients, regional loss of wall thickness was found, two patients with CS (Figs. 5A and 5B),and one with coronary artery disease. Twelve of the 22 patients with abnormal CMR studies were diagnosed with CS according to the modified guideline. Overall, the diagnosis of CS according to the modified guideline was made in 12 of 58 sarcoidosis patients (21%).
The sensitivity and specificity of contrast-enhanced CMR was 100% (one-sided 95% confidence interval, 78% to 100%) and 78% (95% confidence interval, 64% to 89%), and the positive and negative predictive values were 55% and 100%, respectively, with an overall accuracy of 83%. Cardiovascular magnetic resonance showed one to six contrast-enhancing myocardial lesions in six patients who had not been diagnosed with CS according to the modified guideline.
In eight patients, CMR (five with spin echo, three with spin echo and inversion recovery-gradient echo) diagnosed LGE, although 201thallium scintigraphy was normal. In six of the eight patients, LGE involved only one or two segments, whereas in two patients, six and eight segments, respectively, were involved. In three patients, LGE involved one myocardial layer, sub-endocardial or midmyocardial; in one patient both subendocardial and midmyocardial layers were involved, and in four patients patchy involvement of all three myocardial layers was present (Fig. 6),without confluent transmural involvement.
The prognosis of sarcoidosis is mainly determined by pulmonary and cardiac involvement (12,13). Multivariate analysis identified New York Heart Association functional class, left ventricular end-diastolic diameter, and the presence of sustained VTs as independent predictors of mortality (14).
It is important to accurately diagnose cardiac involvement. The guideline published by the Japanese Ministry of Health and Welfare (1993) provides us with an excellent framework for diagnosis, but the techniques utilized lack sensitivity and specificity in the absence of a diagnostic endomyocardial biopsy.
Magnetic resonance imaging is a robust imaging technique that enables us to evaluate cardiac structure, function, and tissue characteristics with high-image resolution. It may guide the cardiologist when taking endomyocardial biopsies and increase the sensitivity of this technique (15,16). Serial CMR studies are possible because of the absence of exposure to ionizing radiation, and they may evaluate disease activity and extent in response to therapy.
Postmortem studies in sarcoid patients have revealed the presence of varying amounts of myocardial scar tissue, which is considered to be the substrate for lethal ventricular arrhythmias (4,5,12–14). Gadolinium-DTPA (Gd-DTPA) is an extracellular CMR contrast agent. Histological assessment of Gd-DTPA-enhanced myocardium has been correlated with local fibrosis and active myocarditis (16–18). Wagner et al. (19) have demonstrated the superior ability of gadolinium-enhanced CMR to diagnose even small amounts of myocardial scar tissue in patients with coronary artery disease when compared with myocardial scintigraphy.
Several case reports and small single-center patient series have demonstrated the diagnostic potential of CMR in CS (20–28). So far no study has systematically evaluated the diagnostic accuracy of CMR for the presence of CS using the diagnostic Japanese guideline as the gold standard. The current study is part of a prospective initiative that aims to evaluate the prevalence of cardiac involvement in patients with sarcoidosis and determine the most accurate and cost-effective diagnostic strategy for CS.
The diagnostic accuracy of CMR compares well to the techniques employed in the diagnostic framework of the Japanese guideline.
The fact that the combination of ECG and CMR saves valuable time at equal cost compared with our previously employed diagnostic pathway of ECG, echocardiography, and SPECT (cost in the Netherlands, respectively, €222 and €205) makes it an attractive alternative.
The low positive predictive value of 55% reflects the superior spatial resolution of CMR; CMR is able to detect small myocardial lesions that have not resulted in conduction delay, re-polarization abnormalities, or regional changes in wall thickness or function, and, hence, are not detected by ECG, echocardiography, or SPECT.
Unfortunately, even small myocardial scars may result in arrhythmias, and the follow-up of this patient population will determine the significance of our findings. For this reason, CMR may become very important for the early detection of cardiac involvement and for identifying pulmonary sarcoidosis in patients at risk of sudden death.
Most of the enhancing lesions (73%) were localized in the basal and lateral left ventricular wall. These findings correlate with the findings at postmortem assessment of sarcoidosis patients, where most lesions were found in the mentioned segments (4,5).
Although in some patients LGE was transmural, resulting in loss of wall thickness and regional wall motion abnormalities, lesions in most patients were patchy, affecting several myocardial layers. The presence of patchy LGE has also been reported in patients with dilated cardiomyopathy, but our findings clearly differ from the distribution of LGE in patients with coronary artery disease (29).
Considering the diagnostic limitations of electrocardiography, 25% of patients with extensive cardiac involvement in the study by Roberts et al. (5) had normal ECGs, and because of the superior spatial resolution of CMR compared with scintigraphy, new diagnostic guidelines need to be compiled that include CMR.
In patients with sarcoidosis, CMR is a useful and cost-effective diagnostic tool to determine cardiac involvement. The combination of ECG with CMR was as accurate but more time- and cost-effective compared with ECG, ambulatory ECG, echocardiography, and SPECT for the diagnosis of CS. Cardiovascular magnetic resonance diagnosed small myocardial lesions, not diagnosed by ECG, echocardiography, or SPECT, that might be of prognostic relevance.
Ideally, CMR findings should correlate with CMR-guided endomyocardial biopsy (i.e., myocardial histology). In our study, CMR findings were compared with clinical guidelines. In only four patients, myocardial histology was obtained.
In only 16 of 58 (28%) patients was the inversion recovery-gradient echo studies performed. Because inversion recovery-gradient echo increases contrast between unenhanced and gadolinium-enhanced myocardium up to 500%, this technique increases the detection rate of scar tissue (30). Although we used only spin echo sequences to assess for the presence of late enhancement in 42 patients, and might have underestimated the presence and extent of gadolinium enhancement in some patients, we were still able to detect enhancement in nine (21%) of these patients.
Recommendations for further study
There is a need for multicenter studies that will determine the diagnostic accuracy of CMR and studies into the prognostic implications of contrast-enhanced CM-detected CS not detected by conventional methods. Early treatment may possibly prevent sudden death and deterioration of ventricular function and result in improved prognosis.
The authors gratefully acknowledge Dr. H. Kuehl, MD, PhD, Aachen University Medical Centre, and Dr. A. M. Beek, MD, Free University Medical Centre, Amsterdam, for assessing the CMR studies. We thank Prof. A. F. Doubell, MMed(Int), PhD, Cardiac Unit, Tygerberg Hospital, Capetown, Republic of South Africa, and Dr. J. H. M. Schreur, Medical Centre Haaglanden, the Hague, for allowing us to include their patients in our study.
- Abbreviations and Acronyms
- cardiovascular magnetic resonance
- cardiac sarcoidosis
- late gadolinium enhancement
- single-photon emission computed tomography
- ventricular tachycardia
- Received July 27, 2004.
- Revision received January 13, 2005.
- Accepted January 25, 2005.
- American College of Cardiology Foundation
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