Sarcoidosis

Study objectives: QT dispersion (QTd) is the maximal interlead difference in QT interval on surface 12-lead ECG. An increase in QTd is found in various cardiac diseases. Sarcoidosis augments inhomogeneity in ventricular repolarization by sarcoid granuloma, which significantly correlates with ventricular fibrillation. Changes in QTd in the course of sarcoidosis have not been investigated previously.

Design: The study included 35 patients with systemic sarcoidosis. The diagnosis of systemic sarcoidosis was made by biopsy. Thallium scintigraphy was performed in all patients with systemic sarcoidosis. Cardiac sarcoidosis was diagnosed in 16 patients based on abnormal thallium scintigraphy and normal coronary arteriography results. QTd, corrected QTd (cQTd), maximum QT (QTmax), maximum corrected QT (cQTmax), minimum QT, and minimum corrected QT intervals were measured. Twenty-four healthy subjects represented the control group for QT interval analysis.

Measurements and results: In the cardiac sarcoidosis group, mean QTd [+ or -] SD) was significantly greater than in the noncardiac sarcoidosis group and control group (49.50 [+ or -] 10.86 ms, 28.14 [+ or -] 11.02 ms, and 27.08 [+ or -] 10.41 ms, respectively; p < 0.001). cQTd was significantly greater in the cardiac sarcoidosis group than in the noncardiac sarcoidosis group and control group (53.17 [+ or -] 10.44 ms, 30.61 [+ or -] 10.94 ms, and 29.01 [+ or -] 10.52 ms, respectively; p < 0.001). QTmax (440 [+ or -] 15.01 ms, 409 [+ or -] 14.86 ms, and 410 [+ or -] 13.21 ms; p < 0.001) and cQTmax (449 [+ or -] 16.31 ms, 417 [+ or -] 12.51 ms, and 418 [+ or -] 11.76, respectively; p < 0.001) were also significantly greater in patients with cardiac sarcoidosis. In a limited follow-up group (11 cardiac and 9 noncardiac sarcoidosis patients), the incidence of premature ventricular contraction (PVC) on ECG was greater in the cardiac sarcoidosis group than in the noncardiac sarcoidosis group (36% and 0%, respectively; p < 0.05). A medium correlation existed between QTd and PVC (r = 0.331, p < 0.05).

Conclusions: QTd, cQTd, QTmax, and cQTmax are prolonged in patients with cardiac sarcoidosis compared to the patients with noncardiac sarcoidosis and control subjects. The incidence of PVC on ECG was greater in the cardiac sarcoidosis group than in the noncardiac sarcoidosis group.

Key words: sarcoidosis; sarcoidosis heart; QT intervals

Abbreviations: ACE = angiotensin-converting enzyme; cQTd = corrected QT dispersion; cQTmax = maximum corrected QT; PVC = premature ventricular contraction; QTd = QT dispersion; QTmax = maximum QT; QTmin = minimum QT; VT = ventricular tachycardia

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Sarcoidosis is a multisystem disorder of unknown etiology characterized by infiltration of several organ systems by noncaseating granulomas. The lungs, skin, and eyes are most commonly affected. Sarcoidosis is an uncommon disease with a prevalence of approximately 20/100.000. (1) Clinically recognizable sarcoid involvement of the heart occurs in < 10% of patients, although cardiac granulomas are found in as many as 30% at autopsy. (2) In general, sarcoidosis has a mortality rate of only 0.2/100.000, (1) but the prognosis when the heart is involved is very much worse, approximately 40% by 5 years. (3) In Japan, approximately 73% of patients with myocardial sarcoidosis have died, (4) and sudden death was accepted as the most common manifestation of clinically significant myocardial involvement. (5-7)

A potential clinical application of interlead QT difference was proposed in 1990 by Day et al, (8) termed, QT dispersion (QTd). The potential value of QTd for risk stratification was examined in populations vulnerable to sudden cardiac death, such as patients with ischemia, (9) congestive heart failure, (10,11) or after myocardial infarction. (12,13) Changes in QTd in the course of sarcoidosis have not been investigated. We hypothesized that QTd would increase in patients with cardiac sarcoidosis, which may be responsible for arrhythmic events including sudden death.

MATERIALS AND METHODS

Study Groups

Forty-one consecutive outpatients with transbronchial biopsy specimen-proved pulmonary sarcoidosis were recruited from a specialized chest disease hospital clinic between January 1, 2000, and October 31, 2001. Six patients were excluded from the study because of the presence of one or more of the following criteria: presence of lung disease other than sarcoidosis, presence of known ischemic or structural heart disease, systemic hypertension, anemia, diabetes mellitus, pregnancy, alcoholism, any arrhythmia, and conduction defects. One of six patients was excluded due to not having ECG criteria. Thus, the patient group included 35 patients who had a mean [+ or -] SD disease duration of 21 [+ or -] 12 months (range, 1 to 43 months). Patients with systemic sarcoidosis were further classified into two subgroups depending on the myocardial thallium involvement. Cardiac sarcoidosis was diagnosed in 16 patients on the basis of abnormal thallium scintigraphy and normal coronary angiography results. The control group consisted of 24 healthy volunteers without a history of cardiovascular disease and risk factors who had normal clinical examinations.

Study Protocol

Patients were informed about the study protocol, consent was obtained from each patient, and approval was made by the local ethical committee. Echocardiographic examination and thallium scintigraphy were performed in all patients with systemic sarcoidosis. Coronary angiography was performed in patients with abnormal thallium scintigraphy results.

Echocardiographic Examination

Transthoracic echocardiography was performed by one of the authors who did not have any information of the clinical data (Vingmed System Five; GE Medical Systems; Milwaukee, WI; with a 2.5-MHz phased-array transducer). Recordings were made on patients positioned in the left lateral decubitus position. The left ventricular ejection fraction was measured using a modified Simpson rule. (14)

Thallium Scintigraphy

Myocardial [sup.201]Tl scintigraphy was performed in all patients with systemic sarcoidosis. After an overnight fast, 1.5 mCi of [sup.201]Tl was administered IV at peak exercise, and scans were recorded with a high-resolution scintillation camera, with a high-resolution, low-energy, parallel-hole collimator. Images were obtained in the anterior, 45[degrees] left anterior oblique, and left lateral projections. Resting images were obtained 2 h later with the same protocol, and the tomographic images of the vertical long axis, horizontal long axis, and short axis were reconstructed. Scans were evaluated visually by two physicians. In the presence of normal coronary arteries, perfusion defects, especially reverse redistribution on [sup.201]Tl imaging in a patient with biopsy-proven systemic sarcoidosis, were accepted as a sign of cardiac involvement. (15)

QTd Analysis

All standard 12-lead ECGs were obtained simultaneously using a recorder (Pagewriter 300 pi; Hewlett Packard; Andover, MA) set at paper speed of 50 mm/s and 2 mV/cm standardization. The ECGs were numbered and presented to the analyzing investigators without name and date information. All QT interval measurements were performed manually and blindly by two medically qualified investigators. The QT interval was measured from the onset of the QRS complex to the end of the T wave, defined as the return to the T-P isoelectric line. The measurements were carried out with a precision of 0.01 mm (0.4 ms). If a U wave was present, the QT interval was measured to the nadir between the T and U waves. If the T wave could not be clearly determined, that lead was excluded. An average value of three readings was calculated for each lead. Only recordings with more than eight analyzable leads were included. Maximum QT (QTmax) was determined as the lead with the longest QT interval. Minimum QT (QTmin) was determined as the lead with the shortest QT interval. QTd was defined as the difference between the longest and shortest QT intervals; rate correction was performed with the Bazett formula (16): corrected QTd (cQTd) = Qtd/[square root of (R-R interval)] in milliseconds. This traditional correction procedure is intended to obviate the dependence of QT interval on heart rate. We quantified the reliability of each investigator by having them remeasure a random sample of 15 ECGs.

Statistical Analysis

All statistical studies were carried out using statistical software (SPSS version 10.0; SPSS; Chicago, IL). Quantitative variables were expressed as mean [+ or -] SD, and qualitative variables were expressed as a percentage. Spearman p correlation analysis was performed between premature ventricular contraction (PVC) and QTd. All numeric variables showed normal distribution, and the variance between the study groups was similar. Thus, comparison among the study groups for various numeric parameters was carried out by one-way analysis of variance and the post hoc Tukey honestly significantly different test for multiple comparisons. Comparisons of proportions were performed by using a [chi square] test. The reliability of each operator was estimated from repeated ECGs, using the formula: 1 - [S.sup.2]d/[S.sup.2]x, where: [S.sup.2]d = variance of the difference in the two readings, and S2x = variance of the average of the two readings; p < 0.05 was considered statistically significant.

RESULTS

Demographics and Patient Characteristics

There were no differences in age and sex between groups. All subjects were normotensive, and there were no significant differences in systolic or diastolic BPs and echocardiographic ejection fraction among study groups (Table 1). Radiologic stages were not significantly different between groups with cardiac sarcoidosis (stage 1, 46%; stage 2, 48%; stage 3, 8%) and noncardiac sarcoidosis (stage 1, 30%; stage 2, 55%; stage 3, 15%). There was no difference in disease duration between groups with cardiac sarcoidosis and noncardiac sarcoidosis (21 [+ or -] 13 months vs 22 [+ or -] 12 months, respectively). Pulmonary function tests such as [FEV.sub.1] and FVC, angiotensin-converting enzyme (ACE) levels, and [Ca.sup.++] levels were not different between sarcoidosis patients with and without thallium involvement (Table 2).

ECG Characteristics

In the cardiac sarcoidosis group, QTd, cQTd, QTmax, and corrected QTmax (cQTmax) were significantly greater than in the noncardiac sarcoidosis group and control group (p < 0.001). There were no differences in QTd, cQTd, QTmax, and cQTmax between the noncardiac sarcoidosis group and the control group. Also, there were no differences in QTmin, corrected QTmin durations, ST-segment depression, and T-wave inversion ratios between study groups. The estimates of reliability for the measurement of QTd were 0.88 and 0.90 for readers 1 and 2, respectively, and 0.89 and 0.91 for cQTd (Table 3).

Follow-up Characteristics of Patients

Twenty patients are still undergoing follow-up: 11 patients with cardiac sarcoidosis and 9 patients with noncardiac sarcoidosis. Five patients (45%) with cardiac sarcoidosis and three patients (33%) with noncardiac sarcoidosis are being treated with prednisolone. None of the study patients have heart failure, syncope, or presyncope. In the last examination, which was made 2 months ago, four cardiac sarcoidosis patients who were receiving prednisolone had unifocal bigeminy PVCs on ECG. They had no cardiac or other noncardiac diseases. PVCs on ECG were greater in the cardiac sarcoidosis group than in the noncardiac sarcoidosis group (36% vs 0%, p < 0.05; Table 4). Therefore, the prednisolone dose was increased. A medium significant correlation existed between PVC and QTd (r = 0.331, p < 0.05). Figures 1, 2 show the [sup.201]Tl scan picture and ECG of the same patient with cardiac sarcoidosis, respectively.

[FIGURES 1-2 OMITTED]

DISCUSSION

To our knowledge, the present study is the first to use QT interval analysis in patients with sarcoidosis. This study shows that QTd, cQTd, QTmax, and cQTmax are affected in patients with cardiac sarcoidosis. We observed that the incidence of PVC is greater in the cardiac sarcoidosis group and that there is a significant correlation between QTd and PVC. In one study, (17) QTd was greater in 56 patients with inducible ventricular tachycardia (VT), compared with 106 noninducible patients; both groups of patients had greater QTd than the 144 healthy control subjects. A second study (18) of 66 patients reported that increased QTd predicts inducible VT with a sensitivity of 67% and a specificity of 94%. De Bruyne and colleagues (19) studied 5,812 men and women [greater than or equal to] 55 years old in the Rotterdam Study using the modular ECG analysis system. During a mean follow-up of 4 years, cardiac death, sudden cardiac death, and total mortality rates were increased in the highest cQTd tertile compared with the lowest tertile. A second large-scale, population-based study (20) of 1,839 Native American Indians enrolled in the Strong Heart Study also demonstrated that QTd predicts mortality; QTd was found to be a significant predictor of all-cause mortality and cardiovascular mortality during a mean follow-up of 3.7 years. It has also been suggested that QTmax may also be predictive of cardiac death. (21-23) Rossing et al (22) in a study of patients with type I diabetes, reported that QTmax was more predictive of cardiac death than cQTd, but these data were unadjusted for underlying ischemia as reflected by Minnesota coding. Although there are data about congestive heart failure and Qtd, (10,11) we have no information about infiltrative cardiomyopathies other than cardiac sarcoidosis and QTd.

For cardiac diagnosis, endomyocardial biopsy, (5) echocardiography, (24) myocardial perfusion scintigraphy, (25) and 24-h Holter recordings (26) are used. Twenty-four-hour Holter monitoring has been used to screen arrhythmias and conduction defects in suspected sarcoidosis, (26) but the usefulness as a noninvasive indicator of sudden death in sarcoidosis has not been established or investigated. Two thirds of patients with cardiac sarcoidosis die suddenly. VT is one of the most frequently reported cardiac arrhythmias and, together with complete heart block, is presumed to be the cause of sudden death in most patients with myocardial sarcoidosis. (27) The authors accepted that granulomas and development of ventricular aneurysms provide a substrate for VT and ventricular fibrillation. Cardiac sarcoidosis, with alteration of the normal kinetic of involved area of the heart, could induce an abnormal mechanical stimulation of the receptors in the myocardial wall with a reflex increase of the sympathetic activity. Sarcoid granuloma can develop a focus for automaticity or develop reentrant arrhythmia. In our study, prolongation of QTd, cQTd, QTmax, and cQTmax in patients with cardiac sarcoidosis was found in comparison with noncardiac sarcoidosis patients and a control group of healthy subjects. PVCs are significantly frequent in cardiac sarcoidosis patients than in noncardiac sarcoidosis patients, and there is a medium correlation between QTd and PVC. Therefore, these parameters might be risk factors for sudden death in patients with cardiac sarcoidosis, and ECG analysis might be used as a part of risk stratification. Interestingly, the results of our study showed that increased QTd, cQTd, QTmax, and cQTmax may indicate cardiac involvement. Accordingly, these parameters may be used to differentiate the patients with and without cardiac involvement. Prospective studies should be done to examine this phenomenon.

Study Limitations

Measurement of the QT interval and its dispersion is not standardized. In this study, we used the method suggested by Day et al. (8) All measurements were obtained in a blinded manner and were highly reproducible; however, this study and previous investigations are affected by fundamental limitations in the use of QTd measurements. The accuracy of QT interval and dispersion measurements has been limited by difficulties with reliable identification of T-wave offset. (28) The reliability of both automatic and manual measurement of QTd is low. Efforts should be directed toward established as well as new methods for assessment and quantification of repolarization abnormalities, such as principal component analysis of the T wave, T-loop descriptors, and T-wave morphology and wavefront direction descriptors. (29)

We used [sup.201]Tl scintigraphy for the detection of cardiac involvement. Myocardial thallium involvement with normal coronary arteries was accepted as cardiac sarcoidosis. This criterion may be criticized because the endomyocardial biopsy or autopsy was suggested for definitive diagnosis of cardiac sarcoidosis. (30) However, we studied live patients, and endomyocardial biopsy has a low yield of diagnostic accuracy. (30)

We have a limited number of follow-up patients (20 of 35 patients, 57%), and we have no data about Holter recordings of group, especially the patients with PVCs. Therefore, we need large study groups with perfect follow-up and Holter recordings.

CONCLUSION

QTd, cQTd, QTmax, and cQTmax intervals are prolonged in patients with cardiac sarcoidosis compared to patients with noncardiac sarcoidosis and control subjects. The incidence of PVC, which shows significant correlations with QTd, is greater in patients with cardiac sarcoidosis. This study calls attention to the importance of ECG, a useful, simple, noninvasive, broadly accessible, easily repeatable/ applied, and affordable tool in the differentiation of the patients with and without cardiac involvement in sarcoidosis.

Manuscript received April 9, 2005; revision accepted May 25, 2005.

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Huseyin Uyarel, MD; Nevzat Uslu, MD; Ertan Okmen, MD; Zeynep Tartan, MD; Hulya Kasikcioglu, MD; Sennur Unal Dayi, MD; and Nese Cam, MD

* From the Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul, Turkey.

Correspondence to: Huseyin Uyarel, MD, Dumlupmar Mh. Mandwa Cad., Volkangul Sok. Recep Nak Apt. 28/9, 34710 Fikirtepe-Kadzkoy, Istanbul, Turkey; e-mail: uyarel@yahoo.com

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