Sarcoidosis is a chronic multisystem disorder of unknown etiology1 that is most commonly seen in young and middle-aged adults. It is a worldwide disease, with a prevalence of about 4.7-64 per 100000.1 Non-caseating granulomas are the pathological hallmark and are most often associated with pulmonary involvement, but may also involve the heart, liver, peripheral lymph nodes, spleen, skin, eyes, phalangeal bones, parotid glands or other organs and tissues. Recent studies suggest that the disease may be an immunological response to an unidentified antigenic trigger.2 Given the multisystem nature of the disease, its systemic presentations are myriad. Even the cardiac manifestations of the disease vary widely from patient to patient. Symptomatic cardiac involvement is detected clinically in perhaps 5% of patients with pulmonary or systemic sarcoidosis, although cardiac granulomas are found in as many as 30% at autopsy.2 Imaging studies have found asymptomatic cardiac involvement in 3.7-54.9% of patients with extracardiac sarcoidosis.3 In particular, early-stage sarcoidosis has a silent progression in most patients despite the presence of cardiac involvement. Clinicians have come to recognize cardiac sarcoidosis (CS) as an uncommon but potentially fatal condition.4 The clinical manifestations of CS are dependent on the location, extent, and activity of the disease.5 The three principal sequelae of CS are conduction abnormalities, ventricular arrhythmias, and heart failure.3,5

A potential clinical application of interlead QT difference, termed QT dispersion (QTd), was proposed in 1990 by Day et al.6 Increased QTd on the surface electrocardiogram (ECG) has been linked to increased heterogeneity of ventricular repolarization, which is implicated in the genesis of ventricular arrhythmias, and has been associated with an adverse prognosis in a variety of patient populations.7–9 Myocardial repolarization has been assessed by various methods, including QT dispersion, corrected QT dispersion (cQTd), and transmural dispersion of repolarization. Studies have shown that T-peak to T-end interval (Tpe), the interval between the peak and the end of the T wave on the ECG, can be used as an index of total dispersion of repolarization (TDR).10 TDR reflects the heterogeneity rather than the total duration of repolarization.10 Recently, a new index, the Tpe/QT ratio, has been proposed as a more accurate measure of the dispersion of ventricular repolarization compared to QTd, cQTd and Tpe intervals, and is independent of alterations in heart rate.11

Changes in QTd in the course of sarcoidosis have been investigated before. Previous studies show that QTd, cQTd, maximum QT interval (QTmax), and maximum corrected QT interval (cQT) are affected in patients with CS.12 To our knowledge, the present study is the first to use Tpe interval analysis in patients without cardiac involvement in sarcoidosis. The present study hypothesized that QT and Tpe intervals are significantly prolonged in sarcoidosis patients without cardiac involvement.

Among the 110 participants included in the study, 54 had stage I or II sarcoidosis (49 stage I, five stage II) and 56 were healthy. There were no statistically significant differences between the two groups regarding age, gender, systolic or diastolic blood pressure, heart rate, body mass index or smoking (Table 1). None of the patients with sarcoidosis was receiving oral or inhaled steroids. There was no clinical finding suggestive of cardiac involvement in any of the patients.

Echocardiographic assessment revealed no significant differences between the two groups regarding left ventricular end-systolic and end-diastolic diameters, LVEF, or annular velocity determined by tissue Doppler (Table 2). LVEF calculated by the modified Simpson's method was 61.8±7.8% in the sarcoidosis group vs. 64.1±2.7% in the control group (p=0.04). Left ventricular interventricular septum thickness, posterior wall thickness and relative wall thickness were significantly greater in the sarcoidosis group than in the control group (p<0.001).

The electrocardiographic parameters of the groups are presented in Table 3. Although QTmax, QT dispersion and QTc intervals were not different between groups, QTc dispersion and Tpe interval were significantly greater in the sarcoidosis group compared to the control group (59.9±22.5 vs. 44.4±23.8, p=0.001, and 79.4±9.3 vs. 70.7±7.03, p<0.001, respectively). We also found that the Tpe/QT ratio was significantly higher in sarcoidosis patients compared to controls (0.21±0.02 vs. 0.18±0.23, p<0.001).

CS is a rare clinical entity, affecting perhaps 5% of patients with systemic sarcoidosis; however, it is associated with a spectrum of clinically significant conduction abnormalities and arrhythmias.1 Cardiac involvement remains a morbid and potentially lethal manifestation of sarcoidosis. Clinicians should maintain a high degree of suspicion for cardiac involvement in patients with extracardiac sarcoidosis and likewise should consider CS in patients with unexplained ventricular tachyarrhythmia, high-degree heart block, or cardiomyopathy. The first manifestation of CS may be high-degree atrioventricular block, sustained atrial arrhythmias, or malignant ventricular arrhythmia (including sudden death). The substrate for arrhythmias may be active granuloma formation in the myocardium or myocardial fibrosis.

Dispersion of repolarization of the ventricular myocardium is thought to be an important factor in the pathogenesis of arrhythmias.16 Electrical instability of the heart muscle can be detected by QTd on the surface ECG17 but simple QTd provides only an imperfect estimate of the degree of heterogeneity of repolarization. Several studies have suggested that QTd helps identify patients at increased risk of ventricular arrhythmias or clinical events in a variety of clinical settings.10 However, the value of QTd in risk stratification is the subject of debate.

In the Rotterdam Study, de Bruyne et al.8 studied cQTd using the Modular ECG Analysis System. During follow-up, risk for cardiac death, sudden cardiac death, and total mortality were higher in the highest cQTd tertile. In a study of patients with familial Mediterranean fever (FMF), Nussinovitch et al.18 reported that amyloidosis of FMF is associated with increased QT variability index compared with controls, but it remains unknown whether this finding is solely amyloidosis-related or whether it has any prognostic significance. Kunisek et al.,19 studying 187 patients with left ventricular hypertrophy (LVH), found no significant association of QTc interval with the degree and type of LVH. Analysis by gender showed that men with severe concentric and eccentric LVH had higher QTc interval and QTd values than those with asymmetric LVH (not significant). In another study,12 QTd, cQTd, QTmax, and maximum cQT were prolonged in patients with CS compared to patients with noncardiac sarcoidosis and control subjects. This study highlights the importance of the ECG, a useful, simple, noninvasive, broadly accessible, easily repeatable and applied, and affordable tool in the differentiation of patients with and without cardiac involvement in sarcoidosis. Unlike this study, we investigated Tpe interval, Tpe/QT and Tpe/QTc ratio in sarcoidosis patients compared to control subjects.

Tpe interval is a measure of transmural dispersion of left ventricular repolarization and is accepted as a surrogate for increased risk of ventricular arrhythmogenesis. The underlying mechanism of Tpe prolongation and ventricular repolarization abnormalities was proposed by Antzelevitch et al.20 and other authors to be related to the different types of cells in ventricular myocardium. Previous studies showed that Tpe interval prolongation is associated with increased mortality in Brugada syndrome, long QT syndrome, hypertrophic cardiomyopathy, and myocardial infarction.21 Recently, Tpe interval and Tpe/QT ratio have emerged as novel electrocardiographic markers of increased dispersion of ventricular repolarization.10 Tpe/QT ratio has been shown to be a more sensitive index of ventricular repolarization and arrhythmogenesis than Tpe interval and, unlike the latter, was found to remain constant despite dynamic changes in heart rate.

Yan et al.22 proposed that changes in Tpe interval may predict the risk of ventricular arrhythmia, while Demir et al. showed that Tpe interval and Tpe/QT ratio were prolonged in nondipper patients.23 Zehir et al.24 found that slow coronary flow (SCF) is associated with increased Tpe interval and Tpe/QT ratio and that measurement of these two parameters ratio can be used to indicate increased risk of SCF-related adverse cardiovascular events.

Our results demonstrated that QTc dispersion, Tpe interval, and Tpe/QT and Tpe/QTc ratios were increased in sarcoidosis patients compared to the control group. To our knowledge, the present study is the first to use analysis of Tpe intervals and the Tpe/QT ratio in patients with sarcoidosis.

In conclusion, cardiac involvement is an independent predictor of mortality in sarcoidosis, and is associated with poor prognosis.25 It is therefore important to detect cardiac involvement during the subclinical stage, before the occurrence of symptoms. Variability in clinical presentation, disease severity, organ involvement, and response to steroids make it difficult to determine the natural history and prognosis of sarcoidosis. The risk of arrhythmia in this disease should be borne in mind, and consideration should be given to prophylactic implantation of a cardioverter-defibrillator, particularly in the presence of ventricular arrhythmias or reduced LVEF.

The measurement of Tpe interval and Tpe/QT ratio may be used to indicate increased risk of sarcoidosis-related adverse cardiovascular events. According to the current study's findings, the risk of development of ventricular arrhythmia may be increased in sarcoidosis patients due to myocardial voltage gradients resulting from heterogeneity of repolarization.

Further studies are required to determine the relation between Tpe interval and Tpe/QT ratio and ventricular arrhythmia in patients with sarcoidosis.

Our study revealed that QTc dispersion, Tpe interval, and Tpe/QT and Tpe/QTc ratios were greater in sarcoidosis patients compared to the control group. Tpe interval and Tpe/QT ratio may be promising markers for cardiovascular morbidity and mortality due to ventricular arrhythmias in patients with and without cardiac involvement in sarcoidosis.

The authors report no conflicts of interest, sources of financial support or corporate involvement, and confirm that the contents have not been partially or wholly published elsewhere.