Abstract
Objectives Sarcoidosis is an inflammatory granulomatous disease of unknown cause that involves multiple organ systems. Myocardial involvement is usually associated with poor prognosis, but diagnosis of cardiac sarcoidosis is frequently difficult. The aim of this study was to investigate the atrial conduction time in patients with sarcoidosis by using high-usefulness tissue Doppler echocardiography.
Methods The study population included 49 patients with sarcoidosis (19 men; mean age, 40.5 ± 9.8 years; mean disease duration, 35.7 ± 15.3 months) and 45 healthy control subjects (17 men; mean age, 40.7 ± 7.2 years). From the 12-lead electrocardiogram, P wave dispersion (PWD) was calculated. The timing of atrial contractions (PA) was measured as the intervals between the onset of P wave on electrocardiogram and the beginning of A-wave on TDI, and atrial electromechanical delay (EMD) was calculated from the lateral (PA lateral) and septal (PA septal) mitral annulus and lateral tricuspid annulus (PA tricuspid).
Results Both PA lateral and PA septal were significantly longer in patients with sarcoidosis than control subjects (67.9 ± 16.1 vs 56.3 ± 13.1, P < 0.001; and 54.8 ± 15.2 vs 45.1 ± 14.2 ms, P = 0.002, respectively). Intra-atrial (PA septal-PA tricuspid) and interatrial (PA lateral-PA tricuspid) EMD were significantly higher in sarcoidosis groups (12.6 ± 7.5 vs 8.0 ± 7.1, P = 0.003; and 25.7 ± 9.8 vs 19.3 ± 7.7 ms, P = 0.001, respectively). Similarly, maximum P-wave duration and PWD were significantly longer in patients with sarcoidosis than control subjects (105.2 ± 11.8 vs 96.7 ± 15.4, P = 0.004 and 24.7 ± 5.6 vs 19.7 ± 7.1 ms, P = 0.001, respectively). There were significant positive correlations between the disease duration and interatrial EMD (r = 0.56, P < 0.001) and intra-atrial EMD (r = 0.66, P < 0.001). Positive correlation also was present between the disease duration and PWD (r = .62, P < 0.001).
Conclusions Atrial EMD was found prolonged in patients with sarcoidosis. We also have demonstrated that PWD, interatrial and intra-atrial EMD were significantly correlated with disease duration. This study calls attention to measurement of atrial conduction time that may be clinically helpful in the recognition of cardiac involvement.
Sarcoidosis is an inflammatory granulomatous disease of unknown cause that involves multiple organ systems, including the lungs, heart, eyes, liver, and skin.1Cardiac involvement has a reported incidence of approximately 25% in US autopsy studies to nearly 60% in Japan patients with sarcoidosis.2However, only 5% to 7% of patients are clinically symptomatic from cardiac sarcoidosis.3Involvement of the heart in sarcoidosis including heart block, atrial arrhythmias, and ventricular arrhythmias, such as sustained or nonsustained ventricular tachycardia, frequent ventricular ectopy and premature ventricular complexes, congestive heart failure, diastolic dysfunction, left ventricular wall motion abnormalities, pericardial and valvular heart disease, and sudden cardiac death.1-4
Atrial fibrillation (AF) is a common arrhythmia that is related with increased morbidity and mortality.5Systemic inflammation plays a significant role in AF pathogenesis.6Supraventricular arrhythmias (eg, AF and atrial flutter), although less common than ventricular arrhythmias, estimate in approximately 19% of patients with sarcoidosis.3These arrhythmias may be secondary to atrial dilatation, autonomic dysfunction, and deformation, caused by chronic inflammatory atrial zone, left ventricular dysfunction, and atrial involvement.
Previous studies investigated that atrial conduction abnormalities were assessed with noninvasive techniques by using electrocardiograph (P-wave dispersion) and tissue Doppler imaging (TDI) echocardiography.7-9The prolongation of atrial electromechanical time has been demonstrated by using TDI in various disease, such as rheumatic mitral stenosis, paroxysmal AF, ankylosing spondylitis, type I diabetes mellitus, Familial Mediterranean fever (FMF), slow coronary artery flow, and dilated cardiomyopathy.10-16However, the usefulness as a noninvasive indicator of atrial arrhythmias in sarcoidosis has not been established or investigated. In the present study, we investigated atrial conduction times measured by TDI and P-wave dispersion in patients with sarcoidosis.
METHOD
Study Population
The study population included 49 consecutive patients with sarcoidosis who were referred from our Chest Disease Department (19 men; mean age, 40.5 ± 9.8 years; and mean disease duration, 35.7 ± 15.3 months) and 45 healthy subjects as controls (17 men; mean age, 40.7 ± 7.2 years). The diagnosis of sarcoidosis was established according to the American Thoracic Society recommendations.17Age, sex, body mass index (BMI), biochemical measurements, fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-sensitive C-reactive protein (CRP) levels were recorded. The demographic characteristics and clinical features of the patients and the controls are given in Table 1.
The control subjects had no cardiovascular or any other organ system disease and had normal physical examination, chest roentgenogram, electrocardiogram, and 2-dimensional and Doppler echocardiogram. None of the patients had hypertension, renal failure, diabetes mellitus, left ventricle (LV) ejection fraction lower than 50%, severe valvular regurgitation and moderate or severe valvular stenosis, coronary artery disease, chronic obstructive pulmonary disease, and AF. The patients with poor echocardiographic image quality also were excluded. This study complied with the Declaration of Helsinki and was approved by the Ethics Committee and the institutional review board of Erciyes University Medical School; informed consent was obtained from each patient.
Thirty-seven percent of the patients (n = 18) received oral corticosteroids, and 12% received noncorticosteroid immunosuppressive agents, including azathioprine (n = 4), cyclophosphamide (n = 1), and methotrexate (n = 1). Only 2 patients who complained of palpitations had been using calcium channel blockers.
Conventional Echocardiography
All patients underwent complete transthoracic echocardiographic studies including 2-dimensional, color flow, and spectral Doppler as well as TDI with a GE-Vingmed Vivid 7 system (GE-Vingmed Ultrasound AS, Horten, Norway) using a 2.5-MHz transducer. Echocardiographic measurements were taken with patients in the left lateral decubitus position using Standard parasternal long- and short-axis and apical views. At least 3 consecutive beats in sinus rhythm were recorded, and the average values were taken. All measurements were performed according to published criteria of the American Society of Echocardiography.18The LV end-diastolic and end-systolic dimensions, interventricular septal, and posterior wall thicknesses were measured from M-mode recordings of LV cavity with the cursor at the tip of the mitral valve leaflets in the parasternal long axis view. The left ventricular mass was calculated by using Devereux's formula.19Pulmonary hypertension was diagnosed if systolic pulmonary artery pressure (PAP) exceeded the upper limits of normal for age- and body mass index-adjusted reference ranges.
Tissue Doppler Echocardiography
For tissue Doppler imaging, the same echocardiograph machine was used to acquire TDI data at high frame rates. The Nyquist limit was set at 15 to 20 cm/s, and minimal optimal gain was used. Peak early diastolic velocity (E), peak atrial filling velocity (A), E/A ratio, E wave deceleration time (DT), and isovolumic relaxation time (IVRT) were measured from the LV and RV filling recordings. Myocardial tissue Doppler velocities (Peak systolic [Sm], early diastolic [Em], and late diastolic velocities [Am]) were recorded using spectral pulsed Doppler from the LV free wall, septum, and RV free wall from the apical 4-chamber view.20
The time interval from the onset of the atrial electrical activity (P wave on surface electrocardiography [ECG]) to the beginning of the mechanical atrial contraction (late diastolic A wave) was defined as atrial electromechanical delay (EMD) (Fig. 1). Values were averaged over 3 consecutive beats. It was obtained from the lateral mitral annulus (PA lateral), septal mitral annulus (PA septal), and RV tricuspid annulus (PA tricuspid). The difference between PA lateral and PA tricuspid (PA lateral-PA tricuspid) was defined as interatrial EMD, the difference between PA septum and PA tricuspid (PA septum-PA tricuspid) was defined as intra-atrial EMD, and the difference between PA lateral and PA septum (PA lateral-PA septum) was defined as left atrial EMD.12
Electrocardiography
All standard 12-lead ECGs were obtained simultaneously using a recorder (M1771A pagewriter 200; Hewlett Packard, PaloAlto, CA), which was set at a 50-mm/s paper speed and 20-mm/mV standardization. The ECGs were numbered and presented to the analyzing investigators without name and date information. All P wave measurements were performed manually and blindly by 2 medically qualified observers. The beginning of the P wave was defined as the point where the initial deflection of the P wave intersected the isoelectric line, and the end of the P wave was defined as the point where the final deflection of the P wave intersected the isoelectric line.14The ECG recordings with measurable P waves in less than 10 leads also were excluded (3 patients) from the analysis. The derivations in which the beginning or the end of the P wave could not be clearly identified were excluded. P-wave dispersion (PWD) was defined as the difference between the longest (Pmax) and shortest P-wave (Pmin) duration.
Pulmonary Evaluation
Patients with sarcoidosis underwent posteroanterior chest radiography to determine disease stage using standard radiographic staging for the disease according to the Scadding criteria.21Stage 0 describes no visible intrathoracic findings. Stage I is bilateral hilar lymphadenopathy (BHL) with normal lung parenchyma. Stage II is BHL and parenchymal infiltration. Stage III is bilateral infiltration without BHL, and stage IV is pulmonary fibrosis/fibrocystic parenchymal involvement (honey-combing, hilar retraction, bullae, cysts, and emphysema).
Intraobserver and Interobserver Variability
Intraobserver and interobserver variability for conventional Doppler and TDI-derived variables (PA lateral, PA septal, and PA tricuspid) ranged from 4% to 7%.
Statistical Analysis
Continuous variables were given as mean ± SD or median (range); categorical variables were defined as percentage. Independent-sample t test or Mann-Whitney Test were used to compare the study variables between sarcoidosis patients and control subjects. Correlation analyses were performed using the Pearson coefficient of correlation. A probability value of P < 0.05 was considered significant, and 2-tailed P values were used for all statistics. All statistical analyses were carried out using statistical software (SPSS, version 13.0 for Windows; SPSS, Chicago, IL).
RESULTS
Clinical Characteristics of the Study Subjects
Characteristics of the study groups are shown in Table 1. According to the basic clinical and demographic characteristics, both groups of the study were similar with regard to age, BMI, fasting glucose, and cholesterol levels. All subjects were normotensives, and no significant differences were observed in systolic or diastolic blood pressures and heart rate between the 2 groups. However, the mean plasma levels of CRP were significantly higher in the patients with sarcoidosis as compared with the controls (7.3 [3.0-5.4] vs 1.4 [1.0-2.0] mg/L, P = 0.01). Clinical features of sarcoidosis also are given in Table 1.
Ninety-two percent of patients had pulmonary involvement, and 39% of the patients (n = 19) with sarcoidosis had an extrapulmonary involvement. These patients have had multiple organ involvement, with 4 (8%) having 2 organs involved and 1 (2%) having 3 organs involved. However, 14 patients had only 1 organ involvement. Two patients have had cardiac involvement by cardiac magnetic resonance imaging.
Echocardiographic and Electrocardiographic Findings of the Study Subjects
Comparisons of the baseline echocardiographic values among sarcoidosis patients and healthy controls were summarized in Table 2. There was no difference regarding left ventricular diameters, ejection fraction, and left ventricular diastolic filling parameters (E, A, E/A, E-Dec). Additionally, IVRT values were higher in the patients with sarcoidosis than the controls (113.8 ± 15.4 vs 92.2 ± 19.0 ms, P = 0.001). On the other hand, systolic PAP was significantly higher in sarcoidosis patients than in healthy controls (28.6 ± 5.6 vs 25.1 ± 5.5 mm Hg, P = 0.005).
The atrial conduction parameters measured by TDI are reported in Table 2. In the sarcoidosis group, PA lateral and PA septum durations were significantly greater than in the control group (67.9 ± 16.1 vs 56.3 ± 13.1, P < 0.001; and 54.8 ± 15.2 vs 45.1 ± 14.2 ms, P = 0.002, respectively). There was no difference in PA tricuspid duration between the 2 groups (42.1 ± 16.8 vs 37.0 ± 11.4, P ≥ 0.05). Furthermore, intra-atrial EMD and interatrial EMD significantly longer in patients with sarcoidosis compared with controls (12.6 ± 7.5 vs 8.0 ± 7.1, P = 0.003; and 25.7 ± 9.8 vs 19.3 ± 7.7 ms, P = 0.001, respectively). Left atrial EMD was similar between the 2 groups (13.1 ± 7.2 vs 11.3 ± 4.7, P ≥ 0.05). Maximum P-wave duration and PWD on surface ECG were significantly longer in the sarcoidosis group than in the control group (105.2 ± 11.8 vs 96.7 ± 15.4, P = 0.004; and 24.7 ± 5.6 vs 19.7 ± 7.1 ms, P = 0.001, respectively). However, minimum P-wave duration was similar between the 2 groups (80.5 ± 10.8 vs 77.0 ± 12.9, P ≥ 0.05).
There were significant positive correlations between the disease duration and interatrial EMD (r = 0.56, P < 0.001) and intra-atrial EMD (r = 0.66, P < 0.001) (Fig. 2). Positive correlation also was present between the disease duration and PWD (r = 0.62, P < 0.001) (Fig. 3). P-wave dispersion also was positively correlated with interatrial EMD (r = 0.47, P = 0.001) and intra-atrial EMD (r = 0.42, P = 0.002). Treatment with corticosteroid was not associated with atrial conduction parameters (P = 0.17). We did not find significant correlation between atrial conduction parameters and hs-CRP, disease stage according to the Scadding criteria and age.
DISCUSSION
In the present study, we investigated the atrial conduction time by using high-usefulness TDI and surface ECG in patients with sarcoidosis. We have demonstrated that intra-atrial and interatrial EMD, Pmax, and PWD were higher in patients with sarcoidosis compared with the control subjects. Additionally, PWD, intra-atrial and interatrial EMD were significantly correlated with disease duration. We also have shown that PAP and hs-CRP was notably higher in patients with sarcoidosis than in healthy subjects. To our knowledge, this is the first study that shows an impaired atrial conduction time among patients with sarcoidosis.
Sarcoidosis is a systemic granulomatous disease that involves nearly every organ of the body.1-4Clinical evidence of myocardial involvement is present in approximately 5% of patients with sarcoidosis.22Myocardial involvement is usually associated with poor prognosis because of the development of fatal arrhythmias, atrioventricular conduction disorder, or refractory congestive heart failure.23Atrial arrhythmias incidence have been occurred in patients with sarcoidosis approximately 9%.3These are usually due to autonomic dysfunction, atrial dilatation, and deformation, caused by chronic inflammatory atrial zone and left ventricular dysfunction. Unfortunately, diagnosis of cardiac sarcoidosis is frequently difficult, and those patients need to have more aggressive therapy (corticosteroid and immunosuppressive and immune modulator agents). For diagnosis cardiac involvement in patient with sarcoidosis, endomyocardial biopsy, ECG, echocardiography, myocardial perfusion scintigraphy, and 24-hour Holter recordings are used.24,25However, these strategies have limited sensitivity and specific diagnostic test for cardiac sarcoidosis.
Indicator of sudden death and arrhythmias were evaluated in previous studies, but intra-atrial EMD and P wave dispersion that are noninvasive indicators of atrial arrhythmias have not been investigated in patient with sarcoidosis.25,26Atrial conduction time can be measured with invasive and noninvasive methods. Recently, increased interatrial and intra-atrial EMD as measured by TDI was observed in patients with paroxysmal atrial fibrillation (AF) compared with the control subjects.9,16The slowing of intra-atrial conduction is triggered to initiation of reentry, therefore lead to development of atrial fibrillation or atrial flutter.27Previous studies found that P-wave dispersion and intra-atrial and interatrial EMD was increased in several diseases including mitral stenosis, type 1 diabetes mellitus, FMF, slow coronary flow, ankylosing spondylitis, cardiomyopathy, and Behcet disease.10-15,28Simultaneously, investigators demonstrated that P-wave prolongation has been identified in these patients groups, and they also showed the significant correlation between PWD and atrial EMD.
Atrial fibrillation, the most common sustained arrhythmia seen in clinical practice, is associated with an increased risk of stroke, heart failure, death, cognitive dysfunction, and a reduced quality of life.6-8Although AF commonly occurs in individuals with underlying cardiac disorders, including valvular heart disease, congestive heart failure, coronary artery disease, hypertension, and congenital heart disease.29-31Several previous publications have reported other important risk factors, such as acute and chronic systemic inflammation, nutritional factors, oxidative stress, alcohol, and obesity for the occurrence of atrial fibrillation.32-37Retrospective and prospective studies published that PWD is a simple and useful parameter for the prediction of atrial arrhythmias.25P wave dispersion is accepted as the most reliable noninvasive marker of inhomogeneous and discontinuous atrial conduction. Andrikopoulos et al.38suggested that P wave dispersion could be used for the prediction of idiopathic paroxysmal AF. Dilaveris et al.8showed that P wave dispersion value of 40 milliseconds separated patients from the control subjects, with a sensitivity of 83% and a specificity of 85% for the prediction of idiopathic paroxysmal AF.
The inflammatory response in sarcoidosis is characterized by the accumulation of activated T cells and macrophages at sites of ongoing inflammation, and these cells spontaneously release interferon-gamma (IFN-gamma) and interleukin (IL) 2. Furthermore, increased release of cytokines, such as IL-1, IL-6, IL-8,IL-12, IL-15, IL-16, tumor necrosis factor α, and growth factors. Most of these cytokines favor granuloma formation and organ damage.21Aviles et al.35have demonstrated that CRP not only is associated with the presence of AF but also may also predict patients at increased risk for future development of AF. Similarly, Chung et al.32have suggested that elevated CRP may reflect an inflammatory state that promotes the persistence of AF. On the other hand, previous studies have reported that release of proinflammatory cytokines or CRP related with AF after cardiac surgery. In the present study, we have found that there was positive correlation between the duration of the disease and atrial EMD. During the course of the disease, the sustained exposure of the atrial zone to increased circulating cytokine levels may cause atrial EMD. This mechanism may partly explain the relation of abnormal EMD with the duration of the disease observed in our study.
Acar et al.10demonstrated that plasma level of CRP was closely associated with atrial conduction times in patients with FMF. We found that plasma hs-CRP level, reflecting the degree of inflammation higher than control subjects. However, there was no significant correlation between hs-CRP and atrial conduction parameters. This situation can be explained by the fact that stages III and IV included only 18% of patients, and 49% of the patients (n = 24) received oral corticosteroids and noncorticosteroid immunosuppressive agents.
Isovolumetric relaxation time represents the earliest phase of diastole and described as the time from aortic valve closure to mitral valve opening. Previous studies39-41reported that diastolic dysfunction was found in 14% to 63% of the patients with sarcoidosis. In our study, left ventricular diastolic dysfunction was detected in 36% of all patients with sarcoidosis. Additionally, IVRT was significantly longer in patients with sarcoidosis than controls. Increased left ventricular end-diastolic pressure and impaired atrial systolic function may extend this period.
Frustaci et al.42investigated endomyocardial biopsies of the right atrial septum and ventricles in patients with paroxysmal lone atrial fibrillation refractory to conventional antiarrhythmic treatment. They found that biopsies taken from the interatrial septum were compatible with a diagnosis of myocarditis in 66% of patients, with a noninflammatory cardiomyopathic process in 17% and with patchy fibrosis in the remaining 17%. Also, previous studies have established that elevated systolic blood pressure is associated with increases in left atrial fibrosis and incident atrial fibrillation.43The data obtained from the literature show that the sustained inflammation could be a cause of myocardial fibrosis. Myocardial fibrosis may be associated with atrial conduction delay in patients with sarcoidosis. Several studies published that steroids were used on the basis of the positive results obtained with steroids and immunosuppression in ventricular arrhythmias related with myocarditis.44The use of steroids and immunosuppression agents are reduced cardiac effects by inflammation in patients with sarcoidosis, and these agents may improve atrial conduction delay. However, more comprehensive studies on this issue need to be investigated in the future.
Study Limitations
The major limitation is that this is a cross-sectional design of the study. Patients with sarcoidosis could not be observed prospectively for supraventricular arrhythmic events. Thus, prolongation of EMD to predict future arrhythmic events in patients with sarcoidosis is unknown. Interatrial conduction abnormalities were not evaluated by P wave signal averaged ECG and invasive electrophysiological techniques. We did not investigate frequency of premature atrial contractions on Holter monitoring in patients with sarcoidosis and healthy subjects. In this population, invasive cardiac electrophysiological studies are needed to identify mechanism of arrhythmias, such as refractory periods and conduction velocities. Another limitation in our study was that we did not measure inflammatory cytokines, such as tumor necrosis factor α, IL-1, or IL-6. Furthermore, we do not have data before and after initiation of therapy with corticosteroid to see whether this treatment affects atrial conduction time. Serum angiotensin-converting enzyme (ACE) is a product of granuloma. Angiotensin-converting enzyme is mostly used as markers of disease activity in sarcoidosis. Furthermore, studies are needed to show the relationship between serum ACE levels and atrial conduction delay. Nevertheless, we showed that treatment with corticosteroid was not associated with atrial conduction time. For this reasons, long-term follow-up and large-scale prospective studies are required to establish the predictive value of atrial conduction parameters for the future development of supraventricular arrhythmia in patients with sarcoidosis.
In conclusion, intra-atrial and interatrial EMD, Pmax, and PWD were higher in patients with sarcoidosis compared with the control subjects. We also have demonstrated that PWD and intra-atrial and interatrial EMD were significantly correlated with disease duration. These results have indicated that increased values of atrial conduction delay may have related to the inflammation process of sarcoidosis. This study calls attention to measurement of atrial conduction time that may be clinically helpful in the recognition of cardiac involvement.