© 2015, Wiley Periodicals, Inc. DOI: 10.1111/echo.12963
Echocardiography
Assessment of Left Atrial Function in Patients with Celiac Disease € ksel C ırcı, M.D.,* Nermin Bayar, M.D.,* Ayhan Hilmi C ß ekin, M.D.,† Sßakir Arslan, M.D.,* Go ß ag € klu € , M.D.,* and Selcßuk Ku € cßu € kseymen, M.D.* Zehra Erkal, M.D.,* Serkan C ß ay, M.D.,‡ Erkan Ko *Cardiology Department, Antalya Education and Research Hospital, Antalya, Turkey; †Gastroenterology € ksek Department, Antalya Education and Research Hospital, Antalya, Turkey; and ‡Cardiology Department, Yu _Ihtisas Education and Research Hospital, Ankara, Turkey
Background: There is some evidence suggesting increased risk of atrial fibrillation (AF) in patients with celiac disease (CD). Impaired left atrial function plays a significant role in the development of AF. This study aimed at assessing the electrical and mechanical functions of the left atrium in patients with CD. Methods: A total of 71 patients with biopsy-proven, antibody-positive CD and 52 age-matched healthy controls were included in this prospective study. P-wave dispersion (PWD) was measured to assess the electrical functions of the left atrium through the use of surface electrocardiography. A tissue Doppler echocardiography was performed to determine the atrial conduction and electromechanical delay (EMD) time. To evaluate the mechanical functions of the left atrium, maximum, minimum, and presystolic atrial volumes were estimated to calculate the contractile, conduit, and reservoir functions. Results: In terms of transthoracic echocardiographic parameters, CD and control subjects were not significantly different. However, as compared to controls, patients with CD had significantly increased PWD (median 52 ms [interquartile range 46–58 ms] vs. 38 [36–40], P < 0.001). Also, significantly higher interatrial (49 ms [32–60] vs. 26 ms [22–28], P < 0.001), intra-left atrial (26 ms [17–44] vs. 14 ms [12–18], P < 0.001), and intra-right atrial (15 ms [8–22] vs. 10 ms [8–14], P < 0.001) EMD was found among CD subjects than controls. Despite an increase in the left atrial volume in patients with CD, conduit and reservoir functions were comparable. Conclusions: Although atrial mechanical functions are preserved in patients with CD, a slower electrical conduction was found, suggesting an increased risk of AF in this group of patients. (Echocardiography 2015;32:1802–1808) Key words: celiac disease, atrial fibrillation, echocardiography, P-wave dispersion, left atrial function Celiac disease (CD) is an autoimmune disease primarily involving the small intestine, but with potential effects in other organ systems. In patients with CD, dietary intake of gluten triggers an inflammatory reaction with development of secondary cryptic hyperplasia and villous atrophy. The resulting small intestinal dysfunction is associated with malabsorption and several nutritional deficiencies. Also, the ongoing systemic inflammation and concomitant nutritional deficiencies may lead to functional impairment in other organs.1,2 There has been a substantial increase in the prevalence of CD over the last 50 years.3 Celiac disease is often assumed to have its onset in childhood, and clinical manifestations vary according to age-group. Adults who develop CD may present with diarrhea, but they can Address for correspondence and reprint requests: Nermin itim ve Arasßtırma Hastanesi, Varlık Bayar, M.D., Antalya Eg uksu, Antalya, Turkey. Fax: Mah. Kazım Karabekir Cad., Sog 0090 (242) 249 44 62; E-mail: [email protected]
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also have silent manifestations such as anemia. Metabolic bone disease, dermatitis herpetiformis, peripheral neuropathy, endothelial dysfunction, thyroid diseases, and infertility can occur in CD more frequently than in the general population.4,5 There are some data suggesting an increased risk of cardiovascular events and stroke in patients with CD.6 For instance, in two large population-based studies, an increased risk of atrial fibrillation has been reported in patients with CD.6,7 It is also possible that cardiac rhythm disturbances such as AF may be associated with the observed increase in the risk of stroke. The role of systemic inflammation in the development of AF has been previously established, with fibrotic changes in the atrium due to systemic inflammation being a substrate for the development of AF.8,9 Persistent systemic inflammation is a common occurrence in individuals with CD, and this may have an impact on atrial functions.10 Thus, this study was conducted to examine the electrical and mechanical functions of the
Celiac Disease and Atrial Fibrillation
left atrium in patients with CD in the context of the risk of atrial fibrillation. Methods: In this prospective study, we evaluated patients with a diagnosis of CD with both histopathology and serology (plasma antitissue transglutaminase and anti-endomysial antibodies) who have been followed by Gastroenterology Department of Antalya Education and Research Hospital and a total of 71 subjects with CD and 52 healthy controls were included. Patients’ baseline demographic characteristics were recorded. Patients with heart failure, moderate-to-severe cardiac valvular disease, coronary artery disease, diabetes mellitus, hypertension, permanent atrial fibrillation, acute infections, collagen tissue disease, malignancy, inflammatory conditions other than CD, steroid use, thyroid/renal/hepatic dysfunction, or hematological conditions were excluded. A total of 71 patients with CD were examined as to their compliance in our study, and four patients with concomitant diabetes mellitus, two patients with hypertension, the presence of active infection in three patients, and two patients due to thyroid dysfunction were excluded from the study. The study protocol was approved by the local ethics committee. In addition, the patients signed consent forms about information for the purpose of this study. Heart rate and blood pressure were measured in all participants. A 12-lead electrocardiography (ECG) recording (Nihon Kohden, Tokyo, Japan) was performed in all patients. The P-wave dispersion (PWD) was determined on the basis of the difference between the shortest and longest Pwave durations. All patients underwent 2-dimensional, Mmode, pulsed, and color flow Doppler echocardiographic examinations (Philips EPIQ 7 Cardiac Ultrasound, Bothell, WA, USA). During echocardiography, a single-lead electrocardiogram was recorded simultaneously. Data were recorded from the average of three cardiac cycles. Mmode and Doppler measurements were per-
formed according to American Society of EchoConventional cardiography guidelines.11 measurements were carried out using transthoracic echocardiography, and left atrial volume and functions were estimated.12 All atrial volumes were measured on a uniplanar area–length (apical 4-chamber) formula. Maximal LA volume (LAVmax), minimal LA volume (LAVmin), and atrial precontraction LA volume (LAVpre-a) were calculated (Fig. 1). Left atrium (LA) volumes were recorded by indexing according to body surface area (BSA).
• • •
Reservoir volume, calculated as the difference between maximal and minimum LA volumes. Conduit volume, calculated as the difference between maximum and pre-atrial contraction LA volume (=passive emptying volume). Contractile volume, calculated as the difference between minimum and pre-atrial contraction LA volume (=active emptying volume).
The following formulas were used for the calculations of the left atrial functions: Reservoir function ð%Þ: ðLAVmax LAVmin Þ= LAVmax Þ 100 Conduit function ð%Þ: ðLAVmax LAVprea Þ= LAVmax Þ 100 Pumping function ð%Þ: ðLAVprea LAVmin Þ= LAVprea Þ 100 The distensibility index: ðLAVmax LAVmin Þ= LAVmin Tissue Doppler echocardiography was performed with transducer frequencies of 3.5–4.0 MHz by adjusting the spectral pulsedDoppler signal filters until a Nyquist limit of 15 to 20 cm/s was reached and using the minimal
Figure 1. Maximum A. minimum B. and the pre-atrial systolic C. volume measurements of left atrium were made by transthoracic echocardiography on apical four-chamber window.
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Bayar, et al.
Figure 2. Atrial electromechanical coupling (PA’), the time interval from the onset of the P-wave on the surface electrocardiogram to the beginning of the late diastolic wave A’ [in a patient with Celiac disease (CD) A. and normal individual B.].
optimal gain. The monitor sweep speed was set at 100 mm/s. In the apical four-chamber view, the pulsed-Doppler sample volume was placed at the level of LV lateral mitral annulus, septal mitral annulus, and RV tricuspid annulus. Atrial electromechanical coupling (PA’), the time interval from the onset of the P-wave on the surface electrocardiogram to the beginning of the late diastolic wave (A’), was obtained from the lateral mitral annulus (PA’lateral), septal mitral annulus (PA’septal), and tricuspid annulus (PA’tricuspid) (Fig. 2). The difference between PA’lateral and PA’tricuspid was defined as the interatrial electromechanical delay (EMD), while the difference between PA’septal and PA’tricuspid was defined as the intra-right atrial EMD and difference between PA’septal and PA’lateral was defined as the intra-left atrial EMD. Routine biochemical tests and complete blood count (CBC) were performed after 12 hours of fasting from antecubital venous sampling. The blood samples were routinely centrifuged, and serum samples were collected. The CRP levels (normal range: 0–5 mg/L) were analyzed with a Beckman Coulter Inc. (Image 800; Fullerton, CA, USA). CBC including white blood cell (WBC), neutrophil, and lymphocyte counts was performed using an automated CBC device (Abott Cell Dyn, Abbott Park, IL, USA). Neutrophil/lymphocyte (N/L) ratio was calculated using data obtained from the CBC. Statistical Analysis: Data were analyzed with the SPSS software version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean + SD, and categorical variables are expressed as percent. The chi-square test and Fisher’s exact test were used to compare categorical variables. The Kolmogorov–Smirnov test was used to assess the distribution of continuous variables. Student’s t-test was used for variables with 1804
normal distribution, and the values were presented as mean SD. Continuous variables without normal distribution were analyzed using Mann–Whitney U-test, and obtained values were presented as median (50th) values and interquantile ranges (25th and 75th). A two-tailed Pvalue of
Echocardiography
Assessment of Left Atrial Function in Patients with Celiac Disease € ksel C ırcı, M.D.,* Nermin Bayar, M.D.,* Ayhan Hilmi C ß ekin, M.D.,† Sßakir Arslan, M.D.,* Go ß ag € klu € , M.D.,* and Selcßuk Ku € cßu € kseymen, M.D.* Zehra Erkal, M.D.,* Serkan C ß ay, M.D.,‡ Erkan Ko *Cardiology Department, Antalya Education and Research Hospital, Antalya, Turkey; †Gastroenterology € ksek Department, Antalya Education and Research Hospital, Antalya, Turkey; and ‡Cardiology Department, Yu _Ihtisas Education and Research Hospital, Ankara, Turkey
Background: There is some evidence suggesting increased risk of atrial fibrillation (AF) in patients with celiac disease (CD). Impaired left atrial function plays a significant role in the development of AF. This study aimed at assessing the electrical and mechanical functions of the left atrium in patients with CD. Methods: A total of 71 patients with biopsy-proven, antibody-positive CD and 52 age-matched healthy controls were included in this prospective study. P-wave dispersion (PWD) was measured to assess the electrical functions of the left atrium through the use of surface electrocardiography. A tissue Doppler echocardiography was performed to determine the atrial conduction and electromechanical delay (EMD) time. To evaluate the mechanical functions of the left atrium, maximum, minimum, and presystolic atrial volumes were estimated to calculate the contractile, conduit, and reservoir functions. Results: In terms of transthoracic echocardiographic parameters, CD and control subjects were not significantly different. However, as compared to controls, patients with CD had significantly increased PWD (median 52 ms [interquartile range 46–58 ms] vs. 38 [36–40], P < 0.001). Also, significantly higher interatrial (49 ms [32–60] vs. 26 ms [22–28], P < 0.001), intra-left atrial (26 ms [17–44] vs. 14 ms [12–18], P < 0.001), and intra-right atrial (15 ms [8–22] vs. 10 ms [8–14], P < 0.001) EMD was found among CD subjects than controls. Despite an increase in the left atrial volume in patients with CD, conduit and reservoir functions were comparable. Conclusions: Although atrial mechanical functions are preserved in patients with CD, a slower electrical conduction was found, suggesting an increased risk of AF in this group of patients. (Echocardiography 2015;32:1802–1808) Key words: celiac disease, atrial fibrillation, echocardiography, P-wave dispersion, left atrial function Celiac disease (CD) is an autoimmune disease primarily involving the small intestine, but with potential effects in other organ systems. In patients with CD, dietary intake of gluten triggers an inflammatory reaction with development of secondary cryptic hyperplasia and villous atrophy. The resulting small intestinal dysfunction is associated with malabsorption and several nutritional deficiencies. Also, the ongoing systemic inflammation and concomitant nutritional deficiencies may lead to functional impairment in other organs.1,2 There has been a substantial increase in the prevalence of CD over the last 50 years.3 Celiac disease is often assumed to have its onset in childhood, and clinical manifestations vary according to age-group. Adults who develop CD may present with diarrhea, but they can Address for correspondence and reprint requests: Nermin itim ve Arasßtırma Hastanesi, Varlık Bayar, M.D., Antalya Eg uksu, Antalya, Turkey. Fax: Mah. Kazım Karabekir Cad., Sog 0090 (242) 249 44 62; E-mail: [email protected]
1802
also have silent manifestations such as anemia. Metabolic bone disease, dermatitis herpetiformis, peripheral neuropathy, endothelial dysfunction, thyroid diseases, and infertility can occur in CD more frequently than in the general population.4,5 There are some data suggesting an increased risk of cardiovascular events and stroke in patients with CD.6 For instance, in two large population-based studies, an increased risk of atrial fibrillation has been reported in patients with CD.6,7 It is also possible that cardiac rhythm disturbances such as AF may be associated with the observed increase in the risk of stroke. The role of systemic inflammation in the development of AF has been previously established, with fibrotic changes in the atrium due to systemic inflammation being a substrate for the development of AF.8,9 Persistent systemic inflammation is a common occurrence in individuals with CD, and this may have an impact on atrial functions.10 Thus, this study was conducted to examine the electrical and mechanical functions of the
Celiac Disease and Atrial Fibrillation
left atrium in patients with CD in the context of the risk of atrial fibrillation. Methods: In this prospective study, we evaluated patients with a diagnosis of CD with both histopathology and serology (plasma antitissue transglutaminase and anti-endomysial antibodies) who have been followed by Gastroenterology Department of Antalya Education and Research Hospital and a total of 71 subjects with CD and 52 healthy controls were included. Patients’ baseline demographic characteristics were recorded. Patients with heart failure, moderate-to-severe cardiac valvular disease, coronary artery disease, diabetes mellitus, hypertension, permanent atrial fibrillation, acute infections, collagen tissue disease, malignancy, inflammatory conditions other than CD, steroid use, thyroid/renal/hepatic dysfunction, or hematological conditions were excluded. A total of 71 patients with CD were examined as to their compliance in our study, and four patients with concomitant diabetes mellitus, two patients with hypertension, the presence of active infection in three patients, and two patients due to thyroid dysfunction were excluded from the study. The study protocol was approved by the local ethics committee. In addition, the patients signed consent forms about information for the purpose of this study. Heart rate and blood pressure were measured in all participants. A 12-lead electrocardiography (ECG) recording (Nihon Kohden, Tokyo, Japan) was performed in all patients. The P-wave dispersion (PWD) was determined on the basis of the difference between the shortest and longest Pwave durations. All patients underwent 2-dimensional, Mmode, pulsed, and color flow Doppler echocardiographic examinations (Philips EPIQ 7 Cardiac Ultrasound, Bothell, WA, USA). During echocardiography, a single-lead electrocardiogram was recorded simultaneously. Data were recorded from the average of three cardiac cycles. Mmode and Doppler measurements were per-
formed according to American Society of EchoConventional cardiography guidelines.11 measurements were carried out using transthoracic echocardiography, and left atrial volume and functions were estimated.12 All atrial volumes were measured on a uniplanar area–length (apical 4-chamber) formula. Maximal LA volume (LAVmax), minimal LA volume (LAVmin), and atrial precontraction LA volume (LAVpre-a) were calculated (Fig. 1). Left atrium (LA) volumes were recorded by indexing according to body surface area (BSA).
• • •
Reservoir volume, calculated as the difference between maximal and minimum LA volumes. Conduit volume, calculated as the difference between maximum and pre-atrial contraction LA volume (=passive emptying volume). Contractile volume, calculated as the difference between minimum and pre-atrial contraction LA volume (=active emptying volume).
The following formulas were used for the calculations of the left atrial functions: Reservoir function ð%Þ: ðLAVmax LAVmin Þ= LAVmax Þ 100 Conduit function ð%Þ: ðLAVmax LAVprea Þ= LAVmax Þ 100 Pumping function ð%Þ: ðLAVprea LAVmin Þ= LAVprea Þ 100 The distensibility index: ðLAVmax LAVmin Þ= LAVmin Tissue Doppler echocardiography was performed with transducer frequencies of 3.5–4.0 MHz by adjusting the spectral pulsedDoppler signal filters until a Nyquist limit of 15 to 20 cm/s was reached and using the minimal
Figure 1. Maximum A. minimum B. and the pre-atrial systolic C. volume measurements of left atrium were made by transthoracic echocardiography on apical four-chamber window.
1803
Bayar, et al.
Figure 2. Atrial electromechanical coupling (PA’), the time interval from the onset of the P-wave on the surface electrocardiogram to the beginning of the late diastolic wave A’ [in a patient with Celiac disease (CD) A. and normal individual B.].
optimal gain. The monitor sweep speed was set at 100 mm/s. In the apical four-chamber view, the pulsed-Doppler sample volume was placed at the level of LV lateral mitral annulus, septal mitral annulus, and RV tricuspid annulus. Atrial electromechanical coupling (PA’), the time interval from the onset of the P-wave on the surface electrocardiogram to the beginning of the late diastolic wave (A’), was obtained from the lateral mitral annulus (PA’lateral), septal mitral annulus (PA’septal), and tricuspid annulus (PA’tricuspid) (Fig. 2). The difference between PA’lateral and PA’tricuspid was defined as the interatrial electromechanical delay (EMD), while the difference between PA’septal and PA’tricuspid was defined as the intra-right atrial EMD and difference between PA’septal and PA’lateral was defined as the intra-left atrial EMD. Routine biochemical tests and complete blood count (CBC) were performed after 12 hours of fasting from antecubital venous sampling. The blood samples were routinely centrifuged, and serum samples were collected. The CRP levels (normal range: 0–5 mg/L) were analyzed with a Beckman Coulter Inc. (Image 800; Fullerton, CA, USA). CBC including white blood cell (WBC), neutrophil, and lymphocyte counts was performed using an automated CBC device (Abott Cell Dyn, Abbott Park, IL, USA). Neutrophil/lymphocyte (N/L) ratio was calculated using data obtained from the CBC. Statistical Analysis: Data were analyzed with the SPSS software version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean + SD, and categorical variables are expressed as percent. The chi-square test and Fisher’s exact test were used to compare categorical variables. The Kolmogorov–Smirnov test was used to assess the distribution of continuous variables. Student’s t-test was used for variables with 1804
normal distribution, and the values were presented as mean SD. Continuous variables without normal distribution were analyzed using Mann–Whitney U-test, and obtained values were presented as median (50th) values and interquantile ranges (25th and 75th). A two-tailed Pvalue of
