International Journal of Cardiology 189 (2015) 25–29
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Evaluation of ventricular repolarization in pregnant women with intrahepatic cholestasis Ozgur Kirbas a, Ebru Hacer Biberoglu b, Ayse Kirbas b,⁎, Korkut Daglar b, Ozge Kurmus c, Nuri Danisman b, Kutay Biberoglu d a
Department of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey Department of Perinatology, Zekai Tahir Burak Women Health Care, Education and Research Hospital, Ankara, Turkey Department of Cardiology, Ataturk Education and Research Hospital, Ankara, Turkey d Gazi University Medical School, Department of Obstetrics and Gynecology, Ankara, Turkey b c
a r t i c l e
i n f o
Article history: Received 21 January 2015 Received in revised form 6 March 2015 Accepted 1 April 2015 Available online 3 April 2015 Keywords: Arrhythmia Bile acid Pregnancy QT dispersion Cholestasis
a b s t r a c t Background: Bile acids can induce arrhythmia by altering cardiomyocyte contractility or electrical conduction. The aim of this study was to investigate, by means of QT dispersion parameter detected by simple standard electrocardiogram (ECG), ventricular repolarization changes in pregnant women with and without intrahepatic cholestasis of pregnancy (ICP). Methods: In this case–control study including 75 pregnant women with cholestasis and 35 healthy, uncomplicated pregnancy cases, electrocardiographic QT interval durations and QT dispersion (QT-disp) parameters, corrected for the patients' heart rate using the Hodges formula, were investigated. Results: Maximum corrected QT interval values were significantly higher in the severe ICP group than in the control group (p b 0.001) and significantly higher in the severe ICP group than in the mild ICP group (p = 0.01). The values of the mild ICP and control groups were similar. Corrected QT-disp values were also significantly higher in both ICP groups than in the control group and significantly higher in the severe ICP group than in the mild ICP group. Conclusion: Cholestatic diseases predispose patients to cardiovascular complications. Our data clearly demonstrated that QT-disp values were significantly altered in pregnant women with cholestasis when compared to the normal ones. This simple ECG parameter can be used to screen high-risk women, in order to better target counseling regarding lifestyle modifications and to conduct closer follow up and management of women with a history of ICP. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Intrahepatic cholestasis of pregnancy (ICP) is a transient form of cholestasis that is characterized by elevated serum bile acid (BA) levels and/or liver enzymes, as well as pruritus localized to the abdomen, legs, and palms. It typically occurs in the second half of pregnancy [1]. The main cause of ICP has not yet been identified; heterogeneous and multiple factors have been suggested in the pathophysiology [1–3]. Elevated total BA level (N10 μmol/L) is the most sensitive and specific diagnostic hallmark of ICP [1].
⁎ Corresponding author at: Department of Perinatology, Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey. E-mail addresses: [email protected] (O. Kirbas), [email protected] (E.H. Biberoglu), [email protected], [email protected] (A. Kirbas), [email protected] (K. Daglar), [email protected] (O. Kurmus), [email protected] (N. Danisman), [email protected] (K. Biberoglu).
http://dx.doi.org/10.1016/j.ijcard.2015.04.001 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
ICP is associated with increased risk of adverse fetal outcomes, including preterm labor, fetal distress, unexplained fetal death [4,5], and fetal dysrhythmia [6]. It has been suggested that elevated BA levels in ICP could alter cardiomyocyte contractility or electrical conduction, causing fetal arrhythmia or death [7,8]. The QT interval (QT) is defined as the interval from the onset of the QRS complex, the first sign of ventricular depolarization, to the end of the T wave, the final sign of ventricular repolarization. QT interval dispersion (QT-disp) is defined as the difference between the maximal and minimal QT durations recorded from multiple surfaces ECG leads. Abnormalities in the duration of the QT and QT-disp reflect abnormalities in ventricular repolarization [9,10]. Both prolonged QT duration and increased QT-disp have been identified as being related to electrical instability and increased risk of ventricular arrhythmias [10–12]. In contrast to the known arrhythmogenic effects of BAs on the fetal heart, little is known about their potential implications for the adult heart. Therefore, our aim was to investigate the ventricular repolarization
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O. Kirbas et al. / International Journal of Cardiology 189 (2015) 25–29
changes, readily detectable by simple standard ECG criteria, via QT-disp in pregnant women with and without intrahepatic cholestasis. 2. Material and methods This case–control study was conducted at the Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey. The local Institutional Review Board of the hospital approved the study, and the universal principles of the Helsinki Declaration were applied. Seventy-five consecutive pregnant women with ICP (41 with mild and 34 with severe disease) and 35 healthy women with uncomplicated pregnancy (as the control group) all in the third trimester and matched for maternal and gestational ages, were recruited between December 2013 and November 2014. ICP was diagnosed when a pregnant woman had pruritus and elevated total bile acid (TBA) (≥10 μmol/L) and/or aminotransferase levels in the blood sample. The patients were classified with mild or severe ICP based on TBA concentrations of 10–40 or ≥40 μmol/L, respectively [1]. The presence of any pregestational liver or heart disease; multiple gestation or trophoblastic disease; history of systemic, inflammatory, endocrine, gastrointestinal, psychiatric, immunologic, or oncologic disease; smoking; alcohol consumption; or active labor were among the exclusion criteria. The age, body mass index (BMI), resting heart rate, blood pressure, and TBA levels of each participant were recorded. The perinatal outcome parameters, including gestational age at delivery, preterm delivery, stillbirth, birth weight, 5-minute Apgar score, neonatal intensive care unit admission, and meconium-stained amniotic fluid, were also assessed. All of the pregnant women were in sinus rhythm; there were no symptoms of arrhythmia, such as palpitation, chest pain, dizziness, or fainting. To exclude electrolyte abnormality, maternal serum sodium, potassium, calcium and magnesium levels were checked at admission. None of the patients were taking medications known to affect the cardiovascular system, such as anti-arrhythmics and antihypertensives. Patients on ursodeoxycholic acid treatment were also excluded from the study groups, due to the well-known anti-arrhythmogenic effects [13]. All of the cases and controls underwent standard ECG and 2D echocardiography. The patients in both groups were asked not to consume caffeinated beverages within 3 h prior to the procedure. The 12-lead ECG was obtained at a paper speed of 50 mm/s and 1-mV/cm standardization. The ECGs were recorded when the patients first came to our unit, during
the daytime, between 8:00 and 11:00 am, in a quiet room with the subjects in the resting position. As it is well known that the heart rate modifies the QT interval, several formulas, such as Bazett's, which is still considered one of the most popular ones, have been used to correct the heart rate effect. However, these formulas are not accurate or sufficient enough to avoid the potential of false QT prolongations [14,15]. In view of all this, The American Heart Association (AHA), The American College of Cardiology Foundation (ACCF), and The Heart Rhythm Society (HRS) have recommended the application of linear regression functions rather than Bazett's formula. Therefore, the standardization and interpretation of the ECG, including the correction of QT intervals, were carried out according to the AHA, ACCF, and HRS recommendations [9]. A single experienced cardiologist without knowledge of the clinical characteristics of the patient and control groups analyzed all the ECGs. To improve the accuracy, the measurements were performed with calipers and a magnifying lens to define the ECG deflection. ECGs without clearly identifiable QT waves were excluded from the QT wave analysis. QT wave duration was evaluated in all 12 leads. Pregnant women with measurable QT waves in more than nine ECG leads were included in the study. QT interval was measured from the start of the Q wave to the end of the T wave. QT intervals were corrected for the patients' heart rate using the Hodges formula (QTc = QT + 1.75 (heart rate − 60)). When Uwaves were present, the QT was measured to the lowest point of the curve between the T- and U-waves. Maximum (QT max) and minimum (QT min) QT-wave durations were defined as the longest and shortest measurable QT-wave durations, respectively, in any lead. Accordingly, corrected QT dispersion (QTc-dis) was calculated as the difference between maximal and minimal QTc intervals. Blood samples were obtained from the antecubital vein early in the morning, following 10 h of fasting, as well as 2 h postprandial; TBA levels were determined by enzymatic assay. All of the other blood analyses were carried out within 2 h of blood sampling, using a hematology analyzer (GEN-S; Beckman-Coulter Inc., Brea, CA) at the central laboratories of Zekai Tahir Burak Women's Hospital. 3. Reproducibility Thirty electrocardiograms were randomly selected for evaluation of the inter-observer variability of QT interval measurements by two independent observers. The same measurement was repeated twice, 3 days apart, to calculate the intra-observer variability. Mean percent error was
Table 1 The comparison of patient characteristics in the control (group 1) and intrahepatic cholestasis (group 2 mild & group 3 severe disease) pregnant groups.
Maternal age, year Gravidity (range) Gestational week at assessment BMI at assessment, kg/m2 Fasting BA (μmol/L) Postprandial BA (μmol/L) Heart rate, bpm Systolic BP, mmHg Diastolic BP, mmHg Maximum QTc interval (ms) Minimum QTc interval (ms) Mean QTc interval QTc dispersion (ms)
Group 1 (n = 35)
Group 2 (n = 41)
Group 3 (n = 34)
27.1 ± 2.4 1 (1–3) 35.2 ± 1.5 26.4 ± 2.16 2.25 ± 1.2 2.88 ± 1.06 – 80.1 ± 7 116.0 ± 8.2 71 ± 6.8 419 ± 26 373.6 ± 27.5 396.4 ± 26.1 45.7 ± 12
28.7 ± 5.0 1 (1–2) 35.6 ± 1.5 26.6 ± 3.1 21.5 ± 5,8 27.6 ± 7.7
29.3 ± 4.1 1 (1–3) 34.7 ± 2.14 27.03 ± 1.5 59.9 ± 15.4 65.2 ± 30.6
82 ± 8.7 113.7 ± 7.6 77 ± 10.7 433.3 ± 29 374.1 ± 29.3 403.7 ± 27.5 59.5 ± 20
78 ± 6.9 117.5 ± 7.8 72 ± 10 455.2 ± 36 369.3 ± 33.9 412.3 ± 33.6 87.6 ± 13.9
Data expressed as mean ± SD, BA, bile acids; BMI, body mass index; bpm, beats per min; BP, Blood pressure, min: minutes, ms, millisecond. a The mean difference is significant at the 0.05 level.
P value (groups) 1 vs 2
1 vs 3
2 vs 3
0.98 0.83 0.56 0.60 b0.001a b0.001a
0.23 0.85 0.47 0.63 b0.001a b0.001a
0.33 1 0.95 0.97 b0.001a b0.001a
0.35 0.37 0.53 0.14 0.99 0.55 0.002a
0.16 0.15 0.97 b0.001a 0.84 0.08 b0.001a
0.39 0.82 0.96 0.01a 0.78 0.45 b0.001a
O. Kirbas et al. / International Journal of Cardiology 189 (2015) 25–29
100 90 87.6
80 70 60 59.5
50 40
QTc dispersion 45.7
30 20 10 0 Control
Mild ICP
Severe ICP
Fig. 1. The mean values QTc dispersion (ms) in pregnant with and without ICP.
calculated as the absolute difference divided by the average of the two observations. 4. Statistical analysis Statistical analysis was performed using SPSS version 18 (Statistical Package for the Social Sciences, Chicago, IL). The data were summarized as mean ± standard deviation and median (minimum–maximum). Comparisons of parametric variables between the groups with a normal distribution were made by one-way analysis of variance. The Scheffé test was used as a post hoc test in pairwise comparisons between the groups. The Kruskal–Wallis test was performed to compare continuous variables that did not have a normal distribution. A Chi-square test was performed for nominal or ordinal variables between groups, where appropriate. Pearson's partial correlation coefficient was used to assess the relationship between fasting and postprandial BAs and QT-disp. Adjustments were made for QT max and QT min. Results were considered significant when the p value was b0.05. 5. Results Three pregnant women had to be excluded from the study groups: echocardiographic examination revealed mitral valvular prolapse in two patients and mild mitral stenosis in another. Two other patients had to be released from the study due to right bundle branch block, also detected on the ECG examination. This study included 110 pregnant women: 41 with mild ICP, 34 with severe ICP, and 35 healthy pregnant women. Age, gravidity, BMI, gestational week at assessment, maternal resting heart rate, and blood pressure were comparable among all three groups. As expected, both fasting and postprandial BA concentrations were significantly higher in the severe ICP group than in the mild ICP group (p b 0.001). The characteristics of the groups are presented in Table 1. There were no differences in corrected QTc min interval values among the groups. QTc max interval values were significantly higher in the severe ICP group than in the control group (p b 0.001); they were also higher in the severe ICP group than in the mild ICP group
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(p = 0.01). The values of the mild ICP and control groups were comparable. QTc-disp values were significantly higher in the ICP group than in the control group and significantly higher in the severe group than in the mild ICP group (Fig. 1). There were no differences in ECG findings among the groups (Table 2). The duration of pregnancy was significantly shorter in the ICP groups compared to the healthy pregnant women (p b 0.001). While the mean birth weight was lower in pregnant women with severe ICP compared with the control group, the difference between the mild and severe ICP groups was not significant. The perinatal outcomes of the pregnant women with ICP and the control cases are shown in Table 3. Pearson's partial correlation analysis data are presented in Table 4. Both groups of patients with ICP were included in the analysis and adjustments were made for QTc max and QTc min. There was a significant positive correlation between QTc-disp and F-TBA (r = 0.322, p = 0.005) and postprandial TBA (r = 0.702, p = 0.0001). The intra-observer mean percent errors for QT interval measurements were 7.6 ± 5.6% and 5.0 ± 2.5%, respectively. The interobserver mean percent errors for QT interval measurements were 8.4 ± 6.2% and 6.0 ± 4.2%, respectively.
6. Discussion In this study, we demonstrated, for the first time in the literature, that QTc-disp values were significantly altered in pregnant women with ICP compared with healthy pregnant women. In addition, the higher QTc-disp values differentiated the severe ICP cases from the mild ones. BAs are not only physiological detergents, but also signaling molecules and metabolic regulators. They play crucial roles in the regulation of cellular biology, metabolism, and the function of many organs, with potential effects, including the heart [16]. It is now known that BAs act as regulatory molecules by activating specific nuclear receptors (farnesoid X receptor; pregnane X receptor; vitamin D receptor; plasma membrane-bound, G protein-coupled, bile acid receptor; muscarinic receptors), Ca++ activated K+ channels, and cell signaling pathways in cells [17,18]. These receptors are expressed in many different organs and cells, with varying degrees of expression, primarily in the liver, gastrointestinal tract, kidneys, heart, and endothelial and vascular smooth muscle cells. Activation of these receptors is involved in the regulation of BA, glucose, fatty acid, lipoprotein, and energy metabolism [16–18]. BA receptors are expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells; however, the mechanisms explaining the relationship between BAs and cardiovascular function remain poorly understood. It has actually been known for many years that high levels of BAs are “toxic” to the heart [19,20]. Negative chronotropic and negative inotropic effects of BAs and BA-induced bradycardia in rats have been reported [21]. Subsequently extensive studies in rats and dogs have demonstrated that BAs alter the rate and rhythm of cardiomyocyte contractility, prevent cardiomyocyte synchronization, reduce action
Table 2 The echocardiographic findings of the control (group 1) and intrahepatic cholestasis (group 2 mild & group 3 severe disease) pregnant groups.
LVEDD (mm) LVESD (mm) IVS Thickness (mm) LAD (mm) EF (%) AAD (mm)
Group 1 (n = 35)
Group 2 (n = 41)
Group 3 (n = 34)
P value (groups) 1 vs 3 2 vs 3 1 vs 2
46.02 ± 4.7 29.3 ± 5.1 0.82 ± 0.65 31.1 ± 4.3 66.9 ± 1.4 26.5 ± 1.75
45.04 ± 3.5 28.9 ± 2.7 0.82 ± 0.82 32.1 ± 3.8 67.04 ± 1.5 26.3 ± 1.82
46.3 ± 4.9 30 ± 3.3 0.81 ± 0.9 30.9 ± 3.6 66.3 ± 1.7 26.4 ± 1.74
NS NS NS NS NS NS
AAD, ascending aorta diameter; EF, ejection fraction; IVS, interventricular septum; LAD, left atrial diameter; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; NS: non-significant.
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O. Kirbas et al. / International Journal of Cardiology 189 (2015) 25–29
Table 3 The comparison of the perinatal outcomes in the control (group 1) and intrahepatic cholestasis (group 2 mild & group 3 severe disease) pregnant groups cases.
Gestational week at delivery Birth weight (grams) Delivery b37 weeks (n, range) Meconium staining of amniotic fluid (n, range) 5 minute Apgar b 7 (n, range) NICU admission (n, range)
Group 1 (n = 35)
Group 2 (n = 41)
Group 3 (n = 34)
P value (groups) 1 vs 2
1 vs 3
2 vs 3
40.1 ± 2.4 3348 ± 350 1 (4%) 2 (8%) 0 0
39.5 ± 2.6 3209 ± 329 1 (6.6%) 2 (12.2%) 0 0
37.6 ± 1.6 3048 ± 326 2 (12.2%) 2 (12.2%) 1 (6.6%) 1 (6.6%)
0.005a NS NS NS – –
b0.001a b0.001a 0.05a NS – –
b0.001a 0.05a 0.06 NS – –
Data expressed as number (%), mean ± SD; NICU, neonatal intensive care unit, NS: non-significant. a The mean difference is significant at the 0.05 level.
potential in ventricular myocytes, and induce abnormal calcium destabilization [7,22,23]. It has also been demonstrated that high concentrations of BAs increase extra arrhythmic contractions in the human atrial trabeculae, and it has been suggested that BAs alter the “pacemaker” function of cardiomyocytes [24]. QTc-disp has been accepted as a marker of regional heterogeneity in myocardial repolarization, which is believed to be significant in arrhythmogenesis; this concept might be useful in the prediction of arrhythmia risk [12,25,26]. Prolongation of the QT interval is also seen in adults and children with cirrhosis, and it has been associated with the severity of the disease [27,28]. It has been suggested that in ICP, arrhythmias related to the high concentrations of BAs are the cause of fetal death. Despite the welldemonstrated adverse effects of BAs on the fetal heart, little is known about their potential roles in the development of ECG abnormalities in women with ICP. Our group recently demonstrated the correlation between altered ECG P-wave parameters and the possible increased risk of atrial arrhythmia in women with ICP [29]. 7. Study limitations and conclusion In the current study, we demonstrated that QTc-disp which a noninvasive marker of potentially lethal ventricular tachyarrhythmias is elevated in women with ICP. The major limitations of the present study are the relatively small population size and short-term follow-up. Other limitations are the absence of data related to Holter monitoring and strain rate parameters, as well as the lack of electrophysiological evaluation. Despite these limitations, our study is the first of its kind to investigate the relationship between cardiovascular disease risk and intrahepatic cholestasis by measuring QTc interval and QTc-disp characteristics during pregnancy. However, the exact effect of the predictive value of altered QTc and QTc-disp on severe ICP outcome needs to be clarified further. Conflict of interest None of the authors has any conflict of interest. Table 4 Correlation analysis within Q-wave parameters, fasting and post-prandial total bile acid levels.
QTcd
Fasting-TBA
Post-prandial TBA
a
r P n r P n r P n
QTcd
Fasting-TBA
Post-prandial TBA
1 – 75 .322 .005 75 .301 .010 75
.322 .005 75 1 – 75 .702a .000 75
.301 .010 75 .702a .000 75 1 – 75
Pearson partial correlation is significant at the 0.01 level (2-tailed).
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Evaluation of ventricular repolarization in pregnant women with intrahepatic cholestasis Ozgur Kirbas a, Ebru Hacer Biberoglu b, Ayse Kirbas b,⁎, Korkut Daglar b, Ozge Kurmus c, Nuri Danisman b, Kutay Biberoglu d a
Department of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey Department of Perinatology, Zekai Tahir Burak Women Health Care, Education and Research Hospital, Ankara, Turkey Department of Cardiology, Ataturk Education and Research Hospital, Ankara, Turkey d Gazi University Medical School, Department of Obstetrics and Gynecology, Ankara, Turkey b c
a r t i c l e
i n f o
Article history: Received 21 January 2015 Received in revised form 6 March 2015 Accepted 1 April 2015 Available online 3 April 2015 Keywords: Arrhythmia Bile acid Pregnancy QT dispersion Cholestasis
a b s t r a c t Background: Bile acids can induce arrhythmia by altering cardiomyocyte contractility or electrical conduction. The aim of this study was to investigate, by means of QT dispersion parameter detected by simple standard electrocardiogram (ECG), ventricular repolarization changes in pregnant women with and without intrahepatic cholestasis of pregnancy (ICP). Methods: In this case–control study including 75 pregnant women with cholestasis and 35 healthy, uncomplicated pregnancy cases, electrocardiographic QT interval durations and QT dispersion (QT-disp) parameters, corrected for the patients' heart rate using the Hodges formula, were investigated. Results: Maximum corrected QT interval values were significantly higher in the severe ICP group than in the control group (p b 0.001) and significantly higher in the severe ICP group than in the mild ICP group (p = 0.01). The values of the mild ICP and control groups were similar. Corrected QT-disp values were also significantly higher in both ICP groups than in the control group and significantly higher in the severe ICP group than in the mild ICP group. Conclusion: Cholestatic diseases predispose patients to cardiovascular complications. Our data clearly demonstrated that QT-disp values were significantly altered in pregnant women with cholestasis when compared to the normal ones. This simple ECG parameter can be used to screen high-risk women, in order to better target counseling regarding lifestyle modifications and to conduct closer follow up and management of women with a history of ICP. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Intrahepatic cholestasis of pregnancy (ICP) is a transient form of cholestasis that is characterized by elevated serum bile acid (BA) levels and/or liver enzymes, as well as pruritus localized to the abdomen, legs, and palms. It typically occurs in the second half of pregnancy [1]. The main cause of ICP has not yet been identified; heterogeneous and multiple factors have been suggested in the pathophysiology [1–3]. Elevated total BA level (N10 μmol/L) is the most sensitive and specific diagnostic hallmark of ICP [1].
⁎ Corresponding author at: Department of Perinatology, Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey. E-mail addresses: [email protected] (O. Kirbas), [email protected] (E.H. Biberoglu), [email protected], [email protected] (A. Kirbas), [email protected] (K. Daglar), [email protected] (O. Kurmus), [email protected] (N. Danisman), [email protected] (K. Biberoglu).
http://dx.doi.org/10.1016/j.ijcard.2015.04.001 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
ICP is associated with increased risk of adverse fetal outcomes, including preterm labor, fetal distress, unexplained fetal death [4,5], and fetal dysrhythmia [6]. It has been suggested that elevated BA levels in ICP could alter cardiomyocyte contractility or electrical conduction, causing fetal arrhythmia or death [7,8]. The QT interval (QT) is defined as the interval from the onset of the QRS complex, the first sign of ventricular depolarization, to the end of the T wave, the final sign of ventricular repolarization. QT interval dispersion (QT-disp) is defined as the difference between the maximal and minimal QT durations recorded from multiple surfaces ECG leads. Abnormalities in the duration of the QT and QT-disp reflect abnormalities in ventricular repolarization [9,10]. Both prolonged QT duration and increased QT-disp have been identified as being related to electrical instability and increased risk of ventricular arrhythmias [10–12]. In contrast to the known arrhythmogenic effects of BAs on the fetal heart, little is known about their potential implications for the adult heart. Therefore, our aim was to investigate the ventricular repolarization
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changes, readily detectable by simple standard ECG criteria, via QT-disp in pregnant women with and without intrahepatic cholestasis. 2. Material and methods This case–control study was conducted at the Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey. The local Institutional Review Board of the hospital approved the study, and the universal principles of the Helsinki Declaration were applied. Seventy-five consecutive pregnant women with ICP (41 with mild and 34 with severe disease) and 35 healthy women with uncomplicated pregnancy (as the control group) all in the third trimester and matched for maternal and gestational ages, were recruited between December 2013 and November 2014. ICP was diagnosed when a pregnant woman had pruritus and elevated total bile acid (TBA) (≥10 μmol/L) and/or aminotransferase levels in the blood sample. The patients were classified with mild or severe ICP based on TBA concentrations of 10–40 or ≥40 μmol/L, respectively [1]. The presence of any pregestational liver or heart disease; multiple gestation or trophoblastic disease; history of systemic, inflammatory, endocrine, gastrointestinal, psychiatric, immunologic, or oncologic disease; smoking; alcohol consumption; or active labor were among the exclusion criteria. The age, body mass index (BMI), resting heart rate, blood pressure, and TBA levels of each participant were recorded. The perinatal outcome parameters, including gestational age at delivery, preterm delivery, stillbirth, birth weight, 5-minute Apgar score, neonatal intensive care unit admission, and meconium-stained amniotic fluid, were also assessed. All of the pregnant women were in sinus rhythm; there were no symptoms of arrhythmia, such as palpitation, chest pain, dizziness, or fainting. To exclude electrolyte abnormality, maternal serum sodium, potassium, calcium and magnesium levels were checked at admission. None of the patients were taking medications known to affect the cardiovascular system, such as anti-arrhythmics and antihypertensives. Patients on ursodeoxycholic acid treatment were also excluded from the study groups, due to the well-known anti-arrhythmogenic effects [13]. All of the cases and controls underwent standard ECG and 2D echocardiography. The patients in both groups were asked not to consume caffeinated beverages within 3 h prior to the procedure. The 12-lead ECG was obtained at a paper speed of 50 mm/s and 1-mV/cm standardization. The ECGs were recorded when the patients first came to our unit, during
the daytime, between 8:00 and 11:00 am, in a quiet room with the subjects in the resting position. As it is well known that the heart rate modifies the QT interval, several formulas, such as Bazett's, which is still considered one of the most popular ones, have been used to correct the heart rate effect. However, these formulas are not accurate or sufficient enough to avoid the potential of false QT prolongations [14,15]. In view of all this, The American Heart Association (AHA), The American College of Cardiology Foundation (ACCF), and The Heart Rhythm Society (HRS) have recommended the application of linear regression functions rather than Bazett's formula. Therefore, the standardization and interpretation of the ECG, including the correction of QT intervals, were carried out according to the AHA, ACCF, and HRS recommendations [9]. A single experienced cardiologist without knowledge of the clinical characteristics of the patient and control groups analyzed all the ECGs. To improve the accuracy, the measurements were performed with calipers and a magnifying lens to define the ECG deflection. ECGs without clearly identifiable QT waves were excluded from the QT wave analysis. QT wave duration was evaluated in all 12 leads. Pregnant women with measurable QT waves in more than nine ECG leads were included in the study. QT interval was measured from the start of the Q wave to the end of the T wave. QT intervals were corrected for the patients' heart rate using the Hodges formula (QTc = QT + 1.75 (heart rate − 60)). When Uwaves were present, the QT was measured to the lowest point of the curve between the T- and U-waves. Maximum (QT max) and minimum (QT min) QT-wave durations were defined as the longest and shortest measurable QT-wave durations, respectively, in any lead. Accordingly, corrected QT dispersion (QTc-dis) was calculated as the difference between maximal and minimal QTc intervals. Blood samples were obtained from the antecubital vein early in the morning, following 10 h of fasting, as well as 2 h postprandial; TBA levels were determined by enzymatic assay. All of the other blood analyses were carried out within 2 h of blood sampling, using a hematology analyzer (GEN-S; Beckman-Coulter Inc., Brea, CA) at the central laboratories of Zekai Tahir Burak Women's Hospital. 3. Reproducibility Thirty electrocardiograms were randomly selected for evaluation of the inter-observer variability of QT interval measurements by two independent observers. The same measurement was repeated twice, 3 days apart, to calculate the intra-observer variability. Mean percent error was
Table 1 The comparison of patient characteristics in the control (group 1) and intrahepatic cholestasis (group 2 mild & group 3 severe disease) pregnant groups.
Maternal age, year Gravidity (range) Gestational week at assessment BMI at assessment, kg/m2 Fasting BA (μmol/L) Postprandial BA (μmol/L) Heart rate, bpm Systolic BP, mmHg Diastolic BP, mmHg Maximum QTc interval (ms) Minimum QTc interval (ms) Mean QTc interval QTc dispersion (ms)
Group 1 (n = 35)
Group 2 (n = 41)
Group 3 (n = 34)
27.1 ± 2.4 1 (1–3) 35.2 ± 1.5 26.4 ± 2.16 2.25 ± 1.2 2.88 ± 1.06 – 80.1 ± 7 116.0 ± 8.2 71 ± 6.8 419 ± 26 373.6 ± 27.5 396.4 ± 26.1 45.7 ± 12
28.7 ± 5.0 1 (1–2) 35.6 ± 1.5 26.6 ± 3.1 21.5 ± 5,8 27.6 ± 7.7
29.3 ± 4.1 1 (1–3) 34.7 ± 2.14 27.03 ± 1.5 59.9 ± 15.4 65.2 ± 30.6
82 ± 8.7 113.7 ± 7.6 77 ± 10.7 433.3 ± 29 374.1 ± 29.3 403.7 ± 27.5 59.5 ± 20
78 ± 6.9 117.5 ± 7.8 72 ± 10 455.2 ± 36 369.3 ± 33.9 412.3 ± 33.6 87.6 ± 13.9
Data expressed as mean ± SD, BA, bile acids; BMI, body mass index; bpm, beats per min; BP, Blood pressure, min: minutes, ms, millisecond. a The mean difference is significant at the 0.05 level.
P value (groups) 1 vs 2
1 vs 3
2 vs 3
0.98 0.83 0.56 0.60 b0.001a b0.001a
0.23 0.85 0.47 0.63 b0.001a b0.001a
0.33 1 0.95 0.97 b0.001a b0.001a
0.35 0.37 0.53 0.14 0.99 0.55 0.002a
0.16 0.15 0.97 b0.001a 0.84 0.08 b0.001a
0.39 0.82 0.96 0.01a 0.78 0.45 b0.001a
O. Kirbas et al. / International Journal of Cardiology 189 (2015) 25–29
100 90 87.6
80 70 60 59.5
50 40
QTc dispersion 45.7
30 20 10 0 Control
Mild ICP
Severe ICP
Fig. 1. The mean values QTc dispersion (ms) in pregnant with and without ICP.
calculated as the absolute difference divided by the average of the two observations. 4. Statistical analysis Statistical analysis was performed using SPSS version 18 (Statistical Package for the Social Sciences, Chicago, IL). The data were summarized as mean ± standard deviation and median (minimum–maximum). Comparisons of parametric variables between the groups with a normal distribution were made by one-way analysis of variance. The Scheffé test was used as a post hoc test in pairwise comparisons between the groups. The Kruskal–Wallis test was performed to compare continuous variables that did not have a normal distribution. A Chi-square test was performed for nominal or ordinal variables between groups, where appropriate. Pearson's partial correlation coefficient was used to assess the relationship between fasting and postprandial BAs and QT-disp. Adjustments were made for QT max and QT min. Results were considered significant when the p value was b0.05. 5. Results Three pregnant women had to be excluded from the study groups: echocardiographic examination revealed mitral valvular prolapse in two patients and mild mitral stenosis in another. Two other patients had to be released from the study due to right bundle branch block, also detected on the ECG examination. This study included 110 pregnant women: 41 with mild ICP, 34 with severe ICP, and 35 healthy pregnant women. Age, gravidity, BMI, gestational week at assessment, maternal resting heart rate, and blood pressure were comparable among all three groups. As expected, both fasting and postprandial BA concentrations were significantly higher in the severe ICP group than in the mild ICP group (p b 0.001). The characteristics of the groups are presented in Table 1. There were no differences in corrected QTc min interval values among the groups. QTc max interval values were significantly higher in the severe ICP group than in the control group (p b 0.001); they were also higher in the severe ICP group than in the mild ICP group
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(p = 0.01). The values of the mild ICP and control groups were comparable. QTc-disp values were significantly higher in the ICP group than in the control group and significantly higher in the severe group than in the mild ICP group (Fig. 1). There were no differences in ECG findings among the groups (Table 2). The duration of pregnancy was significantly shorter in the ICP groups compared to the healthy pregnant women (p b 0.001). While the mean birth weight was lower in pregnant women with severe ICP compared with the control group, the difference between the mild and severe ICP groups was not significant. The perinatal outcomes of the pregnant women with ICP and the control cases are shown in Table 3. Pearson's partial correlation analysis data are presented in Table 4. Both groups of patients with ICP were included in the analysis and adjustments were made for QTc max and QTc min. There was a significant positive correlation between QTc-disp and F-TBA (r = 0.322, p = 0.005) and postprandial TBA (r = 0.702, p = 0.0001). The intra-observer mean percent errors for QT interval measurements were 7.6 ± 5.6% and 5.0 ± 2.5%, respectively. The interobserver mean percent errors for QT interval measurements were 8.4 ± 6.2% and 6.0 ± 4.2%, respectively.
6. Discussion In this study, we demonstrated, for the first time in the literature, that QTc-disp values were significantly altered in pregnant women with ICP compared with healthy pregnant women. In addition, the higher QTc-disp values differentiated the severe ICP cases from the mild ones. BAs are not only physiological detergents, but also signaling molecules and metabolic regulators. They play crucial roles in the regulation of cellular biology, metabolism, and the function of many organs, with potential effects, including the heart [16]. It is now known that BAs act as regulatory molecules by activating specific nuclear receptors (farnesoid X receptor; pregnane X receptor; vitamin D receptor; plasma membrane-bound, G protein-coupled, bile acid receptor; muscarinic receptors), Ca++ activated K+ channels, and cell signaling pathways in cells [17,18]. These receptors are expressed in many different organs and cells, with varying degrees of expression, primarily in the liver, gastrointestinal tract, kidneys, heart, and endothelial and vascular smooth muscle cells. Activation of these receptors is involved in the regulation of BA, glucose, fatty acid, lipoprotein, and energy metabolism [16–18]. BA receptors are expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells; however, the mechanisms explaining the relationship between BAs and cardiovascular function remain poorly understood. It has actually been known for many years that high levels of BAs are “toxic” to the heart [19,20]. Negative chronotropic and negative inotropic effects of BAs and BA-induced bradycardia in rats have been reported [21]. Subsequently extensive studies in rats and dogs have demonstrated that BAs alter the rate and rhythm of cardiomyocyte contractility, prevent cardiomyocyte synchronization, reduce action
Table 2 The echocardiographic findings of the control (group 1) and intrahepatic cholestasis (group 2 mild & group 3 severe disease) pregnant groups.
LVEDD (mm) LVESD (mm) IVS Thickness (mm) LAD (mm) EF (%) AAD (mm)
Group 1 (n = 35)
Group 2 (n = 41)
Group 3 (n = 34)
P value (groups) 1 vs 3 2 vs 3 1 vs 2
46.02 ± 4.7 29.3 ± 5.1 0.82 ± 0.65 31.1 ± 4.3 66.9 ± 1.4 26.5 ± 1.75
45.04 ± 3.5 28.9 ± 2.7 0.82 ± 0.82 32.1 ± 3.8 67.04 ± 1.5 26.3 ± 1.82
46.3 ± 4.9 30 ± 3.3 0.81 ± 0.9 30.9 ± 3.6 66.3 ± 1.7 26.4 ± 1.74
NS NS NS NS NS NS
AAD, ascending aorta diameter; EF, ejection fraction; IVS, interventricular septum; LAD, left atrial diameter; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; NS: non-significant.
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O. Kirbas et al. / International Journal of Cardiology 189 (2015) 25–29
Table 3 The comparison of the perinatal outcomes in the control (group 1) and intrahepatic cholestasis (group 2 mild & group 3 severe disease) pregnant groups cases.
Gestational week at delivery Birth weight (grams) Delivery b37 weeks (n, range) Meconium staining of amniotic fluid (n, range) 5 minute Apgar b 7 (n, range) NICU admission (n, range)
Group 1 (n = 35)
Group 2 (n = 41)
Group 3 (n = 34)
P value (groups) 1 vs 2
1 vs 3
2 vs 3
40.1 ± 2.4 3348 ± 350 1 (4%) 2 (8%) 0 0
39.5 ± 2.6 3209 ± 329 1 (6.6%) 2 (12.2%) 0 0
37.6 ± 1.6 3048 ± 326 2 (12.2%) 2 (12.2%) 1 (6.6%) 1 (6.6%)
0.005a NS NS NS – –
b0.001a b0.001a 0.05a NS – –
b0.001a 0.05a 0.06 NS – –
Data expressed as number (%), mean ± SD; NICU, neonatal intensive care unit, NS: non-significant. a The mean difference is significant at the 0.05 level.
potential in ventricular myocytes, and induce abnormal calcium destabilization [7,22,23]. It has also been demonstrated that high concentrations of BAs increase extra arrhythmic contractions in the human atrial trabeculae, and it has been suggested that BAs alter the “pacemaker” function of cardiomyocytes [24]. QTc-disp has been accepted as a marker of regional heterogeneity in myocardial repolarization, which is believed to be significant in arrhythmogenesis; this concept might be useful in the prediction of arrhythmia risk [12,25,26]. Prolongation of the QT interval is also seen in adults and children with cirrhosis, and it has been associated with the severity of the disease [27,28]. It has been suggested that in ICP, arrhythmias related to the high concentrations of BAs are the cause of fetal death. Despite the welldemonstrated adverse effects of BAs on the fetal heart, little is known about their potential roles in the development of ECG abnormalities in women with ICP. Our group recently demonstrated the correlation between altered ECG P-wave parameters and the possible increased risk of atrial arrhythmia in women with ICP [29]. 7. Study limitations and conclusion In the current study, we demonstrated that QTc-disp which a noninvasive marker of potentially lethal ventricular tachyarrhythmias is elevated in women with ICP. The major limitations of the present study are the relatively small population size and short-term follow-up. Other limitations are the absence of data related to Holter monitoring and strain rate parameters, as well as the lack of electrophysiological evaluation. Despite these limitations, our study is the first of its kind to investigate the relationship between cardiovascular disease risk and intrahepatic cholestasis by measuring QTc interval and QTc-disp characteristics during pregnancy. However, the exact effect of the predictive value of altered QTc and QTc-disp on severe ICP outcome needs to be clarified further. Conflict of interest None of the authors has any conflict of interest. Table 4 Correlation analysis within Q-wave parameters, fasting and post-prandial total bile acid levels.
QTcd
Fasting-TBA
Post-prandial TBA
a
r P n r P n r P n
QTcd
Fasting-TBA
Post-prandial TBA
1 – 75 .322 .005 75 .301 .010 75
.322 .005 75 1 – 75 .702a .000 75
.301 .010 75 .702a .000 75 1 – 75
Pearson partial correlation is significant at the 0.01 level (2-tailed).
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