- Email: [email protected]
QT ratio
Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health journal homepage: www.elsevier.com/locate/preghy
Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio Ayse Kirbas a,⇑, Ozgur Kirbas b, Korkut Daglar a, Hasan Ali Inal c, Ozge Kurmus d, Ozgur Kara a, Hakan Timur a, Gulenay Gencosmanoglu a, Nuri Danisman a a
Department of Perinatology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey Department of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey Department of Obstetrics and Gynecology, Konya Education and Research Hospital, Konya, Turkey d Department of Cardiology, Mersin State Hospital, Mersin, Turkey b c
a r t i c l e
i n f o
Article history: Received 23 November 2015 Accepted 19 January 2016 Available online xxxx Keywords: Heart Hypertension Ventricular arrhythmia SFlt-1
a b s t r a c t Objective: There is increasing evidence that preeclampsia (PE) may also be a risk factor for future cardiovascular diseases (CVDs), including arrhythmia. In this study we aimed to evaluate the association between PE and ventricular repolarization using novel electrocardiogram markers: QT interval duration, Tp-e interval, and Tp-e/QT ratio. Materials and Methods: In this controlled cross-sectional study sixty-four pregnant women with PE (31 with mild and 33 with severe disease) and 32 healthy women with uncomplicated pregnancies in the third trimester were compared by measuring QT parameters, Tp-e interval, and Tp-e/QT ratio. Results: Tp-e interval and Tp-e/QT ratio values were significantly higher in both the mild and severe PE groups compared to the healthy pregnant group. Conclusion: Prevention of CVD requires that patients be aware of their risk factors, be educated about their risk, and perhaps most importantly perceive them to be at risk. In this study, we documented that PE has a significant effect on ventricular repolarization. This alteration could, in part, explain the increased cardiovascular risk in women with a history of PE. This important association can be used to screen women for increased risk in order to better target counseling regarding lifestyle modifications and to follow up and manage women with a history of hypertensive disease of pregnancy more closely. Ó 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
1. Introduction Preeclampsia (PE) is a human pregnancy-specific, placental mediated, multisystemic disease. It complicates 3–5% of pregnancies, and it is still one of the main causes of maternal, fetal, and neonatal mortality and morbidity worldwide [1]. PE is characterized by new onset hypertension, usually after the second trimester of pregnancy. It is occasionally associated with proteinuria, although proteinuria is no more a necessity for the diagnosis of PE [2].
⇑ Corresponding author. E-mail addresses: [email protected], [email protected] (A. Kirbas), [email protected] (O. Kirbas), [email protected] (K. Daglar), [email protected] (H.A. Inal), [email protected] (O. Kurmus), [email protected] (O. Kara), [email protected] (H. Timur), [email protected] (G. Gencosmanoglu), [email protected] (N. Danisman).
Contrary to previous thinking, maternal complications are not limited to the pregnancy period, and they can leave permanent vascular and metabolic damage [3]. There is increasing evidence that PE is a risk factor for future cardiovascular diseases (CVDs), including arrhythmia. The mechanisms by which PE and future CVD are associated are uncertain, although shared constitutional risk factors likely contribute to features of endothelial dysfunction characteristic of both [4–8]. It has been shown that non-specific electrocardiographic variations are critical in the prediction of morbidity and mortality due to CVD in future years and an acceptable instrument in screening hypertensive patients for risk estimation [9,10]. Electrocardiographic QT interval duration, QT dispersion (defined as the difference between the maximal and minimal QT duration durations), Tp-e interval (the interval between the peak and the end of the T wave), and Tp-e/QT ratio are novel electrocardiographic ventricular repolarization markers used to predict cardiac arrhythmias in several conditions. It has been suggested that these markers can
http://dx.doi.org/10.1016/j.preghy.2016.01.002 2210-7789/Ó 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002
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A. Kirbas et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2016) xxx–xxx
be used to identify patients at increased risk of ventricular arrhythmia [11–13]. In this study, we prospectively assessed the association between preeclampsia and ventricular repolarization using Tp-e and QT intervals, Tp-e/QT ratio, and QT dispersion parameters for the first time in the literature.
II, V2, and V5, and then adjusted to the heart rate (cTp-e). When the T wave deflections were found to be biphasic or negative, the QT interval was measured from the time it last returned to the baseline. The Tp-e/mean QTc ratios were calculated from these values. 3. Reproducibility
2. Material and methods Sixty-four consecutive primipara pregnant with PE and 32 healthy primipara pregnant matched for age and body mass index (BMI) underwent a standard 12-lead electrocardiogram (ECG) between May 2014 and September 2015 at Zekai Tahir Burak Research and Training Hospital. The Institutional Research Ethics Committee approved the study, and informed consent was obtained from all pregnant. The diagnosis of PE was based on a systolic blood pressure of P140 mmHg or diastolic blood pressure P90 mmHg, after the 20th gestational week, as well as 300 mg/dL proteinuria detected in a 24-h urine sample. In the absence of proteinuria, hypertension together with evidence of systemic disease (thrombocytopenia, increased levels of liver transaminases, renal failure, pulmonary edema, or visual or cerebral disturbances) was accepted for a diagnosis of PE. The diagnosis of severe PE was based on the presence of any of the following criteria: systolic blood pressure P160 mmHg or diastolic blood pressure P110 mmHg on two separate measurements, performed at least at six-hour intervals; elevated serum creatinine level; headache; visual impairment; epigastric pain; elevated hepatic transaminases (P40 IU/ml); thrombocytopenia; or pulmonary edema [2]. The exclusion criteria were the presence of any pregestational heart disease; history of systemic, psychiatric, or endocrine disease; smoking; alcohol consumption; or active labor. The age, gestational week at the time of assessment, BMI, resting heart rate, blood pressure and biochemical results of participant were recorded. Maternal serum electrolytes were checked to rule out any electrolyte imbalance. The 12-lead ECG scans were performed at a standardized speed of 25 mm/s and 2 mV/cm with the patients in a resting position. All of the patients were in sinus rhythm; none of the patients were using antiarrhythmic drugs, magnesium, or any other antihypertensive drug that could affect their cardiovascular system during the ECG scan. Two experienced cardiologists with no knowledge of the clinical characteristics of the participants analyzed all of the ECGs. The maximum and minimum QT and Tp-e interval durations were measured manually. The measurements were performed with calipers and a magnifying lens to define the ECG deflection for improving accuracy. ECGs in which Tp-e intervals and QT segments could not be analyzed properly were excluded from the study. Participants whose QT waves could be measured in more than nine ECG leads were included in the study. The QT interval was measured from the start of the Q wave to the end of the T wave. Using the Hodges formula [QTc = QT + 1.75 (heart rate 60)], the QT waves of the patients were corrected according to their heart rates [14,15]. When the U wave was seen, the QT measurement was made from 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-d) was calculated as the difference between maximal and minimal QTc intervals. The Tp-e interval was defined as the interval from the top of the T wave to the end of the same T wave. It was shown as the intersection of the isoelectric line and the tangent of the downslope of the T wave. The Tp-e interval was measured in leads
To assess the variation of the QT and Tp-e intervals between the two independent observers who performed the measurements, 25 ECGs were chosen randomly. The same measurement was repeated twice, with a two-day interval. The correlations within observers and between observers were 2.3% and 2.9%, respectively. 4. Results All of the patients were nulliparous and in their third trimester (33–38 weeks), and they were matched for maternal age and BMI. The obstetric and demographic characteristics of the groups are presented in Table 1. The laboratory characteristics of the PE and control groups at initial admission are presented in Table 2. The electrocardiographic findings of the all pregnant are presented in Table 3. Although there were no differences in minimum QTc values among the groups, maximum QTc and QTc dispersion values were significantly higher in the severe PE group than in the mild PE and control groups (p < 0.001). Regarding the primary endpoint parameters of the study, Tp-e interval and Tp-e/QTc ratio values were significantly higher in the severe (p < 0.01) and mild (p < 0.01) PE groups than in the healthy subjects (Fig. 1). 5. Discussion In this study, we demonstrated that Tp-e interval and Tp-e/QTc ratio, as indices of ventricular arrhythmogenesis, were significantly higher in pregnant patients with PE compared with healthy pregnant women. In addition, the higher Tp-e interval and Tp-e/QTc ratio values differentiated the severe PE cases from the mild ones. Our finding of higher Tp-e and Tp-e/QTc ratio in patients with PE is important, as this is the first study to evaluate the association between PE and parameters of ventricular repolarization in pregnancy using those markers. Our results may contribute to the knowledge of the pathophysiological mechanisms of increased prevalence of ventricular arrhythmias in pregnant women with PE later in life. The exact cause of PE is still unknown, but there is consensus that the placenta plays a cardinal role in the pathogenesis. It is thought to occur in two stages, with poor placentation leading to maternal systemic inflammatory response [15]. Abnormal, poor placentation resulting in placental ischemia is thought to be the primary event leading to placental release of factors such as inflammatory cytokines and antiangiogenic proteins that cause systemic endothelial dysfunction [15,16]. The balance between proangiogenic (vascular endothelial growth factor [VEGF] and placental growth factor [PlGF]) and antiangiogenic (soluble Fms-like tyrosine kinase 1 [sFlt-1]) factors determines normal development. SFlt1 antagonizes VEGF and PlGF, binding their endothelial cell receptors and thus exhibiting antiangiogenic effects and inducing maternal systemic metabolic, inflammatory, and endothelial dysfunction, leading to the classical symptoms and signs of PE. [15]. Many studies have confirmed the increased levels of sFlt-1 and decreased levels of PlGF and VEGF in women with PE [16,17]. PlGF is expressed not only in the placenta, but also in cardiac and lung tissue. Therefore, it is not surprising that changes in the
Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002
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A. Kirbas et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2016) xxx–xxx Table 1 Characteristics of the study population.
Maternal age, years (±SD) Gestational week at assessment BMI at assessment Heart rate, bpm Systolic BP, mmHg Diastolic BP, mmHg
Control group (n = 32)
Mild PE (n = 31)
Severe PE (n = 33)
26.81 ± 4.9 36.31 ± 1.2 28.34 ± 3.1 78.65 ± 5.7 110 (100–137) 70.50 (54–87)
27.77 ± 5.3 36.65 ± 2.3 30.34 ± 3.7 80.83 ± 6.7 142 (120–155) 91 (70–105)
28.33 ± 5.2 34.34 ± 3.6 29.06 ± 3.5 81.21 ± 5.7 161 (150–187) 105 (90–120)
Data expressed as number (%), mean ± SD, median (minimum
p value (groups) 1 vs 2
1 vs 3
2 vs 3
0.74 0.92 0.064 0.498 <0.001 <0.001
0.46 0.07 0.683 0.212 <0.001 <0.001
0.90 0.09 0.309 0.850 <0.001 <0.001
maximum). The mean difference is significant at the 0.05 level.
Table 2 Laboratory tests results of the study population at assessment.
Hemoglobin (g/dl) Platelet (103) – /lL AST – U/L ALT – U/L BUN (mg/dl) Creatinine (mg/dl) Total protein (g/dl) Albumin (g/dl)
Control group (n = 32)
Mild PE (n = 31)
Severe PE (n = 33)
12.5 ± 0.8 231.00 ± 92 15 (6–25) 9 (6–22) 15.4 ± 4.4 0.46 ± 0.09 6.99 ± 0.46 4.2 ± 0.3
12.4 ± 1.2 222.97 ± 48 20 (12–50) 20 (8–43) 22.8 ± 5.6 0.66 ± 0.12 6.30 ± 0.43 3.5 ± 0.3
13.3 ± 1.6 202.26 ± 44 25 (12–433) 19 (7–900) 33.7 ± 14.2 0.74 ± 0.28 5.20 ± 0.91 2.8 ± 0.5
p value (groups) 1 vs 2
1 vs 3
2 vs 3
0.85 0.42 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.03 0.87 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.009 0.19 0.002 0.56 0.01 0.37 <0.001 <0.001
Table 3 The electrocardiographic findings of the study population.
Maximum QTc interval (ms) Minimum QTc interval (ms) QTc dispersion (ms) Mean QTc interval Tp-e interval (ms) Tp-e/QTc ratio
Control group (group 1) (n = 31)
Mild PE (group 2) (n = 31)
Severe PE (group 3) (n = 33)
415.4 ± 21.8 366.8 ± 26.1 46.8 ± 10.7 388.1 ± 26.7 74.1 ± 9.4 0.18 ± 0.01
417.1 ± 24.5 358.8 ± 31.1 53.5 ± 10.8 391.4 ± 22.7 83.8 ± 7.3 0.21 ± 0.01
448.3 ± 25.5 373.0 ± 21.2 74.5 ± 11.4 409.9 ± 22.2 97.5 ± 5.87 0.23 ± 0.01
QTc dispersion and Tp-e interval 120
p value (groups) 1 vs 2
1 vs 3
2 vs 3
0.96 0.45 0.044 0.84 <0.001 <0.001
<0.001 0.65 <0.001 0.007 <0.001 <0.001
<0.001 0.08 <0.001 0.001 <0.001 <0.001
Tp-e / QTc ratio 0.25
100
0.23
0.2
0.21
80 0.15
60 40
0.1
20
0.05
0 QTc disp Control
Tp-e interval Mild PE
0.18
0 Control
Mild PE
Severe PE
Severe PE
Fig. 1. QT dispersion, Tp-e interval, and Tp-e/QT values in the groups.
sFlt-1/PlGF ratio may have cardiac or pulmonary effects [21]. Similar imbalances between sFlt-1 and PlGF were recently observed in fetuses with heart defects. It has been suggested that angiogenic mechanisms may be part of a shared pathway in PE and congenital
heart defects in the offspring of PE patients [25–28]. Several studies have reported increased circulating sFlt1 levels in patients with acute coronary syndrome and congestive heart failure in adults [22,23]. It has also been suggested that excessive antiangiogenic
Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002
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signaling in the peripartum period may cause peripartum cardiomyopathy and subclinical cardiac dysfunction in women [24]. The association between PE and future CVD has been an increasing area of interest in recent years. PE has been suggested as an early warning of later emerging conventional CVD risk factors. Although PE is resolved by delivery of the placenta, the underlying abnormalities (permanent vascular damage and altered angiogenesis due to antiangiogenic proteins, exaggerated inflammation and oxidative stress, endothelial dysfunction and a hypercoagulable state) have been associated with long-term CVD risk [18,19]. Alternatively, it has been suggested that pre-pregnancy risk factors and PE itself might both contribute to the development of long-term CVD risk. PE shares many proposed etiologies and risk factors with CVD, including inflammation, oxidative stress, hypercoagulability, obesity, insulin resistance, dyslipidemia, and endothelial dysfunction, which can predispose the patient to both placental dysfunction and atherosclerosis. For this reason, PE is sometimes referred to as the ‘‘metabolic syndrome of pregnancy.” Furthermore, PE has been accepted as an independent genderspecific CVD risk factor [20]. Ray et al. demonstrated retrospectively that women who experienced PE, especially in the presence of fetal compromise, independent of recognized coronary artery disease, were at increased risk of premature dysrhythmias [7]. The Tp-e interval and Tp-e/QT ratio have emerged as novel ECG markers for increased dispersion of ventricular repolarization [12,13]. Moreover, the Tp-e/QT ratio is is not affected by changes in body weight or heart rate it is considered to be a more sensitive index of arrhythmogenesis compared with the single use of either the Tp-e or QT intervals [29]. In conclusion, in the present study Tp-e intervals and Tp-e/QTc ratios were increased in the PE patients, which might imply an indicator of risk of ventricular arrhythmias in this group of patients. This important connection can be used to screen for elevated risk in order to better target counseling about lifestyle modifications and to follow up and manage women with a history of PE intimately. Our hypothesis was based on previous data suggesting that pregnancy itself may act as an early natural ‘‘stress test,” unmasking underlying defects and thus identifying women at high risk of CVD later in life. Prevention of heart disease requires that patients be aware of their risk factors, be educated about their risk, and perhaps most importantly, perceive them to be at risk. Acknowledgment None. References [1] B.W. Mol, C.T. Roberts, S. Thangaratinam, L.A. Magee, C.J. de Groot, G.J. Hofmeyr, Pre-eclampsia, Lancet (2015), http://dx.doi.org/10.1016/S0140-6736 (15)00070-7. pii: S0140-6736(15)00070-7. [2] American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy, Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy, Obstet. Gynecol. 122 (2013) 1122–1131. [3] M.C. Gongora, N.K. Wenger, Cardiovascular complications of pregnancy, Int. J. Mol. Sci. 16 (2015) 23905–23928. [4] V.D. Garovic, K.R. Bailey, E. Boerwinkle, S.C. Hunt, A.B. Weder, D. Curb, et al., Hypertension in pregnancy as a risk factor for cardiovascular disease later in life, J. Hypertens. 28 (2010) 826–833. [5] E.B. Magnussen, L.J. Vatten, G.D. Smith, P.R. Romundstad, Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors, Obstet. Gynecol. 114 (2009) 961–970. [6] M.L. Mongraw-Chaffin, P.M. Cirillo, B.A. Cohn, Pre-eclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort, Hypertension 56 (2010) 166–171.
[7] J.G. Ray, M.J. Vermeulen, M.J. Schull, D.A. Redelmeier, Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study, Lancet 366 (2005) 1797–1803. [8] J.G. Ray, M.J. Schull, J.C. Kingdom, M.J. Vermeulen, Heart failure and dysrhythmias after maternal placental syndromes: HAD MPS Study, Heart 98 (2012) 1136–1141. [9] B. Triola, M.B. Olson, S.E. Reis, P. Rautaharju, C.N. BaireyMerz, S.F. Kelsey, et al., Electrocardiographic predictors of cardiovascular outcome in women. The national heart, lung and blood institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study, J. Am. Coll. Cardiol. 46 (2005) 51–56. [10] O. Kirbas, E.H. Biberoglu, A. Kirbas, H.K. Daglar, O. Kurmus, D. Uygur, et al., Pwave duration changes and dispersion in preeclampsia, Eur. J. Obstet. Gynecol. Reprod. Biol. 183 (2014) 141–145. [11] H. Jain, R. Avasthi, Correlation between dispersion of repolarization (QT dispersion) and ventricular ectopic beat frequency in patients with acute myocardial infarction: a marker for risk of arrhythmogenesis?, Int J. Cardiol. 93 (2004) 69–73. [12] Y. Castro-Torres, R. Carmona-Puerta, R.E. Katholi, Ventricular repolarization markers for predicting malignant arrhythmias in clinical practice, World J. Clin. Cases 16 (2015) 705–720. [13] K. Karaman, F. Altunkasß, M. Çetin, M. Karayakali, A. Arısoy, I. Akar, et al., New markers for ventricular repolarization in coronary slow flow: Tp-e interval, Tpe/QT ratio, and Tp-e/QTc ratio, Ann. Noninvasive Electrocardiol. 20 (2015) 338–344. [14] P.M. Rautaharju, B. Surawicz, L.S. Gettes, J.J. Bailey, American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology, American College of Cardiology Foundation, Heart Rhythm Society, AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology, J. Am. Coll. Cardiol. 53 (2009) 982–991. [15] C.E. Powe, R.J. Levine, S.A. Karumanchi, Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease, Circulation 123 (2011) 2856–2869. [16] R.J. Levine, S.E. Maynard, C. Qian, K.H. Lim, L.J. England, K.F. Yu, et al., Circulating angiogenic factors and the risk of preeclampsia, N. Engl. J. Med. 350 (2004) 672–683. [17] K.R. Palmer, T.J. Kaitu’u-Lino, R. Hastie, N.J. Hannan, L. Ye, N. Binder, et al., Placental-specific sFLT-1 e15a protein is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity, Hypertension (2015) (pii: HYPERTENSIONAHA.115.05883 [Epub ahead of print]). [18] P.R. Romundstad, E.B. Magnussen, G.D. Smith, L.J. Vatten, Hypertension in pregnancy and later cardiovascular risk: common antecedents?, Circulation 122 (2010) 579–584 [19] V.D. Garovic, S.R. Hayman, Hypertension in pregnancy: an emerging risk factor for cardiovascular disease, Nat. Clin. Pract. Nephrol. 3 (2007) 613–622. [20] E.B. Magnussen, L.J. Vatten, T.I. Lund-Nilsen, K.A. Salvesen, G. Davey Smith, P.R. Romundstad, Prepregnancy cardiovascular risk factors as predictors of preeclampsia: population based cohort study, BMJ 335 (2007) 978. [21] A. Luttun, M. Tjwa, P. Carmeliet, Placental growth factor (PlGF) and its receptor flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders, Ann. N. Y. Acad. Sci. 979 (2002) 80–93. [22] K. Onoue, S. Uemura, Y. Takeda, S. Somekawa, H. Iwama, K. Imag-awa, et al., Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis, Circulation 120 (2009) 2470–2477. [23] B. Ky, B. French, K. Ruparel, N.K. Sweitzer, J.C. Fang, W.C. Levy, et al., The vascular marker soluble fms- like tyrosine kinase 1 is associated with disease severity and adverse outcomes in chronic heart failure, J. Am. Coll. Cardiol. 58 (2011) 386–394. [24] I.S. Patten, S. Rana, S. Shahul, G.C. Rowe, C. Jang, L. Liu, et al., Cardiac angiogenic imbalance leads to peripartum cardiomyopathy, Nature 485 (2012) 333–338. [25] E. Llurba, O. Sánchez, Q. Ferrer, K.H. Nicolaides, A. Ruíz, C. Domínguez, et al., Maternal and foetal angiogenic imbalance in congenital heart defects, Eur. Heart J. 35 (2014) 701–707. [26] K. Brodwall, E. Leirgul, G. Greve, S.E. Vollset, H. Holmstrøm, G.S. Tell, et al., Possible common aetiology behind maternal preeclampsia and congenital heart defects in the child: a cardiovascular diseases in Norway Project Study, Paediatr. Perinat. Epidemiol. (2015 Oct 19), http://dx.doi.org/10.1111/ ppe.12252. [27] N. Auger, W.D. Fraser, J. Healy-Profitós, L. Arbour, Association between preeclampsia and congenital heart defects, JAMA 314 (2015) 1588–1598. [28] M. Sugimoto, H. Oka, A. Kajihama, K. Nakau, S. Kuwata, C. Kurishima, et al., Ratio between fms-like tyrosine kinase 1 and placental growth factor in children with congenital heart disease, Pediatr. Cardiol. 36 (2015) 591–599. [29] P. Gupta, C. Patel, H. Patel, S. Narayanaswamy, B. Malhotra, J.T. Green, et al., T (p-e)/QT ratio as an index of arrhythmogenesis, J. Electrocardiol. 41 (2008) 567–574.
Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002
Contents lists available at ScienceDirect
Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health journal homepage: www.elsevier.com/locate/preghy
Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio Ayse Kirbas a,⇑, Ozgur Kirbas b, Korkut Daglar a, Hasan Ali Inal c, Ozge Kurmus d, Ozgur Kara a, Hakan Timur a, Gulenay Gencosmanoglu a, Nuri Danisman a a
Department of Perinatology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara, Turkey Department of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey Department of Obstetrics and Gynecology, Konya Education and Research Hospital, Konya, Turkey d Department of Cardiology, Mersin State Hospital, Mersin, Turkey b c
a r t i c l e
i n f o
Article history: Received 23 November 2015 Accepted 19 January 2016 Available online xxxx Keywords: Heart Hypertension Ventricular arrhythmia SFlt-1
a b s t r a c t Objective: There is increasing evidence that preeclampsia (PE) may also be a risk factor for future cardiovascular diseases (CVDs), including arrhythmia. In this study we aimed to evaluate the association between PE and ventricular repolarization using novel electrocardiogram markers: QT interval duration, Tp-e interval, and Tp-e/QT ratio. Materials and Methods: In this controlled cross-sectional study sixty-four pregnant women with PE (31 with mild and 33 with severe disease) and 32 healthy women with uncomplicated pregnancies in the third trimester were compared by measuring QT parameters, Tp-e interval, and Tp-e/QT ratio. Results: Tp-e interval and Tp-e/QT ratio values were significantly higher in both the mild and severe PE groups compared to the healthy pregnant group. Conclusion: Prevention of CVD requires that patients be aware of their risk factors, be educated about their risk, and perhaps most importantly perceive them to be at risk. In this study, we documented that PE has a significant effect on ventricular repolarization. This alteration could, in part, explain the increased cardiovascular risk in women with a history of PE. This important association can be used to screen women for increased risk in order to better target counseling regarding lifestyle modifications and to follow up and manage women with a history of hypertensive disease of pregnancy more closely. Ó 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
1. Introduction Preeclampsia (PE) is a human pregnancy-specific, placental mediated, multisystemic disease. It complicates 3–5% of pregnancies, and it is still one of the main causes of maternal, fetal, and neonatal mortality and morbidity worldwide [1]. PE is characterized by new onset hypertension, usually after the second trimester of pregnancy. It is occasionally associated with proteinuria, although proteinuria is no more a necessity for the diagnosis of PE [2].
⇑ Corresponding author. E-mail addresses: [email protected], [email protected] (A. Kirbas), [email protected] (O. Kirbas), [email protected] (K. Daglar), [email protected] (H.A. Inal), [email protected] (O. Kurmus), [email protected] (O. Kara), [email protected] (H. Timur), [email protected] (G. Gencosmanoglu), [email protected] (N. Danisman).
Contrary to previous thinking, maternal complications are not limited to the pregnancy period, and they can leave permanent vascular and metabolic damage [3]. There is increasing evidence that PE is a risk factor for future cardiovascular diseases (CVDs), including arrhythmia. The mechanisms by which PE and future CVD are associated are uncertain, although shared constitutional risk factors likely contribute to features of endothelial dysfunction characteristic of both [4–8]. It has been shown that non-specific electrocardiographic variations are critical in the prediction of morbidity and mortality due to CVD in future years and an acceptable instrument in screening hypertensive patients for risk estimation [9,10]. Electrocardiographic QT interval duration, QT dispersion (defined as the difference between the maximal and minimal QT duration durations), Tp-e interval (the interval between the peak and the end of the T wave), and Tp-e/QT ratio are novel electrocardiographic ventricular repolarization markers used to predict cardiac arrhythmias in several conditions. It has been suggested that these markers can
http://dx.doi.org/10.1016/j.preghy.2016.01.002 2210-7789/Ó 2016 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002
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be used to identify patients at increased risk of ventricular arrhythmia [11–13]. In this study, we prospectively assessed the association between preeclampsia and ventricular repolarization using Tp-e and QT intervals, Tp-e/QT ratio, and QT dispersion parameters for the first time in the literature.
II, V2, and V5, and then adjusted to the heart rate (cTp-e). When the T wave deflections were found to be biphasic or negative, the QT interval was measured from the time it last returned to the baseline. The Tp-e/mean QTc ratios were calculated from these values. 3. Reproducibility
2. Material and methods Sixty-four consecutive primipara pregnant with PE and 32 healthy primipara pregnant matched for age and body mass index (BMI) underwent a standard 12-lead electrocardiogram (ECG) between May 2014 and September 2015 at Zekai Tahir Burak Research and Training Hospital. The Institutional Research Ethics Committee approved the study, and informed consent was obtained from all pregnant. The diagnosis of PE was based on a systolic blood pressure of P140 mmHg or diastolic blood pressure P90 mmHg, after the 20th gestational week, as well as 300 mg/dL proteinuria detected in a 24-h urine sample. In the absence of proteinuria, hypertension together with evidence of systemic disease (thrombocytopenia, increased levels of liver transaminases, renal failure, pulmonary edema, or visual or cerebral disturbances) was accepted for a diagnosis of PE. The diagnosis of severe PE was based on the presence of any of the following criteria: systolic blood pressure P160 mmHg or diastolic blood pressure P110 mmHg on two separate measurements, performed at least at six-hour intervals; elevated serum creatinine level; headache; visual impairment; epigastric pain; elevated hepatic transaminases (P40 IU/ml); thrombocytopenia; or pulmonary edema [2]. The exclusion criteria were the presence of any pregestational heart disease; history of systemic, psychiatric, or endocrine disease; smoking; alcohol consumption; or active labor. The age, gestational week at the time of assessment, BMI, resting heart rate, blood pressure and biochemical results of participant were recorded. Maternal serum electrolytes were checked to rule out any electrolyte imbalance. The 12-lead ECG scans were performed at a standardized speed of 25 mm/s and 2 mV/cm with the patients in a resting position. All of the patients were in sinus rhythm; none of the patients were using antiarrhythmic drugs, magnesium, or any other antihypertensive drug that could affect their cardiovascular system during the ECG scan. Two experienced cardiologists with no knowledge of the clinical characteristics of the participants analyzed all of the ECGs. The maximum and minimum QT and Tp-e interval durations were measured manually. The measurements were performed with calipers and a magnifying lens to define the ECG deflection for improving accuracy. ECGs in which Tp-e intervals and QT segments could not be analyzed properly were excluded from the study. Participants whose QT waves could be measured in more than nine ECG leads were included in the study. The QT interval was measured from the start of the Q wave to the end of the T wave. Using the Hodges formula [QTc = QT + 1.75 (heart rate 60)], the QT waves of the patients were corrected according to their heart rates [14,15]. When the U wave was seen, the QT measurement was made from 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-d) was calculated as the difference between maximal and minimal QTc intervals. The Tp-e interval was defined as the interval from the top of the T wave to the end of the same T wave. It was shown as the intersection of the isoelectric line and the tangent of the downslope of the T wave. The Tp-e interval was measured in leads
To assess the variation of the QT and Tp-e intervals between the two independent observers who performed the measurements, 25 ECGs were chosen randomly. The same measurement was repeated twice, with a two-day interval. The correlations within observers and between observers were 2.3% and 2.9%, respectively. 4. Results All of the patients were nulliparous and in their third trimester (33–38 weeks), and they were matched for maternal age and BMI. The obstetric and demographic characteristics of the groups are presented in Table 1. The laboratory characteristics of the PE and control groups at initial admission are presented in Table 2. The electrocardiographic findings of the all pregnant are presented in Table 3. Although there were no differences in minimum QTc values among the groups, maximum QTc and QTc dispersion values were significantly higher in the severe PE group than in the mild PE and control groups (p < 0.001). Regarding the primary endpoint parameters of the study, Tp-e interval and Tp-e/QTc ratio values were significantly higher in the severe (p < 0.01) and mild (p < 0.01) PE groups than in the healthy subjects (Fig. 1). 5. Discussion In this study, we demonstrated that Tp-e interval and Tp-e/QTc ratio, as indices of ventricular arrhythmogenesis, were significantly higher in pregnant patients with PE compared with healthy pregnant women. In addition, the higher Tp-e interval and Tp-e/QTc ratio values differentiated the severe PE cases from the mild ones. Our finding of higher Tp-e and Tp-e/QTc ratio in patients with PE is important, as this is the first study to evaluate the association between PE and parameters of ventricular repolarization in pregnancy using those markers. Our results may contribute to the knowledge of the pathophysiological mechanisms of increased prevalence of ventricular arrhythmias in pregnant women with PE later in life. The exact cause of PE is still unknown, but there is consensus that the placenta plays a cardinal role in the pathogenesis. It is thought to occur in two stages, with poor placentation leading to maternal systemic inflammatory response [15]. Abnormal, poor placentation resulting in placental ischemia is thought to be the primary event leading to placental release of factors such as inflammatory cytokines and antiangiogenic proteins that cause systemic endothelial dysfunction [15,16]. The balance between proangiogenic (vascular endothelial growth factor [VEGF] and placental growth factor [PlGF]) and antiangiogenic (soluble Fms-like tyrosine kinase 1 [sFlt-1]) factors determines normal development. SFlt1 antagonizes VEGF and PlGF, binding their endothelial cell receptors and thus exhibiting antiangiogenic effects and inducing maternal systemic metabolic, inflammatory, and endothelial dysfunction, leading to the classical symptoms and signs of PE. [15]. Many studies have confirmed the increased levels of sFlt-1 and decreased levels of PlGF and VEGF in women with PE [16,17]. PlGF is expressed not only in the placenta, but also in cardiac and lung tissue. Therefore, it is not surprising that changes in the
Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002
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A. Kirbas et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2016) xxx–xxx Table 1 Characteristics of the study population.
Maternal age, years (±SD) Gestational week at assessment BMI at assessment Heart rate, bpm Systolic BP, mmHg Diastolic BP, mmHg
Control group (n = 32)
Mild PE (n = 31)
Severe PE (n = 33)
26.81 ± 4.9 36.31 ± 1.2 28.34 ± 3.1 78.65 ± 5.7 110 (100–137) 70.50 (54–87)
27.77 ± 5.3 36.65 ± 2.3 30.34 ± 3.7 80.83 ± 6.7 142 (120–155) 91 (70–105)
28.33 ± 5.2 34.34 ± 3.6 29.06 ± 3.5 81.21 ± 5.7 161 (150–187) 105 (90–120)
Data expressed as number (%), mean ± SD, median (minimum
p value (groups) 1 vs 2
1 vs 3
2 vs 3
0.74 0.92 0.064 0.498 <0.001 <0.001
0.46 0.07 0.683 0.212 <0.001 <0.001
0.90 0.09 0.309 0.850 <0.001 <0.001
maximum). The mean difference is significant at the 0.05 level.
Table 2 Laboratory tests results of the study population at assessment.
Hemoglobin (g/dl) Platelet (103) – /lL AST – U/L ALT – U/L BUN (mg/dl) Creatinine (mg/dl) Total protein (g/dl) Albumin (g/dl)
Control group (n = 32)
Mild PE (n = 31)
Severe PE (n = 33)
12.5 ± 0.8 231.00 ± 92 15 (6–25) 9 (6–22) 15.4 ± 4.4 0.46 ± 0.09 6.99 ± 0.46 4.2 ± 0.3
12.4 ± 1.2 222.97 ± 48 20 (12–50) 20 (8–43) 22.8 ± 5.6 0.66 ± 0.12 6.30 ± 0.43 3.5 ± 0.3
13.3 ± 1.6 202.26 ± 44 25 (12–433) 19 (7–900) 33.7 ± 14.2 0.74 ± 0.28 5.20 ± 0.91 2.8 ± 0.5
p value (groups) 1 vs 2
1 vs 3
2 vs 3
0.85 0.42 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.03 0.87 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.009 0.19 0.002 0.56 0.01 0.37 <0.001 <0.001
Table 3 The electrocardiographic findings of the study population.
Maximum QTc interval (ms) Minimum QTc interval (ms) QTc dispersion (ms) Mean QTc interval Tp-e interval (ms) Tp-e/QTc ratio
Control group (group 1) (n = 31)
Mild PE (group 2) (n = 31)
Severe PE (group 3) (n = 33)
415.4 ± 21.8 366.8 ± 26.1 46.8 ± 10.7 388.1 ± 26.7 74.1 ± 9.4 0.18 ± 0.01
417.1 ± 24.5 358.8 ± 31.1 53.5 ± 10.8 391.4 ± 22.7 83.8 ± 7.3 0.21 ± 0.01
448.3 ± 25.5 373.0 ± 21.2 74.5 ± 11.4 409.9 ± 22.2 97.5 ± 5.87 0.23 ± 0.01
QTc dispersion and Tp-e interval 120
p value (groups) 1 vs 2
1 vs 3
2 vs 3
0.96 0.45 0.044 0.84 <0.001 <0.001
<0.001 0.65 <0.001 0.007 <0.001 <0.001
<0.001 0.08 <0.001 0.001 <0.001 <0.001
Tp-e / QTc ratio 0.25
100
0.23
0.2
0.21
80 0.15
60 40
0.1
20
0.05
0 QTc disp Control
Tp-e interval Mild PE
0.18
0 Control
Mild PE
Severe PE
Severe PE
Fig. 1. QT dispersion, Tp-e interval, and Tp-e/QT values in the groups.
sFlt-1/PlGF ratio may have cardiac or pulmonary effects [21]. Similar imbalances between sFlt-1 and PlGF were recently observed in fetuses with heart defects. It has been suggested that angiogenic mechanisms may be part of a shared pathway in PE and congenital
heart defects in the offspring of PE patients [25–28]. Several studies have reported increased circulating sFlt1 levels in patients with acute coronary syndrome and congestive heart failure in adults [22,23]. It has also been suggested that excessive antiangiogenic
Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002
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signaling in the peripartum period may cause peripartum cardiomyopathy and subclinical cardiac dysfunction in women [24]. The association between PE and future CVD has been an increasing area of interest in recent years. PE has been suggested as an early warning of later emerging conventional CVD risk factors. Although PE is resolved by delivery of the placenta, the underlying abnormalities (permanent vascular damage and altered angiogenesis due to antiangiogenic proteins, exaggerated inflammation and oxidative stress, endothelial dysfunction and a hypercoagulable state) have been associated with long-term CVD risk [18,19]. Alternatively, it has been suggested that pre-pregnancy risk factors and PE itself might both contribute to the development of long-term CVD risk. PE shares many proposed etiologies and risk factors with CVD, including inflammation, oxidative stress, hypercoagulability, obesity, insulin resistance, dyslipidemia, and endothelial dysfunction, which can predispose the patient to both placental dysfunction and atherosclerosis. For this reason, PE is sometimes referred to as the ‘‘metabolic syndrome of pregnancy.” Furthermore, PE has been accepted as an independent genderspecific CVD risk factor [20]. Ray et al. demonstrated retrospectively that women who experienced PE, especially in the presence of fetal compromise, independent of recognized coronary artery disease, were at increased risk of premature dysrhythmias [7]. The Tp-e interval and Tp-e/QT ratio have emerged as novel ECG markers for increased dispersion of ventricular repolarization [12,13]. Moreover, the Tp-e/QT ratio is is not affected by changes in body weight or heart rate it is considered to be a more sensitive index of arrhythmogenesis compared with the single use of either the Tp-e or QT intervals [29]. In conclusion, in the present study Tp-e intervals and Tp-e/QTc ratios were increased in the PE patients, which might imply an indicator of risk of ventricular arrhythmias in this group of patients. This important connection can be used to screen for elevated risk in order to better target counseling about lifestyle modifications and to follow up and manage women with a history of PE intimately. Our hypothesis was based on previous data suggesting that pregnancy itself may act as an early natural ‘‘stress test,” unmasking underlying defects and thus identifying women at high risk of CVD later in life. Prevention of heart disease requires that patients be aware of their risk factors, be educated about their risk, and perhaps most importantly, perceive them to be at risk. Acknowledgment None. References [1] B.W. Mol, C.T. Roberts, S. Thangaratinam, L.A. Magee, C.J. de Groot, G.J. Hofmeyr, Pre-eclampsia, Lancet (2015), http://dx.doi.org/10.1016/S0140-6736 (15)00070-7. pii: S0140-6736(15)00070-7. [2] American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy, Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy, Obstet. Gynecol. 122 (2013) 1122–1131. [3] M.C. Gongora, N.K. Wenger, Cardiovascular complications of pregnancy, Int. J. Mol. Sci. 16 (2015) 23905–23928. [4] V.D. Garovic, K.R. Bailey, E. Boerwinkle, S.C. Hunt, A.B. Weder, D. Curb, et al., Hypertension in pregnancy as a risk factor for cardiovascular disease later in life, J. Hypertens. 28 (2010) 826–833. [5] E.B. Magnussen, L.J. Vatten, G.D. Smith, P.R. Romundstad, Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors, Obstet. Gynecol. 114 (2009) 961–970. [6] M.L. Mongraw-Chaffin, P.M. Cirillo, B.A. Cohn, Pre-eclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort, Hypertension 56 (2010) 166–171.
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Please cite this article in press as: A. Kirbas et al., Novel indexes of arrhythmogenesis in preeclampsia: QT dispersion, Tp-e interval, and Tp-e/QT ratio, Preg. Hyper: An Int. J. Women’s Card. Health (2016), http://dx.doi.org/10.1016/j.preghy.2016.01.002