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QTc Ratios as Indices of Ventricular Arrhythmogenesis
HLC 1560 No. of Pages 6
ORIGINAL ARTICLE
Heart, Lung and Circulation (2014) xx, 1–6 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2014.03.016
Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis € ¨ r Otlu c, Hakan Tas¸olar a*, Mehmet Ballı a, Adil Bayramog˘lu b, Yılmaz Omu Mustafa C ¸ etin a, Burak Altun d, Musa C ¸ akıcı a a
Adiyaman University, Training and Research Hospital, Department of Cardiology, Adiyaman, Turkey Elbistan State Hospital, Department of Cardiology, Kahramanmaras, Turkey Kars State Hospital, Department of Cardiology, Kars, Turkey d 18 Mart University, Faculty of Medicine, Department of Cardiology, C ¸ anakkale, Turkey b c
Received 2 December 2013; accepted 8 March 2014; online published-ahead-of-print xxx
Background
Smoking may lead to ventricular arrhythmias and sudden cardiac death via altering ventricular recovery time dispersion indices such as QT interval and QT dispersion (QTd). The Tp-e/QT and Tp-e/QTc ratios are also known as predictors of ventricular arrhythmogenesis. The aim of this study was to evaluate the relationship between cigarette smoking and ventricular repolarisation dispersion using these novel electrocardiographic parameters.
Methods
One hundred and twenty-one chronic smokers and 70 age- and sex-matched non-smoker controls were included in our study. The Tp-e interval and Tp-e/QT ratio were measured by 12-lead electrocardiogram, and corrected for heart rate.
Results
QTd (34.2 8.4, 27.2 10.4, P < 0.001) and corrected QTd (37.3 8.9, 29.8 11.2, P < 0.001) were significantly increased in the smokers compared to the non-smoker control group. The Tp-e interval (76.5 6.3, 70.3 6.8, P < 0.001), cTp-e interval (83.5 8.0, 77.1 8.7, P < 0.001), Tp-e/QT (0.20 0.03, 0.19 0.02, P < 0.001) and Tp-e/QTc ratios (0.19 0.02, 0.17 0.02, P < 0.001) were increased in the patient group when compared to the controls. Significant positive correlations were also found between the level of smoking with the cTp-e interval (r = 0.836, P < 0.001), and Tp-e/QT (r = 0.714, P < 0.001) and Tp-e/QTc ratios (r = 0.448, P < 0.001).
Conclusion
We found in our study that cTp-e interval, Tp-e/QT and Tp-e/QTc ratios were increased in smokers and significantly correlated to the amount of smoking.
Keywords
Smokers Nicotine Tp-e interval Tp-e/QT ratio Ventricular arrhythmogenesis
Introduction Cigarette smoking is increasingly a major cardiovascular risk factor for atherosclerotic diseases [1]. Although the effects and mechanisms of cigarettes on cardiovascular morbidity and mortality have been investigated comprehensively, their
influence on ventricular arrhythmogenesis is limited to a small number of studies [2–4]. Ventricular repolarisation is commonly assessed using QT interval and T wave measurements. The Tp-e interval, the interval between the peak and the end of the T wave, could also be used as an index of the total dispersion of
¨ niversitesi Eg˘itim ve Aras¸tırma Hastanesi, Hastane Cad. Merkez/Adiyaman TURKEY. *Corresponding author at: T.C. Sag˘lık Bakanlıg˘ı Adiyaman U Tel.: +904162161015 / 1387; fax: +9 0 416 214 25 25, Email: [email protected] © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
HLC 1560 No. of Pages 6 H. Tas¸olar et al.
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repolarisation [5,6]. However, it was recently determined that the Tp-e/QT ratio is a more accurate measurement of ventricular repolarisation, independent of alterations in heart rate [7–9]. To our knowledge, no study has examined the Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios as indices of ventricular arrhythmogenesis, comparing healthy smoker with healthy non-smoker populations. The aim of this study was to evaluate the relationship between cigarette smoking and ventricular repolarisation dispersion using these novel electrocardiographic parameters.
Materials and Methods Patient and Control Groups The patient population consisted of 121 patients (mean age 34.6 5.3) who had no risk factors for cardiac arrhythmias other than smoking. Subjects who had never smoked were volunteers from office staff in our hospital who were age and gender matched, and used as the control group (mean age, 33.5 5.4). The study subjects were classified as smokers when they reported a history of cigarette smoking, with a minimum of 10 cigarettes per day, for at least one year, and had never stopped smoking before the day of evaluation. The level of smoking was calculated by multiplying the number of cigarettes (defined as number of packs) smoked per day by the duration of smoking (defined as years), and expressed as pack-years. The study was approved by the local ethics committee and all subjects gave written informed consent. Physical examination, medical history of patients and blood biochemistry were examined in all groups to exclude systemic diseases such as diabetes mellitus, thyroid dysfunction, anaemia, hypercholesterolaemia and electrolyte imbalance. Patients with coronary artery disease, heart failure, rheumatic valve disease, primary cardiomyopathy, obesity, hypertension, chronic lung disease, bundle branch block and
atrioventricular conduction abnormalities on electrocardiogram (ECG) were excluded. ECGs without clearly analysable Tp-e interval and QT segment were also excluded from the study. All of the patients were in sinus rhythm and none of them were taking medications affecting QT and Tp-e intervals such as antibiotics, antiarrhythmics, tricyclic antidepressants, antihistaminics and antipsychotics.
Echocardiographic and Electrocardiographic Examination All echocardiographic examinations (HD 11 XE, Philips Medical Systems, Bothell, WA) were performed by cardiologists blinded to the experimental design and patient histories. Measurements were performed according to the criteria of the American Society of Echocardiography, and three consecutive cycles were averaged for each parameter. The 12-lead ECG was performed at a paper speed of 50 mm/s with the subject at rest in the supine position. The resting heart rate was then measured from the ECG data. ECG measurements of QT and Tp-e intervals were performed manually by two cardiologists, using calipers and a magnifying glass to decrease measurement errors. Subjects with U waves on their ECGs were excluded from the study. The average value of three examinations was calculated for each lead. The QT interval was measured from the beginning of the QRS complex to the end of the T wave, and corrected for heart rate using the Bazett formula.7 The QTd was defined as the difference between the maximum (QTmax) and minimum QT (QTmin) intervals of the 12 leads. The difference between the corrected QTmax (cQTmax) and corrected QTmin (cQTmin) was defined as corrected QTd (cQTd) [10]. Measurements of the Tp-e interval were performed from precordial leads [11]. The Tp-e interval was defined as the interval from the peak to the end of T wave, and was corrected for heart rate (cTp-e). Tp-e/QT and Tp-e/QTc ratios were then calculated from these values. The interobserver
Table 1 Clinical characteristics, laboratory, and echocardiographic findings of the study population. Patients
Control
(n = 121)
(n = 70)
P value
Age (years)
34.6 5.3
33.5 5.4
0.168
BMI (kg/m2)
22.2 1.5
21.9 2.0
0.438
Systolic BP (mmHg)
117.9 7.3
116.0 7.2
0.426
Diastolic BP (mmHg) LV EF (%)
74.7 6.6 62.7 2.5
74.9 5.0 62.1 2.7
0.772 0.099
LV EDD (mm)
4.51 0.20
4.48 0.25
0.163
LV ESD (mm)
3.10 0.17
3.07 0.16
0.227
LA (mm)
32.5 2.9
32.4 3.3
0.808
Number of cigarettes/day
22.2 11.4
-
<0.0001
Pack-years
13.6 8.5
-
<0.0001
BMI = body mass index, BP = blood pressure, LV = left ventricular, EF = ejection fraction, LVEDD = LV end-diastolic dimension, LVESD = LV end-systolic dimension, LA = Left atrial dimension.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
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Tp-e interval, Tp-e/QT and Tp-e/QTc ratios in smokers
Table 2 Electrocardiographic findings of the study population. Patients
Control
(n = 121)
(n = 70)
P value
72.2 10.9
69.6 7.4
0.031
QTmax (ms)
379.4 26.7
370.6 24.9
0.022
cQTmax (ms)
413.8 25.5
405.5 25.1
0.031
QTmin (ms) cQTmin (ms)
345.2 23.2 376.5 21.9
343.3 21.5 375.7 22.8
0.571 0.820
QTd (ms)
34.2 8.4
27.2 10.4
<0.001
cQTd (ms)
37.3 8.9
29.8 11.2
<0.001
Tp-e (ms)
76.5 6.3
70.3 6.8
<0.001
cTp-e (ms)
83.5 8.0
77.1 8.7
<0.001
Tp-e/QT
0.20 0.03
0.19 0.02
<0.001
Tp-e/QTc
0.19 0.02
0.17 0.02
<0.001
HR (beat/min)
HR = Heart rate, QTmax = QT maximum, cQTmax = corrected QT maximum, QTmin = QT minimum, cQTmin = corrected QT minimum, QTd = QT dispersion, cQTd = corrected QT dispersion, Tp-e = transmural dispersion of repolarisation, cTp-e = corrected transmural dispersion of repolarisation.
and intraobserver coefficients of variation of these measurements were 2.8%, 3.2% and 3.1%, 3.0% respectively.
Statistical Analysis Statistical study was performed with SPSS 20.0 statistical program (SPSS Inc., Chicago, Ill.). All variables were given as mean standard deviation. Continuous variables were compared between groups using the Student t test or Mann–Whitney U test, according to whether normally distributed as tested by the Kolmogorov–Smirnov test. Chisquare test was used to assess differences between categorical variables. Pearson’s correlation coefficients were used to assess relationship between continuous variables. P value <0.05 was considered significant.
Results Clinical characteristics of study population are presented in Table 1. Two groups are similar with respect to age, BMI, systolic BP, diastolic BP, LV end diastolic diameter, LV end sistolic diameter, left atrial dimension and ejection fraction. Results of electrocardiographic indices are presented in Table 2. Heart rate, considered to be due to chronic sympathetic stimulation, was significantly higher in the smoker group than in the controls (P = 0.031). The QTmax (P = 0.022), cQTmax (P = 0.031), QT min (P = 0.571), cQTmin (P = 0.820), QTd (P < 0.001) and cQTd (P < 0.001) were significantly increased in the smoker patients compared to the control group. The Tp-e interval (P < 0.001), cTp-e interval (P < 0.001), Tp-e/QT
Figure 1 Correlation between the level of smoking and the cTp-e interval.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
HLC 1560 No. of Pages 6 H. Tas¸olar et al.
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Figure 2 Correlations between the level of smoking with Tp-e/QT (A) and Tp-e/QTc ratios (B).
(P < 0.001) and Tp-e/QTc ratios (P < 0.001) were also increased in the patient group when compared to the controls. Significant positive correlations were also found between the level of smoking with the cTp-e interval (r = 0.836, P < 0.001) (Figure 1), and Tp-e/QT (r = 0.714, P < 0.001) (Figure 2A) and Tp-e/QTc ratios (r = 0.448, P < 0.001) (Figure 2B).
Discussion Our study showed that the Tp-e and cTp-e intervals, and the Tp-e/QT and Tp-e/QTc ratios, were increased in smokers compared with controls. These ECG parameters were also significantly correlated with the level of smoking. Cigarette smoking is a well-known risk factor for cardiovascular disease, which is a leading cause of death worldwide [12]. Specifically, cigarette smoking has an adverse effect of numerous cardiovascular events, including: (i) reduction in the oxygen carrying capacity of blood, mediated by carbon monoxide (CO); (ii) increased myocardial work; (iii) induction of endothelial cell dysfunction; and (iv) catecholamine release [13]. Although the effect of smoking on atherosclerotic disease is well known [1], the specific effects of cigarette smoking on cardiac and ventricular arrhythmias are less clear. Cigarette smoke contains many toxic chemicals such as nicotine, tar, and CO. The effects of nicotine and CO on the cardiovascular system have been well studied. Fundamentally, nicotine has acute and chronic cardiovascular effects, particularly through sympathetic activation, while CO causes heart disease by promoting hypoxia [14–16]. Specifically, nicotine causes cardiac rhythmic disorders (including transient sinus arrest and/or bradycardia), sinus tachycardia, atrial fibrillation, and ventricular tachyarrhythmia [17]. In one important study, Mehta et al. revealed dose-dependent arrhythmogenicity of nicotine. Whereas smaller doses of nicotine did not exert significant effects, higher doses may generate cardiac arrhythmias, ranging from simple to severe,
in dogs [18]. It has been hypothesised that nicotine leads to significant increases in the serum catecholamine concentration, and blocks the inward potassium channels, both of which can promote arrhythmias [17]. By reducing the oxygen-carrying capacity and oxygen release of haemoglobin, CO changes the automaticity, and decreases the exercise capacity of the heart [19]. The ventricular fibrillation threshold is decreased by CO in animal models of experimentally induced ischaemia [20,21]. The hypoxia caused by CO also has direct myocardial toxic effects [22]. A pathophysiological mechanism for cardiac arrhythmia induced by cigarette smoking has been suggested, where the combination of nicotine and CO induce fibrosis at different cardiac sites, generating a structural remodelling that leads to arrhythmia. However, the amount of fibrosis induced by cigarette smoking may vary among individuals [17]. Moreover, CO intoxication is shown to be related to increased QT dispersion [23]. Previous studies indicated that increased dispersion of repolarisation might predispose patients to ventricular arrhythmias [24–26]. Previously, QTd, cQTd, and transmural dispersion of repolarisation have been used to evaluate myocardial repolarisation, and thus estimate the arrhythmogenic risk of the heart [5,27]. Nevertheless, studies reported contradictory results on the effect of smoking on QT duration in healthy individuals [2,28–30]. While Ileri et al. showed significant differences in the QT intervals and dispersion in healthy smokers [28], Mestre et al. found that smoking habits do not have a significant influence on the QTc interval [30]. Moreover, Dilaveris et al. showed that QT max and QTmin were decreased significantly in smokers, but that there was no difference in QTd [2]. One explanation for these contradictory reports is the presence of uncontrolled variables, including the number of cigarettes smoked per day, the nicotine content of the cigarettes, and patient lifestyle [31]. In our study, consistent with previous observations, QT max, QT min, and QTd were extended in smokers.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
HLC 1560 No. of Pages 6
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Tp-e interval, Tp-e/QT and Tp-e/QTc ratios in smokers
In recent years, Tp-e interval and Tp-e/QT ratio have been used as new electrocardiographic markers of the increased dispersion of ventricular repolarisation [5,8]. An association between prolonging the Tp-e interval and ventricular arrhythmogenesis and sudden cardiac death has also been reported [9,11]. An increased Tp-e interval is also likely to be a useful index to predict ventricular arrhythmias and cardiovascular events [32,33]. However, the Tp-e/QT ratio is considered to be a more sensitive index of arrhythmogenesis compared with the sole use of either the Tp-e or QT intervals, as it is not affected by variations in body weight and heart rate [8]. This improves the signal-to-noise ratio, and provides unique information to predict arrhythmogenesis [8]. The Tp-e/QT ratio also provides an estimate of the dispersion of repolarisation relative to the total duration of repolarisation [9]. Moreover, a higher Tp-e/QT ratio has been associated with arrhythmic events in many clinical conditions, such as Brugada syndrome, long QT syndromes, hypertrophic cardiomyopathy, and undergoing primary percutaneous coronary intervention for myocardial infarction [8]. Electrophysiological studies showed that a prolonged Tp-e interval was correlated with VT induction and the spontaneous occurrence of VT [32,33]. Although ventricular repolarisation was previously evaluated using QT interval measurements in smokers [2–4], this is the first study to evaluate the new parameters of Tp-e interval and Tp-e/QT ratio. In our study, we observed that the Tp-e interval, and Tp-e/QT, and Tp-e/QTc ratios were increased in healthy smokers compared with the normal population. Significant correlations were also found between the amount of smoking and these parameters. Based on these data, we propose that healthy smokers may have an increased risk of ventricular arrhythmia compared with non-smokers, consistent with previous reports. The main limitations of our study were its cross-sectional design and lack of patient follow-up, since the study population could not be followed prospectively for ventricular arrhythmias. We could therefore not categorically evaluate the potential prognostic role of the ECG ventricular repolarisation parameters with respect to future cardiac events.
Conclusion Our study showed that the Tp-e interval and Tp-e/QT and Tp-e/QTc ratios (as parameters of ventricular arrhythmogenesis) were increased in healthy smokers. These ECG indices of ventricular repolarisation were also significantly correlated with the amount of smoking. Our study is important to show that smoking exerts a deleterious, harmful effect on ventricular repolarisation, which potentially could lead to increased risk of ventricular arrhythmias.
Conflict of interest None declared.
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Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
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[25] Shimizu M, Ino H, Okeie K, Yamaguchi M, Nagata M, Hayashi K, et al. T-peak to T-end interval may be a better predictor of highrisk patients with hypertrophic cardiomyopathy associated with a cardiac troponin I mutation than QT dispersion. Clin Cardiol 2002;25: 335–9. [26] Haarmark C, Hansen PR, Vedel-Larsen E, Pedersen SH, Graff C, Andersen MP, et al. The prognostic value of the Tpeak-Tend interval in patients undergoing primary percutaneous coronary intervention for STsegment elevation myocardial infarction. J Electrocardiol 2009;42 (Nov-Dec (6)):555–60. [27] Antzelevitch C, Shimizu W, Yan GX, Sicouri S. Cellular basis for QT dispersion. J Electrocardiol 1998;30:168–75. [28] Ileri M, Yetkin E, Tandog˘an I, Hisar I, Atak R, Senen K, et al. Effect of habitual smoking on QT interval duration and dispersion. Am J Cardiol 2001;88(Aug 1 (3)):322–5. [29] Fauchier L, Maison-Blanche P, Forhan A, D’Hour A, Le´pinay P, Tichet J, et al. Association between heart rate-corrected QT interval and coronary risk factors in 2,894 healthy subjects (the DESIR Study]. Data from an
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Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
ORIGINAL ARTICLE
Heart, Lung and Circulation (2014) xx, 1–6 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2014.03.016
Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis € ¨ r Otlu c, Hakan Tas¸olar a*, Mehmet Ballı a, Adil Bayramog˘lu b, Yılmaz Omu Mustafa C ¸ etin a, Burak Altun d, Musa C ¸ akıcı a a
Adiyaman University, Training and Research Hospital, Department of Cardiology, Adiyaman, Turkey Elbistan State Hospital, Department of Cardiology, Kahramanmaras, Turkey Kars State Hospital, Department of Cardiology, Kars, Turkey d 18 Mart University, Faculty of Medicine, Department of Cardiology, C ¸ anakkale, Turkey b c
Received 2 December 2013; accepted 8 March 2014; online published-ahead-of-print xxx
Background
Smoking may lead to ventricular arrhythmias and sudden cardiac death via altering ventricular recovery time dispersion indices such as QT interval and QT dispersion (QTd). The Tp-e/QT and Tp-e/QTc ratios are also known as predictors of ventricular arrhythmogenesis. The aim of this study was to evaluate the relationship between cigarette smoking and ventricular repolarisation dispersion using these novel electrocardiographic parameters.
Methods
One hundred and twenty-one chronic smokers and 70 age- and sex-matched non-smoker controls were included in our study. The Tp-e interval and Tp-e/QT ratio were measured by 12-lead electrocardiogram, and corrected for heart rate.
Results
QTd (34.2 8.4, 27.2 10.4, P < 0.001) and corrected QTd (37.3 8.9, 29.8 11.2, P < 0.001) were significantly increased in the smokers compared to the non-smoker control group. The Tp-e interval (76.5 6.3, 70.3 6.8, P < 0.001), cTp-e interval (83.5 8.0, 77.1 8.7, P < 0.001), Tp-e/QT (0.20 0.03, 0.19 0.02, P < 0.001) and Tp-e/QTc ratios (0.19 0.02, 0.17 0.02, P < 0.001) were increased in the patient group when compared to the controls. Significant positive correlations were also found between the level of smoking with the cTp-e interval (r = 0.836, P < 0.001), and Tp-e/QT (r = 0.714, P < 0.001) and Tp-e/QTc ratios (r = 0.448, P < 0.001).
Conclusion
We found in our study that cTp-e interval, Tp-e/QT and Tp-e/QTc ratios were increased in smokers and significantly correlated to the amount of smoking.
Keywords
Smokers Nicotine Tp-e interval Tp-e/QT ratio Ventricular arrhythmogenesis
Introduction Cigarette smoking is increasingly a major cardiovascular risk factor for atherosclerotic diseases [1]. Although the effects and mechanisms of cigarettes on cardiovascular morbidity and mortality have been investigated comprehensively, their
influence on ventricular arrhythmogenesis is limited to a small number of studies [2–4]. Ventricular repolarisation is commonly assessed using QT interval and T wave measurements. The Tp-e interval, the interval between the peak and the end of the T wave, could also be used as an index of the total dispersion of
¨ niversitesi Eg˘itim ve Aras¸tırma Hastanesi, Hastane Cad. Merkez/Adiyaman TURKEY. *Corresponding author at: T.C. Sag˘lık Bakanlıg˘ı Adiyaman U Tel.: +904162161015 / 1387; fax: +9 0 416 214 25 25, Email: [email protected] © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
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repolarisation [5,6]. However, it was recently determined that the Tp-e/QT ratio is a more accurate measurement of ventricular repolarisation, independent of alterations in heart rate [7–9]. To our knowledge, no study has examined the Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios as indices of ventricular arrhythmogenesis, comparing healthy smoker with healthy non-smoker populations. The aim of this study was to evaluate the relationship between cigarette smoking and ventricular repolarisation dispersion using these novel electrocardiographic parameters.
Materials and Methods Patient and Control Groups The patient population consisted of 121 patients (mean age 34.6 5.3) who had no risk factors for cardiac arrhythmias other than smoking. Subjects who had never smoked were volunteers from office staff in our hospital who were age and gender matched, and used as the control group (mean age, 33.5 5.4). The study subjects were classified as smokers when they reported a history of cigarette smoking, with a minimum of 10 cigarettes per day, for at least one year, and had never stopped smoking before the day of evaluation. The level of smoking was calculated by multiplying the number of cigarettes (defined as number of packs) smoked per day by the duration of smoking (defined as years), and expressed as pack-years. The study was approved by the local ethics committee and all subjects gave written informed consent. Physical examination, medical history of patients and blood biochemistry were examined in all groups to exclude systemic diseases such as diabetes mellitus, thyroid dysfunction, anaemia, hypercholesterolaemia and electrolyte imbalance. Patients with coronary artery disease, heart failure, rheumatic valve disease, primary cardiomyopathy, obesity, hypertension, chronic lung disease, bundle branch block and
atrioventricular conduction abnormalities on electrocardiogram (ECG) were excluded. ECGs without clearly analysable Tp-e interval and QT segment were also excluded from the study. All of the patients were in sinus rhythm and none of them were taking medications affecting QT and Tp-e intervals such as antibiotics, antiarrhythmics, tricyclic antidepressants, antihistaminics and antipsychotics.
Echocardiographic and Electrocardiographic Examination All echocardiographic examinations (HD 11 XE, Philips Medical Systems, Bothell, WA) were performed by cardiologists blinded to the experimental design and patient histories. Measurements were performed according to the criteria of the American Society of Echocardiography, and three consecutive cycles were averaged for each parameter. The 12-lead ECG was performed at a paper speed of 50 mm/s with the subject at rest in the supine position. The resting heart rate was then measured from the ECG data. ECG measurements of QT and Tp-e intervals were performed manually by two cardiologists, using calipers and a magnifying glass to decrease measurement errors. Subjects with U waves on their ECGs were excluded from the study. The average value of three examinations was calculated for each lead. The QT interval was measured from the beginning of the QRS complex to the end of the T wave, and corrected for heart rate using the Bazett formula.7 The QTd was defined as the difference between the maximum (QTmax) and minimum QT (QTmin) intervals of the 12 leads. The difference between the corrected QTmax (cQTmax) and corrected QTmin (cQTmin) was defined as corrected QTd (cQTd) [10]. Measurements of the Tp-e interval were performed from precordial leads [11]. The Tp-e interval was defined as the interval from the peak to the end of T wave, and was corrected for heart rate (cTp-e). Tp-e/QT and Tp-e/QTc ratios were then calculated from these values. The interobserver
Table 1 Clinical characteristics, laboratory, and echocardiographic findings of the study population. Patients
Control
(n = 121)
(n = 70)
P value
Age (years)
34.6 5.3
33.5 5.4
0.168
BMI (kg/m2)
22.2 1.5
21.9 2.0
0.438
Systolic BP (mmHg)
117.9 7.3
116.0 7.2
0.426
Diastolic BP (mmHg) LV EF (%)
74.7 6.6 62.7 2.5
74.9 5.0 62.1 2.7
0.772 0.099
LV EDD (mm)
4.51 0.20
4.48 0.25
0.163
LV ESD (mm)
3.10 0.17
3.07 0.16
0.227
LA (mm)
32.5 2.9
32.4 3.3
0.808
Number of cigarettes/day
22.2 11.4
-
<0.0001
Pack-years
13.6 8.5
-
<0.0001
BMI = body mass index, BP = blood pressure, LV = left ventricular, EF = ejection fraction, LVEDD = LV end-diastolic dimension, LVESD = LV end-systolic dimension, LA = Left atrial dimension.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
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Tp-e interval, Tp-e/QT and Tp-e/QTc ratios in smokers
Table 2 Electrocardiographic findings of the study population. Patients
Control
(n = 121)
(n = 70)
P value
72.2 10.9
69.6 7.4
0.031
QTmax (ms)
379.4 26.7
370.6 24.9
0.022
cQTmax (ms)
413.8 25.5
405.5 25.1
0.031
QTmin (ms) cQTmin (ms)
345.2 23.2 376.5 21.9
343.3 21.5 375.7 22.8
0.571 0.820
QTd (ms)
34.2 8.4
27.2 10.4
<0.001
cQTd (ms)
37.3 8.9
29.8 11.2
<0.001
Tp-e (ms)
76.5 6.3
70.3 6.8
<0.001
cTp-e (ms)
83.5 8.0
77.1 8.7
<0.001
Tp-e/QT
0.20 0.03
0.19 0.02
<0.001
Tp-e/QTc
0.19 0.02
0.17 0.02
<0.001
HR (beat/min)
HR = Heart rate, QTmax = QT maximum, cQTmax = corrected QT maximum, QTmin = QT minimum, cQTmin = corrected QT minimum, QTd = QT dispersion, cQTd = corrected QT dispersion, Tp-e = transmural dispersion of repolarisation, cTp-e = corrected transmural dispersion of repolarisation.
and intraobserver coefficients of variation of these measurements were 2.8%, 3.2% and 3.1%, 3.0% respectively.
Statistical Analysis Statistical study was performed with SPSS 20.0 statistical program (SPSS Inc., Chicago, Ill.). All variables were given as mean standard deviation. Continuous variables were compared between groups using the Student t test or Mann–Whitney U test, according to whether normally distributed as tested by the Kolmogorov–Smirnov test. Chisquare test was used to assess differences between categorical variables. Pearson’s correlation coefficients were used to assess relationship between continuous variables. P value <0.05 was considered significant.
Results Clinical characteristics of study population are presented in Table 1. Two groups are similar with respect to age, BMI, systolic BP, diastolic BP, LV end diastolic diameter, LV end sistolic diameter, left atrial dimension and ejection fraction. Results of electrocardiographic indices are presented in Table 2. Heart rate, considered to be due to chronic sympathetic stimulation, was significantly higher in the smoker group than in the controls (P = 0.031). The QTmax (P = 0.022), cQTmax (P = 0.031), QT min (P = 0.571), cQTmin (P = 0.820), QTd (P < 0.001) and cQTd (P < 0.001) were significantly increased in the smoker patients compared to the control group. The Tp-e interval (P < 0.001), cTp-e interval (P < 0.001), Tp-e/QT
Figure 1 Correlation between the level of smoking and the cTp-e interval.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
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Figure 2 Correlations between the level of smoking with Tp-e/QT (A) and Tp-e/QTc ratios (B).
(P < 0.001) and Tp-e/QTc ratios (P < 0.001) were also increased in the patient group when compared to the controls. Significant positive correlations were also found between the level of smoking with the cTp-e interval (r = 0.836, P < 0.001) (Figure 1), and Tp-e/QT (r = 0.714, P < 0.001) (Figure 2A) and Tp-e/QTc ratios (r = 0.448, P < 0.001) (Figure 2B).
Discussion Our study showed that the Tp-e and cTp-e intervals, and the Tp-e/QT and Tp-e/QTc ratios, were increased in smokers compared with controls. These ECG parameters were also significantly correlated with the level of smoking. Cigarette smoking is a well-known risk factor for cardiovascular disease, which is a leading cause of death worldwide [12]. Specifically, cigarette smoking has an adverse effect of numerous cardiovascular events, including: (i) reduction in the oxygen carrying capacity of blood, mediated by carbon monoxide (CO); (ii) increased myocardial work; (iii) induction of endothelial cell dysfunction; and (iv) catecholamine release [13]. Although the effect of smoking on atherosclerotic disease is well known [1], the specific effects of cigarette smoking on cardiac and ventricular arrhythmias are less clear. Cigarette smoke contains many toxic chemicals such as nicotine, tar, and CO. The effects of nicotine and CO on the cardiovascular system have been well studied. Fundamentally, nicotine has acute and chronic cardiovascular effects, particularly through sympathetic activation, while CO causes heart disease by promoting hypoxia [14–16]. Specifically, nicotine causes cardiac rhythmic disorders (including transient sinus arrest and/or bradycardia), sinus tachycardia, atrial fibrillation, and ventricular tachyarrhythmia [17]. In one important study, Mehta et al. revealed dose-dependent arrhythmogenicity of nicotine. Whereas smaller doses of nicotine did not exert significant effects, higher doses may generate cardiac arrhythmias, ranging from simple to severe,
in dogs [18]. It has been hypothesised that nicotine leads to significant increases in the serum catecholamine concentration, and blocks the inward potassium channels, both of which can promote arrhythmias [17]. By reducing the oxygen-carrying capacity and oxygen release of haemoglobin, CO changes the automaticity, and decreases the exercise capacity of the heart [19]. The ventricular fibrillation threshold is decreased by CO in animal models of experimentally induced ischaemia [20,21]. The hypoxia caused by CO also has direct myocardial toxic effects [22]. A pathophysiological mechanism for cardiac arrhythmia induced by cigarette smoking has been suggested, where the combination of nicotine and CO induce fibrosis at different cardiac sites, generating a structural remodelling that leads to arrhythmia. However, the amount of fibrosis induced by cigarette smoking may vary among individuals [17]. Moreover, CO intoxication is shown to be related to increased QT dispersion [23]. Previous studies indicated that increased dispersion of repolarisation might predispose patients to ventricular arrhythmias [24–26]. Previously, QTd, cQTd, and transmural dispersion of repolarisation have been used to evaluate myocardial repolarisation, and thus estimate the arrhythmogenic risk of the heart [5,27]. Nevertheless, studies reported contradictory results on the effect of smoking on QT duration in healthy individuals [2,28–30]. While Ileri et al. showed significant differences in the QT intervals and dispersion in healthy smokers [28], Mestre et al. found that smoking habits do not have a significant influence on the QTc interval [30]. Moreover, Dilaveris et al. showed that QT max and QTmin were decreased significantly in smokers, but that there was no difference in QTd [2]. One explanation for these contradictory reports is the presence of uncontrolled variables, including the number of cigarettes smoked per day, the nicotine content of the cigarettes, and patient lifestyle [31]. In our study, consistent with previous observations, QT max, QT min, and QTd were extended in smokers.
Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016
HLC 1560 No. of Pages 6
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Tp-e interval, Tp-e/QT and Tp-e/QTc ratios in smokers
In recent years, Tp-e interval and Tp-e/QT ratio have been used as new electrocardiographic markers of the increased dispersion of ventricular repolarisation [5,8]. An association between prolonging the Tp-e interval and ventricular arrhythmogenesis and sudden cardiac death has also been reported [9,11]. An increased Tp-e interval is also likely to be a useful index to predict ventricular arrhythmias and cardiovascular events [32,33]. However, the Tp-e/QT ratio is considered to be a more sensitive index of arrhythmogenesis compared with the sole use of either the Tp-e or QT intervals, as it is not affected by variations in body weight and heart rate [8]. This improves the signal-to-noise ratio, and provides unique information to predict arrhythmogenesis [8]. The Tp-e/QT ratio also provides an estimate of the dispersion of repolarisation relative to the total duration of repolarisation [9]. Moreover, a higher Tp-e/QT ratio has been associated with arrhythmic events in many clinical conditions, such as Brugada syndrome, long QT syndromes, hypertrophic cardiomyopathy, and undergoing primary percutaneous coronary intervention for myocardial infarction [8]. Electrophysiological studies showed that a prolonged Tp-e interval was correlated with VT induction and the spontaneous occurrence of VT [32,33]. Although ventricular repolarisation was previously evaluated using QT interval measurements in smokers [2–4], this is the first study to evaluate the new parameters of Tp-e interval and Tp-e/QT ratio. In our study, we observed that the Tp-e interval, and Tp-e/QT, and Tp-e/QTc ratios were increased in healthy smokers compared with the normal population. Significant correlations were also found between the amount of smoking and these parameters. Based on these data, we propose that healthy smokers may have an increased risk of ventricular arrhythmia compared with non-smokers, consistent with previous reports. The main limitations of our study were its cross-sectional design and lack of patient follow-up, since the study population could not be followed prospectively for ventricular arrhythmias. We could therefore not categorically evaluate the potential prognostic role of the ECG ventricular repolarisation parameters with respect to future cardiac events.
Conclusion Our study showed that the Tp-e interval and Tp-e/QT and Tp-e/QTc ratios (as parameters of ventricular arrhythmogenesis) were increased in healthy smokers. These ECG indices of ventricular repolarisation were also significantly correlated with the amount of smoking. Our study is important to show that smoking exerts a deleterious, harmful effect on ventricular repolarisation, which potentially could lead to increased risk of ventricular arrhythmias.
Conflict of interest None declared.
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Please cite this article in press as: Tas¸olar H, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc Ratios as Indices of Ventricular Arrhythmogenesis. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.03.016