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Exercise-Induced Repolarization Changes in Patients With Stable Coronary Artery Disease

      Exercise is a classic trigger of ventricular arrhythmias in the setting of coronary artery disease (CAD). The aim of this study was to examine the changes of novel indexes of repolarization in patients with stable CAD who underwent exercise stress testing. Sixty-seven consecutive patients (mean age 62 ± 9 years, 60 men) who underwent treadmill exercise stress testing according to the Bruce protocol and completed the test without evidence of ischemia were enrolled. Baseline clinical and demographic characteristics were recorded, and indexes of repolarization such as corrected QT (QTc) interval, T peak-to-end (Tpe) interval, and Tpe/QT ratio were assessed at baseline and at peak exercise. A similar group of control subjects without CAD (n = 68, mean age 60 ± 11 years, 52 men) were also studied. All participants successfully completed the test. In the patient group, the QTc interval significantly increased from baseline to peak exercise (median 385 ms [25th percentile 357 ms, 75th percentile 407 ms] vs 418 ms [381 ms, 447 ms], p <0.001). The Tpe interval and the Tpe/QT ratio were also significantly increased at peak exercise (42 ms [36 ms, 60 ms] vs 78 ms [60 ms, 84 ms], p <0.001; and 0.17 [0.14, 0.22] vs 0.21 [0.16, 0.25], p = 0.015). In the control group, the QTc interval did not change significantly, the Tpe interval decreased at peak exercise (62 ms [41 ms, 80 ms] vs 48 ms [40 ms, 78 ms], p = 0.05), and the Tpe/QT ratio did not show a significant change (0.18 [0.12, 0.22] vs 0.16 [1.14, 0.21], p = 0.39). In patients with stable CAD and normal treadmill exercise stress test results, the QTc interval, the Tpe interval, and the Tpe/QT ratio increased during exercise. In conclusion, it is reasonable to assume that despite the absence of inducible ischemia, the spatial dispersion of repolarization is increased during exercise, exposing these patients to increased arrhythmic risk.
      Coronary artery disease (CAD) is the condition most commonly associated with malignant ventricular arrhythmias and sudden cardiac death (SCD).
      • Chugh S.S.
      • Reinier K.
      • Teodorescu C.
      • Evanado A.
      • Kehr E.
      • Al Samara M.
      • Mariani R.
      • Gunson K.
      • Jui J.
      Epidemiology of sudden cardiac death: clinical and research implications.
      Exercise is a classic trigger of ventricular arrhythmias in this setting, although the significance of exercise-induced arrhythmias in predicting future morbidity and mortality is controversial.
      • Corrado D.
      • Migliore F.
      • Basso C.
      • Thiene G.
      Exercise and the risk of sudden cardiac death.
      • Elhendy A.
      • Chandrasekaran K.
      • Gersh B.J.
      • Mahoney D.
      • Burger K.N.
      • Pellikka P.A.
      Functional and prognostic significance of exercise-induced ventricular arrhythmias in patients with suspected coronary artery disease.
      • Eckart R.E.
      • Field M.E.
      • Hruczkowski T.W.
      • Forman D.E.
      • Dorbala S.
      • Di Carli M.F.
      • Albert C.E.
      • Maisel W.H.
      • Epstein L.M.
      • Stevenson W.G.
      Association of electrocardiographic morphology of exercise-induced ventricular arrhythmia with mortality.
      Vigorous exertion increases the risk for cardiac arrest, especially in patients who are not physically active.
      • Corrado D.
      • Migliore F.
      • Basso C.
      • Thiene G.
      Exercise and the risk of sudden cardiac death.
      Terminal repolarization, calculated as the interval from the peak to the end of the T wave, has been related to SCD risk. A well-known pathogenetic factor for ventricular arrhythmias is the increased dispersion of repolarization, which reflects the heterogeneity rather than the total duration of repolarization.
      • Antzelevitch C.
      Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes.
      In fact, the T peak-to-end (Tpe) interval and the Tpe/QT ratio represent novel electrocardiographic (ECG) indexes of arrhythmic risk that possibly correspond to the spatial dispersion of ventricular repolarization.
      • Antzelevitch C.
      Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes.
      • Gupta P.
      • Patel C.
      • Patel H.
      • Narayanaswamy S.
      • Malhotra B.
      • Green J.T.
      • Yan G.X.
      T(p-e)/QT ratio as an index of arrhythmogenesis.
      • Kors J.A.
      • Ritsema van Eck H.J.
      • van Herpen G.
      The meaning of the Tp-Te interval and its diagnostic value.
      In this study, we sought to investigate the effects of exercise on the aforementioned ECG indexes in patients with stable CAD who underwent regular exercise stress testing.

      Methods

      In this observational study, consecutive patients with stable CAD who were referred for regular treadmill exercise stress testing were screened. In addition, we checked subjects referred for exercise stress testing because of atypical chest pain or in the context of a regular checkup (control group). Exclusion criteria were recent acute coronary syndromes within the past 6 months, recent percutaneous coronary intervention or cardiac surgery, any physical disability, congestive heart failure with New York Heart Association class >II, history of channelopathies, history of syncope, presence of nonsustained ventricular tachycardia on Holter monitoring, presence of bundle brunch block, QRS duration >120 ms, presence of second- or third-degree atrioventricular block, atrial fibrillation, previous implantation of a pacemaker or a defibrillator, administration of antiarrhythmic drugs, administration of drugs that prolong the QT interval, thyroid dysfunction, acute and chronic infections or inflammatory diseases, renal failure, and electrolyte disturbances. All participants were able to perform normal daily activities, and their functional capacity was satisfactory, but they were not following regular exercise programs.
      The participants underwent treadmill exercise stress testing according to the Bruce protocol. We analyzed subjects who successfully completed the test without clinical or ECG evidence of ischemia. Demographic, clinical, and ECG indexes of repolarization were carefully recorded. The ECG indexes were assessed at baseline in the supine position and at the peak of exercise.
      Specifically, the QT and QTpeak intervals were measured manually on ECG recordings at a paper speed of 50 mm/s. QT interval was assessed as the time between the first deflection of the QRS complex and the point of return of the T wave to the isoelectric line. The Tpe interval was calculated as QT − QTpeak. The QT interval was measured in as many of the 12 leads as possible, while the Tpe interval was assessed in the precordial leads.
      • Gupta P.
      • Patel C.
      • Patel H.
      • Narayanaswamy S.
      • Malhotra B.
      • Green J.T.
      • Yan G.X.
      T(p-e)/QT ratio as an index of arrhythmogenesis.
      The Tpe interval and the Tpe/QT ratio were calculated using the corresponding values from each lead. The measurements were obtained in 3 consecutive complexes of each lead, and the resulting average value was accepted. To avoid diurnal variation, we performed the stress tests during the same time interval (from 9 to 11 am). QT interval corrected for heart rate (QTc) was calculated using Bazett's formula (QTc = QT/RR−2).
      • Goldenberg I.
      • Moss A.J.
      • Zareba W.
      QT interval: how to measure it and what is “normal.”.
      The Tpe and QTc reported values were the maximum obtained values. All measurements were performed by 1 experienced investigator unaware of the clinical characteristics of the study participants. To identify intraobserver variability, the ECG tracings of 10 randomly selected patients were reexamined 10 days after the initial evaluation. Intraobserver variation was <5%.
      Continuous variables are expressed as mean ± SD or as median (25th percentile, 75th percentile) if their values were not normally distributed. The examination of normality was performed by the Kolmogorov-Smirnov test. Categorical variables are presented as absolute numbers and frequencies. Comparisons of continuous ECG variables were performed using the nonparametric Wilcoxon signed-rank test. A 2-tailed p value <0.05 was considered significant. All analyses were performed using SPSS version 13.0 (SPSS, Inc., Chicago, Illinois).

      Results

      A total of 67 consecutive patients with stable CAD successfully completed the protocol. The baseline clinical and demographic characteristics of the patients are listed in Table 1, and the exercise stress test parameters are listed in Table 2. The QTc interval significantly increased from baseline to peak exercise (Table 3). The Tpe interval and the Tpe/QT ratio were also significantly increased at peak exercise (Table 3). No significant ventricular arrhythmias were observed. In 3 patients, some premature ventricular beats were observed during the third stage of the protocol, while 1 additional patient had premature ventricular beats and bigeminy during the first 3 minutes of recovery. Heart rate recovery during the first 3 minutes is listed in Table 2.
      Table 1Clinical and demographic characteristics of the patients (n = 67)
      VariableValue
      Age (years)62 ± 9
      Men60 (89.5%)
      Body mass index (kg/m2)27.4 ± 2.8
      Previous myocardial infarction38 (56.7%)
      Diabetes9 (13.4%)
      Hypertension26 (38.8%)
      Congestive heart failure9 (13.4%)
      Left ventricular ejection fraction42.9 ± 5.5
      Drugs
       β-blockers55 (82%)
       ACE inhibitors/ARBs41 (61%)
       Aspirin56 (83%)
       Clopidogrel44 (66%)
       Statins63 (94%)
       Nitrates17 (25%)
       Diltiazem2 (3%)
      Data are expressed as mean ± SD or as number (percentage).
      ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.
      Table 2Exercise stress test parameters in the group of patients (n = 67)
      VariableValue
      Heart rate at baseline (beats/min)66 (57, 79)
      Heart rate at peak exercise (beats/min)134 (123, 146)
      Systolic arterial pressure at baseline (mm Hg)130 (120, 140)
      Diastolic arterial pressure at baseline (mm Hg)80 (77, 85)
      Systolic arterial pressure at peak exercise (mm Hg)170 (160, 182)
      Diastolic arterial pressure at peak exercise (mm Hg)84 (78, 90)
      METs10.5 (9.1, 11.7)
      Heart rate recovery, first minute (beats/min)20 (15, 26)
      Heart rate recovery, second minute (beats/min)38 (30, 47)
      Heart rate recovery, third minute (beats/min)47 (40, 56)
      Data are expressed as median (25th percentile, 75th percentile).
      Table 3Electrocardiographic repolarization parameters in patients with coronary artery disease (n = 67)
      VariableBaselinePeak Exercisep Value
      QT interval (ms)360 (320, 400)280 (260, 320)<0.001
      QTc interval (ms)385 (357, 407)418 (381, 447)<0.001
      Tpe interval (ms)42 (36, 60)78 (60, 84)<0.001
      Tpe/QT ratio0.17 (0.14, 0.22)0.21 (0.16, 0.25)0.015
      Data are expressed as median (25th percentile, 75th percentile).
      The control group consisted of 68 patients (mean age 60 ± 11 years, 52 men, 19% with diabetes, 41% with hypertension) without known histories of CAD. These subjects successfully completed the exercise stress test protocol (METs achieved 10 [7.9, 10.9], baseline heart rate 74 beats/min [66 beats/min, 81 beats/min], peak heart rate 148 beats/min [131 beats/min, 160 beats/min]). The QTc interval did not change significantly, the Tpe interval decreased at peak exercise, and the Tpe/QT ratio did not show a significant change in this group (Table 4).
      Table 4Electrocardiographic repolarization parameters in control subjects (n = 68)
      VariableBaselinePeak Exercisep Value
      QT interval (ms)360 (310, 390)270 (240, 280)<0.001
      QTc interval (ms)406 (380, 436)418 (381, 447)0.108
      Tpe interval (ms)62 (41, 80)48 (40, 78)0.05
      Tpe/QT ratio0.18 (0.12, 0.22)0.16 (0.14, 0.21)0.39
      Data are expressed as median (25th percentile, 75th percentile).

      Discussion

      The results of the present study demonstrate that QTc interval, Tpe interval, and Tpe/QT ratio significantly increase at peak exercise in patients with stable CAD who complete normal treadmill exercise stress tests. It can therefore be assumed that despite the absence of inducible ischemia, the spatial dispersion of repolarization is increased during exercise, exposing these patients to increased arrhythmic risk. In contrast, subjects without history of CAD show decreases of Tpe interval at peak exercise, while the QTc interval and the Tpe/QT ratio remain unchanged.
      A recent study performed in 19 healthy young volunteers showed that the QT interval shortens from the first to the last minute of exercise, while the Tpe interval does not shorten with exercise, remaining unchanged. The investigators concluded that the dispersion of repolarization remains long, even after QT shortening, and therefore may contribute to the increased risk for SCD during and after exercise.
      • Kannankeril P.J.
      • Harris P.A.
      • Norris K.J.
      • Warsy I.
      • Smith P.D.
      • Roden D.M.
      Rate-independent QT shortening during exercise in healthy subjects: terminal repolarization does not shorten with exercise.
      No data on the Tpe/QT ratio were provided.
      The Tpe interval represents a novel index of arrhythmic risk. Regardless of the controversy over whether it is a marker of transmural or global dispersion of repolarization,
      • Gupta P.
      • Patel C.
      • Patel H.
      • Narayanaswamy S.
      • Malhotra B.
      • Green J.T.
      • Yan G.X.
      T(p-e)/QT ratio as an index of arrhythmogenesis.
      • Kors J.A.
      • Ritsema van Eck H.J.
      • van Herpen G.
      The meaning of the Tp-Te interval and its diagnostic value.
      • Antzelevitch C.
      • Sicouri S.
      • Di Diego J.M.
      • Burashnikov A.
      • Viskin S.
      • Shimizu W.
      • Yan G.X.
      • Kowey P.
      • Zhang L.
      Does Tpeak-Tend provide an index of transmural dispersion of repolarization?.
      it has been clearly associated with increased risk for malignant ventricular arrhythmias in a variety of conditions, including long-QT syndrome (acquired and congenital), short-QT syndrome, Brugada syndrome, acute ST-segment elevation myocardial infarction, and hypertrophic cardiomyopathy.
      • Gupta P.
      • Patel C.
      • Patel H.
      • Narayanaswamy S.
      • Malhotra B.
      • Green J.T.
      • Yan G.X.
      T(p-e)/QT ratio as an index of arrhythmogenesis.
      • Yamaguchi M.
      • Shimizu M.
      • Ino H.
      • Terai H.
      • Uchiyama K.
      • Oe K.
      • Mabuchi T.
      • Konno T.
      • Kaneda T.
      • Mabuchi H.
      T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity.
      • Lubinski A.
      • Lewicka-Nowak E.
      • Kempa M.
      • Baczynska A.M.
      • Romanowska I.
      • Swiatecka G.
      New insight into repolarization abnormalities in patients with congenital long QT syndrome: the increased transmural dispersion of repolarization.
      • Topilski I.
      • Rogowski O.
      • Rosso R.
      • Justo D.
      • Copperman Y.
      • Glikson M.
      • Belhassen B.
      • Hochenberg M.
      • Viskin S.
      The morphology of the QT interval predicts Torsade de Pointes during acquired bradyarrhythmias.
      • Watanabe N.
      • Kobayashi Y.
      • Tanno K.
      • Miyoshi F.
      • Asano T.
      • Kawamura M.
      • Mikami Y.
      • Adachi T.
      • Ryu S.
      • Miyata A.
      • Katagiri T.
      Transmural dispersion of repolarization and ventricular tachyarrhythmias.
      • Castro Hevia J.
      • Antzelevitch C.
      • Tornés Bárzaga F.
      • Dorantes Sánchez M.
      • Dorticós Balea F.
      • Zayas Molina R.
      • Quiñones Pérez M.A.
      • Fayad Rodríguez Y.
      Tpeak-Tend and Tpeak-Tend dispersion as risk factors for ventricular tachycardia/ventricular fibrillation in patients with the Brugada syndrome.
      • Haarmark C.
      • Hansen P.R.
      • Vedel-Larsen E.
      • Pedersen S.H.
      • Graff C.
      • Andersen M.P.
      • Toft E.
      • Wang F.
      • Struijk J.J.
      • Kanters J.K.
      The prognostic value of the Tpeak-Tend interval in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.
      • Shimizu M.
      • Ino H.
      • Okeie K.
      • Yamaguchi M.
      • Nagata M.
      • Hayashi K.
      • Itoh H.
      • Iwaki T.
      • Oe K.
      • Konno T.
      • Mabuchi H.
      T-peak to T-end interval may be a better predictor of high-risk patients with hypertrophic cardiomyopathy associated with a cardiac troponin I mutation than QT dispersion.
      • Letsas K.P.
      • Weber R.
      • Astheimer K.
      • Kalusche D.
      • Arentz T.
      Tpeak-Tend interval and Tpeak-Tend/QT ratio as markers of ventricular tachycardia inducibility in subjects with Brugada ECG phenotype.
      The spatial dispersion of repolarization reflects the heterogeneity of repolarization, which creates voltage gradients and thus promotes ventricular arrhythmias. The Tpe interval represents a promising marker of total dispersion of ventricular repolarization (transmural, apicobasal, or global).
      • Gupta P.
      • Patel C.
      • Patel H.
      • Narayanaswamy S.
      • Malhotra B.
      • Green J.T.
      • Yan G.X.
      T(p-e)/QT ratio as an index of arrhythmogenesis.
      However, the Tpe/QT ratio appears to be a more sensitive arrhythmogenic index, because it remains constant despite changes in the heart rate (dynamic changes in the Tpe and QT intervals occur in a proportional and parallel fashion).
      • Gupta P.
      • Patel C.
      • Patel H.
      • Narayanaswamy S.
      • Malhotra B.
      • Green J.T.
      • Yan G.X.
      T(p-e)/QT ratio as an index of arrhythmogenesis.
      • Yamaguchi M.
      • Shimizu M.
      • Ino H.
      • Terai H.
      • Uchiyama K.
      • Oe K.
      • Mabuchi T.
      • Konno T.
      • Kaneda T.
      • Mabuchi H.
      T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity.
      • Letsas K.P.
      • Weber R.
      • Astheimer K.
      • Kalusche D.
      • Arentz T.
      Tpeak-Tend interval and Tpeak-Tend/QT ratio as markers of ventricular tachycardia inducibility in subjects with Brugada ECG phenotype.
      The Tpe/QT ratio is increased in acute myocardial infarction, in long-QT and short-QT syndromes, and in patients with Brugada syndrome with inducibility of ventricular arrhythmias during programmed ventricular stimulation.
      • Gupta P.
      • Patel C.
      • Patel H.
      • Narayanaswamy S.
      • Malhotra B.
      • Green J.T.
      • Yan G.X.
      T(p-e)/QT ratio as an index of arrhythmogenesis.
      • Letsas K.P.
      • Weber R.
      • Astheimer K.
      • Kalusche D.
      • Arentz T.
      Tpeak-Tend interval and Tpeak-Tend/QT ratio as markers of ventricular tachycardia inducibility in subjects with Brugada ECG phenotype.
      Taking into account the aforementioned considerations, we focused on the measurement of the novel indexes Tpe interval and Tpe/QT ratio to investigate the effects of exercise on the dispersion of ventricular repolarization in patients with stable CAD. We did not measure the older index QTc dispersion, because accumulated evidence substantiates the theory that it actually represents the dispersion of ventricular repolarization.
      • Rautaharju P.M.
      A farewell to QT dispersion Are the alternatives any better?.
      Exercise represents a well-known triggering factor of ventricular arrhythmias in patients with CAD, mainly because of the increase in sympathetic activity and release of catecholamines.
      • Corrado D.
      • Migliore F.
      • Basso C.
      • Thiene G.
      Exercise and the risk of sudden cardiac death.
      Furthermore, changes in repolarization may have a specific role in this setting. In fact, instability in repolarization during exercise is a manifestation of arrhythmic vulnerability in high-risk subjects.
      • Haigney M.C.
      • Kop W.J.
      • Alam S.
      • Krantz D.S.
      • Karasik P.
      • DelNegro A.A.
      • Gottdiener J.S.
      QT variability during rest and exercise in patients with implantable cardioverter defibrillators and healthy controls.
      Even in healthy subjects, the terminal repolarization (Tpe), a surrogate marker of dispersion of repolarization, does not shorten with exercise, perhaps contributing to the increased risk for SCD during exercise.
      • Kannankeril P.J.
      • Harris P.A.
      • Norris K.J.
      • Warsy I.
      • Smith P.D.
      • Roden D.M.
      Rate-independent QT shortening during exercise in healthy subjects: terminal repolarization does not shorten with exercise.
      In our study, we showed for the first time that this phenomenon is exaggerated in patients with CAD.
      Some limitations are apparent. First, we must acknowledge that this was a small study, and there was a predominance of men in our population. Second, half of our patients had histories of myocardial infarction (ST-segment elevation or non-ST segment elevation). Previous myocardial infarction is a well-known marker of arrhythmic risk. Also, our patients had moderately depressed left ventricular ejection fractions. Subgroup analyses were not feasible, because of the small number of patients. Thus, our results cannot be extrapolated in patients with CAD and no previous myocardial infarctions or in patients with preserved left ventricular systolic function. Third, we did not evaluate the potential prognostic role of the exercise-induced changes of the repolarization indexes with respect to future untoward events.

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