Heart Rate Acceleration and Recovery Indices are Not Related to the Development of Ventricular Premature Beats During Exercise Test

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1 Original Article Acta Cardiol Sin 2014;30: Electrophysiology & Arrhythmia Heart Rate Acceleration and Recovery Indices are Not Related to the Development of Ventricular Premature Beats During Exercise Test Zafer Buyukterzi, Ozcan Ozeke, Mehmet Fatih Ozlu, Aytun Canga, Ozgul Malcok Gurel, Tumer Erdem Guler, Veli Kaya, F1rat Ozcan, Serkan Cay, Serkan Topaloglu and Dursun Aras Background: Changes in heart rate (HR) during exercise and recovery from exercise are mediated by the balance between sympathetic and vagal activity. HR acceleration (HRA) and recovery (HRR) are important measures of cardiac autonomic dysfunction and directly correlated with sympathetic and parasympathetic activity. It is not known if the autonomic nervous system related to ventricular arrhythmias during exercise. The purpose was to evaluate the HRA and HRR in patients with and without premature ventricular complex (PVC) during exercise, and to examine the factors that might affect HRA and HRR. Methods: The records of consecutive patients undergoing routine exercise test were reviewed. The characteristics and the HRA and HRR were compared between patients with and without PVC during exercise. Results: A total of 232 patients (145 men) were recruited; 156 (103 men) developed PVCs during the exercise. Max HR was significantly lower in men with PVCs than in those without, which were not mirrored in women. There was no difference in HRA and HRR between the patients with and without exercise-induced PVCs in both genders. Compared to the men with PVCs, women had higher body mass index, shorter total exercise time, and higher HRA indices after the 3 and 6 minutes exercise. In patients with PVCs, the HRA and HRR indices were similar regardless of the presence of coronary artery disease and the phase of exercise test where PVC developed. Conclusions: Although exercise performance may be different between the genders, the HRA or HRR indices were not related to the development of PVC during exercise in both genders. Key Words: Exercise-induced arrhythmias Heart rate acceleration Heart rate recovery INTRODUCTION Ventricular arrhythmias are a common finding during clinical exercise stress testing (EST). 1 Exercise-induced premature ventricular contractions (PVC) may be found in up to 30% of healthy subjects, in 60% of those Received: March 3, 2013 Accepted: June 7, 2013 Turkiye Yuksek Ihtisas Training and Research Hospital, Department of Cardiology, Ankara, Turkey. Address correspondence and reprint requests to: Dr. Ozcan Ozeke, Turkiye Yuksek Ihtisas Hospital, Kardiyoloji Klinigi, Ankara, Turkiye. Tel: ; Fax: ; ozcanozeke@ gmail.com Any relationship with industry: No. with heart disease and in all patients who have experienced sustained ventricular tachycardia. 2,3 There is conflicting evidence about the relationship between exercise-induced PVCs and coronary artery disease (CAD) or to cardiovascular risk, and the prognostic significance of these ectopies is controversial. Recently, researches focused on the possible mechanisms of exercise-induced PVCs. The autonomic nervous system is suggested to play an important role in the genesis of ventricular arrhythmias, and cardiovascular autonomic dysfunction is associated with significantly increased cardiovascular mortality. 4 Heart rate (HR) responses in both the exercise and recovery phase of EST have been used as markers of 259 Acta Cardiol Sin 2014;30:

2 Zafer Buyukterzi et al. autonomic functions and shown to have prognostic values. 4-6 The rise in HR during exercise is considered to be due to the activation of the sympathetic nervous system and the simultaneous suppression of the parasympathetic nervous system. On the other hand, the fall in HR immediately after exercise is regarded to be a function of the parasympathetic reactivation together with sympathetic withdrawal. 1 It was suggested that alterations in the autonomic control of cardiac functions, characterized by augmented sympathetic and reduced vagal activity, may play a major role in cardiovascular mortality. 1 Both abnormally elevated HR responses at the onset of an EST 5 and impaired early 4 or late 6 heart rate recovery (HRR) responses have emerged as important predictors of survival. Moreover, attenuated vagal reactivation during recovery might be associated with ventricular ectopy that is not suppressed. 7 It is not known whether patient age, heart rate variability, turbulence or recovery, and other markers of autonomic tone would contribute to the development of ventricular arrhythmia during routine exercise test. In the present study, we evaluated heart rate acceleration (HRA) and HRR indices in patients with and without PVCs during exercise test and examined the potential factors that might affect HRA and HRR in these patients. METHOD We reviewed the records of consecutive patients undergoing routine clinical EST at our institutions for the presence or absence of pathologic arrhythmia during EST, and were diagnosed to have exercise-induced PVC(Group1).MembersofGroup1wereanalyzedand compared to those without exercise-induced PVC (Group 2). In the second step, Group 1 was divided into two groups: exercise-induced PVC in patients with and without CAD. Any CAD was defined as a > 50% luminal stenosis of the left main coronary artery or a > 70% stenosis of any other major epicardial coronary artery or major branch. In the third step, Group 1 was divided into three subgroups: (a) patients with exercise-induced PVC during only exercise phase, (b) patients with exercise-induced PVC during only recovery phase and (c) patients with exercise-induced PVC during both phases. In all groups and subgroups, HRA and HRR indices were compared. Patients underwent EST using the Bruce protocol after withdrawal of any drugs that might have affected the EST. The predicted peak HR was calculated as (220- age),withanaimtoreachatleast85%oftheage-predicted HR. The electrocardiography (ECG) was continuously recorded during the EST. Qualified exercise physiologists collected physiologic and hemodynamic data during testing, including symptoms, HR, heart rhythm, blood pressure, and estimated functional capacity in metabolic equivalents. HRA indices were defined as the increase in the HR at the 3rd and 6th minutes to pretest HR (HRA 3 and HRA 6, respectively). Following peak exercise, patients walked for a 5-minute cool-down period at 1.5 mph at a 2.5% grade. The HRR indices were defined as the reduction in the HR from the HR at peak exercise to the HR at the first-, second, third and fifth minute after the cessation of EST. These results were expressed as HRR 1,HRR 2,HRR 3,andHRR 5,respectively. Patients with chronotropic incompetence during the EST 8 were excluded from the study, which was defined accordingly to the following criteria: (a) peak HR 85% of age-predicted peak HR and/or (b) failure to achieve 80% of HR reserve (HR reserve = age-predicted peak HR resting HR). The SPSS statistical software package (version 16.0; SPSS Inc, Chicago, IL, USA) was used to perform all statistical calculations. Continuous variables were expressed as mean SD. Categorical variables were expressed as numbers and percentages, and compared using the chi-squared test. Two group comparisons were performed using an unpaired t-test or nonparametric Mann-WhitneyUtestaccordingtonormalitytestresults,andan analysis of variance (ANOVA) test with Tukey s Honestly Significant Difference (HSD) post-hoc test was used for comparison of three groups. A p-value less than 0.05 was defined as statistically significant. RESULTS The medical records of 232 patients (including 87 females and 145 males) undergoing exercise test were reviewed. Among them, 156 patients (including 53 females and 103 males) developed PVCs during the exer- Acta Cardiol Sin 2014;30:

3 Heart Rate Recovery Indices in Exercise-Induced PVC cise test. The maximal HR was significantly lower in male patients, with bpm, than in those without PVCs during exercise ( bpm, p = 0.01), which was not seen in female patients. However, there were no differences in baseline characteristics, other parameters of exercise test, and both HRA and HRR between the two groups (Table 1). The characteristics and the exercise test performance of the patients with PVCs during exercise-based test are further shown by gender in Table 2. For PVCs patients, the BMI was greater, the total exercise time was significantly shorter, and both HRA indices after the 3rd and 6th minutes of the exercise period were significantly higher in females than in males. However, there was not any difference with regard to HRR indices between the genders. Table 3 showed the comparison of the results of exercise testing indices in PVC patients with and without CAD. For male PVC patients, both the maximal HR and achieved age-predicted HR during exercise were significantlylowerinthosewithcadthaninthosewithout CAD. There was no difference in other parameters including the HRA and HRR indices in male patients. There was also no difference in all the parameters in female PVC patients with and without CAD. Table 4 showed the comparison of exercise testing indices with regard to the phase of exercise test where PVC occurred. In female patients, the HRA indices after the 6th minute of the exercise period was significantly higher when PVCs developed during the recovery phase than those during exercise phase or during both phases. There was no difference in other parameters during the Table 1. The comparison of the results of exercise testing indices in patients with and without EIPVC EIPVC (+) (n = 156) EIPVC (-) (n = 76) p value Female Patient number Age (year) BMI (kg/m2) Pretest HR (bpm) Maximal HR (bpm) Exercise time (min) Achieved age-predicted HR HRA3 (bpm) HRA6 (bpm) HRR1 (bpm) HRR2 (bpm) HRR3 (bpm) HRR5 (bpm) Male Patient number Age (year) BMI (kg/m2) Pretest HR (bpm) Maximal HR (bpm) Exercise time (min) Achieved age-predicted HR HRA3 (bpm) HRA6 (bpm) HRR1 (bpm) HRR2 (bpm) HRR3 (bpm) HRR5 (bpm) BMI, body mass index; bpm, beats per minute; EIPVC, exercise-induced premature ventricular complex; HR, heart rate; HRA, heart rate acceleration; HRR, heart rate recovery. 261 Acta Cardiol Sin 2014;30:

4 Zafer Buyukterzi et al. Table 2. The comparison of the results of exercise testing indices for both sexes EIPVC (+) Female (n = 53) Male (n = 103) p value Age (year) BMI (kg/m2) CAD (yes/no) 21/32 54/ Pretest HR (bpm) Maximal HR (bpm) Exercise time (min) <0.001< Achieved age-predicted HR EIPVC at only-recovery phase (%) EIPVC at only-exercise phase (%) EIPVC at both phase (%) HRA3 (bpm) < < HRA6 (bpm) < < HRR1 (bpm) HRR2 (bpm) HRR3 (bpm) HRR5 (bpm) BMI, body mass index; bpm, beats per minute; CAD, coronary artery disease; EIPVC, exercise-induced premature ventricular complex; HR, heart rate; HRA, heart rate acceleration; HRR, heart rate recovery. Table 3. The comparison of the results of exercise testing indices in EIPVC patients with and without CAD EIPVC(+) CAD (+) CAD (-) p value Female n=21 n=32 Age (year) BMI (kg/m2) Pretest HR (bpm) Maximal HR (bpm) Exercise time (min) Achieved age-predicted HR HRA3 (bpm) HRA6 (bpm) HRR1(bpm) HRR2 (bpm) HRR3 (bpm) HRR5 (bpm) Male n=54 n=49 Age (year) BMI (kg/m2) Pretest HR (bpm) Maximal HR (bpm) Exercise time (min) Achieved age-predicted HR HRA3 (bpm) HRA6 (bpm) HRR1 (bpm) HRR2 (bpm) HRR3 (bpm) HRR5 (bpm) BMI, body mass index; bpm, beats per minute; CAD, coronary artery disease; EIPVC, exercise-induced premature ventricular complex; HR, heart rate; HRA, heart rate acceleration; HRR, heart rate recovery. Acta Cardiol Sin 2014;30:

5 Heart Rate Recovery Indices in Exercise-Induced PVC Table 4. A comparison of the results of exercise testing indices with regard to phase of EIPVC occurred EIPVC (+) Only in exercise phase Only in recovery phase In both phases p value Female n=23 n=12 n=18 Age (year) BMI (kg/m2) Pretest HR (bpm) Maximal HR (bpm) Exercise time (min) Achieved age-predicted HR HRA3 (bpm) HRA6 (bpm) HRR1 (bpm) HRR2 (bpm) HRR3 (bpm) HRR5 (bpm) Male n=25 n=22 n=56 Age (year) BMI (kg/m2) Pretest HR ( bpm) Maximal HR (bpm) Exercise time (min) Achieved age-predicted HR HRA3 (bpm) HRA6 (bpm) HRR1 (bpm) HRR2 (bpm) HRR3 (bpm) HRR5 (bpm) BMI, body mass index; bpm, beats per minute; EIPVC, exercise-induced premature ventricular complex; HR, heart rate; HRA, heart rate acceleration; HRR, heart rate recovery. different phase in females and neither in any parameters during the difference phase in males. DISCUSSIONS Although it is well-known that the autonomic nervous system plays an important role in the genesis of ventricular arrhythmias, and there are numerous studies about HRA/HRR indices and cardiac mortality and arrhythmogenesis in the literature, 4 we did not detect any association between the HRA or HRR indices and the development of PVCs during exercise test in both genders. In the current study, max HR was significantly lower in male patients with PVCs than in those without, which was not seen in females. Compared to the male patients with PVCs, the female ones had higher body mass index, shorter total exercise time, and higher HRA indices after the 3rd and 6th minutes of the exercise period. However, there was no difference in HRA and HRR indices between the patients with and without exercise-induced PVC in both genders. Furthermore, in patients with PVCs, the HRA and HRR indices were similar, regardless of the presence or absence of coronary artery disease or the phase of exercise test where PVC developed (exercise phase, recovery phase, or both). Accordingly, the causes of the development of PVCs are still not known. Changes in heart rate during exercise and recovery from exercise are mediated by the balance between sympathetic and vagal activity. Parasympathetic reactivation is thought to be the underlying mechanism of HRR during recovery phase 9,10 and abnormalities in parasympathetic activation have been suggested as the link to arrhythmogenesis and mortality. 4 In the absence 263 Acta Cardiol Sin 2014;30:

6 Zafer Buyukterzi et al. of normal vagal reactivation, HRR is attenuated, with an associated increase in mortality Jouven et al. demonstrated that an HRR of < 25 beats/min after the first minute of exercise recovery was associated with an increased relative risk of 2.2 for sudden cardiac death as compared with a cohort that had > 40 beats/min drop. 15 Nishime et al. reported that when HRR decreases to less than 12 beats/min, risk of death increases markedly. 11 In fact, the mechanisms of adverse outcome associated with abnormal HRR are unclear, and a major challenge in the use of HRR in routine clinical exercise testing has been how best to characterize it. 12,13 One-minute HR recovery (HRR1) first emerged as an important predictor of survival more than a decade ago and is directly associated with parasympathetic activity. Dramatic physiologic changes occur during this time and HRR1 predominantly reflects early parasympathetic reactivation after exercise, with elevated HRR indicating greater parasympathetic reactivation. 4 Recently, there has been an increased focus on the prognostic significance of late HR recovery (HRR2 and HRR5), which is an index of persistent sympathetic tone and/or late vagal withdrawal immediately preceding sympathetic activation. 6 In fact, it has been shown that parasympathetic effects reach a peak approximately 2 minutes into recovery from exercise; sympathetic effects dissipate more slowly, with significant increases in plasma catecholamines and HR. 16 Whereas Imai et al. reported that the initial HRR within 30 s is mediated primarily by vagal reactivation, 10 Savin et al. suggested that sympathetic withdrawal contributes more to HRR soon after peak exercise cessation, with parasympathetic activation playing a greater role later in recovery at lower heart rates. 17 Kannankeril et al. 18 evaluatedheartratesin10healthysubjectsat maximal exercise and recovery under normal physiologic conditions as well as during selective parasympathetic blockade with atropine. These data indicated that parasympathetic effects persist during high-intensity exercise, and a large parasympathetic effect on the heart rate was noted in 1 min, increased until 4 min, and then remained stable until 10 min into the recovery period. In the present study, we did not detect any difference in early or late HRR indices between patients with and without exercise-induced PVC. The relative prognostic significance of exercise and recovery-period exercise-induced PVC also remains un- clear.whilesomehavefoundthatrecoveryexercise- induced PVC is more robustly associated with adverse prognosis than exercise period exercise-induced PVC, 7 other results suggest a different connection. 19 Dewey et al. reported that whereas exercise-induced PVCs were related to the HR increase with exercise, recovery PVCs were related to CAD and ST-segment depression. 20 They demonstrated that recovery-only exercise-induced PVCs also have prognostic significance that augments established risk factors, whereas exercise-only exercise-induced PVCs have limited prognostic significance. We could not detect HRA and HRR indices with regard to phase of occurrence of exercise-induced PVC in current study. Although an association between the occurrence of exercise-induced PVCs and CAD has been described, a consensus has not arisen regarding the relationship between exercise-induced PVC to CAD or to cardiovascular risk because of the conflicting results from the available studies There was not any difference in HRA and HRR indices in exercise-induced PVC patients with and without CAD in the present study. There were some limitations of the study. The main limitation of the present study was its retrospective design. Second, there was a relatively small sample size in the female group. Third, HRR was strongly dependent on the type of recovery protocol used (e.g., complete cessation of exercise or cool-down in recovery and its position such as supine, sitting, standing). 24 The first reports of HRR were based on patients who underwent an upright cool-down protocol with a slow walk during the first 2 minutes after exercise. A HRR value of 12 bpm at 1 minute was identified as a best-value cut point for upright position in recovery phase, and an abnormal HRR was defined as failure of the HR to fall by more than 12 beats during the first minute after exercise. 4,11 However, in patients undergoing different kinds of protocols, such as those undergoing stress echocardiography 14 or those sitting down after exercise, 12 HRR values tend to be higher. Thus, for patients undergoing stress echocardiography, an abnormal value of 18 bpm has been reported for supine position, 14 whereas in patients undergoing a more classic type of recovery protocol, the abnormal reported value has been < 22 bpm over 2 minutes of recovery for sitting position. 12,19 However, we could not use a specific cut-off point for HRR. Acta Cardiol Sin 2014;30:

7 Heart Rate Recovery Indices in Exercise-Induced PVC CONCLUSIONS In this study, while exercise performance may be different between the genders, the HRA or HRR indices were not related to the development of PVC during the exercise test in both genders. The presence of CAD and the exercise phase of PVC development did not modify the HRA or HRR indices in patients with PVC during exercise test. There is still no optimal risk stratification strategy for the development of PVC during exercise. Future experiments are required to clarify this issue. ACKNOWLEDGEMENT The abstract section of the current study has been already presented at the 29th Annual Congress of the Turkish Society of Cardiology [26-29 October 2013 Antalya-Turkey; 821]. REFERENCES 1. Beckerman J, Wu T, Jones S, Froelicher VF. Exercise test-induced arrhythmias. Prog Cardiovasc Dis 2005;47: Candinas RA, Podrid PJ. Evaluation of cardiac arrhythmias by exercise testing. Herz 1990;15: McHenry PL, Morris SN, Kavalier M, Jordan JW. Comparative study of exercise-induced ventricular arrhythmias in normal subjects and patients with documented coronary artery disease. Am J Cardiol 1976;37: Cole CR, Blackstone EH, Pashkow FJ, et al. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999;341: FalconeC,BuzziMP,KlersyC,SchwartzPJ.Rapidheartrateincrease at onset of exercise predicts adverse cardiac events in patients with coronary artery disease. Circulation 2005;112: Johnson NP, Goldberger JJ. Prognostic value of late heart rate recovery after treadmill exercise. A J Cardiol 2012;110: Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent ventricular ectopy after exercise as a predictor of death. Am J Cardiol 2003;348: Lauer MS, Francis GS, Okin PM, et al. Impaired chronotropic response to exercise stress testing as a predictor of mortality. JAMA 1999;281: Arai Y, Saul JP, Albrecht P, et al. Modulation of cardiac autonomic activity during and immediately after exercise. Am J Physiol 1989;256:H Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994;24: Nishime EO, Cole CR, Blackstone EH, et al. Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG. JAMA 2000;284: Shetler K, Marcus R, Froelicher VF, et al. Heart rate recovery: validation and methodologic issues. J Am Coll Cardiol 2001;38: Gibbons RJ. Abnormal heart-rate recovery after exercise. Lancet 2002;359: Watanabe J, Thamilarasan M, Blackstone EH, et al. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 2001;104: Jouven X, Empana JP, Schwartz PJ, et al. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 2005; 352: Wang NC, Chicos A, Banthia S, et al. Persistent sympathoexcitation long after submaximal exercise in subjects with and without coronary artery disease. Am J Physiol Heart Cric Physiol 2011;301:H Savin WM, Davidson DM, Haskell WL. Autonomic contribution to heart rate recovery from exercise in humans. J Appl Physiol Respir Environ Exerc Physiol 1982;53: Kannankeril PJ, Le FK, Kadish AH, Goldberger JJ. Parasympathetic effects on heart rate recovery after exercise. J Investig Med 2004;52: Morshedi-Meibodi A, Evans JC, Levy D, et al. Clinical correlates and prognostic significance of exercise-induced ventricular premature beats in the community: the Framingham Heart Study. Circulation 2004;109: Dewey FE, Kapoor JR, Williams RS, et al. Ventricular arrhythmias during clinical treadmill testing and prognosis. Arch Intern Med 2008;168: Sami M, Chaitman B, Fisher L, et al. Significance of exerciseinduced ventricular arrhythmia in stable coronary artery disease: a coronary artery surgery study project. Am J Cardiol 1984;54: Elhendy A, Chandrasekaran K, Gersh BJ, et al. Functional and prognostic significance of exercise-induced ventricular arrhythmias in patients with suspected coronary artery disease. Am J Cardiol 2002;90: Marieb MA, Beller GA, Gibson RS, et al. Clinical relevance of exercise-induced ventricular arrhythmias in suspected coronary artery disease. Am J Cardiol 1990;66: Kligfield P, Lauer MS. Exercise electrocardiogram testing: beyond the ST segment. Circulation 2006;114: Acta Cardiol Sin 2014;30: