Heart Rate Variability During Exercise 1 Journal of Exercise Physiologyonline (JEPonline) Volume 10 Number 4 August 2007 Managing Editor Fitness and Training Tommy Boone, Ph.D. Editor-in-Chief Jon Linderman, Ph.D. EFFECTS OF HIGH-INTENSITY INTERVAL TRAINING ON Review Board HEART RATE VARIABILITY DURING EXERCISE Todd Astorino, Ph.D. Julien Baker, Ph.D. Lance Dalleck, Ph.D. LENISE FRONCHETTI1,2, FÁBIO Y. NAKAMURA2, FERNANDO R. DE- Dan Drury, DPE. OLIVEIRA1,3, ADRIANO E. LIMA-SILVA1,5, JORGE R. P. DE LIMA4. 1 Hermann Engels, Ph.D. Laboratory of Morphological and Functional Research – University of Santa Eric Goulet, Ph.D. Robert Gotshall, Ph.D. Catarina State, Florianópolis, Brazil. 2 Len Kravitz, Ph.D. Group of Studies on Physiological Adaptations to the Training – Londrina James Laskin, Ph.D. State University, Londrina, Brazil. 3 Jon Linderman, Ph.D. Nucleus of Studies of Human Movement – Federal University of Lavras, M. Knight-Maloney, Ph.D. Lavras, Brazil. Derek Marks, Ph.D. 4 Cristine Mermier, Ph.D. Laboratory of Motor Assessment, Federal University of Juiz de Fora, Juiz de Daryl Parker, Ph.D. Fora, Brazil. 5 Robert Robergs, Ph.D. Laboratory of Multidisciplinar Measurement – Bom Jesus/IELUSC, Brazil. Brent Ruby, Ph.D. Jason Siegler, Ph.D. Greg Tardie, Ph.D. ABSTRACT Lesley White, Ph.D. Chantal Vella, Ph.D. Fronchetti L, Nakamura FY, De-Oliveira FR, Lima-Silva AE, Lima Thomas Walker, Ph.D. Ben Zhou, Ph.D. JRP. Effects of high-intensity interval training on heart rate variability during exercise. JEPonline 2007; 10(4): 1-9. Heart rate variability (HRV), as indicated by SD1, decreases gradually during progressive Official Research Journal incremental exercise, and presents a saturation point at ~3 ms (HRV of The American Society of Exercise Physiologists threshold). The objective of this study was to assess the effects of high- (ASEP) intensity interval training on HRV threshold and HR-work rate curve during progressive incremental exercise. Twenty subjects were ISSN 1097-9751 randomly assigned to two groups: training (T) and control (C). They underwent a progressive incremental test until exhaustion before and after experimental periods. The T group performed nine sessions of high intensity interval training on a cycle ergometer during 3-weeks (1-min at 130% of maximal aerobic work rate with 1-min rest intervals until volitional exhaustion). HRV was determined using the plot method of Poincaré. High intensity training induced an increase of HRV threshold in the T group (from 95.30 ± 21.9 to 130.0 ± 31.7 W, p ≤ 0.05), but had no effect in the C group. Submaximal HR decreased significantly in T group but did not decrease in the C group. We concluded that 3-weeks of high intensity training induced an increase of HRV threshold and a decrease of submaximal HR. These alterations may be due to the delay of parasympathetic withdrawal during incremental exercise. Key Words: Cardiac Autonomic Modulation, Heart Rate Variability Threshold, Training Heart Rate Variability During Exercise 2 INTRODUCTION It is widely recognized that exercise training induces acute and chronic adaptations in heart rate (HR), but the exact mechanisms that mediate these changes are not clear (1,2,3,4). It is hypothesized that training can affect autonomic regulation causing reduction in the sympathetic nerve activity and increase in the parasympathetic outflow (5, 6). Previous studies have shown that the autonomic modulation of HR can be studied by non-invasive methods utilizing heart rate variability (HRV) (7, 8, 9, 10, 11, 12). The HRV is associated with sympathovagal balance and it can be a practical and accurate method to assess the effects of acute exercise and training on the autonomic modulation of HR (6, 13). It is derived from analysis of consecutive beat-to-beat oscilations of sinus rhythm in time or frequency domains, which are mainly mediated by the autonomic nervous system branches’ activities. However, other neural, humoral, and metabolic factors might also induce changes on HR and on HRV parameters. Tulppo et al. (14) reported that HRV decreases exponentially during progressive exercise and there is almost complete removal of parasympathetic modulation at ~ 50-60% of VO2max. In our laboratory, studies demonstrated that HRV-work rate curve presents a saturation point that occurs at ~ 3 ms. We have named this point as “HRV threshold”. It was not significantly different from lactate threshold and these indices were highly correlated (15, 16). It can be speculated that HRV threshold represents the transition from parasympathetic to sympathetic domain of HR modulation during progressive protocols. Another study investigated the effects of aerobic training on HRV response during a progressive cycle ergometer test (17). The training involved cycling during 30 min at 50% of the difference between peak work rate during the progressive test and HRV threshold. The sessions were performed three times per week throughout three weeks. The results showed that moderate-intensity training caused an increase in work rate at HRV threshold while no significant changes were observed in the control group. However, during progressive exercise test, the effects of high-intensity interval training on HRV response have not been established yet. Therefore, the purpose of this study was to investigate the effects of high-intensity interval training on HRV threshold and on HRV-work rate curve during progressive exercise. We have hypothesized that significant changes would occur in the autonomic cardiac control in response to this form of training and consequently, HRV-work rate curve during progressive exercise would be shifted to the upward and to the right directions, with concomitant reduction in heart rate in submaximal stages. METHODS Subjects Twenty healthy sedentary subjects from both genders (males = 11 and females = 9) took part in the investigation. All subjects signed an informed consent statement and they were not engaged in training programs for the previous six months. The subjects were advised to avoid any alcohol or caffeine ingestion and severe exercise 24 h before the tests. All procedures were reviewed and approved by the local Ethics Committee. Subsequently, subjects were randomly assigned into two groups: training (T) and control (C). The physical characteristics of both groups are presented in table1. Table 1. Subjects` characteristics (mean ± S.D). Group Age (yr) Height (cm) Weight (kg) T (n = 13) 20.4 ± 1.2 173.8 ± 7.7 68.5 ± 10.1 C (n = 7) 22.7 ± 3.1 165.6 ± 10.8 63.5 ± 14.6 Heart Rate Variability During Exercise 3 Procedures Progressive Test Prior to the training program and two to five days after the last training session, both groups performed a progressive test on a mechanical cycle ergometer (Monark®, Sweden). The subjects remained seated for 3-min on the cycle ergometer to allow for resting HR and HRV measurements. The test started with the subjects pedaling without resistance during 1-min, with increments of 90 kpm·min-1 (~ 14.6 W) every minute until volitional exhaustion. The subjects were instructed to maintain the pedal cadence at ~60 rpm, and all subjects were consistently encouraged throughout the session. High-Intensity Interval Training The subjects of T group performed nine sessions of high-intensity interval training during a period of three weeks. The sessions were performed three times per week, separated by at least one day of rest. The work rate of the cycle ergometer for the exercise training was set at 130% of the individual peak work rate obtained during a progressive test. The subjects cycled for 1-min interspersed with 1- min rest periods until volitional exhaustion. The training was designed to cause exhaustion within 5 and 10 bouts of exercise. Work load adjustments throughout the three weeks of training were necessary to maintain the target number of exercise bouts. All training sessions were performed on the same ergometer and the pedal cadence was kept at ~ 60 rpm. During the training period of T group, C group did not perform any systematic training and were asked to maintain their normal habits. Data Analyses HR and HRV were measured during all tests using a heart rate monitor (Polar Electro Oy, S810i). The data was downloaded to a computer and HRV of each stage was calculated by Poincaré plot analysis (Polar Precision Performance software). The instantaneous beat-to-beat variability of the data was derived from SD1 index. Details of SD1 analysis were described previously (14, 18). The SD1 index was plotted against work rate and the first intensity at which the SD1 index reached values equal to or lower than 3 ms was defined as the HRV threshold (15, 16). The mean HR of each stage was also calculated and plotted against work rate to estimate the HR at HRV threshold. The maximal work rate and maximal HR computed during the incremental tests were also compared in the pre- and post- training. Statistical Analyses The following results are presented as means ± SD. Data between pre- and post-training and T and C groups were compared using a two-way ANOVA followed by Scheffé post hoc test to identify the differences. Statistical significance was set at 5%. RESULTS The work rate utilized during training sessions was progressively increased from the first to the third weeks in order to maintain the total initial relative workload, but the differences were not significant (see methods). Values for average work rate performed during each week are presented in Table 2. Table 2. Work rate applied during the 3 weeks of training regimen (values are means, standard deviation, minimum and maximum). Week Mean ± SD Minimum Maximum first 251.5 ± 52.3 189.5 335.2 second 257.1 ± 50.0 189.5 335.2 third 263.1 ± 5165 189.5 349.8 Heart Rate Variability During Exercise 4 The mean HRV threshold, peak work rate, and maximal heart rate in the progressive test for both pre- and post-training are presented in Table 3. The work rate at post-training HRV threshold was significantly greater than the pre-training only in the T group (95.3 ± 21.9 W vs. 130.1 ± 31.7 W, p ≤ 0.05), whereas no significant differences were observed in C group. The values of post-training in the T group were significantly greater than the pre- and post-training values in the C group. Similar tendency was observed when HRV threshold was expressed in percentage of peak work rate. In contrast, the maximal work rate obtained in progressive test did not change in any groups. On the other hand, the T group started the program with greater peak work rate than the C group, and the difference persisted until the end of program (p ≤ 0.05). Table 3. HRV threshold and peak variables during the incremental test for pre- and post-training in both groups (values are means ± S.D). Training group (n=13) Control group (n=7) Pre Post Pre Post a,b,c HRV threshold (W) 95.3 ± 21.9 130.1 ± 31.7 85.4 ± 41.6 95.8 ± 43.6 a,b HRV threshold (%) 47.7 ± 9.5 61.6 ± 13.4 46.1 ± 17.1 59.2 ± 22.2 HRV threshold (bpm) 134 ± 9 139 ± 14 130 ± 18 136 ± 14 c b,c peak work rate (W) 201.8 ± 41.6 210.8 ± 32.4 179.1 ± 33.4 158.2 ± 24.4 peak heart rate (bpm) 189 ± 7 182 ± 13 182 ± 13 179 ± 17 HRV threshold (%) is HRV threshold expressed in percentage of maximal work rate. ª Significantly different from T b c pre-training (p ≤ 0.05); Significantly different from C pre-training (p ≤ 0.05); Significantly different from C post- training (p ≤ 0.05). Figure 1 shows that the point where SD1 index reached ≤ 3 ms (HRV threshold) was shifted to right in the T group but was not altered in the C group. In addition, the HR at submaximal stages was significantly reduced in the T group whereas no difference was found in the C group (figure 2). However, exercise training had no effect on the HR at HRV threshold or maximal HR during the incremental test (table 3). Figure 1. Mean heart rate variability (HRV) curve during incremental test in the pre- and post-training. The T group data are presented in the left panel and C group data in the right panel. The point where SD1 index reached 3 ms (HRV threshold) is indicated by narrows. Heart Rate Variability During Exercise 5 Figure 2. Mean heart rate (HR) curve during incremental test in the pre- and post training. The T group data are presented in the left panel and C group data in the right panel. DISCUSSION The present study has shown that the autonomic modulation during the incremental exercise was altered by high-intensity interval training. In addition, the work load at HRV threshold, which can indicate the transition from parasympathetic to sympathetic domain, was significantly greater after the training period. These findings can not be attributed to test familiarization because no significant changes were found in the control group. The effects of exercise training on HR have been demonstrated in the literature. Several studies have shown that aerobic training affects HR during rest and exercise, at least in part due to the changes in sympathetic and parasympathetic modulation (6, 19, 20, 21). It can be postulated that HRV is increased when HR is controlled predominantly by parasympathetic activity. On the other hand, when HR is controlled by sympathetic activity, the HRV decreases (22, 23, 24, 25). It may be hypothesized that parasympathetic withdrawal caused the progressive reduction observed in HRV until SD1 index reached ~ 3 ms. Thus, HRV threshold may indicate the removal of parasympathetic modulation; from this point the HR is mainly mediated by sympathetic activity. In the present study, the HRV values for submaximal stages were greater in the post-training than in pre-training for T group, which suggests that high-intensity interval training affects autonomic modulation and “delays” the sympathetic activation. A number of studies have also shown that aerobic training increases the work load of lactate and ventilatory thresholds. For example, Lucía et al. (26) found in well-trained cyclists that work load corresponding to lactate and ventilatory thresholds were significantly increased during prolonged training periods. Laursen et al. (27) also found effects of 4-weeks of high-intensity interval training on the ventilatory threshold. Based on the lactate and ventilatory threshold changes, it is reasonable to assume that similar changes may also occur on HRV threshold. It is speculated that in exercise performed above HRV threshold there is a disproportionate increase in plasma catecholamine concentrations. It would be associated with increased muscle glycogen breakdown and blood lactate production (28, 29). Heart Rate Variability During Exercise 6 The post-training HRV curve presented the HRV threshold shifted upward and to the right (T group: 95.3 ± 21.9 W vs. 130.1 ± 31.7 W, p ≤ 0.05), it is possible that high-intensity interval training can delay the catecholamine release, thereby blood lactate accumulation is postponed. However, the hypothesis must be tested in future. It is suggested in the literature that training significantly increases the HRV in the submaximal stages (5, 6, 11). For instance, Carter et al. (5) investigated the effects of 12-weeks of aerobic training on autonomic regulation. They found that HRV increased during rest and submaximal exercise while maximal HR was decreased. Hautala (11) showed that aerobic training at an intensity corresponding to 70–80% of maximal HR during 8-weeks also caused a significant increase on parasympathetic modulation during submaximal exercise. Indirect evidence of the effect of training status on the HRV during submaximal exercise was obtained by Tulppo et al. (6) who found an impairment of parasympathetic modulation (decrease on SD1 index) in individuals with poor aerobic fitness, (i.e., VO2max < 37 ml·kg-1·min-1), compared with groups with higher aerobic power. These results support the notion that HRV in the submaximal stages potentially increases with training and can shift to the right the point where SD1 index reach ≤ 3 ms. Therefore, this study showed that the cardiovascular autonomic modulation presented positive adaptations in response to a short-term training period with high intensity sessions. The heart rate adaptations induced by the training was probably affected by neural and functional changes (30, 31, 32, 33). It should be emphasized that maximal HR during the progressive test was not altered by training. These results are in disagreement with that found by Tulppo et al. (6), who demonstrated significant reduction of maximal HR following 8-weeks of training at 70-80% of maximal HR. The authors attributed these modifications to the increase on high frequency component (vagal activity) and decrease on low frequency component (sympathetic and parasympathetic tonus) of spectral analysis indices. However, in the present study, submaximal HR response in post-training were lower than in the pre-training and it can be linked to an increase of parasympathetic activity and/or a decrease of sympathetic activity. It is possible that 3-weeks of training had not been sufficient to decrease the maximal HR. Although submaximal HR has been reduced due to high-intensity interval training, no effect was observed on HR at HRV threshold. This result is supported by the findings of Lucía et al. (26) who found no alteration of the HR at lactate and ventilatory thresholds throughout the training periods, despite increased work load at threshold intensities. It is suggested, therefore, that HR at HRV threshold can be considered a non-modifiable parameter of training. It is not ruled out that morphological and functional changes could have also occurred and contributed to the HR reduction. It is well established that training induces adaptations of plasma volume (30, 31), stroke volume (32), and end-diastolic left ventricular diameter (33, 34). Yamamoto et al. (33) observed a significant reduction on HR at rest until the 28th day of training. It was associated with a significant increase of parasympathetic modulation whereas the changes of end-diastolic left ventricular diameter were observed only between the 28 th and 42th days of training. Laursen et al. (27) also demonstrated no changes in plasma volume with 4-weeks of high intensity interval training. These findings may suggest that high-intensity interval training provides a significant effect on autonomic modulation of HR in the initial phases of training, while morphological and functional changes entail a more marked effect into the latter phases. The maximal work load during the progressive test was not different between any of the trials and suggests that 3-weeks of high-intensity interval training have no effect on this variable. It is important to emphasize that HRV threshold, in the present study, was significantly increased only in the T group Heart Rate Variability During Exercise 7 when expressed in absolute and relative terms. These results suggest that high-intensity interval training applied for 3-weeks may exert effects primarily on submaximal variables, i.e. HRV threshold. Maximal work load change, therefore, would be probably detectable only during a more prolonged time of training. CONCLUSIONS In summary, the present study shows that 3-weeks of high-intensity interval training induces a significant increase on the work load at HRV threshold. Because HRV-work rate curve was shifted to the right and upward directions, it is suggested that 3-weeks of high-intensity interval training results in delay of parasympathetic withdrawal during progressive exercise. It has been suggested that enhanced parasympathetic activity may have a cardioprotective effect (6, 35), and exercise above the level of parasympathetic withdrawal may lead to an increased cardiac vulnerability (14). The present study supports the notion that high-intensity interval training can be utilized for both increased parasympathetic modulation of HR and can delay transition from the parasympathetic to the sympathetic domain. Thus, the HRV threshold is likely a parameter that can be applied to evaluate the aerobic capacity, specifically for training interventions. ACKNOWLEDGEMENTS The authors would like to thank the contributions of Cesar Adornato de Aguiar and Andreo Fernando Aguiar in the development of this research, and also the assistance of Dr. Gleber Pereira. Address for correspondence: Lenise Fronchetti, Laboratory of Morphological and Functional Research – University of Santa Catarina State. R. Pascoal Simone 358, Florianópolis, SC, 88080- 350. phone: (48) 3321 8641; Email: firstname.lastname@example.org REFERENCES 1. Wahlund J. Determination of physical working capacity. Acta Med Scand Suppl. 1948; 215:1-78. 2. Åstrand P-O, Saltin B. Maximal oxygen uptake and heart rate in various types of muscular activity. J Appl Physiol 1961; 16: 977-981. 3. Ekblom B, Astrand PO, Saltin B, Stenberg J, Wallstrom B. Effect of training on circulatory response to exercise. J Appl Physiol 1968; 24: 518-528. 4. Linnarson D. Dynamics of pulmonary gas exchange and heart rate changes at start and end of exercise. Acta Physiol Scand. 1974; 415: l-68. 5. Carter JB, Banister EW, Blader AP. The effect of age and gender on heart rate variability after endurance training. Med Sci Sport Exer 2003: 35 (8):1333 -1340. 6. Tulppo MP, Hautala AJ, Mäkikallio TH., Laukkanen RT, Nissilä S, Hughson RL, Huikuri HV. Effects of aerobic training on heart rate dynamics in sedentary subjects. J Appl Physiol 2003; 95: 364 – 372. 7. Malliani A, Pagani M, Lombardi F, Cerutti S. (1991) Cardiovascular neural regulation explored in the frequency domain. Circulation 1991; 84: 482-492. 8. Bootsma M, Swenne CA, Van Bolhuis HH, Chang PC, Cats VM, Bruschke AV. Heart rate and heart rate variability as indexes of sympathovagal balance. Am J Physiol (Heart Circ. Physiol.) 1994; 266: H1565-H1571. 9. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology: Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93: 1043 – 1065. 10. Stauss HM. Heart rate variability. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2003; 285: R927–R931. Heart Rate Variability During Exercise 8 11. Hautala A. Effect of physical exercise on autonomic regulation of heart rate. Academic Dissertation (Faculty of Medicine) - University of Oulu, Finland, 2004; 76p. 12. Fronchetti L, Nakamura FY, Aguiar CA, De-Oliveira FR. Indicadores de regulação autonômica cardíaca em repouso e durante exercício progressivo - Aplicação do limiar de variabilidade de freqüência cardíaca . Rev Port Cien Desporto 2006; 6 (1): 21 – 28. 13. Mourot L, Bouhaddi M, Perrey S, Rouillon JD, Regnard J. Quantitative Poincaré plot analysis of heart rate variability: effect of endurance training. Eur J Appl Physiol 2004; 91: 79–87. 14. Tulppo MP, Mäkikallio TH, Takala T, Seppänen T, Huikuri HV. Quantitative Beat-To-Beat Analysis Of Heart Rate Dynamics During Exercise. Am J Physiol 1996; 271: H244 – 252. 15. Lima, J.R.P. Heart rate in graded exercise: sigmoidal fit, inflection point and heart rate variability threshold. Doctoral Thesis, University of São Paulo, São Paulo. 1997; 1-129. (In Portuguese: English abstract). 16. Lima, J.R.P, Kiss, M.A.P.D. Heart variability threshold. Med Sci Sport Exer (Suppl.) 1998; 30: S250. 17. Nakamura FY, Aguiar CA, Fronchetti L, Aguiar AF, Perrout de Lima JR. Alteração do limiar de variabilidade da freqüência cardíaca após treinamento aeróbio de curto prazo. Motriz (UNESP) 2005; 11 (1):1-10. 18. Tulppo MP, Mäkikallio TH, Seppänen T, Laukkanen RT, Huikuri HV. Vagal modulation of heart rate during exercise: effects of age and physical fitness. Am J Physiol (Heart Circ. Physiol.) 1998; 274 (2): H424-H429. 19. Maciel BC, Gallo L, Marin Neto JA, Lima Filho EC, Martins LEB. Autonomic nervous control of the heart rate during dynamic exercise in normal man. Clin Sci 1986; 71: 457- 460. 20. Almeida MB, Araújo CGS. Effects of aerobic training on heart rate. Rev Bras Med Esporte 2003; 9 (2): 104 – 112. 21. Lee CM, Wood RH, Welsch MA. Influence of short-term endurance exercise training on heart rate variability. Med Sci Sport Exer 2003; 35 (6): 961-969. 22. Nakamura Y, Yamamoto Y, Muraoka I. Autonomic control of heart rate during physical exercise and fractal dimension of heart rate variability. J Appl Physiol 1993; 74 (2): 875 – 881. 23. Alonso DO, Forjaz CLM, Rezende LO, Braga AMFW, Barreto ACP, Negrão CE, Randon MUPB. Comportamento da freqüência cardíaca e da sua variabilidade durante as diferentes fases do exercício físico progressivo máximo. Arq Bras Cardiol 1998; 71 (6): 787 – 792. 24. Tulppo MP, Mäkikallio TH, Laukkanen RT, Huikuri HV. Differences in autonomic modulation of heart rate during arm and leg exercise. Clin Physiol 1999; 19 (4): 294 – 299. 25. Hautala AJ, Mäkikallio TH, Seppänen T, Huikuri HV, Tulppo MP. Short-term correlation properties of R-R interval dynamics at different exercise intensity levels. Clin Physiol Func Imaging 2003; 23 (4): 215-223. 26. Lucía A, Hoyos J, Pérez M, Chicharro JL. Heart rate and performance parameters in elite cyclists: a longitudinal study. Med Sci Sport Exer 2000; 32 (10): 1777- 1782. 27. Laursen PB, Shing CM, Peake JM, Coombes JS, Jenkins DG. Influence of high-intensity interval training on adaptations in well-trained cyclists. J Strength Cond Research 2005; 19 (3): 527-533. 28. Mazzeo RS, Marshal P. Influence of plasma catecholamines on the lactate threshold during graded exercise. J Appl Physiol 1989; 67: 1319 -1322. 29. Urhausen A, Weiler B, Coen B, Kindermann W. Plasma catecholamines during endurance exercise of different intensities as related to the individual anaerobic threshold. Eur J Appl Physiol 1994; 69: 16-20. 30. Roy BD, Green HJ, Grant SM, Tarnopolsky MA. Acute plasma volume expansion alters cardiovascular but not thermal function during moderate intensity prolonged exercise. Can J Physiol Pharmacol 2000; 78: 244-250. Heart Rate Variability During Exercise 9 31. Sawka MN, Convertino VA, Eichner ER, Schnieder SM, Young AJ. Blood volume: importance and adaptations to exercise training, environmental stresses, and traumas/sickness. Med Sci Sport Exer 2000; 32 (2): 332-348. 32. Mier CM, Turner MJ, Ehsani AA, Spina RJ. Cardiovascular adaptations to 10 days of cycle exercise. J Appl Physiol 1997; 83 (6): 1900 - 1906. 33. Yamamoto K, Miyachi M, Saitoh T, Yoshioka A, Onodera S. Effects of endurance training on resting and post-exercise cardiac autonomic control. Med Sci Sport Exer 2001; 33 (9):1496 – 1502. 34. Goodman JM, Peter PL, Howard JG. Left ventricular adaptations following short-term endurance training. J Appl Physiol 2005; 98: 454–460. 35. Hull SSJr, Vanoli E, Adamson PB, Verrier RL, Foreman RD, Schwartz PJ. Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia. Circulation 1994; 89: 548–552.