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doi:10.1152/japplphysiol.01328.2005 100:896-906, 2006. First published 1 December 2005;J Appl Physiol

George E. Billman and Monica Kukielkaregulationprotection is not due to enhanced cardiac vagalvariability and susceptibility to sudden cardiac death: Effects of endurance exercise training on heart rate

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Effects of endurance exercise training on heart rate variability andsusceptibility to sudden cardiac death: protection is not due to enhancedcardiac vagal regulation

George E. Billman and Monica KukielkaDepartment of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio

Submitted 19 October 2005; accepted in final form 23 November 2005

Billman, George E., and Monica Kukielka. Effects of enduranceexercise training on heart rate variability and susceptibility to suddencardiac death: protection is not due to enhanced cardiac vagal regu-lation. J Appl Physiol 100: 896–906, 2006. First published December1, 2005; doi:10.1152/japplphysiol.01328.2005.—Low heart rate vari-ability (HRV) is associated with an increased susceptibility to ven-tricular fibrillation (VF). Exercise training can increase HRV (anindex of cardiac vagal regulation) and could, thereby, decrease therisk for VF. To test this hypothesis, a 2-min coronary occlusion wasmade during the last min of a 18-min submaximal exercise test in dogswith healed myocardial infarctions; 20 had VF (susceptible), and 13did not (resistant). The dogs then received either a 10-wk exerciseprogram (susceptible, n � 9; resistant, n � 8) or an equivalentsedentary period (susceptible, n � 11; resistant, n � 5). HRV wasevaluated at rest, during exercise, and during a 2-min occlusion at restand before and after the 10-wk period. Pretraining, the occlusionprovoked significantly (P � 0.01) greater increases in HR (suscepti-ble, 54.9 � 8.3 vs. resistant, 25.0 � 6.1 beats/min) and greaterreductions in HRV (susceptible, �6.3 � 0.3 vs. resistant, �2.8 � 0.8ln ms2) in the susceptible dogs compared with the resistant animals.Similar response differences between susceptible and resistant dogswere noted during submaximal exercise. Training significantly re-duced the HR and HRV responses to the occlusion (HR, 17.9 � 11.5beats/min; HRV, �1.2 � 0.8, ln ms2) in the susceptible dogs; similarresponse reductions were noted during exercise. In contrast, thesevariables were not altered in the sedentary susceptible dogs. Posttrain-ing, VF could no longer be induced in the susceptible dogs, whereasfour sedentary susceptible dogs died during the 10-wk control period,and the remaining seven animals still had VF when tested. Atropinedecreased HRV but only induced VF in one of eight trained suscep-tible dogs. Thus exercise training increased cardiac vagal activity,which was not solely responsible for the training-induced VF protec-tion.

parasympathetic nervous system; ventricular fibrillation; myocardialischemia; myocardial infarction

REDUCTIONS IN CARDIAC PARASYMPATHETIC control have beenassociated with an increase risk for sudden death (44). Kleigerand coworkers (3, 28) found that the patients recovering frommyocardial infarctions with the smallest heart rate variability[HRV; a noninvasive index of cardiac parasympathetic regu-lation (6, 40, 47)] had the greatest risk of dying suddenly. Therelative risk of mortality was 5.3 times greater in patients withan R-R interval variability �50 ms compared with patientswith variability �100 ms. This initial observation has beenconfirmed in numerous clinical studies (1, 21). For example,the ATRAMI (Autonomic Tone and Reflexes After Myocardial

Infarction) group found that postmyocardial infarction patientswith either low HRV or reduced baroreflex sensitivity had amuch greater risk of sudden death than those with well-preserved cardiac vagal function (31).

Similar results have been obtained in animal studies. Ourlaboratory previously reported that HRV was much lower inanimals susceptible to ventricular fibrillation compared withanimals resistant to these malignant arrhythmias (7, 12, 18, 22).In particular, the susceptible animals exhibited a much greaterreduction (withdrawal) of vagal activity in response to eithersubmaximal exercise (7, 18, 22) or acute myocardial ischemia(12, 18, 22) than did the resistant dogs. In a similar manner,bilateral vagotomy (13) or the cholinergic antagonist atropineincreased arrhythmia formation (14), whereas cholinergic ago-nists or electrical stimulation of the vagus nerves increasedventricular fibrillation threshold, antagonized the effects ofsympathetic stimulation, and decreased the incidence of ven-tricular fibrillation (4, 27, 29, 48). These data demonstrate thatsubnormal cardiac parasympathetic regulation increases therisk for malignant arrhythmias, whereas interventions thatenhance cardiac vagal function can protect against ventricularfibrillation. However, to be an effective antiarrhythmic ther-apy, an intervention not only must increase baseline vagalactivity but also must maintain this enhanced activity when theheart is stressed, as during myocardial ischemia. Indeed, lowdoses of cholinergic antagonists paradoxically increased thebaseline cardiac vagal activity (30) but failed to maintain thisincrease in HRV when the heart was stressed by either sub-maximal exercise or a coronary artery occlusion (18). As aconsequence, this intervention proved to be ineffective in theprevention of lethal arrhythmias induced by acute myocardialischemia (18, 25).

It is well established that regular exercise can improvecardiac autonomic balance (increasing parasympathetic whiledecreasing sympathetic regulation of the heart) (5, 42). In bothhumans and animals, heart rate at submaximal workloads islower in trained individuals compared with sedentary controls(5, 42), while the presence of a resting bradycardia is fre-quently used to confirm that training has been effective (17, 34,45). Exercise training programs can increase HRV in patientsrecovering from myocardial infarction (32, 33, 35, 39) and mayreduce the incidence of sudden death and arrhythmias in bothhuman and animal models (8, 23, 32, 37, 38, 41). In a similarmanner, meta-analysis of 22 randomized trials of rehabilitationwith exercise after myocardial infarction found that exercise

Address for reprint requests and other correspondence: G. E. Billman, Dept.of Physiology and Cell Biology, The Ohio State Univ., 304 Hamilton Hall,1645 Neil Ave., Columbus, OH 43210-1218 (e-mail: [email protected]).

The costs of publication of this article were defrayed in part by the paymentof page charges. The article must therefore be hereby marked “advertisement”in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

J Appl Physiol 100: 896–906, 2006.First published December 1, 2005; doi:10.1152/japplphysiol.01328.2005.

8750-7587/06 $8.00 Copyright © 2006 the American Physiological Society http://www. jap.org896


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training elicited significant reductions in both reinfarction andthe incidence of sudden death (38). In animals, regular exerciseeither increased the electrical current necessary to induceventricular fibrillation (37, 41) or reduced the susceptibility toventricular fibrillation induced by myocardial ischemia (8, 24).However, the contributions of changes in cardiac autonomicbalance to the protection afforded by exercise training were notextensively examined in these studies and remain largely to bedetermined. Although exercise training has been shown toincrease baseline HRV in animals prone to lethal arrhythmias(24), the effects of this intervention on HRV when the heart isstressed (i.e., during exercise or coronary occlusion) remain tobe determined.

Therefore, it was the purpose of this study to investigate theeffects of exercise training on HRV and susceptibility toventricular fibrillation using a conscious canine model ofsudden death. Specifically, the hypothesis that exercise trainingwould increase HRV even during physiological stress (exerciseor acute ischemia) and, thereby, could prevent ventricularfibrillation induced by myocardial ischemia was tested.

The present study demonstrates that exercise training im-proves cardiac autonomic function such that cardiac vagalregulation is maintained even when the heart is stressed byeither exercise or acute myocardial ischemia in animals withhealed infarctions. Furthermore, exercise training completelysuppressed ventricular fibrillation induced by myocardial is-chemia. However, because atropine pretreatment did not rein-troduce lethal arrhythmias in these dogs, the exercise-inducedprotection from ventricular fibrillation did not result solelyfrom enhanced cardiac vagal regulation.

METHODS

The principles governing the care and use of animals as expressedby the Declaration of Helsinki, and as adopted by the AmericanPhysiological Society, were followed at all times during this study. Inaddition, the Ohio State University Institutional Animal Care and UseCommittee approved all the procedures used in this study.

Surgical preparation. Sixty heartworm-free mongrel dogs weigh-ing 15.4–24.5 kg (19.1 � 0.4 kg) were used in this study. The animalswere anesthetized and instrumented as previously described (7, 12, 18,22). Briefly, using strict aseptic procedures, a left thoracotomy wasmade in the fourth intercostal space. The heart was exposed andsupported by a pericardial cradle. The left circumflex coronary arterywas dissected free of the surrounding tissue. Both a 20-MHz pulsedDoppler flow transducer and a hydraulic occluder were then placedaround this vessel. Two pairs of silver-coated copper wires were alsosutured on the epicardial surface of the heart and used to obtain aventricular electrogram (from which heart rate and various indexes ofHRV were measured, see below). One pair of electrodes was placedin the potentially ischemic area (lateral left ventricular wall, an areaperfused by the left circumflex artery) and the other pair in anonischemic region (right ventricular outflow tract). A two-stageocclusion of the left anterior descending artery was then performedapproximately one-third the distance from its origin to produce ananterior wall myocardial infarction. This vessel was partially occludedfor 20 min and then tied off.

HRV protocols. The studies began 3–4 wk after the production ofthe myocardial infarction (see flow chart, Fig. 1). First, over the periodof 3–5 days, the dogs learned to run on a motor-driven treadmill. Thecardiac response to submaximal exercise was then evaluated asfollows: exercise lasted a total of 18 min with workload increasingevery 3 min. The protocol began with a 3-min warm-up period, duringwhich the dogs ran at 4.8 kilometers per hour (kph) at 0% grade. The

speed was then increased to 6.4 kph, and the grade increased every 3min (0, 4, 8, 12, and 16%). The submaximal exercise test was repeatedthree times (1/day). Before the third submaximal exercise test, acatheter was placed percutaneously in a cephalic vein to administerthe muscarinic antagonist, atropine sulfate (50 �g/kg), 3 min beforethe end of the exercise period. On a subsequent day, with the dogslying quietly unrestrained on a table, a 2-min left circumflex coronaryocclusion was made. At least 48 h after the completion of thesestudies, the animals were tested for susceptibility to ventricularfibrillation using an exercise plus ischemia test that is described in thefollowing section. Heart rate, left circumflex blood flow, and HRVwere monitored continuously throughout the exercise or occlusionstudies. These studies were repeated after the completion of the 10-wkexercise training or the 10-wk sedentary time period.

Exercise plus ischemia test: classification of the dogs. The suscep-tibility to ventricular fibrillation was tested as previously described (7,12, 18, 22) (Fig. 1). Briefly, the animals ran on a motor-driventreadmill while workload progressively increased until a heart rate of70% of maximum (�210 beats/min) had been achieved. During thelast minute of exercise, the left circumflex coronary artery wasoccluded, the treadmill stopped, and the occlusion maintained for anadditional minute (total occlusion time � 2 min). The exercise plusischemia test reliably induced ventricular flutter that rapidly deterio-rated into ventricular fibrillation. Therefore, large metal plates (11-cmdiameter) were placed across the animal’s chest so that electricaldefibrillation (Zoll M series defibrillator, Zoll Medical, Burlington,MA) could be achieved with a minimal delay but only after the animalwas unconscious (10–20 s after the onset of ventricular fibrillation).Of the 60 animals that underwent surgery, 21 animals could not betested due to either death within 72 h of the myocardial infarction(n � 14, 23.3%) or occluder failure (n � 7). Thus the exercise plusischemia test was performed on 39 of the original 60 animals. Theocclusion was immediately released if ventricular fibrillation oc-curred. Twenty-six dogs developed ventricular fibrillation (suscepti-ble), whereas the remaining 13 did not (resistant). Three susceptibleanimals were not successfully defibrillated and, as such, were notavailable for additional studies. This exercise plus ischemia test, using

Fig. 1. Flow chart illustrating the sequences of events in this study. Three tofour weeks after myocardial infarction, the dogs were classified as susceptibleor resistant to ventricular fibrillation (VF) with an exercise plus ischemia test.The animals were then randomly assigned to either 10-wk exercise (Ex)training program or a 10-wk sedentary period. The exercise plus ischemia testwas repeated at the end of the 10-wk period. n, No. of animals; defib,defibrillate.

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the same exercise intensity, was repeated after the completion of a10-wk exercise training or a 10-wk sedentary time period (see below).

Exercise training protocol. The susceptible (n � 23) and resistantdogs (n � 13) were randomly assigned to either a 10-wk exercisetraining period (susceptible, n � 9; resistant, n � 8) or an equivalentsedentary period (susceptible, n � 14; resistant, n � 5) (Fig. 1). Thedogs in the exercise training group ran on a motor-driven treadmill for10 wk, 5 days/wk, at �70–80% of maximum heart rate. The exerciseintensity and duration progressively increased as follows: 1st wk, 20min at 4.8 kph/0% grade; 2nd wk, 40 min at 5.6 kph/10% grade; 3rdwk, 40 min at 6.4 kph/10% grade; 4th wk, 60 min at 6.4 kph/10%grade; 5th wk, 60 min at 6.4 kph/12% grade; 6th wk, 75 min at 6.4kph/12% grade; 7th week, 90 min at 6.4 kph/12% grade; 8th to 10thwk, 90 min at 6.4 kph/14% grade. Each exercise session included5-min warm-up and 5-min cooldown periods (running at a lowintensity: 0% grade and speed of 4.8 kph). The dogs in the sedentarygroup were placed in transport cage for equivalent time periods butwithout exercise. All 17 animals (both the susceptible and resistantdogs) in the exercise group successfully completed the trainingprogram. Four dogs in the susceptible sedentary group died sponta-neously between the 6th and the 10th wk of the sedentary period andwere eliminated from the study. The exercise plus ischemia test couldnot be repeated in three of the sedentary susceptible animals due tofailure of the coronary artery occluder, and these animals were alsoeliminated from the study (Fig. 1). Finally, the exercise plus ischemiatest was repeated after the administration of the muscarinic antagonistatropine sulfate (50 �g/kg iv bolus 3 min before the occlusion) in theexercise-trained susceptible dogs (n � 8).

Citrate synthase assay. The effects of exercise on skeletal muscleoxidative capacity were evaluated by measuring citrate synthaseactivity in the diaphragm. After the completion of the 10-wk exercisetraining or 10-wk sedentary studies, the animals were anesthetized(pentobarbital sodium, 50 mg/kg iv; Abbott Laboratories, NorthChicago, IL). The heart was rapidly removed, and tissue samples werefrozen in liquid nitrogen and stored in a �80°C freezer. At the sametime, a small piece of the diaphragm was also placed in liquidnitrogen. The citrate synthase activity of this skeletal muscle wasassayed using the modified technique described by Srere (46). Theskeletal muscle was harvested at least 48 h after the last exercisesession.

Echocardiography studies. Left ventricular free wall thickness wasdetermined by echocardiography 3–4 wk after surgery (i.e., myocar-dial infarction) and at the end of the 10-wk exercise training or the10-wk sedentary period. These studies were performed before theanimals were classified by the exercise plus ischemia test. Briefly, thedogs were lightly sedated with acepromazine (0.5 mg/kg im; Ft.Dodge Animal Health, Ft. Dodge, IA) before the studies. A conven-tional M-mode echocardiogram was obtained using a Sonos 1000system (Hewlett-Packard, Palo Alto, CA) with a 5.5-MHz transducer.

Data analysis. All data are reported as means � SE. The data weredigitized (1 kHz) and recorded using a Biopac MP-100 data-acquisi-tion system (Biopac Systems, Goleta, CA). HRV was obtained usinga Delta-Biometrics vagal tone monitor triggering off the electrocar-diogram R-R interval (Urbana-Champaign, IL). This device employsthe time-series signal processing techniques as developed by Porges(40) to estimate the amplitude of respiratory sinus arrhythmia. Detailsof this analysis have been described previously (6). Data were aver-aged over 30-s intervals during either exercise or the coronary occlu-sion. The following three indexes of HRV were determined: vagaltone index, the high-frequency (0.24–1.04 Hz) component of R-Rinterval variability; R-R interval range, the difference between thelongest and shortest R-R interval for the same 30-s time period; andstandard deviation of the R-R intervals for the same 30-s time period.The heart rate response to the exercise plus ischemia test was aver-aged over the last 5 s before the occlusion and at the 60-s time point(or ventricular fibrillation onset) after occlusion onset.

The data were compared using ANOVA for repeated measures(NCSS statistical software, Kaysville, UT). For example, the effect ofexercise training on the HRV data (heart rate; vagal tone index, i.e.,0.24- to 1.04-Hz component of the R-R interval variability; SD of R-Rinterval; and R-R interval range) were analyzed using a three-wayANOVA [group (2 levels) � pretraining � posttraining (2 levels) �exercise level (7 levels), or occlusion time (6 levels)] with repeatedmeasures on two factors (pretraining � posttraining and exerciselevel, or occlusion time). Comparisons between the susceptible andresistant dogs were made using a two factor (group � exercise level,or occlusion time) ANOVA with repeated measures on one factor(exercise level or occlusion time). A similar two-factor (group �pretraining � posttraining) ANOVA with repeated measures on onefactor (pretraining-posttraining) was used to evaluate the effects of theinterventions on left ventricular systolic wall thickness. Becauserepeated-measures ANOVA depends on the homogeneity of covari-ance, this sphericity assumption (i.e., the assumption that the varianceof the difference scores in a within-subject design are equal across thegroups) was tested using Mauchley’s test (23). If the sphericityassumption was violated, then the F-ratio was corrected using Huynh-Feldt correction (23). If the F-ratio was found to exceed a criticalvalue (P � 0.05), then the difference between the means was deter-mined using Scheffe’s test. The effect of exercise training on theincidence of ventricular fibrillation was evaluated using Fisher’s exacttest. Finally, citrate synthase activity data (exercise trained vs. seden-tary) were evaluated using Student’s t-test.

RESULTS

Confirmation of exercise training. There was no significantdifference in body weight between the sedentary and trainedanimals for either the resistant (trained, 20.4 � 1.1; sedentary,19.6 � 1.8 kg) or the susceptible (trained, 20.0 � 0.6; seden-tary, 19.8 � 0.8 kg) dogs. However, left ventricular systolicwall thickness was significantly larger (P � 0.025) in bothsusceptible (pretraining, 10.0 � 0.6 vs. posttraining, 11.1 �0.4 mm; wall thickness increased by 10.1 � 4%) and resistant(pretraining, 8.8 � 0.5 vs. posttraining, 9.4 � 0.5 mm; wallthickness increased by 8.0 � 2.6%) animals after training butwas unchanged in the sedentary dogs (susceptible pretrainingsedentary 9.8 � 0.4; posttraining sedentary 9.6 � 0.3 vs.resistant pretraining sedentary 10.1 � 0.7; posttraining seden-tary 10.7 � 0.4 mm), indicating that the training had produceda small ventricular hypertrophy. In the susceptible dogs, exer-cise training provoked significant (P � 0.0025) reductions inthe peak heart rate response to exercise (pretraining 209.0 �7.4 vs. posttraining 184.4 � 5.3 beats/min) that were accom-panied by significant increases in R-R interval variability (e.g.,vagal tone index, P � 0.04; pretraining 1.0 � 0.3 vs. post-training 2.4 � 0.3 ln ms2), whereas these variables did notchange in the sedentary animals (peak exercise response: HR,pretraining sedentary 209.4 � 6.0 vs. posttraining sedentary211 � 5.3 beats/min; vagal tone index pretraining sedentary1.2 � 0.1 vs. posttraining sedentary 1.5 � 0.3). Similar butsmaller changes were noted for the exercise trained resistantdogs (peak exercise response: HR, pretraining 200.2 � 3.4 vs.posttraining 178.4 � 7.4 beats/min; vagal tone index, pretrain-ing 2.4 � 0.3 vs. posttraining 2.8 � 0.4 ln ms2). Finally, citratesynthase activity was significantly (P � 0.02) higher in skeletalmuscle obtained from exercise-trained (n � 10, 11.6 � 1.0�mol �ml�1 �min�1) compared with sedentary (n � 10, 7.5 �1.4 �mol �ml�1 �min�1) dogs. Because there were no differ-ences between resistant and susceptible dogs, these data werepooled for the analysis. These data confirm the exercise train-

898 EXERCISE TRAINING IMPROVES CARDIAC VAGAL REGULATION



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ing program was effective; that is, there was a significantskeletal muscle and cardiac adaptation induced by the trainingprogram.

Pretraining HRV responses. The heart rate and HRV re-sponses to submaximal exercise before training are displayedin Fig. 2. Submaximal exercise elicited significant (both P �0.001) increases in heart rate for both the susceptible and theresistant dogs. Furthermore, the heart rate increase was signif-icantly (group � exercise level, P � 0.01) greater in thesusceptible dogs (peak heart rate change from preexercisevalues, susceptible 91.8 � 2.0 vs. resistant 84.8 � 3.1 beats/min) compared with the resistant dogs. The exercise-inducedincreases in heart rate were accompanied by significant (all,P � 0.001) reductions in all three markers of HRV (vagal toneindex, i.e., 0.24- to 1.04-Hz component of the R-R intervalvariability; SD of R-R interval; and R-R interval range).Greater reductions (group � exercise level, P � 0.001) wereagain noted in the susceptible animals compared with theresistant dogs (Fig. 2).

The contribution of cardiac parasympathetic regulation tothe HRV response to submaximal exercise was also evaluatedby the intravenous injection of atropine during the last exerciselevel. Atropine provoked larger increases (P � 0.01) in heartrate (resistant, 28.2 � 3.6 vs. susceptible, 17.9 � 2.8 beats/min), and reductions in the HRV indexes (e.g., vagal toneindex: resistant, �2.1 � 0.2 vs. susceptible �1.1 � 0.3 ln ms2)in the resistant animals compared with the susceptible dogs. Infact, heart rate and HRV were no longer different betweengroups after the atropine treatment.

The heart rate and HRV responses to the coronary occlusionat rest before training are displayed in Fig. 3. The coronaryartery occlusion elicited significantly (group � occlusion time,P � 0.001) larger increases in heart rate in the susceptible

compared with the resistant dogs. The coronary occlusioninduced increases in heart rate were accompanied by largerreductions (group � occlusion time, P � 0.001) in all threeHRV indexes (vagal tone index, i.e., 0.24- to 1.04-Hz compo-nent of the R-R interval variability; SD of R-R interval; andR-R interval range) in the susceptible animals compared withthe resistant dogs.

Posttraining HRV responses. The heart rate and HRV re-sponses to submaximal exercise for the susceptible dogs afterthe 10-wk training or 10-wk sedentary period are displayed inFig. 4. Submaximal exercise elicited significant increases inheart rate (P � 0.001) for both the sedentary and trainedsusceptible dogs. However, the heart rate increase was signif-icantly (group � exercise, P � 0.001) greater in the sedentarydogs compared with the exercise-trained animals. The exer-cise-induced increases in heart rate were also accompanied bysignificant (all P � 0.001) reductions in all three markers ofHRV (vagal tone index, i.e., 0.24- to 1.04-Hz component of theR-R interval variability; SD of R-R interval; and R-R intervalrange). Once again, greater reductions (group � exercise, P �0.01) were noted in the sedentary animals compared with theexercise-trained dogs (Fig. 4). Similar, but smaller, differenceswere noted between the sedentary and trained resistant dogs(data not shown). After exercise training, the susceptible andresistant dogs exhibited similar heart rate and HRV responsesto exercise; that is, no statistically significant differences werenoted when comparing these animals (Fig. 5).

The contribution of cardiac parasympathetic regulation tothe HRV responses to submaximal exercise was also evaluatedafter either the 10-wk exercise training or 10-wk sedentarytime period by the intravenous injection of atropine during thelast exercise level. Atropine injection elicited larger increases(P � 0.01) in heart rate and greater reductions (P � 0.01) in

Fig. 2. Heart rate and heart rate variability responses tosubmaximal exercise in animals susceptible or resistant toventricular fibrillation. Exercise elicited significantlygreater increases in heart rate that were accompanied bygreater reductions in the various indexes of cardiac vagalregulation in the susceptible animals compared with theresistant dogs. Exercise levels: 1 � 0 kilometers per hour(kph)/0% grade, 2 � 4.8 kph/0% grade, 3 � 6.4 kph/0%grade, 4 � 6.4 kph/4% grade, 5 � 6.4 kph/8% grade, 6 �6.4 kph/12% grade, 7 � 6.4 kph/16% grade. Values aremeans � SE. *P � 0.01 susceptible vs. resistant.




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HRV in the susceptible trained (heart rate, 36.8 � 3.2 beats/min; vagal tone index �2.3 � 0.3 ln ms2) compared with thesusceptible sedentary dogs (heart rate, 23.7 � 5.4 beats/min;vagal tone index, �1.1 � 0.5 ln ms2).

The heart rate and HRV responses to the coronary occlusionat rest after either the 10-wk exercise training or 10-wksedentary period are displayed in Fig. 6. The coronary arteryocclusion elicited significantly (group � occlusion time, P �

Fig. 3. Heart rate and heart rate variability responses to a2-min coronary occlusion in animals susceptible or resistantto ventricular fibrillation. The coronary occlusion elicitedmuch larger increases in heart rate that were accompaniedby greater reductions in the various indexes of cardiac vagalregulation in the susceptible animals compared with theresistant dogs. Pre, last 30 s before the coronary occlusion;Post, 1 min after coronary occlusion release (i.e., averageover 30–60 s post release). Values are means � SE. P �0.01 susceptible vs. resistant.

Fig. 4. Effect of the 10-wk exercise training or 10-wksedentary period on the heart rate and the heart rate vari-ability responses to submaximal exercise in animals sus-ceptible to ventricular fibrillation. Exercise elicited signifi-cantly smaller increase in heart rate and smaller reductionsin the various indexes of cardiac vagal activity in theexercise-trained dogs compared with animals that receiveda similar sedentary period. The posttraining response in thesusceptible exercise-trained dogs was no longer differentfrom that noted for the resistant (exercise trained or seden-tary) dogs. Exercise levels: 1 � 0 kph/0% grade, 2 � 4.8kph/0% grade, 3 � 6.4 kph/0% grade, 4 � 6.4 kph/4%grade, 5 � 6.4 kph/8% grade, 6 � 6.4 kph 12% grade, 7 �6.4 kph/16% grade. Values are means � SE. *P � 0.01exercise trained vs. sedentary.




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0.001) larger increases in heart rate in the sedentary animalscompared with the exercise-trained dogs. The coronary occlu-sion-induced increases in heart rate were accompanied bylarger reductions (group � occlusion time, P � 0.001) in theHRV (vagal tone index, i.e., 0.24- to 1.04-Hz component of theR-R interval variability; and R-R interval range) indexes in the

sedentary susceptible compared with the susceptible traineddogs (Fig. 6). After training, the response to the coronaryocclusion in the resistant and susceptible dogs was indistin-guishable (Fig. 7). Thus, after the completion of exercisetraining, the susceptible animals exhibited a “resistant” HRVresponse pattern consistent with an increase in cardiac para-

Fig. 5. Effect of exercise training on the heart rate and heartrate variability responses to submaximal exercise in animalssusceptible or resistant to ventricular fibrillation. Note thatthere no longer were any differences between the suscepti-ble and resistant animals. Exercise levels: 1 � 0 kph/0%grade, 2 � 4.8 kph/0% grade, 3 � 6.4 kph/0% grade, 4 �6.4 kph/4% grade, 5 � 6.4 kph/8% grade, 6 � 6.4 kph 12%grade, 7 � 6.4 kph/16% grade. Values are means � SE.

Fig. 6. Effect of the 10-wk exercise training or 10-wksedentary period on the heart rate and the heart rate vari-ability responses to a 2-min coronary occlusion in animalssusceptible to ventricular fibrillation. The coronary occlu-sion elicited significantly smaller increase in heart rate andsmaller reductions in the various indexes of cardiac vagalregulation in the exercise-trained dogs compared with ani-mals that received a similar sedentary period. The posttrain-ing response in the susceptible exercise trained animals wasno longer different from that noted for the resistant (eitherexercise trained or sedentary) dogs. Pre, last 30 s before thecoronary occlusion; Post, 1 min after coronary occlusionrelease (i.e., average over 30–60 s after release). Values aremeans � SE. *P � 0.01 exercise trained vs. sedentary.




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sympathetic regulation. In contrast, the HRV response in thesusceptible sedentary dogs did not change over time.

Effect of training on susceptibility to ventricular fibrillation.The exercise plus ischemia test was repeated after the comple-tion of the either the 10-wk exercise training period (suscep-tible n � 9, resistant n � 8) or 10-wk sedentary period(susceptible n � 7, resistant n � 5). The heart rate responsesto the coronary occlusion are displayed in Fig. 8. The coronaryocclusion elicited significant (P � 0.0002) increases in heartrate in both the sedentary and the exercise-trained susceptibleanimals but did not alter heart rate in the resistant dogs. Boththe preocclusion and occlusion heart rate were lower (P �0.04) in the susceptible exercise-trained animals comparedwith the sedentary dogs. However, the change in heart rateelicited by the coronary occlusion was similar in both groupseither before (sedentary 31.0 � 8.5, trained 32.4 � 11.1beats/min) or after the 10-wk period (sedentary 32.5 � 7.4,trained 29.3 � 11.9 beats/min). In addition, the exercise plusischemia test provoked a similar ST segment depression in thesedentary and exercise-trained susceptible dogs both before(sedentary �4.8 � 1.2 vs. exercise trained �4.7 � 0.4 mm)and at the end of the 10-wk period (sedentary �4.8 � 1.7 vs.exercise trained �4.8 � 0.4 mm). When considered together,these data suggest that the coronary occlusion elicited a similarischemic response before and at the end of the 10-wk sedentaryor 10-wk exercise training period.

Exercise training significantly (Fisher’s exact test P �0.0014) reduced the incidence of ventricular fibrillation in thetrained susceptible animals, protecting all nine animals tested.In marked contrast, ventricular fibrillation was induced in allseven sedentary susceptible dogs. In addition, four susceptibleanimals died spontaneously during the 10-wk sedentary period.The exercise plus ischemia test failed to induce ventricularfibrillation in any of the resistant dogs in either the sedentary orthe exercise-trained groups.

The exercise plus ischemia test was repeated after pretreat-ment with atropine in the susceptible exercise-trained dogs.Atropine significantly (P � 0.01) increased heart rate (36.8 �3.2 beats/min) and reduced HRV (�2.3 � 0.3 ln ms2) bothbefore and during the coronary occlusion (Fig. 9). Despitethese changes, this intervention only reintroduced ventricularfibrillation, or any other arrhythmia, in one of eight dogs tested.

Fig. 7. Effect of exercise training on the heart rate and heartrate variability responses to a 2-min coronary occlusion inanimals susceptible and resistant to ventricular fibrillation.Note that after exercise training there no longer were anydifferences between the susceptible and resistant dogs. Pre,last 30 s before the coronary occlusion; Post, 1 min aftercoronary occlusion release (i.e., average over 30–60 s afterrelease). Values are means � SE.

Fig. 8. Heart rate responses to the exercise plus ischemia test in sedentary andexercise-trained animals susceptible and resistant to ventricular fibrillation.Coronary occlusion elicited a significant heart rate increase in the both thesedentary and exercise-trained susceptible animals. Heart rate before andduring the coronary occlusions was reduced in the exercise-trained susceptibleanimals. Values are means � SE. *P � 0.01 preocclusion vs. occlusion. #P �0.01 sedentary vs. exercise trained.




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DISCUSSION

The present study demonstrates the following: 1) Exercise oracute myocardial ischemia provoked greater increases in heartrate that were accompanied by greater reductions in three HRVmarkers (indexes of cardiac vagal regulation) in animals sub-sequently shown to be susceptible to ventricular fibrillationcompared with animals resistant to malignant arrhythmias. 2)Endurance exercise training reduced heart rate and increasedHRV even when the heart was stressed by either exercise oracute ischemia in the susceptible animals, such that the cardiacautonomic regulation was similar to that noted in resistantdogs. 3) Exercise training completely suppressed ventricularfibrillation induced by acute myocardial ischemia, protectingall nine susceptible dogs that completed the 10-wk exerciseprogram. In marked contrast, an equivalent sedentary periodnot only failed to protect any of the susceptible dogs thatcompleted the 10-wk period but also four dogs died spontane-ously during this period. 4) Treatment with the cholinergicantagonist, atropine, provoked large increases in heart rate andreductions in HRV yet failed to reintroduce arrhythmias in themajority of the trained susceptible animals, triggering ventric-ular fibrillation in only one of eight dogs tested. These datasuggest that exercise training can restore a more normal cardiacautonomic balance by increasing cardiac parasympathetic reg-ulation and also reduce the incidence of malignant arrhythmias.However, this protection did not solely result from the training-induced enhanced cardiac vagal control. To the best of ourknowledge, these findings represent the first demonstration thatexercise training can improve cardiac parasympathetic controlin diseased hearts even when the heart is stressed by acutemyocardial ischemia or by an episode of submaximal exercise.

HRV and susceptibility to ventricular fibrillation. HRV hasgained widespread acceptance as a noninvasive marker ofcardiac parasympathetic regulation (47). An ever-growingnumber of clinical studies have established a firm link betweenlow HRV and a greater propensity for sudden death (1, 3, 6, 21,28, 31, 40, 47). In agreement with the present study, our

laboratory previously reported HRV was reduced by myocar-dial infarction and that the dogs with the greatest reductionwere also more susceptible to ventricular fibrillation (7, 12, 18,22) than those dogs in which cardiac vagal regulation was notimpaired by the ischemic injury. In particular, the susceptibleanimals exhibited a much greater reduction (withdrawal) ofvagal activity in response to either submaximal exercise (7, 18,22) or acute myocardial ischemia (12, 18, 22). When consid-ered together, these clinical and experimental studies clearlysuggest that reductions in cardiac parasympathetic regulationplay an important role in the development of sudden cardiacdeath. Thus one would predict that interventions that altercardiac parasympathetic control should also alter susceptibilityto ventricular fibrillation.

Exercise training and susceptibility to ventricular fibrilla-tion. Exercise training can alter autonomic neural balance byboth increasing cardiac parasympathetic and decreasing sym-pathetic activity (5, 42). In both humans and animals, the heartrate at submaximal workloads is reduced in trained individualscompared with sedentary controls (5, 42). Furthermore, ace-tylcholine content and cholineacetyl transferase activity isincreased in the hearts of trained rats (15). In humans, exercisetraining can increase HRV in patients recovering from myo-cardial infarction (32, 33, 35, 38, 39). In the present study,HRV was higher in trained dogs compared with the sedentarytime-control animals. Importantly, the enhanced HRV wasmaintained even when the heart was challenged by eitherexercise or acute ischemia. Furthermore, atropine elicitedmuch greater increases in heart rate in the exercise-trainedanimals than was noted for the sedentary dogs, data that areconsistent with training-induced increases in the cardiac vagalregulation. Thus endurance exercise training can elicit changesin cardiac autonomic control that could, in turn, protect againstventricular fibrillation.

Regular exercise is also associated with a lower risk forarrhythmias and sudden death in both humans and animals (5).For example, Bartels et al. (2) found that the incidence ofsudden cardiac death was inversely related to the level ofregular physical activity; that is, sedentary individuals had thehighest rate of sudden death (4.7 deaths per 105 person-years),whereas those in the most active group had the lowest (0.9deaths per 105 person-years). Furthermore, meta-analysis of 22randomized trials of rehabilitation with exercise after myocar-dial infarction found that exercise training elicited significantreductions in both the reinfarction rate and the incidence ofsudden death (38). There was an overall reduction in cardiacmortality of 20% (due largely to the reduction in suddendeath), a reduction that is comparable to the mortality reduc-tions noted for -adrenoceptor antagonists (19, 26).

Experimental studies also report that exercise training de-creases the risk for arrhythmias (5, 8, 24) or increases theelectrical current necessary to induce ventricular fibrillation(37, 41). In agreement with the present study, Billman et al. (8)and Hull et al. (24) reported that daily exercise preventedventricular fibrillation induced by acute ischemia in dogs withhealed anterior wall myocardial infarctions, a protection thatwas accompanied by an improved baroreflex sensitivity (8) andan increase in baseline HRV (24). However, neither groupexamined the effects of training on autonomic regulation inresponse to physiological stressors such as exercise or acuteischemia. Improvement in the autonomic balance at rest might

Fig. 9. Effect of atropine on the heart rate responses to the exercise plusischemia in exercise-trained susceptible dogs. Atropine (50 �g/kg iv given asa bolus 3 min before the coronary occlusion) elicited a large increase in heartrate. Values are means � SE. *P � 0.01 preocclusion vs. occlusion. #P � 0.01No drug vs. atropine.




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not provide sufficient protection against arrhythmias when theheart is stressed during dynamic situations. Indeed, the obser-vation that low doses of cholinergic antagonists paradoxicallyincreased the level of cardiac vagal activity (31) led to theproposal that this treatment could provide an acceptable meansof enhancing cardiac parasympathetic activity in patients (10,49). However, Halliwill et al. (18) and Hull et al. (25) bothdemonstrated that, although low doses of cholinergic antago-nists increased baseline cardiac vagal activity (R-R intervalvariability), this treatment failed to prevent ventricular fibril-lation induced by myocardial ischemia. Halliwill et al. (18)further demonstrated that the enhanced baseline vagal activitywas not maintained when the heart was stressed by eitherexercise or myocardial ischemia. As such, it was not surprisingthat this therapy failed to prevent ventricular fibrillation. Itwould appear that to be an effective antiarrhythmic therapy, anintervention must not only increase baseline vagal activity but,more importantly, must also maintain this enhanced activitywhen the heart is stressed.

The present study confirms and extends these previousstudies. Training enhanced cardiac vagal control (as noted byincreases in HRV), whereas an equivalent sedentary timeperiod did not change cardiac parasympathetic regulation. Therestoration of a more normal cardiac parasympathetic regula-tion, however, was not solely responsible for the protectionsassociated with exercise training. The cholinergic antagonistatropine did not reintroduce malignant arrhythmias in themajority of animals, inducing ventricular fibrillation in only ofone of eight dogs tested. Other factors must play a more centralrole in the protection that results from training. Exercisetraining also alters sympathetic regulation. Our laboratorypreviously reported that the susceptible dogs, in addition toreduced parasympathetic control, exhibit an enhanced 2-adrenoceptor responsiveness (9). Therefore, training could alsoimprove -adrenoceptor balance by decreasing the enhanced2-adrenoceptor and could, thereby, remove the trigger formalignant arrhythmias during myocardial ischemia. The ef-fects of exercise training on 2-adrenoceptor responsivenessmerit further investigation.

Limitations of the study. There are a few limitations with thepresent study that could affect the interpretations of the results.First, dogs have extensive coronary collateral vessels (36) thatexercise training may (43) or may not (11) increase. Therefore,exercise training-induced increases in coronary collateral cir-culation could contribute to the protection noted in the suscep-tible dogs. However, acute myocardial ischemia provokedsimilar increases in heart rate in the susceptible sedentary(pretraining 31.0 � 8.5 beats/min) and in the susceptibletrained (pretraining 32.4 � 1.1 beats/min) dogs before or afterthe 10-wk period (posttraining sedentary 32.5 � 7.4, posttrain-ing sedentary 29.3 � 1.9 beats/min). In addition, the exerciseplus ischemia test provoked a similar ST segment depression inthe sedentary and exercise-trained susceptible dogs both before(sedentary �4.8 � 1.2 vs. exercise trained �4.7 � 0.4 mm)and at the end of the 10-wk period (sedentary �4.8 � 1.7 vs.exercise trained �4.8 � 0.4 mm). When considered together,these data suggest that the coronary occlusion elicited a similarischemic response before and at the end of the 10-wk sedentaryor exercise training period.

Second, myocardial infarction size could also contribute tothe differences noted between susceptible and resistant dogs;

animals with larger infarctions would be expected to havepoorer ventricular function and a higher risk for ventricularfibrillation. Myocardial infarction size was not measured in thepresent study (the hearts were removed for in vitro studies).Therefore, we performed a retrospective analysis of animals inwhich infarction size had been determined and found that thesusceptible dogs had larger infarctions (susceptible, n � 93,17.7 � 0.9%; resistant, n � 50, 12.6 � 1.4%). Because theexercise program did not begin until after the myocardialinfarction was healed (at least 4 wk after the induction of theinfarction), it seems unlikely that training would reduce theinfarction size in these animals.

Third, exercise training reduced the peak heart rate achievedduring either exercise or acute myocardial ischemia. By de-creasing metabolic demand, a lower heart rate per se couldreduce the risk for arrhythmias. However, atropine pretreat-ment elicited large increases in heart rate, increases that ex-ceeded the maximum heart rate values induced by the coronaryocclusion before training, yet only modestly increased thearrhythmia frequency. Thus heart rate reductions, alone, cannotbe responsible for the training-induced protection from ven-tricular fibrillation.

Fourth, it must be acknowledged that in the present study,cardiac vagal regulation was only indirectly evaluated usingvarious measures of HRV. This study did not measure theparasympathetic nerve activity directly. However, previousinvestigations have verified that HRV provides an accuraterepresentation of parasympathetic function (16). Additionally,in the present study, atropine effectively eliminated the heartrate and HRV differences noted between the susceptible andresistant dogs; that is, heart rate increased and HRV fell to zeroin both groups after atropine treatment. These data are consis-tent with an atropine-induced inhibition (removal) of cardiacvagal regulation. Therefore, it is reasonable to conclude thatthe method used in the present study provided reliable indirectmeasurements of cardiac parasympathetic regulation.

Finally, it is well established that both respiratory rate andtidal volume can alter HRV (20). As such, differences in therespiratory response after exercise training could indirectlycontribute to the differences in the cardiac vagal indexes in thesusceptible and resistant animals. Respiratory parameters werenot measured in this study because of the profound pantingresponse induced by exercise in both groups of animals (beforeand after exercise training). It is possible that, despite thepanting, respiratory rate or tidal volume was altered in thetrained animals. However, the coronary occlusion at rest didnot elicit any obvious change in respiration (or induce panting)either before or after training, yet HRV was profoundly in-creased in the exercise-trained susceptible animals. Further-more, our laboratory previously demonstrated that exerciseelicited similar respiratory rate changes in resistant and sus-ceptible dogs and that panting did not alter HRV (7, 18, 22). Itseems unlikely that training-induced changes in respiration canexplain HRV increase or the protection from ventricular fibril-lation.

In conclusion, the present study demonstrates that exercisetraining improves cardiac autonomic function such that cardiacvagal regulation is maintained even when the heart is stressedby either exercise or acute myocardial ischemia in animals withhealed infarctions. Furthermore, exercise training completelysuppressed ventricular fibrillation induced by myocardial is-




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chemia. However, because atropine pretreatment did not rein-troduce lethal arrhythmias in these dogs, the exercise-inducedprotection from ventricular fibrillation did not result solelyfrom enhanced cardiac vagal regulation. The mechanisms bywhich exercise training improved cardiac vagal regulation andprevented ventricular fibrillation remain to be determined.

ACKNOWLEDGMENTS

The Authors Thank Moustafa B. Moustafa for performing the citratesynthase assay.

GRANTS

These studies were supported by National Heart, Lung, and Blood InstituteGrant HL-68609.

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