Run for your life … at a comfortable speed and not too far James H O’Keefe, 1,2 Carl J Lavie 3,4 During the Greco-Persian War in 490 BCE, Phidippides, a 40-year-old herald messenger ( professional running-courier) ran the 26 miles from a battlefield near Marathon, Greece, into Athens carrying momentous news of Greek victory. Upon arriving at the Acropolis, he proclaimed: ‘Joy, we have won!’ and then immedi- ately collapsed and died. 1 Fast-forward about 2500 years to an era when the baby-boomer ’s came of age and long- distance running boomed. The prevailing logic held that aerobic exercise is clearly good for one’s health and that, if some is good, more must be better. In 1975, Dr Thomas Bassler, a physician/runner, boldly proclaimed that, if you could run a marathon, you were immune to death from coronary heart disease (CHD). 2 This urban myth has long since been dispro- ven; indeed an emerging body of evidence suggests the opposite: extreme endurance exercise may exact a toll on cardiovascular (CV) health. ‘ SHOW ME THE BODIES’ After our recent articles on this topic, 13–5 Amby Burfoot, winner of the 1968 Boston Marathon and Editor-at-Large for Runner ’s World Magazine, challenged our assertions about the dangers of extreme endurance efforts by demanding, ‘Show me the bodies’. Amby has a good point: the risk of dropping dead in a marathon is remote, about 0.5 to 1 in 100,000 participants. 6 But the occasional marathoner or triathlete who dies while strenuously exercising is the ‘canary in the coal mine’. Chronic extreme exercise appears to cause excessive ‘ wear-and-tear ’ on the heart, inducing adverse structural and electrical remodelling, which offsets some of the CV benefits and longevity improvements conferred by mod- erate physical activity. Thus, even though chronic extreme exercise may not kill you, it may erase many of the health advantages of regular moderate exercise. Indeed, regular vigorous exercise is prob- ably the single best step a person can take to ensure robust CV health. In a study of 416 000 adults followed for a mean of 8 years, 40–50 min per day of vigorous exercise reduced risk of death by about 40% ( figure 1). 7 In that study, at about 45 min, a point of diminishing returns is reached whereby longer exercise efforts do not appear to translate into lower death risk. Light to moderate physical activity reduced death rates too, albeit not as strongly, but in this case more physical activity appeared to be better, with no plateau out to 110 min daily. Indeed, if we had a pill that confers all the benefits of exercise, many physicians might be looking for work. Approximately 30– 45 min of daily vigorous exercise signifi- cantly reduces risks for many maladies including early death, Alzheimer ’s disease, CHD, diabetes, osteoporosis and depres- sion. 45 Yet, as can be expected with any potent drug, an insufficient dose will not confer the optimal benefits, while an excessive dose can cause harm, and even death in extreme overdoses. The ‘survival of the fittest’ concept does not fully apply to the modern world, where it appears that even the moderately fit have an excellent CV prognosis and superb longevity. Studies of CV fitness, as measured by peak performance on a tread- mill, show a curvilinear relationship whereby improvements from unfit to moderately fit confer dramatic reductions in morbidity and mortality ( figure 2). 8 However, fitness levels above 12 metabolic equivalents do not seem to translate into additional gains in CV health and longev- ity. Thus, if one is training to be able to run at speeds above 7.5 miles per hour, this is being done for some reason other than further improvements in life expectancy. CV DAMAGE FROM EXCESSIVE EXERCISE High-intensity exercise sessions lasting beyond 1–2 h cause acute volume over- load of the atria and right ventricle (RV), which can bring about overstretching and micro-tears in the myocardium, as evi- denced by a transient rise in cardiac bio- markers, including troponin and B-natriuretic peptide and a fall in the RV ejection fraction. 9 Although within 1 week, these transitory abnormalities usually return to baseline, 9 after years to decades of excessive exercise and repeti- tive injury, this pattern can lead to patchy myocardial fibrosis, particularly in the pliable walls of the heart such as the atria and RV, creating a substrate foratrial and potentially malignant ventricular arrhythmias. 1 3–5 In addition, long-term excessive exercise may accelerate aging in the heart, as evidenced by increased cor- onary artery calcification, diastolic ven- tricular dysfunction, and large-artery wall stiffening. 13–5 At rest, the heart pumps about 5 litres/ min; with strenuous aerobic exercise, the cardiac output can rise 5–7-fold, pumping up to 25–35 litres/min. This massive increase in cardiac work is what the heart is designed to do for short bursts, or even for up to as long as 30 or 50 min Figure 1 Duration of daily exercise and reduction in long-term all-cause mortality. 7 1 Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, USA; 2 University Of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA; 3 Department of Cardiology, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, Louisiana, USA; 4 Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA Correspondence to Dr James H O’Keefe, Saint Luke’s Mid America Heart Institute,4330 Wornall Road, Suite 2000 Kansas City, MO 64111 phone: 816-751-8480 fax: 816-756-3645 [email protected]Heart Month 0 Vol 0 No 0 1 Editorial Heart Online First, published on November 29, 2012 as 10.1136/heartjnl-2012-302886 Copyright Article author (or their employer) 2012. 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Transcript
Run for your life… at acomfortable speed and not too farJames H O’Keefe,1,2 Carl J Lavie3,4
During the Greco-Persian War in 490BCE, Phidippides, a 40-year-old heraldmessenger (professional running-courier)ran the 26 miles from a battlefield nearMarathon, Greece, into Athens carryingmomentous news of Greek victory. Uponarriving at the Acropolis, he proclaimed:‘Joy, we have won!’ and then immedi-ately collapsed and died.1 Fast-forwardabout 2500 years to an era when thebaby-boomer ’s came of age and long-distance running boomed. The prevailinglogic held that aerobic exercise is clearlygood for one’s health and that, if someis good, more must be better. In 1975,Dr Thomas Bassler, a physician/runner,boldly proclaimed that, if you could run amarathon, you were immune to deathfrom coronary heart disease (CHD).2 Thisurban myth has long since been dispro-ven; indeed an emerging body of evidencesuggests the opposite: extreme enduranceexercise may exact a toll on cardiovascular(CV) health.
‘SHOW ME THE BODIES’After our recent articles on this topic,1 3–5
Amby Burfoot, winner of the 1968 BostonMarathon and Editor-at-Large for Runner’sWorld Magazine, challenged our assertionsabout the dangers of extreme enduranceefforts by demanding, ‘Show me thebodies’. Amby has a good point: the risk ofdropping dead in a marathon is remote,about 0.5 to 1 in 100,000 participants.6 Butthe occasional marathoner or triathlete whodies while strenuously exercising is the‘canary in the coal mine’. Chronic extremeexercise appears to cause excessive‘wear-and-tear ’ on the heart, inducingadverse structural and electrical remodelling,which offsets some of the CV benefits and
longevity improvements conferred by mod-erate physical activity. Thus, even thoughchronic extreme exercise may not kill you, itmay erase many of the health advantages ofregular moderate exercise.Indeed, regular vigorous exercise is prob-
ably the single best step a person can taketo ensure robust CV health. In a study of416 000 adults followed for a mean of8 years, 40–50 min per day of vigorousexercise reduced risk of death by about40% (figure 1).7 In that study, at about45 min, a point of diminishing returns isreached whereby longer exercise efforts donot appear to translate into lower deathrisk. Light to moderate physical activityreduced death rates too, albeit not asstrongly, but in this case more physicalactivity appeared to be better, with noplateau out to 110 min daily. Indeed, if wehad a pill that confers all the benefits ofexercise, many physicians might belooking for work. Approximately 30–45 min of daily vigorous exercise signifi-cantly reduces risks for many maladiesincluding early death, Alzheimer ’s disease,CHD, diabetes, osteoporosis and depres-sion.4 5 Yet, as can be expected with anypotent drug, an insufficient dose will notconfer the optimal benefits, while anexcessive dose can cause harm, and evendeath in extreme overdoses.The ‘survival of the fittest’ concept
does not fully apply to the modern world,where it appears that even the moderatelyfit have an excellent CV prognosis andsuperb longevity. Studies of CV fitness, as
measured by peak performance on a tread-mill, show a curvilinear relationshipwhereby improvements from unfit tomoderately fit confer dramatic reductionsin morbidity and mortality (figure 2).8
However, fitness levels above 12 metabolicequivalents do not seem to translate intoadditional gains in CV health and longev-ity. Thus, if one is training to be able torun at speeds above 7.5 miles per hour,this is being done for some reason otherthan further improvements in lifeexpectancy.
CV DAMAGE FROM EXCESSIVEEXERCISEHigh-intensity exercise sessions lastingbeyond 1–2 h cause acute volume over-load of the atria and right ventricle (RV),which can bring about overstretching andmicro-tears in the myocardium, as evi-denced by a transient rise in cardiac bio-markers, including troponin andB-natriuretic peptide and a fall in the RVejection fraction.9 Although within1 week, these transitory abnormalitiesusually return to baseline,9 after years todecades of excessive exercise and repeti-tive injury, this pattern can lead topatchy myocardial fibrosis, particularly inthe pliable walls of the heart such as theatria and RV, creating a substrate for atrialand potentially malignant ventriculararrhythmias.1 3–5 In addition, long-termexcessive exercise may accelerate aging inthe heart, as evidenced by increased cor-onary artery calcification, diastolic ven-tricular dysfunction, and large-artery wallstiffening.1 3–5
At rest, the heart pumps about 5 litres/min; with strenuous aerobic exercise, thecardiac output can rise 5–7-fold, pumpingup to 25–35 litres/min. This massiveincrease in cardiac work is what the heartis designed to do for short bursts, or evenfor up to as long as 30 or 50 min
Figure 1 Duration of daily exercise and reduction in long-term all-cause mortality.7
1Saint Luke’s Mid America Heart Institute, Kansas City,Missouri, USA; 2University Of Missouri-Kansas CitySchool of Medicine, Kansas City, Missouri, USA;3Department of Cardiology, John Ochsner Heart andVascular Institute, Ochsner Clinical School, TheUniversity of Queensland School of Medicine, NewOrleans, Louisiana, USA; 4Pennington BiomedicalResearch Center, Baton Rouge, Louisiana, USA
Correspondence to Dr James H O’Keefe, Saint Luke’sMid America Heart Institute,4330 Wornall Road, Suite2000 Kansas City, MO 64111 phone: 816-751-8480fax: [email protected]
Heart Month 0 Vol 0 No 0 1
Editorial Heart Online First, published on November 29, 2012 as 10.1136/heartjnl-2012-302886
Copyright Article author (or their employer) 2012. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
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continuously. However, with protractedefforts, these high volumes can over-stretch the chambers, eventually disrupt-ing cardiac muscle fibres and causingmicro-tears in the myocardium.10 Thepresence of sustained exercise-induced ele-vations in catecholamines andpro-oxidant free radicals worsen the situ-ation by adding inflammation to theinjury, leading eventually to scarring andstiffening of the CV structures.10
A trial randomised 60 male patientswith CHD to vigorous exercise sessionsof either 30 or 60 min.11 The 30 min exer-cise workouts improved arterial elasticityand produced minimal oxidant stress. Incontrast, the 60 min sessions increasedoxidant stress and worsened vascularstiffness as measured by pulse wave vel-ocity, particularly in those over the ageof 50. MRI scans of runners who havebeen participating in marathons fordecades show a threefold increased inci-dence of scattered fibrosis and scarring inthe walls of the atria, interventricular
septum and RV (figure 3).12 Cardiologistsfrom Minnesota evaluated a group ofrunners who had completed at least 25marathons over 25 years and found a 60%increase in coronary plaque burden com-pared with sedentary age-matched con-trols.1 These findings were replicated by agroup from Germany, who showedincreased coronary plaque in 108 chronicmarathoners compared with sedentarycontrols.13 This scarring can set the stagefor dangerous heart rhythms, such asatrial fibrillation, which is increasedapproximately fivefold in veteran endur-ance athletes.10 Ventricular tachycardiaand sudden cardiac arrest can also beseen in endurance athletes even inthe absence of CHD and hypertrophiccardiomyopathy.1 5
An enlightening study by Benito et alreinforced the concept of cardiac damagefrom chronic excessive exercise. Miceafter being forced to run to exhaustionevery day for 4 months showed thesame cardiac enlargement, scarring and
predisposition to dangerous ventriculardysrhythmias that have been documentedin some veteran extreme endurance ath-letes.14 Encouragingly, when the micewere withdrawn from the ‘Iron-Mouse’training regimen and allowed to resumenormal mouse physical activity levels,their cardiac abnormalities showedmarked improvements, even showingregression of myocardial fibrosis and reso-lution of the tendency toward seriousventricular dysrhythmias.14
PHIDIPPIDES CARDIOMYOPATHYBorn to Run is a non-fiction bestsellerbook published in 2009 that glamorisesultra-endurance running. The story ’shero is Micah True, an American whodropped out of modern civilisation tolive and run with the TarahumaraIndians in Mexico. Nicknamed CaballoBlanco, or white horse, for his legendaryrunning endurance, he routinely randaily distances of 25–100 miles. ThisMarch on a 12-mile training run in NewMexico, Micah True dropped dead at age58. On autopsy, his heart was enlargedand thickened with ‘focal areas of inter-stitial chronic inflammatory infiltrate’ inthe myocardium; the coronary arterieswere ‘focally thickened with mild coron-ary arteriosclerosis’. Chief MedicalInvestigator Ross Zumwalt, MD sum-marised the findings as, ‘Unclassified car-diomyopathy, which resulted in a cardiacdysrhythmia during exertion’.15 Whenconsidered in the context of True’sdecades-long lifestyle of daily ultra-marathon running, we suspect that theautopsy findings were an example of‘Phidippides cardiomyopathy’—the con-stellation of cardiac pathology that hasbeen in observed in the hearts of someveteran extreme endurance athletes.1
Figure 3 MRI scans showing scattered scarring (red arrows) in the heart, especially in the interventricular septum.14
Figure 2 Death rates as a function of cardiovascular fitness as measured by metabolicequivalents achieved on maximal exercise treadmill testing.8 CVD, cardiovascular disease.
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MODERATE EXERCISE: THESWEET-SPOT FOR LONGEVITYTwo very recent studies presented inabstract form at major national meetingsmay revolutionise our thinking aboutrunning and its health effects.16 17 One isa prospective observational study thatfollowed 52 600 people for up to threedecades.17 The 14 000 runners in thatstudy had a 19% lower risk of death com-pared with the 42 000 non-runners. Yet,when they sub-grouped the runners byweekly mileage, those who ran over 20 or25 miles per week seemed to lose theirsurvival advantage over the non-runners(figure 4). On the other hand, those whoran between 5 and 20 miles total perweek enjoyed a 25% decrease in risk ofdeath during follow-up. The samepattern emerged for speed of running: thefast runners, those running typically over8 miles an hour, appeared to get no mor-tality benefit compared with the non-runners, whereas those who fared bestusually ran about 6–7 miles per hour—acomfortable jog for most people. In add-ition, the individuals who ran 6 or 7 daysper week appeared to lose the mortalitybenefits, whereas the survival advantagesaccrued best for those who ran 2–5 daysper week.16
The Copenhagen City Heart Studyshowed remarkably similar results. Afterfollowing 20 000 Danes since 1976, theyfound that the joggers lived about 6 yearslonger than the non-runners, with a 44%lower risk of death during the study.17
Intriguingly, those who did best were thepeople who jogged at a slow to averagepace, for one to 2.5 h per week total,accumulated during two or three sessions.According to Dr Peter Schnohr, thestudy’s director, ‘The relationship appearsmuch like alcohol intakes—mortality islower in people reporting moderatejogging than in non-joggers or thoseundertaking extreme levels of exercise’.17
THE U-CURVEHippocrates, the father of medicine and acontemporary of Phidippides in ancientGreece, taught, ‘The right amount ofnourishment and exercise, not too much,not too little, is the safest way tohealth’.1 If you listen to your body, this isjust common sense. Yet, nothing we havepublished previously has stirred so muchcontroversy, especially among the generalpublic. Increasingly our culture is one ofextremes: during the past 30 years,obesity has tripled in the USA and hasincreased in much of the Western World,while during the same time the numberof people completing a marathon hasrisen 20-fold. On one side of the U-curve,the couch loungers/channel surfersembrace this message as justification forcontinuing their sedentary lifestyle. And,on the far end of the U-curve, theextreme exercise aficionados want toignore the message and instead kill themessenger. As with many things inlife, the safe and comfortable zone atthe bottom of the U curve—moderateexercise—is the ‘sweet spot’ for whichmost should try to aim.Sitting is the new smoking; a sedentary
lifestyle will cause disability and disease,and will shorten life expectancy. We arenot so much born to run as born to walk.Ethnographic research indicates that, inthe environment of human evolution, ourancient ancestors walked 4–10 miles aday.4 Walking is superior to running formechanical efficiency and musculoskeletaldurability. Indeed, we advise our patientsthat they can walk or garden hours a daywithout concern about CVoveruse injury.So while it is true that exercise confers
powerful health benefits, the commonbelief that more is better is clearly nottrue. The unique and potent benefits ofexercise are best bestowed by moderateexercise and physical activity. The exer-cise patterns for maximising CV fitness/
peak aerobic capacity are very differentfrom those that best confer CV health,durability and overall longevity. So, ifone’s goal in life is to compete in themarathon or triathlon of the RioOlympics in 2016, this will certainlyrequire high-intensity exercise for hours aday. But, for those whose goal is to bealive and well while watching the 2052Olympics from the stands, then exerciseand physical activity at lower intensitiesand durations would be more ideal.
CONCLUSIONThe take home message for most is tolimit one’s vigorous exercise to 30–50 min/day. If one really wants to do amarathon or full-distance triathlon etc, itmay be best to do just one or a few andthen proceed to safer and healthier exer-cise patterns. On the other hand, light ormoderate intensity exercise does notpresent the dose-dependent risks asso-ciated with excessive endurance exercise.A routine of moderate physical activitywill add life to your years, as well asyears to your life. In contrast, runningtoo fast, too far, and for too many yearsmay speed one’s progress towards thefinish line of life.
Contributors JHO and CJL contributed.
Competing interests None.
Provenance and peer review Commissioned;internally peer reviewed.
Author note A video presentation on this topic isavailable on the internet: You Tube, TEDx Talk, JamesO’Keefe, Run for your life… at a comfortable pace andnot too far.
9. Ector J, Ganame J, van der Merwe N, et al.Reduced right ventricular ejection fraction inFigure 4 All-cause mortality by running distance per week.16
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endurance athletes presenting with ventriculararrhythmias: a quantitative angiographic assessment.Eur Heart J 2007;28:345–53.
10. La GA, Burns AT, Mooney DJ, et al. Exercise-inducedright ventricular dysfunction and structuralremodelling in endurance athletes. Eur Heart J2012;33:998–1006.
11. Michaelides AP, Soulis D, Antoniades C, et al.Exercise duration as a determinant of vascularfunction and antioxidant balance in patients withcoronary artery disease. Heart 2011;97:832–7.
12. Breuckmann F, Mohlenkamp S, Nassenstein K,et al. Myocardial late gadolinium enhancement:prevalence, pattern, and prognostic relevance inmarathon runners. Radiol 2009;251:50–7.
13. Mohlenkamp S, Lehmann N, Breuckmann F, et al.Running: the risk of coronary events : Prevalence andprognostic relevance of coronary atherosclerosis inmarathon runners. Eur Heart J 2008;29:1903–10.
14. Benito B, Gay-Jordi G, Serrano-Mollar A, et al.Cardiac arrhythmogenic remodeling in a rat model oflong-term intensive exercise training. Circulation2011;123:13–22.
15. Zumwalt R. Autopsy Report TRUE, MICAH RANDALL.In: Investigator OotM, ed. Albuquerque: University ofNew Mexico Health Sciences Center, 2012:5. http://extremelongevity.net/wp-content/uploads/2401-12AutRpt.pdf accessed august 24, 2012
16. Lee DC, Pate RR, Lavie CJ. Running and all-causemortality risk—is more better? In: Medicine ACoS,
ed. Medicine & Science in Sports & Exercise.American College of Sports Medicine San Francisco,CA: 2012:S699.
17. Schnohr P. Assessing prognosis: a glimpse of thefuture. Jogging healthy or hazard? In: Cardiology ESo,ed. EuroPRevent 2012. Dublin, Ireland: EuropeanHeart Journal, 2012.
18. O'Keefe JH, Patil HR, Lavie CJ, et al. In reply.Potential, but unobserved, adverse cardiovasculareffects from endurance exercise. Mayo Clin Proc2012 Nov;87(11):1133-4.
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Potential Adverse Cardiovascular Effects FromExcessive Endurance ExerciseJames H. O’Keefe, MD; Harshal R. Patil, MD; Carl J. Lavie, MD; Anthony Magalski, MD;Robert A. Vogel, MD; and Peter A. McCullough, MD, MPH
Abstract
A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases andimproves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may inducepathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for andcompeting in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very longdistance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transientreductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normalwithin 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchymyocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrialand ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronaryartery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypotheticaland there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have lowmortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive enduranceexercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulatephysical fitness regimens for conferring optimal CV health and longevity.
FIp(OISQcPsSto(ddence Park Heart Institute,Novi, MI (P.A.M.).
R egular exercise is one of the cornerstones oftherapeutic lifestyle changes for producingoptimal cardiovascular (CV) and overall
health. Physical exercise, though not a drug, pos-sesses many traits of a powerful pharmacologicalagent. A routine of daily physical activity (PA) stim-ulates a number of beneficial physiologic changes inthe body and can be highly effective for preventionand treatment of many of our most prevalent andpernicious chronic diseases, including coronaryheart disease (CHD), hypertension, heart failure,obesity, depression, and diabetes mellitus.1 Peoplewho exercise regularly have markedly lower rates ofdisability and a mean life expectancy that is 7 yearslonger than that of their physically inactive contem-poraries.2,3 Accordingly, physicians are increasinglyprescribing regular exercise training (ET) for theirpatients. The potential benefits of regular ET arelisted in Table 1.4
However, as with any pharmacological agent, asafe upper-dose limit potentially exists, beyondwhich the adverse effects (musculoskeletal trauma,metabolic derangements, CV stress, etc) of physicalET may outweigh its benefits. A very large recentstudy found that in sedentary individuals, even amodest dose of PA, as little as 15 minutes per day,5
confers substantial health benefits and that thesebenefits accrue in a dose-dependent fashion up toabout an hour per day of vigorous PA, beyond which
more ET does not yield further benefits (Figure 1).5,6 i
Mayo Clin Proc. � June 2012;87(6):587-595 � http://dx.doi.org/10.1016www.mayoclinicproceedings.org
Similarly, a 15-year observational study of 52,000adults found that runners had a 19% lower risk ofall-cause mortality compared with nonrunners, withU-shaped mortality curves for distance, speed, and fre-quency. Running distances of about 1 to 20 miles perweek, speeds of 6 to 7 miles per hour, and frequenciesof 2 to 5 days per week were associated with lowerall-cause mortality, whereas higher mileage, fasterpaces, and more frequent runs were not associatedwith better survival.7 A randomized crossover trial as-signed 60 male patients with CHD to ET sessions ofeither 30 or 60 minutes. The 30-minute exercise ses-sions produced less oxidant stress and improved arte-rial elasticity, whereas 60-minute sessions worsenedoxidant stress and increased vascular stiffness as mea-sured by pulse wave velocity, mainly in older patients.8
Thus, the benefits of ET are attainable withomparatively modest levels of PA. Highly trainedndurance athletes often perform strenuous aerobicxercise for several hours daily, often accumulatingorkloads of 200 to 300 metabolic equivalent hours
metabolic equivalents � hours) per week, which ispproximately 5- to 10-fold greater than the stan-ard ET dose recommended for prevention ofHD.1,9 The aim of this review is to explore theypothesis that long-term excessive endurance ET
n some individuals may induce adverse CV struc-ural and electrical remodeling that might diminishome of the benefits conferred by more moderate
rom Mid America Heartnstitute of Saint Luke’s Hos-ital of Kansas City, MOJ.H.O., H.R.P., A.M.); Johnchsner Heart and Vascular
nstitute, Ochsner Clinicalchool–The University ofueensland School of Medi-
ine, New Orleans, LA, andennington Biomedical Re-earch Center, Louisianatate University System, Ba-on Rouge (C.J.L.); Universityf Maryland, BaltimoreR.A.V.); and St. John Provi-ence Health System Provi-
SUDDEN CARDIAC DEATH AND ENDURANCE ETOver the past 35 years, the number of Americansparticipating in a marathon annually has risen 20-fold; in 2010, an estimated half-million runnerscompleted a marathon in the United States.10 Sud-den cardiac death (SCD) among marathoners is veryrare, with 1 event per 100,000 participants.6,7,11,12
Although that per-participant risk has not changedover the decades, absolute mortality rates have in-creased as the number of participants has risen. Thefinal 1 mile of the marathon course represents lessthan 5% of the total distance of 26.2 miles yet ac-counts for almost 50% of the SCDs during therace.12,13
The fatality rate for triathlons is approximatelytwice that of marathons, largely because of increasedCV events and drownings during the swim portionof the races.14 The incidence of SCD among colle-giate athletes during competition is about 1 per40,000 participants per year for all athletes.15 It isextremely important to keep in mind that the occur-rence of SCD during marathons, triathlons, and col-legiate athletic events is rare and should not deterindividuals from participating in vigorous ET; thebenefits of regular PA to the individual and tosociety as a whole far outweigh potential risks. Atthe same time, long-term training for and compet-ing in extreme endurance events may predisposeto CV issues that are not seen in more moderate
regularly have markedly lower rates of disability
ectancy that is 7 years longer than that of their
ntemporaries. However, a safe upper-dose limit
yond which the adverse effects of exercise may
.
sustained exercise can cause patchy myocardial
the atria, interventricular septum, and right ven-
trate for atrial and ventricular arrhythmias.
ustained exercise may also be associated with
fication, diastolic dysfunction, and large-artery wall
thletes in sports such as marathon or ultramara-
essional cycling have been noted to have a 5-fold
lence of atrial fibrillation.
ercise efforts often cause elevation in biomarkers
(troponin and B-type natriuretic peptide), which
transient reductions in right ventricular ejection
forms of PA. V
Mayo Clin Proc. � June 2012;8
The causes of SCD during or after extreme ex-rtion in individuals younger than 30 years mostommonly include genetic causes such as hypertro-hic cardiomyopathy, anomalous coronary arteries,ilated cardiomyopathy, and congenital long QTyndrome. In athletes older than 30 years, CHD andcute myocardial infarction16 and ischemia are the
predominant causes of exercise-related SCD.17-23
ANIMAL STUDIESIn an elegant animal model of excessive enduranceET, rats were trained (in part by prodding with elec-trical shocks to maintain high-intensity effort) torun strenuously and continuously for 60 minutesdaily for 16 weeks, and then they were comparedwith control sedentary rats.8,24 The running rats de-eloped hypertrophy of the left ventricle (LV) andhe right ventricle (RV), diastolic dysfunction, andilation of the left atria and the right atria (RA); theylso showed increased collagen deposition and fi-rosis in both the atria and ventricles (Figure 2).
running rats vs only 6% of the sedentary rats (P�.05).Importantly, the fibrotic changes caused by 16 weeksof intensive ET had largely regressed to normal by 8weeks after the daily running regimen ceased.
This animal study found that daily excessive,strenuous, uninterrupted running replicated the ad-verse cardiac structural remodeling and proarrhyth-mia substrate noted in observational studies of ex-treme endurance athletes. These findings supportthe hypothesis that in some individuals, long-termstrenuous daily endurance ET, such as marathonrunning or professional long-distance cycling, insome individuals may cause cardiac fibrosis (espe-cially in the atria and the RV and interventricularseptum), diastolic dysfunction, and increased suscep-tibility to atrial and ventricular arrhythmias. Many pre-vious animal studies have also found acute, adversecardiac effects of prolonged (up to 6 hours) enduranceexercise, sometimes employing a rat model of cold-water swimming in which the animals were forced toswim to avoid drowning.25 These studies are of uncer-tain clinical relevance because of the excessively stress-ful nature of the imposed exercise.
ATHLETE’S HEARTChronic ET imposes increased hemodynamic de-mands that alter the loading conditions of the heart,particularly among athletes participating in sports re-quiring sustained elevations in cardiac work, such aslong-distance running, rowing, swimming, and cy-cling.26 Highly trained individuals develop cardiac ad-aptations including enlarged LV and RV volumes, in-creased LV wall thickness and cardiac mass, andincreased left atrial size.21-23 In the general population,these structural changes are associated with poor car-diac prognosis.27 However, these structural altera-tions, together with a preserved LV ejection fraction(EF), have been considered typical findings of the “ath-lete’s heart.”18-20,28 Of concern, accumulating infor-mation suggests that some of the remodeling thatoccurs in endurance athletes may not be entirelybenign.17,29-32 For example, in elite athletes, cardiacdimensions do not completely regress to normal levelseven several years after the athlete has retired fromcompetition and heavy ET.33
BIOMARKER EVIDENCE FOR CARDIAC DAMAGEWITH EXTREME ENDURANCE ETRunning is a prototypical natural PA and often playsan integral and important role in an active, healthylifestyle.9,34-36 However, uninterrupted very longdistance running as is generally done while trainingfor and participating in marathons and other ex-treme endurance events may produce adverse CVeffects in susceptible individuals. Serologic markers
of cardiac damage, including cardiac troponin, cre- s
Mayo Clin Proc. � June 2012;87(6):587-595 � http://dx.doi.org/10.10www.mayoclinicproceedings.org
atine kinase MB, and B-type natriuretic peptide,have been documented to increase in up to 50% ofparticipants during and after marathon run-ning7,10-14 (Figure 3).9,12,37-40 Additionally, tran-ient renal dysfunction has been observed with ex-reme endurance ET efforts causing volumeepletion and diminished renal filtration, with ele-ations in serum urea nitrogen, serum creatinine,nd cystatin C.41 Increased levels of cardiac bio-
markers including troponin after extreme ET endur-ance events, such as marathons, may reflect myocar-dial cell damage at the sites of myocyte slippage ofone cell along another due to loss of integrity of des-mosomal connections.15,42 However, the significanceof the elevated cardiac biomarkers after endurance ef-forts remains uncertain, and it has been argued thatthese may be entirely benign transient increases result-ing from CV adaptations to long-term ET.12,16,38,43
ADVERSE STRUCTURAL REMODELINGAccumulating evidence suggests that the adverse ef-fects of both short-term intense PA and cumulativeendurance exercise are most apparent in the right-sided cardiac chambers. Cardiac output at rest isapproximately 5 L/min but typically increases 5-foldto about 25 L/min during vigorous ET.21 Long-term
aily sessions of hours of continuous strenuous PAause dilation of the RA and RV. During the postex-rcise period, the cardiac geometric dimensions areestored, but with this recurrent stretch of the cham-ers and reestablishment of the chamber geometry,ome individuals may be prone to the developmentf chronic structural changes including chronic di-atation of the RV and RA with patchy myocardial
50
40
30
20
10
00 10 20 30 40 50
Daily physical activity duratio
All-
caus
e m
orta
lity
redu
ctio
n (%
)
60 70
14%
20%
29%
FIGURE 1. Relationship between dose of physicalin all-cause mortality. The mortality benefits of exesmall amounts of daily exercise and peak at 50 to 6exercise per day. From Lancet,5 with permission.
VigorousModerateTotal
n (min)
80 90 100 110
35%
activity and reductionrcise appear with even0 minutes of vigorous
load and excessive cardiac strain.17-19,29,44 Theseabnormalities are often asymptomatic and probablyaccrue over many years; they might predispose toserious arrhythmias such as atrial fibrillation and/orventricular arrhythmias (VAs).
A prospective study of 25 runners (13 womenand 12 men) found that running a marathon causedacute dilation of the RA and RV, with a sudden de-crease in the RVEF.32 La Gerche et al45 studied acohort of 40 highly trained aerobic athletes aftercompeting in endurance events including marathon(mean time to completion, 3 hours), half-ironmantriathlon (5.5 hours), full-ironman triathlon (11hours), and alpine bicycle race (8 hours). Theyfound that these intense endurance exercise effortscaused elevations in biomarkers of myocardial in-jury (troponin and B-type natriuretic peptide),which were correlated with reductions in RVEF(Figure 4), but not LVEF, on immediate (mean, 45minutes) post-race echocardiography. The reduc-tions in RVEF and the increases in RV volumes,
6
Exercise
Sedentary
5
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3
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Fibr
osis
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0RV FW LV FWIVS
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4 wk
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osis
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1
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A
B
FIGURE 2. A, Picrosirius-stained photomicrographrats show widespread interstitial collagen depositioB, Mean � standard error of the mean collagen covs sedentary rats). FW � free wall; IVS � intervventricle. From Circulation,24 with permission.
which returned entirely to baseline within 1 week,
Mayo Clin Proc. � June 2012;8
were seen most often in races of longer durations(Figure 5). Of this cohort of endurance athletes, 5(12.5%) had myocardial scarring as detected by fo-cal gadolinium enhancement on cardiac magneticresonance imaging (MRI) (Figure 6). The myocar-dial scarring and chronic RV remodeling were morecommon in athletes with the largest cumulative ex-perience in competitive endurance events.45 Insummary, this study suggests that intense endur-ance exercise induces acute RV dysfunction whilelargely sparing the LV. Even when short-term RVrecovery appears complete, long-term training forand competing in extreme endurance exercise maylead to myocardial fibrosis and remodeling in asmall subgroup.9,20,21,45
Ector et al29 reported that the decrease in RVEFis less significant in athletes with no symptoms ofarrhythmia than in endurance athletes who havesymptoms of arrhythmias, in whom the RV size in-creases and the RVEF is significantly lower. Anotherstudy of endurance athletes who have symptoms of
LV FWIVS
wk 6
5
4
3
2
Fibr
osis
(%)
1
0RV FW LV FWIVS
16 wk*
200 µm
16 wk
RV FW sections
Sedentary
Exercise
RV sections. By 16 weeks, the RVs of exercisingith disarray of myocardial architecture (arrows).t in RV FW, IVS, and LV FW. *P�.05 (exercisingicular septum; LV � left ventricle; RV � right
normalities by MRI.46 This RV dysfunction is likelyinduced by recurrent extreme and sustained high-level PA, with marked elevations in pulmonaryartery pressures of up to 80 mm Hg in some ath-letes,9 which eventually may cause scattered areas ofmyocardial injury (as evidenced by the increases introponin) with subsequent fibrotic scarring, typi-cally in the RV and atria.17,22,23,29,31,32 Theseobservations have led to speculation about the exis-tence of a syndrome of exercise-induced arrhythmo-genic RV cardiomyopathy that shares some featureswith the familial RV disease but is caused by chronichigh-level endurance ET rather than a geneticpredisposition.9
Another study using MRI to assess the effects oflong-term very long distance running on myocardialstructure31 comprised 102 ostensibly healthy malerunners ranging in age from 50 to 72 years who hadcompleted at least 5 marathons during the previous3 years, compared with 102 age-matched con-trols.31 Approximately 12% of these apparentlyhealthy marathon runners have evidence ofpatchy myocardial scarring, manifested as late gado-linium enhancement; this was 3-fold more commonthan in age-matched controls. Of additional concern,the CHD event rate during 2-year follow-up was sig-nificantly higher in the marathon runners than in con-trols (P�.0001).31 A similar smaller study foundpathologic myocardial fibrosis by cardiac MRI in 6 of12 asymptomatic men (50%) who were lifelong vet-eran endurance athletes, but no cases in younger en-durance athletes and age-matched controls.24
Aortic stiffness and arterial pulse wave velocity,which are markers for adverse CV prognosis,47,48
may be increased in veteran ultraendurance athletes.A study of 47 individuals who trained extensivelyfor and competed in marathons found that pulsewave velocity and aortic stiffness were significantlyhigher in the group of marathoners compared withcontrols.49 It is possible that the sustained shearstress caused by protracted endurance efforts even-tually may induce fibrotic changes and decreases inarterial wall elasticity. Diastolic dysfunction of boththe RV and LV has also been observed in individualsdoing long-term extreme ET and racing.50,51
CORONARY ARTERY CHANGESVeteran endurance marathon runners in one studyhad coronary arteries that, at resting baseline, weresimilar in size to those of sedentary controls, but themarathoners had greater coronary artery dilating ca-pacity.52 Mohlenkamp et al30 studied 108 middle-aged German long-term marathon runners andcompared them with matched nonrunner controls.They observed a greater atherosclerotic burden inthe marathoners as documented by higher coronary
artery calcium (CAC) scores. Additionally, during
Mayo Clin Proc. � June 2012;87(6):587-595 � http://dx.doi.org/10.10www.mayoclinicproceedings.org
follow-up the adverse CV event rates in the mara-thoners were equivalent to those in a populationwith established CHD.30 In a similar study,Schwartz et al53 reported on a US cohort of long-term marathon runners, defined as individuals who
100
75
50
25
hs-c
TnT
conc
entr
atio
n (n
g/L)
0
Upperreference
limit (14 ng/L)
1 wk before race
Immediately after race
24after
FIGURE 3. High-sensitivity cardiac troponin T (hsbefore, immediately after, and 24 and 72 hours afteMed Sci Sports Exerc,40 with permission.
55
P=.05050
45,47
40
35Baseline Post-race Delayed
RV
ejec
tion
frac
tion
(%)
Marathon (3 h)Endurance triathlon (5.5 h)
Alpine cycling (8 h)Ultratriathlon (11 h)
FIGURE 4. Duration-dependent effect of endur-ance events on right ventricular (RV) ejection frac-tion. From Eur Heart J,45 with permission.
25 years, and found higher than expected levels ofCAC and calcified coronary plaque volume. Thatstudy, utilizing computed tomographic coronaryangiography, found that the long-term marathonershad significantly more calcified plaque volume thansedentary controls (mean, 274 mm3 vs 169 mm3).In a case report, Goel et al54 observed a 49-year-oldmarathoner who had significant obstructions in all 3major epicardial coronary arteries without associ-ated risk factors and who generated protracted oxi-dative stress with prolonged running.
In another study of veteran endurance athletes,mean LV mass, as determined by MRI, was signifi-cantly greater in a group of marathon runners thanin controls, and the increased LV mass correlatedwith higher CAC scores. Specifically, those mara-thoners with an LV mass greater than 150 g had asignificantly higher CAC score than those with anLV mass less than 150 g.30 The investigators alsofound a mismatch between the risk factor profileand the amount CAC, particularly in the marathon-
line Post-race
+9 mLP=.015
–7 mLP=.003
+13 mLP<.001
–5 mLP=.011
150±23 mL
66±14 mL
ffect of prolonged intense exercise on right andaseline volumes are shown on the left, and therace are shown on the right. Right ventricularpost-race setting, whereas left ventricular vol-
ng in a decrease in right ventricular ejectionicular ejection fraction. From Eur Heart J,45 with
ers with an LV mass greater than 150 g. m
Mayo Clin Proc. � June 2012;8
PATHOPHYSIOLOGY OF LONG-TERM EXTREME ETFigure 7 shows the pathophysiology and possibleadverse CV consequences (fibrosis, atrial arrhyth-mias, VAs, and SCD) associated with enduranceET and competition, such as marathon running.Individuals who do long-term ET and race oververy long distances induce sustained (often for 1to several hours daily) elevations in heart rate,blood pressure, cardiac output, and cardiacchamber volumes.9 Heavy and sustained ET gen-erates large quantities of free radicals55 that likelyoutstrip the buffering capacity of the system, leav-ing these individuals susceptible to oxidativestress and transient cardiomyocyte dysfunction.45
This repetitive cycle may stimulate immune cells,including lymphocytes, macrophages, and mastcells, to secrete cytokines that signal the myofi-broblasts to proliferate and secrete procollagen,which is then cross-linked to form mature colla-gen,41 eventually resulting in fibrosis deposited in
atches in the myocardium and more diffusely inhe large arteries.9,46
PROARRHYTHMIC EFFECTS OF EXCESSIVEENDURANCE ETAlthough it has been recognized that elite-levelendurance athletes commonly have electrocardio-graphic abnormalities and atrial and ventricularectopy,28,44,54 these functional adaptations tradi-ionally have not been thought to predispose to se-ious arrhythmias or SCD. However, it appears thatdverse cardiac remodeling induced by excessive ETan create an arrhythmogenic substrate, and rhythmbnormalities may be the most common CVroblems encountered by veteran endurance ath-
etes.29,31,54 Indeed, long-term sustained vigorouserobic ET such as marathon or ultramarathon run-ing or professional cycling has been associatedith as much as a 5-fold increase in the prevalencef atrial fibrillation.19,30,31,37,55-63
Potential mechanisms underlying the associationf long-term excessive exercise and atrial fibrillationre speculative but may include increased vagal andympathetic tone, bradycardia, inflammatory changes,trial wall fibrosis, and increased atrial size.59 Someata indicate that atrial size may be larger in veteranndurance athletes than in age-matched sedentaryontrols.64 Indeed, the left atrium may be enlarged in
as many as 20% of competitive athletes, and this maybe a predictor for atrial fibrillation.59,64
In addition, complex ventricular ectopy, in-luding ventricular tachycardia and rarely SCD,11
occurs even in very fit individuals.12,29 Despite theact that these studies generally excluded athletesith findings suggestive of familial arrhythmogenicV dysplasia, the VAs typically originate from a
End-diastolicvolume
End-systolicvolume
Base
170±30 mL
83±17 mL
FIGURE 5. Differential eleft ventricular volumes. Bchanges in volume post-volumes increased in theumes decreased, resultifraction but not left ventrpermission.
ildly dysfunctional RV and/or the interventricular
septum.20,29,46,65,66 The patchy myocardial fibrosis(fibrillary collagen deposition) that may develop as areparative response to damaged myocardium canfavor reentry, which is well established as a substratefor arrhythmia.29,51
Long-term extreme endurance ET and competi-tion also stimulate multiple other disruptions, includ-ing episodic release of excessive catecholamines withresultant coronary vasoconstriction, chronic elevationsof heart rate, changes in free fatty acid metabolism,lactic acidosis, and metabolic derangements.41
RISK STRATIFICATION FOR ENDURANCEATHLETESCurrently, we have no proven screening methodsfor detecting potential CV pathologic changes asso-ciated with extreme endurance ET. A logical strategyfor now might be to deploy postcompetition cardiacbiomarkers, echocardiography, and/or advanced im-aging such as cardiac MRI to identify individuals at riskfor and/or with subclinical adverse structural remodel-ing and substrate for arrhythmias, but the cost wouldlikely be prohibitive.65 Computed tomography forCAC scoring may be useful, particularly for those olderthan 50 years who have been training extensively forand competing in extreme endurance events. Exercisetesting generally has not been found to be helpful inscreening extreme endurance athletes, nor has cost-effectiveness or clinical yield been found with the othertesting described earlier.
An obligatory pattern of compulsive and exces-sive daily exercise has been described that may haveadverse long-term mental and physical health con-sequences.67 A questionnaire developed to identifyobligatory exercisers may be useful for screeningveteran endurance athletes.68
CONCLUSIONIn some individuals, long-term excessive endurance ETmay cause adverse structural and electrical cardiac re-modeling, including fibrosis and stiffening of the atria,RV, and large arteries. This theoretically might provide asubstrate for atrial and ventricular arrhythmias and in-creaseCVrisk.Further investigation iswarranted to iden-tify the exercise threshold for potential toxicity, screeningfor at-risk individuals, and ideal ET regimens for optimiz-ing CV health. For now, on the basis of animal and hu-man data, CV benefits of vigorous aerobic ET appear toaccrue in a dose-dependent fashion up to about 1 hourdaily, beyond which further exertion produces diminish-ing returns and may even cause adverse CV effects insome individuals.
Consensus Guidelines for Physical Activity and
Public Health from the American Heart Association
Mayo Clin Proc. � June 2012;87(6):587-595 � http://dx.doi.org/10.10www.mayoclinicproceedings.org
Normal
FIGURE 6. Delayed gadolinium enhancement in 5 athletes. Images of 5athletes in whom focal delayed gadolinium enhancement was identified inthe interventricular septum (arrows), compared with a normal study in anathlete (top left). From Eur Heart J,45 with permission.
Long-term effects↑↑Cardiac chamber sizesPatchy areas of fibrosis
↑ Atrial arrhythmias↑ Ventricular arrhythmias
↑ Incidence of SCD
Chronic trainingLV dilatation
LV hypertrophy↑LV mass
Extreme exercise efforts(eg, marathon)
CatecholamineO2 Demand
↑↑↑↑↑↑Preload and ↑afterload↑Troponin, ↑CK-MB, ↑BNP
↑
Immediate effects
Right heart strainRA/RV dilatationRV hypokinesis
Diastolic dysfunction
↑
Subacute effects
Cardiac fibrosis
↑
FIGURE 7. Proposed pathogenesis of cardiomyopathy in endurance ath-letes. BNP � B-type natriuretic peptide; CK-MB � creatine kinase MB;LV � left ventricle; RA � right atrium; RV � right ventricle; SCD �sudden cardiac death.
and American College of Sports Medicine call for atleast 150 minutes per week of moderate ET or 75minutes per week of vigorous ET in the general adultpopulation.1 Those guidelines also suggest thatlarger doses of ET may be necessary in some groups,such as those with or at risk for CHD (30 to 60minutes daily), adults trying to prevent the transi-tion to overweight or obesity (45 to 60 minutes perday), and formerly obese individuals trying to pre-vent weight regain (60 to 90 minutes per day). Theguidelines also caution that high-intensity ET in-creases risk of musculoskeletal injuries and adverseCV events.1
Abbreviations and Acronyms: CAC � coronary arterycalcium; CHD � coronary heart disease; CV � cardiovascu-lar; EF � ejection fraction; ET � exercise training; LV � leftventricular; MRI � magnetic resonance imaging; PA � phys-ical activity; RA � right atrium; RV � right ventricular;SCD � sudden cardiac death; VA � ventricular arrhythmia
Correspondence: Address to James H. O’Keefe, MD, 4330Wornall Rd, Ste 2000, Kansas City, MO 64111 ([email protected]).
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