{610262 !rINy wo Aq Mo'sjeumoleyR/raayy WOH popeofuoc Endurance Exercise and the Right Ventricle Weak Link, Innocent Bystander, or Key Ingredient? Meagan M. Wash he cardiovascular response to high-intensity exercise has irigued clinicians and scientists for more than a cen tury. Since the inal reports of eardiae enlargement among Nordic skiers! and rowers, grea deal has been lesmed about hhow the heart and vasculature remodel in response to endur- ance exercise. Through the efforts of many investigators and their athletic subjects, we now recognize the heart as an organ characterized by tremendous plasticity that permits chamber lation and myocardial hypertrophy in response tothe hemo- ‘dynamic stressors inherent in endurance sporting activity. Our contemporary view of the endurance athlete's heart includes attributes such as biventricular and biawial dilation, mild to moderate ventricular hypertrophy, and normal to mildly reduced resting biventricular systolic function (as defined by ejection fractions).” Functionally, this remodeling pattern facilitates stroke volume augmentation and thus increases cardise output reserve during exercise. Yt, ate these adapta ions that facilitate successful endarance sport participation and ead to optimal athletic performance cost free? More spe- xf Lo» afm} 5 14 a id d » > xl } 2] re 3 +s] “panes 10] p00 pros q 7 7 Peak Exercine ‘Right Ventricte (EA wa. NA) Pa ‘ © ence smn SS seamen La ae i 14 “room of | awe prec d Figure 1 Changes in end-systolic wal etrse with maximal exerci. Ina cohort of ables and non-athletes, RV wal stress (RVES-c) wat lower ac rest but increased to a greater extent such that It approx raved LV val stress (LVES-o) a peak exercise (A) LV ES-a increases with exercise were modest and did not differ between athletes and non-athletes (8), whereas exercise resuted ina greater RVES-c'nath- letes as compared with non athletes (Q). Reproduced with permission (romLa Gorche otal? can be substan. Augmentation in CO during exercke requires increasing fling volumes wahin shorter dastalc fling ties. This can be achievedby means cf greater ventric suction greater atria prestres, cor both Nonog' etal demonstrated that early dato ventricular suc- tion increases during exercise a a result improvements inactive vere ‘ticular relaxation"” but these were relatively modest and insufficient in thei on gh to generate the carcac flows required of ete sports per- formance (m excess of 40 Linn"), Such outputs require an increase inatia pressure to augment fow in adtion to the enhanced veniuar diastole properties. Relatively few stules have assessed left ail {5802 tenBny of uo is0n6 fa ZeEZGORISGHI/ZI/EL iRoensae-epIue sa:nseroIpJeO;NOD dno mwepEDe/sdiN WOH papeaUMCDBvercise and the RV 1501 » ow on 3 bn o . Sooo 0: me Figure 2 Greater RV coronary oxygen demand during exerce. Relation between myocardial oxygen conzumption (MV) and caro- ‘nary venous oxygen tension (CVFOs} inthe right verte (RV) and the left vervicle (LY) in dogs during treséil exercise. This demon strates that 25 exercise demand increases (progrestvaly greater MVO)), the amount of oxygen used i far greater forthe RV thereby suggesting that RV work creases disproportionate in the RV elaive tothe LV during exercise, Figure 3 Grester RV remodeling ina thoroughbred horse ‘Thoroughbreds are condoned for aerobic exercise and tras have been refined over mutiple generations ofin-breeing tis curious that inan anal wth one ofthe highest exercise care ourputs tht here Is relatively much grater RV remodeling The RV (enfid here with blue arrows is of sini wall thickness co the LV (redarrowa).A poten- ‘alexplanation for ths increase in RV walltcres is that the very car ac lowe during exercise raqure very bigh RV pressures and reautant Increasasin RY wallthickness, Pressures during exorcise but those that have suggest a progressive increase in left atrial pressures with exercise. Reeves etal measured pul- monary artery wedge pressures (PAWP ~ a surrogate of lef atrial pres sures) in eight heathy volunteers during intense exercise and a eee eee eee eee eee) documented marked increases in PAWP (up to 35 mg) and a fay strong correlation between exercise capacity, maximal CO and peak PAWP.'S Lewis etal also observed a strong correlation between PAP and CO in control subjects and measured an increase in PAWP of 1.1 CO (mmHg) for every litre of CO (Urnin).albet within a group with substantially more modest exercise capacity. Thus, avaiable evidence suggests that let atrial pressures increase in everyone but more 50 in ‘those with abnormalities in (ef ventricular function. This then also ‘wansiates to higher pulmonary artery pressures and RV load Furthermore, the increases in left atrial pressures ae associated with a decrease in pulmonary vascular compliance In patents with proven or suspected heart faltre or pulmonary vascular disease, Tedford et ol demonstrated that increases in left atrial pressures resulted in an increase in RV pulsatile load” and this has been recently validate in ‘heathy adits using a combination of invasive measures and cardiac 792" Thus, increases in left atrial pressures amply RV toad during ‘exercise. ivan thatthe RV has less mas, less wall thickness and possbly less comtractie reserve.” this dsproportanate increase in load has the potential o taste capacky of the RV. ‘The concept of ventricular interaction asan in series crcut ie simpli. 1c Increases in left atrial pressure are transferred back through the put monary circulation and amplified by the resulting nerease in pulmonary vascular stifness (reduced compliance). However, in addition, there are ‘Compiex in paral interactions by which the increases in RV afterload ‘may serve to lit overall CO. The heart is constrained wehina relatively Sti pericardium and, Inthe case of endurance athletes, constrained by ‘the anatomical constraints of a markedly enlarged heart within a core fined intrathoracic space Furthermore, ventricular volumes are tu fenced by the changes in intrathoracic prassures due to respiration, a significant pump for venous retum that's seldom considered.” In same settings such as congestive heart falure in which eareaefilng can poten- tially exceed the limits of the Frank-Starlng mechanism. increases in Fight ventricular fling can cause leftward shift ofthe interventricular sep- ‘umm because perkcardal constraint inhibits further dstension of the RV ‘ree wall? This septal shift can be further exacerbated by the combina- tion of inspiration (urther loading the RV by vencus return)" and by delayed contraction of the RV when the contractile reserves approach- ngs tits The result is that LV volume can be constrained in early diastole due to the inward movement ofthe interventricular septum on ‘one the side and the constrained pericardium on the other side. Thus, there i potential for an increase in LV early filing pressures despite a reduction in volumes. This mechani has been elegetly elucidated in patients with tricuspid regurgitation” and in heart falure where reduc- tions in venous filing can result in & paradoxical increase in early diastolic LV volumes The observation by Reeves etal. that there is @ strong Felationship between increases in lft and right atrial pressures during ‘exercise suggests that pericardial constraint hat an important infuence ‘on cardia function during exercise in trained individuals" but the extent 10 which this can contrbute to raised LY filing pressures has not been determined. Using real-time exercise CMR, we have documented a 14% increase in RV end-systolic volumes and an 8% decrease in LV volumes during the increased venous retum of inspiration ™ Ths implies ventric- Lar interaction through pericardial constraint and we observed that this persists throughout exercise, This raises the possiblity ofa vicious circle inwhich the brishness of LV early fling is attenuated by ventricular inter= action (via pericardial constraint induced Intervertricular septal shi) resulting in raised left atrial pressures and further Increases in RV aer~ load (see Figure 4). This concept of exercise limitation fs supported by evidence in rats, dogs, and pigs in which pericardectomy results in an ‘LOZ WnGny oF uo 80n6 ka ZEEzBOHEEHHIZEIC: LoeRsge-oHie/sesDSeRDpIEA/wOD'cno-oMUapeDEY|sdAy WOH PopeoUNEGAL Gerche eta 1502 opine nytt E a @ Figure 4 Summary of exercise physiology in a wellwrained subject. ‘Atrest when card flows are low, there are modest atriowenticlar Pressure gradients, (ow left atrial pressures and low RV pressures During exerci, the high-low state resus n substan tral ligand presiure build up during systole when the ario-vencular valves are loved (represented by the bie symbols). The rsuing increase in lef arial pressures Is ransfered back through the pulmonary ecla- ‘don and resuit in raed RV afterload, The increased RV load aterloas ‘causes RV dlaton (and potentally also some sight delay in RV contrac- ton), Because of pericardial constraint, the increase in RV volumes causes septal sh toward the lef ventricle in ewrty dastoe (lle arrows) that has the potential to artenvate erly caso fling of the LV and farther increase eft atrial pressures. Ths increases in RV after- load become a ental constrant during high intensity exercise in heathy subjects, increase in LV volumes, CO and maximal exercise capaci. but is dificult to test in humans lnrgungly, Kil eto. are investigating novel methods to enable minimal invasive percardectomy” 3s a means of testing the hypothesis that pericardial constraint may bea source of ii- tation when RV ciation is combined with the haemodynamic chalenge ‘of exercise, Heart falure with preserved ejection fracton in te sering ofobesity sone such example ‘Thus, RV aterioad increases sgnifianty during exercise because of several complex downstream factors. Given that increases in RV after- load may have greater potental to mit augmentation of stroke vol. ume.” probably as = result of ts lesser contractile mass, it sands t0 reason that itis the chamber that is most lly Co fatigue and iit CO during prolonged exercise bours 1.2 Prolonged intense exercise proportionately affects the RV “The increase in load onthe RV during exerci trarlaes a an increase in work, contacity and metabotc demands During bre tense exer cle. the RVs able to meet these demands such that arerio-entricuar couping is maiwaied, We have demonstrated that RV sstle strain rate and the RV end-ystoe pressure area relationship, two aon- RV Elect Fraction 04 Figure 5 Durationdependent increase right ventricular dysfunc ‘lon. RV ection faction decreased inthe post-race sting There was 1 gremer reduction in fnetion in those completing the longest event (ltrasriathion) relative to shorter events suggesting ‘dose-dependent fect of exercise on RY function. Reproduced wth permision from LaGerche erat invasive inices that best approximate intrinsic RV contractility. increase progressively during brief intense exercise in proportion tothe increase In pulmonary artery pressures." However, when intense exercise is _intaned for several hours, RV dysfunction resus, As summarizedina, recent meta-cnatysis, virtually all recent studies that have assessed RV function ater endurance exercise have identified sigfiant RV dysfunc: tion?® The degree of dysfunction seems to be greater the longer the intense exercise is sustained (see Figure §) and some studies have reported 2 correlation between the extent of RV dysfunction and car diac biomarker release In contrast, evidanca for LV dysfunction after prolonged intense exercise is inconsgtent with modest or no changes in function. A meta-analysis of avalabe information reported a negigble 2% change LV function in this setting” These post-race changes have almost always been measured during recovery soon after the intense ‘exercige bout thereby giving rise to the question as to whether these postrace changes were due to transient factors independent of intrinsic card funetion such as dehydration or vagal excess. However, two studs have been recently conducted toward the end of a prolonged ‘exercise bout, one using echocardiography and the other using exercise cardiac magnetic resonance imaging™” Both studies demonstrated reductions in RV function during intense exercise whist LV function was vnaffected 1.3 Chronic exercise-induced changes in cardiac morphology Given rat intense exerciser attocated wah disproportionate greater RY wal tres and resultant fig when compared wth the LV chronic 400mL which i appronimately ‘ie the size of normal cardiac dimensions. Mean RV end-dastotc vol tues of between 230 and 280 mL have been consirtently reported in ‘the tteratare 405505" Ths, when considering ranges of oral using, Standard deviation and bootstrapping volumes of 350-A00mL may be considered normal, Notably, ventricular volumes quantfied using 3D echocardiography are substantially less, perhaps reflecting the fact that echocardiography tends to underestimate volumes, particularly in the apex and outiow tract °5* These increases in volumes can result in Lunusval morphology, Bulging ofthe basal free wal ofthe RV and around ‘he moderator band canbe 2 commonly observad feature ofthe volume loaded RV.""” as exerpifed in gure 6. These features can easly be rmistaken for wall motion abnormalities or aneurysms, particulary when clinicians are unforilar with assessing che hears of endurance athletes. Mathematical the same stroke volume elected from an increaingty large RV rests in a progressively smaller RV ejection fraction (RVEF) This may be part ofthe explanation as to why athletes have low meat- ures of RV systolic function. RVEF measuring between 40% and 45% canbe observed in up to 15% of elite endurance athletes“ Simtarty. RV fractional area change (2 2-cimensional approximation of RVEF) is low in endurance ahletes"*?** jn a cohort of 63 elte endurance ath- letes, Teske tot" measured RVFAC values of 372:5% translating to approximately half ofthe athletes being below normal cutoff valves. Similarly, measures of strain and strain rate are reduced (ess negative) in elte athletes, partcerly amongst those with greatest RV Siaton Figure 6 Prominent RV remodeling in heathy athlete creating sppearancesthat could be confused with pthology. These carcae mage Peli resonance scan illstrate commen features reauting from RV. {lation = busing of the Eas! fee wall (Nghlghted with red ine and blue arrows and mild fetening of the terventrculr sepsur). Tie ‘paeudo-aneurysmal’ appearance can ety be confised with archyt> smogenic carlomyopathy. 14 wos popEqLMIOG reseiosencipregoo dno awopeat oz venBny of uo s0n6 Aq zeezeonisarL ener mnensae-o1504 AL. Gerche etal it would seem loa tit the high prevalence of dition and tow functional measures ofthe RV cannot be signs of pathology in the clear mejor ofatletes given ther excallent heath outcomes *” This ere esa signfeae issu: 3t what pont should the cian be concerned about RV remodeling in the athlete and how should the ahete be ‘ranted? These ae questions that are et to be answered. Large pro spective studies are required to assess wheather those athletes with more extreme RV remodeling are at risk of clineat events such as arythmas. In te meantime, gven tht the prevalence of serious RV pathology amongst ostensibly heathy and asymptomatic athletes is lkaly to below, mest RV changes are ely tbe Benign and may not require comprehensive evaluation. Furthermore, there is 90 current ‘evidence to suggest that asymptomatic athletes with more profound RV remodeling should moderate thei training, However, ful evalua ‘Bon shouldbe undertaken in athletes reporting symptoms such as pal ators, syncope, fatigue, or unexpned reductions in exercse ‘capacity. Evluaton shoud ineude a ofthe diagnose test encom pussed by the ARVC Task Force Criteria fh aden, eis may consider referal to a centre with experts in athete evaluation and some of the novel tests dscused below tht may have some novel agnostic uty inthis setting such as exercise RV raging’ and ele. ‘wophysiologcal testing!" 2.2 Overlap between arrhythmogenic RV cardiomyopathy and athlete's heart — environmental genetic interaction “There is potenal fr dagostic overlap between arrhythmogenic right verteubr eardemyopaty (ARVC) and athletic cardac remodeling pve that athletes commonty have markedly dlited RV volumes and ‘reduced meatures of RV function, Moreover there i sore evidence to suppor the concept thatthe extrema haemodynamic stress of exercie may promote arbythmogenc remodeling in some ahetes even inthe absence ofa recognized fail precspostion. ARC Is 2 fala carmyopathy associated with abnormalities in the structure, fiction and eectroptysologal prapertes of the myo- card. A genet mutton can be idetfid in approximately half of ARC patients, most Frequent n one ofthe fay f genes astciated with he Incegrty ofthe ceemosomal genes a provide tructralineg- rey between the care myocytes. For reasons that are incompletely understood, there Is considerable phenotypic variably such that the same mutation may cause severe heart fale and arrhythmias in ne patient and no symptoms in another These dferences might be explained by addonal genet factors such 28 variation in mor {genes Silat, undscovered genetic mutations may explain the ha of ARV pauent in which current genetic tess prove negative, On the other hand is pote that tis phenovypcvarlason may Be due to eevironmental factors ar ntracton between envronmentaland gece influences. Gven the profound effect that exercise has an RV function and srucure, would sem a logic candidate as an environmental stressor that may exacerbate any Intrinsic decency in structural neg rity of the myocarsum. The concept of a genetic envconmentl interaction fs an atractive typothes to explain phenotypic variably and there are few examples that are as well evidenced 25 the interaction between exercise and [ARVC Evidence spars the spectrum from purely genetic dsorder to predominantly ewrormenta cause of a common phenotype (ln identical condion. In highly waned endurance athetes, Heschel et ol. proposed that ARVC could be cause by extreme exercise, Independent of any genetic risk. After observing a recurring clinical pat tern of RV arhythmias and mild RV dyshunetion amongst professional 50h per year of intense aerobic exercise As compared with the non-athletic subject, e—\HA ‘endurance athletes developed symptoms at @ younger age, were more likely to meet TasksForce criteria for ARVC. to develop ventricular arrhythmias and to suffer hear falura Smialy, in 2 large United States Patient registy, participation in endurance sport was associated with s- lease onset one decade earlier than sedentary subjects or those engaged in recreational exercise and competitive athletes hag twice the rate of ventricular arrhythmias and sudden death.” Finally, an elegant study by Saberniak et al demonstrates that amongst patients with ARVG, athletes had reduced measures of RV function by echocardiography and MRL wher compared with non-athletes. They documented a moderate Inverse relationship between the amount of regular exercise performed and measures of both RV and LV ejection fraction,” Thue the evidence supporting a relationship beween strenuous endurance exercite and severity of ARVC disease expression is competing. The degree to which cther environmental factors (eg, intercurrent linesses and nutrition) contribute to disease expression is yet tobe determined. 2.3 New tools for discriminating between disease and health The difecentation bewreenathstic cada remodeling ad carionys pay can be exremely calengn, ts very important bat he Gog. rosti proces Goes not rayon resting measures of arin volumes and function alone. As ras been cused exon in te review, meas ures nathletes are requenty well ose the bounds of that absense inthe general populavon an do notecersary sgn pathology in thir cum ight Petaps one of the masimporant signs in ent puch ofyis he presence of symptoms. Thre ne current evidence to sug ast that RV remodeling shletes can be a harbinger ofa Serious Underlying digrasisn the absence of symptoms Some advanced technique hive ben proposed oastin the eval- son of heather with suspcicu symptom and abeormaies on frst line evasion of cardae structure, functon and elec-ophyiology Heidouche eta reported thatinducbitycuringanelecrophyseloget study was the ony cna tol that could pret ates a ak fer ‘ous arrhythmias with reascnable accuracy? Corrado et al used vos pope9.mog1506 AL Gerehe ett Prenotypicexpresion isk Figure 9 Threshold for phenotypic expression for arhythmogenic ‘cardiomyopathy (ARVC) a8 a spectrum of genetic and erironmental ‘sk. Genetic and environmental factors. such as exercise combine © reach a threshold at which the ARVC phenonpe is expressed large {genetic can cause cic ARV with ile exacerbation fom exer- ‘cee. However, more madest genetic risk may requre significant adc- tional modicaton from exercise stress. Whether extreme exercise can cause an ARV phenotype with ttle or no genetic rk remains controvers lectroanatomieal mapping to define areas of low voltages suggestive of «car in the RV outflow tact and demonstrated that this was associated ‘with inflnmation and scar consistant with ARVC in all cates! ‘Somewhat n contrast to these findings, Venlet et ol. performed electroa- ‘atomical mapping ofthe RV and reported that scar extending beyond the RV outlow tract to the sub tricuspid region was highly suggestive of ARV whereas scar locaized to the RV outflow tact occurred excl: sively in endurance athletes, was not astociated with a diagnosis of| ‘ARVC but did have the potental for fest sustained ventricular arhyth- ‘mias and possible ventricular fbrilation®* Thus, the endurance athiete phenotype is complex but ths data may explain some ofthe association between ARVC-lke disease inthe absence of genetic disease, The dsad- ‘vantage ofthese techniques is that they involve invasive procedures and highly specalized techniques. The Bordeaux group of Haisaguerre reported excelent diagnostic accuracy of using a high-dose isoprenaline Infusion to induce complex RV arrhythmias as a marker of underhing, ARV.” The extent to which this technique may be applied to athletic ‘cohorts is yet to be determined, Finally, we approached the issue of aif: fecentiating athletes with complex RV arthythmias from heathy athletes ‘withthe assumption that arrhythmias were an early manifestation of subtle cardiomyopathic process (ie. exercise-induced arrhythmogenic RV cardiomyopathy) and hypothesized that the haemodynamic stress of ‘exercise would accentuate RV dysfunction in athletes with arrhythmias ‘even inthe absence of normal resting RV function. Whilst echocardiog- raphy and CMR measures were simiar between groups at rest. RV func tion id not augment with exercise when compared with a normal Increase in contractile function in heathy athletes and non-athietes? These data support the concept that acute RV load excess during exer cise can be used to identify sub-clnical myocardial dysfunction that is associated with pocentialy serious arrhythmias in athletes. This concept supports observations in other disease settings. Exercise and pharmaco- logical stress can be used to identify sub-tnical RV dysfunction in other conditions including pulmonary hypertension?" heart failre”*”” ‘and vallar heart disease.” In each ofthese situations, the abnormally ‘Increased load on the RV is increased further wth exercise and can ran= estas RV dyshinction. 2.4 Therapeutic implications “The substantive evidence inking endurance exerclte with early expres- sion and accelerated progression of ARVC would suggest that abet. rence from intense exercise isan important therapeutic intervention in predisposed individuals. As discussed earlier, competitive sports precip- tates disease expression at an earier stage in individuals with genetic susceptiality but no clinical evidence of disease (the so-caled ‘gen- (0+ velpheno-ve patients’. Similarly, in those with clinical features of disease, arrhythmias and premature death are more frequent amongst competitive endurance athletes” Thus, it would seem that advice to limit exercise isan important therapeutic intervention in patents with [ARVC. Some recent guidelines reflect these advances in the under- standing of disease modi ters and recommend avoidance of competitive fr endurance exercise in subjects with clinical or genetic evdence of lisence Another intrigue is whether the interaction between exercise and [ARVC will prove to be 2 prototype for discovery into environmental and genetic interactions in other cardiomyopathies, The effect of exer- cise on the expression of hypertrophic cardiomyopathy and diated car= iomyopathes has received lle attention. fit long recognised that ‘exercise may serve as a trigger of arhythmic events in predisposed ind= viduals butt remains to be determined whether exercise can ater the underlying dsease substrate in some settngs. 3. Conclusion Exercise & associated with unequivocal health benets and resus ‘mary structural ane fonctional changes ofthe myocardum tha enhance performance and prevent heart flue, However, interes exercise a6 presents a spine hemodynamic change I which the righesied hear chambers are exposed toa deproporionate increase in aertoad and wal sess that cn manifest az myocar fatigue or even damage if intense exere is tustaned for proionged periods, The long-term eect of repeated bouts of intense endurance exercise isa sghly greater cnargemant ofthe cgheaided heart chambers as compared with the leftsided chambers. Inthote minor of athletes who develop ventriu= lar arrhythmias, the argh of arya s most ely oe i he RV and is requenty asociated with more pronounced remodeling and rl dyson of he RV, Thus, the right-sided heart chambers should be carefully appraised when astessng endurance athletes presenting ‘ith symptoms thas been wel established that chere san teraction between exercise and genetic abnormalves in cardiac seuctral e- ments that can manifest as arrhythmogenic cardiomyopathy. These cbienations suggest that endurance exercise should be avoided In invidsls with cnkal or genetic evidence of arrhythmogenic «cardiomyopathy. Conflict of interest none declared Funding ALA G sported bya Career Development Fellowship from the Nasional Heath and Medical Reseach Counc (NHMRC 1089039) and a Faure Leaders Fefowstp from the Natioral Heart Foundation (NEF 100409) of Ara 6102 wsnfny oF uo 9n8 faq ZEEZBOMESPLIZLIEL LNdEAsGe-eIUe/seL2SeAOIpIEORLOD dho-OEPEDE/SCIY WOH PSpEORNOGExercise and the RV 1507 References 1. pei SE. Baber GO, Semper, Robison BF, Bunmalé &, haar of ‘he rely responce eras upg exarese mnovm state ne pect woh nese nie Crs 1967367019106. 2 Guyan AC Repston of care uous Engl Med 1967277808-81, 51 1a Gerebe A. Heder! M Burne AT Mooney O) Tar AL Poger HE. ne Wh Macsae A. Por DL Diprooortorazeexerese io an ramos the th lees rae verre Wes So Spor une 0414874 981 41a Gerche Miche A, Barn A. Mooney D) nde” Wi Voi N Hedbce Pree OL Pmonaytancof guts const 2 asecated wh enboed puro ‘ay vasase reser ad gh rewalar eelon durng tare. A. Pel (2965) 010409 97-207, 5. DAndren A NsfeR, Dato Argo P Gls E Cocoa Rig See BR Linongelh G. O Sth, Gre Riza P. Rutto MG, Cabra Boxers & ange in pulmonary artery ysl presixe among phy Saned thee hee aorta 798-795, 46 Argento #. Chase NL Fule PL Dato M ossoneE. Unger Nani R sere sas echcarogpy fr he sty othe pmonay cretion Er Resp] 210, asim, 7 ows G Betis A Schl, OlchonsiH Pumerry arena presse surg eat and earose sty subjects 4 aaterae revem ar Rape) 200934 aoe 8 Chesay G La Garhe A Voi JU, Dana §, Sena F Feit T Wllons Cas. Osron M Heche. Aacray of choca ogy to eae puts rary sear ad RV neta ur everce ACE Crs age 291695923 9 UGorthe A. Caeser Dyna, VoiU. De ack» Vachon Oroopne i Wan Cleampi Cau? Haithchel HBr nce rig verti Se funn asia wh vente hyn in enarace ate Pu Heo) poisaatvie 2010 1 Lew GD. Bosioe E Nasje R Grane €, Serf Lancelot P, Go 5. var | iptopn 5 Oud Ruban MPumonay water nemadjnane ripore fe setae ncardonumarary Siete Coon OVIAIRIE7O 107. 11 Hone. Ls BM, StborO, See L Maran, Gone, dor Fa Pret Ginher 5, Huber, Soneeny 6, Carts D. Cite for aprons exes pulmanary peterson, a Fees 201846 728-797 12. Gere A'Chsen 6 Vin ae rane A Pay Nan Clann Gia Boge | OyrarowahS CaurP, Hach H Care MR nw god tard fer veurear vole qunutenton cng hahrotnetyexarcie. Ge Coton ogre 20186325-338 13, Duck Bache) Reguston of coronary blood am dng arc Pry 200886051088, 14 La Gee A Clete C. eened fw, din val, end upteam pres: He ‘shybogea calnges a ava consequences of ve were AC Cais rap tea 1891391 1S, Reo Groves Bt Cmernan , Suton J, Wagte FO, Tuanch D, Houston (CS Opersion Evrs I ere Nlrgpramures aig cycle vere te ev ep Py 9508087-154 16 Lew GD. Marghy RM. Sah RY, Pappaganpouls FR, hows R ioe KD. Sprom Di, Semiran Ml Pulmonary wiser resprse pater sig exec int vowrieuir stoke ercsan bade tare copcny and atcmes Cre Motel one 6-25 17, NonogH, Hess OM Rita M Krayerbuehl HP. Dino propa of he rer le venue dregs exc. rhea 98860 20-38 18. Lede BD. Yama wnt co we nn, Sd whe owe lad tka? ysl (ng 20065863526. 19, Tesord Rj Hasioun PH, Maha SC, Gg RE, Rul SD, Temasn DR, Cag (OH, Md J, Borg BA, Reid HP, Lederer Kass OA Paavo ein) ‘wedge pressure signers righ vercua pulling. Cit 2OT242S 9-097 20. Wt SP. Graton J, Ets. Goodran M, Mak S.The elton of pln sary vcr rsa ard eamglane Fo unoray ay mec pest oe bra exerci ea ober acts) Pe ae) 20158949007-105, 2, Casea G. Li Gerte A. Dyin § Clas P Beero ML Heche! Purorary asin and ng erreur reeree pen ith naman sing Inenosames ar pubnorary endarterectomy on Hoar Sune DIS 4001662, BFA Yonagah§ area ¥Myanak.Sheahae M, Baa G Toro H Ioeearg cron pram presiute on dtl snd apie perormance Drorouneed nat vee han me veereie, Cars as GIN E- 23. enews A tyra PM. Seeendy P. Lansnburh B®, de Roos A Bat Dares rzgans ofthe right ar lei vei to budge orale an eth pla HR sty na animals omput ss Targ HBARSD- 57 24 Chasen G Chu P, Cera Boge. La Gee A Heche Heaton Leonean eration i ip erat et vena vooas arate arg eee a a rates cine agree renrance sv), ) Pia! Moot Ce Syl aoven06ere Hae 25, Ahern J More TD. Lele $5, Thomson HL, Gata, ee | Tybee Fromm “P Oestole verter meriton in etane har Tue tes 97 Bar 720-174 26 Pew J. Gan CT. Zanerbug J. Boon A, Art CP, Gaste My. Vork Noorderaaf A tent mechanical jen in pdronsy ar yer tenson: eto gre dl in pak shrtening a rete cari nel crrond set vr andeiing Ay Cot Cre OBST 750-87 17 Arcarsen | Nahmurs RA Bs A. The hamodprami bn of exer ne nce m eurpd roprgaten Gr eat Fa 20147919 17 2. Heamond He Wit FC hargva V, Shit. Hewt se rd asin cardiac ‘ouput ar lrted by ne erator A Pye 126M DTS SE 28 Srar-Guncesen | men Haeet GE, Swan OP Orbyay GA Mice The tet of prea en sna urge carsanpton nina crdoe cu pur mancaned dope Cc fer 1965852) 590 29 Cooley JD, Somze H. Care hyperwapiy: smergi eecs of prety ser eer 2 PS Bp al ed ITS HORS 31, Ku AML suk A. Desimone Cv Gab P Suter Power Lang O Lerman LO, doraug 8A, Aon) exing he vatesion fey wd sty of tperestaneous petrotamy 00. Casino Ea! 207728257 6%, 532 Chote Ready YR Paar SV, Maeno Boru BA rence sporting the entece of dsnet abe renctpe of hr ure wih peared eatin tractor crane 207 4366-18 53. MeN WPnopylloy of or plore hy shrane ctevucve perarcy i ste Part Or. Am ar re Cae Med 194450 899-052 Ur Gersne A tums AT Droog | case Al Hedtkel Prior OL Exerc Sain eateieapog derenses real gm veel case rest td Chines amoguout rnng mentor exdrace ites jn Sc Eero? amaasasiae et 35. hose AD. La Geehe A The ight tic folowing proenged enrnce eerie: tre we ovrookig te more Mporant se fe hear A tans ey pore Med 30549727. 36 La Garche A Burs AT. Moone Oder Wh, Tair Al, ager | Masse A Vettuthel Hi Pror DL Geren neces np venredir ncion a sar reroclieg erduanessheter Er Hert) 207299998108, 27, Frddeton N’ Save George K. Wyte G. Har Anz GL vert funcson mmasaly flowing polrges wareze 2 retary Mad 5 Spo Fame CEH 38. Stevare GM, Yaracs A, Hasler L, Kavaagh I Ch Koen 6, Wood €. ‘Sapthy 5 uence of exec ery sd arn 9 fut are ache Calpertuontans te hen barf Pe 20163943031-2044 39, Chasen GUIDO. Cnc PRT, Ghyne STEFAN, Varnerch PETER, Dprariowss STEVEN, LA Gerche ANDRE Heath HEIN. ig ven gue desonng unre tcurance stress an ener rae rap ora sy ed Spo Gere 20847172 2 Bot. Strader G Lnnmweter L Raniah A, Kemer Abbe inderrann We. Meer T, Snag} Rh ad wera tion ae ao mle ete maser sees 2 conroiad eraseennanend crdowcu Mage sora uty Cec IH6ADDIRI-1935 Peregin G De Coball FEigosta A Latah S, Tera La Tore A Baton inv. Seto De Masons A tu Alber GER 9! he porting che an ‘he ee and let vents merplog and oben of te ule teace ener 2 rrapece reson inagrg tne owas 31 spetctopy soy An Pas J doorsasas37-o42 42 ArbabZase A. Pestana Howcen F Parece RM. Znang Adm Mant Hipkowsty tH) Lovina BD. Care readeirg 9 ceronee to year of wre senurance ning Crafton 20¢44302°52-2168 “48 DaAscane F. Piet C. Cael 5 Ds Polo FU patio A lic A RY remodel Jag in Opp Atietes IAC Coco egg 2017 10385-395, ‘4 Baron Ch Tne HBr RG otrion WWE, Bagel Chaba Hon A ee orton AG ima, Buenhe DA Kam SM Pye ato and mgt veneer socture aed incon The VEER Right ante Susy Am] Rep Crt Cre Med ovina ate 48 Pratken NFL vas Tore Al, Moser A Mab WU. Cramer. Care retrece sles or ahees aa onabeas coracnd for 906 he a ih: lng hours wea rl se aan Pr Rha 201047 198-20, 46 Toe A Patten Ni De Bowe BV, Ves BK Mari EF, Dacveeins PA Creer Ecrocaropaphe tue ceforraton egg of nt rosa Se felon m enance dean. ur Per 20830969-979 47 Kim Pt Nesey 2 MeCary D Yaree, Weer Wang F, Wood M, utr aM Pears nt Bapgeh AL Silence of lctroedapaehe re onde Urn ‘Sock in waned wee. df Gedo! 2181071089 1089, 46. Way 4 OnLue | Ware Baktrere 8 Aken KE. Earn A Lewis GO, ue” Ar, Weiner RB Baggy ALEC Mangan compete rowers normative {23 and he prelaee of brernaltee vig cotpory saering Tecan isons Br Spon ee 2015:49200-206. 49. Braman Mba Gerche A. Karun |, Lo W, Falion &. Maca A, Por DL Comparion of recueey of se eecrocetoqrptiesbnorrltis tend sce versa renansrace lee A Coe 4449 1587-1072 50 Brosnan Mj lesen G neisucre! H, Por DP. La Geren A Rig precordial T ave iveson in has endure atten ca be explana by erat ope tren of te ard apex MOC On Ect 21S 1 BM, 6102 nSny oF uo sen6 Aq ZEeZBOMEERLCLICL LMDeASGe-oPiE/seioeRNOpIENRHO dno OWOREDE/ SHY Woy paPeOUNOG1508 AL Gerche eral St. Madea PA Yat 5, ero Ceo, Lae C ers AP, Boa, Gene (GF. Diferere pron actor acon he the rit and ik vets n exper telune ove Hypeeeen 200643107108. 5, Rea YN OosaaM.Oean PG Matera ¥ Nat KA, Boi BA. Longa ca dort cage lowing reson of areroweno in pants wth age ev ee Ex Heat 2047 de 0107 are (esha of pet 53. Stang KE H,Bubve T. Grin M, Moen H, Wale 8 Arua eleven between cardacdivesens and pedk ygenwptac.j Coca Ma esen 2010428 4.12 Garebe A Bure AT. Tafoe Ab. Mace Al. Helduchal H, Pir DL Maxima ‘nye cnsunpon i best preted by mewures of crue rae an foe ‘on inte ads Eu] Ap Pl 2012412213214. 5, Overs A Rel, Hom 5, SeanfleR Str G,Caceha R. Gola Maron 5. Di Sivo G. Longo G Paco G Bostone E, Claro R Russo MG igh er ‘weske morphology tt function epee set reese enor togaphi sy An Sex Een 201225 1268- 1276. 54, Pratien NH, Tete Aj Caner Moser A. beter AC, Mal WF, Desens PA, Vetoss 8 Heuston! conparton between schocrogry ae ce lint evan fhe thins heat 8] Sue Med 2012630 356 57, Pror Dts Gere A Theres ar Hear 207290947 95, 5. Clute Pt Waker 5 Mayen A aon Wh. Hojrars Seer DM, Sil ef the ese rvospacove cohort tof he lange of Orete macs nthe ro eners any 201234528508 59 Majon ET, Aner cquoin EI Helou N.Barthlt G, Celerra OS Bougsun W, CorbesH. Hermne O, Empana J, Rey , Taunt Joos X orally of Fech partians i te Tour de France (1947-2012) Ear Heo 0. Mares FL Metanra Wy, Sher, Bsso C. Bouck & Bluenke DA, Care Conade D, Cox MG, Dauber P Fontan G, Gear Hauer Nia A ard Frotanoaros N.S Sanborn OM, Stibrg Tan There G, Tontin JA Tesopouos A Wier T, Zeta Dagnows ot wrmogene tt ve ‘wake ansomyepsbyldapacs propored modteon of he tak ore oer (een 20104241593-1541 1. Vetet| Pers SA. onpied J, Aneois AF, Nee Y, den Ui DW, Kapl Roa Man Tien. BargeSchapvlé DO, Seal, Zappa’ Koes fepewdal gm venrearouow tract tar In ahater wh vane “Tacha dr Cok Crbel 201789597507 {42 Como D, Beno C, Lert Toba 8 Turin Sauce 8 ighre FP A “Tari G, Napocane Ramon A, Su G leo 5. Thane G Treedimer- sora eleoanstomes vgs mappig and hstooge evict of mca sre rahe veneer etlow sack teryearsa. J An Cal Carl 200884 1, acct HM, Hoogneen Fae. Vaeus Er H. Wan Van Lie ih prelance orgy vertu ivan endurance theres wth ene lsraryenie Role of an sacvophyslage Fyn nk rsfeaon Eur He pooae 148, {4 Cora DLink M5, Cains H_Arrytmogee rif venta cardemopahy. N [Eng eg 201737665-72 LLsGerea A Rbbereht C Kaper C Napa O, ilar de Reel, Mats {G Heschel H. Lower than expected demovomal gene rtetonprelenee# ‘cure sles wih comple verre army of rg veer orga non 20V096:266 1274. (6% Shwant AC, honsle Ae Re AS, Tcl, Murty Rush SO, Tan H. “eoford Rg DP. Caer H, ames CA Exerc ns 9 dipropetote re ‘te puhogens of enhytimegen rit verklr dplatlearsemyepey = punts shout demorarsl matxions. Jr Het Anse 20143001471 cot Fors Zane M, Wet H,StfersM,ZaternofS at M.A T ile ibs HAC Beabure Rue P, Wetter T, Les B Age and ears “ cepandert demlopmant of rycen rg vet crsomyopity i ‘corygunpielobn- etre ce raktin 200 4147991906, (6 Sem Chowahry 8 Sens Ward D. Aaah A Sel 6 Mans YM, Cine and ete carteriscon of filer weh arhenoge rh errr yal ‘aréomopathy poder rove ugh io. patars ef dusee preston, (Geaagen 2007461710-1720, 6. jes CA Bone A Te C Mary B, Rs SD, Tacs Tedd Rh Je DP, Cabs HExercie inves agreed penerwce ad wfc ek rihnimogee rah sennesar dypaealardomyopstn. arom Seer ‘ration cars j al Cdl 20 382:1290-1297, 7, Roald AC. Marci F Een NA 3rd Lik M, MENS, Pray 8, Cains H Tent JA on A, Zeb W. Asscinion of compete ad reenon Por aropiton wen araac evn In peveres wih armyemogene ng ere ‘récenypuy: render he Noth Aran muacay say of arth ogee ght vere exrdomyoprby. a Heat] 201596 75-178, 71, Storm Hassberg NE. Borat RPatonoy PC. Suva. Sh Hl Abe M Hot AG, Eavarsen T, Haun Rit Vigrous physical acivtympas myocral fireson my prbent wth arhynmogene mgt wear cory ad ‘muaton pote amy mombers Eu Har Fal 1OMNGDIT-ABA 172 Deis A Schr F Dera N in Hs. Cocet H. Shah A Only Mls X Rano i Rematsu ¥, Zrmoura A. Anrac 5 iter P,P, Borda , Hoc [iP Haimaguere 8 Oagosie va of roprotrena eng aeytmngee ap weer earemopaty, Cc Ayn Ear 0147590 97 72 Sma T, Lau M, Chausrery P, Torso 7. Mance PA Smeone UR Nace R (Celersjer OS. Dabwamin srs er evan of igh verre rear nl rmorry ara hypetesion Eu es] 20754.70- 708. 74 Cesena Gerene A, Wand, gue} Van Coorg Ws W, Cie P. Der M. Mecoec H Eerie pathophysiology and sent eocs dtvonc tomboentoic pdronay hypeanson Heat 107540167 644, 7. Hi 5 Houston 84 Tapas © Scher AC. Rhode PS, Mata SC. Oaric RL, a 1M, Hammers LX Stan AA, Mein Z Coronlsiton C, Zine SL Wiley Ft. Hassoun PY, Kans DA, Tediord Ripe veneer nto reece pulmonary ater hypertension. Cron 2018433247242 76 Gunes Mia 5, Goat! 6, Ferraro OF Petegno M, Alone Labte V, (Gac Sapmoo Bandera Ra venta eantacle reserve ae prone Crcution couping aurng our chalange he re atopy wd tlnes prenanpes ACE Hear Fal 2164 25-35, 77 Gaz Nato Avra Corr U. Go 5, Forfa P Rous A. Cat F andere Temporal. Eehoeadopasty of fe vreau coping combined wth Cauopuinorary exerce trong t preset secon rear fre. Ce 045 ‘ane 2 28. KusonoseK Popovic 28, Motch H, Marwick TH. Promote ile of ear: Induced ght veer aceon in sympromatecepnareve ME eg on Cae Conta tang 20726 167-176 78, Coro D, Wetter T Lk MS, Haver RN, Machin FE, Anas A, Bac 8 fans C.Searcore C. Tasvopoulow A Tanai H, Pal MScvsd Pec A, Dara. FrotentaresN. Estes NM 3 McKeon W). Thin GPs FL Cans H. Tresmane of ytmogene re vere crlonyopaylannia: 2 Incarnation Tae Force Coens Snover. racton 201542441453 ‘1 Maron By Uceuon Je Borow RO, Natura RA Achean MCs NA 2d ‘Cooper UT kM Maron MS. Egy and Gaquaton renee {or compeve ait with ardonredar normale Task Force Hyper fhe caromyonaty, arthnogete right venta carder an ter ‘exdomyoputhes ad myosin» scene ratener rm the American Hear ‘Asocuten sd Ararcan Cobee of Caolopy | Ao) Cll Graal 201586 Bann 11 Heda! H. Por DL La Gerebe A. Vicar ayes ected wh rt {rm endrance sors wh te vide Be) Spare Med 2¥RAbA 0, 6102 18nOny o€ uo is0n8 Ka ZeczBOMESPL/ZI/Es LMDeNSAE-ApILESANSEAO|pIeoNUCD'dro oRUApeDe/sdaY Woy PaneOUMER,