My patient wants to perform strenuous endurance exercise. What's the right advice?

    My patient wants to perform strenuous endurance exercise. What’s the right advice? Fabian Sanchis-Gomar, Alejandro Santos-Lozano, Nuria Garatachea, Helios Pareja-Galeano, Carmen Fiuza-Luces, Michael J. Joyner, Alejandro Lucia PII: DOI: Reference:

S0167-5273(15)01315-7 doi: 10.1016/j.ijcard.2015.06.014 IJCA 20670

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

18 February 2015 7 May 2015 12 June 2015

Please cite this article as: Sanchis-Gomar Fabian, Santos-Lozano Alejandro, Garatachea Nuria, Pareja-Galeano Helios, Fiuza-Luces Carmen, Joyner Michael J., Lucia Alejandro, My patient wants to perform strenuous endurance exercise. What’s the right advice?, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.06.014

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Title: My patient wants to perform strenuous endurance exercise. What's the right advice?

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Running title: Strenuous endurance exercise and the heart Authors:

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Fabian Sanchis-Gomar, MD, PhD1, Alejandro Santos-Lozano, PhD1, Nuria Garatachea, PhD2, Helios Pareja-Galeano, PhD1,3, Carmen Fiuza-Luces, PhD1,3,Michael J. Joyner, MD, PhD4, Alejandro Lucia, MD, PhD1,4

Research Institute of Hospital 12 de Octubre ('i+12'), Madrid, Spain

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Faculty of Health and Sport Science, University of Zaragoza, Huesca, Spain

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European University, Madrid, Spain

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Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA

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Manuscript Type: Short Review

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Word Count: 5105

Author for correspondence: Fabian Sanchis-Gomar, MD, PhD Research Institute of Hospital 12 de Octubre („i+12‟). Avda. de Córdoba s/n 28041 Madrid, Spain. Phone: +34 91 779 2784; Fax: +34 91 390 8544 E-mail: [email protected]

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Abstract Prolonged strenuous endurance exercise (SEE) such as marathon running has recently

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been associated with potential deleterious cardiac effects, particularly increased risk of

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atrial fibrillation (AF). This topic is medically important due to the increasing number

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of participants in SEE events lasting several hours, including older people. The aim of this narrative review is to provide a summary of the evidence available on SEE and

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related issues such as cardiovascular mortality, AF, potential cardiac remodeling, cardiovascular events during exertion, or the need for pre-participation screening (with a

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special focus on beginners). This type of information can help physicians giving advice

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to their patients and the general public regarding safe SEE practice.

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Key Words: strenuous endurance exercise; health; sudden cardiac death; atrial

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fibrillation; arrhythmia; pre-participation screening.

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Abbreviations and Acronyms AF = atrial fibrillation

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AHA = American Heart Association

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CA = cardiac arrest

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CHD = coronary heart disease CRF = cardiorespiratory fitness

ESC = European Society of Cardiology

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HCM = hypertrophic cardiomyopathy HR = hazard ratio

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LA = left atrium

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LV = left ventricle PA = physical activity

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CVD = cardiovascular disease

RA = right atrium

RV = right ventricle

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SCD = sudden cardiac death

SEE = strenuous endurance exercise SMR = standard mortality ratio OR = odds ratio PPS = pre-participation screening

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Introduction The marathon running race (42.195km) commemorates the death of Pheidippides (530-

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490BC), a Greek messenger who is said to have died (perhaps of cardiac arrest (CA))

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shortly after running from Marathon to Athens (~40km) to announce that the invading Persians had been defeated. Whether this event is myth or real, prolonged strenuous endurance exercise (SEE) has recently been hypothesized to have potential deleterious

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cardiac effects, and a „safety‟ threshold of ~1hour/day been recently postulated [1]. The “too much exercise” topic is medically important due to the increasing number of

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participants in SEE events lasting several hours. Thus, the aim of this narrative review is to summarize the evidence available so that physicians can adequately advise their

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patients and the general public regarding SEE training and participation. We searched

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for publications on SEE and mortality, atrial fibrillation (AF), cardiac remodeling,

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cardiovascular events and pre-participation screening (with no restriction on the starting date and up to April 30, 2015). The abovementioned terms were used primarily in the literature search, or combinations of 1 or more of these terms, with restrictions to

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English-language scientific articles (excluding congress abstracts) indexed in the Medline and Web of Science databases. We also extended the search spectrum to the “related articles”, and additional studies were identified from reference lists and the authors‟ knowledge of in press studies. Two authors independently assessed the records obtained for each of the main topics we addressed.

SEE and mortality Around ~1/3 of adults are essentially totally inactive [2], which remarkably increases the risk of chronic diseases and mortality [3]. Conversely, there is strong evidence that moderately-vigorous endurance („aerobic‟) exercise (e.g., brisk walking, intensity ~3-6

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metabolic equivalents (METs), with 1MET equaling resting energy expenditure, 3.5mLO2/kg/min) is associated with longer life expectancy, especially as weekly

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exercise time increases to 450+min [4].

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The existence of a dose-response benefit of SEE remains more uncertain compared with

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less intense exercise, although no dose-related harm has been convincingly demonstrated. In a 15-yr follow-up of 55,137 adult men/women, even low-volume

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running (<51min/wk) reduced the risk of mortality due to cardiovascular disease (CVD), and persistent running over time was more strongly associated with mortality

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reduction, but no dose-response benefit was found [5]. A study of 1,878 joggers reported highest mortality benefits for ≤150min/wk at a slow/average speed, but

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mortality was lower among joggers than non-joggers irrespective of training loads [6].

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A study with 416,175 adults of both genders found no additional mortality benefits for >50min/day of SEE [7]. A 21-yr follow-up showed that 538 runners of both genders

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aged ≥50yrs and performing SEE~270min/week had 39% lower mortality than those engaging in ~70min/week [8]. A 7.7-yr longitudinal analysis of 35,402 male runners

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showed that, compared to <3km/day, running >9km/day decreased angina (-65%), nonfatal CHD (-29%), and both fatal/nonfatal CHD risk (-26%) [9]. A recent prospective cohort study with 204,542 Australian adults aged 45-75yrs found that, among those who reported performing any physical activity (PA), engaging in SEE (e.g., jogging, cycling) was associated with risk reductions for all-cause mortality of 9% to 13%, even after adjusting for the total amount of PA [10]. Another recent prospective study on a large sample cohort reported that the upper threshold for all-cause mortality benefit occurred at 3 to 5 times the minimum 2008 PA Guidelines for Americans (150min of moderate-intensity PA, e.g., walking, or 75min of vigorous-intensity PA,

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e.g., brisk walking, jogging) and showed no evidence of harm at 10+ times the recommended minimum [11].

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Exercise-related CVD-mortality benefits are still present in extreme endurance

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exercisers. A recent meta-analysis estimated a 27% lower CVD standard mortality ratio

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(SMR) in elite athletes (n=12,119, mostly men, including Tour de France finishers or former Olympic marathoners), compared with the general population [12]. Albeit the

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heterogeneity of athletes‟ specialties (endurance but also „explosive‟/„power‟ sports) is a major limitation, these findings do not support the notion that SEE above some sort of

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safety threshold may lead to a chronic cardiac damage that would ultimately limit the longevity benefits of exercise. A recent 50-yr follow-up of Finnish athletes found higher

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life expectancy in endurance athletes (79.1 yrs;95%CI:76.6-80.6) than in controls

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(72.9yrs;95%CI:71.8-74.3) [13]. Data from 49,219 men and 24,403 women participating in 90km or 30km cross-country ski races, respectively, showed a CVD-

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SMR of 0.43 (95%CI:0.35-0.51), with the lowest SMRs found amongst older participants and those who participated in several races [14].

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Long-term SEE and AF Light-moderate exercise (e.g., walking) is associated with lower AF risk in older adults [15]. A recent meta-analysis in non-athletes (n=96,526) found no significant association between regular exercise and higher AF risk compared with sedentary lifestyle (odds ratio (OR)=1.08;95%CI:0.97-1.21) [16]. A recent pooled analysis of 4 studies (n=112,784 participants) showed no association between increasing amount of time spent on exercise and AF (0.95;95%CI:0.72-1.26) [17]. In contrast, long-term practice of SEE can be associated with higher risk of AF, particularly lone AF [18-22]. Although

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there is no universal consensus [23,24], the association seems stronger in highly competitive athletes.

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A meta-analysis including 655 athletes and 895 controls found a 5.29-fold higher risk (95%CI:3.57-7.85) in the former [25]. A longitudinal study of 309,540

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Norwegian men and women aged 40-45yrs showed that men who reported SEE were more often prescribed flecainide than sedentary people (HR=3.14;95%CI:2.17-4.54)

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[26]. In 52,755 long-distance cross-country skiers, higher competition and experience level were associated with higher risk of any arrhythmias (HR=1.30;95%CI:1.04-1.62)

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and AF (HR=1.20;95%CI:0.93-1.55) [27]. A recent meta-analysis also found a significant association between history of sports participation and AF risk (1.98;

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95%CI:1.00–3.94) [17]. Elderly men with a history of long-term SEE practice had a 6%

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higher AF risk (95%CI:0.8-11.1) compared with elderly men in the general population

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[28]. Grabs et al recently performed continuous ECG monitoring in 20 male runners (age 45±8yrs) during a marathon race [29]. Interestingly, the prevalence of arrhythmias (atrial and ventricular premature complexes) decreased during and after the run and no

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malignant arrhythmias were reported. Potential factors triggering AF in previously healthy long-term exercisers include left-atrial (LA) enlargement or fibrosis, increased parasympathetic tone and inflammation [30-33]. Self-reporting of AF is a significant limitation of some studies in this field [28], since this might include not only paroxysmal (vs. stable) AF, but also palpitations and other symptoms that might be erroneously interpreted as AF by sportspeople. Other types of arrhythmias (e.g., ventricular tachycardia) which are relatively common in CVD/CHD-free people who are starting to practice exercise can also be interpreted as palpitations.

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Long-term SEE-induced remodeling? SEE sports events (marathon, half-ironman triathlon, full-ironman triathlon, alpine

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bicycle racing) can cause acute cardiac changes such as RA and right ventricle (RV)

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dilation, accompanied by decreased RV ejection fraction and elevation of biomarkers of myocardial stress/injury (troponin, B-type natriuretic peptide) [7,34,35], with an apparent dose-effect of event duration [34,35]. A recent meta-analysis found that RV

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function is the most impaired variable post-SEE, while left ventricle (LV) function is relatively unaffected [36]. Short-term recovery of the SEE-induced disturbances is

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usually complete, with no evidence of actual tissue damage [37-39]. However, LV or RV diastolic dysfunction might persist in some participants for 1 [35,40] up to ~4wk

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post-race [41]. No significant post-marathon changes in cardiac-troponin have been

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reported in old experienced (>60yrs) runners [42]. When these do occur in older

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runners, post-marathon alterations follow a similar pattern compared to younger runners [43], and return to normal within 2wk [43]. Post-marathon occurrence [44] or persistence of cardiac alterations were found to be more frequent in less trained runners

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(<56km/wk) [41], although this evidence was contradicted in another study [35]. The long-term clinical consequences of repeated exposure to the abovementioned SEEinduced alterations remain to be clearly determined. Rats exposed to long-term, daily forced (tail shock) intense treadmill-running developed arrhythmogenic areas of RA and RV fibrosis [45]. Yet these findings cannot be easily translated to humans because training intensity was beyond that sustainable by extreme endurance elite athletes, including Tour de France participants [46]. Highly endurance-trained athletes might show a significant increase in the LV mass-to-volume ratio instead of a proportional increase in both LV wall thickness and internal diameter

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[47], with a ~15% subset showing striking LV cavity enlargement [48], or also enlarged RA and RV [49]. A mildly dysfunctional RV might be the substrate for ventricular

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arrhythmias even in asymptomatic athletes [50,51], although the RV systolic function of

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former highly elite endurance athletes, most of whom were still active competitors

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(mean age 55yrs), was recently reported as normal [52]. Moreover, competitive Master‟s level (>65yrs) endurance athletes were found to have preserved, youthful

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levels of LV compliance and distensibility [53,54] and highly trained endurance runners (33-65yrs) demonstrated greater dilating capacity of their epicardial coronary arteries

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compared with inactive men [55].

Solid evidence is lacking that athlete‟s heart remodeling leads to long-term

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CVD, but this possibility, especially RV enlargement, cannot be excluded in some high-

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level athletes and deserves further scrutiny [48]. On the other hand, unsuitable cardiac

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remodeling is unlikely to affect runners with a lower training/competition level. In sedentary people who trained intensively for 12 months to compete in a marathon, the LV showed concentric remodeling during the first 6-9 months, and thereafter dilated

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and restored the baseline mass-to-volume ratio whereas the RV responded with a balanced remodeling throughout the program [56].

SEE and cardiovascular events The relative risk of sudden cardiac death (SCD) increases 16.9-fold during or up to 30min after exercise at ≥6METs intensity, but the absolute risk is extremely low (1/1.51M episodes of exertion) and further decreases with habitual exercise [57]. SEErelated SCD is considerably less frequent compared to non-sports related SCD, e.g., 1.12/100,000 athlete-years over 6yrs in Danish athletes (aged 12-35yrs) vs. 3.76/ 100,000 person-yr in the general population [58]. The recently reported incidence of 9

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SCD in US was 0.39 [59] or 0.75/100,000 runners for half-marathons/marathons [60] and 1.5/100,000 participants for triathlons [61]. The incidence proportion of CA in

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recent US marathons (2000-2010) [59] and in a 90-yr follow-up of a 90km ski-race in

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Sweden was 1.01/100,000 runners and 2.16/100,000 skiers [59]. Middle-aged men

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(especially poorly trained runners) were the high-risk group, and hypertrophic cardiomyopathy (HCM) and CHD (especially the former in runners [59]) were the

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major predisposing cause. Although CA mainly occurred during the last quarter for runners, it was more frequent in the first third of the ski race, suggesting the existence

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of different trigger mechanisms for CA induction in different temperatures. An interesting comparison between running and ski races was that the fatality rates were

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75% and 71%, respectively, with initiation of bystander-administered cardiopulmonary

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resuscitation during the first minutes being strong survival predictors.

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The increasing popularity of extreme endurance sports has resulted in a growing number of poorly trained participants with underlying CVD, and this might have contributed to the growth of SEE-related CA over the last decade [59], thus supporting

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the importance of establishing reliable preventive screening.

Pre-participation screening (PPS) PPS aimed to identify athletes at risk of SCD or disease progression due to sports participation [62,63], is recommended by major medical and sporting societies, the American Heart Association (AHA) [63], the European Society of Cardiology (ESC) [64], and the International Olympic Committee [65]. Although there is an ongoing debate regarding the actual preventive value of PPS, and especially which screening strategy is more effective, the inclusion of ECG should be promoted [62]. Screening young athletes with 12-lead ECG together with cardiovascular-focused history and 10

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physical examination may be cost-effective [66]. Baseline ECG screening reduced the incidence of SCD by 89% in young Italian athletes [67]. However, this positive

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outcome could not be replicated in other cohort studies [68,69]. Modern imaging

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techniques can certainly improve our understanding of the athlete's heart, e.g., by

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determining the prognostic relevance of small patches of delayed gadolinium enhancement in highly-trained athletes. Nonetheless, there is yet no accumulated

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evidence to support their inclusion in athletes‟ PPS [70].

The growing number of non-competitive participants engaging in SEE has

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increased the importance of PPS for this population, and poses problems in terms of logistics and incremental cost [71]. The overall predictive value of exercise-ECG for

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SEE-related cardiovascular appears limited, e.g., with a reported 18% sensitivity and

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92% specificity of positive test results in asymptomatic, hypercholesterolemic men aged

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35–59yrs [72]. Despite the lack of solid scientific data to guide PSS in non-competitive athletes, several Associations of Cardiology and Sports Medicine have addressed the issue by consensus [73,74] with a common recommendation that individuals at a higher

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CHD risk, e.g., those with diabetes mellitus, undergo maximal exercise testing before engaging in SEE [71]. In contrast, the US Preventive Services Task Force has stated that there is insufficient evidence supporting screening with exercise testing [75]. A PPS flowchart for middle-aged/senior individuals engaged in leisure SEE has been proposed by the European Association of Cardiovascular Prevention and Rehabilitation including [74]: (i) thorough risk assessment with history, physical examination, baseline ECG and risk score assessment within 10yrs using the ESC Systematic Coronary Risk Evaluation (SCORE, based on age, sex, blood pressure, blood cholesterol, and smoking history) [76,77]; followed by ii) maximal exercise testing, but only in individuals with high risk of coronary events. 11

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Master athletes (40+yrs), especially men, represent a special concern. The AHA Science advisory committee recommends PPS with thorough family history and

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physical examination with the main purpose of detecting previously undiagnosed CHD,

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and those with a moderate-to-high CHD risk should undergo exercise testing [78].

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These „risk‟ athletes include men aged >40-45yrs or women >50-55yrs (or postmenopausal) with ≥1 independent coronary risk factor (hypercholesterolemia/

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dyslipidemia, hypertension, current/recent cigarette smoking, diabetes mellitus, or history of myocardial infarction or SCD in a first-degree relative <60yrs old). All

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veteran athletes with symptoms suggestive of underlying CHD, and all ≥65yrs old (even if asymptomatic or without risk factors) should undergo exercise testing [78].

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Of note in the discussions of the risk of participation in SEE is recent data from

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137,580 runners during 2007-2013 showing that serious heat stroke-related events were

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10-fold more prevalent than CA events [79]. These provocative findings suggest there is additional risk posed by SEE in hot weather conditions that might be difficult to screen for. An additional factor to prevent SEE-related SCD outside PPS is access to rapid

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defibrillation and trained medical personnel [80]. Finally, because in almost two third of cases people suffering sports-related CA present with a previously documented CVD or symptoms prior to the event, implementation of educational and general awareness might be a beneficial preventive strategy [81].

Conclusions and medical recommendations for beginners SEE training (e.g., preparation for a marathon) is cardio-healthy for CVD-free participants, that is, subjects with normal baseline and exercise ECG, no history of CHD/CVD, normotensive and non-diabetic [82]. The evidence available does not support that the risk of SEE-related events in long-term participants is related to specific 12

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training-induced functional and structural cardiac adaptations, i.e., the „athlete‟s heart‟ [51,83,84] whereas the main risk factors for CVD (obesity, diabetes, hypertension,

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hypercholesterolemia [85]), are positively modulated by long-term SEE. Recommendations for healthy beginners. A distinction should be ideally made

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between previously sedentary, unfit beginners (i.e., with a total previous weekly energy expenditure during physical activity (PA) <2MET-hour) and individuals who are

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already active (i.e., ≥2MET-hour/week, even if not practicing any sport) [74] or have a high cardiorespiratory fitness (CRF -see below). In this regard, physicians should be

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aware that, although there is no ideal measure of an individual‟s PA levels, PA can be determined by motion sensors (pedometers, accelerometers), heart rate monitors or

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more easily with PA questionnaires [86,87]. On the other hand, CRF (sometimes also

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referred to as „aerobic capacity‟ or „maximal aerobic capacity) may be indirectly

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assessed by simple field tests such as the Cooper walk run test, the Shuttle test or the step test [88,89] or objectively evaluated in a laboratory setting during maximal incremental exercise (treadmill or cycle-ergometry testing). The latter provides a wealth

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of clinically diagnostic and prognostic information, especially through determination of gas-exchange parameters such as mainly the peak oxygen uptake (VO2peak) [90]. Those middle-age adults (men and women) not fit enough to run (i.e., VO2peak<8METs, with 8METs being the metabolic cost of running at a slow pace or jogging) are at higher risk of CVD and CHD events [91]. In contrast, the risk of CVD-death is very low in those with a CRF≥10METs [92,93], and especially if CRF>14METs [94]. Sedentary adults who wish to start practicing SEE should be evaluated by trained health care professionals/clinicians. If the physician-led evaluation is negative, the individual is eligible for low-moderate exercise or even SEE whereas the presence

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of positive signs requires further evaluation and appropriate management. Yet SEE leading to exhaustion as well as engagement in competition should be avoided in the

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early stages of training and/or reconditioning, especially for the less fit beginners.

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Consequently, sedentary individuals who are starting a SEE training program should be

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strongly advised to gradually increase the duration and intensity of exercise sessions. Although active/fit individuals have a considerably lower risk for cardiovascular

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complications during exertion compared with their sedentary peers, physicians should be warned when these people show a marked decrease in exercise performance [95].

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Indeed, sudden declines in the level of exercise performance have been associated with an increased risk of cardiac events, especially in males [96]. All healthy individuals

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contemplating to take up SEE or already performing SEE should be evaluated by a

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qualified physician even in the absence of symptoms or risk factors for CVD. Further,

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adult/senior active individuals showing a positive (abnormal) evaluation by the qualified physician should undergo additional maximal exercise testing and if the latter is normal the individual is eligible for SEE. In the event of a positive exercise test,

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further evaluation is necessary to confirm/refute the presence of CVD/CHD [77]. Other useful considerations for apparently healthy beginners are as follows: (i) all individuals who wish to practice SEE should undergo PPS and annual follow-up [82]; (ii) those wishing to finish a marathon or an ironman should have previous experience (≥1yr) in hard events (i.e., half-marathon/ironman) and make realistic goals in terms of performance, especially under difficult race weather conditions; (iii) they should be also aware of the warning signs or symptoms of CVD (angina pectoris, anginal equivalents, impaired consciousness), or the sudden appearance of a cardiovascular event associated with intense training [97].

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Recommendations for patients. In contrast, SEE is to be discouraged in patients with: atherosclerotic CHD; congenital and valvular heart diseases; systemic hypertension;

catecholaminergic polymorphic ventricular tachycardia); inherited (HCM,

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cardiomyopathy,

arrhythmogenic

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cardiomyopathies

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syndrome,

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myocarditis; Marfan‟s syndrome [78]; channelopathies (long/short QT, Brugada

cardiomyopathy) [98,99]. These patients can participate in leisure low-moderate

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intensity exercise [98,99]. Moderate-exercise recommendations depend on individual clinical judgment for patients with the following high-risk conditions: history of

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important cardiac symptoms (syncope, episodes of impaired consciousness); prior cardiac operation (e.g., septal myectomy for obstructive HCM or aortic root

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reconstruction for Marfan syndrome) or heart transplantation; implanted cardioverter-

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arrhythmias [97].

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defibrillator or pacemaker; or clinically overt and potentially life-threatening

Conflict of interests

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None of the authors have any conflict of interest.

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Figure 1 legend Main evidence-based information regarding SEE that should be kept in mind by

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clinicians. See text for abbreviations.

Highlights

 Running marathons has recently been associated with potential deleterious cardiac effects.  This topic is medically important due to the increasing number of participants.  We provide a summary of the evidence available on strenuous endurance exercise.  This type of information can help physicians give advice to their patients and the general public.

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