|Year : 2016 | Volume
| Issue : 4 | Page : 113-124
Marathon running for amateurs: Benefits and risks
Nitin Burkule MD, DM, DNB, FACC, FASE
Department of Cardiology, Jupiter Hospital, Thane, Maharashtra, India
|Date of Web Publication||20-Oct-2016|
Jupiter Hospital, Eastern Express Highway, Thane - 400 606, Maharashtra
Source of Support: None, Conflict of Interest: None
The habitual level of physical activity of the human race has significantly and abruptly declined in the last few generations due to technological developments. The professional societies and government health agencies have published minimum physical activity requirement guidelines to educate the masses about the importance of exercise and to reduce cardiovascular (CV) and all-cause mortality at the population level. There is growing participation in marathon running by amateur, middle-aged cases with a belief that more intense exercise will give incremental health benefits. Experts have cautioned the nonathlete amateurs about the "exercise paradox" and probable deleterious effects of high-intensity prolonged exercise on CV and musculoskeletal system. The epidemiological studies suggest a "reverse J shaped" relationship between running intensity and CV mortality. The highest benefits of reduction in CV and all-cause mortality are achieved at a lower intensity of running while the benefits tend to get blunted at a higher intensity of running. The physicians should have a balanced discussion with the amateur runners training for a marathon, about risks and benefits of high-intensity exercise, and should evaluate them to rule out the occult coronary disease.
Keywords: Cardiovascular mortality, exercise paradox, marathon running, physical activity
|How to cite this article:|
Burkule N. Marathon running for amateurs: Benefits and risks. J Clin Prev Cardiol 2016;5:113-24
| Introduction|| |
Marathon running is a rapidly growing sports hobby among middle aged, non athletic population. There are diverse views about habitual high intensity exercise circulated in both scientific literature and lay press. The physician should analyze the conflicting data with scientific rigor and take a balanced view while advising our patients about high intensity exercise.
| Physical Activity through the Ages|| |
"Homo0" sapiens species evolved about 2.4 million years ago. For 84,000 generations, human beings survived in wild as hunter-gatherers. They required to perform a variety of daily physical activity just for survival.  The agricultural revolution approximately 350 generations ago ushered in the dawn of civilization. The human beings as farmers or artisans continued to be physically active to meet the demands of earning their livelihood. However, with the advent of Industrial Revolution, about seven generations ago there was a great disruptive change in the lifestyle of the humanity. The machines took over a lot of physical labor from day-to-day life. This resulted in a significant reduction of physical activity in a large section of the society. The digital revolution about two generations ago made office work, entertainment, and daily life chores available at fingertips causing an epidemic of sedentary behavior.
A multitude of epidemiological studies showed health and survival benefits of regular physical activity through exercise and sports. ,, Intuitively, the society assumes that higher the level of intense physical activity higher is the health benefit.  The highly accomplished sportsperson in extreme sports are regarded as the epitome of health. The participation of amateur runners in highly advertised and sponsored marathon events has increased 25-fold in last two decades.  Many amateur runners take up to running in their late thirties, train vigorously in their leisure time and may be exposing themselves to overuse musculoskeletal injuries, adverse cardiac events and addicting effects of exercise-induced endorphin release.
| The Great Divide|| |
The modern society is sharply divided into a growing number of intense exercise enthusiasts and a much larger section of highly sedentary individuals.  Marathon running participation has increased  from 25,000 runners in 1976 to approximately 2 million in 2010. The current recommendation of physical activity, for optimum reduction of cardiovascular (CV) morbidity and mortality in the society, is 150 min/week of moderate intensity exercise or 75 min/week of vigorous intensity exercise. , The training duration in the amateur marathon runners far exceeds these public health recommendations. 
The lay press and the scientific literature have both high-pitched "alarmist" proclaiming deleterious effect of intense physical training and "ardent" supporters claiming incremental benefit. The percentage of sudden cardiac deaths (SCDs) of the runners during a marathon is very small and accounts for only 5%-6% of all SCD in the general population.  Although rare, marathon-related SCD has got prominent headlines causing a shock wave in the community.  To advise our nonathlete patients diligently, the physician needs to review the scientific evidence, mostly coming from the epidemiological studies, thoroughly and then take a balanced view.
| A Physician's Dilemma|| |
The majority of sports-related SCD (approximately 94%) occurs in individuals older than 35 years.  Since increasing numbers of older people are participating in city marathon events, the incidence of running-related SCD is expected to rise in near future. 
Individuals planning to participate in popular city marathons often consult physicians for advice regarding preparticipation preventive check-up and to certify them fit for endurance sport. Most of the new recruits of the marathon are middle-aged, amateur, and leisure time runners with minimal or no background of regular sports activity during school or college years. Some of them have rapidly switched from sedentary life to daily jogging and may be harboring occult coronary artery disease (CAD) due to earlier poor lifestyle.  Asymptomatic patients with stable CAD, remote acute coronary syndrome, or previous coronary revascularization also aspire to take part in the marathons.
The guidelines for preparticipation screening of athletes for National and Olympic level competitive sports are published which offer effective history questionnaires and highly selective referral for a physical examination.  Routine use of electrocardiogram and echocardiography is contraindicated due to very low-pretest probability and high false positive results. Recommendations and consensus documents are published for screening nonathlete amateur runners with the above-mentioned clinical profile. ,
Amateur runners who are training regularly may consult the physician for new onset of symptoms such as chest pain, easy fatigue, declining performance, dizziness, or palpitation. The intensity of these symptoms is often understated due to the effects of high level of endorphin release during endurance sports. The physician should carefully evaluate even minimal symptoms in these middle-aged runners. Even after diagnosing potentially hazardous CV condition, the physician is faced with a challenge to dissuade successfully, the running addicted patient, from participating in the next marathon.
| Cardiac Remodeling with Exercise|| |
High level of endurance sports activity like long-distance running cause morphological and functional adaptive changes in the heart. The "athlete's heart" syndrome is a variable extent of morphological and electrical remodeling in response to the sporting activities such as endurance (long-distance running), power (lifting or throwing heavy objects), or a combination of power and endurance (cycling and rowing).  Its accurate differentiation from cardiomyopathies is critical. 
The upper limits of remodeling of the athlete's heart on echocardiography are defined in the literature , [Table 1]. Normalizing the cardiac dimensions for body surface area removes most of the differences between male and female runners. The eccentric hypertrophy of left ventricle (LV), increased LV and left atrial (LA) volume, increased right ventricular (RV) volume, resting bradycardia, and lower resting LV ejection fraction (EF) are the typical findings in endurance athletes.  They are considered as physiologic adaptations, and their upper limits serve to distinguish athlete's heart from hypertrophic or dilated cardiomyopathies. 
|Table 1: Echocardiographic measurements in male and female ultramarathon athletes|
Click here to view
In a cardiac magnetic resonance imaging (MRI) study  of 33 competitive elite male endurance athletes (age 30-60 years) with a training history of 29 ± 8 years, indexed LV mass and RV mass and indexed LV end-diastolic volume and RV end-diastolic volume were significantly higher in athletes as compared with controls [Table 2]. The RV EF did not differ between athletes and controls.
|Table 2: Cardiac magnetic resonance imaging measurements in elite endurance master athletes and control cases|
Click here to view
In a study  of previously sedentary cases (age 25-35 years), who embarked upon training for a marathon, cardiac MRI for RV and LV volumes was performed at baseline and after 3, 6, 9, and 12 months of training. LV and RV mass increased progressively with training and reached levels similar to those of elite endurance athletes. LV initially showed concentric remodeling during the first 6-9 months of endurance training. Thereafter, LV showed dilatation (eccentric remodeling) and restored the baseline mass-to-volume ratio. The RV responded with eccentric remodeling at all levels of training. This study gives insight into the time frame required for training to make the heart "marathon ready."
A follow-up echocardiographic study  of 114 Italian Olympic athletes (78% male; mean age 22 ± 4 years) undergoing intensive and uninterrupted training over 4-17 years for 2-5 consecutive Olympic Games (total 344 Olympic events) did not show adverse effects of athlete's adaptive cardiac remodeling. The global LVEF remained unchanged, and new wall motion abnormalities were absent. The LV volumes and LV mass index remained unchanged, and LV filling patterns remained within normal limits. The LA dimension showed a mild increase in follow-up. Therefore, in young Olympic athletes, extreme and uninterrupted endurance training, over a long period did not show deterioration of LV systolic and diastolic function or progression of LV hypertrophy.
Some experts caution about the overlap of morphometric values of the athlete's heart with the clinical cardiomyopathies and also doubt the assumed "physiological" nature of the cardiac remodeling in endurance athletes.  In general, compensatory chamber hypertrophy in cardiac diseases is counterproductive. The myocardial hypertrophy with myocardial fibrosis alters the chamber compliance leading to clinical heart failure and arrhythmias.
| Benefits of Physical Activity|| |
Regular exercise has a lot of pleiotropic health benefits through positive modulation of plethora of physiological processes [Table 3]. Exercise at minimum recommended level positively affects all the modifiable coronary risk factors,  improves CV function,  modulates genomic expression,  and reduces the incidence of malignancies. Exercise promotes psychological health and improves sleep pattern.
Interestingly, when an individual switch from sedentary habit to an active lifestyle, a large quantum of CV benefits, and improved life expectancy is already accrued at the much lower intensity of regular physical activity. , Simply standing >2 h/day is associated with a 10% reduction in all-cause mortality compared with standing <2 h/day. The lowest mortality was achieved in individuals standing >8 h/day.  Even 15 min of brisk walking per day (half of current public health recommendation) reduced mortality from ischemic heart disease by 25% and increased life expectancy by 3-year.  Running only 10 min/day at slow speed <6 miles/h, weekly running <51 min, <6 miles, 1-2 times, or <506 metabolic equivalents (METS)-min are sufficient to substantially reduce risk of mortality, compared with not running. , This amount of light exercise is easily achievable, can cause 30% and 45% reduction in all-cause and CV mortality, respectively, and add 3 years of gain in life expectancy.  Data extracted from 26 cohort studies show that increment of 1 MET h/week of energy expenditure, which is equivalent to 2-3 min of moderate to vigorous physical activity per day, results in a 0.8% reduction of the average relative risk (RR) of mortality from noncommunicable diseases.  The Japanese Public Health recommendation of daily 10+ min of moderate to vigorous activity, of any nature, aims at reducing RR by 3.2% at the population level. 
Both brisk walking and running can achieve an equivalent level of reduction in CV events except that the time spent in walking should be 2-4 times that of running.  Walking is much easier to perform daily, is sustainable and safe with regards to musculoskeletal injuries, and gives an opportunity for social networking. Young individuals with busy lifestyle and time crunch can achieve significant CV benefits by short bouts of running even 10 min a day 3-4 times, less than an hour per week. ,
The relation of CV mortality reduction and quantum of physical activity is not linear but curvilinear. , This observation suggests that at a higher level of exercise further gain in CV benefits is less or may plateau for every additional METS of exercise performed. , It is unclear whether there is a ceiling dose of exercise. According to some experts, there is no significant benefit beyond 9 METS of exercise in women and 10 METS of exercise in men per session , or 3-10 times the recommended physical activity level  or beyond 120 min/week of exercise.  Even among the extremely active Ache Hunters of Paraguay, who had much superior cardiorespiratory fitness than people in developed world, the average daily distance covered for aging was approximately 6 miles.  A moderate range of intensity, frequency, and duration of exercise may be important for maximizing health and longevity benefits.  The human race has been evolutionarily adapted to a variety of physical activities performed intermittently at moderate intensities for moderate durations and not to just one type of endurance activity like long distance running. 
| The Exercise Paradox|| |
It seems that the first marathon run claimed a life! In 490 B.C. Pheidippides, the Greek professional courier, ran from Marathon to Athens and declared the Greek's victory over Persians saying "Nike" and then collapsed and died.  However, historians think that it is a myth and in reality Pheidippides further continued to run to Sparta to carry the message for military help. 
There is sufficient evidence to suggest that there is a short-term rise in myocardial infarction (MI) and SCD during the hour-long period of exercise and recovery than during the rest 23 h when the individuals are less active. , The risk of MI with each bout of physical activity is approximately doubled even for a fit individual who regularly performs vigorous exercise 5 times a week.  However, the RR of MI during intense physical activity is 50 times higher in habitually sedentary individuals who suddenly get engaged in exercise bout than the individuals who are regularly performing moderate to high level of exercise.  The overall RR of SCD within 30 min of vigorous exercise is seven-fold higher in those who exercise less than once per week as compared to those who exercise >5 times per week.  Although exercise increases the acute risk of SCD and MI, paradoxically "regular" exercise of moderate to high intensity is highly protective and reduces the exercise induced the risk of SCD by 7-10-fold and of MI by 50-fold. 
The risk of SCD during marathon events is as small as 0.8-2/100,000 marathon runners and the risk of all sports-related SCD is as insignificant as 4-5/1 million population of the nation. , In a marathon, runners >30 years of age, approximately 80% of SCD are caused by atherosclerotic CAD. , In this age group, a small fraction of SCDs are attributed to cardiomyopathies, myocarditis, congenital coronary anomalies, trauma, heat stroke, or channelopathies.  For leisure time joggers, the annual incidence of SCD is higher than marathon events (13 SCD per 100,000 joggers per year).  Their imaging and autopsy studies reveal nonobstructive coronary plaques, with a thin cap ruptured in the center of the plaque, with large overlying thrombus.  This suggests a role of hemodynamic shear force on the vessel wall and adrenergic hypercoagulable state during intense and prolonged exercise.
The epidemic of atrial fibrillation (AF) in the later part of life is increasingly viewed as lifestyle disease. There is a strong evidence to suggest that middle-aged individuals who are habitually physically active have a lesser incidence of AF in the later part of life. , Exercise effectively controls the risk factors for AF such as hypertension, obesity, and obstructive sleep apnea and prevent age-related decline in LV compliance. For every 1-MET increase in cardiorespiratory fitness level, there is an associated 7% decrease in the risk of AF.  Paradoxically, individuals engaged in an extreme level of sports activity in the early part of life have a higher incidence of AF in the later part of life. In a study  of 44,410 Swedish men, intense exercise of more than 5 h per week at the age of 30 years increased the risk of developing AF later in life. In contrast, moderate intensity of physical activity such as walking or bicycling, in the middle age, decreased the risk of AF.
The increased risk of AF is thought to be mediated through adaptive cardiac remodeling such as LA dilatation due to increased cardiac output, increased atrial conduction time, LA fibrosis, and resting bradycardia with intermittent exposure to high-catecholamine levels with training. 
| Challenges of Interpreting Epidemiological Studies of Physical Activity|| |
Population-based epidemiological studies of physical activity have given unambiguous scientific evidence of a reduction in all-cause mortality and CV mortality with an active lifestyle. ,, One should be aware of certain aspects and limitations of these studies. It is highly challenging to measure exact exercise dose at the individual level. There is no standard definition of what constitutes an athlete, intense exercise, or endurance exercise.  Change of lifestyle from sedentary to active promotes incremental health and feeling of well-being in an individual. The healthier individual in turn is likely to exercise more, thus blurring or confounding the simple exercise dose and health effect relationship. 
Most of the studies rely on cases' self-reporting of exercise with regards to perceived intensity, time duration per session, and frequency per week. From this data, a parameter called "METS-hour per week" of energy expenditure is calculated which is a product of predicted METS per unit time for the kind of exercise Χ time duration per session Χ frequency per week.  Moderate intensity activities are 3.0-5.9 METS, whereas vigorous activities are >6.0 METS. However, the definition of intense exercise used in the cardiology literature is 10 METS which may be perceived as a warm-up for elite competitive athletes.  Even in amateur runners, the perceived intensity of similar jogging pace may be "strenuous'" for a deconditioned middle-aged man while it may be "light" for a young active teen. 
There are also significant differences between amateur runners and the elite athletes.  The athletes start their strenuous exercise program in first or early second decade of life before the significant atherosclerotic process can start in the coronaries. It is highly likely that they are genetically endowed for physical excellence. They exercise under professional guidance for exercise technique, cross training, and diet. They maintain overall healthy lifestyle and take adequate rest for the healing of overuse injuries.  Postcareer, they systematically reduce the training intensity and duration. In the developed world, athletes maintain high standards of living and have access to medical care which can also contribute to increased longevity. For the same reason of high standards of living, even Nobel Prize or Oscar Award winners have a superior life expectancy as compared to the general population. 
In contrast, amateur runners are lay people who take up running in middle age when the occult atherosclerotic process may have already set in. Professional athletes usually perform >80% of their training sessions at subjectively light intensities (50%-70% of their maximal heart rate) compared with novice runners who often train relatively and subjectively at too high intensities.  In fact, numerous middle-aged and poorly prepared runners start strenuous running programs immediately after CV disease diagnosis.  Although many nonathletic people get addicted to running, not all of them stop smoking or make healthy dietary choices.  Many of them, during training, drink excess of insulin spiking and high-carbohydrate energy drinks. Most of them enter into grueling training schedule without compromising their working hours but add their exercise schedule to the demands of a job, marriage, and parenting. There is no adequate rest period for healing overuse injuries such as plantar fasciitis, Achilles tendonitis, shin splints, and patellar chondromalacia.  Not all of them have easy access to professional exercise trainers and higher medical care. Hence, increased longevity data of athletes cannot be extrapolated to amateur runners just because they are engaged in the same kind of physical activity.
There are also a difference in leisure time running and marathon training for amateur runners. The leisure time running is noncompetitive with adequate time to relax. While marathon training as referred to earlier is competitive, arbitrarily structured, and compromises adequate rest in busy, working individuals. Novice amateur runners may fail to optimize their running performance and CV health by blindly following modern training methods used by elite athletes. 
The epidemiological studies of jogging divide the observational cohort into different groups, namely sedentary controls, predefined mild, moderate, high, and extremely high levels of joggers. In general population, a number of individuals in the groups at high to extremely high level of habitual exercise are distinctly underrepresented. Small events of all-cause mortality in these groups get proportionately magnified with wide confidence intervals (CIs).
With these limitations in mind, let us explore the evidence of health benefits and hazards with the increasing dose of running.
| Is There a Harm with High-intensity Exercise?|| |
Few animal experiments (marathon rats) and some large population-based observational studies have indicated deleterious effects on the heart with high-intensity prolonged exercise. "Cardiac fatigue" is a phrase coined to describe transient functional and biochemical changes in myocardium after extraordinary endurance events  [Table 4]. The theoretical hazards involved with intense exercise are as follows:
- Increased troponin and B-type natriuretic peptide (BNP) release  was noted during marathon running suggesting myocardial injury, which may compound over time to cause myocardial fibrosis. In Boston Marathon Study  of sixty nonelite participants, at the end of the race, 60% had increased troponins above the 99 th percentile of normal and 40% had troponin levels above the diagnostic threshold for MI. Compared with athletes training 45 miles/week, athletes who trained 35 miles/week demonstrated higher troponins and BNP
- In ultra-endurance triathlon participants, reduced LVEF, reduced LV fractional shortening, and segmental wall motion abnormalities in a nonvascular distribution have been documented on echocardiography, immediately after the race. , The biochemical and functional abnormalities of LV and RV may last 3-17 h after endurance events.  Increased myocardial fibrosis and increased susceptibility to arrhythmia are seen in experimental marathon rats 
- Transient RV dilatation and dysfunction and rise in pulmonary artery pressure are documented in marathon  and triathlon athletes.  A cardiac MRI study  reported that marathon running caused acute dilation of the right atrium and the right ventricle, reduction in the RV EF, parallel with elevations in cardiac troponin I and BNP. Extraordinary endurance exercise may cause acute fatigue of cardiac muscles, which seems to be more prominent in the right than the LV.  However, this recovers quickly even after a very long event. The repetitive postexercise RV abnormalities may have potential to cause permanent RV injury, fibrosis, and risk of arrhythmias ,
- Cardiac MRI has shown increased incidence of late gadolinium enhancement (LGE) in both coronary (subendocardial) and noncoronary (septal insertion sites) distribution in endurance athletes.  Almost half of older lifelong endurance athletes had shown evidence of myocardial fibrosis, whereas age-matched controls or young athletes had no fibrosis on LGE-MRI.  The cause may be acute myocardial injury, myocardial edema  leading to permanent septal or RV fibrosis with putative future arrhythmic risk
- In a study  of 108 healthy, middle-aged (50 years) marathon runners, cardiac computed tomography (CT) showed a higher level of coronary artery calcium score (CAC) compared to Framingham risk score-matched population but a similar level of CAC compared to age- and sex-matched sedentary population. This population is representative of typical amateur runners since they started training within the preceding decade and their exercise training volume was relatively modest. More than half of these cases were previous smokers, and their body mass indices were at the higher end of normal range. Thirty-six percent of these marathon runners had CAC score 100 or more and 9% of these required coronary revascularization during 2 years of follow-up indicating no protective effect of running for atherosclerosis in late life 
- LGE was observed in 12% of these athletes. CAC percentile values and number of marathons independently predicted the presence of LGE. Runners with LGE had higher subclinical CAD burden and had higher increases in troponin I during marathon, suggesting a causal relationship. Higher CAC scores and LGE are shown to be associated with higher coronary event rates on long-term follow-up. , Some marathoners may have higher levels of CAC due to an increase in PTH levels during running 
- A study  comparing coronary angiograms of marathon runners with that of sedentary, age-matched controls showed that male veterans (who ran at least one marathon each year for 25 consecutive years) had significantly increased amounts of both hard and soft coronary plaques. It is unlikely that the high-dose vigorous exercise causes atherosclerosis but it may potentiate the existing atherosclerosis process by increasing repetitive arterial shear stress and chronic pro-inflammatory state 
- Significantly higher incidence of late-life AF is seen in individuals participating in prolonged high-intensity exercise in the early part of life. In a rat model,  chronic endurance exercise increased AF susceptibility due to autonomic changes, increased vagal tone, atrial dilation, and fibrosis. In a Swedish study,  52,755 participants in Vasaloppet, a 90 km cross-country skiing event, from the year 1989 to 1998 were followed up until the year 2005. AF and bradyarrhythmias were experienced by 919 participants. A faster finishing time and a high number of completed races were associated with higher risk of AF. In a meta-analysis  of six case-control studies of 655 athletes and 895 controls, AF was documented in 23% of athletes and 12.5% in controls. The odds ratio (OR) for AF in the athlete group was 5.29 (95% CI 3.57-7.85). In a study  of 115 cases of athletes with AF, compared with 57 age-matched controls, the OR for new AF was 4.52 for cumulative heavy sports activity (>2000 h) which was almost equivalent to cases with sleep apnea (OR 5.04) and higher than even sedentary individuals (OR 3.85)
- Majority of SCD occur in full marathons than in half marathons and that too strikingly in the final quartile of full marathons.  The cause may be multifactorial such as sympathetic overactivation, electrolyte imbalance, activation of hemostatic system, shear stress on vulnerable coronary plaques, or hemorrhage into the plaque.  The heat stroke may be a major cause of SCD during endurance running events 
- The risk of myocardial biomarker release, acute MI, and SCD during marathon running or training is higher in poorly trained marathon runners as compared to highly trained athletes. The musculoskeletal injuries with running are common and can be severe enough to stop participation in aerobic exercise. In an 8-week training session for 4 miles run, 25% of participants developed significant musculoskeletal injuries requiring cessation of training 
- Among individuals who carry a desmosome mutation for RV cardiomyopathy, the endurance training can cause deterioration of RV function and accelerate the phenotype expression of RV cardiomyopathy. ,
The counter view
Except for higher incidence of AF, there is no clear evidence of highly significantly increased the risk of ventricular arrhythmias, heart failure, CV, or all-cause mortality in endurance athletes and active individuals from epidemiological studies.  The risk for SCD from running is negligible and is as low as 4/1 million. 
The elite athletes have fewer hospitalizations, require less asthma, CV, and anti-inflammatory medications, and live longer than nonathletic people.  In Vasaloppet, the 90 km cross-country skiing event, there was no increase in ventricular tachycardia, ventricular fibrillation, or cardiac arrest.  The cross-country skiers had 52% reduction in all-cause mortality, with the highest life expectancy found in older participants and athletes who participated in multiple races.  More than 15,174 Olympic medalists from nine different country groups were followed up over decades after their first medal.  The participants of the endurance sports had higher survival (2.8 years) compared to age- and sex-matched controls from the general population in those countries.  Finnish skiers and world-class endurance athletes demonstrated an increased life expectancy of 2.8-6 years compared with reference cohorts. ,, Masters athletes, who had been training for more than 25 years, competing successfully in multiple marathons, triathlons had LV compliance, vascular age, and vasodilatory function similar to young adults.  Their ventricular-arterial coupling was superior so that they could increase more than two times their stroke volume for any given increase in left ventricular filling pressure.
Commencing from 1986, a 22 years long, biennial questionnaire-based follow-up study  of 44,551 men, aged 40-75 years, showed that increasing amounts of vigorous activity remains inversely associated with CV and malignancy disease risk. This relationship existed even among men in the highest categories of intense exercise. Running ≥5 h a week was associated with the lowest CV risk. Vigorous intensity of exercise at 10 METS h/week further reduced mortality by 4% points over the moderate intensity of exercise of identical energy expenditure. A recent study  showed that the committed exercisers, who have trained regularly, 4-5 days a week for most of their adult lives, have ventricles that are almost as compliant as those of master athletes. In contrast, casual exercisers, who trained not more than 2-3 times per week, had no apparent benefit in terms of LV compliance. Recreational marathon training reduces CV risk factors (obesity and lipid levels) and increases CV efficiency (improved peak oxygen consumption and diastolic function). 
Both views, for and against habitual strenuous exercise, should be interpreted cautiously and should not be used indiscriminately to dissuade strenuous physical activity in trained, healthy athletes or to encourage strenuous physical activity in ill-trained amateur runners.
| The Reverse J Shape Relationship of Running and Mortality|| |
The epidemiological studies in general population studying the relationship of the quantum of running and mortality reduction consistently show a reverse J shape pattern. ,
In the Copenhagen City Heart Study,  1098 healthy joggers and 3950 healthy nonjoggers were prospectively followed up since 2001. Joggers were categorized as light (n = 576), moderate (n = 262), and strenuous joggers (n = 40) depending on the combination of self-reported pace (slow, average, and fast), quantity (<2.5 h/week, 2.5-4 h/week, and >4 h/week), and frequency (<3 times/week, >3 times/week). For example, a case with slow or average pace jogging for <2.5 h/week and <3 times/week will be categorized as "light jogger" whereas a case with fast pace jogging for >2.5 h/week and >3 times/week will be categorized as "strenuous jogger." The lowest hazards ration (HR) for mortality was found in light joggers (HR: 0.22; 95% CI: 0.10-0.47), followed by moderate joggers (HR: 0.66; 95% CI: 0.32-1.38) and strenuous joggers (HR: 1.97; 95% CI: 0.48-8.14). Jogging up to 2.5 h/per week at a slow or average pace and a frequency of <3 times per week was associated with the lowest mortality. Those who jogged >4 h/week, at a fast pace, and >3 times/week appeared to lose many of the longevity benefits. In other words, light and moderate joggers have lower mortality than sedentary nonjoggers whereas strenuous joggers have a mortality rate not statistically different from that of sedentary nonjoggers (U-shaped association). The study was criticized for nonobjective "self-reporting" of pace  and low number of strenuous joggers exaggerating the HR in this group ( n = 40 with two deaths). Similar reverse J shape findings for intensity and duration of exercise were not found in the studies of walking and cycling by the same authors. ,
Cooper Clinic in Dallas, Texas, followed up of 55,137 adults for 15-year to examine associations of running with all-cause and CV mortality. , They used five quintiles of running so there would be an equal number of cases across different doses of running. CV mortality appeared to be relatively higher in those with higher doses of running compared with lower doses (reverse J-shaped association) and a slight nonsignificant trend of less benefit, for all-cause mortality, with higher doses of running compared with lower doses of running. However, there continued to be significantly lower risks of mortality in the highest quintiles of running time (>176 min/week) and frequency (>6 times/week) compared to the nonrunners (no U-shaped association).
Despite all the limitations of methodologies in these studies, few distinct trends emerge, which are hypothesis generating [Figure 1]. More is definitely not better  but may not be harmful. , The benefit of maximal reduction in mortality is achieved at light to moderate intensity of regular jogging as compared to habitual sedentary behavior. There is no further reduction in mortality with a higher dose of jogging but rather the benefits tend to get blunted or reduced at a higher intensity or extreme level of running.
|Figure 1: Conceptual graph of the approximate relationship of "intensity of jogging" (time, distance, speed, frequency, and metabolic equivalents min/week) and reduction in "cardiovascular mortality" derived from data of Lee et al.  showing reverse J shape. There is significant reduction in cardiovascular mortality at the lower quintiles of running intensity, while the benefits appear to get blunted at higher quintiles of running intensity|
Click here to view
The reverse J shape relation of exercise and mortality has also been shown in post-MI patients and patients with stable CAD. In a study  of 2377 MI survivors, 15% average risk reduction in CV mortality was achieved for every additional 1 MET h/day of exercise (equivalent of running 1 km/day) only till 7.2 MET h/day. Regular exercise above this level, in this post-MI population, did not benefit but rather increased CV events. Relative to the CV risk reduction at 7.2 MET h/day exercise, the CV risk of exercising above 7.2 MET h/day increased 3.2-fold. In another study of 1038 cases  with stable CAD, the frequency of strenuous leisure time physical activity was assessed over 10 years of follow-up. The CV events, mortality, and all-cause mortality were highest in the sedentary group and then progressively declined from infrequent (1-4 times a month) to moderate activity (2-4 times a week) groups. However, the CV events, CV mortality, and all-cause mortality again climbed progressively in the frequent (5-6 times a week) to daily strenuous activity group. The all-cause mortality rate per 1000 persons-year was 44.3 in sedentary group, 14.1 in infrequent activity (1-4 times a week) group, 7.6 in moderate activity (2-4 times a week) group, 8.7 in frequent activity (5-6 times a week) group, and 16.2 in daily strenuous activity group.
It is controversial and probably not true that individuals lose all the benefits of exercise at habitual high or extremely high intensity of exercise and the mortality climbs back to that of sedentary level  (the U-shaped relation). Therefore, the strenuous level of running is not better for sure but not necessarily harmful.  A weekly cumulative dose of vigorous exercise of not more than 5 h may be the safe upper range for optimal CV health and life expectancy. It may be beneficial to take 1 or 2 days a week off from vigorous exercise and not to perform high-intensity exercise on a daily basis. 
| Screening of Amateur Runners|| |
The preparticipation electrocardiography (ECG) screening of young athletes is controversial considering financial and logistics cost of ECG acquisition and interpretation, high rate of false-positive findings, cost of follow-up testing after abnormal ECG, and the problems of future insurability of athletes with abnormal ECG.  However, the risk of SCD in older athletes is 5-fold higher during training than during the marathon event.  The physician has to diligently screen for occult CAD in the sedentary individuals, above the age of thirty, who wish to first-time start training for a marathon. There are three published documents for preparticipation screening of the older athlete for risk stratification. ,,
A comprehensive history as outlined in the questionnaire  is very useful to detect patients needing detail physical examination and ECG [Table 5]. A high-risk case can be identified by clinical features  For example, strong family history of premature CAD or SCD, Framingham risk score >5%, high-body mass index, high-LDL cholesterol, or diabetes with microalbuminuria. When the patient has high-CAD risk profile and the gap between his/her daily physical activity and planned training level is large, the physician should perform a maximal stress test.  The incremental value of the selective use of echocardiography, cardiac MRI, or CT coronary calcium score is not defined in this population.
|Table 5: Preparticipation self-assessment questionnaire for amateur runners|
Click here to view
| Counseling of the Amateur Runners|| |
Physicians should have a detail and balanced discussion with the amateur runner training for the marathon. Most of these individuals are performing physical activity far more than the minimal recommendations for the society.  It should be made clear that exercise benefits far outweigh the risks at every level of exercise. Although no optimal dose of exercise exists, the maximal CV benefits are already achieved at a moderate intensity of exercise. Although the routine performance of high level of exercise bestows relative protection from CV mortality, unfortunately no level of exercise gives complete immunity from CV disease or mortality.  The higher level of training does not mean better CV benefits. Higher running dose is associated with higher level of cardiorespiratory fitness, but this does not translate into better survival (which already peaks at low dose of exercise).  The exercise paradox must be discussed when counseling both habitual sedentary individuals and also the exercise enthusiasts. The inherent risks and benefits of high-dose exercise should be made clear.  This is especially more relevant for patients with established stable CAD. The marathon running may be looked upon as thrilling or adventure sport and not as ideal workout for maximal health benefit.
The importance of gradual increment in training should be emphasized in middle-aged runners to avoid precipitation of SCD,  acute coronary events, or musculoskeletal injury. A gradually incremental and long-term training schedule may reduce the risk of SCD substantially in the habitual sedentary cases.  The frequency of physical activity (not the intensity) should be emphasized as the initial goal. The previously inactive person should start with brisk walking 3-4 times a week and then upgrade to light pace jogging at 50%-75% of age-predicted maximum heart rate (MHR), and finally to moderate pace running at 70%-85% of age-predicted MHR. Each stage should last for 6-8 weeks.  As described earlier, exercise-induced cardiac adaptive remodeling is a slow process and takes 9-12 months of training to reach its maximal potential. 
The amateur runners should be instructed to observe even mild symptoms of chest pain, dizziness, small decrements in exercise capacity, or new onset fatigability and should seek physician's consult.  This must be especially more emphasized in patients with established stable CAD. The amateur runners should be made aware of the importance of cross training to achieve maximal aerobic fitness and avoid overuse injury.  The amateur runners must be instructed to stick to the healthy lifestyle including healthy dietary choices, quitting smoking, and excess alcohol consumption.  Although statins are prescribed for eligible patients in accordance with 2015 ACC/AHA guidelines, the statin-induced myalgia is often more troublesome in the runners.  The use of low-dose aspirin (75-100 mg) as primary prevention in middle-aged runners with traditional coronary risk factors is uncertain,  but the benefit may outweigh the risk. 
| Wisdom of Hippocrates|| |
After reviewing the of emerging data of exercise and its effects on health, the following quote from Hippocrates appears to be more relevant than ever. 
"If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health."
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
O′Keefe JH, Vogel R, Lavie CJ, Cordain L. Exercise like a hunter-gatherer: A prescription for organic physical fitness. Prog Cardiovasc Dis 2011;53:471-9.
Wen CP, Wai JP, Tsai MK, Yang YC, Cheng TY, Lee MC, et al.
Minimum amount of physical activity for reduced mortality and extended life expectancy: A prospective cohort study. Lancet 2011;378:1244-53.
Lee DC, Pate RR, Lavie CJ, Sui X, Church TS, Blair SN. Leisure-time running reduces all-cause and cardiovascular mortality risk. J Am Coll Cardiol 2014;64:472-81.
Arem H, Moore SC, Patel A, Hartge P, Berrington de Gonzalez A, Visvanathan K, et al.
Leisure time physical activity and mortality: A detailed pooled analysis of the dose-response relationship. JAMA Intern Med 2015;175:959-67.
Franklin BA. Preventing exercise-related cardiovascular events: Is a medical examination more urgent for physical activity or inactivity? Circulation 2014;129:1081-4.
O′Keefe JH, Franklin B, Lavie CJ. Exercising for health and longevity vs peak performance: Different regimens for different goals. Mayo Clin Proc 2014;89:1171-5.
2008 Physical Activity Guidelines for Americans. U.S. Department of Health and Human Services. Available from: https://health.gov/paguidelines/pdf/paguide.pdf. [Last accessed on 2016 Oct 15].
Eijsvogels TM, Molossi S, Lee DC, Emery MS, Thompson PD. Exercise at the extremes: The amount of exercise to reduce cardiovascular events. J Am Coll Cardiol 2016;67:316-29.
Chugh SS, Weiss JB. Sudden cardiac death in the older athlete. J Am Coll Cardiol 2015;65:493-502.
Chandra N, Bastiaenen R, Papadakis M, Sharma S. Sudden cardiac death in young athletes: Practical challenges and diagnostic dilemmas. J Am Coll Cardiol 2013;61:1027-40.
Maron BJ, Araújo CG, Thompson PD, Fletcher GF, de Luna AB, Fleg JL, et al.
Recommendations for preparticipation screening and the assessment of cardiovascular disease in masters athletes: An advisory for healthcare professionals from the working groups of the World Heart Federation, the International Federation of Sports Medicine, and the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation 2001;103:327-34.
Borjesson M, Urhausen A, Kouidi E, Dugmore D, Sharma S, Halle M, et al.
Cardiovascular evaluation of middle-aged/senior individuals engaged in leisure-time sport activities: Position stand from the sections of exercise physiology and sports cardiology of the European Association of Cardiovascular Prevention and Rehabilitation. Eur J Cardiovasc Prev Rehabil 2011;18:446-58.
La Gerche A, Taylor AJ, Prior DL. Athlete′s heart: The potential for multimodality imaging to address the critical remaining questions. JACC Cardiovasc Imaging 2009;2:350-63.
George KP, Warburton DE, Oxborough D, Scott JM, Esch BT, Williams K, et al.
Upper limits of physiological cardiac adaptation in ultramarathon runners. J Am Coll Cardiol 2011;57:754-5.
Bohm P, Schneider G, Linneweber L, Rentzsch A, Krämer N, Abdul-Khaliq H, et al.
Right and left ventricular function and mass in male elite master athletes: A controlled contrast-enhanced cardiovascular magnetic resonance study. Circulation 2016;133:1927-35.
Arbab-Zadeh A, Perhonen M, Howden E, Peshock RM, Zhang R, Adams-Huet B, et al.
Cardiac remodeling in response to 1 year of intensive endurance training. Circulation 2014;130:2152-61.
Pelliccia A, Kinoshita N, Pisicchio C, Quattrini F, Dipaolo FM, Ciardo R, et al.
Long-term clinical consequences of intense, uninterrupted endurance training in olympic athletes. J Am Coll Cardiol 2010;55:1619-25.
Chomistek AK, Cook NR, Flint AJ, Rimm EB. Vigorous-intensity leisure-time physical activity and risk of major chronic disease in men. Med Sci Sports Exerc 2012;44:1898-905.
Schnohr P, O′Keefe JH, Marott JL, Lange P, Jensen GB. Dose of jogging and long-term mortality: The Copenhagen City Heart Study. J Am Coll Cardiol 2015;65:411-9.
van der Ploeg HP, Chey T, Ding D, Chau JY, Stamatakis E, Bauman AE. Standing time and all-cause mortality in a large cohort of Australian adults. Prev Med 2014;69:187-91.
Lee DC, Lavie CJ, Vedanthan R. Optimal dose of running for longevity: Is more better or worse? J Am Coll Cardiol 2015;65:420-2.
Miyachi M, Tripette J, Kawakami R, Murakami H. "+10 min of Physical Activity per Day": Japan Is Looking for Efficient but Feasible Recommendations for Its Population J Nutr Sci Vitaminol (Tokyo). 2015;61 Suppl:S7-9.
Wen CP, Wai JP, Tsai MK, Chen CH. Minimal amount of exercise to prolong life: To walk, to run, or just mix it up? J Am Coll Cardiol 2014;64:482-4.
Blair SN, Kohl HW 3 rd
, Paffenbarger RS Jr., Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989;262:2395-401.
Schnohr P. Physical activity in leisure time: Impact on mortality. Risks and benefits. Dan Med Bull 2009;56:40-71.
Wasfy MM, Baggish AL. Exercise dose in clinical practice. Circulation 2016;133:2297-313.
Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med 1984;311:874-7.
Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ, Muller JE. Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators. N Engl J Med 1993;329:1677-83.
Albert CM, Mittleman MA, Chae CU, Lee IM, Hennekens CH, Manson JE. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med 2000;343:1355-61.
Maron BJ, Poliac LC, Roberts WO. Risk for sudden cardiac death associated with marathon running. J Am Coll Cardiol 1996;28:428-31.
Marijon E, Tafflet M, Celermajer DS, Dumas F, Perier MC, Mustafic H, et al.
Sports-related sudden death in the general population. Circulation 2011;124:672-81.
Thompson PD, Funk EJ, Carleton RA, Sturner WQ. Incidence of death during jogging in Rhode Island from 1975 through 1980. JAMA 1982;247:2535-8.
Drca N, Wolk A, Jensen-Urstad M, Larsson SC. Atrial fibrillation is associated with different levels of physical activity levels at different ages in men. Heart 2014;100:1037-42.
Thompson PD. Physical fitness, physical activity, exercise training, and atrial fibrillation: First the good news, then the bad. J Am Coll Cardiol 2015;66:997-9.
Bhatt AG, Monahan KM. Fitness and the development of atrial fibrillation. Circulation 2015;131:1821-3.
Shiroma EJ, Lee IM. Physical activity and cardiovascular health: Lessons learned from epidemiological studies across age, gender, and race/ethnicity. Circulation 2010;122:743-52.
La Gerche A, Heidbuchel H. Response to letters regarding article, "can intensive exercise harm the heart? You can get too much of a good thing". Circulation 2015;131:e526.
Andersen LB. Light and moderate joggers do not have lower mortality rates than strenuous joggers. J Am Coll Cardiol 2015;65:2670-1.
Burtscher M, Pesta D. Absolute or relative jogging pace: What makes the difference? J Am Coll Cardiol 2015;65:2671-2.
Bhella PS, Levine BD. The heart of a champion. J Am Coll Cardiol 2010;55:1626-8.
Neilan TG, Januzzi JL, Lee-Lewandrowski E, Ton-Nu TT, Yoerger DM, Jassal DS, et al.
Myocardial injury and ventricular dysfunction related to training levels among nonelite participants in the Boston marathon. Circulation 2006;114:2325-33.
Rifai N, Douglas PS, O′Toole M, Rimm E, Ginsburg GS. Cardiac troponin T and I, echocardiographic [correction of electrocardiographic] wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon. Am J Cardiol 1999;83:1085-9.
Douglas PS, O′Toole ML, Hiller WD, Hackney K, Reichek N. Cardiac fatigue after prolonged exercise. Circulation 1987;76:1206-13.
La Gerche A, Connelly KA, Mooney DJ, MacIsaac AI, Prior DL. Biochemical and functional abnormalities of left and right ventricular function after ultra-endurance exercise. Heart 2008;94:860-6.
Wilson M, O′Hanlon R, Prasad S, Deighan A, Macmillan P, Oxborough D, et al.
Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes. J Appl Physiol 2011;110:1622-6.
Möhlenkamp S, Lehmann N, Breuckmann F, Bröcker-Preuss M, Nassenstein K, Halle M, et al.
Running: The risk of coronary events: Prevalence and prognostic relevance of coronary atherosclerosis in marathon runners. Eur Heart J 2008;29:1903-10.
Schwartz RS, Kraus SM, Schwartz JG, Wickstrom KK, Peichel G, Garberich RF, et al
. Increased coronary artery plaque volume among male marathon runners. Missouri Medicine 2014;111:85-90.
Andersen K, Farahmand B, Ahlbom A, Held C, Ljunghall S, Michaëlsson K, et al.
Risk of arrhythmias in 52 755 long-distance cross-country skiers: A cohort study. Eur Heart J 2013;34:3624-31.
Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis. Europace 2009;11:1156-9.
Yankelson L, Sadeh B, Gershovitz L, Werthein J, Heller K, Halpern P, et al.
Life-threatening events during endurance sports: Is heat stroke more prevalent than arrhythmic death? J Am Coll Cardiol 2014;64:463-9.
Guasch E, Benito B, Qi X, Cifelli C, Naud P, Shi Y, et al.
Atrial fibrillation promotion by endurance exercise: Demonstration and mechanistic exploration in an animal model. J Am Coll Cardiol 2013;62:68-77.
Trivax JE, Franklin BA, Goldstein JA, Chinnaiyan KM, Gallagher MJ, deJong AT, et al.
Acute cardiac effects of marathon running. J Appl Physiol 2010;108:1148-53.
Levine BD. Can intensive exercise harm the heart? The benefits of competitive endurance training for cardiovascular structure and function. Circulation 2014;130:987-91.
Heidbüchel H, Hoogsteen J, Fagard R, Vanhees L, Ector H, Willems R, et al.
High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias. Role of an electrophysiologic study in risk stratification. Eur Heart J 2003;24:1473-80.
La Gerche A, Burns AT, Mooney DJ, Inder WJ, Taylor AJ, Bogaert J, et al.
Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. Eur Heart J 2012;33:998-1006.
Breuckmann F, Möhlenkamp S, Nassenstein K, Lehmann N, Ladd S, Schmermund A, et al.
Myocardial late gadolinium enhancement: Prevalence, pattern, and prognostic relevance in marathon runners. Radiology 2009;251:50-7.
Calvo N, Ramos P, Montserrat S, Guasch E, Coll-Vinent B, Domenech M, et al
. Emerging risk factors and the dose-response relationship between physical activity and lone atrial fibrillation: A prospective case-control study Europace. 2016;18:57-63.
Buist I, Bredeweg SW, Bessem B, van Mechelen W, Lemmink KA, Diercks RL. Incidence and risk factors of running-related injuries during preparation for a 4-mile recreational running event. Br J Sports Med 2010;44:598-604.
Kim JH, Malhotra R, Chiampas G, d′Hemecourt P, Troyanos C, Cianca J, et al.
Cardiac arrest during long-distance running races. N Engl J Med 2012;366:130-40.
Farahmand BY, Ahlbom A, Ekblom O, Ekblom B, Hållmarker U, Aronson D, et al.
Mortality amongst participants in Vasaloppet: A classical long-distance ski race in Sweden. J Intern Med 2003;253:276-83.
Clarke PM, Walter SJ, Hayen A, Mallon WJ, Heijmans J, Studdert DM. Survival of the fittest: Retrospective cohort study of the longevity of Olympic medallists in the modern era. BMJ 2012;345:e8308.
Karvonen MJ, Klemola H, Virkajärvi J, Kekkonen A. Longevity of endurance skiers. Med Sci Sports 1974;6:49-51.
Sarna S, Sahi T, Koskenvuo M, Kaprio J. Increased life expectancy of world class male athletes. Med Sci Sports Exerc 1993;25:237-44.
Garatachea N, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Emanuele E, et al.
Elite athletes live longer than the general population: A meta-analysis. Mayo Clin Proc 2014;89:1195-200.
Bhella PS, Hastings JL, Fujimoto N, Shibata S, Carrick-Ranson G, Palmer MD, et al.
Impact of lifelong exercise "dose" on left ventricular compliance and distensibility. J Am Coll Cardiol 2014;64:1257-66.
Zilinski JL, Contursi ME, Isaacs SK, Deluca JR, Lewis GD, Weiner RB, et al.
Myocardial adaptations to recreational marathon training among middle-aged men. Circ Cardiovasc Imaging 2015;8:e002487.
Schnohr P, Scharling H, Jensen JS. Intensity versus duration of walking, impact on mortality: The Copenhagen City Heart Study. Eur J Cardiovasc Prev Rehabil 2007;14:72-8.
Schnohr P, Marott JL, Jensen JS, Jensen GB. Intensity versus duration of cycling, impact on all-cause and coronary heart disease mortality: The Copenhagen City Heart Study. Eur J Prev Cardiol 2012;19:73-80.
Williams PT, Thompson PD. Increased cardiovascular disease mortality associated with excessive exercise in heart attack survivors. Mayo Clin Proc 2014;89:1187-94.
Mons U, Hahmann H, Brenner H. A reverse J-shaped association of leisure time physical activity with prognosis in patients with stable coronary heart disease: Evidence from a large cohort with repeated measurements. Heart 2014;100:1043-9.
Baggish AL, Wood MJ. Athlete′s heart and cardiovascular care of the athlete: Scientific and clinical update. Circulation 2011;123:2723-35.
Pescatello LS, American College of Sports Medicine. ACSM′s Guidelines for Exercise Testing and Prescription. 9 th
ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins Health; 2014.
Balady GJ, Chaitman B, Driscoll D, Foster C, Froelicher E, Gordon N, et al.
Recommendations for cardiovascular screening, staffing, and emergency policies at health/fitness facilities. Circulation 1998;97:2283-93.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|This article has been cited by|
||Aronia juice consumption prior to half-marathon race can acutely affect platelet activation in recreational runners
| ||Vuk Stevanovic,Ana Pantovic,Irena Krga,Milica Zekovic,Ivana Šarac,Maria Glibetic,Nevena Vidovic |
| ||Applied Physiology, Nutrition, and Metabolism. 2019; : 1 |
|[Pubmed] | [DOI]|
||Prevention of sudden cardiac death in athletes, sportspersons and marathoners in India
| ||Amit Vora,Nitin Burkule,Ashish Contractor,Kartikeya Bhargava |
| ||Indian Heart Journal. 2017; |
|[Pubmed] | [DOI]|