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Dr Larry Creswell

Dr. Larry Creswell on athletes and heart health.
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USAT Webinar: Heart Health and Endurance Sport

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Last week I recorded a one-hour webinar entitled “Heart Health and Endurance Sport.”  You can download the webinar for free at the USA Triathlon (USAT) website.

The webinar is a consequence of my recent work with USAT regarding race safety.  At the conclusion of our work, we felt that USAT was in a position to provide some educational offerings to members of our triathlon community that might lead to safer training and competing for athletes and to better safety and event planning by race organizers.

Obviously the topic is broad and one hour is pretty short.  I decided to organize the discussion into 5 topics that I thought were most important:

1.  The heart and general health benefits of exercise.

2.  The heart’s adaptation to exercise and the “athlete’s heart.”

3.  Sports-related sudden cardiac death.

4.  Other potential adverse consequences of endurance sport.

5.  How to care for your heart for the long term.

Take a listen.  I hope there’s some useful information that might let you take better charge of your own heart health and train and race safely.  There’s a “homework” project at the end; I’d be happy to hear from you….and so would your athlete friends.

Related Posts:

1.  USAT Fatality Incidents Study
2.  Athletes, Sudden Death, and CPR
3.  Recent Safety Initiatives in Triathlon

Ask the Experts: Pre-participation Heart Screening for Adult Endurance Athletes

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It’s the time of year when many endurance athletes are considering their medical and health preparations for the upcoming season, whatever their sport.  One important consideration is pre-participation screening for heart problems.  I get inquiries like:

Should I see the doctor before training?

I’m concerned about the heart risks.  Should I get my heart checked out?

Do I need an EKG?  An echocardioam?

These are all good questions.  But the answers really do depend upon an athlete’s circumstance.  There’s no one-size-fits-all prescription here.

I thought I’d gather a group of experts to give you their opinions about 4 fictitious athlete scenarios.  You’ll get to see how these experts approach the athletes’ situation and how they’d handle the issue of pre-participation screening for each.  None of these fictitious athletes will match your own situation, but you can learn from these scenarios so that you’re better able to have a conversation with your doctor about how to make plans that are suited for your circumstances.

The Experts

John M. Mandrola, MD, is a cardiologist in Louisville, Kentucky who specializes in electrophysiology, the field of cardiology that focuses on the prevention, diagnosis, and treatment of arrhythmias.  He is an avid cyclist and occasional triathlete.  Follow Dr. Mandrola on Twitter at @drjohnm and read his blog about medicine and cyling at www.drjohnm.org.

Jonathan A. Drezner, MD, is a member of the Family Medicine faculty at the University of Washington, with a clinical focus in sports medicine.  He also serves as Team Physician for the University’s Department of Intercollegiate Athletics.  Dr. Drezner has an international reputation in the areas of automatic external defibrillators (AEDs) in sports settings; emergency preparedness for sports-related sudden cardiac death; and pre-participation screening in young competitive athletes.  Dr. Drezner is the current President of the American Medical Society for Sports Medicine.  He is also active with charitable organizations that promote awareness for heart conditions that affect young athletes, including Parent Heart Watch, the Sudden Cardiac Arrest Association, and Heart Screen America.

James G. Beckerman, MD, is a cardiologist in Portland, Oregon who focuses on preventive and sports cardiology.  He serves as Team Cardiologist for the Portland Timbers soccer team and as Medical Director for the Play Smart Youth Heart Screenings Program.  Follow Dr. Beckerman on Twitter at @jamesbeckerman.

Philip F. Skiba, DO, is the Program Director for Sports Medicine at Lutheran General Hospital, in Chicagoland and Acting Program Director for Sport and Exercise Medicine at The University of Exeter, UK.  He is the CEO of PhysFarm Training Systems and has coached a number of world-class triathletes.

The Assignment

I asked each of the experts to comment on the 4 athlete scenarios, with the following instructions:

What would you recommend for the athlete if he/she contacted you about pre-participation health screening–if YOU were going to be the athlete’s doctor?  Please discuss your approach in light of the history provided by the patient in a short telephone conversation.  Assume that the athlete has typical employer-based health insurance, with $1000 annual deductible, and no special wellness benefits.  Would you schedule an office visit for history and physical examination?  If so, what would be your focus?  Would you plan any diagnostic testing–chest x-ray, blood tests, EKG, echocardiogram, stress test, etc.?  If the answer is “maybe,” discuss how you (and the athlete) would decide.

The experts’ responses are listed with each scenario.

Scenario #1

24-year-old woman wants to join her girlfriends in training for her first 5k run.  She is slightly overweight, but sees this as an opportunity to lose weight.  She has no chronic medical problems and has no family history of heart disease.  She sees a primary care physician annually and reports that her last physical examination was 8 months ago.  She takes an oral contraceptive.

Dr. Mandrola:  I would do nothing.

Dr. Drezner:  I would encourage her to start her training program, and offer a more comprehensive heart screen that would include an ECG.  The risk of sudden cardiac death in young athletes is lower in females than males, but I would still offer a screen.  Most young athletes with a pathologic heart condition have no symptoms.  An ECG helps to identify silent diseases that place athletes at risk of sudden cardiac death.

Dr. Beckerman:  No diagnostic testing.  I would counsel her that it is possible that she will not experience significant weight loss from the 5k training, but would emphasize the health benefits–short and long term.

Dr. Skiba:  If I were the primary care physiciansh e sees annually, I would clear her for participation, with the caveat that she should immediately contact me for any strange symptoms, and I would carefully delineate signes or symptoms that should trigger concern.  If I were not her primary care physician, I would not clear her without the pre-participation history and physical exam I provide to all athletes.

Scenario #2

35-year-old man is a former high school track athlete, is currently a recreational runner, and now wants to begin structured training for his first-ever marathon.  He is a former smoker, having quit at age 28 after smoking 1 pack per day for 8 years.  His last complete physical examination was during high school.  He injured his ankle a year ago, prompting an ER visit where he learned it was sprained.  At that visit, his blood pressure was high.  About 8 months ago, along with his wife, he visited a health fair where he had his cholesterol tested.  The cholesterol and LDL were elevated.  His mother has high blood pressure.  He currently takes a fish oil supplement.

Dr. Mandrola:  I would recommend a complete physical exam, including an ECG and stress ECG.  Even if they were normal, I would advise him to begin training very slowly and consider delaying his marathon a year or two.  This will allow him to embark on such a lofty goal when he is fitter and likely with a better blood pressure.  This last caveat comes from personal experience.  It took me 3 years to successfully run a marathon, as each attempt was felled by an over-training related injury.

Dr. Drezner:  This patient has multiple risk factors for atherosclerotic coronary heart disease–the usual culprit in adults over 30 years old that causes heart attacks or sudden cardiac arrest.  I would strongly encourage this patient to come in for an evaluation, counseling and treatment of his high blood pressure and high cholesterol, and discussion of an exercise stress test.  An exercise stress test is the best way to look for coronary artery disease and recommended for adults with cardiovascular risk factors who are starting a new or more intensive training program.

Dr. Beckerman:  If he has normal blood pressure today, I would not recommend any diagnostic testing.  I would recommend some dietary changes and would recheck his lipids in 3 months.  Warrants a full cardiac exam to focus on blood pressure, murmurs, abdominal bruit if BP elevated.

Dr. Skiba:  I would provide the patient with a preparticipation history and physical exam.  As exercise is effective treatment for both hypertension and hypercholesterolemia, my advice would depend upon the level of elevationand,  whether he required urgent treatment or whether a trial of exercise would be appropriate.

Scenario #3

44-year old woman is currently a competitive masters swimmer who wants to take up triathlon in the upcoming season.  She has no chronic medical problems.  There is a remote history of goiter for which she had subtotal thyroidectomy.  She has two healthy children.  Her mother and sister have high blood pressure.  She takes a daily multivitamin with iron.  She reports that she “blacked out” 3 years ago at the conclusion of a swim workout, but had no specific medical evaluation or treatment.  She occasionally has bothersome palpitations.  Her last complete physical examination was 3 years ago.

Dr. Mandrola:  I would recommend a history and physical with an ECG.  If the ECG and exam were completely normal, I would stop.  If the QT was borderline or the palpitations struck me as ominous, I would likely add a Holter monitor and treadmill.  The Holter to look for AF [atrial fibrillation] or other arrhythmia and the treadmill to look for exercise induced arrhythmia or abnormal QT response.

Dr. Drezner:  This patient needs an evaluation to check her blood pressure, ECG and stress test, and perhaps a 24 hour Holter monitor.  Passing out is not normal.  Although it is usually benign when it occurs after exercise (not during), everybody who passes out should have at least one ECG.  Her age suggests a stress test is also indicated for exercise related passing out.  She also has palpitations which may indicate the presence of an arrhythmia.  Extended ECG monitoring (ie, 24 hours) can sometimes capture an abnormal heart rhythm if present.

Dr. Beckerman:  I would check an ECG.  If palpitations are nonexertional, I would consider a Holter monitor or event monitor based on frequency.  If palpitations exertional, consider exercise treadmill test.  Check TSH.  Warrants a full cardiac exam with a focus on murmurs.

Dr. Skiba:  This is an athlete who deserves a thorough workup.  Syncope during or at the end of a swim workout could be the result of shallow water blackout (depending on what she was trying to do during that last bit of swimming), or could be the sign of something more sinister (i.e., an arrhythmia).  The chances that an isolated syncopal episode 3 years ago were a sign of some cardiac issue that has not presented itself again is admittedly somewhat remote, however in the setting of continued palpitations I am more suspicious.  She should at least get at EKG, with possible addition of an echocardiogram and/or Holter monitoring depending on where the workup goes.

Scenario #4

56-year-old man, currently a triathlete, wants to begin structured training in preparation for his first-ever Ironman triathlon.  He is particularly concerned about his heart risk because a friend, and fellow triathlete, recently died after a heart attack.  He is a former smoker, having quit at age 38 after smoking 1 pack per day for 15 years.  He currently takes an ACE inhibitor for high blood pressure and a daily aspirin.  His father died at age 52 of a heart attack.  Although he visits annually with his primary care provider, his last complete physical examination was 4 years ago.  He feels that he is about 20 pounds overweight.

Dr. Mandrola:  I would do a history and physical, blood sugar, lipid panel, ECG and stress test.  If these were normal, I would stop.  I can’t believe I’m saying this, but given his medium risk, a coronary CT scan might help here.  In the presence of coronary calcium, I would recommend statin therapy and strongly explain the risk of doing long-distance marathon/triathlons.

Dr. Drezner:  This patient has multiple risk factors for coronary heart disease, including his past history of smoking, high blood pressure, and his father’s history.  A family history of early heart attacks should be taken seriously, as genetics often dictate one’s risk and the timing of potential events.  Combined with his other risk factors, his family history places him at high risk for heart disease.  Before he enters a vigorous exercise program, I would want to screen for coronary artery disease.  A CT scan for coronary calcium scoring can detect calcium deposits in atherosclerotic plaques and provide some assessment of risk.  A stress test, or in this case a stress echocardiogram, will show if there is an obstructive lesion that limits blood flow to the heart during exercise.

Dr. Beckerman:  Full physical exam.  Check ECG.  If normal, exercise treadmill test.  If abnormal, stress echocardiogram.  Check Chem 7 [serum electrolytes] and CBC [complete blood count].  Recommend screening colonoscopy.

Dr. Skiba:  This is another patient who requires more careful monitoring.  In addition to a pre-participation history and physical exam, I would be concerned with how well the patient’s blood pressure was controlled, as well as how his lipid panel looked.  By strict interpretation of guidelines, he may not require testing because e is seemingly not symptomatic.  However, in roughly half of people the first sign of cardiac pathology is death.  I would therefore very carefully question him with respect to symptoms he might be ignoring or “brushing off.”  Given that he is hypertensive, he has a long smoking history, and a strong family history, my inclination would be to stress test him, especially if he is not (or has not) been training vigorously.

Elite Triathletes and Heart Problems

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A bunch of recent and contemporary elite triathletes have had problems with heart disease.  I thought I’d gather some of their stories here….and I’ll try to add to the list over time.  Please post a comment to let me know who to add.  The collection of stories shows the variety of heart problems that confront endurance athletes and certainly makes the point that fitness does not always equate with heart health.
I haven’t met any of these athletes, and outside of a few emails and Twitter conversations with a couple, I know their stories only from what’s been reported in the popular press or shared at the athletes’ blogs or websites.  So I’ll apologize in advance if I have any of the details confused….and be prepared to set the record straight, if need be.  I’ve done my best!
Steve Larsen was a former American professional road cyclist, a teammate of Lance Armstrong on the Motorola cycling team, who also enjoyed successful careers with mountain biking, track cycling, and cyclocross before turning to triathlon.  Larsen’s career is well chronicled in an article at Slowtwitch.  He collapsed with sudden cardiac death during a track running workout in Bend, Oregon on May 29, 2009 at age 39 and is survived by his wife and five young children.  An autopsy showed severe coronary artery disease (CAD), blockages in the coronary arteries that are the typical cause of myocardial infarction, or “heart attack.”  Dr. Alex McDonald offers a nice article about CAD and its implications at xtri.com.  I’ll also share a link to a website with a collection of photographs and kind rememberances about Larsen.
Torbjorn Sindballe was a Danish professional triathlete whose career highlights include wins at the 2000 and 2006 ITU long course world championships and a 3rd place finish at the 2007 Ironman World Championship (pictured above).  Starting in 2005 he was bothered by intermittent chest pains and underwent evaluation that showed he had a bicuspid aortic valve (BAV).  I’ve written about this condition here at the blog.  At the time of his diagnosis, his aorta had a normal diameter and there was no problem with the aortic valve.  He continued to compete, with occasional re-evaluation.  On June 30, 2009 he announced his retirement from triathlon, citing concerns about enlargement of the aorta or damage to the aortic valve with continued participation.  There is a great Q&A with Sindballe in an article at Slowtwitch where he is very candid about his heart problem.  Sindballe now exercises recreationally and is a member of Ironheart Racing Team, a Seattle-based team of multisport athletes from all over the country (and world) with various heart problems.
Normann Stadler is a retired German professional triathlete whose career highlights included wins at the 2004 and 2006 Ironman World Championships.  More recently, as shown in the picture, he was a member of the Commerzbank Triathlon Team.  In the summer of 2011 he was bothered by chest seemingly mild breathing difficulties and an unexplained fall-off in performance and sought evaluation.  He was found to have bicuspid aortic valve (BAV), severe aortic valve regurgitation (leaking), and a very large (7 cm) aortic aneurysm of the ascending aorta.  He underwent urgent surgery on July 4, 2011 for repair of his aortic valve and replacement of the beginning portion of the aorta.  I’ve written here at the blog about athletes and BAV and shared some thoughts in an article at Endurance Corner about the surprising turn of events for Stadler.  Stadler gives a great interview with Bob Babbitt, sharing his thoughts about his heart troubles.  It’s a remarkable story.
Samantha Warriner is a professional triathlete from New Zealand whose career includes an overall ITU World Cup series win.  She recalls problems with irregular rapid heart beat as a child, but no specific diagnosis was made back then.  This arrhythmia problem became worse as her career progressed in triathlon and was particularly bothersome in the 2010 season and especially during the run portions of 70.3 races.  She can recall episodes where her heart rate would be as high as 230 beats per minute.  With careful evaluation, she was found to have a supraventricular tachycardia (SVT)–ana rhythmia that involves the upper chambers (atria) of the heart–and underwent a successful ablation procedure for this arrhythmia at age 39 on December 1, 2010.  She made a quick recovery and went on to be the winner at the Ironman New Zealand race in March, 2011, just 3 months later.  You can read an interesting Q&A with Warriner in an article at Slowtwitch.
Erin Densham is a professional triathlete from Australia whose career already includes an U23 world championship in 2006, a 22ndplace finish in the Olympics in 2008, and a bronze medal most recently at the 2012 London Olympics.  Thinking back, she can recall troubles with a “racing heart” early in her childhood.  Her difficulties with an arrhythmia were very evident when she had to be rescued from the water at the 2009 Hy-Vee Triathlon in Des Moines, Iowa.  She was found to have a supraventricular tachycardia (SVT) and underwent a successful ablation procedure after in December, 2009.  Since then, she reports that she’s had no problems with recurrent arrhythmias.  You can read more about Densham’s story in an article at Inside Triathlon.
Gina Ferguson (Crawford) is a professional triathlete from New Zealand with multiple Ironman victories to her credit.  Her heart troubles came to light after she fainted after the bike portion of the 2009 Challenge Roth triathlon and was unable to finish the race.  Ferguson shares the tale at her blog.  She was found to have bicuspid aortic valve (BAV), a congenital condition where the aortic valve has 2, rather than the normal 3 cusps.  I’ve written about this condition here at the blog.  She presumably has no significant narrowing (stenosis) or leakage (regurgitation) of the valve and no enlargement of the nearby aorta.  She continues to train and compete, with periodic monitoring of her condition.

Justin Park is an American professional triathlete whose heart problems date to his high school days.  He had several episodes of fainting, or syncope, and was found to have congenital long QT syndrome (LQTS).  I’ve written about this condition here at the blog.  Individuals with LQTS are predisposed to have episodes of syncope or even sudden cardiac death, so Park received a recommendation that he not continue to participate in sports.  A number of years later, his physicians determined that his risk for these problems was not high and he took up triathlon.  Interestingly, he has also had difficulty with at least one episode of atrial fibrillation in 2010 that may have been due to underlying thyroid disease.  He writes about these issues at his blog.

Greg Welch is a retired Australian professional triathlete with a storied career at all distances of triathlon.  His victories include the 1990 ITU World Championship, 1993 World Duathlon Championship, 1994 Long Course World Championship, and 1994 Ironman World Championship.  His first problems with heart disease manifested during the swim portion of the 1999 Ironman World Champship.  He had trouble with breathing that he described as asthma-like.  He continued on in the race, had multiple episodes of near-syncope (blacking out), and struggled to an 11th place finish–a remarkable feat.  He would go on to compete a week later at the Xterra World Championship before seeking complete evaluation.  He was found to have ventricular tachycardia (VT).  He’s had a number of heart procedures, including implantation of an internal cardioverter-defibrillator (ICD) that can provide a life-saving shock should the arrhythmia recur.

Chris Legh is an Australian professional triathlete who has enjoyed considerable success over many years in long course triathlon, with 2 Ironman wins and many 70.3 wins to his credit.  He is also a 6-time Australian champion in Xterra. Starting in 2003 he had difficulties with breathing during the later stages of races that prompted evaluation that disclosed a patent foramen ovale (PFO), a type of atrial septal defect (ASD)–a (usually) small hole in the heart between the left and right atrium.  In his case, there must have been enough blood flow through that opening to cause fluid build-up in the lungs and difficulty breathing.  I’ve written here at the blog about athletes and ASD.  In a  Q&A with Slowtwitch, Legh talks about this condition and other health problems he’s dealt with in recent years.

Emma Carney is a retired Australian professional triathlete and one of the greatest Australian triathletes in history.  She claims 19 ITU World Cup wins and ITU World Championship titles in 1994 and 1997.  She retired from competition in 2004 after suffering a sudden cardiac arrest from which she was successfully resuscitated.  Her arrhythmia was ventricular tachycardia (VT) and she underwent implantation of an internal cardioverter-defibrillator (ICD) that same year.  Although she was advised not to continue in sports, for fear of recurrent arrhythmias that might cause loss of consciousness as well as a shock from the ICD, she continues to train and compete in various endurance and multisport events.  I’ve written here at the blog about a unique registry at the Yale University School of Medicine, where athletes with an ICD who choose to exercise/train/compete are followed longitudinally in an effort to quantify the actual–not just predicted–risks to the athletes.
Amanda Lovato is an American professional triathlete who focuses on long course triathlon.  She recalls being bothered as early as 2003 with abnormally high heart rates, seemingly without explanation, during both training and competition.  Her condition was recently diagnoses as a supraventricular tachycardia (SVT) and she underwent a successful ablation procedure in November, 2012.  At her blog, Lovato writes about the troubles leaading up to her diagnosis and shares her experience with the ablation experience and returning to training.

In the News: Athletes and Vitamins

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In the past few weeks, 3 scientific articles about vitamins caught my eye.  Two articles published in the Journal of the American Medical Association reported on findings from the Physicians’ Health Study II Randomized Control trial of multivitamins–in the areas of cancer prevention and cardiovascular disease prevention.  The third article reported on a survey of Canadian high-performance athletes and their dietary supplement practices.

Multivitamins and Cancer Prevention [1]

Multivitamins are the most common dietary supplement in the United States, used by as many as 30% of Americans.  Data regarding their efficacy in preventing various forms of chronic disease have often been conflicting.  As a result, in 2006 a National Institutes of Health consensus conference could offer no specific recommendation regarding the use of multivitamins to prevent chronic disease.

The Physicians’ Health Study II is an investigation that involved 14,641 American male physician subjects (mean age, ~64 years) who were randomized to receive either a daily multivitamin or a placebo tablet.  Enrollment began in 1999 and follow-up continued for a mean of 11.2 years.  At 4 years, the compliance rate (the percentage of subjects still taking the multivitamin or placebo) was approximately 70% and this declined further to approximately 67% by the end of the study period.

Compared with placebo, the subjects taking a daily multivitamin had signficantly fewer total cancers develop during the study period (17.0 vs. 18.3 cancers per 1000 person-years).  It appears that multivitamin use did not affect the incidence of new prostate or colon cancers.  And despite the findings regarding total cancers, there was no difference in cancer mortality between the 2 groups.

The investigators concluded that daily multivitamin use produced a small but meaningful reduction in cancer incidence.  Whether the findings can be generalized to a broader population (including women and younger individuals) is not certain.

Multivitamins and Cardiovascular Disease Prevention [2]

Also from the Physicians’ Health Study II, but reported separately and more recently, the investigators studied several cardiovascular endpoints, including:  composite end point of major cardiovascular events (nonfatal myocardial infarction [MI] plus nonfatal stroke plus cardiovascular death) and separate end points of MI or stroke, alone.

The study design was the same as noted above for the multivitamin study.

It turns out that multivitamin use was not associated with a discernible reduction in any of the end points studied.  Essentially, a negative study.  Again, whether the findings might be generalizable to a broader population is not certain.

Athlete Supplement Survey [3]

In a 2012 report in the International Journal of Sport Nutrition and Exercise Metabolism, a group of investigators from Calgary reported on a survey that was administered to 440 elite athletes (mean age, ~20 years) from a variety of sports who were affiliated with that country’s 8 Canadian Sport Centres.  The top 10 sports represented included “athletics,” but did not include triathlon or cycling.  The represented sports included endurance as well as power sports.

The survey results noted that 87% of athletes had taken at least 3 supplements during the preceding 6 months.  The most common supplements were:  sports drinks, in 24%; multivitamin and minerals, in 16%; and carbohydrate sports bar, in 11%.

Interestingly, among athletes training 21-25 hours per week, multivitamin use was reported by 63% of athletes and the usage was 59% in those training >25 hours per week.

Athletes reported a variety of sources for their information about supplements, including:  family and friends, in 20%; strength trainer, in 14%; and teammates in 11%.  Physicians were reported as an information source by only 4% of respondents.

My Take

For athletes, there may well be a need for vitamin supplementation and a daily multivitamin is probably the easiest and safest way.  The scientific literature regarding mega-dose supplementation with various individual vitamins as well as the relationship between vitamin supplementation and performance remains murky at best.  I’m not certain the Physicians’ Health Study is particularly applicable to young, healthy athletes, but it appears there might be a small benefit in terms of cancer prevention but no benefit in terms of prevention of cardiovascular disease.  Given the complexities of cancer and cardiovascular disease, many authorities would say the findings aren’t surprising.

The Canadian athlete survey is interesting because I’ve seen very little simple reporting on dietary supplementation practices among athletes.  It would be fascinating to see such information about age-group participants in running, cycling, swimming, and triathlon.  What’s clear from the Canadian study is that athletes’ information about supplementation may not come from the most authoritative sources and the medical and sports physiology communities could probably do a better job with their educational roles.

References

1.  Gaziano JM et al.  Multivitamins in the prevention of cancer in men:  the Physicians’ Health Study II randomized controlled trial.  JAMA 2012;308:1871-1880.

2.  Sesso HD et al.  Multivitamins in the prevention of cardiovascular disease in men:  the Physicians’ Health Study II randomized controlled trial.  JAMA 2012;308:1751-1760.

3.  Lun V et al.  Dietary supplementation practices in Canadian high-performance athletes.  International J Sport Nutrition Exercise Metabol 2012;22:31-37.

A Primer on EPO

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Lance Armstrong was certainly in the news this year, with the ongoing–and seemingly endless–saga of the USADA investigation into the use of performance enhancing drugs (PED) in professional cycling.  I’ve gotten several inquiries about erythropoeitin (EPO) and thought that I’d write a short piece about the agent, its effects on the heart and vascular system, its use as a PED, and a little about the detection of its use.

The Hormone

The first thing to understand is that erythropoetin is a naturally occurring glycoprotein hormone.  The existence of this hormone was theorized as early as the 1950’s and the hormone was given the name erythropoeitin, but its isolation proved to be very difficult.  The human body produces more than a half ton of blood in a lifetime, but only enough EPO to make a tiny pill.  Early efforts sought to isolate the hormone from patients who were thought to have increased levels of EPO–those with anemia of various sorts.  It was the serendipitous observation that excess erythropoeitin was excreted in the urine that eventually led to the isolation of the hormone.  In 1977, Eugene Goldwasser from the University of Chicago isolated 8 mg of erythropoeitin from the dried concentrate of 2,550 liters of urine colleted from a group of aplastic anemia patients in Japan.

We know today that EPO is produced primarily in the kidney, and less so in the liver, and acts to stimulate production of red blood cells (RBCs) in the bone marrow.

The Blood

It helps with this discussion to have an understanding about blood itself.  We often take for granted this liquid that courses through the body’s arteries and veins.  There is a cellular component to blood–cells that we typically call red or white.  The RBCs far outnumber the white blood cells (WBCs), and it is the RBCs that are important for today’s discussion.  The non-cellular component of blood is the plasma, made up predominantly of water, but containing a large variety of proteins, minerals, and other substances.

The body produces RBCs in a process known as erythropoeisis.  In adults, new RBCs are produced primarily in the bone marrow of the sternum (breast bone), vertebral column, and pelvic bones in a process that takes about a week.  Immature RBCs are called reticulocytes and comprise about 1% of the total population of RBCs.  RBCs have a lifespan of about 4 months and are then destroyed in the spleen or liver.  The typical adult has about 20-30 trillion or so RBCs.

One measure of the amount of RBC’s in the blood is called the hematocrit.  If we take a small tube of blood, centrifuge it for a period, we’d be left with cells (mostly RBC’s because they outnumber the other cells, by far) in the bottom of the tube and plasma at the top of the tube.  The ratio of cells to plasma, expressed as a percentage, is the hematocrit.  At my hospital’s laboratory, the normal range for the hematocrit is 36.2% – 46.3% for adult men and 32.9% – 41.2% for adult women.

The RBCs contain the iron-containing protein, hemoglobin, that allows the red blood cells to carry oxygen to the body’s tissues.  Nearly 99% of the blood’s oxygen is bound to the hemoglobin molecules; only about 1% is actually dissolved in the blood’s plasma.  In medical school, we learned that the RBCs with hemoglobin are the “box cars” of the train that delivers oxygen to the body’s tissues.

The amount of hemoglobin in the blood can be measured.  At my hospital’s laboratory, the normal range is 11.9 – 15.4 g/dL for adult men and 10.6 – 13.5 g/dL for adult women.

There is a feedback mechanism in which low blood oxygen levels stimulate production of Epo by the kidney, which in turn stimulates production of RBCs in the bone marrow.

The Drug

The protein structure of EPO was worked out in the early 1980’s and the agent was commercially available by 1985.  The U.S. Food and Drug Administration (FDA) approved epoeitin alpha in June, 1989.  Today, the agent is a made by genetic engineering techniques and produced in bacteria.  The first commercially available product was Epogen, manufactured by Amgen Pharmaceuticals, but there are now several other formulations that are available.

One common brand of epoeitin alpha is Procrit, manufactured by Janssen Pharmaceuticals.  I’ll summarize the information provided by Janssen about their drug in their product insert, but the information will be similar for all of the formulations of epoeitin alpha.

Procrit is used for the treatment of anema due to:  chronic kidney disease; the use of Zidovudine in patients with HIV infection; and the use of chemotherapy agents in patients with cancer.  It is also indicated for reduction of RBC transfusion in patients undergoing elective, noncardiac, nonvascular surgery.  The drug is an injectable agent that can be administered intravenously or by subcutaneous (beneath the skin) injection.  The appropriate dosage depends upon the reason for its use.

Procrit produces an increase in the reticulocyte count within 10 days and an increase in the hematocrit and hemoglobin over a 2- to 6-week period.  The rate of increase in each of these measured outcomes depends upon the dosage administered.

The use of agents like Procrit must be monitored carefully because there are potentially serious side effects or unwanted consequences, including myocardial infarction (“heart attack”), stroke, venous thromboembolism, thrombosis (clotting) of vascular access, tumor progression or recurrence, and even death.  Indeed, the over-use of EPO would be implicated as a possible link to the deaths of 18 Dutch and Belgian cyclists from 1987 to 1990.

EPO as a Performance Enhancing Drug

Dating back to at least the 1960’s athletes were aware of the potentially performance-enhancing effects of blood doping.  You may recall that the 1968 Summer Olympic Games were held in Mexico City, at an elevation of 7,350 feet.  It was recognized at those Games that athletes from higher altitudes performed well in the endurance events, presumably because of chronic adaptations to altitude that included an increased red blood cell mass.  There are many descriptions of athletes using autologous transfusion (of their own banked blood) to enhance athletic performance in the subsequent couple decades.  It wasn’t until after the 1984 Olympic Games in Los Angeles that blood doping was banned by the International Olympic Committee (IOC).  But as I mentioned above, it was in the mid-1980’s that EPO became available and this would become a new avenue for increasing athletic performance.

The physiologic aspects of blood doping are worth considering for a moment, even in a simplistic fashion.  In the endurance sports, athletes are limited by the amount of oxygen that can be delivered and used by the body’s skeletal muscles.  We might say that the aerobic capacity is related to the cardiac output (the amount of blood pumped per minute), the hemoglobin mass (the amount of hemoglobin in that blood), and the rate of oxygen extraction in the muscles.  In the trained athlete, the hemoglobin mass might be the most easily influenced variable–one that is increased by blood doping or by the use of EPO.

In a previous blog post, I talked about the common heart-related medications that are included in the World Anti-Doping Agency’s Prohibited List.  In addition to banning blood doping–the transfusion or administration of blood, blood products, or blood substitutes–the Prohibited List in section S2.1 specifically bans erythropoeisis-stimulating agents such as EPO.  All similar agents, as well as genetic methods related to erythropoeisis, are banned as well.

Detection of EPO

When Epo was first available, there was no method for detecting this PED in athletes.  As an indirect method, professional cycling first conducted pre-race tests of the hematocrit, banning male athletes with a hematocrit >50% and female athletes with a hematocrit >47%.  Keep in mind that in a retrospective study of blood donors in Denmark, 3.9% of non-athletes and 10.4% of elite rowers were found to have a hematocrit >51%.  So measurement of the hematocrit alone is not a realistic way to identify use of EPO as a PED.

In 2000, the French national anti-doping laboratory developed a urine test that could identify the difference between an athlete’s naturally-occurring endogenous EPO and synthetic EPO taken as a PED.  This test took advantage of the the fact that each EPO type is actually a family of substances, each with the same protein structure but differing glycosylation, producing molecules of differing electric charge which were separable by the technique of electrophoresis.

This test was first used at the 2002 Salt Lake City Olympic Games, where 3 athletes (who had won 8 medals) were disqualified because of the detection of synthetic EPO in the urine.

In 2009, WADA has begun the use of a “biological passport” program to further enhance its ability to identify athletes who have used blood doping or the use of EPO.  With this program, longitudinal profiles (over time) are kept of an athlete’s blood-related parameters:  hematocrit, hemoglobin, additional RBC parameters, the reticulocyte count, and serum EPO level.  At its simplest, the measurements of serum EPO and reticulocyte count INCREASE after administration of synthetic EPO; these same measurements DECREASE after RBC transfusion or stopping the use of synthetic EPO.  Unexplained changes in the parameters over time, particularly when linked temporally to competitions, can then be the evidence of doping.