Cardiovascular Effects of Performance-Enhancing Drugs

The health of athletes and the reputation of modern competitive sports is being challenged by performance-enhancing drugs (PEDs). Revelations of endemic use and institutional-sponsored PED programs are becoming so routine that even the most passionate fans find themselves questioning every performance. We are transfixed by the fight to be first across the line that is so pure in its simplicity and yet requires a complex and rare mix of favorable genetics, obsessiveness, and skill. However, when reflecting on the remarkable physical feats in the recent Olympics in Brazil, we are faced with the reality that some of these feats may have been assisted by the use of banned substances.

Sport is a powerful medium, and governing bodies throughout the world recognize the contribution of sports to national identity. It has been estimated that some first-world countries would invest ≈$7 million of public funding for each Olympic gold medal won.¹ Yet, the economic returns from television rights, sponsorship, and infrastructure are an excellent return on this investment. From a public health perspective, there are even greater potential benefits to be realized through a health legacy in which the inspired population may be more likely to increase levels of physical activity. Relative to the general population, Olympic athletes have superb health outcomes^2,3 and should be ideal ambassadors in the fight against the morbidity associated with sedentary behavior.⁴ However, research suggests that this trickle-down impact on public health may be more theoretical than real,⁵ and the disillusionment caused through rumors of ubiquitous PED use cannot be helping in translating podium success to playground inspiration. Even worse, the increasing use of PEDs among recreational athletes suggests that it is the worst aspects of professional sports that are being emulated in the community.⁶

It could be argued that PEDs are simultaneously a consequence of the commercialization of modern sports and a threat to their ongoing public support. Sports fans, sponsors, and sporting infrastructure are all indirectly affected by the revelations of PED abuse, but the greatest victims are undoubtedly the athletes: accolades hijacked by drug-taking winners and performances sullied by implication and the distrust of fellow competitors. What is portrayed to the public as a black-and-white choice for the athlete is far more complex. Athletes are encouraged to seek any legal advantage that does not include agents contained within the World Anti-Doping Authority’s list of banned substances. As will be discussed at length in this review, this creates a problematic gray area in which athletes may experiment with agents that are yet to be listed as a banned substance. There are ongoing health risks associated with the search for the next drug that may provide a window of advantage before detection. This issue will not be addressed by the current system of playing catch-up with a list of substances that will always be years behind. We will argue that the alternative of a short permitted list should be considered and would more accurately reflect the broadly excellent health of the young athletes who should require few or no pharmacological interventions.

This review will focus on 2 novel concepts related to the cardiovascular effects of PEDs. First, in addition to the direct effects of PEDs on the cardiovascular system, the strain imposed through an athlete’s enhanced ability to exert him- or herself at superhuman levels may be a cause of cardiac injury. Second, the risk of experimental drugs not on the World Anti-Doping Agency’s banned substance registry poses a potentially greater risk than that from the continued abuse of known drugs. We seek not only to describe the extent of the problem, but also to provide some novel suggestions on how we may be able to reduce PED use and the resultant health risks.

The list of potentially PEDs and performance-enhancing supplements used by competitive athletes is extensive. Table 1 summarizes many of the agents listed by the World Anti-Doping Agency (WADA) as being banned or on a watch list of commonly detected agents. Despite assertions that drug cheats will be caught, many of these drugs are not detectable with routine drug testing, or via the modern approach of the Athlete Biological Passport. Although the cardiovascular side effects of some of the drug classes can be anticipated, many athletes will use multiple agents and the effects of drug combinations is almost nonexistent. It is also critical to note that of potentially greater risk to athletes’ health are the many agents that are likely to be in use currently that are unknown to authorities. The known side effects of some of the more commonly abused agents are presented below but, given the limited evidence base, these should be considered a best guess.

Much of the medical literature focuses appropriately on the adverse health effects of PEDs, but these deterrents have proved insufficient to discourage some athletes. The evidence for efficacy of PEDs in improving performance is more limited than might be expected given the widespread belief that they are in many cases a game changer. This may relate to the fact that few scientists are willing to study PEDs given the complex ethics of providing evidence that may be used to support doping and reinforced by the refusal of some journals to accept any articles pertaining to PEDs. However, it is often argued that the drug cheats are 1 step ahead, and it could be argued that concerted efforts from reputable scientists are required to develop the knowledge base that will anticipate drug use and to develop tests that can accurately identify known and novel PEDs in the dosing regimens used in modern sports.

For endurance athletes, the most efficacious PEDs appear to be those that increase oxygen availability to the working muscles. This is achieved by increasing oxygen content in the blood, improving cardiac output, or improving peripheral oxygen extraction. Blood doping (usually consisting of transfusion of autologous blood collected some time earlier) has been used for decades, is extremely difficult to detect, and has been shown to quite dramatically improve endurance sports performance.^7,8 In 1987, recombinant erythropoietin (EPO) was introduced to the European market, resulting in a rapid and dramatic transformation of endurance sports. EPO stimulates hemoglobin (Hb) production, and the mean values of participants’ Hb and hematocrit climbed steadily over the ensuing years with a simultaneous increase in race speeds.⁹ Birkeland et al¹⁰ demonstrated an increase in maximal oxygen consumption following 4 weeks of recombinant EPO in a double-blind, placebo-controlled study with only a small cohort (n=10) needed to demonstrate a large treatment effect (63.6 versus 68.1 mL·min^–1·kg^–1, P<0.0001). Different EPO formulations, direct EPO receptor agonists, and microdosing techniques have enabled athletes to continue to abuse these agents with minimal risk of being detected. The potential risks are underlined by a prospective cross-sectional study of 3000 healthy older adults, which found that each doubling in serum EPO level was independently associated with a 25% increase in risk of incident heart failure over a mean follow-up of 10 years.¹¹ EPO has been rumored to be responsible for a number of cases of sudden cardiac death among athletes in the late 1980s and early 1990s.⁹ The extent to which these events represent myth or reality has been debated. Bernat Lopez¹² has argued that the evidence surrounding these cases is spurious and that there is no evidence that EPO has potential for adverse cardiovascular effects. However, one must also acknowledge that concrete evidence of doping is frequently elusive and that the aforementioned risk of thrombotic cardiovascular events with very modest increases in EPO¹¹ would at least raise the possibility of risks associated with very large EPO doses and hematocrit increments.

Rather than increasing the blood oxygen content (like EPO), theoretically the same effect may be achieved by increasing the amount of O₂ that Hb can deliver to the surrounding tissues. A number of agents with these properties have been reportedly used by athletes to aid performance, and the list is growing. Cobalt chloride, is a water-soluble compound that can stimulate erythropoiesis and angiogenesis, presumably because of the activation of hypoxia-inducible factor signaling.¹³ Although the direct cardiovascular (CV) effect in humans has not been prospectively studied, unintentional ingestion of cobalt has been associated with the development of a dilated cardiomyopathy.^14,15 Right-shifting reagent 13 (RSR13,or efaproxiral) is a synthetic modifier of Hb, with in vivo studies demonstrating a shift in the Hb/O₂ dissociation curve to the right, thereby increasing the dissociation of O₂ in the peripheral muscles (see Figure 1). RSR13 has been shown to increase oxygen consumption in stimulated canine skeletal muscle¹⁶ when inspired O₂ was supplemented. However, in humans breathing sea level air, the right shift of the O₂ curve by RSR13 causes significant hypoxemia under resting conditions¹⁷ that is likely to be further exacerbated by exercise. The side effects associated with exercising in a hypoxemic state are not known, and it is unlikely that the physiology and potential risks are known to the athletes in whom it is being used. In 2001, a cyclist’s room was raided during the Giro D’Italia cycle tour and multiple experimental agents, including a synthetic Hb-based blood substitute (Hemassist) and RSR13, were found. During the 2003 Tour De France, a cyclist who collapsed and was taken to the hospital was found to have been infused with a synthetic blood substitute that had been approved for veterinary use only.¹⁸ The willingness of athletes to use agents with no proven efficacy or safety data should be an alert to sports governing bodies.

There have also been attempts to improve muscle oxygen delivery by improving cardiac output. Specific pulmonary vasodilators such as sildenafil are rumored to be widely used among some endurance athletes. The rationale would seem that, by reducing pulmonary vascular resistance, it may be possible to reduce cardiac work, particularly of the right ventricle, thereby enabling the heart to maintain a high level of function for longer.¹⁹ This is especially relevant given that exercise seems to place a disproportionate load on the pulmonary circulation and right ventricle.²⁰ A number of studies have assessed whether pulmonary vasodilators can improve exercise performance in healthy volunteers and athletes. Ghofrani et al²¹ documented improvements in exercise capacity in a randomized, double-blind, placebo-controlled trial in 14 healthy subjects during normobaric hypoxia (10% O₂) and at altitude (Mount Everest base camp, 5245 m above sea level). However, although studies using both phosphodiesterase type 5 receptor and endothelin antagonists have consistently demonstrated improvements in hemodynamics and exercise performance in hypoxic conditions, they have failed to show any benefit in normoxia.^22–24 These agents are not banned by WADA, who has stated that they are continuing to evaluate the science to assess whether they are performance enhancing. This stance has the potential to tacitly condone the athletes’ search for a perceived or real advantage using off-label indications for medications with sometimes very questionable safety profiles.

The WADA list of banned androgenic anabolic steroids (AASs) is extensive, and the identification of these substances is responsible for ≈60% of positive doping results. They represent one of the oldest classes of drugs of abuse and, accordingly, their effects have been most extensively investigated. When combined with exercise training, AASs increase muscle mass and strength and reduce fat.^25,26 Significant increases in strength have been observed in double-blinded randomized trails comparing 12 weeks of AAS versus placebo in small cohorts (n=10).²⁷ A common misconception is that they are used exclusively by strength athletes, but they are also used to aid in recovery and strength in endurance pursuits. The concomitant use of anabolic agents with EPO is common both in strength and endurance athletes.²⁸ This concept of using multiple agents to train harder and faster will be explored further in the subsequent section on the indirect CV effects of PEDs.

Mortality among athletes using AASs is estimated to be 6- to 20-fold that of clean athletes, and approximately one-third of these deaths can be attributed to CV causes.²⁹ Cardiomyopathy, myocardial infarction, dyslipidemia, cardiac conduction abnormalities, and coagulation abnormalities are well acknowledged CV side effects of AASs.^28,30–32 A series of postmortem studies and studies using echocardiography and cardiac MRI have confirmed the existence of AAS-induced cardiomyopathy, which shares characteristics similar to hypertrophic cardiomyopathy, with greater cardiac mass, greater left ventricular wall thickness (left ventricular hypertrophy), a greater prevalence of cardiac fibrosis, and impairment of systolic and diastolic left ventricular function.^32–36 The pathogenesis and prevalence of arrhythmic events in AAS users has not been well detailed, but both myocardial fibrosis and atherogenesis are plausible substrates. It is intriguing that evidence suggests that AAS may have confounded the popular understanding of exercise-induced cardiac remodeling. The Morganroth hypothesis contends that concentric remodeling of the myocardium occurs in response to the heightened afterload of strength training. However, when Luijckx et al³⁵ compared power-trained athletes with a history of AAS use with those who had not used AAS, they found that cardiac hypertrophy was only significantly increased in the former group.

Synthetic androgen receptor modulators (eg, thymosin beta 4) are a newer class of drugs, designed to dissociate the androgenic and anabolic effects of AAS, thereby making detection more difficult. Little is known about the CV side effects of the many peptides designed to modulate androgen receptor activity. It is likely that both the performance enhancement and side effects are less than AAS but it is very difficult to know for certain.

Human growth hormone is an endogenous neurohormone that is purported to have anabolic effects when used in supraphysiological doses. Although it is rumored to be widely used, there is little evidence that recombinant human growth hormone improves performance, although it may aid more rapid recovery from soft tissue damage.²⁸ Little is known about the direct CV effects of excessive human growth hormone administration in athletes, but growth hormone excess in patients with acromegaly results in hypertension, congestive cardiac failure, and cardiomyopathy.²⁸

l-Carnitineis an amino acid produced naturally in the body, but supplementation is believed to enhance fatty acid oxidation and stimulate the production of ATP, aiding muscular contraction during prolonged aerobic exercise, although evidence supporting performance enhancement is not compelling.³⁷ There is no evidence of CV toxicity with l-carnitine. Rather, there is some evidence for antihypertensive and antifibrotic effects in hypertensive mice.³⁸ Currently l-carnitine is not on the WADA list of banned substances. Meldonium (mildronate) is licensed for clinical use in some Eastern European countries as an antianginal with a mechanism of action that is believed to be modulated, at least in part, by lowering of l-carnitine availability and reducing mitochondrial energy production.³⁹ Thus, in these 2 agents that are believed to be widely used by athletes, there are opposing mechanisms of action. Neither agent has established efficacy or safety data for use during strenuous exercise. After anecdotal reports of widespread use at the London 2012 Olympics, meldonium was detected in the urine of 9% of athletes at the 2015 European Games.⁴⁰ It was included in the list of banned substances by WADA in January 2016, but its widespread off-label use (presuming 9% of the world’s best athletes did not have angina) highlights the problem with the current drug enforcement strategy that enables athletes to experiment widely with unproven and potentially dangerous drugs.

β-Alanine is a nonessential amino acid that can be synthesized in the liver and obtained by the diet. Several recent studies and meta-analyses have shown that chronic, high-dose oral supplementation with β-alanine can increase muscle carnosine levels, increase intramuscular buffering capacity, and improve performance of high-intensity and intermittent exercise.^41–43 Studies of adverse CV effects in humans taking oral β-alanine supplements are lacking. However, neurotoxicity, myotonia, and respiratory distress are clinical features in humans with mitochondrial disorders associated with β-alanine excess, and oxidative stress and cell apoptosis was observed in in vitro studies in which rat cardiomyocytes and fibroblasts were directly exposed to β-alanine.⁴⁴ Therefore, it seems plausible that excess supplementation may have deleterious CV effects. Currently, β-alanine supplementation is legal under the WADA code and its use among athletes is widespread, with a self-reported usage of 60% in some sporting codes.⁴⁵

Seldom considered in discussions regarding toxicity is the potential for indirect CV effects associated with the greater training loads and shorter recovery that are facilitated by PED use. It is possible that PEDs enhance CV adaptation beyond the point achievable without performance enhancement. There is some circumstantial evidence provided for this premise in a study by Abergel et al⁴⁶ who studied cardiac size and function in 286 Tour De France cyclists: 148 in the 1995 race, 138 in the 1998 race, and 37 in both (Figure 2). It is widely believed that the use of EPO increased over this period, along with the average speed of the race (1995 won by Miguel Indurain averaging 39.2 km/h versus 1999 won by Marco Pantani averaging 40 km/h before serving a suspension for EPO use). It is intriguing that over this same period, Abergel and colleagues observed that left ventricular internal diameter increased from 59.4 mm to 61.2 mm (P=0.0003) and left ventricular ejection fraction reduced from 63.6% to 59.1% (P<0.0001) despite the groups being comparable in age, weight, and body surface area. In summary, in 2 largely independent cohorts of professional cyclists, the hearts were significantly larger in 1999 than in the 1995. Given that this was also a period in which the use of EPO is alleged to have increased dramatically, it is tempting to speculate a causal relationship in this observed association. The well-established correlation between cardiac size and exercise capacity^47,48 would support the assertion that the more widespread use of EPO directly resulted in greater training loads, greater exercise capacity, and greater cardiac adaptations among cyclists.

Is this of concern? Perhaps as ethicist Julian Savulecu argues, we should legalize PEDs and accept them as part of the human progression toward physical excellence.⁴⁹ However, this is a potentially dangerous proposition given the potential for direct and indirect cardiac toxicity. Although still controversial,⁵⁰ there is evolving evidence to suggest that extreme exercise may result in structural and functional changes leading to scar and arrhythmias in some athletes.^20,51–54 Thus, it is possible that by using PEDs to push physiology beyond normal constraints, athletes may be placed at greater risk of atrial fibrillation or even more sinister arrhythmias. Although this may seem most pertinent to professional athletes, there is an increasing proportion of the amateur sporting population engaged in high-level endurance training and racing in whom exercise-induced cardiac remodeling may be adversely accentuated if combined with PEDs. Without greater transparency regarding the drugs that athletes are taking, and not only those on the banned substance list, we will never be able to address the extent to which the excess in some arrhythmias may be attributable to the direct or indirect effects of PEDs (Figure 3).

There is evidence of increasing use of PEDs among recreational athletes.⁶ The health implications of the off-label and unsupervised use of PEDs in this setting is potentially of even greater significance than among competitive athletes. Although drug surveillance programs may have been ineffective at eliminating the use of PEDs among professional athletes, it would seem that they have been largely successful in restricting athletes to intermittent use and microdosing. However, recreational athletes have fewer constraints on use, less surveillance of health effects, and easy access to an unscrupulous industry profiting from misinformation. As far as we are aware, there have been relatively few campaigns aiming to combat this growing industry or to educate medical practitioners about the potential for PED use among athletes in their care. Perhaps the most important message for practitioners is to be alert to the potential for PED use, to confidentially enquire about the use of drugs while being aware that denial may not discount the possibility. Some physical traits and results from investigations may increase suspicion (see Table 2), but one should definitely not discount the possibility of PED use in the absence of these insensitive signs. Many clinicians limit consideration of PED use with the stereotypical body builder with a massive increase in lean muscle mass but would be surprised to learn that endurance athletes may also seek advantage through anabolic agents and an array of the aforementioned drugs. Direct testing for PEDs has potential pitfalls given the complexity and expense of comprehensive drug testing. Just as in professional athletes, periodization of PED use means that a negative test does not exclude use, but perhaps the biggest issue with testing recreational athletes is the perceived breach of trust that may be encountered regardless of the test result. Often athletes are willing to reveal their use of PED use when discussed in a nonincriminating manner and with confidentiality assured. Otherwise, an open door for the athlete to disclose and discuss on any future occasion may still be preferable to drug testing. This pragmatic suggestion for care of the recreational athlete should not be confused with our responsibilities in professional athletes in which drug testing is mandated.

If the aim of PED enforcement regimes is to protect athlete safety, then we would argue that there needs to be a shift from listing drugs once we know that they are being widely abused to a system in which all drugs are banned unless there is a prior application for use with adequate justification. There needs to be a concerted effort to not only detect illegal drugs, but also to protect athletes from an infrastructure that has a proven record of using athletes for unethical experimentation (Figure 4).

There are multiple issues with the current system that could be addressed by changing from a banned list to a permitted list that only contained medications with proven efficacy for common ailments. Such a list could contain simple analgesics such as nonsteroidal anti-inflammatory drugs, inhaled β₂-agonists, common antibiotics, and vaccines. This would not aim to include all possible drugs that could be used by athletes with valid indication, and, for this purpose, the current system of therapeutic use exemptions could continue. Prescribing physicians should familiarize themselves with Global Dro⁵⁵ or other tools that allow them to check the status of a prescribed medication under the WADA antidoping code. When physicians find themselves in the uncommon circumstance where no other alternative to prescribing a medication requiring a therapeutic use exemption can be found, they should complete the application paperwork with patients, providing adequate medical documentation to confirm the diagnosis, including a typed letter, recent diagnostic results, and justification for why a permitted medication is not being used. In effect every medication being used by an athlete at any time would need to be listed and justified. Unfortunately, this process has also been demonstrated to be subject to questionable levels of tolerance as demonstrated by the recent hacking of WADA computer records and the revelation that former Tour De France winners have been administered powerful corticosteroids in the days before major races.⁵⁶ The use of triamcinolone for the treatment of pollen allergies would seem to contravene usual standards of care and illustrates the way in which boundaries are shifted in the medical treatment of elite sports people.

We contend that a carefully considered list of permitted substances be created and that the process of therapeutic use exemptions be more stringently regulated such that the use of medications accurately reflects community standards of health care. For example, if an athlete is unable to manage allergies with medications accepted as standard of care, then she or he may be unable to race. This would seem both safe and fair. Moreover, it creates a more rigorous and less ambiguous system in which the athletes and the public can have greater trust. Any substance would be considered illegal if it was not listed among the permitted items or a therapeutic use exemption had not been obtained. This would have immediate impact. Currently, athletes and their administrators know that they can experiment freely with any agent that is not on the WADA banned list. If it is detected in blood or urine samples, the athlete is protected from sanction and the findings cannot be publicly disclosed. As discussed above, we contend that far fewer than 9% of athletes would have been using meldonium at the 2015 European Championships if they had to justify its use according to current therapeutic indications. Although some might argue that drugs such as meldonium are unlikely to cause serious adverse effects, the simple point is that the vast majority of agents in the gray area between permitted and banned have very limited safety data. Athletes should be afforded the same safety standards as the general population. Namely, they should not be exposed to drugs that have not undergone adequate safety and efficacy checks.

It could be argued that the biggest threat in the fight against drugs in sports is not what we know, but what we do not know. Accepting this would logically lead to a system in which every unknown drug is illegal. Our proposal is only one of a number of innovative changes that should be considered in a multifaceted approach in which long-term health is afforded appropriate priority. There is also the wider public implication of the constant revelations of polypharmacy, supplements, and drug abuse among elite sports. What are our children meant to believe? We teach them that effort equals reward. We teach them that exercise will make them healthier, and yet the television tells them that many of the top athletes are taking any number of supplements and unpronounceable drugs that are found on the Internet rather than in the pharmacy. Elite sports are sending the wrong messages. Exercise is one of the most positive health interventions available, and, for the protection of its reputation and that of every clean athlete, something needs to be done.