The Cardiac Effects of Performance-Enhancing Medications

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Abstract: Several performance-enhancing or ergogenic drugs have been linked to both significant adverse cardiovascular effects and increased cardiovascular risk. Even with increased scrutiny on the governance of performance-enhancing drugs (PEDs) in professional sport and heightened awareness of the associated cardiovascular risk, there are some who are prepared to risk their use to gain a competitive advantage. Caffeine is the most commonly consumed drug in the world and its ergogenic properties have been reported for decades. Thus, the removal of caffeine from the World Anti-Doping Agency (WADA) list of banned substances, in 2004, has naturally led to an exponential rise in its use amongst athletes. The response to caffeine is complex and influenced by both genetic and environmental factors. Whilst the evidence may be equivocal, the ability of an athlete to train longer or at a greater power output cannot be overlooked. Furthermore, its impact on the myocardium remainsunanswered. In contrast, anabolic androgenic steroids are recognized PEDs that improve athletic performance, increase muscle growth, and suppress fatigue. Their use, however, comes at a cost, afflicting the individual with several side effects, including those that are detrimental to the cardiovascular system. This review addresses the effects of the two commonest PEDs, one legal, the other prohibited, and their respective effects on the heart, as well as the challenge in defining its long-term implications.




1. Introduction


Caffeine (1,3,7-Trimethylxanthine) is a popular workplace substance that has been well-researched, with its ergogenic effects being known for centuries [1]. Caffeine has a wide range of acute benefits that includes an increase in alertness and concentration, accompanied by a reduction in fatigue and pain perception [2,3]. As a result, its use has become highly prevalent amongst athletes, especially after 2004, when it was removed from the World Anti-Doping Agency (WADA) list of banned substances; it was, therefore unsurprising when a study reported that 74% of urine samples from athletes, between 2004 to 2008, demonstrated measurable levels [1]. Common physiological effects of caffeine on the body include an increase in heart rate, catecholamine levels, blood lactate, free fatty acids and glycerol [4]. More significantly, its use has illustrated benefits in both endurance-based and high-intensity exercise, permitting the athlete to train longer and at a greater intensity. A recent meta-analysis yielded a positive relationship of caffeine on muscle strength, muscle endurance, and anaerobic power [5]. As a result, it is recommended that ingestion of 3–9 mg/kg approximately 60 min prior to exercise may provide the extra competitive advantage for the athlete [1]. Nonetheless, the response to caffeine is multifaceted, influenced by both genetic and non-genetic predilections, with there being inter-subject variation in response to caffeine consumption, and this heterogeneous response makes it difficult to extrapolate the objective impact of caffeine as a vital ingredient to athletic prowess.

In contrast, anabolic-androgenic steroids (AASs), synthetic derivatives of testosterone, have been abused by athletes since the 1950s for their ability to increase muscle mass and improve athletic performance. The terms anabolic and androgenic refer to muscle hypertrophy and increased male sex characteristics, respectively. AASs are artificial substances that act on androgen receptors and are commonly used in the treatment of metabolic or catabolic disorders and other chronic conditions related to low testosterone [6]. More significantly, its misuse stems from the means of achieving a lean and muscular body type, with the potential of shielding the user from muscle fiber damage, through enhanced protein synthesis during recovery. There are multiple manufactured forms, most of which are designed to optimize muscle growth whilst minimizing the undesired androgenic effects [6]. Steroid abuse has dramatically increased over the past two decades in the general population who live in an increasingly image-obsessed era. Its users are typically 20–30-year-old males, who participate in recreational exercise largely composed of weight training [6]. Globally, it is estimated that 6.4% of males and 1.6% of females use AASs [7]. The second highest prevalence of users beyond recreational sportspeople (18.4%) is athletes (13.4%) [8]. Whilst anabolic androgenic steroids can play an important role in the clinical treatment of endocrine disorders there are several established adverse outcomes if misused, that includes an increased risk of cardiovascular disease (CVD), risk of tendon ruptures, hepatorenal disorders, and psychiatric symptoms. The doses are often 5–15 times higher than recommended levels, with athletes experiencing a higher probability of adverse cardiovascular events that include stroke and myocardial infarction (MI) [9]. Preceding these events are hypertension and left ventricular (LV) hypertrophy, both independent predictors of cardiovascular mortality and morbidity [10,11]. There are, however, many obstacles to the investigation of the dangers of AASs, due to the dose never being reliably known, to polypharmacy, or the ethical restrictions of conducting research studies [6].

Given such variability in effects of both caffeine and AASs, this review discusses the impact of the two commonest performance-enhancing drugs (PEDs) and its document cardiac sequalae.




3. Results

3.1. Caffeine as a Performance Enhancing Agent

3.1.1. Caffeine Pharmacology and Cardiac Physiology
3.1.2. Caffeine and Risk of Arrhythmia
3.1.3. Caffeine Genetics
3.1.4. Caffeine in Sudden Cardiac Death


3.2. Anabolic-Androgenic Steroids as a Performance Enhancing Agent
3.2.1. AASs Pharmacology and Cardiac Physiology
3.2.2. AASs and Risk of Arrhythmia
3.2.3. AASs Genetics
3.2.4. AASs in Sudden Cardiac Death





4. Discussion

Our findings suggest that whilst caffeine does not have noticeable structural changes on the myocardium, AASs have several. For instance, imaging and histopathological samples have demonstrated left ventricular hypertrophy, cardiomegaly, and interstitial fibrosis, respectively [43]. Such remodeling has ramifications on the CVS, not only immediately but in the long-term as well.Substantial cardiovascular changes include an increase in vascular tone and elevation in blood pressure, alterations in lipid profile, and direct myocardial toxicity, resulting in reduced left ventricular function, cardiac hypertrophy, and arterial and venous thrombosis [43,63].
In contrast, there is a lack of compelling evidence to suggest that caffeine has lasting morphological changes to the myocardium (Figure 4).




5. Conclusions


There is a large growing body of evidence that describes the impact of both caffeine and anabolic-androgenic steroid use on the cardiovascular health of both the athlete and non-athlete. Whilst caffeine may not necessarily give an athlete the essential edge, its use may not disadvantage them either, especially since the majority have consumed such a supplement prior to their sporting event. In contrast, AASs have documented improvement in athletic proficiency. However, it does not negate the several adverse cardiovascular effects that are associated with its use. With the continued use of both caffeine and AASs, regular assessment, which includes evaluating the electrical activity and morphology of the myocardium, using non-invasive imaging and functional methods would be important in identifying those who are at an increased risk of cardiovascular disease or an acute cardiac event.
 

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Figure 1. Caffeine inhibits the action of adenosine through the blockade of A1 and A2 receptors, resulting in elevated heart rate, blood pressure, cardiac contractility, and alertness. Subsequent adverse cardiovascular events during exercise include potentiation of hypoxic damage to cardiac myocytes, through failure in relaxation of the coronary vessels, and arrhythmias (created with BioRender.com).
Screenshot (3764).png
 
Figure 2. Common adverse cardiovascular effects of anabolic-androgenic steroid abuse include vascular calcification, accelerated atherosclerosis, myocardial apoptosis, cardiac hypertrophy, and arrhythmias. Impaired LV relaxation is a cardinal feature of the adverse cardiac effects of anabolic-androgenic steroids (AAS). With long-term abuse, there is evidence of reduced systolic strain and systolic dysfunction with resultant cardiomyopathies. Other sequelae of AAS abuse include increased incidence of thromboembolism and hypertension (created with BioRender.com).
Screenshot (3765).png
 
Figure 3. (A, B). Cardiac magnetic resonance (CMR) images of a 38-year old bodybuilder with anabolic-androgenic steroid use—(A). Cine steady-state free precession (SSFP) in mid-ventricular short-axis view at end-diastole showing hypertrophied interventricular septum (15 mm) and enlarged left ventricle (62 mm) with decreased systolic function (ejection fracTable 44. not shown), (B). Late gadolinium enhancement (LGE) image in 3-chamber view showing midventricular area of fibrosis (non-ischemic) in the basal infero-lateral segment of the left ventricle (asterisk).
Screenshot (3766).png
 
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Figure 4. Comparison between caffeine and AASs and its associated cardiovascular effects (created with BioRender.com).
Screenshot (3767).png
 
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