How toxic is an old friend? A review of the safety of hydroxychloroquine in clinical practice.

Hydroxychloroquine (HCQ) and its close relative chloroquine (CQ) were initially used as antimalarial agents but are now widely prescribed in rheumatology, dermatology and immunology for the management of autoimmune diseases. HCQ is considered to have a better long-term safety profile than CQ and is therefore more commonly used. HCQ has a key role in the treatment of connective tissue diseases including systemic lupus erythematosus (SLE), where it provides beneficial immunomodulation without clinically significant immunosuppression. HCQ can also assist in managing inflammatory arthritis, including rheumatoid arthritis (RA). Debate around toxicity of HCQ in COVID-19 has challenged those who regularly prescribe HCQ to discuss its potential toxicities. Accordingly, we have reviewed the adverse effect profile of HCQ to provide guidance about this therapeutic agent in clinical practice.

The Athlete's Heart-Challenges and Controversies: JACC Focus Seminar 4/4.

Regular exercise promotes structural, functional, and electrical remodeling of the heart, often referred to as the "athlete's heart," with intense endurance sports being associated with the greatest degree of cardiac remodeling. However, the extremes of exercise-induced cardiac remodeling are potentially associated with uncommon side effects. Atrial fibrillation is more common among endurance athletes and there is speculation that other arrhythmias may also be more prevalent. It is yet to be determined whether this arrhythmic susceptibility is a result of extreme exercise remodeling, genetic predisposition, or other factors. Gender may have the greatest influence on the cardiac response to exercise, but there has been far too little research directed at understanding differences in the sportsman's vs sportswoman's heart. Here in part 4 of a 4-part seminar series, the controversies and ambiguities regarding the athlete's heart, and in particular, its arrhythmic predisposition, genetic, and gender influences are reviewed in depth.

Clinical Implications for Exercise at Altitude Among Individuals With Cardiovascular Disease: A Scientific Statement From the American Heart Association.

An increasing number of individuals travel to mountainous environments for work and pleasure. However, oxygen availability declines at altitude, and hypoxic environments place unique stressors on the cardiovascular system. These stressors may be exacerbated by exercise at altitude, because exercise increases oxygen demand in an environment that is already relatively oxygen deplete compared with sea-level conditions. Furthermore, the prevalence of cardiovascular disease, as well as diseases such as hypertension, heart failure, and lung disease, is high among individuals living in the United States. As such, patients who are at risk of or who have established cardiovascular disease may be at an increased risk of adverse events when sojourning to these mountainous locations. However, these risks may be minimized by appropriate pretravel assessments and planning through shared decision-making between patients and their managing clinicians. This American Heart Association scientific statement provides a concise, yet comprehensive overview of the physiologic responses to exercise in hypoxic locations, as well as important considerations for minimizing the risk of adverse cardiovascular events during mountainous excursions.

Electrocardiographic Features Differentiating Arrhythmogenic Right Ventricular Cardiomyopathy From an Athlete's Heart.

OBJECTIVES: This study sought to compare electrocardiogram (ECG) variants in athletic and arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts matched for the confounders of age, sex, and ethnicity. BACKGROUND: Anterior T-wave inversion (TWIV1-V4) is a common electrocardiographic finding in both athletes and patients with ARVC, and is a frequent conundrum in the setting of pre-participation screening. J-point elevation (JPE) has been proposed as an accurate means of identifying athletes, whereas disease markers, including premature ventricular contractions (PVCs) and low-voltage signals, have been associated with ARVC. METHODS: This study examined 200 subjects with TWI V1-V4, including 100 healthy athletes and 100 ARVC patients matched 1:1 for age, sex, and ethnicity (age: 21 ± 5 years for athletes vs. 22 ± 5 years for ARVC patients; 47% male; 97% Caucasian). The presence of TWI, JPE, PVCs, and left ventricular hypertrophy (LVH) were assessed. RESULTS: JPE was observed in 27% of athletes versus 16% of ARVC patients (p = 0.09). Thus, JPE had poor specificity (27%) and accuracy (60%) in identifying healthy athletes. In contrast, ARVC patients demonstrated a greater prevalence of precordial TWI beyond lead V3 (34% vs. 8%; p < 0.001), inferior TWI (31% vs. 3%; p < 0.001), PVCs (18% vs. 0%; p < 0.001), and lower LVH scores (SV1 + RV5; 19 ± 1 mm vs. 30 ± 1 mm; p < 0.001). These combined factors provided more reliable differentiation between health and disease (specificity 82%, accuracy 81%). CONCLUSIONS: PVCs and low QRS voltages are more prevalent among ARVC patients than athletes, whereas JPE is a relatively poor discriminator of health and disease when the confounders of age, sex, and ethnicity are considered.

Drugs in Sport - A Change is Needed, but What?

Performance enhancing drugs (PEDs) confound much of what is considered great about sport. Sport is generally associated with excellent health outcomes that can be challenged by the direct toxicities of PEDs and the indirect effects of enabling the body to push beyond normal physiological reserves, thereby potentiating the risk of some exercise-associated conditions such as atrial fibrillation. Sport should also be a source of aspirational behavioural change but this 'legacy effect' of elite sport is modest, perhaps due in part to the public disillusionment brought about by repeated drug scandals. Elite sport is an extremely lucrative industry and, whilst this money could be used to support grass roots campaigns promoting exercise, it also provides incentive for a "win at all costs" mentality that provides the substrate for drug use to enhance performance. This article discusses these issues and asserts that the destructive influence of PEDs has arguably reached a tipping point at which the reputation of professional sport is starting to become irrevocably damaged. We assert that there is a need for change, and that doctors need to be a part of this change. Repeated attempts by the anti-doping authorities to stay ahead of the PED "industry" have failed, and we argue that new approaches now need to be considered. The controversial concept of a more permissive policy in which physiological limits are set has been championed by some; whilst we propose a more restrictive process in which all drugs are banned except for a few commonly used drugs that are not associated with performance enhancement. This article is not designed to provide definitive answers but rather to promote debate and consideration of novel approaches to what may be sport's greatest challenge - the use of performance-enhancing drugs.

Athlete's ECG - Simple Tips for Navigation.

Regular exercise training results in structural and electrical cardiac adaptations which are reflected in the resting 12-lead electrocardiograph (ECG), thus an athlete's ECG can be quite different to that of a sedentary person of the same age, gender and ethnicity. This has been recognised as an issue in the setting of pre-participation ECG screening of athletes in whom false positive findings are commonplace when using normative ECG values derived from sedentary populations. As such, athlete ECG interpretation guidelines have been devised and modified several times over the past decade, with the ultimate goal of reducing the number of athletes undergoing unnecessary secondary investigations to exclude cardiac pathology whilst maintaining the sensitivity of the ECG in detecting cardiac diseases associated with sudden cardiac death (SCD). By no means exhaustive, the following series of athlete ECG examples is aimed at providing the reader with a basic understanding of what ECG changes are considered normal for an athlete, and what changes should prompt further investigation to exclude cardiac pathology, even in the absence of symptoms.

Differentiating Athlete's Heart From Cardiomyopathies - The Left Side.

In athletes who undertake a high volume of high intensity exercise, the resultant changes in cardiac structure and function which develop as a result of physiological adaptation to exercise (so called "Athlete's Heart") may overlap with some features of pathological conditions. This chapter will focus on the left side of the heart, where left ventricular cavity enlargement, increase in left ventricular wall thickness and increased left ventricular trabeculation associated with athletic remodelling may sometimes be difficult to differentiate from conditions such as dilated cardiomyopathy, hypertrophic cardiomyopathy or isolated left ventricular non-compaction. The distinction between physiological versus pathological changes in athletes is imperative as an incorrect diagnosis can have important consequences, such as exclusion from competitive sport, or false reassurance and missed opportunity for effective therapeutic intervention.

Cardiovascular Effects of Performance-Enhancing Drugs.

Exercise and competitive sports should be associated with a wide range of health benefits with the potential to inspire a positive community health legacy. However, the reputation of sports is being threatened by an ever-expanding armamentarium of agents with real or perceived benefits in performance enhancement. In addition to the injustice of unfair advantage for dishonest athletes, significant potential health risks are associated with performance-enhancing drugs. Performance-enhancing drugs may have an effect on the cardiovascular system by means of directly altering the myocardium, vasculature, and metabolism. However, less frequently considered is the potential for indirect effects caused through enabling athletes to push beyond normal physiological limits with the potential consequence of exercise-induced arrhythmias. This review will summarize the known health effects of PEDs but will also focus on the potentially greater health threat posed by the covert search for performance-enhancing agents that have yet to be recognized by the World Anti-Doping Agency. History has taught us that athletes are subjected to unmonitored trials with experimental drugs that have little or no established efficacy or safety data. One approach to decrease drug abuse in sports would be to accept that there is a delay from when athletes start experimenting with novel agents to the time when authorities become aware of these drugs. This provides a window of opportunity for athletes to exploit with relative immunity. It could be argued that all off-label use of any agent should be deemed illegal.

Relationship between Inflammatory Cytokines and Indices of Cardiac Dysfunction following Intense Endurance Exercise.

OBJECTIVES: Pro-inflammatory cytokines have been noted to increase following exercise but their relationship to exercise-induced cardiac dysfunction has not previously been investigated. We sought to evaluate whether exercise-induced cardiac dysfunction was associated with increases in cytokines, particularly the pro-inflammatory cytokines IL-1ß, IL-12p70 and TNFα, which have been most implicated in cardiac pathology. METHODS: 40 well-trained endurance athletes underwent evaluation prior to and immediately following one of four endurance sporting events ranging from 3 to 11 hours duration. Cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were analyzed by flow cytometry from serum samples collected within 50 minutes of race completion. Cardiac troponin (cTnI) and B-type natriuretic peptide were combined with an echocardiographic assessment of cardiac function, and a composite of cTnI > 0.04 µg/L, BNP increase > 10 ng/L and a decrease in right ventricular ejection (RVEF) > 10% were prospectively defined as evidence of myocardial dysfunction. RESULTS: Relative to baseline, IL-6 IL-8 and IL-10 increased 8.5-, 2.9-, and 7.1-fold, respectively, P<0.0001. Thirty-one (78%), 19 (48%) and 18 (45%) of the athletes met the pre-specified criteria for significant cTnI, BNP and RVEF changes, respectively. TNFα, IL-12p70 were univariate predictors of ΔRVEF and ΔBNP whilst none of the anti-inflammatory cytokines were significantly associated with these measures. Ten athletes (25%, all athletes competing in the endurance event of longest duration) met criteria for exercise-induced myocardial dysfunction. In these 10 athletes with myocardial dysfunction, as compared to those without, there was significantly greater post-race expression of the pro-inflammatory cytokines IL-12p70 (8.1±3.8 pg/ml vs. 2.5±2.6 pg/ml, P<0.0001) and TNFα (6.5±3.1 pg/ml vs. 2.0±2.5 pg/ml, P<0.0001). CONCLUSION: Cardiac dysfunction following intense endurance exercise was associated with increased expression of pro-inflammatory cytokines. This does not prove a causal relationship but provides rationale for further investigations into whether inflammation mediates exercise-induced myocardial dysfunction.

Early repolarization patterns associated with increased arrhythmic risk are common in young non-Caucasian Australian males and not influenced by athletic status.

BACKGROUND: Early repolarization (ER) with a horizontal ST segment (ST-h) and high-amplitude J waves in the inferior leads is associated with an increased risk of cardiac arrhythmic death. The effect of ethnicity and athletic status on this increased-risk ER pattern has not been established. Aboriginal Australian/Torres Strait Islander and Pacific Islander/Maori (non-Caucasian [non-C]) subjects are well represented in Australian sport; however, the patterns and prevalence of ER in these populations are unknown. OBJECTIVE: The purpose of this study was to assess the prevalence and effect of athletic activity on ER patterns in young non-C and Caucasian (C) subjects. METHODS: Twelve-lead ECGs of 726 male athletes (23.8% non-C) and 170 male controls (45.9% non-C) aged 16-40 years were analyzed for the presence of ER, defined as J-point elevation (J wave, QRS slur, or discrete ST elevation) ≥0.1 mV in ≥2 inferior (II, III, aVF) or lateral (I, aVL,V4-V6) leads. ST morphology was coded as horizontal (ST-h) or ascending (ST-a). "Increased-risk ER" was defined as inferior ER with ST-h and J waves >2 mV. RESULTS: Regardless of athletic status, ER and increased-risk ER were more prevalent in non-C than in C subjects (53.8% vs 32% and 7.6% vs 1.2%, respectively, P <.0001). Whereas lower heart rate, larger QRS voltage, and shorter QRS duration were predictors of ER, non-C ethnicity was the only independent predictor of increased-risk ER (odds ratio 17.621, 95% confidence interval 4.98-62.346, P < .0001). CONCLUSION: ER patterns associated with increased arrhythmic risk are more common in young non-C than C subjects and were not influenced by athletic status. The long-term clinical significance of ER in these populations is yet to be determined.

Signs of RV overload on the athlete's ECG.

There is increasing evidence that regular intense endurance exercise can promote structural and electrical remodeling of the right ventricle (RV). These physiological changes can be profound and are frequently accompanied by ECG changes in the right precordial leads, thereby mimicking features observed in arrhythmogenic right ventricular cardiomyopathy (ARVC). Because the 12-lead ECG is used as both a screening and diagnostic tool for the detection of conditions associated with sudden death in athletes, it is of fundamental importance to have a good understanding of the ECG features that distinguish physiological adaptations to endurance exercise from those related to RV pathology as well as their potential overlap. This article describes ECG findings observed in healthy endurance athletes versus athletes with underlying RV pathology and illustrates their differentiation using 4 case presentations.

Right Precordial T-Wave Inversion in Healthy Endurance Athletes Can Be Explained by Lateral Displacement of the Cardiac Apex.

OBJECTIVES: The objective of this study was to test the hypothesis that T-wave inversion in the right precordial leads (TWIV2-3) reflects lateral displacement of the heart such that the surface electrocardiographic (ECG) leads overlie a greater proportion of the right ventricle (RV). BACKGROUND: TWIV2-3 on ECG is more frequently observed among endurance athletes (EAs) than in the general population, the underlying mechanism for which is unclear. METHODS: Sixty-eight EAs and 41 nonathletic control subjects underwent ECG and cardiac magnetic resonance imaging (CMRI). In addition to standard measurements of biventricular function and volume, novel measurements of cardiac displacement and orientation were analyzed from horizontal long-axis images. These included RV wall thickness in diastole (RVd), cardiac-to-hemithorax area ratio (CHTx%), percentage of circumferential displacement of the RV apex toward the axilla (%LatD), and the angle of interventricular septum with respect to the thoracic midline (∠septal). RESULTS: All cardiac volume, RVd, CHTx%, %LatD, and ∠septal values were greater in EAs than in controls. Compared to EAs without TWIV2-3, EAs with TWIV2-3 (n = 26) did not have greater RV wall thickness or cardiac volumes (RVd = 4.9 vs. 4.8 mm, p = 0.695; LVEDV = 231 vs. 229 ml, p = 0.856; RVEDV = 257 vs. 254 mL, p = 0.746), but all measurements of cardiac displacement toward the axilla were greater (%LatD = 45.6% vs. 37.9%, respectively, p < 0.0001; ∠septal = 54.23° vs. 48.63°, respectively, p = 0.001; and CHTx% = 46.3% vs. 41.9%, respectively, p = 0.048). CONCLUSIONS: In healthy EAs, TWIV2-3 is associated with displacement of the RV toward the left axilla rather than RV dilatation or hypertrophy. TWIV2-3 may be explained by the position of the RV relative to that of the surface ECG leads.

Modest agreement in ECG interpretation limits the application of ECG screening in young athletes.

BACKGROUND: Athlete ECG screening has been recommended by several international sporting bodies; however, a number of controversies remain regarding the accuracy of ECG screening. An important component that has not been assessed is the reproducibility of ECG interpretation. OBJECTIVE: The purpose of this study was to assess the variability of ECG interpretation among experienced physicians when screening a large number of athletes. METHODS: A sports cardiologist, a sports medicine physician, and an electrophysiologist analyzed 440 consecutive screening ECGs from asymptomatic athletes and were asked to classify the ECGs according to the 2010 European Society of Cardiology criteria as normal (or demonstrating training related ECG changes) or abnormal. When an abnormal ECG was identified, they were asked to outline what follow-up investigations they would recommend. RESULTS: The reported prevalence of abnormal ECGs ranged from 13.4% to 17.5%. Agreement on which ECGs were abnormal ranged from poor (κ = 0.297) to moderate (κ = 0.543) between observers. Suggested follow-up investigations were varied, and follow-up costs ranged from an additional A$30-A$129 per screening episode. Neither of the 2 subjects (0.45%) in the cohort with significant pathology diagnosed as a result of screening were identified correctly by all 3 physicians. CONCLUSION: Even when experienced physicians interpret athletes' ECGs according to current standards, there is significant interobserver variability that results in false-positive and false-negative results, thus reducing the effectiveness and increasing the social and economic cost of screening.

Comparison of frequency of significant electrocardiographic abnormalities in endurance versus nonendurance athletes.

Most data assessing the accuracy of electrocardiographic (ECG) screening in identifying cardiac pathology in athletes are derived from relatively unselected cohorts of subjects involved in competitive sports. We hypothesized that the prevalence of ECG abnormalities may be greater in athletes performing the greatest combination of exercise intensity and duration, namely professional endurance athletes. A total of 1,007 male and 254 female elite adult athletes underwent cardiovascular screening inclusive of an electrocardiogram, interpreted using the 2010 European Society of Cardiology guidelines. Training-related ECG changes (group 1) were more common in endurance athletes (EAs) than nonendurance athletes (NEAs; 90.8% vs 86.0%, p = 0.04), as were multiple (≥2) training-related changes (78.9% vs 53.5%, p <0.0001). Group 2 ECG changes (previously considered uncommon and training unrelated) were seen in 18.1% of subjects and were twice as prevalent in EAs compared with NEAs (29.9% vs 15.1%, p <0.0001). Right ventricular hypertrophy (4.4% EAs vs 1.5% NEAs, p <0.005) and deep right precordial T-wave inversion (14.3% EAs vs 4.7% NEAs, p <0.0001) were 3 times as common in EAs. Both group 1 and group 2 changes were similarly prevalent among elite male and female athletes and were more common in EAs regardless of gender. In conclusion, ECG abnormalities are very common in elite athletes and are more common in EAs than NEAs. Right ventricular hypertrophy and deep right precordial T-wave inversion are particularly common in EAs, possibly because of increased structural and/or electrical right ventricular remodeling in this subgroup. The predictive value of ECG screening and criteria for abnormal findings in elite EAs requires specific appraisal.

The Seattle Criteria increase the specificity of preparticipation ECG screening among elite athletes.

BACKGROUND: In 2010, the European Society of Cardiology (ESC) released recommendations for the interpretation of the 12-lead ECG in athletes, dividing changes into group 1 (training related) and group 2 (training unrelated). Recently, the 'Seattle Criteria', a series of revisions to these recommendations, was published, with the aim of improving the specificity of ECG screening in athletes. OBJECTIVES: First, to assess the prevalence of ECG abnormalities in a cohort of elite Australian athletes using the 2010 ESC recommendations and determine how often group 2 ECG changes correlate with the evidence of significant cardiac pathology on further investigation. Second, to assess the impact of the 'Seattle Criteria' in reducing the number of athletes with ECG abnormalities in whom further cardiac testing is unremarkable ('false positives'). DESIGN: 1197 elite athletes underwent cardiovascular screening between 2011 and 2012, of whom 1078 aged 16-35 years volunteered and were eligible to participate. RESULTS: 186 (17.3%) had an abnormal ECG according to ESC recommendations and a further 30 (2.8)% had unclassified changes. Three athletes (0.3%) were found to have a cardiac abnormality on further investigation. Using the Seattle Criteria, the number of athletes classified as abnormal fell to 48 (4.5%, p<0.0001) and the three with an underlying cardiac abnormality were still identified. The improved specificity was due to reclassification of 71 athletes (6.6%) with an equivocal QTc interval, 42 (3.9%) with T wave inversion isolated to V1-2 and 22 (2%) with either isolated right axis deviation or right ventricular hypertrophy on voltage criteria. CONCLUSIONS: The 'Seattle Criteria' reduced the false-positive rate of ECG screening from 17% to 4.2%, while still identifying the 0.3% of athletes with a cardiac abnormality.