Sudden Death in Athletes

Etiology

Sudden unexpected death in athletes has been primarily viewed as a disease of cardiac etiology. 

Cardiac Etiologies

Structural Abnormalities

• Hypertrophic obstructive cardiomyopathy (HOCM)
• Dilated cardiomyopathy
• Coronary artery anomaly
• Left ventricular hypertrophy
• Atherosclerotic coronary artery disease
• Left ventricular noncompaction
• Arrhythmogenic right ventricular dysplasia
• Aortopathy
• Congenital aortic stenosis
• Mitral valve prolapse

Structurally Normal Heart

• Wolff-Parkinson-White syndrome
• Congenital long QT syndrome
• Acquired long QT syndrome
• Brugada syndrome
• Atrioventricular blocks
• Catecholaminergic polymorphic ventricular tachycardia
• Short QT syndrome
• Early repolarisation syndrome
• Idiopathic ventricular fibrillation
• Mixed sodium channel disease 
• Stray electric currents created by the athlete's chest muscles
• Environmentally created static electricity

Other

• Stimulant use
• Anabolic steroid use
• Commotio cordis
• Aortic rupture
• Myocarditis

Epidemiology

The frequency of sudden cardiac death in athletes in the current literature is variable depending on the methodology used to gather the data. The general range reported is 1 in 40000 to 1 in 80000. However, there are reports with rates as high as 1 in 3000. The variability is likely due to the applied definition of sudden cardiac death. The various definitions range from those who experienced sudden cardiac death during exertion, rest, or survived resuscitation.[5] 

The most frequent cause of sudden death in athletes is hypertrophic obstructive cardiomyopathy (HOCM) and severe left ventricular hypertrophy, followed by other structural cardiac defects. HOCM is seen in roughly 1 in 500 people and is more common in men.[6] Coronary artery anomalies are the second most common cause of sudden death in athletes and occur in up to 1.2% of the population. An estimated 20% of coronary artery anomalies may be life-threatening when found in an athlete.[7][8] Arrhythmogenic right ventricular dysplasia (ARVD) is another known cause of sudden death in athletes and occurs in 1 in 2000 to 1 in 5000 people.[9] 

While structural cardiac defects are primarily genetic, anabolic steroid use is a known etiology of severe left ventricular hypertrophy. The prevalence of left ventricular hypertrophy is prominent among steroid users, but its significance varies depending on the specific agents used and various confounding factors.[10]

Non-structural etiologies of sudden cardiac death largely involve ion channelopathies and electrical defects which induce potentially lethal arrhythmias. Congenital long QT syndrome is known to occur in approximately 1 in 2000 births.[11][12] Wolff-Parkinson-White (WPW) syndrome and preexcitation pathways occur at an approximate rate of 1.5 in 1000. Other illnesses include Brugada syndrome, which occurs at a rate of 0.15%, and catecholaminergic polymorphic ventricular tachycardia which occurs in approximately 1 in 10000 people.[13] 

The occurrence of isolated congenital illnesses is relatively low in the general population but, in summation, is common enough to be a viable health risk given the large number of young athletes.

Pathophysiology

The function of the heart is to effectively pump blood throughout the body, and hence disturbing the blood flow and/or the rhythm of the heartbeats negatively impacts the heart's functional goals. Structural defects prevent the heart from effectively pumping blood, especially during times of increased demand. Ion channel defects disturb the regularity of necessary electrolytes, which maintain the heart's rate and rhythm. Consequently, untreated, structural defects can result in arrhythmia, while persistent arrhythmia may lead to structural heart changes. An example of this is dilated cardiomyopathy which can develop due to an excessive premature ventricular contraction (PVC) burden.

As the most common cause of sudden cardiac death, hypertrophic obstructive cardiomyopathy involves outflow obstruction of blood flow. The ventricular wall becomes rigid as a result, and the left ventricular end-diastolic pressure (LVEDP) and left atrial pressures rise, contributing to pulmonary congestion. Ultimately, this predisposes patients with HOCM to lethal arrhythmias. A similar process occurs in anabolic steroid-induced left ventricular hypertrophy. ARVD involves fatty infiltration of the right ventricle making the heart susceptible to frequent PVCs and ventricular arrhythmias, particularly during strenuous exercise. Other structural defects such as coronary artery anomalies are considered dangerous depending on the specific anomaly. Left or right coronary arteries originating from the pulmonic artery are considered potentially serious.[14] 

Ion channelopathies are due to genetic defects which lead to malformation of the channel proteins. The outcome is electrolyte derangement; specifically potassium, calcium, sodium, and magnesium. Aside from ion channel defects, accessory pathways are another cause of arrhythmias. If a separate electrical pathway, besides the atrioventricular (AV) node, is communicating from the atria to the ventricles, rapid rate and arrhythmias may occur.

Acquired cardiac disease in athletes mostly ties to atherosclerotic coronary artery disease and/or drug-induced cardiac changes. Middle-aged and older athletes are naturally prone to atherosclerosis and may be at risk of plaque rupture within the coronary arteries during strenuous exercise.[15] Drug-associated cardiac illness in athletes categorizes into those caused by anabolic agents and those caused by stimulants. Most anabolic steroids and peptide hormones induce left ventricle hypertrophy, often to highly significant degrees increasing the risk of heart failure. In contrast, stimulants may impact the cardiovascular system acutely by inducing arrhythmias with long-term hypertensive and ionotropic effects, also inducing cardiac changes.

History and Physical

Younger athletes should undergo a comprehensive physical examination by a physician prior to participating in competitive sports or any intense physical activity. 

All athletes should have an assessment for any history of syncope, presyncope, dizziness, palpitations, chest pain, shortness of breath, seizures, severe fatigue, and inability to palpate their pulse. The clinician should ask the athlete about whether these symptoms occur during exercise and/or during rest. While presyncope and syncope are most commonly a result of a vasovagal event and/or due to extreme heat, they are often the initial indication of existing cardiac disease in younger age groups. Palpitations will generally be due to benign ectopic ventricular or atrial heartbeats, but a high burden may be a result of existing structural heart disease. Chest pain and dyspnea can be expected in structural heart disease: specifically obstructive cardiomyopathy. Seizures and the inability to palpate one's pulse may suggest episodes of torsades de pointes, which occurs in those with long QT syndrome. It also points towards the occurrence of an unstable rhythm, such as catecholaminergic polymorphic ventricular tachycardia.

Family history is also essential to assess the existence of genetic heart disorders. Given that these genetic disorders are all inherited and potentially fatal, they may have gone undiagnosed among family members and relatives. Hence, it is vital to ask about any relatives who unexpectedly passed away.

Athletes should be questioned about the usage of performance-enhancing drugs (PEDs), specifically anabolic steroids and stimulants. These agents induce the risk of sudden cardiac death through multiple mechanisms. The most common mechanism is left ventricular hypertrophy in anabolic steroid users, while arrhythmias and vascular injury also occur. High doses of testosterone, use of growth factors, classic agents such as stanozolol, and commonly used injectable drugs like trenbolone; all induce severe left ventricular hypertrophy. Different athletes experience this to variable degrees, and hence knowledge of this history is critical. Also, the usage of stimulants increases the likelihood of arrhythmias, especially in those with existing cardiac illnesses. Some pre-workout supplements contain potentially dangerous compounds that induce a high burden of ectopic heartbeats, prolong QT, and can produce clinical symptoms. Examples of such compounds include 1,3-dimethylamylamine (DMAA), which has been banned in numerous countries. Lastly, blood doping and erythropoietin (EPO) use is of concern, particularly in endurance athletes, and has correlated with sudden cardiac arrest.[16][17][18]

A physical examination is necessary for all young athletes. A general full-body exam should be done, including a neurological assessment, a musculoskeletal examination, and a thorough cardiovascular assessment. A thorough cardiac exam consists of listening to rate and rhythm, S1 and S2, the presence of S3 or S4, and/or any palpable heaves, lifts, or thrills. The existence of any murmurs should be noted and evaluated while increasing or decreasing the preload and afterload using physical maneuvers.

Evaluation

Electrocardiogram

The initial diagnostic assessment of any athlete undergoing screening for cardiac diseases and/or an athlete undergoing assessment for syncope is an ECG. The ECG will provide information on the rate and rhythm of the heart and can indicate structural abnormalities. Assessment of the ECG should include the following: 

• Shortened PR interval and/or accessory pathways
• Long QTc interval (greater than 480 ms)
• Short QTc interval (less than 340 ms)
• Brugada type 1 pattern
• Premature ventricular contractions (greater than 1)
• Doublets or triplets
• Mobitz type II atrioventricular block
• Complete left bundle branch block (LBBB)
• T wave inversion (unless in V1-V3 and also under age 16)
• QRS greater than 140ms
• Epsilon wave

Other significant findings that can present on an ECG include pathological Q waves, significant ST-segment changes, and third-degree atrioventricular blocks.[19] 

Normal Physiologic Findings On ECGs

Athletes may have findings on their ECG that would otherwise be considered abnormal in the general population. Sinus bradycardia (under 60 beats per minute) is among the most common benign abnormal ECG findings, but very low heart rates should not be ignored. Infrequent PVCs and premature atrial contractions (PACs) are also considered normal among the general population and physically active people. However, specific findings on ECGs considered normal among athletes but abnormal in other populations include:

• Left ventricular hypertrophy (QRS voltage criteria)
• Right ventricular hypertrophy (QRS voltage criteria)
• Sinus arrhythmia
• Early repolarisation
• First-degree atrioventricular block

Left and right axis deviation and left or right atrial enlargement may or may not be considered abnormal depending on other findings and the clinical context. If present in isolation, they are generally not considered abnormal. However, coexistence with other borderline or abnormal findings warrants further investigation.[20][21]

Holter Monitor

Two types of athletes will qualify for a 24 or 48-hour Holter monitor: athletes with abnormal ECG findings and/or athletes with symptoms caused by potential cardiac pathology. The Holter monitor will provide greater insight into the athlete's electrophysiology over a greater period compared to an ECG. Arrhythmias will be detected on the Holter monitor, and the etiology of symptoms, such as palpitations, can potentially be uncovered. The Holter monitor is especially useful for assessing the burden of PVCs, given that their frequency of occurrence largely points to their significance. People with ARVD will generally have a high PVC burden and may also experience non-sustained ventricular tachycardia (NSVT).[22][23]

Stress Test

A stress test allows for the reproduction of potentially dangerous arrhythmias that may occur during exercise but are infrequent at rest. 

Echocardiogram

An echocardiogram allows for a general overview of the heart's structure. Evaluating the four cardiac chambers, valvular structures, and the heart's ejection fraction can be made using an echocardiogram.

Multiple criteria exist that combine clinical evaluation, ECGs, and echocardiograms. They carry variable levels of evidence, and hence their utility is subject to use within a clinical context. An example of well-established criteria is the Schwartz scoring scale for evaluating long QT syndrome. 

Long QT syndrome is a known cause of syncope and sudden death among the general population and athletes. The most common cause of prolonged QT on an ECG is secondary to medication use.[24] The absence of medication-induced QT prolongation warrants further investigation into a possible congenital etiology. A normal QTc in men is less than 440ms, and in women, it is less than 460ms.

The following represents a scoring system to assess the probability of long QT syndrome in a patient. 

• QTc greater than 480 ms = 3 points 
• QTc 460 to 479 mc = 2 points
• QTc 450 to 459 (male) = 1 point
• QTc greater than 480 ms after 4th minute of exercise = 1 point
• Torsades de pointes = 2 points
• T wave alternans = 1 point
• Notched T wave in 3 leads = 1 point
• Clinical bradycardia = 1 point
• Syncope with stress or exertion = 2 points
• Syncope at rest = 1 point
• Congenital deafness = 0.5 points
• Family members with diagnosed Long QT syndrome = 1 point
• Unexplained sudden death under age 30 among immediate family members = 0.5 points
• A score of less than or equal to 1 is equal to low probability, a score of 2 to 3 is equal to intermediate probability, and a score greater than 3.5 is equal to a high probability of congenital long QT syndrome. In patients with a high probability of congenital long QT syndrome and/or patients with intermediate probability where clinical suspicion exists, genetic testing may be warranted. As of 2019, there are 17 different known types of congenital long QT known, with the first three types being the most common.[25][26] 

Physiologic versus Pathologic Left Ventricular Hypertrophy

Left ventricular hypertrophy is a common occurrence among athletes. A mild to moderate degree of hypertrophy occurs as a natural response to exercise, particularly endurance-based and isometric exercise. Large levels of hypertrophy are generally noted to be pathological and are known to be induced either genetically and/or as a result of anabolic steroid or peptide hormone use. One differentiating factor between physiological and pathological left ventricular hypertrophy is the wall thickness itself. On an echocardiogram, a normal ventricle will be 6 mm to 11 mm. Under 13 mm is generally not considered to be hypertrophic from a clinical perspective, although 11to 13 mm is borderline thickened. Over 16 to 18 mm is considered significantly enlarged and crosses over into the territory of hypertrophic obstructive cardiomyopathy.[27]

The grey area of 13 mm to 16 mm requires clinical evaluation to differentiate between physiological adaptations to exercise and cardiomyopathy. 

Symptomatically, athletes may experience syncope, dizziness, and dyspnea during exercise. They will also generally be younger. 

ECGs will be done to assess athletes for the voltage criteria for left ventricular hypertrophy, of which three criteria exist. Although positive voltage findings are often normal in athletes, the degree of their elevation provides information to be used within a clinical context. 

Sokolow-Lyon index: S in V1 + R in V5 or V6 greater than or equal to 35 mm or R in aVL greater than or equal to 11 mm

Cornell Voltage criteria: Men = S in V3 + R in aVL greater than 28 mm / Women = S in V3 + R in aVL greater than 20 mm

The Romhilt-Estes point score system may also be useful, which looks at similar voltage criteria as well as ST-T abnormalities, left axis deviation, and QRS duration. Other indications of HOCM on an ECG are pathological Q waves, ST-segment depressions, LBBBs, and T wave inversions.[28][29] 

Aside from measuring left ventricular wall thickness on an echocardiogram, asymmetrical septal hypertrophy and a small left ventricular cavity diameter are additional indicators of cardiomyopathy. As well, evidence of outflow obstruction is a key factor in assessing the risk of sudden cardiac death.

Additional diagnostic tools will generally be used if there exists significant suspicion of cardiomyopathy in a young athlete; this includes cardiac magnetic resonance imaging (MRI) which will give detailed insight into differentiating physiological and pathological hypertrophy, allow for visualization of fatty infiltration in ARVD, and also reveal many potential congenital abnormalities. Angiography is another available tool and is the gold standard for the diagnosis of coronary anomalies and ARVD. Electrophysiology studies are an option for the evaluation of arrhythmias, particularly when the etiology remains unidentified.

Outside of cardiac testing, the use of genetic testing is quite prevalent in assessing for any congenital issues. An extensive range of congenital illnesses may undergo an evaluation with genetic testing, but definite answers will not always be apparent. 

Treatment / Management

Heart disease in athletes involves a combination of general treatments and specific treatments. From a lifestyle standpoint, many athletes may be asked to avoid strenuous exercise and other aggravating factors for a brief period. Physical and/or mental stress increases cardiac demand but also may trigger potentially fatal arrhythmias. Upon establishing a long-term treatment regime, there should be a process of shared decision-making in regards to the athlete returning to their sport of choice. The athlete will undergo a phase of risk stratification, and many variables will play a role in determining their risk of sudden death and the appropriate treatment regime. Aside from the athlete's physiology, their specific sport also can significantly affect the long-term risk. Although earlier views in literature were that many forms of heart disease in athletes should end their athletic careers, the literature in 2019 holds the view that many athletes can safely return to their sport of choice if they undergo a correct treatment process.[30] (B3)

Medical management generally involves the goal of increasing blood flow and lowering the risk of arrhythmias. Hence, beta-blockers are a commonly used medication in these patients. Calcium channel blockers may also be an option. Surgical and percutaneous choices also exist for certain structural defects, such as surgical septal myomectomy or alcohol septal ablation in HOCM. In congenital arrhythmias, ablation may be performed to eradicate the electrical source of the arrhythmia. When the risk of sudden death is appreciated, an implantable cardioverter-defibrillator (ICD) may be placed in case the patient goes into cardiac arrest. ICD placement has dramatically improved the prognosis in all athletes with congenital heart defects and has even allowed for continued sports participation. The last option in certain defects is a heart transplant.[31]

In all patients affected with congenital heart disease, it is also essential to maintain adequate hydration, electrolyte levels and to follow up with a physician routinely. Unfortunately, a specific diagnosis may warrant abstaining from sports, but this should always be a result of a shared decision-making process between the physician and the patient.

Differential Diagnosis

The evaluation of sudden death in athletes must include non-cardiac etiologies.

• Blunt trauma
• Drowning (sports dependent)
• Heatstroke 
• Dehydration

Given that syncope in athletes a key alarming symptom, other probable etiologies should be considered in evaluating syncope.

• Vasovagal events will be a common cause of syncope in both the general population and athletes
• Heatstroke
• Dehydration 
• Anorexia in female athletes and associated electrolyte abnormalities
• Anemia
• Seizures
• Hyponatremia

Prognosis

The prognosis for athletes diagnosed with cardiac disease depends on the specific illness, the degree of pathology, and the treatment regime.

Hypertrophic obstructive cardiomyopathy: Near normal life expectancy, often asymptomatic. ICDs are highly effective in those at risk of sudden cardiac death.[32]

Coronary artery anomaly: Pathological anomalies have an unknown risk of sudden death. Other anomalies are benign, and no evidence exists to show a shorter than normal life expectancy.

Arrhythmogenic Right Ventricular Dysplasia

Good long-term outcome in those who are treated and do not have left ventricular involvement. ICD can drastically improve the prognosis. Many athletes may be forced to abstain from sports.[33] 

Congenital long QT syndrome: Low risk of sudden cardiac death if adequately treated. The risk drops lower after the age of 40. 

Wolff-Parkinson-White syndrome: Sudden cardiac death is a rare occurrence if treated. 

Brugada syndrome: Risk stratification is done to assess the need for interventional treatment. Asymptomatic patients have a near-normal life expectancy, whereas symptomatic patients can have a life expectancy as low as 40 years old. No strong and direct association to athletics.[34] 

Catecholaminergic Polymorphic Ventricular Tachycardia

Poor prognosis if it is not diagnosed early as it often presents in childhood. ICDs and beta-blockers drastically improve outcomes. 

Other conditions may either have an unknown prognosis or have a highly variable prognosis dependent on response to treatment. Lastly, compliance with treatment is also a concern, especially in younger athletes. Many athletes may need to abstain from sports for some time until they receive a thorough evaluation and a treatment regime is finalized. Compliance with the period of abstinence, adherence to the treatment regime, and avoidance of other aggravating factors are all instrumental in the prognosis. 

Complications

The most serious complication in athletes with cardiac illness is sudden cardiac death. Syncope, presyncope, and dizziness are frequently experienced, particularly during exertion. Dyspnea and chest pain are common complaints.