Hypertrophic cardiomyopathy screening program in the athlete - second in series

Background

Hypertrophic Cardiomyopathy (HCM) causes disability and death in patients of all ages, with the most devastating component of its natural history being sudden death in youth: For example in American athletes under the age of 30, HCM is the first cause of sudden death (36% of total) (1). Thus, there is general agreement that preparticipation screening in all athletes will increase the number of suspected cases of HCM and allow more definitive diagnoses. However, screening modes differ: 

• European investigators promote routine 12-lead ECGs as part of a national mandatory program.
• The US's customary practice is limited to history and physical examinations. 

Cardiologists, fellows and sports medicine physicians must make eligibility or disqualification decisions to prevent sudden cardiac death. Consensus criteria on these determinations have proved useful to the practising community. After a look at the genetic roots of the disorder, the relevant clinical and echocardiographic assessments, and the observations to base stratification on, the case for systematic 12-lead ECG, and the consensus criteria will be reviewed. 

1. Heterogeneity in the disorder

There is marked heterogeneity in the clinical expression, natural history and prognosis in HCM:

• HCM is a mendelian autosomal dominant trait: Hypertrophic cardiomyopathy is inherited as a mendelian autosomal dominant trait. An autosomal dominant trait is passed on by parents from non-sex genes in a 50/50 likelihood. For a detailed look at autosomal dominant mutations see here.
• HCM is caused by gene mutations: A mutant gene is one that has lost, gained, or exchanged some of the material it received from its parent, resulting in a permanent transmissible change in its function. There can be mutations in any 1 of 10 genes which encode proteins of the cardiac sarcomere, the components of which are thick or thin filaments with contractile, structural, or regulatory functions. The three most frequent HCM-causing mutant genes are β-myosin heavy chain (the first to be identified), cardiac troponin T, and myosin-binding protein C. The other genes each account for a minority of HCM cases, namely, cardiac troponin I, regulatory and essential myosin light chains, titin, a-tropomyosin, a-actin, and a-myosin heavy chain (2). 
• Intragenic heterogeneity: Added to the important number of mutant genes, there is in HCM intragenic heterogeneity; more than 150 mutations have been identified, most of which are missense - where a single aminoacid residue is substituted with another. 

Thus, molecular defects responsible for HCM are usually different in unrelated individuals (Table 1), and many other genes and mutations, each accounting for a small proportion of familial HCM, remain to be identified.

Table 1: Genetics of HCM
(by Chapter 19, Sport Cardiology Textbook, Springer 2012).

2. Diagnosis

A) Criteria

Clinical diagnosis of HCM is based on the echocardiographic observation of the typical feature of the disease:

1. Asymmetric hypertrophy of the left ventricle (LVH), 
2. In association with a normal LV dimension 
3. In the absence of another cardiac or systemic disease (eg, hypertension or aortic stenosis) associated with LVH.

The signs suggestive of a dynamic left ventricular outflow tract (LVOT) obstruction such as a systolic heart murmur, a systolic anterior motion (SAM) of the mitral valve or a premature closure of the aortic valve, do not, however, represent diagnostic criteria: indeed, most patients do not have LV outflow tract obstruction at rest and most of the well-documented physical findings (eg, loud systolic heart murmur and bifid arterial pulse) are limited to patients with outflow gradients. 
LVH nevertheless is an independent risk factor for sudden death in young people affected by HCM and is variable in distribution and extension (1,2).

B) Differential

Many patients show diffusely distributed LVH. However, almost one third of patients have only mild wall thickening localised to a single segment (interventricular septum, antero-lateral and posterior wall), or limited to the apex, most common among Japanese people.
Increased LV wall thicknesses range widely from mild (13-15 mm) to massive (30 mm [normal, ≤11 mm]), and up to 60 mm.
In trained athletes, modest segmental wall thickening (ie, 13-15 mm) raises the differential diagnosis between extreme physiologic LVH (ie, athlete’s heart) and mild morphologic expressions of HCM, without outflow obstruction.
The differential diagnosis in this “gray-zone” of overlap (about 2% of elite male athletes) where differentiation of adaptative LVH versus HCM could be facilitated or resolved with some clinical and imaging criteria. 

Echocardiographic criteria: An end-diastolic diameter (EDD) >55 mm and a reduction of the LV wall thickening after three months of detraining (<13 mm) are suggestive of the athlete’s heart (3, 4). Recognition of certain features referring to LV dimensions, diastolic function and brain natriuretic peptide (BNP) is useful (5,6). In a pilot study by Pagourelias ED et al, left ventricular end-diastolic diameter<4,74 cm, mitral deceleration time>200 msec, isovolumic relaxation time>94 msec, tricuspid E/A<1,63, relative wall thickness >0,445 and a BNP value at rest >9,84 pg/ml suggest underlying cardiomyopathy (5).

Magnetic resonance imaging (MRI) may be of diagnostic value when echocardiography is technically inadequate in identifying segmental LVH (7). A model incorporating the LV end diastolic volume (EDV) and end diastolic mass (EDM) ratio (EDV:EDM ratio) has been proposed as a useful tool to distinguish HCM from physiological hypertrophy in athletes (8). This ratio has been found to be lower in patients with HCM in comparison with healthy controls and athletes. 

Late gadolinium enhancement may be helpful in identifying areas of intramyocardial fibrosis (7). However, on the other hand, MRI of endurance athletes has been found to reveal abnormal findings in more than 5% of athletes (9). Thus, cardiac MRI cannot be recommended as a routine examination in athletes.

Cardiopulmonary testing may contribute to the differential diagnosis between HCM and the athlete’s heart: athletes usually have a VO2 peak value >50 ml/kg/min, in comparison with HCM patients who present VO2 peak value in the range of normality (7).

Genetic analyses are useful in distinguishing the benign consequences of systematic athletic training from pathological LVH with the potential for sudden cardiac death. With regard to pedigree assessment, it is mandatory for the proband to be informed of the familial nature and autosomal dominant transmission of HCM. Screening of first-degree relatives, including anamnestic and physical examinations, and 2-dimensional echocardiography and ECG should be encouraged, particularly if adverse HCM-related events have occurred in the family. If a proband is positive for one of the 10 most common HCM-causing mutant genes tested in the panel, the test result is definitive. On the other hand, negative tests in probands may be nondiagnostic because of false negative results. However, if the gene defect responsible for HCM in the family is known, family members can easily be tested definitively and inexpensively (7). Actually, such genetic testing has potential limitations and the debate regarding screening remains controversial. Genetic testing has been increasingly used in the diagnosis of HCM, resulting in a subset of patients with genotype positive-phenotype negative disease; these patients carry the mutation for HCM but lack pathological evidence of disease (10).

3. Risk stratification

Correct risk stratification and relevant sport disqualification are based on the evidence that sudden death may be the first clinical manifestation of the disease, particularly in the young (<30 years). Some observations indicate that, in the presence of cardiovascular disease, physical activity may be a trigger and a precipitating factor for sudden death in athletes:

• No symptoms: The vast majority of athletes who die suddenly with HCM were free of prior symptoms or suspicion of cardiovascular disease (1). 
• Physical exertion: Sudden collapse usually occurs with physical exertion in the late afternoon and early evening hours, corresponding to the peak periods of competition and training, mostly in organised team sports, such as football and basketball (11). 
• Trained vs sedentary: Underlying genetic heart diseases are more likely to cause sudden unexpected death in trained athletes then in their sedentary counterparts. 

• Gender: The vast majority of athletic field deaths occur in men (about 90%). This relative infrequency in women probably reflects lower participation rates, sometimes less intense levels of training, and the fact that women do not engage in some of the higher-risk sports (eg, football). 
• High school: Most athletes are involved in high school sports at the time of death (about 75%), and less commonly in college or professional competition.
• African-Americans: Although the majority of sudden deaths in competitive athletes have been reported in white males, a substantial proportion (more than 40%) are African-Americans (11) (including the majority of HCM-related athletic field deaths). This fact contrasts sharply with the infrequent identification of black patients with HCM in hospital-based populations. These observations emphasise the lesser access to medical care of the African-American, which makes it less likely that young black males will receive the diagnosis of HCM. Consequently, African-American athletes with HCM are also less likely to be disqualified from competition to reduce their risk for sudden death, in accordance with the recommendations of the Bethesda Conference (12-13).

4. 12-lead ECG screening 

A) Screening

Usual practice in the US is usually limited to history and physical examination (12-17). In contrast, Italy has known for the last 25 years a systematic preparticipation screening program. This screening includes a 12-lead ECG which has allowed the identification of athletes previously undiagnosed with HCM. In Italy there is a law on health protection of competitive sports since 1982 that has led to the creation and the revision of cardiological guidelines (called COCIS) which have reached their fourth edition (1989-2009). 
Indeed, the ECG is abnormal in up to 95% of HCM patients (18-21). In particular, Italian investigators have reported a nearly 90% decline in the annual incidence of sudden cardiovascular death in competitive athletes in the Veneto region of northeastern Italy. This change in death rate occurred in parallel with progressive implementation of nationwide mass screening and the increasing identification of affected athletes who were then disqualified from competitive sports.
Maron et al, however, in a recent comparison of US and Italian experiences, described a similar sudden death rate among young competitive athletes in recent years (15). 
As sudden death has a strong impact in sports life, the concept that multiple sources are additive and beneficial in identifying the maximum number of sudden death events should be stressed. In this regard, recently Maron et al proposed identification of cases of sudden deaths in college athletes using internet-based, public domain methodology (22).
The usefulness of ECG remains crucial (Fig 1). The 12-lead ECG is abnormal in 75% to 95% of HCM patients and typically demonstrates a wide variety of patterns, including elevated QRS voltages, intra-atrial or left intraventricular conduction abnormalities, pathologic Q waves (depth>2 mm) and significant repolarisation abnormalities (ST depression, negative T waves). For example, deep T-wave inversion of>2 contiguous anterior or lateral leads (but not aVR and III) are of major concern for sports cardiologists, because they may represent the first and only sign of an inherited heart muscle disease (23). Providing medical clearance for an asymptomatic athlete without a family history of sudden death is especially challenging in the presence of these abnormal repolarisation patterns, highly suggestive of an inherited cardiomyopathy.
However, some ECG patterns observed in athletes and raising a suspicion of HCM have a poor diagnostic value, in the absence of structural abnormalities. Transthoracic echocardiography significantly improves the diagnostic power of screening in the detection of both mild and serious cardiac conditions in the athletic populations (24).

B) Abnormality detected

Nevertheless, despite different pre-participation screening strategies, when a cardiovascular abnormality is identified in a competitive athlete, the following assessments are required:

1. Level of risk for sudden death if participation in organised sports continues
2. Likelihood that risk would be reduced if systematic training and competition are discontinued;
3. Criteria to formulate appropriate eligibility or disqualification decisions.

It should be underscored that the risk associated with intense physical exertion for sports participants with cardiovascular abnormalities is difficult to quantify, given the unpredictable physiologic circumstances to which individual athletes may be exposed. Indeed, only some HCM-related sudden deaths are associated with intense physical activity and not all trained athletes with this disease die suddenly during their competitive phase.

5. Consensus criteria

The American College of Cardiology (ACC) 36th Bethesda Conference and European Society of Cardiology (ESC) offer expert recommendations and clear benchmarks for clinical practice (12,13).

High-risk patients' recommendations

Because of the potential and dramatic event of sudden death among young athletes, especially in case of strong intensity sports, the identification of higher risk athletes is crucial. 

• Young athletes with the unequivocal diagnosis of HCM are discouraged from competitive athletic participation, with the exception of low-intensity sports (eg, golf and bowling).
• Discrimination between physiological LV hypertrophy in trained athletes and pathological hypertrophy in HCM in affected subjects is mandatory. 
• In a HCM diagnosis, an accurate medical qualification decision-making process has to be performed. 

Obviously, this process may be very problematic, given the competing interests of the personal aspirations of the athletes versus the mandate of the physician to protect patients from circumstances which could provoke unacceptable risks. However, if individual risk stratification is difficult, on the other hand the identification of patients at low risk is easier.

HCM patients at low risk of sudden death have the following characteristics:

1. Absence of symptoms, in particular syncope or prolonged, recurrent and palpitations during exercise
2. Mild hypertrophy (<18 mm); absence of atrial enlargement.
3. Absence of dynamic LVOT obstruction or mitral regurgitation at rest and during exercise
4. Absence of effort hypotension (blood pressure reduction >20 mmHg during exercise
5. Normal transmitral flow pattern and normal time Doppler imaging (TDI) of the right ventricle
6. Absence of significant supraventricular and ventricular arrhythmias
7. Absence of late enhancement in MRI

These low risk patients are eligible, under periodic controls, for low intensity sports (eg, golf,  sailing, riding and bowling).

Conclusion

The consensus criteria and recommendations for eligibility and disqualification of athletes with HCM should be useful to the practising community.

Fig. 1: ECG at rest of a non agonistic athlete with a suspicion of Wolf-Parkinson-White. ECG suggests the diagnosis of HCM, later confirmed by imaging (by Chapter 19, Sport Cardiology Textbook, Springer 2012).