The Electrocardiogram and the Phenotypic Expression of Hypertrophic Cardiomyopathy

Stefano Caselli; Antonio Pelliccia


Eur Heart J. 2019;40(12):982-985. 

Hypertrophic cardiomyopathy (HCM) is a heterogeneous cardiac disease with respect to clinical expression and natural history, with sudden cardiac death (SCD) representing the most devastating complication in young individuals, including athletes.[1,2] At present, both American and European recommendations advise precautionary disqualification from most competitive sport in young patients with unequivocal diagnosis of HCM.[3–5]

Diagnosis of HCM may be difficult in the clinical practice. According to guidelines, diagnosis is confirmed 'In an adult, by a wall thickness ≥15 mm in one or more LV myocardial segments—as measured by any imaging technique [echocardiography, cardiac magnetic resonance imaging (CMR), or computed tomography]—that is not explained solely by loading conditions'.[2] However, not infrequently HCM presents with lesser degrees of wall thickening, especially in young athletes (i.e. LV wall thickness of 13–14 mm), 'in these cases, the diagnosis of HCM requires evaluation of other features, including family history, non-cardiac symptoms and signs, electrocardiogram (ECG) abnormalities, laboratory tests, and multi-modality cardiac imaging'.[2] Eventually, strong support to the diagnosis (especially in the context of a family screening) is made by the identification of a definite causative genetic mutation, being HCM inherited as an autosomal dominant disease.[1,2] The relevance of a causative gene anomaly in the setting of HCM diagnosis, however, is limited in the absence of phenotype, and the simple identification of gene mutation in families with genetic forms of HCM does not represent, per se, a sufficient criterion for diagnosis.[2]

The 2005 European Society of Cardiology (ESC) guidelines for competitive sport participation suggest, when a positive genotype is identified, a cautious restriction from sport activities even in the absence of an overt phenotype.[3,4] At the time of that guidelines conception, data describing the long-term clinical outcome of genotype positive (G+), phenotype negative (P−) HCM carriers were scarce, and these recommendations were dictated by a prudent and cautious attitude, having in mind the high prevalence of HCM as a cause of SCD in young competitive athletes.[1] However, in the subsequent years some observations have been reported in this context, giving the proper background for a critical reappraisal of the recommendations. Specifically, Gray et al.[6] reported on 32 G+/P− young patients followed up for 4 ± 3 years; only one of them developed an overt HCM phenotype at the age of 16 years. Jensen et al.[7] observed that out of 12 G+/P− child, two developed evidence for LV hypertrophy over a 12 year follow-up, at the age of 26 and 28 years, respectively. More recently, Vermeer et al.[8] reported that out of 118 individuals G+/P−, 8 subjects (i.e. 7%) developed overt HCM phenotype after a mean follow-up of 8 years, at an age ≤30 years.[7] Although the number of individuals observed, and the period of follow-up is somehow limited, nevertheless it is evident, and of utmost relevance, that no clinical events (namely, SCD/arrest) had occurred in mutation carriers before the development of an overt HCM phenotype.

These observations reinforce the recent statement of the American College of Cardiology/American Heart Association that participation in competitive athletics for asymptomatic, G+ HCM without evidence of LV hypertrophy, is reasonable (Class IIa; Level of Evidence C).[5]

Not uncommonly, ECG abnormalities may be seen in young athletes in the absence of other phenotypic features of HCM, raising the question of early manifestation of the disease.[9,10] In this context, an intriguing question is the significance of marked ECG abnormalities in an individual with a positive genetic background. How should we define and manage an individual with a positive genotype (G+) if marked repolarization abnormalities, i.e. ST-segment depression and inverted T-waves in infero-lateral leads, are incidentally observed?

Figure 1 shows a typical case of an individual (a 31-year-old Caucasian athlete), presenting with a markedly abnormal ECG pattern and positive genetic testing. The 12-lead ECG shows negative T-waves in infero-lateral leads. The athlete was asymptomatic and the family history reported the TakoTsubo syndrome in the old mother. Genetic testing identified a missense mutation of beta-myosin light-chain (MYL3), and both the echocardiographic and CMR scans showed absence of either segmental or diffuse LV hypertrophy. This subject was aiming to participate in international competitive rugby and represents just an example of few of such cases that we were called to evaluate in the more recent years.

Figure 1.

Findings from a 31-year-old Caucasian asymptomatic athlete with a beta-myosin light-chain mutation is shown. The 12-lead electrocardiogram shows negative T-waves in infero-lateral leads. Cardiac magnetic resonance scan shows absence of either segmental or diffuse LV hypertrophy.

We know that the specificity of ECG abnormalities is low when found in isolation,[2–4] but in association with causative gene mutation, or in the context of familial disease, should the ECG abnormalities be more properly considered as early phenotypic expression of the disease, and therefore, implicitly confirm the diagnosis of HCM?

As a matter of fact, we already reported that abnormal ECG patterns are not uncommonly the initial expression of a cardiomyopathy and represent the first phenotypic manifestation of a disease that will become clinically overt only after several years.[11]

The term phenotype, which comes from the Greek 'phainein' meaning, 'appear' and 'typos' meaning 'type' refers to the appearance of morphological traits of the disease in an individual, which in the case of HCM should reasonably include the electrocardiographic characteristics. The presence of major ECG abnormalities (as the diffusely inverted T-wave observed in our case) realistically represents an expression of depolarization and/or repolarization abnormalities in the context of subclinical myocardial disorder. However, since the diagnostic hallmark of the disease according to the guidelines[2] is the presence of LV hypertrophy, currently we could not legitimately state the diagnosis of HCM based on the ECG.

It is easy to predict that number of these intriguing cases is going to increase, due to the widespread diffusion of the ECG-screening programme in competitive athletes and larger access to the Next Generation Sequencing DNA analysis for research of the causative pathogenic mutations.

These subjects may be defined as G+/P−/ECG+ to distinguish them from those with normal ECG (G+/P−/ECG−) and could represent a further challenge regarding the proper clinical management. Does the combined presence of pathogenic gene mutation and markedly abnormal ECG increase the probability for the development of the full morphological (i.e. LV hypertrophy) and clinical expression (i.e. events) of the disease, suggesting a more cautious and prudent management?

To solve this clinical conundrum, a few previous observations may be considered.

It was clear in our previous investigation that vast majority (i.e. >80%) of the individuals with marked ECG abnormalities in the absence of any phenotypic expression of cardiomyopathies do not develop LV hypertrophy over a prolonged time period (average 9 years) and maintain the same ECG pattern as the only abnormal clinical finding.[11] These individuals, moreover, remain free of symptoms and were able to participate in professional athletic career for a lifelong period.[12] The few individuals incurring symptoms and events over time (about 6% of the initial cohort) were all characterized by the appearance of structural changes, namely LV hypertrophy in HCM.[11]

Therefore, from the available scientific evidence it appears that both causative gene mutation and/or ECG abnormalities are deprived of adverse clinical consequences, at least until structural changes (i.e. LV hypertrophy) will develop.

In the clinical practice, we suggest that these individuals are evaluated in experienced centres and are discussed in the context of the 'athlete's heart team' including the sport physician, cardiologist, cardiac genetics, and imaging experts. Specifically, the evaluation of a cardiac geneticist is important to interpret the findings in the context of the family history and to confirm the pathogenic nature of the mutation and not a variant of uncertain significance. Regarding cardiac imaging, it is of utmost importance in this setting, that echocardiography (as the first line imaging technique), should carefully consider the criteria to distinguish physiological from pathological hypertrophy.[13] However, even in absence of abnormalities, echocardiography should not be considered as the sole imaging technique and CMR with late gadolinium imaging should be considered mandatory, as may reveal certain abnormalities, such as small areas of focal hypertrophy not evident on a trans-thoracic echocardiogram.

When after a comprehensive evaluation, the morphological traits of HCM are not found, it is wise to assume that the condition we defined as G+/P−/ECG+ should not be viewed as a pathological condition itself, and the individual should be reassured as being not affected by the disease and informed about the significance of being a 'carrier'. Consequently, we believe that no restriction of active lifestyle, including participation in professional sport activity, should be advised in these individuals (Figure 2).

Figure 2.

Proposed algorithm management for athletes identified with a genetic mutation for hypertrophic cardiomyopathy in the context of a family screening. CMR, cardiac magnetic resonance; ECG, electrocardiogram; G, genotype; HCM, hypertrophic cardiomyopathy; LGE, late gadolinium enhancement; P, phenotype.

However, it is extremely important that all G+/P− individuals undergo serial clinical controls, which should be primarily aimed to search by the imaging techniques the development of LV hypertrophy. Adolescent and young subjects should have cardiac evaluation on annual basis, in consideration of the greatest proclivity of the disease to develop phenotypically in association with the body growth. On the other hand, since penetrance decreases with age, we advise adults and senior athletes to undergo serial controls with a larger interval (2 year or more), having in mind that development of HCM phenotype is still possible even in adult age.[1,2]

As a final consideration, it is worthy to mention that recent observations support the concept that the role of sport activity on triggering SCD in HCM may be lower than what was considered until now.[14–18] In our recent study on a small cohort of individuals with mild phenotypic expression of HCM, we reported no events among those who continued competitive sports, as a sudden cardiac arrest occurred out of the context of sport activity in a subject who practiced leisure-time tennis.[15] These observations further support a more liberal attitude in terms of sport prescription in those carrier individuals that do not have an overt phenotype.

In conclusion, we believe that these considerations and the new evidences represent a reasonable background for the revision of the previous ESC eligibility criteria for competitive sports, on which the sports cardiology nucleus of the European Association of Preventive Cardiology is currently working, and which will likely represent the most updated scientific knowledge in the field.