Reversible Apical Hypertrophy in a Young Competitive Athlete with Familiar Hypertrophic Cardiomyopathy

Background

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease responsible for sudden cardiac arrest and death in young athletes [1–4]. It is not rare, occurring at the rate of about 1 in 500 people, and possibly is underestimated. The differential diagnosis for HCM includes physiological remodeling seen in athlete’s heart [5]. Differentiating between athlete’s heart and HCM is sometimes a real challenge since intensive endurance training can cause a distinct pattern of functional and structural changes of the cardiovascular system. The athlete’s heart shows an eccentric biventricular hypertrophy with wall thicknesses under 15 mm and a moderately dilated left ventricle (LV) (end-diastolic diameter [EDD] up to 58 mm). HCM is commonly characterized by asymmetric left ventricular hypertrophy (LVH) with a normal\ reduced LV-diameter. The main characteristic is the regression of this structural change with deconditioning [5]. Whether intensive exercise and competitive sport may impact the phenotypic presentation and even the clinical course of HCM is largely unknown. Only a few reports have addressed this controversial issue [6,7]. Specifically, it is not known if regular exercise training can trigger the development or increase the extent of myocardial hypertrophy in the presence of pathogenic sarcomeric mutations.

Case Report

A 19-years-old male soccer player was referred to our institution because of abnormalities of ventricular repolarization (AVR) on 12-lead ECG observed during pre-participation screening.

The athlete had recently joined a new team, playing at a higher championship level and he had undergone a net increase in training load, with 5 weekly workouts of 2 hours each plus the Sunday game. In addition, he was engaged in a variety of daily gym exercises, totaling a training load of more than 20 hours per week. Of note, in the previous years, he trained for an average of 6 hours per week. In the past, he had periodic cardiological evaluations for pre-participation screening, with resulted always within normal limits.

At our medical evaluation the athlete was asymptomatic. He denied SARS-CoV-2 infection. The family history was positive for obstructive hypertrophic cardiomyopathy in the maternal grandmother. The mother was known (by family screening) to carry a troponin T2 (TNNT2) heterozygous mutation but refused to undergo any imaging evaluation.

The physical examination was unremarkable. The 12-lead ECG (Figure 1) showed diffuse AVR with deep and symmetrical inversion of the T-wave in the left precordial leads (V4-V5-V6) and T-wave inversion in the inferior leads (DII-DIII-aVF). Exercise ECG testing showed no significant changes of AVR during effort, no arrhythmias, and blood pressure profile during effort was normal. Transthoracic echocardiography (TTE) revealed normal LV cavity size (EDD 53 mm) with increased wall thickness at mid-basal septal level (13 mm) and at mid-apical postero-lateral wall thickening (13–14 mm) with systolic obliteration of the apex. LV global systolic function was high-normal (ejection fraction, EF >70%). There was inversion of the septal E’\A’ (<1) ratio on tissue Doppler (TDI), with E\E’ ratio 11.5 (Figure 2). Cardiovascular magnetic resonance (CMR) imaging confirmed the extent and distribution of LV hypertrophy (Figure 3). Maximum wall thickness at the mid-basal septum was 15 mm and at the apex 14 mm with complete obliteration in end-systole and microaneurysm at the apex. No left ventricle outflow tract (LVOT) obstruction was observed. No areas of late gadolinium enhancement (LGE) were found.

Genetic testing confirmed the presence of familial variant c853C>T, p.(Arg 285Cys) on TNNT2 gene, considered to be a variant of uncertain significance (VUS).

Eventually, diagnosis of hypertrophic cardiomyopathy with predominant apical distribution was made. Based on guidelines in force in Italy [8], the athlete was excluded from competitive soccer and periodic cardiological follow-up was requested. No pharmacological therapy was prescribed given the absence of symptoms and sinus bradycardia.

Over the following 18 months, also consequent to the SARSCOV2 pandemic, the athlete observed a prolonged period of complete deconditioning where he stopped playing sports completely. When he returned for cardiological follow-up the ECG showed a complete normalization of the repolarization pattern (Figure 4). The new CMR showed an impressive reduction of the wall thickness with no evidence of hypertrophy, and confirmed the absence of LGE (Figure 5).

Due to the reversibility of LVH, the absence of family history for sudden cardiac death, symptoms, and ventricular arrhythmias, the patient was advised to have periodic monitoring. Therefore, monitoring devices or implantable cardioverter defibrillator were not recommended.

Discussion

HCM is a genetic primitive muscular disorder characterized by LVH, with no dilated cavity, in the absence of abnormal cardiac loading conditions. It is one of the most common causes of SCD in athletes [9]. HCM is very heterogenous both geno-typically and phenotypically and can be modulated by several environmental and genetic factors [10,11].

Our athlete had a TNNT2 heterozygous mutation. TNNT2 gene encodes the cardiac isoform of troponin T, located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial HCM as well as with dilated cardiomyopathy [12,13].

It must be noted that our patient was an athlete, with the potential of a remodeling process related to intensive training, most likely facilitating the development of LVH.

The differential diagnosis between athlete’s heart and HCM can be a real challenge. In our case, the typical ECG changes, the asymmetrical hypertrophy at the LV apex, the diastolic dysfunction, and the familial genetic mutation were all consistent with the diagnosis of HCM rather than athlete’s heart. However, since the morphological LV remodeling was observed during a period of intense athletic conditioning, it is possible that the athlete’s intensive training may have triggered the phenotypic expression of apical HCM in the setting of pathological substrate.

Flett et al [14] defined as relative apical HCM that does not meet conventional hypertrophy criteria (15 mm) and nowadays are not recognized in a precise definition, but will probably develop complete phenotypic expression. Diagnosis includes major (ECG deep T-wave inversion without other evident causes and apical hypertrophy <15 mm) and minor criteria (myocar-dial scarring by LGE CMR, apical aneurysm or microaneurysm, left atrial dilatation and apical cavity obliteration ≥20 mm [14]. In our case, the patient presented both major criteria and apical microaneurysm.

The main feature of this case is the regression of hypertrophy with deconditioning. This observation is clinically relevant, because LVH regression after detraining has been, so far, described only in physiological LV hypertrophy of athlete’s heart and is considered an important feature in the differential diagnosis of athlete’s heart when in the grey zone [5].

There is a lack of solid data about the LVH regression after detraining in HCM. Pelliccia et al reported no changes in maximum LV wall thickness, cavity size, and atrial dimensions in a cohort of 60 HCM adult athletes (mean age, 31 years), during a 7-year period of follow-up, regardless of whether the patients had completely terminated their athletic career or pursued training and competition [6]. Similar results were recently reported by Basu and Sharma [7] in a group of 53 HCM adult patients (mean age, 39 years) followed for a 5-year period during which there was no change in cardiac dimensions, including maximum LV wall thickness, while they remained engaged in professional sport activities. These observations, therefore, supported the idea that, at least in adult patients, the myocardial hypertrophy in HCM was not significantly affected by the athletic lifestyle, suggesting that the hypertrophic phenotype is unlikely to be modified by exercise and sport participation.

The present case, instead, questions this hypothesis, by showing a clear induction and subsequent reduction of the hyper-trophic LV pattern in an young patient, in association with changes in exercise training schedule.

Although there is no consensus explanation for this phenomenon, it seems likely that age is a key factor: we initially observed the present young patient when he was engaged, for the first time, in a very intensive exercise program (at that time the hypertrophic pattern became evident) followed by a prolonged period of inactivity (when the hypertrophy regressed). It seems reasonable that myocardial hypertrophy in the initial stages is mostly due to increase in myocyte volume, which is responsible for LV wall thickening, with no or minimal change of the interstitial fibrillar component. If so, the loss of the hypertrophy’s triggering stimulus may be followed by myocyte slimming and return to original LV wall thickness.

In adult patients, instead, when myocardial hypertrophy has remained stable for years, the initial myocyte growth is likely to be associated with an increased extracellular fibrillar component, which remains largely unresponsive to changes in exercise programs.

Conclusions

Our case shows that an intensive exercise schedule in a young athlete with familial HCM was associated with pathological ECG changes and clinically evident apical HCM, suggesting a potential triggering role in the phenotype induction.

Even more interesting, we observed the regression of the ECG abnormalities and hypertrophic LV apical pattern after detraining. This case emphasizes the need for more investigations assessing the relation between young age, sport activity, and activation of sarcomeric pathogenic mutations in the development of HCM phenotype.