Les rhabdomyomes cardiaques dans la sclérose tubereuse de Bourneville : perturbations fonctionnelles cardiaques et perspectives thérapeutiques

Background: Tuberous Sclerosis Complex is caracterised by the formation of benign tumors in various organs, including the heart. It is caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. RHM (rhabdomyomas) regress spontaneously in most cases but can be complicated by serious arrhythmias or obstruction that may compromise cardiac output requiring treatement. The main objectives of this work were to study functional and electrical cardiac desorders and to analyze the heart rate variability in population of TSC with cardiac rhabdomyoma. Methods: We conducted this cross-sectional study between February 2013 and March 2015 to determine the impact of HMR on the cardiac conduction system and on autonomic nervous homeostasis. Thirty subjects with TSC were recruited to participate in this study and compared to 13 healthy controls that were free family members of RHM. The serial echocardiograms that were previously recorded were used to document the size of the tumor during early childhood. A 24-hour Holter record was performed for possible arrhythmia detection and heart rate variability (VFC) analysis. Results: The median follow-up time was 4.5 years. The prevalence of RHM was 46.8% (37 RHM) between 0-5 years, 39.2% (31 RHM) between 12-33 years and 13.9% (11 RHM) between 6-11 years. RHM causes in 20% an obstacle to inflow or outflow tract. The encountered benign arrhythmias founded were isolated ventricular premature beats (55%) and supraventricular premature beats (50%), which were 2 times fold and 4 times fold more compared to reported prevalence in the general pediatric population, respectively (p<0.05). Significant arrhythmias were noted in 3 (30%) patients with large RHM: one patient with Wolff Parkinson White syndrome had supraventricular tachycardia, one with atrial fibrillation, a third patient had symptomatic paroxysmal supraventricular tachycardia. There was a trend which did not reach statistical significance difference in the prevalence of cardiac arrhythmias between cases with small versus large RHM (p=0.07). In this study heart rate variability was increased in patients with TSC according to time, frequency and non-linear domains. For this heart rate variabity TSC patients with RHM showed an inversed relationship towards age compared to controls, Studies from four everolimus treated cases were compared to 10 controls. Compared to historic controls, everolimus treated patients had a RHM size regression  rate 11.8 times faster (linear regression slope -0.0285 vs. -0.0024; p<0.001). The average time to 50% size reduction was 1.13 ± 0.33 month (range 0.66 to 1.4 months) for everolimus treated patients compared to 72.9 ± 53.03 months in the historic controls (p = 0.026). No significant side effect were observed. Conclusion: In this series, arrhythmia was more prevalent in TSC compared to general pediatric population, with a trend towards higher prevalence in cases with larger RHM. Everolimus is effective for size reduction of RHM during the neonatal period. With limited safety data this approach should be used with caution, only in selective cases.

Keyphrases: Everolimus, Tuberous sclerosis complex, Cardiac rhabdomyomas, Everolimus, Arythmias