Novel pharmacological approaches for paediatric hypertrophic cardiomyopathy

Primary diseases of the myocardium (cardiomyopathies) with paediatric onset are relatively rare but extremely challenging from a clinical standpoint. Newly published case series revealed that patients with paediatric-onset hypertrophic cardiomyopathy (HCM) have a four-time higher risk of lethal arrhythmic events and progression towards terminal heart failure as compared with adult-onset HCM patients. These studies also pointed out that specific mutations (e.g. mutations in thin-filament protein genes) are associated with poor outcome both in children and in adults. At present, there are no effective pharmacological strategies to reduce the risk of lethal arrhythmias and adverse disease progression in those patients, as all indications derive from a few studies conducted in adult HCM patients. New pharmacological agents with a high safety profile and a solid antiarrhythmic efficacy are sought after. Given the risk related with carrying specific mutations (e.g. thin-filament), healthy carriers identified in their childhood may be eligible for a long-term preventive pharmacological treatment to stop, delay or at least soften disease presentation and progression. In this review, we will discuss the role of late sodium current blocker ranolazine as a novel pharmacological option to reduce the risk of lethal arrhythmias in HCM. Moreover, we will speculate on the possible role of ranolazine as a possible preventive agent to be used in paediatric carriers of high-risk mutations. We will then describe several pharmacological approaches that have been attempted or will be tested in the near future to modify HCM phenotype development and disease progression. Finally, we will discuss new gene therapy approaches to correct cardiomyopathies at genetic level, also employing the CRISPR-CAS9 gene-editing framework. All-in-all, the studies presented in this review confirm that paediatric cardiomyopathies are severe conditions that can be managed by focusing our efforts on testing novel drugs and technologies using personalized research platforms.