*Sudden cardiac death risk factors: Type, definition, AHA/ACC and ESC guidelines criteria for SCD risk assessment in primary prevention (upper side). Recommendations for ICD implantation in primary prevention according to AHA/ACC and ESC guidelines, separately (lower side).*

*Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

obstruction to the outflow and quality of life in patients with HOCM. Therefore, Mavacamten represents a valid new therapeutic option (but still not available) for patients with HCM and severe obstruction to the outflow tract despite maximal doses of beta-blocker, calcium channel blockers and disopyramide and before opting for a surgical approach [192].

**Ion channels Regulation***.* HCM is associated with enhanced late sodium current (iNaL) activity due to enzyme-induced sodium-channel phosphorylation which results in increased intracellular sodium (Na+), and in turn, calcium (Ca2+) overload through ion exchange [193]. Dysregulated Ca2+ and Na + handling may contribute to altered cardiomyocyte mechanics (hyper-contractility and impaired relaxation) and predispose the myocardium to arrhythmias. Ranolazine is an inhibitor of iNaL with several potential beneficial effects in HCM, mainly related to the improvement in myocardial relaxation and both anti-ischemia and arrhythmia effects [193]. Although a open-label study (RHYME, NCT01721967) demonstrated positive effects on clinical outcomes, data from a phase II trial (RESTYLE-HCM) failed to demonstrate a significant effect on objective measures (peak VO2, serum B-type natriuretic peptide, diastolic function), while a reduction in premature ventricular complex burden [194] has been reported. For these reasons, ranolazine still remains an intriguing area of research in the field of HCM therapeutic options.

**Fibrosis***. S*everal therapies have attempted to address fibrosis and disease progression in HCM, although nowadays no drug has shown convincing benefits, this target represents an interesting field of research in cardioyopathies. While losartan, valsartan and spironolactone was demonstrated to be ineffective [195–198], atorvastatin demonstrated effects on suppression of hypertrophy in pre-clinical models [199] but had no effect and poor treatment adherence in a small early feasibility study in humans [200].

**Genome editing and gene silencing.** Advances in genome editing technology have sparked excitement about the potential for therapeutic use in cardiovascular disease; however, there remain important hurdles prior to implementation in clinical practice [201, 202]. Current techniques including CRISPR/Cas9 cause a doublestranded DNA break at a desired genetic locus followed by intrinsic cellular repair that is virtually error-free and recently, high-fidelity gene repair in human embryos carrying HCM mutations was shown to be feasible [203]. Using sperm from a heterozygous MYBPC3 mutation carrying male patient, oocytes from healthy women were inseminated. Simultaneous injection of a mutation-specific CRISPR/Cas9 system during early metaphase resulted in editing of the mutation 100% of the time [204]. Allele-specific gene silencing is another gene-based therapeutic technology that holds promise for monogenic diseases. This typically involves the transduction of an adenovirus vector containing short-interfering ribonucleic acid segments designed to suppress expression of a specific pathogenic allele – a method more broadly defined as ribonucleic acid interference (RNAi). In pre-clinical models, RNAi was demonstrated to attenuate the phenotype of specific mutations causing catecholaminergic polymorphic ventricular tachycardia [205], HCM [206] and restrictive cardiomyopathy [207].

*Cardiomyopathy - Disease of the Heart Muscle*

#### **Author details**

Davide Lazzeroni1 \* and Claudio Stefano Centorbi2

1 IRCCS Fondazione Don Gnocchi, Florence, Italy

2 Fondazione Don Gnocchi, Parma, Italy

\*Address all correspondence to: davide.lazzeroni@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

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