Faculty Bibliography

PURPOSE OF REVIEW: In this article, we summarize the main features of the most common inherited channelopathies, focusing on the findings that advanced the field in the last few years. RECENT FINDINGS: The progress in genetics prompted the discovery of several new genes associated with ion-channel disorders, elucidating new molecular pathways and new arrhythmogenic mechanisms. The diffusion and availability of genetic screening gave a new relevance to the application of genetics not only for diagnosis, but also for risk assessment and therapeutic decisions. As a consequence, the present challenge in the field is represented by the need to use genetic data to develop personalized clinical approaches. SUMMARY: Over a few years, the field of inherited arrhythmogenic diseases has rapidly expanded, thus reshaping clinical management for these conditions. It is now clear that to handle these patients a specialized expertise is needed, able to translate the discoveries derived from basic science studies into the clinical care of the patients.

Since the discovery of the genetic bases of the long QT syndrome, several new genetically mediated arrhythmias have been described, defining a new group of syndromes, called inherited arrhythmogenic diseases. This allowed clarifying the substrate of several cases of juvenile sudden death, previously defined as 'idiopathic ventricular fibrillation'. Studies derived from this field also contributed to advance the field of electrophysiology, elucidating some of the mechanisms that regulate the cardiac electrical properties of the heart. Recently, new genes and new proteins have been called into play, expanding the knowledge on the complexity of the regulatory processes modulating the cardiac action potential. Moreover, the collaboration between clinicians and basic scientists opened new approaches in the management of patients affected by genetic arrhythmias. This body of knowledge has then moved into the realization that genetic variations may also influence the predisposition to acquired cardiac diseases. The new exciting challenges that investigators are now facing are connected to the possibility of expanding the field towards the use of these information to shape a newer vision in the management and cure of patients

Introduction: Mutations in the RyR2 cardiac ryanodine receptor are associated with Catecholaminergic POlymorphic Ventricular Tachycardia (CPVT). So far 155 different RyR2 mutations have been rePOrted in patients with clinical manifestations of the disease. Based on the localization of these mutations it has been suggested that screening of the RyR2 gene for diagnostic purPOses should be limited to the regions in which mutations have been rePOrted. In order to assess whether this approach is correct we screened 139 probands from our CPVT cohort and 131 affected family members (AFM) to define whether the limited screening is appropriate. Methods: Open reading frame/splice junction analysis of all the 105 exons of RyR2 was performed by PCR and DNA sequencing. New variants were defined pathogenetic if absent in 400 controls and when they co-segregated with the phenotype in AFM. Results: RyR2 mutations were found in 82/139 probands (59%); all were symptomatic (40/82 survived cardiac arrest). 12/82 (15%) carried mutations outside the regions conventionally screened. 6/82 (7%) probands (all symptomatic and 4 resuscitated from cardiac arrest) had mutations in the 39 exons not screened by a commercial panel of 66/105 exons. Screening of family members in these 6 families identified 3 silent mutation carriers among first degree relatives. Conclusions: Our data show that partial screening of RyR2 in CPVT patients misses a substantial proPOrtion of mutations. Such a partial screening prevents the identification of silent mutation carriers leaving them exPOsed to the risk of life threatening arrhythmias

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by a structurally normal heart and high lethality beginning in early childhood. The identification of its genetic bases made possible the discovery that arrhythmias are caused by intracellular calcium dysregulation. In the 9 years since the description of the genetic substrate of the disease, we have witnessed remarkable progress in the unraveling of the molecular mechanisms underlying its arrhythmogenesis. The impact of these discoveries extends beyond the field of inherited arrhythmias and sheds new light on the arrhythmogenic mechanisms in some more prevalent diseases characterized by abnormal calcium regulation, such as heart failure. Additionally, basic research studies led to the exploration of new therapeutic strategies with potential clinical impact in the near future in reducing the still high incidence of sudden death associated with these conditions. In the current review, the authors discuss the clinical and genetic features of CPVT, highlighting pathophysiologic insights derived from experimental research and future therapeutic targets.

In the 8 years since the discovery of the genetic bases of catecholaminergic polymorphic ventricular tachycardia (CPVT), we have witnessed a remarkable improvement of knowledge on arrhythmogenic mechanisms involving disruption of cardiac Ca(2+) homeostasis. Studies on the consequences of RyR2 and CASQ2 mutations in cellular systems and mouse models have shed new light on pathways that are also implicated in arrhythmias occurring in highly prevalent diseases, such as heart failure. This research track has also led to the identification of therapeutic targets of potential clinical impact to abate the burden of sudden death in CPVT. Here, we review the current knowledge on the pathophysiology of CPVT also highlighting the existing controversies and possible future development

Introduction: Brugada syndrome (BrS) is a heritable arrhythmogenic disease characterized by an augmented risk of sudden cardiac arrest (SCA). Studies on the pediatric population are few and on a limited number of patients. We describe the natural history of 90 children with BrS and on 48 genotyped patients with BrS, representing the largest series of child carriers of SCN5A mutations reported to date. Methods: 90 children (63 males) clinically and/or genetically affected by BrS, mean 10+/-6y, from 64 different families were studied using retrospective case review. Results: Type I or II ECG was observed in 40 patients (pts); 21 pts had ECG type I and 19 pts had ECG type II; 25 during protocol drug infusion and 5 with fever; 46 pts were studied because carriers of BrS mutations, despite normal ECG. Among the 21 patients with a spontaneous type I ECG, 4 were symptomatic (19%) and among the 19 patients with a spontaneous type II ECG, 5 were symptomatic (26%). 2/25, patients with a drug-induced phenotype were symptomatic (8%). Male predominance was observed in the symptomatic group (boys, 77%; girls, 30%). Family history of SCA was present in 35/90 pts. EP study, performed in 16 pts, was positive in only 1. ICD was implanted in 6 pts. During a mean follow-up of 50+/-34 months, 1 child experienced syncope; all other pts remained asymptomatic. Genetic screening for SCN5A was performed in 32 probands (pbs): 16 were carriers of a genetic defect. 57 pts were studied because of family history of BrS; 52 were carriers of the mutation found in their pbs, 5 belong to families with unknown genotype, but were clinically affected. Conclusions: In the pediatric population, ECG pattern and clinical manifestation of BrS are present in a small percentage of pts, suggesting a more subtle phenotype. Symptoms or ECG pattern can be precipitated by fever. Also, the role of EP study is not conclusive in pediatric BrS. In contrast to adults, some 50% of pediatric pbs are genetically affected, suggesting that a strict clinical selection of pts for SCN5A screening may lead to higher genotyping success

Many biological processes, such as metabolic rate and life span, scale with body mass (BM) according to the universal law of allometric scaling: Y = aBM(b) (Y, biological process; b, scaling exponent). We investigated whether the temporal properties of ventricular fibrillation (VF), the major cause of sudden and unexpected cardiac death, scale with BM. By using high-resolution optical mapping, numerical simulations and metaanalysis of VF data in 11 mammalian species, we demonstrate that the interbeat interval of VF scales as VF(cycle) (length) = 53 x BM(1/4), spanning more than four orders of magnitude in BM from mouse to horse.