Faculty Bibliography

Inheritable cardiac disorders, which may be associated with cardiomyopathic changes, are often associated with increased risk of sudden death in the young. Early linkage analysis studies in Mendelian forms of these diseases, such as hypertrophic cardiomyopathy and long-QT syndrome, uncovered large-effect genetic variants that contribute to the phenotype. In more recent years, through genotype-phenotype studies and methodological advances in genetics, it has become evident that most inheritable cardiac disorders are not monogenic but, rather, have a complex genetic basis wherein multiple genetic variants contribute (oligogenic or polygenic inheritance). Conversely, studies on genes underlying these disorders uncovered pleiotropic effects, with a single gene affecting multiple and apparently unrelated phenotypes. In this review, we explore these 2 phenomena: on the one hand, the evidence that variants in multiple genes converge to generate one clinical phenotype, and, on the other, the evidence that variants in one gene can lead to apparently unrelated phenotypes. Although multiple conditions are addressed to illustrate these concepts, the experience obtained in the study of long-QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, and in the study of functions related to SCN5A (the gene coding for the α-subunit of the most abundant sodium channel in the heart) and PKP2 (the gene coding for the desmosomal protein plakophilin-2), as well, is discussed in more detail.

Background: Despite the increased prevalence of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM), the efficacy of radiofrequency ablation (RFA) has been characterized over limited follow-up intervals (~1 year). Several large meta-analyses note that patients with HCM have substantially higher rates of arrhythmia recurrence after RFA, compared to patients without HCM. The implication of confirmed HCM mutations on ablation efficacy has similarly only been assessed in small-scale studies.
Objective(s): To assess arrhythmia recurrence after RFA in patients with HCM and paroxysmal AF (PAAF) or persistent AF (PEAF) as well as its relation to their genetic background and LVOT gradient.
Method(s): Arrhythmia recurrence after RFA was assessed in 66 HCM patients and compared to 343 patients without HCM. AF recurrence was defined as AF on EKG or >30s of AF on ICD/pacemaker interrogation or on monitoring devices after a 3-month blanking period. Kaplan-Meier analysis was performed to compare arrhythmia recurrence rate and timing.
Result(s): The EF of HCM patients was higher than that of the non-HCM patients in both the PAAF and PEAF groups (65.5 and 63.0% vs 61.4 and 53.3%, respectively, p<0.001); within the HCM group, the clinical characteristics of the genetically (+) HCM group (n=14) did not differ from those of the genetically (-) group (n=12). Arrhythmia recurrence at 1 year in PAAF and PEAF was not significantly different between HCM and non-HCM patients (18% vs 11%, p=0.2, and 33% vs 26%, p=1), nor was mean time to arrhythmia recurrence (PAAF 193+/-48 vs 181+/-59 days, p=0.8, and PEAF 175+/-58 vs 168+/-20 days, p=0.6). Recurrence rates over the entire follow-up period of the HCM patients were 54 and 85% in the PAAF and PEAF groups (1076+/-187 and 1050+/- 201 days of follow-up), respectively. Amongst HCM patients with LVOT gradients >70mmHg (PAAF, n = 8, and PEAF, n = 3) longer-term rates of arrhythmia recurrence were similar at 88% and 67% (p=0.9).
Conclusion(s): Arrhythmia recurrence at 1 year following AF ablation in HCM patients is similar to that of non-HCM AF patients regardless of the type of AF. Absolute rates of atrial arrhythmia recurrence in HCM patients at >3 years post ablation are considerable. Confirmed HCM mutations and severe LVOT gradients do not modify the outcome of AF ablation.
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Background: Implantable loop recorder (ILR) based monitoring of patients with LQTS allows enhanced arrhythmia surveillance and can help distinguish life-threatening from benign arrhythmias.
Objective(s): We present a case of a child with LQTS and wide complex tachycardia detected by ILR.
Result(s): An asymptomatic 12 year old with LQT2 syndrome, positive for a G648S hERG mutation, with baseline QTc of 510-550ms despite maximally tolerated Nadolol (Figure 1A) was followed in our inherited arrhythmia center. His affected mother has had multiple syncopal events related to polymorphic ventricular tachycardia (VT) and appropriate ICD shocks. We elected to implant him with ILR to allow longitudinal monitoring and early detection of arrhythmia. He presented 6 months later with 2 alerts for asymptomatic polymorphic, wide complex tachycardia at ~200 bpm during sleeping (Figure 1B). Electrophysiology study (EPS) was performed to determine etiology of the arrhythmia. Dual AV node physiology was present. Sinus tachycardia at 200 bpm with left bundle branch block (LBBB) morphology was induced with Isoproterenol and atrio-fascicular pathway was excluded. Respiratory changes resulted in the tachycardia appearing as polymorphic on the ILR during the EPS.
Conclusion(s): This is the first reported case of sinus tachycardia with LBBB aberrancy in a child with LQTS. Pseudopolymorphic wide complex tachycardia was the result of aberrancy and respiratory artifact. Combined ILR monitoring and EP study provided a correct diagnosis, thus avoiding further interventions. [Figure presented]
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Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored. The aim of this study was to investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy.
Methods and Results: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. A cardiac-specific, tamoxifenactivated PKP2 knock-out murine model (PKP2-cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy. Transcriptomic data of PKP2-cKO mice revealed overexpression of genes involved in adenosine-receptor cascades. Treatment with Istradefylline (an adenosine 2A receptorblocker) tempered the progression of fibrosis and mechanical failure observed in PKP2-cKO mice (see Fig. B,C). In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects.
Conclusion(s): Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution. (Figure Presented)

OBJECTIVES/OBJECTIVE:This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY). BACKGROUND:Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT. METHODS:A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic. RESULTS:). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death. CONCLUSIONS:Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.

Background/UNASSIGNED:pathogenic variant in a decedent. Methods/UNASSIGNED:Forensic investigation and molecular autopsy were performed on an 18-year-old female who died suddenly and unexpectedly. Co-segregation family study of the first-degree relatives and functional characterization of the variant were conducted. Findings/UNASSIGNED:arose de novo, which eliminated the need for exhaustive genome testing and annual cardiac follow-up for the parents and four siblings. Interpretation/UNASSIGNED:Molecular testing enables accurate determination of natural causes of death and precision care of the surviving family members in a time and cost-saving manner. We advocate for molecular autopsy being included under the healthcare coverage in US.

The Brugada syndrome is an inherited channelopathy associated with increased risk of ventricular arrhythmias and sudden death, often occurring during sleep or resting conditions. Although this entity has been described more than 20 years ago, it remains one of the most debated among channelopathies, with several open questions on its genetic substrate, arrhythmia mechanisms, and clinical management. Studies on the genetics and physiopathology bases of the Brugada syndrome have opened novel investigative pathways and concepts that are now entering the field of cardiovascular genetics and are applied to other inherited arrhythmias. In this perspective, Brugada syndrome can be seen as an example on how basic science discoveries have influenced clinical management and led to novel therapeutic approaches.