Faculty Bibliography

Background/UNASSIGNED:There is limited information on the long-term outcomes of ICDs in patients with inherited arrhythmia syndromes. Methods/UNASSIGNED:Prospective registry study of inherited arrhythmia patients with an ICD. Incidence of therapies and complications were measured as 5-year cumulative incidence proportions and analyzed with the Kaplan-Meier method. Incidence was compared by device indication, diagnosis type and device type. Cox-regression analysis was used to identify predictors of appropriate shock and device complication. Results/UNASSIGNED:123 patients with a mean follow up of 6.4 ± 4.8 years were included. The incidence of first appropriate shock was 56.52% vs 24.44%, p < 0.05 for cardiomyopathy and channelopathy patients, despite similar ejection fraction (61% vs 60%, p = 0.6). The incidence of first inappropriate shock was 13.46% vs 56.25%, p < 0.01 for single vs. multi-lead devices. The incidence of first lead complication was higher for multi-lead vs. single lead devices, 43.75% vs. 17.31%, p = 0.04. Patients with an ICD for secondary prevention were more likely to receive an appropriate shock than those with primary prevention indication (HR 2.21, CI 1.07-4.56, p = 0.03). Multi-lead devices were associated with higher risk of inappropriate shock (HR 3.99, CI 1.27-12.52, p = 0.02), with similar appropriate shock risk compared to single lead devices. In 26.5% of patients with dual chamber devices, atrial sensing or pacing was not utilized. Conclusion/UNASSIGNED:The rate of appropriate therapies and ICD complications in patients with inherited arrhythmia is high, particularly in cardiomyopathies with multi-lead devices. Risk-benefit ratio should be carefully considered when assessing the indication and type of device in this population.

Arrhythmogenic cardiomyopathy (ACM) is a familial disease, with approximately 60% of patients displaying a pathogenic variant. The majority of genes linked to ACM code for components of the desmosomes: plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2), plakoglobin (JUP) and desmoplakin (DSP). Genetic variants involving the desmosomes are known to cause dysfunction of cell-to-cell adhesions and intercellular gap junctions. In turn, this may result in failure to mechanically hold together the cardiomyocytes, fibrofatty myocardial replacement, cardiac conduction delay and ventricular arrhythmias. It is becoming clearer that pathogenic variants in desmosomal genes such as PKP2 are not only responsible for a mechanical dysfunction of the intercalated disc (ID), but are also the cause of various pro-arrhythmic mechanisms. In this review, we discuss in detail the different molecular interactions associated with desmosomal pathogenic variants, and their contribution to various ACM phenotypes.

PURPOSE/OBJECTIVE:The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS:We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS:). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION/CONCLUSIONS:This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease associated with a high risk of sudden cardiac death. Among other factors, physical exercise has been clearly identified as a strong determinant of phenotypic expression of the disease, arrhythmia risk, and disease progression. Because of this, current guidelines advise that individuals with ARVC should not participate in competitive or frequent high-intensity endurance exercise. Exercise-induced electrical and morphological para-physiological remodelling (the so-called 'athlete's heart') may mimic several of the classic features of ARVC. Therefore, the current International Task Force Criteria for disease diagnosis may not perform as well in athletes. Clear adjudication between the two conditions is often a real challenge, with false positives, that may lead to unnecessary treatments, and false negatives, which may leave patients unprotected, both of which are equally inacceptable. This review aims to summarize the molecular interactions caused by physical activity in inducing cardiac structural alterations, and the impact of sports on arrhythmia occurrence and other clinical consequences in patients with ARVC, and help the physicians in setting the two conditions apart.

Bileaflet mitral valve prolapse (Bi-MVP) is associated with increased risk for cardiac arrest. We describe a patient who presented after a cardiac arrest with Bi-MVP and variants in Lamin A/C (LMNA) and the sodium channel alpha-subunit 5a (SCN5A). Genetic variants may be the culprit for arrhythmogenesis in Bi-MVP patients. (Level of Difficulty: Intermediate.).

Implantable loop recorders (ILRs) can be a valuable tool in monitoring patients with inherited arrhythmia. This paper reports on a family with long QT syndrome (type 2 [LQT2]) in which a pseudopolymorphic wide complex tachycardia detected by ILR was ultimately diagnosed as a supraventricular aberrant rhythm, facilitated by noncompliance with beta-blocker therapy. (Level of Difficulty: Intermediate.).