Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Impact of ventricular tachycardia ablation in subcutaneous implantable cardioverter defibrillator carriers: a multicentre, international analysis from the iSUSI project.

AIMS: Catheter ablation (CA) of ventricular tachycardia (VT) has become an important tool to improve clinical outcomes in patients with appropriate transvenous implantable cardioverter defibrillator (ICD) shocks. The aim of our analysis was to test whether VT ablation (VTA) impacts long-term clinical outcomes even in subcutaneous ICD (S-ICD) carriers. METHODS AND RESULTS: International Subcutaneous Implantable Cardioverter Defibrillator (iSUSI) registry patients who experienced either an ICD shock or a hospitalization for monomorphic VT were included in this analysis. Based on an eventual VTA after the index event, patients were divided into VTA+ vs. VTA- cohorts. Primary outcome of the study was the occurrence of a combination of device-related appropriate shocks, monomorphic VTs, and cardiovascular mortality. Secondary outcomes were addressed individually. Among n = 1661 iSUSI patients, n = 211 were included: n = 177 experiencing ICD shocks and n = 34 hospitalized for VT. No significant differences in baseline characteristics were observed. Both the crude and the yearly event rate of the primary outcome (5/59 and 3.8% yearly event rate VTA+ vs. 41/152 and 16.4% yearly event rate in the VTA-; log-rank: P value = 0.0013) and the cardiovascular mortality (1/59 and 0.7% yearly event rate VTA+ vs. 13/152 and 4.7% yearly event rate VTA-; log-rank P = 0.043) were significantly lower in the VTA + cohort. At multivariate analysis, VTA was the only variable remaining associated with a lower incidence of the primary outcome [adjusted hazard ratio 0.262 (0.100-0.681), P = 0.006]. CONCLUSION: In a real-world registry of S-ICD carriers, the combined study endpoint of arrhythmic events and cardiovascular mortality was lower in the patient cohort undergoing VTA at long-term follow-up. CLINICALTRIALS.GOV IDENTIFIER: NCT0473876.

A worldwide survey on incidence, management, and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: the POTTER-AF study.

AIMS: Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management, and outcome are sparse. METHODS AND RESULTS: This international multicentre registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553 729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed, at 214 centres in 35 countries. In 78 centres 138 patients [0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (P < 0.0001)] were diagnosed with an oesophageal fistula. Peri-procedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8% and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) [odds ratio 7.463 (2.414, 23.072) P < 0.001]. CONCLUSION: Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high.

Programmed Ventricular Stimulation as an Additional Primary Prevention Risk Stratification Tool in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Study.

BACKGROUND: A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value. METHODS: All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia [VT] or fibrillation, [aborted] sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period. RESULTS: Two hundred eighty-eight patients (41.0±14.5 years, 55.9% male, right ventricular ejection fraction 42.5±11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 [2.89-10.17] years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (P<0.001). Inducible ventricular tachycardia predicted clinical sustained VA during the 5-year follow-up and remained an independent predictor after accounting for the calculator-predicted risk (HR, 2.52 [1.58-4.02]; P<0.001). Compared with ARVC risk calculator predictions in isolation (C-statistic 0.72), addition of PVS inducibility showed improved prediction of VA events (C-statistic 0.75; log-likelihood ratio for nested models, P<0.001). PVS inducibility had a 76% [67-84] sensitivity and 68% [61-74] specificity, corresponding to log-likelihood ratios of 2.3 and 0.36 for inducible (likelihood ratio+) and noninducible (likelihood ratio-) patients, respectively. In patients with a ARVC risk calculator-predicted risk of clinical VA events <25% during 5 years (ie, low/intermediate subgroup), PVS had a 92.6% negative predictive value. CONCLUSIONS: PVS significantly improved risk stratification above and beyond the calculator-predicted risk of VA in a primary prevention cohort of patients with ARVC, mainly for patients considered to be at low and intermediate risk by the clinical risk calculator.

Recurrences of ventricular tachycardia after stereotactic arrhythmia radioablation arise outside the treated volume: analysis of the Swiss cohort.

AIMS: Stereotactic arrhythmia radioablation (STAR) has been recently introduced for the management of therapy-refractory ventricular tachycardia (VT). VT recurrences have been reported after STAR but the mechanisms remain largely unknown. We analysed recurrences in our patients after STAR. METHODS AND RESULTS: From 09.2017 to 01.2020, 20 patients (68 ± 8 y, LVEF 37 ± 15%) suffering from refractory VT were enrolled, 16/20 with a history of at least one electrical storm. Before STAR, an invasive electroanatomical mapping (Carto3) of the VT substrate was performed. A mean dose of 23 ± 2 Gy was delivered to the planning target volume (PTV). The median ablation volume was 26 mL (range 14-115) and involved the interventricular septum in 75% of patients. During the first 6 months after STAR, VT burden decreased by 92% (median value, from 108 to 10 VT/semester). After a median follow-up of 25 months, 12/20 (60%) developed a recurrence and underwent a redo ablation. VT recurrence was located in the proximity of the treated substrate in nine cases, remote from the PTV in three cases and involved a larger substrate over ≥3 LV segments in two cases. No recurrences occurred inside the PTV. Voltage measurements showed a significant decrease in both bipolar and unipolar signal amplitude after STAR. CONCLUSION: STAR is a new tool available for the treatment of VT, allowing for a significant reduction of VT burden. VT recurrences are common during follow-up, but no recurrences were observed inside the PTV. Local efficacy was supported by a significant decrease in both bipolar and unipolar signal amplitude.

Impact of cryoballoon application abortion due to phrenic nerve injury on reconnection rates: a YETI subgroup analysis.

AIMS: Cryoballoon (CB)-based pulmonary vein isolation (PVI) is an effective treatment for atrial fibrillation (AF). The most frequent complication during CB-based PVI is right-sided phrenic nerve injury (PNI) which is leading to premature abortion of the freeze cycle. Here, we analysed reconnection rates after CB-based PVI and PNI in a large-scale population during repeat procedures. METHODS AND RESULTS: In the YETI registry, a total of 17 356 patients underwent CB-based PVI in 33 centres, and 731 (4.2%) patients experienced PNI. A total of 111/731 (15.2%) patients received a repeat procedure for treatment of recurrent AF. In 94/111 (84.7%) patients data on repeat procedures were available. A total of 89/94 (94.7%) index pulmonary veins (PVs) have been isolated during the initial PVI. During repeat procedures, 22 (24.7%) of initially isolated index PVs showed reconnection. The use of a double stop technique did non influence the PV reconnection rate (P = 0.464). The time to PNI was 140.5 ± 45.1 s in patients with persistent PVI and 133.5 ± 53.8 s in patients with reconnection (P = 0.559). No differences were noted between the two populations in terms of CB temperature at the time of PNI (P = 0.362). The only parameter associated with isolation durability was CB temperature after 30 s of freezing. The PV reconnection did not influence the time to AF recurrence. CONCLUSION: In patients with cryoballon application abortion due to PNI, a high rate of persistent PVI rate was found at repeat procedures. Our data may help to identify the optimal dosing protocol in CB-based PVI procedures. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03645577?term=YETI&cntry=DE&draw=2&rank=1 ClinicalTrials.gov Identifier: NCT03645577.

STereotactic Arrhythmia Radioablation (STAR): the Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary consortium (STOPSTORM.eu) and review of current patterns of STAR practice in Europe.

The EU Horizon 2020 Framework-funded Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) consortium has been established as a large research network for investigating STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia (VT). The aim is to provide a pooled treatment database to evaluate patterns of practice and outcomes of STAR and finally to harmonize STAR within Europe. The consortium comprises 31 clinical and research institutions. The project is divided into nine work packages (WPs): (i) observational cohort; (ii) standardization and harmonization of target delineation; (iii) harmonized prospective cohort; (iv) quality assurance (QA); (v) analysis and evaluation; (vi, ix) ethics and regulations; and (vii, viii) project coordination and dissemination. To provide a review of current clinical STAR practice in Europe, a comprehensive questionnaire was performed at project start. The STOPSTORM Institutions' experience in VT catheter ablation (83% ≥ 20 ann.) and stereotactic body radiotherapy (59% > 200 ann.) was adequate, and 84 STAR treatments were performed until project launch, while 8/22 centres already recruited VT patients in national clinical trials. The majority currently base their target definition on mapping during VT (96%) and/or pace mapping (75%), reduced voltage areas (63%), or late ventricular potentials (75%) during sinus rhythm. The majority currently apply a single-fraction dose of 25 Gy while planning techniques and dose prescription methods vary greatly. The current clinical STAR practice in the STOPSTORM consortium highlights potential areas of optimization and harmonization for substrate mapping, target delineation, motion management, dosimetry, and QA, which will be addressed in the various WPs.

Efficacy and Safety of Leadless Pacemaker Implantation in Octogenarians.

INTRODUCTION: Long-term complication rates in standard transvenous pacemakers are reported around 4-12% with a higher incidence in the elderly population. We report our experience in octogenarians undergoing leadless pacemaker implantation in two large-volume centers in Switzerland. METHODS: Consecutive patients undergoing leadless pacemaker implantation at two Swiss large volume centers (University Hospital Zurich, Zurich and Cardiocentro Ticino Institute, Lugano) between October 2015 and March 2020 were included in this retrospective analysis. Demographic information, clinical data, and procedural characteristics were recorded at the day of implantation and during follow-up. RESULTS: Two hundred and twenty patients (mean age 80.6 ± 7.7 years, male 66%) were included. The main indication for pacemaker implantation was slow ventricular rate atrial fibrillation (111 of 220 patients, 50.4%). Out of the 220 patients, 124 (56.3%) were ≥80 years. Overall successful implantation rate was 98.6%. In the octogenarian population, the median procedure time (45 ± 20.2 min vs. 40 ± 19.6 min, p = 0.03) and radiation duration (6.1 ± 8.2 min vs. 5.0 ± 7.2 min, p = 0.03) were longer compared to patients <80 years. Major complications (2.7%, n = 6) and device measurements during follow-up were similar between patients ≥80 and <80 years. CONCLUSION: Implantation of a leadless pacemaker device in octogenarians is safe and effective with a similarly low complication rate compared to non-octogenarians.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies.

Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca2+) is crucially important for proper cardiac function, and dysregulation of Ca2+ homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca2+ binding (HRC) protein, relevant for sarcoplasmic reticulum Ca2+ cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban (PLN) c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European-American population (control cohort, 40.3-42.2%) and the different cardiomyopathy cohorts (cohorts 1-3, 40.9-43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the HRC p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes.

Novel plasma biomarkers predicting biventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular involvement in ARVC may lead to heart failure. This study aimed to investigate the role of plasma biomarkers soluble (s)ST2, Galectin-3 (Gal-3) and GDF-15 in predicting biventricular involvement and adverse outcomes in ARVC. METHODS AND RESULTS: ARVC patients from 2 independent cohorts, were studied. The Bejing (Chinese) cohort (n = 108) was the discovery cohort, whereas the Zurich (Swiss) cohort (n = 47) served as validation. All patients had a definite ARVC diagnosis at time of blood withdrawal. Biomarkers were independently correlated with NT-proBNP and left ventricular (LV)-function. ARVC patients with LV involvement had higher levels of sST2 and GDF-15 as compared to controls and patients with isolated right ventricle (RV) involvement. sST2 and GDF-15 were significantly correlated with late gadolinium enhancement in CMR and with adverse heart failure outcomes. Gal-3 was elevated in ARVC patients with and without LV involvement. The combined use of the three biomarkers (sST2, GDF-15 and NT-proBNP) showed the best performance in predicting LV involvement in both cohorts. Plasma drawn from the coronary arteries and coronary sinus indicated a transmyocardial elevation of sST2, but no transmyocardial gradient of GDF-15. After heart transplantation, both sST2 and GDF-15 returned to near-normal levels. CONCLUSION: Our study showed that sST2 and GDF-15 may predict biventricular involvement in ARVC. The combined use of sST2, GDF-15 and NT-proBNP showed the best prediction of biventricular involvement in ARVC.

Sex differences and adherence of patients treated with wearable cardioverter-defibrillator: Insights from an international multicenter register.

AIMS: Treatment with the wearable cardioverter defibrillator (WCD) may protect against sudden cardiac death (SCD) as a bridging therapy until a cardioverter-defibrillator may be implanted. We analyzed in a multicenter setting a consecutive patient cohort wearing WCD to explore sex differences. METHODS AND RESULTS: We analyzed 708 consecutive patients, 579 (81.8%) from whom were males and 129 (18.2%) females (age, 60.5 ± 14 vs. 61.6 ± 17 years old; p = .44). While the rate of ischemic cardiomyopathy (ICM) as a cause of prescription of WCD was significantly higher in males as compared to females (42.7% vs. 26.4%; p = .001), females received it more frequently due to nonischemic cardiomyopathy (NICM) (55.8% vs. 42.7%); p = .009). The wear time of WCD was equivalent in both groups (21.1 ± 4.3 h/days in males vs. 21.5 ± 4.4 h/days in females; p = .27; and 62.6 ± 44.3 days in males vs. 56.5 ± 39 days in females; p = .15). Mortality was comparable in both groups at 2-year-follow-up (6.8% in males vs. 9.7% in females; p = .55). Appropriate WCD shocks and the incidence of ICD implantations were similar in both groups (2.4% in males vs. 3.9% in females; p = .07) (35.1% in males vs. 31.8% in females; p = .37), respectively. In age tertile analysis, compliance was observed more in 73-91 years old group as compared with 14-51 years old group (87.8% vs. 68.3%; p < .001). CONCLUSION: Compliance for wearing WCD was excellent regardless of sex. Furthermore, mortality and the incidence of ICD implantations were comparable in both sexes. Appropriate WCD shocks were similar in both sexes.

Preclinical short QT syndrome models: studying the phenotype and drug-screening.

Cardiovascular diseases are the main cause of sudden cardiac death (SCD) in developed and developing countries. Inherited cardiac channelopathies are linked to 5-10% of SCDs, mainly in the young. Short QT syndrome (SQTS) is a rare inherited channelopathy, which leads to both atrial and ventricular tachyarrhythmias, syncope, and even SCD. International European Society of Cardiology guidelines include as diagnostic criteria: (i) QTc ≤ 340 ms on electrocardiogram, (ii) QTc ≤ 360 ms plus one of the follwing, an affected short QT syndrome pathogenic gene mutation, or family history of SQTS, or aborted cardiac arrest, or family history of cardiac arrest in the young. However, further evaluation of the QTc ranges seems to be required, which might be possible by assembling large short QT cohorts and considering genetic screening of the newly described pathogenic mutations. Since the mechanisms underlying the arrhythmogenesis of SQTS is unclear, optimal therapy for SQTS is still lacking. The disease is rare, unclear genotype-phenotype correlations exist in a bevy of cases and the absence of an international short QT registry limit studies on the pathophysiological mechanisms of arrhythmogenesis and therapy of SQTS. This leads to the necessity of experimental models or platforms for studying SQTS. Here, we focus on reviewing preclinical SQTS models and platforms such as animal models, heterologous expression systems, human-induced pluripotent stem cell-derived cardiomyocyte models and computer models as well as three-dimensional engineered heart tissues. We discuss their usefulness for SQTS studies to examine genotype-phenotype associations, uncover disease mechanisms and test drugs. These models might be helpful for providing novel insights into the exact pathophysiological mechanisms of this channelopathy and may offer opportunities to improve the diagnosis and treatment of patients with SQT syndrome.

Leadless Pacemaker Implantation in the Emergency Bradyarrhythmia Setting: Results from a Multicenter European Registry.

Background. Data on leadless pacemaker (LPM) implantation in an emergency setting are currently lacking. Objective. We aimed to investigate the feasibility of LPM implantation for emergency bradyarrhythmia, in patients referred for urgent PM implantation, in a large, multicenter, real-world cohort of LPM recipients. Methods. Two cohorts of LPM patients, stratified according to the LPM implantation scenario (patients admitted from the emergency department (ED+) vs. elective patients (ED−)) were retrieved from the iLEAPER registry. The primary outcome of the study was a comparison of the peri-procedural complications between the groups. The rates of peri-procedural characteristics (overall procedural and fluoroscopic duration) were deemed secondary outcomes. Results. A total of 1154 patients were enrolled in this project, with patients implanted due to an urgent bradyarrhythmia (ED+) representing 6.2% of the entire cohort. Slow atrial fibrillation and complete + advanced atrioventricular blocks were more frequent in the ED+ cohort (76.3% for ED+ vs. 49.7% for ED−, p = 0.025; 37.5% vs. 27.3%, p = 0.027, respectively). The overall procedural times were longer in the ED+ cohort (60 (45−80) mins vs. 50 (40−65) mins, p < 0.001), showing higher rates of temporary pacing (94.4% for ED+ vs. 28.9% for ED−, p < 0.001). Emergency LPM implantation was not correlated with an increase in the rate of major complications compared to the control group (6.9% ED+ vs. 4.2% ED−, p = 0.244). Conclusion. LPM implantation is a feasible procedure for the treatment of severe bradyarrhythmia in an urgent setting. Urgent LPM implantation was not correlated with an increase in the rate of major complications compared to the control group, but it was associated with longer procedural times.

The genetic architecture of Plakophilin 2 cardiomyopathy.

PURPOSE: 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: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). 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: 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.

Left femoral venous access for leadless pacemaker implantation: patient characteristics and outcomes.

AIMS: Leadless pacing has become an alternative approach for patients requiring a single-chamber pacemaker. Conventionally, leadless Micra Transcatheter Pacing System (TPS) pacemakers are implanted via a right femoral venous access. However, due to various reasons, a left-sided femoral venous approach may be necessary. We hypothesized that a left-sided femoral venous approach is as safe and effective when compared with a right-sided approach. We assessed indications, procedural characteristics, safety and mid-term outcomes of Micra TPS implantation via a left femoral venous approach when compared with the conventional right-sided approach. METHODS AND RESULTS: In this retrospective single-centre analysis, 143 consecutive patients undergoing Micra TPS implantation were included. 87% (125/143) underwent Micra TPS implantation via a right, and 13% (18/143) via a left femoral venous access. The mean age at implantation was 79.8 ± 7.5 years. Acute procedural success, mean procedure and fluoroscopy times as well as device parameters at implantation and follow-up (mean 15 ± 11.5 months) were similar between the two groups. Five major complications (3.5%) were encountered, all using a right-sided approach. After a transfemoral TAVI procedure, left femoral venous access was used in 42% of cases when compared with 8% in the remaining population (P = 0.003). CONCLUSIONS: A left femoral venous access for Micra TPS implantation is safe and effective with an excellent implantation success rate similar to a conventional right femoral venous access without longer implantation and fluoroscopy times. The most frequent reason for choosing left vs. right femoral venous access was a previous transfemoral TAVI procedure.

An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins.

AIMS: Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. METHODS AND RESULTS: For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. CONCLUSION: A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Wearable Cardioverter-Defibrillator-Measured Step Count for the Surveillance of Physical Fitness during Cardiac Rehabilitation.

BACKGROUND: The wearable cardioverter-defibrillator (WCD) has a built-in accelerometer, which allows tracking of patients' physical activity by remote monitoring. It is unclear whether WCD-measured physical activity, step count, and heart rate correlate with established tools for the assessment of cardiopulmonary fitness such as the 6-min walk test (6MWT). OBJECTIVE: To correlate measurements of patient physical activity through the WCD with a supervised 6MWT during in-patient cardiac rehabilitation (CR) and to allow their use as surrogate parameters of cardiopulmonary fitness in an out-patient setting. METHODS: Consecutive patients with a history of WCD use treated at our center and an in-patient CR following an index hospitalization were included. Baseline characteristics, measurements of WCD accelerometer (median daily step count, median daily activity level), median daily heart rate, and clinically supervised 6MWT at admission and discharge of CR were obtained. RESULTS: Forty-one patients with a mean age of 55.5 (±11.5) years were included. Thirty-five patients (85.4%) were male and 28 patients (68%) had a primary prophylactic WCD-indication. The most common underlying heart diseases were ischemic heart disease (24 patients 58.6%) and dilated cardiomyopathy (13 patients, 31.7%). Median CR duration was 20 (IQR 19.75-26.25) days. 6MWT distance increased from a mean of 329 m (±107) to 470 m (±116) during CR (p < 0.0001). The median daily step count and activity level increased significantly, from 5542 steps (IQR 3718-7055) to 8778 (IQR 6229-12,920, p < 0.0001) and median 117 × 106 (IQR 96 × 106-142 × 106) threshold value exceedance (TVE) to 146 × 106 TVE (IQR 110 × 106-169 × 106, p < 0.0001), respectively. The median heart rate was 74.9 bpm (IQR 65.8-84.5) and 70.2 (IQR 64.1-77.3, p = 0.09) at admission and discharge, respectively. Of all three parameters, median daily step count showed the best correlation to the results of the 6MWT at admission and discharge (r = 0.32, p = 0.04 and 0.37, p = 0.02, respectively). CONCLUSIONS: Remote monitoring of median daily step count as assessed by the WCD's accelerometer showed positive correlation with the 6MWT and could serve as a surrogate for cardiopulmonary exercise capacity. Assessment of daily step count and activity level measured remotely by the WCD could help to tailor optimal exercise instruction for patients not attending CR.

Clinical predictors of left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

AIM: The impact of clinical characteristics for predicting patterns of ventricular involvement in arrhythmogenic right ventricular cardiomyopathy (ARVC) are not well defined. The aims of this study were to characterize different patterns of ventricular involvement in patients with ARVC and to stratify them based on clinical characteristics exercise and underlying genetic mutations. METHODS: Sixty-four patients with definite ARVC from the Swiss ARVC Registry were enrolled. Right and left ventricular functions were assessed at baseline and most recent follow-up. All patients received genetic testing. Serum high-sensitivity cardiac Troponin T (hs-cTNT) and N-terminal of pro-brain natriuretic peptide (NT-proBNP) were determined at baseline. RESULTS: Thirty-five patients (55%) had isolated right ventricular (RV) involvement, 12 patients (19%) had biventricular (BiV) involvement at baseline and 17 patients (26%) had no left ventricular (LV) involvement at baseline, but revealed new onset LV involvement at mean follow-up of 7.5 years. Patients with BiV involvement at baseline harbored significantly more desmoplakin and multiple mutations and patients with new-onset LV involvement at follow-up frequently showed non-desmosomal mutations. Patients engaging in competitive sports more often showed LV involvement during follow-up. Baseline hs-cTNT and NT-proBNP levels were higher in patients developing BiV involvement. CONCLUSION: Multiple mutations are more common in ARVC patients with BiV involvement. Competitive exercise is associated with disease progression resulting in BiV involvement. Hs-cTNT and NT-proBNP are elevated in patients with BiV involvement and may help to identify ARVC patients at risk for developing BiV disease.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).