Probst, Vincent

Introduction: Device-related infection is estimated to occur in 1.9% of the Medicare patients with de novo transvenous (TV) implantable cardioverter-defibrillators (ICD) within 2 years post-implant. TV-ICD infection is a serious complication that frequently requires complete device removal for attempted cure, which can be associated with patient morbidity and mortality. The objective of this study is to expand on limited published data and assess mortality risk associated with TV-ICD infection in a large Medicare population with de novo TV-ICD implants. Methods: A survival analysis was conducted using 100% fee-for-service Medicare facility-level claims data to identify patients who underwent de novo TV-ICD implantation between 7/2016 and 1/2018. TV-ICD infection within 2 years of implantation was identified using ICD-10 and CPT codes. Baseline patient risk factors associated with mortality were identified using the Charlson Comorbidity Index categories. Infection was treated as a time-dependent variable in a multivariate Cox proportional hazards model to account for immortal time bias. Results: Among 26,742 Medicare patients with de novo TV-ICD, 518 (1.9%) had a device-related infection. The overall number of decedents was 4,721 (17.7%) over 2 years, with 4,555 (17%) in the non-infection group and 166 (32%) in the infection group. After adjusting for baseline patient demographic characteristics and various comorbidities, the presence of TV-ICD infection was associated with an increase of 2.4 [95% CI: 2.08-2.85] times in the mortality hazard ratio (see attached Figure). Most of the baseline patient risk factors were also associated with higher risk of mortality in the Cox model. Conclusion: The rate of de novo TV-ICD infection and associated mortality in a large, real-world Medicare population is noteworthy. The positive association between device-related infection and risk of mortality further highlights the need to reduce infections.

Abstract Aims Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. Methods and results We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. Conclusion We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

AbstractIntroductionTransvenous implantable cardioverter‐defibrillators (TV‐ICD) infection is a serious complication that frequently requires complete device removal for attempted cure, which can be associated with patient morbidity and mortality. The objective of this study is to assess mortality risk associated with TV‐ICD infection in a large Medicare population with de novo TV‐ICD implants.MethodsA survival analysis was conducted using 100% fee‐for‐service Medicare facility‐level claims data to identify patients who underwent de novo TV‐ICD implantation between 7/2016 and 1/2018. TV‐ICD infection within 2 years of implantation was identified using International Classification of Disease, 10th Edition and current procedural terminology codes. Baseline patient risk factors associated with mortality were identified using the Charlson Comorbidity Index categories. Infection was treated as a time‐dependent variable in a multivariate Cox proportional hazards model to account for immortal time bias.ResultsAmong 26,742 Medicare patients with de novo TV‐ICD, 518 (1.9%) had a device‐related infection. The overall number of decedents was 4721 (17.7%) over 2 years, with 4555 (17%) in the noninfection group and 166 (32%) in the infection group. After adjusting for baseline patient demographic characteristics and various comorbidities, the presence of TV‐ICD infection was associated with an increase of 2.4 (95% CI: 2.08–2.85) times in the mortality hazard ratio.ConclusionThe rate of TV‐ICD infection and associated mortality in a large, real‐world Medicare population is noteworthy. The positive association between device‐related infection and risk of mortality further highlights the need to reduce infections

Background: Infection remains a major complication of cardiac implantable electronic devices (CIEDs) and can lead to significant morbidity and mortality. Extrathoracic devices that avoid epicardial or transvenous leads, such as the subcutaneous implantable cardioverter-defibrillator (S-ICD), can reduce the risk of serious infection-related complications, such as bloodstream infection and infective endocarditis. While the 2017 AHA/ACC/HRS guidelines include recommendations for S-ICD use for patients at high risk of infection, currently, there are no clinical trial data that address best practices for the prevention of S-ICD infections. Therefore, an expert panel was convened to develop consensus on these topics. Methods: An expert process mapping methodology was used to achieve consensus on the appropriate steps to minimize or prevent S-ICD infections. Two face-to-face meetings of high-volume S-ICD implanters and an infectious diseases specialist, with expertise on cardiovascular implantable electronic device infections, were conducted to develop consensus on useful strategies pre-, peri-, and post-implant to reduce S-ICD infection risk. Results: Expert panel consensus of recommended steps for patient preparation, S-ICD implantation, and post-operative management were developed to provide guidance in individual patient management. Conclusion: Achieving expert panel consensus by process mapping methodology for S-ICD infection prevention was attainable, and the results should be helpful to clinicians in adopting interventions to minimize risks of S-ICD infection.

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT. Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]). Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

Introduction: Practice guidelines recommend use of subcutaneous implantable cardioverter-defibrillators (ICD) in patients (pts) at risk of sudden cardiac death and high risk for infection. This has prompted a need to better identify pts at high risk of infection to assist in de novo device selection. The objective of this study is to estimate infection incidence in de novo transvenous (TV) ICD implants and assess risk factors associated with infection in a large Medicare population. Methods: A retrospective cohort study was conducted using 100% Medicare administrative and claims data to identify pts who underwent de novo TV-ICD implantation between 7/2016 and 1/2018. Device-related infection within 2 years of implantation was identified using ICD-10 diagnosis and procedure codes. Baseline pt factors associated with infection were identified by univariable logistic regression analysis of all variables of interest, including factors in Charlson and Elixhauser comorbidity indices, followed by stepwise selection criteria with a p≤0.25 for inclusion in a multivariable model and a backwards, stepwise elimination process with p≤0.1 to remain in the model. A time-to-event analysis was also conducted. Results: Among 26,742 pts with de novo TV-ICD, 519 (1.9%) had a device-related infection over 2 years. The mean pt age with and without infection was 68 and 71 years, respectively. While more than half (54%) of infections occurred within 90 days post implant, infections continued to be diagnosed with 16% of infections occurring between years 1 and 2. Multivariable analysis revealed several significant predictors of infection (Figure) including age <70 years, end stage renal disease with chronic dialysis and diabetes with complications. Conclusion: The rate of de novo TV-ICD infection in a large real-world Medicare population is clinically significant. The factors associated with increased infection risk identified here can be used to help determine device selection.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. Methods: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2 -positive probands, and clinical evaluation was performed. Results: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2 -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). Conclusions: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2 -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

Abstract Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for malignant ventricular arrhythmias during exercise and emotions which may lead to sudden cardiac death. Beta-blockers (BB) are the mainstay of therapy in patients with CPVT, but studies comparing the efficacy of different types of BB are scarce. Our objective was to determine the efficacy of different types of BB in reducing the ventricular arrhythmia (VA) severity on exercise stress test (EST) in patients with CPVT. Data was derived from the International CPVT Registry, a large retrospective cohort study. We included patients who had an EST before (pre-EST) and after start of BB (post-EST). We divided the cohort into five groups based on the first prescribed BB and compared pre-EST and post-EST. We included 428 patients (median age 18.5 [11.7–39.6] years, 240 (56.%) female), 155 (36.2%) probands) of whom 38 (8.9%) used atenolol, 131 (30.6%) bisoprolol, 82 (19.2%) metoprolol, 124 (29.0%) nadolol and 53 (12.4%) propranolol. Sex and history of aborted cardiac arrest were similar in all groups. The age at start of BB differed (p&lt;0,001): patients using bisoprolol were oldest (35.0 [15.7–35.3]) while patients using propranolol were youngest (12.3 [8.8–24.9]). Median daily BB dose in mg/kg was: 1.0 [0.8–2.3] for atenolol, 0.06 [0.05–0.10] for bisoprolol, 0.9 [0.6–1.5] for metoprolol, 1.1 [0.9–1.6] for nadolol and 1.5 [1.1–2.8] for propranolol. Resting heart rate on pre-EST and post-EST was similar in all groups. Patients using metoprolol had a significantly higher maximum heart rate post-EST compared to nadolol and propranolol (161±18 vs 136±19 and 130±22 bpm, p=0,002 and p=0,001, respectively). The VA severity decreased significantly after BB (147 (37.9%) (non-sustained) ventricular tachycardia ((NS)VT) and 120 (30.9%) no or isolated ventricular premature beat (iVPB) pre-EST vs 46 (11.4%) (NS)VT and 184 (45.7%) iVPB post-EST, p&lt;0,001). Examining the different groups, the VA severity decreased significantly after BB in all but atenolol (13 (40.6%) (NS)VT and 8 (25.0%) iVPB pre-EST vs 9 (25.0%) (NS)VT and 15 (41.7%) iVPB post-EST, p=0,103). Based on these results we conclude that all beta-blockers except atenolol are effective in reducing the VA severity on EST in patients with CPVT. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): E-Rare Joint Transnational Call for Proposals 2015 “Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science”

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P =0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

AbstractThis international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.