Comprehensive vs. standard remote monitoring of cardiac resynchronization devices in heart failure patients: results of the ECOST-CRT study.

AIMS: Integrating remote monitoring (RM) into existing healthcare practice for heart failure (HF) patients to improve clinical outcome remains challenging. The ECOST-CRT study compared the clinical outcome of a comprehensive RM scheme including a patient questionnaire capturing signs and symptoms of HF and notifications for HF specific parameters to traditional RM in patients with cardiac resynchronization therapy (CRT) devices. METHODS AND RESULTS: Patients were randomized 1:1 to standard daily RM (notification for technical parameters and ventricular arrhythmias; control group) or comprehensive RM (adding a monthly symptom questionnaire and notifications for biventricular pacing, premature ventricular contraction, atrial arrhythmias; active group). The primary endpoint was all-cause mortality or hospitalization for worsening HF (WHF). Six hundred fifty-two patients (70.4 ± 10.3 years, 73% men, left ventricular ejection fraction 29.1 ± 7.6%, 68% CRT-Defibrillators, 32% CRT-Pacemakers) were enrolled. The COVID-19 pandemic caused an early termination of the study, so the mean follow-up duration was 18 ± 8 months. No statistically significant difference in the primary endpoint was found between the groups [59 (18.3%) control vs. 77 (23.3%) active group; log-rank test P = 0.13]. Among the secondary endpoints, the MLHF questionnaire showed a larger share of patients with improvement of quality of life compared to baseline in the active group (78%) vs. control (61%; P = 0.03). CONCLUSION: The study does not support the notion that comprehensive RM, when compared to standard RM, in HF patients with CRT improves the clinical outcome of all-cause mortality or WHF hospitalizations. However, this study was underpowered due to an early termination and further trials are required. REGISTRATION: Clinical Trials.gov Identifier: NCT03012490.

Sudden cardiac death after myocardial infarction: individual participant data from pooled cohorts.

BACKGROUND AND AIMS: Risk stratification of sudden cardiac death after myocardial infarction and prevention by defibrillator rely on left ventricular ejection fraction (LVEF). Improved risk stratification across the whole LVEF range is required for decision-making on defibrillator implantation. METHODS: The analysis pooled 20 data sets with 140 204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging. Separate analyses were performed in patients (i) carrying a primary prevention cardioverter-defibrillator with LVEF ≤ 35% [implantable cardioverter-defibrillator (ICD) patients], (ii) without cardioverter-defibrillator with LVEF ≤ 35% (non-ICD patients ≤ 35%), and (iii) without cardioverter-defibrillator with LVEF > 35% (non-ICD patients >35%). Primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy. Using a competing risk framework and systematic internal-external cross-validation, a model using LVEF only, a multivariable flexible parametric survival model, and a multivariable random forest survival model were developed and externally validated. Predictive performance was assessed by random effect meta-analysis. RESULTS: There were 1326 primary outcomes in 7543 ICD patients, 1193 in 25 058 non-ICD patients ≤35%, and 1567 in 107 603 non-ICD patients >35% during mean follow-up of 30.0, 46.5, and 57.6 months, respectively. In these three subgroups, LVEF poorly predicted sudden cardiac death (c-statistics between 0.50 and 0.56). Considering additional parameters did not improve calibration and discrimination, and model generalizability was poor. CONCLUSIONS: More accurate risk stratification for sudden cardiac death and identification of low-risk individuals with severely reduced LVEF or of high-risk individuals with preserved LVEF was not feasible, neither using LVEF nor using other predictors.

Long-term major events after hospital discharge for out-of-hospital cardiac arrest.

BACKGROUND: Cardiac arrest remains a global health issue with limited data on long-term outcomes, particularly regarding recurrent cardiovascular events in patients surviving out-of-hospital cardiac arrest. (OHCA). We aimed to describe the long-term occurrence of major cardiac event defined by hospital admission for cardiovascular events or death in OHCA hospital survivors, whichever came first. Our secondary objective were to assess separately occurrence of hospital admission and death, and to identify the factors associated with major event occurrence. We hypothesized that patients surviving an OHCA has a protracted increased risk of cardiovascular events, due to both presence of the baseline conditions that lead to OHCA, and to the cardiovascular consequences of OHCA induced acute ischemia-reperfusion. METHODS: Consecutive OHCA patients from three hospitals of Sudden Death Expertise Center (SDEC) Registry, discharged alive from 2011 to 2015 were included. Long-term follow-up data were obtained using national inter-regime health insurance information system (SNIIRAM) database and the national French death registry. The primary endpoint was occurrence of a major event defined by hospital admission for cardiovascular events and death, whichever came first during the follow-up. The starting point of the time-to-event analysis was the date of hospital discharge. The follow-up was censored on the date of the first event. For patients without event, follow-up was censored on the date of December, 29th, 2016. RESULTS: A total of 306 patients (mean age 57; 77% male) were analyzed and followed over a median follow-up of 3 years for hospital admission for cardiovascular event and 6 years for survival. During this period, 38% patients presented a major event. Hospital admission for cardiovascular events mostly occurred during the first year after the OHCA whereas death occurred more linearly during the all period. A previous history of chronic heart failure and coronary artery disease were independently associated with the occurrence of major event (HR 1.75, 95%CI[1.06-2.88] and HR 1.70, 95%CI[1.11-2.61], respectively), whereas post-resuscitation myocardial dysfunction, cardiogenic shock and cardiologic cause of cardiac arrest did not. CONCLUSION: Survivors from OHCA must to be considered at high risk of cardiovascular event occurrence whatever the etiology, mainly during the first year following the cardiac arrest and should require closed monitoring.

Prognostic value of ventricular arrhythmia in early post-infarction left ventricular dysfunction: the French nationwide WICD-MI study.

BACKGROUND AND AIMS: Prophylactic implantable cardioverter-defibrillators (ICDs) are not recommended until left ventricular ejection fraction (LVEF) has been reassessed 40 to 90 days after an acute myocardial infarction. In the current therapeutic era, the prognosis of sustained ventricular arrhythmias (VAs) occurring during this early post-infarction phase (i.e. within 3 months of hospital discharge) has not yet been specifically evaluated in post-myocardial infarction patients with impaired LVEF. Such was the aim of this retrospective study. METHODS: Data analysis was based on a nationwide registry of 1032 consecutive patients with LVEF ≤ 35% after acute myocardial infarction who were implanted with an ICD after being prescribed a wearable cardioverter-defibrillator (WCD) for a period of 3 months upon discharge from hospital after the index infarction. RESULTS: ICDs were implanted either because a sustained VA occurred while on WCD (VA+/WCD, n = 72) or because LVEF remained ≤35% at the end of the early post-infarction phase (VA-/WCD, n = 960). The median follow-up was 30.9 months. Sustained VAs occurred within 1 year after ICD implantation in 22.2% and 3.5% of VA+/WCD and VA-/WCD patients, respectively (P < .0001). The adjusted multivariable analysis showed that sustained VAs while on WCD independently predicted recurrence of sustained VAs at 1 year (adjusted hazard ratio [HR] 6.91; 95% confidence interval [CI] 3.73-12.81; P < .0001) and at the end of follow-up (adjusted HR 3.86; 95% CI 2.37-6.30; P < .0001) as well as 1-year mortality (adjusted HR 2.86; 95% CI 1.28-6.39; P = .012). CONCLUSIONS: In patients with LVEF ≤ 35%, sustained VA during the early post-infarction phase is predictive of recurrent sustained VAs and 1-year mortality.

Anticoagulation in device-detected atrial fibrillation with or without vascular disease: a combined analysis of the NOAH-AFNET 6 and ARTESiA trials.

BACKGROUND AND AIMS: The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation. METHODS: These pre-specified analyses of the NOAH-AFNET 6 (n=2534 patients) and ARTESiA (n=4012 patients) trials compared anticoagulation to no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death. RESULTS: In patients with vascular disease (NOAH-AFNET 6 56%, ARTESiA 46.0%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6 2.7%/patient-year, ARTESiA 2.3%/patient-year in both randomised groups). Meta-analysis found consistent results across both trials (I2heterogeneity=6%) with a trend for interaction with randomised therapy (pinteraction=0.08). Stroke/SE behaved similarly. Anticoagulation increased major bleeding in vascular disease patients (edoxaban 2.1%/patient-year, no anticoagulation 1.3%/patient-year; apixaban 1.7%/patient-year; no anticoagulation 1.1%/patient-year; incidence rate ratio 1.55 [1.10-2.20]) and without vascular disease (edoxaban 2.2%/patient-year; no anticoagulation 0.6%/patient-year; apixaban 1.4%/patient-year; no anticoagulation 1.1%/patient-year, incidence rate ratio 1.93 [0.72-5.20]). CONCLUSIONS: Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease.

Flecainide to Prevent Atrial Arrhythmia after Patent Foramen Ovale Closure, the AFLOAT Study: A Randomized Clinical Trial.

BACKGROUND: The real incidence of atrial arrhythmia (AA) after patent foramen ovale (PFO) closure and whether this complication can be prevented remain unknown. This study assessed if flecainide is effective to prevent AA during the first 3 months after PFO closure, and if 6 months treatment by flecainide is more effective than 3 months to prevent AA after PFO closure. METHODS: AFLOAT is a prospective, multicentre, randomized, open-label, superiority trial with a blind evaluation of all the endpoints (PROBE design). Patients were randomized in a 1:1:1 ratio after PFO closure to receive flecainide (150 mg once a day in a sustained-release (SR) dose) for 3 months, flecainide (150 mg od SR dose) for 6 months, or no additional treatment (standard-of-care) for 6 months. The primary endpoint was the percentage of patients with at least one episode AA (≥30s) recorded within 3 months after PFO closure on long-term monitoring with an insertable cardiac monitor (ICM). The secondary endpoint was the percentage of patients with at least one episode of AA (≥30s) recorded with ICM during the 3-6 months period after PFO closure. RESULTS: 186 patients were included (mean age 54 years, male 68.8%) and AA (≥30s) occurred in 53 (28.5%) patients during the 6-month follow-up; 86.8% of these AA events occurred in the first month after PFO closure. The primary outcome occurred in 33/123 (26.8%) and 16/63 (25.4%) patients receiving flecainide for at least 3 months or standard of care, respectively [Risk Difference (RD) 1.4%; 95% confidence interval (CI) -12.9% to 13.8%, NS]. The secondary endpoint occurred in 3/60 (5.0%), 4/63 (6.3%), and 5/63 (7.9%) patients receiving flecainide 6 months, 3 months or standard of care, respectively [RD -2.9%; 95% CI -12.7% to 6.9%, and RD -1.6%; 95% CI -11.8% to 8.6%, respectively]. CONCLUSIONS: In the first 6 months following successful PFO closure, AA (≥30s) occurred in 28.5% of cases, mostly in the first month after the procedure. Flecainide did not prevent AA after PFO closure.

Local anaesthetic to reduce injection pain in patients who are prescribed intramuscular benzathine penicillin G: a systematic review and meta-analysis.

Background: Three to 4-weekly intramuscular injections of benzathine penicillin G (BPG) for a prolonged period (e.g., 10 years, until age 40 years, or lifelong) are recommended for preventing group A streptococcal infections that cause recurrent acute rheumatic fever (ARF) and potential progression to rheumatic heart disease (RHD). The duration of treatment, frequency and local pain associated with BPG injections may lead to reduced compliance. Shorter courses of BPG are recommended for the treatment of syphilis and Streptococcal infections. We aimed to assess the effects of local anaesthesia in reducing injection pain in patients who are being treated with BPG. Methods: In this systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Conference Proceedings Citation Index-Science and LILACS from database inception up to May 4, 2024, and performed additional searches for grey literature. Randomised controlled trials comparing BPG vs. BPG administered alongside local anaesthetics were included. Randomized controlled trials using BPG, irrespectively of indication, and testing any local anaesthetic agent for pain alleviation were considered eligible. We applied GRADE to assess the quality of evidence. Summary data were extracted from included trials. The primary outcome was injection pain, assessed through mean differences. A random-effects model was utilized to account for study heterogeneity. This study is registered with PROSPERO, CRD42022342437. Findings: Database searches identified a total of 3958 records, and 3 additional records were retrieved from grey literature searches. After removal of duplicates, screening of abstracts and full-text review, eight trials were included, combining a total of 489 patients (151 patients with RHD). Immediate pain level, as reported by patients, was of high intensity in most studies. Low intensity pain was still reported at 24 h. Administration of lidocaine mixed with BPG was associated with a significant reduction in immediate post-injection pain (mean difference -3.84, 95% confidence interval -6.19 to -1.48, P = 0.0001; 4 studies; I2 = 98%; GRADE: moderate quality), pain at 5 min (mean difference -2.85, 95% CI confidence interval -3.78 to -1.92, P < 0.0001; 1 study; GRADE: moderate quality), and pain at 20 min (mean difference -1.85, 95% confidence interval -2.61 to -1.09, P < 0.0001; 1 study; GRADE: moderate quality) on a 1 to 10 scale. One study assessed lidocaine cream applied to the skin prior to BPG injection and showed no significant reduction in injection pain (mean difference = -0.54, 95% CI confidence interval -1.17 to 0.09, P = 0.13; 1 study; GRADE: low quality). Mepivacaine mixed with BPG in patients with syphilis showed a significant reduction of immediate post-injection pain (mean difference -2.19, 95% CI confidence interval -2.49 to -1.89, P < 0.0001; 1 study; GRADE: moderate quality). Two studies assessed procaine mixed with BPG and reported: lower immediate pain levels or pain assessed at 1 h (mean difference and 95% CI confidence intervals not provided, P = 0.001 and P = 0.008, respectively; 1 study; GRADE: low quality), or less immediate pain and pain at 24 h on the buttock injected with procaine mixed with BPG (mean difference and 95% CI confidence intervals not provided, P < 0.001 for both; 1 study; Grade: low quality). No severe adverse reactions were reported. Interpretation: In patients receiving intramuscular BPG injections, moderate quality quantitative evidence suggests that BPG injections diluted with lidocaine or mepivacaine may improve post-injection pain scores compared to BPG injections diluted with sterile water. Procaine may also have a benefit, but quality of evidence was lower. Most studies included small patient samples and assessed pain levels at different timepoints. Due to insufficient data we were not able to assess the impact of injection volume, and local anaesthetics' dose on pain intensity and duration of pain relief. Funding: WHO.

Long-term antibiotic prophylaxis for prevention of rheumatic fever recurrence and progression to rheumatic heart disease.

BACKGROUND: Rheumatic fever is a non-suppurative, inflammatory sequela of group A Streptococcus pharyngitis that can occur at two to four weeks after infection. Following an episode of rheumatic fever, there is a risk of developing rheumatic heart disease (RHD) later in life that carries significant risk of morbidity and mortality. RHD remains the largest global cause of cardiovascular disease in the young (age < 25 years). The historical literature provides inconclusive evidence that antibiotic prophylaxis is beneficial in reducing the risk of recurrence of rheumatic fever and development of RHD. Antibiotics are thought to work by reducing the carriage of group A Streptococcus and thus reducing the risk of infection. This review was commissioned by the World Health Organization (WHO) for an upcoming guideline. OBJECTIVES: 1. To assess the effects of long-term antibiotics versus no antibiotics (control) for secondary prevention of rheumatic fever recurrence and associated sequelae in people with previous rheumatic fever or RHD. 2. To assess the effects of long-term intramuscular penicillin versus long-term oral antibiotics for secondary prevention of rheumatic fever recurrence and associated sequelae in people with previous rheumatic fever or RHD. SEARCH METHODS: We systematically searched CENTRAL, MEDLINE, Embase, Conference Proceedings Citation Index-Science, clinical trial registers, ISRCTN.com and reference lists without restrictions on language or date up to 10 March 2024. SELECTION CRITERIA: We sought randomised controlled trials or quasi-randomised trials, described in any language, including participants with previous rheumatic fever and/or RHD of any age, based in community or hospital settings. Studies were included if they compared firstly antibiotic prophylaxis with no antibiotic prophylaxis, and, secondly, intramuscular penicillin prophylaxis versus oral antibiotic prophylaxis. DATA COLLECTION AND ANALYSIS: We used standardised methodological, Cochrane-endorsed procedures and performed meta-analyses with risk ratios (RR) and Peto odds ratios (Peto OR). Our primary outcomes were recurrence of rheumatic fever, progression or severity of RHD and cardiac complications. Our secondary outcomes were obstetric complications (maternal and foetal events), mortality, treatment adherence, adverse events and acceptability to participants. We performed comprehensive assessments of risk of bias and certainty of evidence, applying the GRADE methodology. MAIN RESULTS: We included 11 studies (seven RCTs and four quasi-randomised trials) including 3951 participants. The majority of the included studies were conducted in the USA, UK and Canada during the 1950s to 1960s. Most participants with previous rheumatic fever had been diagnosed using the modified Jones criteria (mJC) (four studies), were an average of 12.3 years of age and 50.6% male. We assessed the majority of the included studies to be at high risk of bias, predominantly relating to blinding and attrition bias. Comparison one: antibiotics versus no antibiotics Pooled meta-analysis of six RCTs provides moderate-certainty evidence that antibiotics overall (oral or intramuscular) probably reduce the risk of recurrence of rheumatic fever substantially (0.7% versus 1.7%, respectively) (risk ratio (RR) 0.39, 95% confidence interval (CI) 0.22 to 0.69; 1721 participants). People with early or mild RHD likely have the greatest capacity to benefit from intramuscular antibiotic prophylaxis (8.1%) compared to no antibiotics (0.7%) (RR 0.09, 95% CI 0.03 to 0.29; 1 study, 818 participants; moderate-certainty evidence). Antibiotics may not affect mortality in people with late-stage RHD (RR 1.23, 95% CI 0.78 to 1.94; 1 study, 994 participants; low-certainty evidence). Antibiotics may not affect the risk of anaphylaxis (Peto odds ratio (OR) 7.39, 95% CI 0.15 to 372; 1 study, 818 participants; low-certainty evidence) or sciatic nerve injury (Peto OR 7.39, 95% CI 0.15 to 372; 1 study, 818 participants; low-certainty evidence) compared with no antibiotics, but probably have an increased risk of hypersensitivity reactions (RR 137, 8.51 to 2210; 2 studies, 894 participants; moderate-certainty evidence) and local reactions (RR 29, 1.74 to 485; 1 study, 818 participants; moderate-certainty evidence). Comparison two: intramuscular antibiotics versus oral antibiotics Pooled analysis of two RCTs showed that prophylactic intramuscular benzathine benzylpenicillin likely reduces recurrence of rheumatic fever substantially when compared to oral antibiotics (0.1% versus 1%, respectively) (RR 0.07, 95% CI 0.02 to 0.26; 395 participants; moderate-certainty evidence). Furthermore, it is unclear whether intramuscular benzyl penicillin is superior to oral antibiotics in reducing the risk of mortality in the context of RHD (Peto OR 0.22, 95% CI 0.01 to 4.12; 1 study, 431 participants; very low-certainty evidence). There were no data available on progression of latent RHD or adverse events including anaphylaxis, sciatic nerve injury, delayed hypersensitivity/allergic reactions and local reactions to injection. AUTHORS' CONCLUSIONS: This review provides evidence that antibiotic prophylaxis likely reduces the risk of recurrence of rheumatic fever compared to no antibiotics, and that intramuscular benzathine benzylpenicillin is probably superior to oral antibiotics (approximately 10 times better). Moreover, intramuscular benzathine benzylpenicillin likely reduces the risk of progression of latent RHD. Evidence is scarce, but antibiotics compared with no antibiotics may not affect the risk of anaphylaxis or sciatic nerve injury, but probably carry an increased risk of hypersensitivity reactions and local reactions. Antibiotics may not affect all-cause mortality in late-stage RHD compared to no antibiotics. There is no evidence available to comment on the effect of intramuscular penicillin over oral antibiotics for progression of latent RHD and adverse events, and little evidence for all-cause mortality. It is important to interpret these findings in the context of major limitations, including the following: the vast majority of the included studies were conducted more than 50 years ago, many before contemporary echocardiographic studies; methodology was often at high risk of bias; outdated treatments were used; only one study was in latent RHD; and there are concerns regarding generalisability to low socioeconomic regions. This underlines the need for ongoing research to understand who benefits most from prophylaxis.

Anticoagulation in Patients With Device-Detected Atrial Fibrillation With and Without a Prior Stroke or Transient Ischemic Attack: The NOAH-AFNET 6 Trial.

BACKGROUND: Short and rare episodes of atrial fibrillation (AF) are commonly detected using implanted devices (device-detected AF) in patients with prior stroke or transient ischemic attack (TIA). The effectiveness and safety of oral anticoagulation in patients with prior stroke or TIA and device-detected AF but with no ECG-documented AF is unclear. METHODS AND RESULTS: This prespecified analysis of the NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) trial with post hoc elements assessed the effect of oral anticoagulation in patients with device-detected AF with and without a prior stroke or TIA in the randomized, double-blind, double-dummy NOAH-AFNET 6 trial. Outcomes were stroke, systemic embolism, and cardiovascular death (primary outcome) and major bleeding and death (safety outcome). A prior stroke or TIA was found in 253 patients with device-detected AF randomized in the NOAH-AFNET 6 (mean age, 78 years; 36.4% women). There was no treatment interaction with prior stroke or TIA for any of the primary and secondary time-to-event outcomes. In patients with a prior stroke or TIA, 14 out of 122 patients experienced a primary outcome event with anticoagulation (5.7% per patient-year). Without anticoagulation, there were 16 out of 131 patients with an event (6.3% per patient-year). The rate of stroke was lower than expected (anticoagulation: 4 out of 122 [1.6% per patient-year]; no anticoagulation: 6 out of 131 [2.3% per patient-year]). Numerically, there were more major bleeding events with anticoagulation in patients with prior stroke or TIA (8 out of 122 patients) than without anticoagulation (2 out of 131 patients). CONCLUSIONS: Anticoagulation appears to have ambiguous effects in patients with device-detected AF and a prior stroke or TIA in this hypothesis-generating analysis of the NOAH-AFNET 6 in the absence of ECG-documented AF, partially due to a low rate of stroke without anticoagulation.

Association between change in heart rate over years and life span in the Paris Prospective 1, the Whitehall 1, and Framingham studies.

Heart rate, a measure of the frequency of the cardiac cycle, reflects the health of the cardiovascular system, metabolic rate, and activity of the autonomic nervous system. Whether changes in resting heart rate are related to lifespan has not yet been explored to our best knowledge. In this study, we examined the association between resting heart rate and lifespan using linear regression in the Paris Prospective Study I, the Whitehall I Study, and the Framingham Heart Study. We used Cox proportional hazards regression to relate changes in heart rate over years to mortality risk. We observed a statistically significant association between increases in resting heart rate over a 5-year period and risk of mortality in the Paris Prospective Study I (HR mortality per 10 bpm increase over time: 1.20; 95% CI: 1.13 to 1.27) and over an 8-year period in the Framingham Heart Study (HR: 1.13; 95% CI: 1.07 to 1.19 for men and HR: 1.09; 95% CI: 1.04 to 1.15 for women), after adjusting for classical risk factors and resting heart rate. Our study shows that men and women who increase their resting heart rate over time increase their risk of mortality.

Systematic analysis of SCN5A variants associated with inherited cardiac diseases.

BACKGROUND: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial. OBJECTIVE: We aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. METHODS: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. RESULTS: The study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link. CONCLUSION: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable.

Distinct Substrates of Idiopathic Ventricular Fibrillation Revealed by Arrhythmia Characteristics on Implantable Cardioverter-Defibrillator.

BACKGROUND: Idiopathic ventricular fibrillation (IVF) can be associated with undetected distinct conditions such as microstructural cardiomyopathic alterations (MiCM) or Purkinje (Purk) activities with structurally normal hearts. OBJECTIVES: This study sought to evaluate the characteristics of recurrent VF recorded on implantable defibrillator electrograms, associated with these substrates. METHODS: This was a multicenter collaboration study. At 32 centers, we selected patients with an initial diagnosis of IVF and recurrent arrhythmia at follow-up without antiarrhythmic drugs, in whom mapping demonstrated Purk or MiCM substrate. We analyzed variables related to previous ectopy, sinus rate preceding VF, trigger, and initial VF cycle lengths. Logistic regression with cross validation was used to evaluate the performance of criteria to discriminate Purk or MiCM substrates. RESULTS: Among 95 patients (35 women, age 35 ± 11 years) meeting the inclusion criteria, IVF was associated with MiCM in 41 and Purk in 54 patients. A total of 117 arrhythmia recurrences including 91% VF were recorded on defibrillator. Three variables were mostly discriminant. Sinus tachycardia (≤570 ms) was more frequent in MiCM (35.9% vs 13.4%, P = 0.014) whereas short-coupled (<350 ms) triggers were most frequent in Purk-related VF (95.5% vs 23.1%, P = 0.001), which also had shorter VFCLs (182 ± 15 ms vs 215 ± 24 ms, P < 0.001).The multivariable combination provided the highest prediction (accuracy = 0.93 ± 0.05, range 0.833-1.000), discriminating 81% of IVF substrates with a high probability (>80%). Ectopy were inconsistently present before VF. CONCLUSIONS: Characteristics of arrhythmia recurrences on implantable cardioverter- defibrillator provide phenotypic markers of the distinct and hidden substrates underlying IVF. These findings have significant clinical and genetic implications.

Sudden cardiac arrest in patients with cancer in the general population: insights from the Paris-SDEC registry.

BACKGROUND: Data on the management of patients with cancer presenting with sudden cardiac arrest (SCA) are scarce. We aimed to assess the characteristics and outcomes of SCA according to cancer history. METHODS: Prospective, population-based registry including every out-of-hospital SCA in adults in Paris and its suburbs, between 2011 and 2019, with a specific focus on patients with cancer. RESULTS: Out of 4069 patients who had SCA admitted alive in hospital, 207 (5.1%) had current or past medical history of cancer. Patients with cancer were older (69.2 vs 59.3 years old, p<0.001), more often women (37.2% vs 28.0%, p=0.006) with more frequent underlying cardiovascular disease (41.1% vs 32.5%, p=0.01). SCA happened more often with a non-shockable rhythm (62.6% vs 43.1%, p<0.001) with no significant difference regarding witness presence and cardiopulmonary resuscitation (CPR) performed. Cardiac causes were less frequent among patients with cancer (mostly acute coronary syndromes, 25.5% vs 46.8%, p<0.001) and had more respiratory causes (pulmonary embolism and hypoxaemia in 34.2% vs 10.8%, p<0.001). Still, no difference regarding in-hospital survival was found after SCA in patients with cancer versus other patients (26.2% vs 29.8%, respectively, p=0.27). Public location, CPR by witness and shockable rhythm were independent predictors of in-hospital survival after SCA in the cancer group. CONCLUSIONS: One in 20 SCA occurs in patients with a history of cancer, yet with fewer cardiac causes than in patients who are cancer-free. Still, in-hospital outcomes remain similar even in patients with known cancer. Cancer history should therefore not compromise the initiation of resuscitation in the context of SCA.

A leadless ventricular pacemaker providing atrioventricular synchronous pacing in the real-world setting: 12-Month results from the Micra AV post-approval registry.

BACKGROUND: Advances in leadless pacemaker technology have enabled accelerometer-based atrioventricular (AV) synchronous pacing by sensing atrial mechanical contraction. OBJECTIVE: The purpose of this study was to report the performance of the Micra AV leadless pacemaker from the worldwide Micra AV post-approval registry (PAR) through 12 months. METHODS: The Micra AV PAR is a prospective, single-arm, observational registry designed to assess the safety and effectiveness of Micra AV in a real-world setting. For the present interim analysis, major complications and system revisions through 12 months were summarized and compared to a historical cohort of 2667 patients implanted with a transvenous dual-chamber pacing system. RESULTS: The device was successfully implanted in 796 of 801 patients (99.4%) at 97 centers in 19 countries. Micra AV patients were older (74.1 years vs 71.1 years; P < .0001) with a higher incidence of renal disease (22.3% vs 9.8%; P < .0001) compared with transvenous dual-chamber patients. Through 12 months, the major complication rate was 3.7% in Micra AV patients compared with 8.8% in transvenous dual-chamber patients (hazard ratio 0.42; 95% confidence interval 0.28-0.61; P < .001). The system revision rate was 1.5% in Micra AV patients compared with 5.5% for transvenous dual-chamber patients (hazard ratio 0.25; 95% confidence interval 0.13-0.47; P < .001); this reduction was largely driven by the absence of lead dislodgments requiring revision. The median AV synchrony index was 79.4% (interquartile range 65.2%-86.4%) in patients paced >90%. CONCLUSION: The Micra AV leadless pacemaker was implanted with a high rate of success in patients with multiple comorbidities, with a significantly lower rate of complications and system revisions through 12 months compared to a historical cohort of patients with transvenous dual-chamber pacemakers.

HIV status and lay bystander cardiopulmonary resuscitation initiation for witnessed cardiac arrest.

INTRODUCTION: Early initiation of cardiopulmonary resuscitation (CPR) by bystanders of out-of-hospital cardiac arrest (OHCA) significantly improves survival and neurological outcomes. However, misconceptions about human immunodeficiency virus (HIV) transmission risk during CPR can deter lay bystanders from performing resuscitation. The aim of this study was to compare the rate of CPR initiation by lay bystanders who witnessed OHCA in subjects with and without HIV infection. METHODS: We analysed data from the two French cardiac arrest registries (SDEC and RéAC) from 2012 to 2020. We identified HIV-positive individuals from the French National Health Insurance database for the SDEC registry, and directly from the RéAC registry data. We used logistic regression models to assess the association between CPR initiation by lay bystanders and the victim's HIV status. RESULTS: Of 58,177 witnessed OHCA cases, 192 (0.3%) occurred in HIV-positive subjects. These individuals were younger, more often male, and presented more shockable initial rhythms compared with subjects without HIV. Overall, there was no difference in the CPR initiation rate according to the HIV status (57.3% vs 47.6%, adjusted odds ratio 1.11, 95% confidence interval 0.83-1.48). The CPR initiation rate also did not differ by location between victims with or without HIV (home: 57.7% vs 45.4%; public places: 56.0% vs 53.6%; p for interaction = 0.46). Survival and neurological outcomes at hospital discharge did not differ based on the HIV status. CONCLUSIONS: This study revealed that the rate of CPR initiation by lay bystanders did not differ between HIV and non-HIV subjects during OHCA.

Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce cardiovascular toxicities. OBJECTIVES: To prospectively assess the incidence of major cardiovascular events (MACE) on ICIs in solid cancer patients: myocarditis, pericarditis, acute coronary syndrome, heart failure, high-degree conduction abnormalities or sustained ventricular arrhythmias, or cardiovascular death at 6 weeks (early MACE), including asymptomatic clinical changes by an independent adjudication committee using current recommended diagnostic criteria. The secondary objective was the incidence of the above-mentioned events adding atrial fibrillation (AF) at 6 months (late MACE). RESULTS: Participants underwent pre-ICIs and repeated multimodality cardiac imaging (echocardiogram, cardiac magnetic resonance (CMR)), serum biomarkers (ultrasensitive troponin I), and rhythm surveillance (ambulatory ECG monitoring) at 6 weeks and 6 months. Forty-nine patients (38 (77.6%) male; mean age 64.3 (SD 11.0) years old) were included (June 2020-December 2021). Early MACE were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias, or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P = 0.035) predicted early MACE. At 6 months follow-up, 18 MACE were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias, or conduction disorders, and 4 (8.2%) AF. There was a significant decline in LVEF (P < 0.001) in patients with no MACE (P = 0.003) or HF (P = 0.0028). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P = 0.006) predicted HF on multivariate analysis. There were no significant T1 or T2 mapping changes in our study cohort on repeated CMR. CONCLUSIONS: Cardiotoxicity on ICIs is more frequent than previously described when using a thorough detection strategy, consisting mainly in HF and asymptomatic rhythm disorders.