Li N, Webb A, Kennelly J
… +6 more, Sharma R, Whitson BA, Mohler PJ, Hummel JD, Zhao J, Fedorov VV
Circ Arrhythm Electrophysiol
· 2025 May · PMID 40265247
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BACKGROUND: Despite over a century of clinical electrocardiographic studies showing that women exhibit a faster resting heart rate (HR), the mechanisms underlying sex differences in HR remain unresolved. Moreover, inappr...BACKGROUND: Despite over a century of clinical electrocardiographic studies showing that women exhibit a faster resting heart rate (HR), the mechanisms underlying sex differences in HR remain unresolved. Moreover, inappropriate sinus tachycardia primarily affects women, whereas men are at a higher risk for conduction block and atrial fibrillation. We hypothesized that the sexual dimorphism of genes responsible for sinoatrial node (SAN) pacemaking and signaling pathways may contribute to the sex differences in HR and susceptibility to arrhythmias. METHODS: Human SAN central pacemaker and right atrial tissue were isolated from nondiseased ex vivo donor hearts. Gene expressions were quantified and validated using the transcriptomic panel and quantitative polymerase chain reaction. Gene set enrichment analysis, Ingenuity Pathway Analysis, and human-specific SAN models were utilized to define regulatory mechanisms and functional impacts of sex-biased gene transcription. RESULTS: We identified differentially expressed region- and sex-specific genes, with gene sets enriched in HR regulation (eg, , ) and metabolism (eg, , ) pathways in female SAN. In contrast, differential genes and gene sets involved in collagen biosynthetic processes, fibrogenesis (eg, ), and immune response (eg, , ) pathways were enriched in males SAN and right atrial. Ingenuity Pathway Analysis predicted significant roles for and estradiol in the sex-specific expression of genes involved in SAN function. Computational simulations showed that the sex-specific SAN differences in I (pacemaker current; ) and I(L-type calcium current; ) can explain the faster HR in female SAN, with female SAN having a lower threshold for inappropriate sinus tachycardia, whereas male SAN are more vulnerable to sinus arrest. CONCLUSIONS: The human SAN exhibits region-specific sexual dimorphism in pacemaking gene sets. Higher expression of and in female SAN may underlie faster HR and increased susceptibility to inappropriate sinus tachycardia in women, whereas enriched gene sets related to inflammation and collagen biosynthesis in men may predispose them to conduction impairments and atrial fibrillation risk.
Ostini A, Kléber AG, Rudy Y
… +2 more, Saffitz JE, Kucera JP
Circ Arrhythm Electrophysiol
· 2025 May · PMID 40201954
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BACKGROUND: Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in , the gene for the desmosomal protein plakophilin-2, are being enrolled in gene therapy trials designed to replace the defective allel...BACKGROUND: Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in , the gene for the desmosomal protein plakophilin-2, are being enrolled in gene therapy trials designed to replace the defective allele via adeno-associated viral transduction of cardiac myocytes. Evidence from experimental systems and patients indicates that ventricular myocytes in arrhythmogenic cardiomyopathy have greatly reduced electrical coupling at gap junctions and reduced Na current density. In previous adeno-associated viral gene therapy trials, <50% of ventricular myocytes have generally been transduced. METHODS: We used established computational models of ventricular cell electrophysiology to define the effects of varying levels of successful gene therapy on conduction in patients with arrhythmogenic cardiomyopathy. Conduction velocity and development of conduction block were analyzed in tissue constructs composed of cells with levels of electrical coupling and Na current density observed in experimental studies. RESULTS: We observed a nonlinear relationship between conduction velocity and the proportion of transduced cells. Conduction velocity increased only modestly when up to 40% of myocytes were transduced. Conduction block did not occur in tissue constructs with moderate levels of uncoupling (0.10 or 0.15 of normal) as this degree of coupling was sufficient to allow electrotonic current to pass through diseased cells. Thus, low levels of transduction, likely to occur in phase 1 clinical trials, do not seem to pose a major safety concern. However, our models did not incorporate the potential effects of fibrosis and inflammation, both of which are presumably present in arrhythmogenic cardiomyopathy patients undergoing gene therapy and could impact arrhythmogenesis. CONCLUSIONS: The extent of successful ventricular myocyte transduction anticipated to be achieved in adeno-associated viral gene therapy trials will likely not restore conduction velocity to levels sufficient to decrease the risk of reentrant arrhythmias. Transduction efficiency of 60% to 80% would be required to restore conduction velocity to 50% of normal.
BACKGROUND: The CommandEP system v2 (Sentiar, St. Louis, MO) utilizes an augmented reality headset (Magic Leap, Plantation, FL) to display a real-time 3-dimensional electroanatomic map, catheter locations, and ablation c...BACKGROUND: The CommandEP system v2 (Sentiar, St. Louis, MO) utilizes an augmented reality headset (Magic Leap, Plantation, FL) to display a real-time 3-dimensional electroanatomic map, catheter locations, and ablation catheter contact force data to the electrophysiologist using a hands-free interface. In the intra-PARADIGM study (Procedural Augmented Reality Assessment in a 3-Dimensional Image Guided Modality), the impact of the CommandEP system on the electrophysiologist's ability to navigate accurately, intraprocedural communications, and system usability were studied. METHODS: CommandEP was used prospectively in patients undergoing electrophysiologist studies at 2 sites with 8 users. The electrophysiologist's ability to navigate accurately was calculated as catheter tip displacement from the target using CommandEP versus the electroanatomic mapping system. Physician-mapper interactions were quantified and classified as high- versus low-quality communications (high quality directly impacted navigation, medical decision-making, or patient care). Usability was assessed via survey. RESULTS: A total of 102 patients completed the study with the following diagnoses: atrial fibrillation (n=78/102, 76%), atrial flutter (8/102, 8%), atrial tachycardia/supraventricular tachycardia (n=9/102, 9%), premature ventricular contraction (n=6/102, 6%), and cardiac neuroablation (1/102, 1%). The physician's ability to navigate was more accurate when using the CommandEP system with an average distance of 2.98±2 mm versus electroanatomic mapping system 3.27±2 mm (=0.02); 21% of points navigated using CommandEP versus 28% of points navigated using electroanatomic mapping system were >4 mm from the target (=0.03). In all, 393 communications during study tasks were counted with 30 events when using CommandEP versus 363 events when using electroanatomic mapping system. Subanalysis showed no difference in accuracy pre- versus postcontact force (p=ns) and a slight reduction in both low- and high-quality communications (p=ns). Notably, 94% agreed/strongly agreed that they felt comfortable using the system, and 72% agreed/strongly agreed they would be comfortable using the CommandEP system in most/all EPS. CONCLUSIONS: The CommandEP system improved physicians' ability to navigate accuracy, reduced the number of communications, increased the quality of communications, and had high usability.
Zhang M, Tong Z, Wang N
… +19 more, Lin K, Zhang Y, Wang D, Wang X, Wang P, Yang Q, Kong Y, Wang M, Cui J, Wang Z, Cao M, Li L, Liu Y, Li Z, Fang S, Zhang F, Pan Z, Tian J, Yu B
BACKGROUND: Early identification of out-of-hospital high-risk sudden cardiac death (SCD) after acute myocardial infarction is crucial for timely therapeutic interventions. However, left ventricular ejection fraction as a...BACKGROUND: Early identification of out-of-hospital high-risk sudden cardiac death (SCD) after acute myocardial infarction is crucial for timely therapeutic interventions. However, left ventricular ejection fraction as a standalone clinical stratification tool has major limitations, necessitating improved risk stratification strategies. METHODS: Mass spectrometry measured 6592 peptides and 522 proteins, from which targeted proteomics identified the optimal protein combination to assess out-of-hospital SCD risk. ELISA validated its predictive value by comparing it with a clinical stratification tool (left ventricular ejection fraction ≤35%) and 2 reported models (risk score and out-of-hospital cardiac arrest score) in 3 case-control cohorts nested within diverse contemporary postinfarction populations. RESULTS: In the discovery cohort (105 SCD cases and 105 survivors), mass spectrometry discovered 44 differential proteins associated with SCD, unveiling early circulating features characterized by inflammatory response and complement activation in out-of-hospital SCD cases. Targeted proteomics identified the optimal SCD-warning 3-protein combination, including coronin-1A, haptoglobin, and CFD (complement factor D), to assess out-of-hospital SCD risk. An ELISA-based SCD-warning 3-protein combination model significantly outperformed left ventricular ejection fraction alone (C statistic: 0.752 versus 0.548; <0.001) and improved their performance (ΔC statistic, 0.281; categorical net reclassification improvement, 0.095; continuous net reclassification improvement, 0.952; integrated discrimination improvement, 0.291). Similar incremental discrimination metrics were observed in 2 reported stratification models (risk score and out-of-hospital cardiac arrest score), particularly within the left ventricular ejection fraction-preserved population. These findings were repeatably validated in 2 independent cohorts (n=234 and 48, respectively). CFD inhibition protection for mortality and pro-malignant arrhythmias in acute myocardial infarction mice supported the biological plausibility of the critical protein in SCD-warning 3-protein combination. CONCLUSIONS: In high-risk individuals for out-of-hospital SCD, the SCD-warning 3-protein combination may contribute to enhanced early identification for timely intensive management. These findings suggest pivotal proteins for improving understanding SCD pathophysiology.
Knops RE, Ip JE, Doshi R
… +14 more, Exner DV, Defaye P, Canby R, Bongiorni MG, Shoda M, Hindricks G, Neužil P, Rashtian M, Breeman KTN, Nevo JR, Ganz L, Hubbard C, Bulusu A, Reddy VY
BACKGROUND: A dual-chamber leadless pacemaker can provide bradycardia therapy to most patients with pacemaker indications without the complications associated with a lead or pulse generator. We sought to confirm whether...BACKGROUND: A dual-chamber leadless pacemaker can provide bradycardia therapy to most patients with pacemaker indications without the complications associated with a lead or pulse generator. We sought to confirm whether previously reported 3-month safety and performance outcomes were sustained through 12 months by determining whether 12-month complication-free and performance success rates exceeded their prespecified performance goals. METHODS: Patients were enrolled in the prospective, single-group Aveir DR i2i Study if they had a standard indication for dual-chamber pacing. Enrolled patients were implanted with an Aveir DR dual-chamber leadless pacemaker system, which comprised 2 communicating leadless pacemakers (1 in the right atrium and 1 in the right ventricle). The primary safety outcome evaluated whether freedom from serious device- or procedure-related events through 365 days exceeded the predetermined performance goal of 76.5%. The primary performance outcome determined whether the composite of atrial capture threshold (≤3.0 V at 0.4 ms) and sensing amplitude (P-wave ≥1.0 mV) at the 12-month visit exceeded the predetermined performance goal of 80.0%. RESULTS: Sites attempted implantation in 300 subjects, where 63.3% had sinus-node dysfunction and 33.3% had atrioventricular block as their primary pacing indication. The primary safety end point was achieved, with a Kaplan-Meier 12-month complication-free rate of 88.6% (95% CI, 84.5-91.8; <0.001). The primary performance end point was achieved in 92.8% of patients (95% CI, 89.7-95.8; <0.001). CONCLUSIONS: Both primary safety and performance end points were met after 1 year, demonstrating consistency with previously reported 3-month outcomes of a dual-chamber leadless pacemaker. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05252702.
Matsuda Y, Kudo S, Masuda M
… +13 more, Uematsu H, Sugino A, Ooka H, Fujii S, Okamoto S, Ishihara T, Nanto K, Tsujimura T, Hata Y, Nakao S, Kusuda M, Ariyasu W, Mano T
BACKGROUND: To address the unmet need for a smaller pacemaker for babies, a specially modified implantable pulse generator was developed containing a Medtronic Micra subassembly in a polymer header connecting to a bipola...BACKGROUND: To address the unmet need for a smaller pacemaker for babies, a specially modified implantable pulse generator was developed containing a Medtronic Micra subassembly in a polymer header connecting to a bipolar epicardial lead. The aim of this study was to report midterm follow-up data and outcomes of patients who underwent implantation of this device. METHODS: Deidentified data were collected from 12 of 15 sites in the United States implanting the pediatric implantable pulse generator between March 2022 and February 2024. All 29 patients at these 12 sites within this timeframe were included in the analysis. RESULTS: The median age at implant was 15 days (range, 0 days to 3 years, including 1 outlier). The median weight was 2.3 kg (range, 1.3-11.4 kg). Gestational age was 28.5 weeks to term, with 23 (79%) patients born prematurely. Of those with anatomic information, 25% had congenital heart disease. The average duration of implant was 325 days (73-808 days). The most recent lead impedance mean was 612 ohms (450-840 ohms), ventricular capture threshold mean was 1 V @ 0.4 ms (range, 0.38-2.75 V), and R-wave sensing mean was 12.5 mV (3.6-20 mV). There were 7 generator explants (24%), removed at 6.5 to 31 months of age. CONCLUSIONS: The pediatric implantable pulse generator can be safely implanted in neonates and infants. This multicenter report demonstrates that the devices remain stable, with effective pacing, normal electrical parameters, and battery longevity aligned with projections. This novel pediatric pacemaker provides a viable alternative to standard-size generators and addresses a vital unmet need for these small patients.
Carruth ED, Murray B, Tichnell C
… +4 more, Young K, Calkins H, James CA, Haggerty CM
Circ Arrhythm Electrophysiol
· 2025 Mar · PMID 39989366
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BACKGROUND: Population genomic screening for desmosome variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) may facilitate early disease detection and protective intervention. The validated ARV...BACKGROUND: Population genomic screening for desmosome variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) may facilitate early disease detection and protective intervention. The validated ARVC risk calculator offers a novel means to risk stratify individuals with diagnosed ARVC, but predicted risk in the context of genomic screening identification has not been explored. METHODS: Individuals harboring a pathogenic/likely pathogenic variant in a desmosome gene (, , , or ) were identified through the Geisinger MyCode Genomic Screening and Counseling program. The ARVC risk calculator was applied to patients with a subsequent evaluation of right ventricular function. This predicted risk was compared with outcomes in the first 5 years (range, 0.3-5.0 years) after genetic result return. RESULTS: Of 254 individuals with a clinically confirmed pathogenic/likely pathogenic desmosome variant, 113 (median age, 56 [interquartile range, 42-66]; 71% female) had cardiac imaging in follow-up and no prior sustained ventricular arrhythmia (VA). Eighty-two (73%) had no ARVC task force criteria (TFC) besides the variant (possible diagnosis), 22 (19%) had a single additional minor criterion (borderline diagnosis), and 9 (8%) met criteria for definite diagnosis. The median 5-year predicted VA risk was 3.9% (2.3%-6.6%), notably lower than that of the calculator derivation cohort (20.6%). The risk of fast VA was 1.6% (1.0%-2.9%). The predicted VA risk was higher in individuals with any nongenetic ARVC task force criteria (6.3% [2.5-13.2%]) versus those without (3.7% [2.2-5.6%]; =0.01), and in individuals with variants (6.1% [3.9-7.8%] versus 3.4% [2.2-5.3%]; =0.01). Over a median 3.0 years of follow-up (≤5 years only), no sustained VA events were observed in this cohort. CONCLUSIONS: The predicted 5-year risk of VA in individuals ascertained via population genomic screening for desmosome variants is low (3.9%; 1.6% for fast VA) but may vary by affected gene and ARVC task force criteria burden.
Subati T, Kim K, Yang Z
… +13 more, Murphy MB, Van Amburg JC, Christopher IL, Dougherty OP, Woodall KK, Smart CD, Johnson JE, Fogo AB, Amarnath V, Agrawal V, Barnett JV, Saffitz JE, Murray KT
Circ Arrhythm Electrophysiol
· 2025 Mar · PMID 39989351
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BACKGROUND: The strongest genetic risk factors for atrial fibrillation (AF) are DNA variants on chromosome 4q25 near the transcription factor gene (Pitx2:Paired-like homeodomain transcription factor 2). Mice deficient i...BACKGROUND: The strongest genetic risk factors for atrial fibrillation (AF) are DNA variants on chromosome 4q25 near the transcription factor gene (Pitx2:Paired-like homeodomain transcription factor 2). Mice deficient in () have increased AF susceptibility, although the molecular mechanism(s) remains controversial. encodes a transcription factor that activates an antioxidant response to promote cardiac repair. Increased reactive oxygen species causing oxidation of polyunsaturated fatty acids generates reactive lipid dicarbonyl moieties that adduct to proteins and other macromolecules to promote cellular injury. We tested the hypothesis that oxidative stress, and specifically isolevuglandins, the most reactive lipid dicarbonyls identified, are increased in the setting of deficiency to promote proarrhythmic remodeling and AF. METHODS: and wild-type littermate control mice were treated orally with vehicle, the lipid dicarbonyl scavenger 2-hydroxybenzylamine, or an inactive control compound at weaning, until study at age 16 to 18 weeks. RESULTS: mice demonstrated increased P wave duration indicative of slowed atrial conduction, as well as increased inducible AF burden and sustained AF, compared with wild type, and these abnormalities were prevented by 2-hydroxybenzylamine. Both reactive oxygen species and isolevuglandin protein adducts were elevated in atria with reduced expression of reactive oxygen species-protective genes. High-resolution respirometry demonstrated impaired mitochondrial function in atria, with disruption of mitochondrial integrity and cell-cell junctions with connexin lateralization, as well as decreased mitochondrial biogenesis gene expression. Proarrhythmic ionic current remodeling in atrial myocytes included elevated resting membrane potential, abbreviated action potential duration, and reduced maximum phase 0 upstroke velocity compared with wild type. Most of these abnormalities were ameliorated or prevented by 2-hydroxybenzylamine. CONCLUSIONS: These results demonstrate a critical role for lipid dicarbonyl mediators of oxidative stress in the proarrhythmic remodeling and AF susceptibility that occurs with deficiency, implying the possibility of genotype-specific therapy to prevent AF.
Francia P, Ziacchi M, Migliore F
… +24 more, De Filippo P, Dello Russo A, Viani S, Rapacciuolo A, Falasconi G, Adduci C, Bisignani G, Checchi L, Busacca G, Santini L, Lavalle C, Calvi VI, Curcio A, Silvetti M, Pangallo A, Carbonaro M, Giorgi D, Pittorru R, Lovecchio M, Valsecchi S, Biffi M, D'Onofrio A, Pelliccia A, S-ICD Rhythm Detect Investigators
BACKGROUND: The safety of subcutaneous implantable cardioverter defibrillator (S-ICD) recipients who lead active lifestyles and engage in recreational sports is unknown. We aimed to evaluate the association between lifes...BACKGROUND: The safety of subcutaneous implantable cardioverter defibrillator (S-ICD) recipients who lead active lifestyles and engage in recreational sports is unknown. We aimed to evaluate the association between lifestyle and recreational sports and the occurrence of arrhythmia- and device-related complications, appropriate and inappropriate shocks in S-ICD recipients. METHODS: We assessed a cohort of young-adult (15-65 years) S-ICD patients, evaluated their physical activity with IPAQ (International Physical Activity Questionnaire), and assessed the association between lifestyle and recreational sports on S-ICD safety and shocks. RESULTS: We enrolled 602 S-ICD recipients (77% men; age, 46±14 years). According to the IPAQ, patients were categorized as inactive subjects (26.4%), moderately active subjects (45.2%), or highly active subjects (28.4%). Among moderately/highly active subjects, 163 (27.1%) were recreational athletes. During follow-up (47.3 [interquartile range, 27.0-67.6] months), 23 patients (3.8%) reached the safety end point of arrhythmia- or device-related complications, with moderately and highly active subjects showing in multivariate analysis similar incidence compared with inactive subjects (=0.59 and =0.83, respectively). Forty-four patients had 87 appropriate shocks. In multivariate analysis, moderately and highly active subjects showed a nonsignificantly lower incidence of appropriate shocks compared with inactive subjects (=0.12 and =0.11, respectively). Consistently, there was a nonsignificant lower incidence of appropriate shocks in athletes versus nonathletes (=0.06). Thirty-nine patients had 46 inappropriate shocks. Moderately and highly active subjects had similar incidence of inappropriate shocks compared with inactive subjects (=0.92 and =0.88, respectively). CONCLUSIONS: Young S-ICD patients often lead active lifestyles and participate in sports. Higher activity levels were not associated with increased implantable cardioverter defibrillator-related complications or increased risk of implantable cardioverter defibrillator shocks.
Chakrabarti A, Giudicessi JR, Ezzeddine FM
… +37 more, Delling FN, Dixit S, Lee YJ, Muser D, Magnani S, Van Wijngaarden A, Ajmone Marsan N, Miller MA, Gandhi J, Trivieri MG, Font J, Martins R, McCaffrey JA, Santangeli P, Marchlinski FE, Chapagain H, Mathew D, Kancharla K, Syed FF, Abid A, Cerbin L, Tzou WS, Garg L, Della Rocca DG, Natale A, Mohanty S, Sheldon SH, Kuo L, Haugaa KH, Aabel EW, Enriquez A, Maeda S, Deshmukh A, Ghannam M, Bogun F, Ackerman MJ, Liang JJ
Circ Arrhythm Electrophysiol
· 2025 Mar · PMID 39973752
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BACKGROUND: Patients with arrhythmogenic mitral valve prolapse syndrome are at increased risk for life-threatening ventricular arrhythmias, but studies have been limited by small sample sizes. We sought to assemble an in...BACKGROUND: Patients with arrhythmogenic mitral valve prolapse syndrome are at increased risk for life-threatening ventricular arrhythmias, but studies have been limited by small sample sizes. We sought to assemble an international arrhythmogenic mitral valve prolapse syndrome registry to delineate the clinical, imaging, and treatment characteristics of patients with arrhythmogenic mitral valve prolapse syndrome who survived sudden cardiac arrest (SCA) or had sustained ventricular tachycardia (VT) or ventricular fibrillation. METHODS: In this descriptive registry, we characterized patients with arrhythmogenic mitral valve prolapse syndrome who survived SCA, sustained VT, or ventricular fibrillation. Deidentified data were abstracted locally and combined centrally. RESULTS: We included 148 patients who had SCA or VT/ventricular fibrillation. Patients had a mean age of 43.7±15.4 years; 68% were women, 73% had bileaflet prolapse, 65% had mitral annular disjunction, 67% had nonsustained VT, and 59% had inferolateral T-wave inversions. Syncope (n=54, 48%) and anterolateral T-wave inversion (n=26, 22%) were relatively common. Catheter ablation was performed in 50 (35%) patients for premature ventricular complexes and in 18 (17.7%) patients for VT. Sites of origin for arrhythmias were commonly in the papillary muscles, fascicles, mitral annulus, and inferior/inferolateral left ventricle. CONCLUSIONS: In this international descriptive registry of patients with arrhythmogenic mitral valve prolapse syndrome and SCA, patients were young, women, and had bileaflet mitral valve prolapse, mitral annular disjunction, inferolateral T-wave inversions, and nonsustained VT. A history of syncope and anterolateral T-wave inversions was relatively common in patients who survived SCA or sustained VT/ventricular fibrillation.
Sane M, Jäntti T, Marjamaa A
… +6 more, Pennanen E, Aura C, Torvinen E, Karjalainen L, Raatikainen P, Karvonen J
Circ Arrhythm Electrophysiol
· 2025 Mar · PMID 39973621
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BACKGROUND: Remote monitoring offers an effective and safe method for monitoring patients with cardiovascular implantable electronic devices. The downside of remote monitoring is the overflow of the data. Since many of t...BACKGROUND: Remote monitoring offers an effective and safe method for monitoring patients with cardiovascular implantable electronic devices. The downside of remote monitoring is the overflow of the data. Since many of the remote monitoring transmissions are nonactionable, optimizing alert transmissions could partly overcome this problem. METHODS: We collected data on the number and the causes of all alert-, scheduled-, and patient-initiated transmissions as well as actions initiated by these transmissions in 2023. According to our strategy, all clinically nonrelevant alerts were turned off. The trend of alert transmissions and the proportion of actionable scheduled transmissions are presented. The patient safety was monitored by analyzing the premortem alerts and changes to alert settings in deceased patients, as well as the rate of actionable scheduled or patient-initiated transmissions during follow-up. RESULTS: During the study period 8182 transmissions were generated from 3732 cardiovascular implantable electronic devices. Of these, 2306 (28%) were alert transmissions, of which 57% (n=1290) were considered clinically nonrelevant. The rate of alerts decreased by 44% from January to December (0.07 versus 0.04 per device per month, =0.001). Of the 3335 scheduled transmissions, 11% (364) were actionable, and the proportion of actionable scheduled transmissions remained unchanged during the follow-up period (=0.08). Notably, none of the deaths were linked to the adjustment of alert settings. CONCLUSIONS: Our data indicated that active evaluation of the clinical relevance of all alert transmissions and deactivation of clinically nonrelevant alerts reduce the remote monitoring workload. However, long-term follow-up is needed to ensure that patient safety is not compromised.