PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility. METHODS: Right atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies. RESULTS: In human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (P=2.0×10-2; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (P=1.4×10-6; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10-2 and 6.7×10-3, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (P=5.0×10-6; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (P=1.8×10-2 and 4.1×10-2, respectively; n=6, 6, and 5). CONCLUSIONS: Patients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

In-hospital complications associated with pulmonary vein isolation with adjunctive lesions: the NCDR AFib Ablation Registry.

AIMS: No prior study has been adequately powered to evaluate real-world safety outcomes in those receiving adjunctive ablation lesions beyond pulmonary vein isolation (PVI). We sought to evaluate characteristics and in-hospital complications among patients undergoing PVI with and without adjunctive lesions. METHODS AND RESULTS: Patients in the National Cardiovascular Data Registry AFib Ablation Registry undergoing first-time atrial fibrillation (AF) ablation between 2016 and 2020 were identified and stratified into paroxysmal (PAF) and persistent AF, and separated into PVI only, PVI + cavotricuspid isthmus (CTI) ablation, and PVI + adjunctive (superior vena cava isolation, coronary sinus, vein of Marshall, atypical atrial flutter lines, other). Adjusted odds of adverse events were calculated using multivariable logistic regression. A total of 50 937 patients [PAF: 30 551 (60%), persistent AF: 20 386 (40%)] were included. Among those with PAF, there were no differences in the adjusted odds of complications between PVI + CTI or PVI + adjunctive when compared with PVI only. Among persistent AF, PVI + adjunctive was associated with a higher risk of any complication [3.0 vs. 4.5%, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.07-1.58] and major complication (0.8 vs. 1.4%, OR 1.56, 95% CI 1.10-2.21), while no differences were observed in PVI + CTI compared with PVI only. Overall, there was high heterogeneity in adjunctive lesion type, and those receiving adjunctive lesions had a higher comorbidity burden. CONCLUSION: Additional CTI ablation was common without an increased risk of complications. Adjunctive lesions other than CTI are commonly performed in those with more comorbidities and were associated with an increased risk of complications in persistent AF, although the current analysis is limited by high heterogeneity in adjunctive lesion set type.

Abnormal left atrial body stiffness is predicted by appendage size: impact of appendage occlusion on left atrial mechanics assessed by pressure-volume analysis.

Atrial cardiomyopathy has been recognized as having important consequences for cardiac performance and clinical outcomes. The pathophysiological role of the left atrial (LA) appendage and the effect of percutaneous left atrial appendage occlusion (LAAO) upon LA mechanics is incompletely understood. We evaluated if changes in LA stiffness due to endocardial LAAO can be detected by LA pressure-volume (PV) analysis and whether stiffness parameters are associated with baseline characteristics. Patients undergoing percutaneous endocardial LAAO (n = 25) were studied using a novel PV analysis using near-simultaneous three-dimensional LA volume measurements by transesophageal echocardiography (TEE) and direct invasive LA pressure measurements. LA stiffness (dP/dV, change in pressure with change in volume) was calculated before and after LAAO. Overall LA stiffness significantly increased after LAAO compared with baseline (median, 0.41-0.64 mmHg/mL; P ≪ 0.001). LA body stiffness after LAAO correlated with baseline LA appendage size by indexed maximum depth (Spearman's rank correlation coefficient Rs = 0.61; P < 0.01). LA stiffness change showed an even stronger correlation with baseline LA appendage size by indexed maximum depth (Rs = 0.70; P < 0.001). We found that overall LA stiffness increases after endocardial LAAO. Baseline LA appendage size correlates with the magnitude of increase and LA body stiffness. These findings document alteration of LA mechanics after endocardial LAAO and suggest that the LA appendage modulates overall LA compliance.NEW & NOTEWORTHY Our study documents a correlation of LA appendage remodeling with the degree of chronically abnormal LA body stiffness. In addition, we found that LA appendage size was the baseline parameter that best correlated with the magnitude of a further increase in overall LA stiffness after appendage occlusion. These findings offer insights about the LA appendage and LA mechanics that are relevant to patients at risk for adverse atrial remodeling, especially candidates for LA appendage occlusion.

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction.

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early-onset AF, heart block, and incompletely penetrant nonischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase-4D-interacting-protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that segregated with early-onset AF, heart block, and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the ß2-adrenergic-receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.

Ventricular Fibrillation Conversion Testing After Implantation of a Subcutaneous Implantable Cardioverter Defibrillator: Report From the National Cardiovascular Data Registry.

BACKGROUND: Compared with transvenous implantable cardioverter defibrillators (ICDs), subcutaneous (S)-ICDs require a higher energy for effective defibrillation. Although ventricular fibrillation conversion testing (CT) is recommended after S-ICD implantation to ensure an adequate margin between the defibrillation threshold and maximum device output (80J), prior work found that adherence to this recommendation is declining. METHODS: We studied first-time recipients of S-ICDs (between September 28, 2012, and April 1, 2016) in the National Cardiovascular Database Registry ICD Registry to determine predictors of use of CT, predictors of an insufficient safety margin (ISM, defined as ventricular fibrillation conversion energy >65J) during testing, and inhospital outcomes associated with use of CT. Multivariable logistic regression analysis was used to predict use of CT and ISM. Inverse probability weighted logistic regression analysis was used to examine the association between use of CT and inhospital adverse events including death. RESULTS: CT testing was performed in 70.7% (n=5624) of 7960 patients with S-ICDs. Although deferral of CT was associated with several patient characteristics (including increased body mass index, increased body surface area, severely reduced ejection fraction, dialysis dependence, warfarin use, anemia, and hypertrophic cardiomyopathy), the facility effect was comparatively more important (area under the curve for patient level versus generalized linear mixed model: 0.619 versus 0.877). An ISM occurred in 6.9% (n=336) of 4864 patients without a prior ICD and was more common among white patients and those with ventricular pacing on the preimplant ECG, higher preimplant blood pressure, larger body surface area, higher body mass index, and lower ejection fraction. A risk score was able to identify patients at low (<5%), medium (5% to 10%), and high risk (>10%) for ISM. CT testing was not associated with a composite of inhospital complications including death. CONCLUSIONS: Use of CT testing after S-ICD implantation was driven by facility preference to a greater extent than patient factors and was not associated with a composite of inhospital complications or death. ISM was relatively uncommon and is associated with several widely available patient characteristics. These data may inform ICD system selection and a targeted approach to CT.

Recurrence quantification analysis of complex-fractionated electrograms differentiates active and passive sites during atrial fibrillation.

OBJECTIVES: To differentiate electrograms representing sites of active atrial fibrillation (AF) drivers from passive ones. BACKGROUND: Ablation of complex-fractionated atrial electrograms (CFAEs) is controversial due to difficulty in distinguishing CFAEs representing sites of active AF drivers from passive mechanisms. We hypothesized that active CFAE sites exhibit repetitive wavefront directionality, thereby inscribing an electrogram conformation (Egm-C) that is more recurrent compared with passive CFAE sites; and that can be differentiated from passive CFAEs using nonlinear recurrence quantification analysis (RQA). METHODS: We developed multiple computer models of active CFAE mechanisms (ie, rotors) and passive CFAE mechanisms (ie, wavebreak, slow conduction, and double potentials). CFAE signals were converted into discrete time-series representing Egm-C. The RQA algorithm was used to compare signals derived from active CFAE sites to those from passive CFAEs sites. The RQA algorithm was then applied to human CFAE signals collected during AF ablation (n = 17 patients). RESULTS: RQA was performed in silico on simulated bipolar CFAEs within active (n = 45) and passive (n = 60) areas. Recurrence of Egm-C was significantly higher in active compared with passive CFAE sites (31.8% ± 19.6% vs 0.3% ± 0.5%, respectively, P < .0001) despite no difference in mean cycle length (CL). Similarly, for human AF (n = 39 signals), Egm-C recurrence was higher in active vs passive CFAE areas despite similar CLs (%recurrence 13.6% ± 15.5% vs 0.1% ± 0.3%, P < .002; mean CL 102.5 ± 14.3 vs 106.6 ± 14.4, P = NS). CONCLUSION: Active CFAEs critical to AF maintenance exhibit higher Egm-C recurrence and can be differentiated from passive bystander CFAE sites using RQA.

Outcomes and costs of remote patient monitoring among patients with implanted cardiac defibrillators: An economic model based on the PREDICT RM database.

BACKGROUND: Remote monitoring of implantable cardioverter-defibrillators has been associated with reduced rates of all-cause rehospitalizations and mortality among device recipients, but long-term economic benefits have not been studied. METHODS AND RESULTS: An economic model was developed using the PREDICT RM database comparing outcomes with and without remote monitoring. The database included patients ages 65 to 89 who received a Boston Scientific device from 2006 to 2010. Parametric survival equations were derived for rehospitalization and mortality to predict outcomes over a maximum time horizon of 25 years. The analysis assessed rehospitalization, mortality, and the cost-effectiveness (expressed as the incremental cost per quality-adjusted life year) of remote monitoring versus no remote monitoring. Remote monitoring was associated with reduced mortality; average life expectancy and average quality-adjusted life years increased by 0.77 years and 0.64, respectively (6.85 life years and 5.65 quality-adjusted life years). When expressed per patient-year, remote monitoring patients had fewer subsequent rehospitalizations (by 0.08 per patient-year) and lower hospitalization costs (by $554 per patient year). With longer life expectancies, remote monitoring patients experienced an average of 0.64 additional subsequent rehospitalizations with increased average lifetime hospitalization costs of $2784. Total costs of outpatient and physician claims were higher with remote monitoring ($47 515 vs $42 792), but average per patient-year costs were lower ($6232 vs $6244). The base-case incremental cost-effectiveness ratio was $10 752 per quality-adjusted life year, making remote monitoring high-value care. CONCLUSION: Remote monitoring is a cost-effective approach for the lifetime management of patients with implantable cardioverter-defibrillators.

New skip parameter to facilitate recurrence quantification of signals comprised of multiple components.

Recurrence analyses are typically performed on discretized time series after applying proper embeddings, delays, and thresholds. In our study of atrial electrograms, we found limitations to this approach when sequential bipolar complexes were defined as the timings of the first two zero crosses following the initiation of each event. The reason for this is that each bipolar component consists of two points in odd-even pairings. Since recurrence analysis starts vectors on each sequential point, incorrect even-odd pairings occur for every other vector. To overcome this limitation, a new parameter SKIP is introduced such that recurrence vectors can skip 1 (or 2) points for signals with defined multiple components. To demonstrate the utility of parameter SKIP, we used the Courtemanche model to simulate the electrical activity in the human atrium on a square, two-dimensional plane with 800 × 800 nodes. Over this plane, a grid of 39 × 39 virtual unipoles was created. Neighboring unipoles formed 39 × 38 bipolar pairs, which were recorded as 1482 continuous and synchronous time series. At each unipolar site, the actual wavefront direction was determined by comparing the relative activation timings of the local intracellular potentials. Parameters were set such that the "tissue" exhibited both spiral waves (organized activity) and wave breakups (chaotic activity). For each bipolar complex in the continuous electrogram, discretized electrogram conformation was defined as the timing delays from the start of the complex to the first two zero-crosses. Long sequences of paired zero-cross timings were subjected to recurrence analysis using SKIP values of 0 (no skipping) and 1 (single skipping). Recurrence variables were computed and correlated with the absolute wavefront directions. The results showed that the introduction of the skipping window improved the correlations of some recurrence variables with absolute wavefront directions. This is critically important because such variables may be better markers for wavefront directions in human recordings when the absolute wavefront directions cannot be calculated directly.

Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Several risk factors promote AF, among which diabetes mellitus has emerged as one of the most important. The growing recognition that obesity, diabetes and AF are closely intertwined disorders has spurred major interest in uncovering their mechanistic links. In this article we provide an update on the growing evidence linking oxidative stress and inflammation to adverse atrial structural and electrical remodeling that leads to the onset and maintenance of AF in the diabetic heart. We then discuss several therapeutic strategies to improve atrial excitability by targeting pathways that control oxidative stress and inflammation.

Long-Term Risk for Device-Related Complications and Reoperations After Implantable Cardioverter-Defibrillator Implantation: An Observational Cohort Study.

BACKGROUND: Long-term nonfatal outcomes after implantable cardioverter-defibrillator (ICD) placement are poorly defined. OBJECTIVE: To determine the long-term risk for ICD-related complications requiring reoperation or hospitalization and reoperation for reasons other than complications, and to assess associated patient and device characteristics. DESIGN: Observational cohort study of ICD implantations from the National Cardiovascular Data Registry ICD registry linked with Medicare fee-for-service claims data. SETTING: 1437 U.S. hospitals. PATIENTS: 114 484 patients aged 65 years or older (mean, 74.8 years [SD, 6.2]; 72.4% male) receiving an ICD for the first time from 2006 to 2010 (single-chamber, 19.8%; dual-chamber, 41.3%; cardiac resynchronization therapy with a defibrillator [CRT-D], 38.9%). MEASUREMENTS: Rate and cumulative incidence of ICD-related complications requiring reoperation or hospitalization and reoperation for reasons other than complications. RESULTS: During a median follow-up of 2.7 years (interquartile range, 1.8 to 3.9 years), 40 072 patients died, representing 12.6 (95% CI, 12.5 to 12.7) deaths per 100 patient-years of follow-up. When the risk for death was accounted for, there were 6.1 (CI, 6.0 to 6.2) ICD-related complications per 100 patient-years that required reoperation or hospitalization and 3.9 (CI, 3.8 to 4.0) reoperations per 100 patient-years for reasons other than complications. Overall, 10 patients had complications or reoperation per 100 patient-years of follow-up. Younger age at implantation (65 to 69 vs. >85 years) (hazard ratio [HR], 1.55 [CI, 1.43 to 1.69]), receipt of a CRT-D device (HR, 1.38 [CI, 1.31 to 1.45]) versus a single-chamber device, female sex (HR, 1.16 [CI, 1.12 to 1.21]), and black race (HR, 1.14 [CI, 1.05 to 1.23]) were associated with the greatest increased risks for ICD-related complications. LIMITATION: The analysis was limited to Medicare fee-for-service patients aged 65 years or older. CONCLUSION: Patients have a high rate of device-related complications and reoperation for other causes after ICD implantation. Risks of ICD implantation and strategies to reduce them should be actively considered before implantation. PRIMARY FUNDING SOURCE: American College of Cardiology Foundation's National Cardiovascular Data Registry.

Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices.

AIMS: Atrial tachyarrhythmias (ATs) detected by implanted devices are often atrial fibrillation or flutter (AF) associated with stroke. We hypothesized that introduction and termination of anticoagulation based upon AT monitoring would reduce both stroke and bleeding. METHODS AND RESULTS: We randomized 2718 patients with dual-chamber and biventricular defibrillators to start and stop anticoagulation based on remote rhythm monitoring vs. usual office-based follow-up with anticoagulation determined by standard clinical criteria. The primary analysis compared the composite endpoint of stroke, systemic embolism, and major bleeding with the two strategies. The trial was stopped after 2 years median follow-up based on futility of finding a difference in primary endpoints between groups. A total of 945 patients (34.8%) developed AT, 264 meeting study anticoagulation criteria. Adjudicated atrial electrograms confirmed AF in 91%; median time to initiate anticoagulation was 3 vs. 54 days in the intervention and control groups, respectively (P < 0.001). Primary events (2.4 vs. 2.3 per 100 patient-years) did not differ between groups (HR 1.06; 95% CI 0.75-1.51; P = 0.732). Major bleeding occurred at 1.6 vs. 1.2 per 100 patient-years (HR 1.39; 95% CI 0.89-2.17; P = 0.145). In patients with AT, thromboembolism rates were 1.0 vs. 1.6 per 100 patient-years (relative risk -35.3%; 95% CI -70.8 to 35.3%; P = 0.251). Although AT burden was associated with thromboembolism, there was no temporal relationship between AT and stroke. CONCLUSION: In patients with implanted defibrillators, the strategy of early initiation and interruption of anticoagulation based on remotely detected AT did not prevent thromboembolism and bleeding. CLINICAL TRIAL REGISTRATION: IMPACT ClinicalTrials.gov identifier: NCT00559988 ( http://clinicaltrials.gov/ct2/show/NCT00559988?term=NCT00559988&rank=1 ).

Use of remote monitoring of newly implanted cardioverter-defibrillators: insights from the patient related determinants of ICD remote monitoring (PREDICT RM) study.

BACKGROUND: Current guidelines recommend using remote patient monitoring (RPM) for implantable cardioverter-defibrillators, but the patterns of adoption of this technology have not been described. Successful use of RPM depends on (1) the enrollment of the patient into an RPM system and (2) subsequent activation of RPM by the enrolled patient. We examined RPM enrollment and activation rates and the patient, physician, and institutional determinants of RPM use. METHODS AND RESULTS: Information about the use of RPM-capable devices was obtained from the Boston Scientific Corporation ALTITUDE program and linked to the National Cardiovascular Data Registry ICD Registry. Patients were first categorized as RPM-enrolled and RPM-not enrolled, and the RPM-enrolled patients were further categorized into RPM-active and RPM-inactive groups based on whether they transmitted RPM data. Variables associated with RPM enrollment and activation were identified with the use of multivariable logistic regression. Among 39 158 patients with newly implanted RPM-capable devices, 62% (n=24 113) were RPM-enrolled. Of those enrolled, 76% (n=18 289, or 47% of the entire cohort) activated their device. RPM enrollment was highly variable among institutions. The hospital-specific median odds ratio for RPM enrollment was 3.43, signifying that physician or institutional factors are associated with RPM enrollment. In contrast, the hospital-specific median odds ratio for RPM activation was 1.69. Age, race, health insurance, geographic location, and health-related factors were similarly associated with both RPM enrollment and activation. CONCLUSIONS: RPM technology is used in less than half of eligible patients. Lack of enrollment into RPM systems is the major cause of underutilization, and this primarily relates to the local practice environment.

Observational study protocol for an arrhythmia notification feature.

INTRODUCTION: Screening for atrial fibrillation (AF) in the general population may help identify individuals at risk, enabling further assessment of risk factors and institution of appropriate treatment. Algorithms deployed on wearable technologies such as smartwatches and fitness bands may be trained to screen for such arrhythmias. However, their performance needs to be assessed for safety and accuracy prior to wide-scale implementation. METHODS AND ANALYSIS: This study will assess the ability of the WHOOP strap to detect AF using its WHOOP Arrhythmia Notification Feature (WARN) algorithm in an enriched cohort with a 2:1 distribution of previously diagnosed AF (persistent and paroxysmal) and healthy controls. Recruited participants will collect data for 7 days with the WHOOP wrist-strap and BioTel ePatch (electrocardiography gold-standard). Primary outcome will be participant level sensitivity and specificity of the WARN algorithm in detecting AF in analysable windows compared with the ECG gold-standard. Similar analyses will be performed on an available epoch-level basis as well as comparison of these findings in important subgroups. ETHICS AND DISSEMINATION: The study was approved by the ethics board at the study site. Participants will be enrolled after signing an online informed consent document. Updates will be shared via clinicaltrials.gov. The data obtained from the conclusion of this study will be presented in national and international conferences with publication in clinical research journals. TRIAL REGISTRATION NUMBER: NCT05809362.

Use of intracardiac echocardiography during atrial fibrillation ablation.

As the volume and complexity of catheter ablation of atrial fibrillation (AF) continue to rise, there is increasing attention directed at reducing exposure to ionizing radiation. This has led to the emergence of intracardiac echocardiography (ICE) as a stand-alone imaging modality guiding AF ablation. In addition to directing transseptal puncture, ICE may be used to identify left atrial structures and to guide the manipulation of catheters. ICE may also be used to visualize the esophagus in real-time and to assist with early identification of procedural complications. This review provides detailed step-by-step directions for identification of relevant structures and summarizes the use of ICE during AF ablation.

Predicting Malignant Ventricular Arrhythmias Using Real-Time Remote Monitoring.

BACKGROUND: Although implantable cardioverter-defibrillator (ICD) therapies are associated with increased morbidity and mortality, the prediction of malignant ventricular arrhythmias has remained elusive. OBJECTIVES: The purpose of this study was to evaluate whether daily remote-monitoring data may predict appropriate ICD therapies for ventricular tachycardia or ventricular fibrillation. METHODS: This was a post hoc analysis of IMPACT (Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices), a multicenter, randomized, controlled trial of 2,718 patients evaluating atrial tachyarrhythmias and anticoagulation for patients with heart failure and ICD or cardiac resynchronization therapy with defibrillator devices. All device therapies were adjudicated as either appropriate (to treat ventricular tachycardia or ventricular fibrillation) or inappropriate (all others). Remote monitoring data in the 30 days before device therapy were utilized to develop separate multivariable logistic regression and neural network models to predict appropriate device therapies. RESULTS: A total of 59,807 device transmissions were available for 2,413 patients (age 64 ± 11 years, 26% women, 64% ICD). Appropriate device therapies (141 shocks, 10 antitachycardia pacing) were delivered to 151 patients. Logistic regression identified shock lead impedance and ventricular ectopy as significantly associated with increased risk of appropriate device therapy (sensitivity 39%, specificity 91%, AUC: 0.72). Neural network modeling yielded significantly better (P < 0.01 for comparison) predictive performance (sensitivity 54%, specificity 96%, AUC: 0.90), and also identified patterns of change in atrial lead impedance, mean heart rate, and patient activity as predictors of appropriate therapies. CONCLUSIONS: Daily remote monitoring data may be utilized to predict malignant ventricular arrhythmias in the 30 days before device therapies. Neural networks complement and enhance conventional approaches to risk stratification.