New atrial arrhythmia occurrence in single chamber implantable cardioverter defibrillator patients: A real-world investigation.

INTRODUCTION: A current limitation of single chamber implantable cardioverter defibrillators (ICDs) is the lack of an atrial lead to reliably detect atrial fibrillation (AF) episodes. A novel ventricular based atrial fibrillation (VBAF) detection algorithm was created for single chamber ICDs to assess R-R variability for detection of AF. METHODS: Patients implanted with Visia AF™ ICDs were prospectively enrolled in the Medtronic Product Surveillance Registry from December 15, 2015 to January 23, 2019 and followed with at least 30 days of monitoring with the algorithm. Time to device-detected daily burden of AF ≥ 6 min, ≥6 h, and ≥23 h were reported. Clinical actions after device-detected AF were recorded. RESULTS: A total of 291 patients were enrolled with a mean follow-up of 22.5 ± 7.9 months. Of these, 212 (73%) had no prior history of AF at device implant. However, 38% of these individuals had AF detected with the VBAF algorithm with daily burden of ≥6 min within two years of implant. In these 80 patients with newly detected AF by their ICD, 23 (29%) had a confirmed clinical diagnosis of AF by their provider. Of patients with a clinical diagnosis of AF, nine (39%) were newly placed on anticoagulation, including five of five (100%) patients having a burden >23 h. CONCLUSIONS: Continuous AF monitoring with the new VBAF algorithm permits early identification and actionable treatment for patients with undiagnosed AF that may improve patient outcomes.

Trends in implantable cardioverter-defibrillator programming practices and its impact on therapies: Insights from a North American Remote Monitoring Registry 2007-2018.

BACKGROUND: Recent evidence has revealed the utility of prolonged arrhythmia detection duration and increased rate cutoff to reduce implantable cardioverter-defibrillator (ICD) therapies. Data on real-world trends in ICD programming and its impact on outcomes are limited. OBJECTIVE: The purpose of this study was to evaluate trends in ICD programming and its impact on ICD therapy using a large remote monitoring database. METHODS: A retrospective analysis of patients with ICD implanted from 2007 to 2018 was conducted using the de-identified Medtronic CareLink database. Data on ICD programming (number of intervals to detection [NID] and therapy rate cutoff) and delivered ICD therapies were collected. RESULTS: Among 210,810 patients, the proportion programmed to a rate cutoff of ≥188 beats/min increased from 41% to 49% and an NID of ≥30/40 increased from 17% to 67% before May 2013 vs after February 2016. Programming to a rate cutoff of ≥188 beats/min, a ventricular fibrillation (VF) NID of ≥30/40, or a combined rate cutoff of ≥188 beats/min and VF NID of ≥30/40 were associated with reductions in ICD therapy. The largest reductions in ICD therapy occurred when the combination of rate cutoff ≥ 188 beats/min and VF NID ≥ 30/40 was programmed (antitachycardia pacing: hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.34-0.36; P < .001; shocks: HR 0.67; 95% CI 0.65-0.69; P < .001; and antitachycardia pacing/shocks: HR 0.43; 95% CI 0.42-0.44; P < .001). CONCLUSION: Despite evidence supporting the use of prolonged detection duration and high rate cutoff, implementation of shock reduction programming strategies in real-world clinical practice has been modest. The use of evidence-based ICD programming is associated with reduced ICD shocks over long-term follow-up.

Characteristics of ventricular tachyarrhythmias and their susceptibility to antitachycardia pacing termination in patients with ischemic and nonischemic cardiomyopathy: A patient-level meta-analysis of three large clinical trials.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) reduce all-cause mortality among cardiomyopathy patients. Whether or not antitachycardia pacing (ATP) is equally effective in ischemic (ICM) and nonischemic (NICM) cardiomyopathy patients remains poorly understood. We describe the distribution of monomorphic (MVT) and non-monomorphic (polymorphic ventricular tachycardia/ventricular fibrillation [PVT/VF]) ventricular tachyarrhythmias among ICM and NICM primary prevention patients. METHODS: This patient-level meta-analysis included primary prevention patients from the Shock-Less (n = 3519), PainFree SST (n = 1917), and PREPARE (n = 690) studies. Distribution of MVT and PVT/VF events were compared with χ2 tests. ATP success was estimated using a generalized estimating equation model to correct for multiple episodes for a patient between cohorts for slow (≥320 ms) and fast (240-310 ms) MVTs. RESULTS: Among 6126 patients, 714 (29% NICM, age 66 ± 13 years, female 18%, EF = 29 ± 12%) had a total of 4444 treated ventricular tachyarrhythmia episodes. The rate of individuals treated for MVT or PVT/VF was comparable between ICM (11.9%) and NICM (11.2%) over 21 ± 10 months. In addition, the distribution of MVT (76% ICM vs. 71% NICM) and PVT/VF (15% ICM vs. 20% NICM) was not significantly different (p = .28). Among MVT episodes, the average tachycardia cycle lengths (332 ± 58 ms ICM vs. 313 ± 40 ms NICM; p = .27) were similar, as was the likelihood of ATP-associated termination (74.6% ICM vs. 76.4% NICM; p = .58). Overall, ATP success was higher for slow (≥320 ms) MVT versus faster (240-310 ms) episodes (84.1% vs. 69%; p < .001). CONCLUSION: In a large cohort of primary prevention ICD patients, ICM and NICM patients have similar rates and proportions of MVT and PVT/VF episodes. ATP-associated termination of MVT was comparable between the two groups.

Utilization of implantable cardioverter-defibrillators for the prevention of sudden cardiac death in emerging countries: Improve SCA clinical trial.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are underutilized in Asia, Latin America, Eastern Europe, the Middle East, and Africa. The Improve SCA Study is the largest prospective study to evaluate the benefit of ICD therapy in underrepresented geographies. This analysis reports the primary objective of the study. OBJECTIVES: The objectives of this study was to determine whether patients with primary prevention (PP) indications with specific risk factors (1.5PP: syncope, nonsustained ventricular tachycardia, premature ventricular contractions >10/h, and low ventricular ejection fraction <25%) are at a similar risk of life-threatening arrhythmias as patients with secondary prevention (SP) indications and to evaluate all-cause mortality rates in 1.5PP patients with and without devices. METHODS: A total of 3889 patients were included in the analysis to evaluate ventricular tachycardia or fibrillation therapy and mortality rates. Patients were stratified as SP (n = 1193) and patients with PP indications. The PP cohort was divided into 1.5PP patients (n = 1913) and those without any 1.5PP criteria (n = 783). The decision to undergo ICD implantation was left to the patient and/or physician. The Cox proportional hazards model was used to compute hazard ratios. RESULTS: Patients had predominantly nonischemic cardiomyopathy. The rate of ventricular tachycardia or fibrillation in 1.5PP patients was not equivalent (within 30%) to that in patients with SP indications (hazard ratio 0.47; 95% confidence interval 0.38-0.57) but was higher than that in PP patients without any 1.5PP criteria (hazard ratio 0.67; 95% confidence interval 0.46-0.97) (P = .03). There was a 49% relative risk reduction in all-cause mortality in ICD implanted 1.5PP patients. In addition, the number needed to treat to save 1 life over 3 years was 10.0 in the 1.5PP cohort vs 40.0 in PP patients without any 1.5PP criteria. CONCLUSION: These data corroborate the mortality benefit of ICD therapy and support extension to a selected PP population from underrepresented geographies.

Additional antitachycardia pacing programming strategies further reduce unnecessary implantable cardioverter-defibrillator shocks.

BACKGROUND: Antitachycardia pacing (ATP) is routinely used to terminate ventricular tachyarrhythmias (VTs). However, little guidance exists on the most effective programming of ATP. OBJECTIVE: This study evaluated whether additional ATP sequences are more effective in reducing implantable cardioverter-defibrillator shocks. METHODS: In patients from the Shock-Less study, the number of overall shocks were compared between patients programmed to ≤3 ATP sequences (VT zone) and ≤1 ATP sequence (fast ventricular tachycardia [FVT] zone) (nominal group) and patients programmed to receive additional ATP sequences in VT (>3) or FVT (>1) zones. RESULTS: Of the 4112 patients (15% receiving secondary prevention; 77% men; mean age 65.9 ± 12.6 years), 1532 patients (37%) were programmed with additional ATP sequences (1025 with >3 ATP sequences in the VT zone; 699 patients with >1 ATP sequence in the FVT zone). Over a mean follow-up period of 19.6 ± 10.7 months, 4359 VT/FVT episodes occurred in 591 patients. Compared with the nominal group, in patients with additional ATP programming, there was a 39% reduction in the number of shocked VT episodes (0.46 episodes per patient-year vs 0.28 episodes per patient-year; incidence rate ratio [IRR] 0.61; P < .001) and a 44% reduction in the number of shocked FVT episodes (0.83 episodes per patient-year vs 0.47 episodes per patient-year; IRR 0.56; P < .001). The reduction in shocked VT episodes was observed in both primary (IRR 0.68; 95% confidence interval 0.51-0.90; P = .007) and secondary (IRR 0.51; 95% confidence interval 0.35-0.72; P < .001) prevention patients. CONCLUSION: Programming more than the nominal number of ATP sequences in both the VT and FVT zones is associated with a lower occurrence of implantable cardioverter-defibrillator shocks in clinical practice.

SVT discrimination algorithms significantly reduce the rate of inappropriate therapy in the setting of modern-day delayed high-rate detection programming.

BACKGROUND: Contemporary implantable cardioverter-defibrillator (ICD) programming involving delayed high-rate detection and use of supraventricular tachycardia (SVT) discriminators has significantly reduced the rate of inappropriate shocks. The extent to which SVT algorithms alone reduce inappropriate therapies is poorly understood. METHODS AND RESULTS: PainFree SST enrolled 2770 patients with a single- or dual-chamber ICD or cardiac resynchronization defibrillator. Patients were followed for 22 ± 9 months with SVT discriminators on in 96% of patients. Sustained ventricular tachyarrhythmias and SVT episodes were adjudicated by an independent physician committee. For this analysis, all episodes were subjected to postprocessing computer simulation with SVT discriminators off with and without delayed high-rate detection criteria (ventricular fibrillation zone only, 30/40 at 320 ms). There were 3282 adjudicated SVT episodes of which 115 resulted in an ICD shock and 113 received only ATP (2-year inappropriate shock and therapy rates of 3.1% and 4.1%). Therapy was appropriately withheld for the remaining 3054 SVT episodes. With both SVT discriminators and delayed high-rate detection simulated off, the 2-year inappropriate therapy rate would have been 22.9% (hazard ratio [HR] = 6.24; 95% confidence interval [CI]: 5.20-7.49). With SVT discriminators simulated off and delayed high-rate detection simulated on in all patients, the 2-year rate would have been 6.4% (HR = 1.63; CI: 1.44-1.85). CONCLUSIONS: The use of SVT discriminators has a significant role in reducing the rate of inappropriate ICD therapy even in the setting of delayed high-rate detection settings. Deactivating SVT discriminators would have resulted in an overall increase in the inappropriate ICD therapy rate by 63% and 524% with and without delayed high-rate detection programming, respectively.

What is ventricular fibrillation undersensing?

Ventricular fibrillation (VF), uninterrupted, is fatal within minutes. Implantable cardioverter defibrillators (ICDs) sense ventricular electrograms (EGMs) during VF and detect the VF rhythm (a sequence of VF sensed events) to deliver a shock to terminate VF and save lives. VF sensing and detection in Medtronic ICDs has been reported to be highly sensitive. However, Castellano et al. reported that Medtronic ICDs have the potential for high levels of undersensing in VF, sufficient to underdetect VF and withhold life-saving therapy. This manuscript reviews the process of EGM sensing and VF detection in ICDs and compares the process of sensing in Medtronic ICDs with the process described in this recent publication.

Sensing and detection in Medtronic implantable cardioverter defibrillators.

Ensuring sensing and detection of ventricular tachycardia (VT) and ventricular fibrillation (VF) was a prerequisite for the clinical trials that established the survival benefit of implantable cardioverter defibrillators (ICDs). However, for decades, a high incidence of unnecessary shocks limited patients' and physicians' acceptance of ICD therapy. Oversensing, misclassification of supraventricular tachycardia (SVT) as VT, and self-terminating VT accounted for the vast majority of unnecessary shocks. Medtronic ICDs utilize sensitive baseline settings with minimal blanking periods to ensure accurate sensing of VF, VT, and SVT electrograms. Programmable algorithms reject oversensing caused by far-field R waves, T waves, and non-physiologic signals caused by lead failure. A robust hierarchy of SVT-VT discriminators minimize misclassification of SVT as VT. These features, combined with evidence-based programming, have reduced the 1­year inappropriate shock rate to 1.5 % for dual-/triple-chamber ICDs and to 2.5 % for single-chamber ICDs.

Performance of Atrial Fibrillation Detection in a New Single-Chamber ICD.

BACKGROUND: Patients with implantable cardioverter defibrillators (ICDs) often have a history of atrial fibrillation (AF) or will develop AF after device implant. Optimal management of ICD patients includes early diagnosis of AF and monitoring of AF burden. We evaluated the performance of an algorithm for monitoring AF in single-chamber ICDs. METHODS: The RR interval variability-based detection algorithm determines RR variability by creating a Lorenz plot of the change in RR intervals for the most recent interval pair versus the previous interval pair. A new plot is created every 2 minutes and the AF evidence score of the plot is computed. Patient RR interval data from several Holter databases were pooled to test the performance of the AF detection algorithm. RESULTS: In total, 187 recordings from 186 patients were used to assess the performance of the AF detection algorithm integrated into a single-chamber ICD by comparing the ICD detection results to the Holter annotated truth. Thirty-five of 186 patients had a total of 94 AF episodes in their Holter recordings lasting a total of 250.5 hours (mean episode duration 7.2 hours). The generalized estimating equations-adjusted estimate of episode sensitivity was 94.8% with 95% lower confidence limit of 87.2%. Gross duration sensitivity was 95.0% for AF episodes of at least 6 minutes duration with gross duration specificity of 99.6%. CONCLUSION: This RR interval-based AF detection algorithm performs well with high sensitivity and specificity. Integration of this algorithm into single-chamber ICDs will help monitor and detect AF, thus facilitating optimal therapy to prevent AF-related sequelae.

Extended detection time to reduce shocks is safe in secondary prevention patients: The secondary prevention substudy of PainFree SST.

BACKGROUND: Prolonged ventricular fibrillation (VF) detection has been shown to reduce implantable cardioverter-defibrillator (ICD) therapies and improve prognosis in primary prevention ICD patients. Data in secondary prevention patients are limited. OBJECTIVE: The PainFree SST secondary prevention study is the largest trial of secondary prevention patients randomized between standard and prolonged detection to assess the safety of this strategy in these patients. METHODS: A total of 705 secondary prevention patients implanted with an ICD in the PainFree SST trial were enrolled in this substudy; 353 patients were randomized to VF detection of 18/24 intervals and 352 patients to 30/40. All other VF parameters were standardized by protocol. RESULTS: The 1-year arrhythmic syncope-free rates in the standard and prolonged groups were 97.7% vs 96.9%, respectively, (P = .0034 for noninferiority). Freedom from all-cause syncope was 96% in both arms (P = .0013 for noninferiority). There was no difference in the time to first appropriate or inappropriate VF therapy. However, the rates of treated VF episodes were lower in the prolonged arm (1.48 per patient per year vs 0.44 per patient per year, P = .0001). A trend toward lower mortality in the prolonged group was not statistically different (5.6% 1 year, 12% 2 years vs 3.8% 1 year, 7.7% 2 years, adjusted hazard ratio = 0.60, P = .061). CONCLUSION: This large prospective randomized study shows that prolonged detection can safely be programmed in secondary prevention ICD patients with new or existing devices. This programming strategy decreases the rate of treated events and is not associated with an increased risk of syncope or mortality.

Effect of ICD Therapies on Mortality in the OMNI Trial.

BACKGROUND: Analyses from primary prevention trials on implantable cardioverter defibrillator (ICD) therapy have shown an association between shocks and increased mortality. Recent data suggest a similar association with antitachycardia pacing (ATP). OBJECTIVE: The OMNI study is an observational study of pacemaker and ICD use. We aim to examine associations between ICD therapies and mortality in this setting. METHODS: A total of 2,255 OMNI patients with ICDs were included. Treated episodes were classified as appropriate or inappropriate. Patients were assigned into 1 of 3 groups depending on whether the episode required ATP only, single shock, or multiple shocks, and then followed for all-cause mortality. Additionally, we aimed to determine the frequency with which inappropriate ATP precipitated ventricular arrhythmias that led to shock, since this has been suggested as a mechanism of harm. RESULTS: Over a mean follow-up of 39 ± 19 months, there were a total of 470 deaths (21%). Compared to patients with no treated episodes, patients with appropriate therapy had greater risk of death. Hazard ratios were 1.46 (95% confidence interval [CI] 1.05-2.02; P = 0.023) for the ATP-only group, 2.11 (95% CI 1.51-2.96; P < 0.001) for the single-shock group, and 2.55 (95% CI 1.43-4.57; P = 0.002) for the multishock group. There was no significant association between any type of inappropriate therapy and increased mortality. We identified only 7 instances of inappropriate ATP precipitating ventricular arrhythmia resulting in shock. CONCLUSIONS: Patients receiving appropriate therapy of all types had increased mortality compared to those with no episodes. Furthermore, inappropriate ATP rarely precipitates ventricular arrhythmias.

Sinus rhythm R-wave amplitude as a predictor of ventricular fibrillation undersensing in patients with implantable cardioverter-defibrillator.

BACKGROUND: Ventricular fibrillation (VF) is induced during implantable cardioverter-defibrillator (ICD) implantation to ensure that the ICD will sense, detect, and defibrillate VF. ICD implant guidelines state that the amplitude of the sinus rhythm R wave recorded from the ventricular electrogram should have amplitude ≥5 mV. No study has tested the relationship between sinus rhythm R-wave amplitude and VF sensing using modern, transvenous sensing electrodes. OBJECTIVE: The goal of this study was to determine whether there is a sinus rhythm R-wave amplitude cutoff that can be used to determine which patients are not at risk of VF undersensing. METHODS: A retrospective analysis of induced and spontaneous VF episodes from 2 clinical trials with 2022 patients was performed. Episodes with undersensing during the initial detection of VF were identified, and the distribution of sinus rhythm R-wave amplitudes for patients with and without VF undersensing was analyzed. RESULTS: Only 3% of analyzed induced VF episodes were considered to have VF undersensing, and none had clinically significant detection delays. There was no correlation between device-measured, rectified sinus rhythm R-wave amplitude and VF undersensing at the time of implantation or during follow-up, although <4% of patients had sinus rhythm R-waves with amplitude <3 mV. CONCLUSION: We analyzed true bipolar sensing of induced VF or spontaneous ventricular tachycardia/VF detected in the ICD VF zone. Sensing of VF was so reliable that clinically significant undersensing did not occur. Our findings do not support any recommended minimum sinus rhythm R wave to ensure reliable sensing of VF or the necessity of inducing VF to verify sensing for rectified sinus rhythm R-waves with amplitude ≥3 mV.

Implantable defibrillators with enhanced detection algorithms: detection performance and safety results from the PainFree SST study.

BACKGROUND: Implantable defibrillators (ICD) are highly effective in reducing arrhythmia-related mortality. ICD shock therapy has been shown to increase psychological distress, health care utilization, and is associated with increased mortality. The Protecta ICDs (Medtronic Inc., Minneapolis, MN, USA) have algorithms designed to reduce unnecessary and inappropriate shock therapy. METHODS AND RESULTS: The PainFree SmartShock™ Technology (PainFree SST) study is a prospective, multicenter, clinical trial with two consecutive phases, a premarket phase safety study and a postmarket phase effectiveness study. We report the results of the PainFree SST safety study. The premarket phase aimed to investigate safety in the first year postimplant, and to determine if the novel algorithms (T-wave discrimination, right ventricular lead noise discrimination and confirmation+) affect appropriate ventricular fibrillation (VF) detection. Patients (total: n = 246 [male 78%, mean age 63 year, primary prevention indication in 76%]) were implanted either with a Protecta XT dual-chamber ICD (n = 114 [46%]) or a defibrillator with cardiac resynchronization therapy (n = 132 [54%]). Appropriate VF detection was measured during VF induction at implantation when the novel algorithms were programmed ON. A two-second delay in VF detection was classified as clinically significant. No delay in VF detection was observed with all algorithms programmed ON. No unanticipated serious adverse device effects occurred during first year postimplant. CONCLUSION: The results of the premarket phase of the PainFree SST trial demonstrate the safety of the Protecta XT defibrillators. Detection of induced VF was not delayed with SmartShock™ algorithms ON.

Prognostic significance of atrial arrhythmias in a primary prevention ICD population.

INTRODUCTION: We investigated whether primary prevention implantable cardioverter defibrillator (ICD) patients with atrial arrhythmias are at higher risk for ICD shocks and mortality compared to patients without atrial arrhythmias in a subanalysis of the PREPARE study. METHODS AND RESULTS: Details of the PREPARE study design and results have been previously reported. We now included 537 of the 700 patients enrolled in PREPARE. These patients had a dual or biventricular device and at least one device follow-up after implantation. Continuously collected device diagnostics data were used to classify patients into two groups during follow-up: with (n = 133) or without (n = 404) atrial tachycardia/atrial fibrillation (AT/AF). The primary outcomes were ICD shocks and mortality. Subjects were followed for a mean of 333 ± 73 (range 5-365) days. During a follow-up of 1 year, ICD shocks occurred in 44 (8%) patients. Significantly, more patients with AT/AF received a shock (13.0% vs 6.9%, P = 0.03), with inappropriate shocks accounting for the majority of the difference (6.9% vs 2.6%, P = 0.02). There was no difference in prevalence of shocks between patients with and without a history of AF. Mortality was similar in patients with and without AT/AF, whether detected during the study or prior to the study. In addition, the 34 subjects with high average ventricular rate (≥110 beats per minute) during AT/AF had a higher risk of an inappropriate shock (21.0% vs 2.1%, P < 0.01). CONCLUSION: Primary prevention ICD patients with AT/AF are more likely to receive shocks, especially inappropriate shocks. Mortality was not higher in AT/AF patients. (PACE 2011; 34:1070-1079).

Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial.

OBJECTIVES: The purpose of this trial was to determine whether microvolt T-wave alternans (MTWA) predicts ventricular tachyarrhythmic events (VTEs) in post-myocardial infarction patients with left ventricular ejection fraction (LVEF) < or =30%. BACKGROUND: Previous studies have established MTWA as a predictor for total and arrhythmic mortality, but its ability to identify prophylactic implantable cardioverter-defibrillator (ICD) recipients most likely to experience VTEs remains uncertain. METHODS: This prospective trial was conducted at 50 U.S. centers. Patients were eligible if they met MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) indications for device implant. All patients underwent MTWA testing followed by ICD implantation, with pre-specified programming to minimize the likelihood of therapies for non-life-threatening VTE. Minimum follow-up was 2 years with annual MTWA testing. Initially indeterminate MTWA tests were repeated. RESULTS: Analyses were conducted on 575 patients (84% male; average age +/- SD = 65 +/- 11 years; average LVEF +/- SD = 0.24 +/- 0.05). The final distribution of MTWA results were: MTWA positive in 293 (51%), MTWA negative in 214 (37%), and indeterminate in 68 patients (12%). Over an average follow-up of 2.1 +/- 0.9 years, there were 70 VTEs. A VTE occurred in 48 of 361 (13%, 6.3%/year) MTWA non-negative and 22 of 214 (10%, 5.0%/year) MTWA negative patients. A non-negative MTWA test result was not associated with VTE (hazard ratio: 1.26; 95% confidence interval: 0.76 to 2.09; p = 0.37), although total mortality was significantly increased (hazard ratio: 2.04; 95% confidence interval: 1.10 to 3.78; p = 0.02). CONCLUSIONS: In MADIT-II-indicated ICD-treated patients, the risk of VTE does not differ according to MTWA classification, despite differences in total mortality. (MASTER I-Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients; NCT00305240).

Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study.

OBJECTIVES: Our purpose was to demonstrate that strategically chosen implantable cardioverter-defibrillator (ICD) ventricular tachycardia (VT) or ventricular fibrillation (VF) detection and therapy parameters can reduce the combined incidence of device-delivered shocks, arrhythmic syncope, and untreated sustained symptomatic VT/VF (morbidity index). BACKGROUND: Strategically chosen ICD VT/VF detection and therapy parameters have been shown in previous studies to reduce the number of shocked episodes. In the PREPARE (Primary Prevention Parameters Evaluation) study, these prior strategies were combined with additional strategies specific to primary prevention patients. METHODS: The PREPARE study was a prospective, cohort-controlled study that analyzed 700 patients (biventricular [Bi-V] ICD and non-Bi-V ICD) with primary prevention indications for an ICD from 38 centers followed for 1 year. VT/VF was detected for rates > or =182 beats/min that were maintained for at least 30 of 40 beats. Antitachycardia pacing was programmed as the first therapy for regular rhythms with rates of 182 to 250 beats/min, and supraventricular tachycardia discriminators were used for rhythms < or =200 beats/min. The control cohort consisted of 689 primary prevention patients from the EMPIRIC (Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter Defibrillators Trial) (non-Bi-V ICD, physician arm only) and MIRACLE ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation) (Bi-V ICD) trials for whom VT/VF detection and therapy programming were not controlled. RESULTS: The PREPARE programming significantly reduced the morbidity index incidence density (0.26 events/patient-year for PREPARE study patients vs. 0.69 control cohort, p = 0.003). The PREPARE study patients were less likely to receive a shock in the first year compared with control patients (9% vs. 17%, p < 0.01). The incidence of untreated VT and arrhythmic syncope was similar between the PREPARE study patients and the control cohort. CONCLUSIONS: Strategically chosen VT/VF detection and therapy parameters can safely reduce shocks and other morbidities associated with ICD therapy in patients receiving an ICD for primary prevention indications. (PREPARE-Primary Prevention Parameters Evaluation; NCT00279279).

Identification of nestin-positive putative mammary stem cells in human breastmilk.

Stem cells in mammary tissue have been well characterised by using the mammary stem cell marker, cytokeratin (CK) 5 and the mature epithelial markers CK14, CK18 and CK19. As these markers have never been reported in cells from breastmilk, the aim of this study has been to determine whether mammary stem cells are present in expressed human breastmilk. Cultured cells from human breastmilk were studied by using immunofluorescent labelling and reverse transcription/polymerase chain reaction (RT-PCR). We found a heterogeneous population of cells with differential expression of CK5, CK14, CK18 and CK19. Further, by using the multipotent stem cell marker, nestin, we identified cells in culture that were positive only for nestin or double-positive for CK5/nestin, whereas no co-staining was observed for CK14, CK18 and CK19 with nestin. When cells isolated from breastmilk were analysed by using RT-PCR prior to culture, only nestin and CK18 were detected, thereby indicating that breastmilk contained differentiated epithelial and putative stem cells. Furthermore, fluorescence-activated cell-sorting analysis demonstrated, in breastmilk, a small side-population of cells that excluded Hoechst 33342 (a key property of multipotent stem cells). When stained for nestin, the cells in the side-population were positive, whereas those not in the side-population were negative. The presence of nestin-positive putative mammary stem cells suggests that human breastmilk is a readily available and non-invasive source of putative mammary stem cells that may be useful for research into both mammary gland biology and more general stem cell biology.

Activating transcription factor 2 controls Bcl-2 promoter activity in growth plate chondrocytes.

Activating transcription factor 2 (ATF-2) is expressed ubiquitously in mammals. Mice deficient in ATF-2 (ATF-2 m/m) are slightly smaller than their normal littermates at birth. Approximately 50% of mice born mutant in both alleles die within the first month. Those that survive develop a hypochondroplasia-like dwarfism, characterized by shortened growth plates and kyphosis. Expression of ATF-2 within the growth plate is limited to the resting and proliferating zones. We have previously shown that ATF-2 targets the cyclic AMP response element (CRE) in the promoters of cyclin A and cyclin D1 in growth plate chondrocytes to activate their expression. Here, we demonstrate that Bcl-2, a cell death inhibitor that regulates apoptosis, is expressed within the growth plate in proliferative and prehypertrophic chondrocytes. However, Bcl-2 expression declines in hypertrophic chondrocytes. The Bcl-2 promoter contains a CRE at -1,552 bp upstream of the translation start. Mutations within this CRE cause reduced Bcl-2 promoter activity. We show here that the absence of ATF-2 in growth plate chondrocytes corresponds to a decline in Bcl-2 promoter activity, as well as a reduction in Bcl-2 protein levels. In addition, we show that ATF-2 as well as CREB, a transcription factor that can heterodimerize with ATF-2, bind to the CRE within the Bcl-2 promoter. These data identify the Bcl-2 gene as a novel target of ATF-2 and CREB in growth plate chondrocytes.

Electrocardiographic events preceding onset of atrial fibrillation: insights gained using an implantable loop recorder.

INTRODUCTION: Previous reports demonstrate that individual patients may have distinctive electrocardiographic patterns preceding atrial fibrillation (AF) onset. However, these observations are based on single recordings, and are thus limited by their "snapshot" derivation; it is unclear whether patterns observed on these recordings are consistent over time. We hypothesized that the use of an implantable loop recorder (ILR) would be feasible for serial, long-term characterization of electrocardiographic events preceding AF onset. METHODS AND RESULTS: An ILR was implanted in 29 patients with AF. Patients were instructed to activate the device immediately upon experiencing AF symptoms. Analysis focused on the electrocardiographic segment immediately preceding AF; each segment was classified as one of six patterns: short/long, normal sinus rhythm, absolute sinus bradycardia, relative sinus bradycardia, absolute sinus tachycardia, or relative sinus tachycardia. From a total of 318 device activations, 105 AF onsets were suitable for analysis, acquired from 21 patients over a mean follow-up interval of 7 months. Although AF was frequently triggered by an atrial premature beat that emerged during normal sinus rhythm, most patients demonstrated a variety of onset patterns. Degeneration of uniform atrial tachycardia to AF was rare. Significant delay in device activation relative to AF onset was common, as was activation in the absence of AF. CONCLUSIONS: Using the ILR, serial, long-term characterization of electrocardiographic events preceding AF onset was feasible, and typically demonstrated a varied pattern within individuals. There was significant incongruity between symptomatic and electrocardiographic AF burden. As described here, ILR technology is inadequate for the purpose of accurate characterization of AF burden.

Atrial response to ventricular antitachycardia pacing discriminates mechanism of 1:1 atrioventricular tachycardia.

BACKGROUND: Inappropriate shocks from implantable cardioverter defibrillators (ICD) remain a significant clinical problem despite device discrimination algorithms. The atrial response to antitachycardia pacing (ATP) may determine the mechanism of 1:1 A:V tachycardia. METHODS: For this study we refer to sinus tachycardia, atrial tachycardia (AT), atrial fibrillation, and flutter as atrial tachycardia (AT), and all other tachycardia as "non-AT." Three atrial response patterns during the burst of ATP were determined. The atrial cycle length (ACL) may be unchanged (type 1) indicating AT. The ACL may show variation during ATP (type 2) indicating variable VA block and does not discriminate between an AT and a non-AT mechanism, in which case a default diagnosis of non-AT is made. The ACL may accelerate to the ATP cycle length (type 3) indicating entrainment. A VAAV response at the end of ATP was considered diagnostic of AT (type 3A) whereas a VAV or VVA response was considered a non-AT mechanism (type 3B). This algorithm was applied to ICD tracings from 68 episodes of spontaneous 1:1 A:V tachycardia that had 136 sequences of ATP administered. The rhythm "truth" was determined by consensus of two experienced clinicians. RESULTS: The algorithm correctly identified AT with a sensitivity of 71.9% (95% CI: 67.1-73.6), and specificity of 95% (83.5-99.1). The PPV was 97.2% (90.9-99.5), and NPV 58.5% (51.4-61.0). Kappa was 0.57 (0.43-0.62). If used clinically the algorithm would have aborted 53.3% (8/15) of inappropriate shocks delivered into an AT-mechanism tachycardia and would not have withheld a shock for any episode of VT. CONCLUSION: Analysis of atrial response patterns during and after ventricular ATP can successfully discriminate tachycardia mechanism and may reduce inappropriate ICD shocks.