Economic analyses in cardiac electrophysiology: from clinical efficacy to cost utility.

Cardiac electrophysiology is an evolving field that relies heavily on costly device- and catheter-based technologies. An increasing number of patients with heart rhythm disorders are becoming eligible for cardiac interventions, not least due to the rising prevalence of atrial fibrillation and increased longevity in the population. Meanwhile, the expansive costs of healthcare face finite societal resources, and a cost-conscious approach to new technologies is critical. Cost-effectiveness analyses support rational decision-making in healthcare by evaluating the ratio of healthcare costs to health benefits for competing therapies. They may, however, be subject to significant uncertainty and bias. This paper aims to introduce the basic concepts, framework, and limitations of cost-effectiveness analyses to clinicians including recent examples from clinical electrophysiology and device therapy.

Atrial pacing minimization in sinus node dysfunction and risk of incident atrial fibrillation: a randomized trial.

BACKGROUND AND AIMS: High percentages of atrial pacing have been associated with an increased risk of atrial fibrillation. This study is aimed at evaluating whether atrial pacing minimization in patients with sinus node dysfunction reduces the incidence of atrial fibrillation. METHODS: In a nationwide, randomized controlled trial, 540 patients with sinus node dysfunction and an indication for first pacemaker implantation were assigned to pacing programmed to a base rate of 60 bpm and rate-adaptive pacing (DDDR-60) or pacing programmed to a base rate of 40 bpm without rate-adaptive pacing (DDD-40). Patients were followed on remote monitoring for 2 years. The primary endpoint was time to first episode of atrial fibrillation longer than 6 min. Secondary endpoints included longer episodes of atrial fibrillation, and the safety endpoint comprised a composite of syncope or presyncope. RESULTS: The median percentage of atrial pacing was 1% in patients assigned to DDD-40 and 49% in patients assigned to DDDR-60. The primary endpoint occurred in 124 patients (46%) in each treatment group (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.76-1.25, P = .83). There were no between-group differences in atrial fibrillation exceeding 6 or 24 h, persistent atrial fibrillation, or cardioversions for atrial fibrillation. The incidence of syncope or presyncope was higher in patients assigned to DDD-40 (HR 1.71, 95% CI 1.13-2.59, P = .01). CONCLUSIONS: Atrial pacing minimization in patients with sinus node dysfunction does not reduce the incidence of atrial fibrillation. Programming a base rate of 40 bpm without rate-adaptive pacing is associated with an increased risk of syncope or presyncope.

Cost-effectiveness of an antibacterial envelope for infection prevention in patients undergoing cardiac resynchronization therapy reoperations in Denmark.

AIMS: Use of an absorbable antibacterial envelope during implantation prevents cardiac implantable electronic device infections in patients with a moderate-to-high infection risk. Previous studies demonstrated that an envelope is cost-effective in high-risk patients within German, Italian, and English healthcare systems, but these analyses were based on limited data and may not be generalizable to other healthcare settings. METHODS AND RESULTS: A previously published decision-tree-based cost-effectiveness model was used to compare the costs per quality-adjusted life year (QALY) associated with adjunctive use of an antibacterial envelope for infection prevention compared to standard-of-care intravenous antibiotics. The model was adapted using data from a Danish observational two-centre cohort study that investigated infection-risk patients undergoing cardiac resynchronization therapy (CRT) reoperations with and without an antibacterial envelope (n = 1943). We assumed a cost-effectiveness threshold of €34 125/QALY gained, based on the upper threshold used by the National Institute for Health and Care Excellence (£30 000). An antibacterial envelope was associated with an incremental cost-effectiveness ratio (ICER) of €12 022 per QALY in patients undergoing CRT reoperations, thus indicating that the envelope is cost-effective when compared with standard of care. A separate analysis stratified by device type showed ICERS of €6227 (CRT defibrillator) and €29 177 (CRT pacemaker) per QALY gained. CONCLUSIONS: Cost-effectiveness ratios were favourable for patients undergoing CRT reoperations in the Danish healthcare system, and thus are in line with previous studies. Results from this study can contribute to making the technology available to Danish patients and align preventive efforts in the pacemaker and ICD area.

Rate of device-related infections using an antibacterial envelope in patients undergoing cardiac resynchronization therapy reoperations.

AIMS: Cardiac resynchronization therapy (CRT) reoperations are associated with a particularly high risk of device-related infection (DRI). An antibacterial envelope reduces the occurrence of DRIs in a broad population of moderate-tohigh-risk patients. To investigate the efficacy of an antibacterial envelope in a very high-risk population of patients undergoing CRT reoperation. METHODS AND RESULTS: In this Danish two-centre, observational cohort study, we included consecutive patients who underwent a CRT pacemaker- or defibrillator reoperation procedure between January 2008 and November 2019. We obtained data from the Danish Pacemaker and ICD Register and through systematic medical chart review. Follow-up was restricted to 2 years. A total of 1943 patients were included in the study of which 736 (38%) received an envelope. Envelope patients had more independent risk factors for infection than non-envelope patients. Sixty-seven (3.4%) patients met the primary endpoint of DRI requiring device system extraction; 50 in the non-envelope group and 17 in the envelope group [4.1% vs. 2.3%, adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.30-0.90; P = 0.021]. This difference persisted in propensity score analysis (HR 0.51, 95% CI 0.29-0.90; P = 0.019). CONCLUSION: Use of an antibacterial envelope was associated with a clinically and statistically significant reduction in DRIs in patients undergoing CRT reoperations. Our results were comparable to those recently reported from a large randomized controlled trial, which is suggestive of a proportional effect of the envelope even in very high-risk patients.

Long-term outcomes in a randomized controlled trial of multimodality imaging-guided left ventricular lead placement in cardiac resynchronization therapy.

AIMS: This study aims to investigate the long-term occurrence of the composite endpoint of heart failure (HF) hospitalization or all-cause death (primary endpoint) in patients randomized to cardiac resynchronization therapy (CRT) using individualized multimodality imaging-guided left ventricular (LV) lead placement compared with a routine fluoroscopic approach. Furthermore, this study aims to evaluate whether inter-lead electrical delay (IED) is associated with improved response rate of this endpoint. METHODS AND RESULTS: We reviewed follow-up data until November 2020 for all 182 patients included in the ImagingCRT trial for the occurrence of HF hospitalization and all-cause death. During median (inter-quartile range) time to primary endpoint/censuring of 6.7 (3.3-7.9) years, the rate of the primary endpoint was 60% (n = 53) in the imaging group compared with 52% (n = 48) in the control group [hazard ratio (HR) 1.22, 95% confidence interval (CI) 0.83-1.81, P = 0.31]. Neither the risk of HF hospitalization (HR 1.11, 95% CI 0.62-1.99, P = 0.72) nor of all-cause death differed between treatment groups (HR 1.23, 95% CI 0.82-1.85, P = 0.32). The risk of the primary endpoint was significantly reduced among those with IED ≥100 ms when compared with those with IED <100 ms (HR 0.62, 95% CI 0.39-0.98, P = 0.04). CONCLUSIONS: In this study, an individualized multimodality imaging-guided strategy targeting LV lead placement towards the latest mechanically activated non-scarred myocardial segment during CRT implantation did not reduce HF hospitalization or all-cause death when compared with routine LV lead placement during long-term follow-up. Targeting the latest electrical activation should be studied as an alternative individualized strategy for optimizing LV lead placement in CRT recipients.

Repeat pulmonary vein isolation in patients with atrial fibrillation: low ablation index is associated with increased risk of recurrent arrhythmia.

OBJECTIVES: We aimed to investigate the predictors of recurrent arrhythmia after repeated pulmonary vein isolation (PVI) performed in the era of contact force without additional substrate ablation. One of the predictors studied, ablation index (AI), incorporates power, contact force, and time in a weighted formula and is reported to predict lesion size in animals. Design. Consecutive patients (n = 108) undergoing repeat PVI without additional substrate modification using a contact force sensing catheter were included retrospectively at a tertiary center. All ablation points were analyzed offline. A new variable, normalized AI (AI corrected for the location of the lesion-anterior vs. posterior) was calculated. The patients were systematically followed with clinical visit and 12-lead ECG as well as review of the regional electronic patient files at 3 and 12 months after the procedure with 5-day Holter at 12 months. Results. Electrical reconnection to at least one pulmonary vein (PV) was seen in 97% of the patients. The recurrence rate was 35%. There was no recurrence in patients with nAI above 1.15 (n = 26). Patients with electrical reconnection of up to two PVs had a higher risk of recurrence compared with patients having electrical reconnection of three or four PVs (p = .003), and this risk was especially high in patients with persistent atrial fibrillation (69 [39-91]%). Conclusions. The risk of recurrence is higher in patients with ablations performed with low levels of AI and in patients with reconnection to up to two PVs. Our data may indicate the need for higher target levels of AI during repeat PVI than normally used during de-novo PVI.

Reproducibility and repeatability of identifying the latest electrical activation during mapping of coronary sinus branches in CRT recipients.

INTRODUCTION: Studies have shown an association between the outcome in cardiac resynchronization therapy (CRT) and longer interventricular delay at the site of the left ventricular (LV) lead. Targeted LV lead placement at the latest electrically activated segment increases LV function further as compared with standard treatment. We aimed to determine reproducibility and repeatability of identifying the latest electrically activated segment during mapping of all available coronary sinus (CS) branches in patients receiving CRT. METHODS: We included 35 patients who underwent CRT implantation with protocolled mapping guided LV lead implantation aiming for the site of the latest electrical activation. Three different doctors experienced in electrophysiology and implantation of CRT devices independently measured time interval from the local bipolar right ventricular (RV) electrogram (EGM) to the local unipolar LV EGM at all mapped sites (RV-LV). The segment with the latest electrical activation was defined as the target segment (TS) and the CS tributary containing TS was defined as the target vein (TV). Weighted κ statistics with 95% confidence intervals were computed to assess intra- and interobserver agreement for TS and TV. RESULTS: We mapped 258 segments within 131 veins. Weighted κ values for repeatability were 0.85 (0.81-0.89) for TS and 0.92 (0.89-0.93) for TV, and weighted κ values of interobserver agreement ranged from 0.70 (0.61-0.73) to 0.80 (0.76-0.83) for TS and 0.73 (0.64-0.78) to 0.86 (0.83-0.89) for TV among all three observers. CONCLUSION: The reproducibility and repeatability of identifying the latest electrically activated segment during mapping of all available CS branches in patients receiving CRT range from good to very good.

A randomized trial of contact force in atrial flutter ablation.

AIMS: Contact force (CF) sensing has emerged as a tool to guide and improve outcomes for catheter ablation (CA) for cardiac arrhythmias. The clinical benefit on patient outcomes remains unknown. To study whether CF-guided CA for typical atrial flutter (AFL) is superior to CA not guided by CF. METHODS AND RESULTS: In a double-blinded controlled superiority trial, we randomized patients 1:1 to receive CA for typical AFL guided by CF (intervention group) or blinded to CF (control group). In the intervention group, a specific value of the lesion size index (LSI), estimating ablation lesions size was targeted for each ablation lesion. Patients underwent electrophysiological study (EPS) after 3 months to assess occurrence of the primary endpoint of re-conduction across the cavo-tricuspid isthmus (CTI). We included 156 patients with typical AFL, median age was 68 [interquartile range (IQR) 61-74] years and 120 (77%) patients were male. At index procedure median LSI was higher in the intervention group [6.4 (IQR 5.1-7) vs. 5.6 (IQR 4.5-6.9), P < 0.0001]. After 3 months, 126 patients (58 in intervention group) underwent EPS for primary endpoint assessment. Thirty (24%) patients had CTI re-conduction, distributed with 15 patients in each treatment group (P = 0.62). We observed no difference between treatment groups with regard to fluoroscopy, ablation, or procedure times, nor peri-procedural complications. CONCLUSION: Contact force-guided ablation does not reduce re-conduction across the CTI after 3 months, nor does CF-guided ablation shorten fluoroscopy, ablation, or total procedure times.

Long-term follow-up of abandoned transvenous defibrillator leads: a nationwide cohort study.

AIMS: Commonly, a dysfunctional defibrillator lead is abandoned and a new lead is implanted. Long-term follow-up data on abandoned leads are sparse. We aimed to investigate the incidence and reasons for extraction of abandoned defibrillator leads in a nationwide cohort and to describe extraction procedure-related complications. METHODS AND RESULTS: All abandoned transvenous defibrillator leads were identified in the Danish Pacemaker and ICD Register from 1991 to 2019. The event-free survival of abandoned defibrillator leads was studied, and medical records of patients with interventions on abandoned defibrillator leads were audited for procedure-related data. We identified 740 abandoned defibrillator leads. Meantime from implantation to abandonment was 7.2 ± 3.8 years with mean patient age at abandonment of 66.5 ± 13.7 years. During a mean follow-up after abandonment of 4.4 ± 3.1 years, 65 (8.8%) abandoned defibrillator leads were extracted. Most frequent reason for extraction was infection (pocket and systemic) in 41 (63%) patients. Procedural outcome after lead extraction was clinical success in 63 (97%) patients. Minor complications occurred in 3 (5%) patients, and major complications in 1 (2%) patient. No patient died from complication to the procedure during 30-day follow-up after extraction. CONCLUSION: More than 90% of abandoned defibrillator leads do not need to be extracted during long-term follow-up. The most common indication for extraction is infection. Abandoned defibrillator leads can be extracted with high clinical success rate and low risk of major complications at high-volume centres.

Electrically vs. imaging-guided left ventricular lead placement in cardiac resynchronization therapy: a randomized controlled trial.

AIMS: To test in a double-blinded, randomized trial whether the combination of electrically guided left ventricular (LV) lead placement and post-implant interventricular pacing delay (VVd) optimization results in superior increase in LV ejection fraction (LVEF) in cardiac resynchronization therapy (CRT) recipients. METHODS AND RESULTS: Stratified according to presence of ischaemic heart disease, 122 patients were randomized 1:1 to LV lead placement targeted towards the latest electrically activated segment identified by systematic mapping of the coronary sinus tributaries during CRT implantation combined with post-implant VVd optimization (intervention group) or imaging-guided LV lead implantation by cardiac computed tomography venography, 82Rubidium myocardial perfusion imaging and speckle tracking echocardiography targeting the LV lead towards the latest mechanically activated non-scarred myocardial segment (control group). Follow-up was 6 months. Primary endpoint was absolute increase in LVEF. Additional outcome measures were changes in New York Heart Association class, 6-minute walk test, and quality of life, LV reverse remodelling, and device related complications. Analysis was intention-to-treat. A larger increase in LVEF was observed in the intervention group (11 ± 10 vs. 7 ± 11%; 95% confidence interval 0.4-7.9%, P = 0.03); when adjusting for pre-specified baseline covariates this difference did not maintain statistical significance (P = 0.09). Clinical response, LV reverse remodelling, and complication rates did not differ between treatment groups. CONCLUSION: Electrically guided CRT implantation appeared non-inferior to an imaging-guided strategy considering the outcomes of change in LVEF, LV reverse remodelling and clinical response. Larger long-term studies are warranted to investigate the effect of an electrically guided CRT strategy.

Outcome after catheter ablation for left atrial flutter.

Objectives. Left atrial flutter has been reported in up to 10% of patients following pulmonary vein isolation or cardiac surgery. Left atrial flutter is typically highly symptomatic, responds poorly to medical antiarrhythmic treatment, and is often treated by catheter ablation. We aimed to investigate midterm freedom from recurrent arrhythmia after catheter ablation for left atrial flutter. Design. In the National Danish Ablation Registry, we identified consecutive patients, who had undergone catheter ablation for left atrial flutter between 1 January 2014 and 1 April 2017 at our centre. Results. A total of 53 patients (median age 68 years (IQR 60-71) 37 (70%) male) were included. Forty-two patients had prior left atrial catheter ablation procedures (79%), one patient prior ablation for classic atrial flutter (2%), four patients had prior surgery for congenital heart disease (8%), and six patients (11%) had no previous cardiac intervention. Acute procedural success, defined as non-inducibility of any atrial arrhythmia, was achieved in 45 of 53 patients (85%). During midterm follow-up (mean 20 ± 12 months), 26 patients experienced an episode of recurrent atrial arrhythmia. Median EHRA-score was 3 (range 2-4) before catheter ablation and reduced to median 1 (range 1-3) evaluated at follow-up visits after three and twelve months (both p < .001, Wilcoxon rank test). Conclusion. Left atrial flutter is preceded by catheter ablation or cardiac surgery in 89% of patients. Acute procedural success is achieved in majority of patients and ablation reduces symptoms effectively. During midterm follow-up, almost half the patients experience recurrent atrial arrhythmia.

Reproducibility of measuring QRS duration and implications for optimization of interventricular pacing delay in cardiac resynchronization therapy.

BACKGROUND: QRS narrowing after CRT is a predictor of patient outcome. Further narrowing can be obtained by interventricular pacing delay (VVd) optimization, raising interest to inter and intraobserver variation in manual measurements of QRS duration. METHODS: (a) Variation in intrinsic rhythm QRS duration in CRT patients with LBBB: In 40 intrinsic 12-lead ECGs, six observers measured QRS duration defined as widest QRS in any lead. In 20 of these ECGs, two observers repeated the measurements. (b) Variation in paced QRS duration at different VVd settings and agreement in selecting the narrowest QRS: In 20 CRT patients, five paced ECGs were recorded at different VVds. The most frequently selected VVd(s) estimated to cause the narrowest QRS in each patient defined the optimal VVd. Two observers repeated the measurements and VVd selections. RESULTS: Absolute interobserver difference in measured QRS duration in intrinsic rhythm ECGs was mean 2 ms, range (-40; 40 ms), mean limits of agreement (LoA): -21; 25 ms. Absolute interobserver difference in measured QRS duration in paced ECGs was mean 3 ms, range (-50; 60 ms), mean LoA: -20; 27 ms. There was no difference in LoA between intrinsic and paced QRS duration (lower limit p = 0.68; upper limit p = 0.44). The optimal VVd was included in 17/20 (85%) of the VVd selections by six observers. Interobserver variation was comparable with the intraobserver variation. CONCLUSIONS: Interobserver variation and intraobserver variation in manually measured paced and intrinsic rhythm QRS duration are clinically acceptable and comparable in a cohort of CRT patients. Inter and intraobserver reproducibility for selecting the optimal VVd is good and warrants manual VVd optimization for QRS narrowing in CRT.

Longer inter-lead electrical delay is associated with response to cardiac resynchronization therapy in patients with presumed optimal left ventricular lead position.

Aims: In a randomized trial of cardiac resynchronization therapy (CRT), a presumed optimal left ventricular (LV) lead position close to the latest mechanically activated non-scarred myocardium was achieved in 98% of patients by standard implantation. We evaluated whether inter-lead electrical delay (IED) was associated with response to CRT in these patients. Methods and results: We prospectively included 160 consecutive patients undergoing CRT. Pre-implant speckle-tracking echocardiography radial strain and 99mTc myocardial perfusion imaging determined the latest mechanically activated non-scarred myocardial segment. We measured procedural IED as the time interval between sensed signals in right ventricular and LV lead electrograms. All patients had LV pacing site concordant or adjacent to the latest mechanically activated non-scarred segment verified by cardiac computed tomography. Response to CRT was defined as ≥15% reduction in LV end-systolic volume at 6 months follow-up. Selecting a practical IED cut-off value of 100 ms, more patients with long IED than patients with short IED responded to CRT (87 vs. 68%; P = 0.004). In multivariate logistic regression analysis, IED ≥100 ms remained associated with CRT response after adjusting for baseline characteristics, including QRS duration and scar burden [odds ratio 3.19 (1.24-8.17); P = 0.01]. Categorizing IED by tertiles, CRT response improved with longer IED (P = 0.03). Comparable response rates were observed in patients with a concordant and adjacent LV lead position. Conclusion: A longer IED was associated with more pronounced LV reverse remodelling response in CRT recipients with a presumed optimal LV lead position concordant or adjacent to the latest mechanically activated non-scarred segment.

Recurrence after pulmonary vein isolation is associated with low contact force.

OBJECTIVES: Recurrent arrhythmia after pulmonary vein isolation (PVI) by radiofrequency (RF) ablation in patients with atrial fibrillation (AFIB) remains a significant challenge. Using contact force (CF) sensing ablation catheters, we aimed to identify procedure related parameters associated with recurrence after de-novo PVI in patients with AFIB. METHODS: Consecutive patients undergoing a de-novo PVI procedure (n = 120, 63% paroxysmal and 37% persistent AFIB) employing a force-sensing ablation catheter were included. A clinical control including electrocardiogram and 120 hour of Holter-recording at 12-months was performed in all patients. Recurrence was defined as any documented AFIB or atrial flutter more than 30 seconds on Holter-recording after an initial blanking period of three months. RESULTS: Recurrence occurred in 44 patients (37%). Mean CF was lower in patients with recurrent arrhythmia (22.2 ± 9.5 vs. 28.8 ± 9.3 g, p < .001). In multi-variable analyses lower mean CF (OR 0.9 (95% CI 0.8-1.0), p = .03), and higher percentage of ablation time with a CF <10 grams (OR 1.1 (95% CI 1.0-1.1), p = .004) were both associated with recurrence in two distinct models. Dragging during ablation compared with point-by-point ablation technique was associated with recurrence in both models (OR 19.2 (95% CI 2.9-130.0), p = .002, and OR 21.7 (95% CI 2.7-176.2), p = .004). CONCLUSIONS: Low CF and dragging during ablation as compared with point-by-point ablation technique were associated with recurrent arrhythmia in patients with AFIB undergoing de-novo PVI by RF ablation.

Is the knowledge of contact force beneficial in pulmonary vein antrum isolation?

OBJECTIVE: To investigate the effect of the operator knowing the real-time contact force (CF) on the efficacy of pulmonary vein antrum isolation (PVAI). METHODS: Fifty patients with paroxysmal atrial fibrillation (AF) or short lasting persistent AF were randomized to CF guided PVAI (n = 25) or conventional PVAI (n = 25). In the CF guided group, CF between 10 and 40 g was aimed at. Efficacy of PVAI was measured as reduction in AF burden (AFB) and time to AF recurrence detected by implantable cardiac monitor (ICM), inserted three months before PVAI. Blanking period was three months and follow-up 12 months. RESULTS: All pulmonary veins were isolated in the CF guided group and all but one in the conventional group. Mean CF was 25 g in the CF guided group and 24 g in the conventional group (p = 0.75). Compared to pre-ablation, median [IQR] relative reduction in AFB 3-12 months after ablation was 100 [99-100]% in the CF guided group (p < 0.001) and 99.4 [25-100]% in the conventional group (p < 0.001), not different between groups (p = 0.09). Nine patients (36%) had AF recurrence in the CF guided group and 13 (52%) in the conventional group (p = 0.21, log-rank test). CF differed between operators. When adjusted for operator by regression analysis, patients without recurrent AF had lower proportion of ablation time with CF <10 g than recurrent patients (p = 0.034). No complications occurred. CONCLUSIONS: Operator knowledge of real-time CF had no significant effect on AFB reduction or time to AF recurrence. Larger trials should be done to study benefit of real-time CF.

Isolation and (111)In-Oxine Labeling of Murine NK Cells for Assessment of Cell Trafficking in Orthotopic Lung Tumor Model.

A noninvasive in vivo imaging method for NK cell trafficking is essential to gain further understanding of the pathogenesis of NK cell mediated immune response to the novel cancer treatment strategies, and to discover the homing sites and physiological distribution of NK cells. Although human NK cells can be labeled for in vivo imaging, little is known about the murine NK cell labeling and its application in animal models. This study describes the isolation and ex vivo radiolabeling of murine NK cells for the evaluation of cell trafficking in an orthotopic model of human lung cancer in mice. Scid-Tg(FCGR3A)Blt transgenic SCID mice were used to isolate NK cells from mouse splenocytes using the CD49b (DX5) MicroBeads positive selection method. The purity and viability of the isolated NK cells were confirmed by FACS analysis. Different labeling buffers and incubation times were evaluated to optimize (111)In-oxine labeling conditions. Functionality of the radiolabeled NK cell was assessed by (51)Cr-release assay. We evaluated physiological distribution of (111)In-oxine labeled murine NK cells in normal SCID mice and biodistribution in irradiated and nonirradiated SCID mice with orthotopic A549 human lung tumor lesions. Imaging findings were confirmed by histology. Results showed that incubation with 0.011 MBq of (111)In-oxine per million murine NK cells in PBS (pH 7.4) for 20 min is the best condition that provides optimum labeling efficiency without affecting cell viability and functionality. Physiological distribution in normal SCID mice demonstrated NK cells homing mainly in the spleen, while (111)In released from NK cells was excreted via kidneys into urine. Biodistribution studies demonstrated a higher lung uptake in orthotopic lung tumor-bearing mice than control mice. In irradiated mice, lung tumor uptake of radiolabeled murine NK cells decreased between 24 h and 72 h postinjection (p.i.), which was accompanied by tumor regression, while in nonirradiated mice, radiolabeled NK cells were retained in the lung tumor lesions up to 72 h p.i. without tumor regression. In tumor-bearing mice that were only irradiated but did not receive radiolabeled murine NK cells, a high tumor burden was observed at 72 h p.i., which indicates that irradiation in combination with murine NK cell allocation, but not irradiation alone, induced a remarkable antitumor effect in the orthotopic A549 lung tumor bearing mouse model. In conclusion, we describe a method to evaluate murine NK cell trafficking and biodistribution, which can be used to determine potential effects of immune-mediated therapeutic agents on NK cell biodistribution.

Adding the implantable cardioverter-defibrillator to cardiac resynchronization therapy is associated with improved long-term survival in ischaemic, but not in non-ischaemic cardiomyopathy.

AIMS: Cardiac resynchronization therapy (CRT) improves symptoms, left ventricular function, and survival in patients with heart failure (HF) and wide QRS. The benefit of adding implantable cardioverter-defibrillator (ICD) backup is debated. We analysed the long-term outcome of patients with HF due to ischaemic cardiomyopathy (ICM) or non-ischaemic cardiomyopathy (NICM) treated with a CRT device with or without defibrillator backup. METHODS AND RESULTS: In this observational study, consecutive patients with an ejection fraction ≤35% and QRS width ≥120 ms receiving a CRT device at Aarhus University Hospital, Denmark from 2000 to 2010 were included. Baseline characteristics were retrieved from patient files and survival data were obtained from the Danish Civil Registration System. The primary outcome was all-cause mortality. The effect of ICD backup was estimated using Cox proportional hazards model, and the multivariate analyses were adjusted for a priori selected variables. We included 917 HF patients, 427 with NICM, and 490 with ICM. Median follow-up was 4.0 years. Adjusted hazard ratio (aHR) for all-cause mortality was 0.76 [95% confidence interval (95% CI), 0.60-0.97; P = 0.03] in all patients; 0.96 (95% CI, 0.60-1.51; P = 0.85) in patients with NICM, and 0.74 (95% CI, 0.56-0.97; P = 0.03) in patients with ICM. In patients with NICM, ICD backup seemed to be associated with improved survival among non-responders to CRT (P = 0.08), but not among responders (P = 0.61). CONCLUSION: Adding an ICD backup is associated with better survival in CRT recipients. This effect was evident among patients with ICM, but not in patients with NICM.

Glycoengineering of therapeutic antibodies enhances monocyte/macrophage-mediated phagocytosis and cytotoxicity.

Therapeutic Abs possess several clinically relevant mechanisms of action including perturbation of tumor cell signaling, activation of complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cellular phagocytosis (ADCP), and induction of adaptive immunity. In view of the important role of phagocytic lineage cells in the mechanism of action of therapeutic Abs, we analyzed FcγR receptor-dependent effector functions of monocytes and macrophages triggered by glycoengineered (GE) Abs (having enhanced FcγRIIIa [CD16a] binding affinity) versus their wild-type (WT) counterparts under different experimental conditions. We first defined the precise FcγR repertoire on classical and nonclassical intermediate monocytes--M1 and M2c macrophage populations. We further show that WT and GE Abs display comparable binding and induce similar effector functions (ADCC and ADCP) in the absence of nonspecific, endogenous IgGs. However, in the presence of these IgGs (i.e., in a situation that more closely mimics physiologic conditions), GE Abs display significantly superior binding and promote stronger monocyte and macrophage activity. These data show that in addition to enhancing CD16a-dependent NK cell cytotoxicity, glycoengineering also enhances monocyte and macrophage phagocytic and cytotoxic activities through enhanced binding to CD16a under conditions that more closely resemble the physiologic setting.

¹¹¹In-anti-F4/80-A3-1 antibody: a novel tracer to image macrophages.

PURPOSE: Here, the expression of F4/80 on the cell surface of murine macrophages was exploited to develop a novel imaging tracer that could visualize macrophages in vivo. METHODS: The immunoreactive fraction and IC50 of anti-F4/80-A3-1, conjugated with diethylenetriaminepentaacetic acid (DTPA) and radiolabelled with (111)In, were determined in vitro using murine bone marrow-derived macrophages. In vivo biodistribution studies were performed with (111)In-anti-F4/80-A3-1 and isotype-matched control antibody (111)In-rat IgG2b at 24 and 72 h post-injection (p.i.) in SCID/Beige mice bearing orthotopic MDA-MB-231 xenografts. In some studies mice were also treated with liposomal clodronate. Macrophage content in tissues was determined immunohistochemically. Micro-single photon emission computed tomography (SPECT)/CT images were also acquired. RESULTS: In vitro binding assays showed that (111)In-anti-F4/80-A3-1 specifically binds F4/80 receptor-positive macrophages. The immunoreactivity of anti-F4/80-A3-1 was 75 % and IC50 was 0.58 nM. In vivo, injection of 10 or 100 µg (111)In-anti-F4/80-A3-1 resulted in splenic uptake of 78 %ID/g and 31 %ID/g, respectively, and tumour uptake of 1.38 %ID/g and 4.08 %ID/g, respectively (72 h p.i.). Liposomal clodronate treatment reduced splenic uptake of 10 µg (111)In-anti-F4/80-A3-1 from 248 %ID/g to 114 %ID/g and reduced (111)In-anti-F4/80-A3-1 uptake in the liver and femur (24 h p.i.). Tracer retention in the blood and tumour uptake increased (24 h p.i.). Tumour uptake of (111)In-anti-F4/80-A3-1 was visualized by microSPECT/CT. Macrophage density in the spleen and liver decreased in mice treated with liposomal clodronate. Uptake of (111)In-rat IgG2b was lower in the spleen, liver and femur when compared to (111)In-anti-F4/80-A3-1. CONCLUSION: Radiolabelled anti-F4/80-A3-1 antibodies specifically localize in tissues infiltrated by macrophages in mice and can be used to visualize tumours. The liver and spleen act as antigen sink organs for macrophage-specific tracers.