Visualization of thermal damage using 68 Ga-FAPI-PET/CT after pulmonary vein isolation.

PURPOSE: 68 Ga-fibroblast-activation protein inhibitor (FAPI) positron emission tomography (PET) is a novel technique targeting FAP-alpha. This protein is expressed by activated fibroblasts which are the main contributors to tissue remodeling. The aim of this proof-of-concept study was to assess 68 Ga-FAPI uptake in the pulmonary vein (PV) region of the left atrium after pulmonary vein isolation (PVI) with cryoballoon ablation (CBA) and radiofrequency (RFA) as a surrogate for thermal damage. METHODS: Twelve PVI patients (5 RFA, 7 CBA) underwent 68 Ga-FAPI-PET 20.5 ± 12.8 days after PVI. Five patients without atrial fibrillation or previous ablation served as controls. Standardized uptake values of localized tracer uptake were calculated. RESULTS: Focal FAPI uptake around the PVs was observed in 10/12 (83.3%) PVI patients, no uptake was observed in 2 PVI patients and all controls. Patients after PVI had higher FAPI uptake in PVs compared to controls (SUVmax: 4.3 ± 2.2 vs. 1.6 ± 0.2, p < 0.01; SUVpeak: 2.9 ± 1.4 vs. 1.3 ± 0.2, p < 0.01). All CBA patients had an intense uptake, while in the RFA, group 2 (40%), 1 (20%), and 2 (40%) patients had an intense, moderate, and no uptake, respectively. We observed higher uptake values (SUVpeak) in CBA compared to RFA patients (4.4 ± 1.5 vs. 2.5 ± 0.8, p = 0.02). CONCLUSION: We demonstrate in-vivo visualization of 68 Ga-FAPI uptake as a surrogate for fibroblast activation after PVI. CBA seems to cause more pronounced fibroblast activation following tissue injury than RFA. Future studies are warranted to assess if this modality can contribute to a better understanding of the mechanisms of AF recurrence after PVI by lesion creation and gap assessment.

Novel cryoballoon ablation system for pulmonary vein isolation: multicenter assessment of efficacy and safety-ANTARCTICA study.

AIMS: Pulmonary vein isolation (PVI) either by balloon devices or radiofrequency forms the cornerstone of invasive atrial fibrillation (AF) treatment. Although equally effective cryoballoon (CB)-based PVI offers shorter procedure duration and a better safety profile. Beside the worldwide established Arctic Front Advance system, a novel CB device, POLARx, was recently introduced. This CB incorporates unique features, which may translate into improved efficacy and safety. However, multicentre assessment of periprocedural efficacy and safety is lacking up to date. METHODS AND RESULTS: A total of 317 patients with paroxysmal or persistent AF were included and underwent POLARx CB-based PVI in 6 centres from Germany and Italy. Acute efficacy and safety were assessed in this prospective multicenter observational study. In 317 patients [mean age: 64 ± 12 years, 209 of 317 (66%) paroxysmal AF], a total of 1256 pulmonary veins (PVs) were identified and 1252 (99,7%) PVs were successfully isolated utilizing mainly the short tip POLARx CB (82%). The mean minimal CB temperature was -57.9 ± 7°C. Real-time PVI was registered in 72% of PVs. The rate of serious adverse events was 6.0% which was significantly reduced after a learning curve of 25 cases (9.3% vs. 3.0%, P = 0.018). The rate of recurrence-free survival after mean follow-up of 226 ± 115 days including a 90-day blanking period was 86.1%. CONCLUSION: In this large multicentre assessment, the novel POLARx CB shows a promising efficacy and safety profile after a short learning curve.

Subendothelial matrix components influence endothelial cell apoptosis in vitro.

The programmed form of cell death (apoptosis) is essential for normal development of multicellular organisms. Dysregulation of apoptosis has been linked with embryonal death and is involved in the pathophysiology of various diseases. Specifically, endothelial apoptosis plays pivotal roles in atherosclerosis whereas prevention of endothelial apoptosis is a prerequisite for neovascularization in tumors and metastasis. Endothelial biology is intertwined with the composition of subendothelial basement membrane proteins. Apoptosis was induced by addition of tumor necrosis factor-α to cycloheximide-sensitized endothelial cells. Cells were either grown on polystyrene culture plates or on plates precoated with healthy basement membrane proteins (collagen IV, fibronectin, or laminin) or collagen I. Our results reveal that proteins of healthy basement membrane alleviate cytokine-induced apoptosis whereas precoating with collagen type I had no significant effect on apoptosis by addition of tumor necrosis factor-α to cycloheximide-sensitized endothelial cells compared with cells cultured on uncoated plates. Yet, treatment with transforming growth factor-ß1 significantly reduced the rate of apoptosis endothelial cells grown on collagen I. Detailed analysis reveals differences in intracellular signaling pathways for each of the basement membrane proteins studied. We provide additional insights into the importance of basement membrane proteins and the respective cytokine milieu on endothelial biology. Exploring outside-in signaling by basement membrane proteins may constitute an interesting target to restore vascular function and prevent complications in the atherosclerotic cascade.

Postmortem interrogation of cardiac implantable electrical devices may clarify time and cause of death.

BACKGROUND: Postmortem interrogation of cardiac implantable electrical devices (CIED) in autopsy is not routinely performed. Thus, it remains unclear whether an interrogation might clarify time and cause of death. METHODS: Seventy of 4401 patients (1.6%) undergoing autopsy in 2014 and 2015 presented with a CIED. The explanted CIED were interrogated with respect to time and possible cause of death. Battery and lead parameters, clinical and technical alerts, and arrhythmia episodes were reviewed and afterwards correlated with the results of autopsy and clinical data. RESULTS: Twenty-five implantable cardioverter defibrillators (ICD) and 45 pacemaker (PM) devices were analyzed. Death was classified as cardiac by autopsy in 17 of 70 patients. Accordingly, presumably lethal ventricular arrhythmias were documented in six patients (8.6%; 5 ICD, 1 PM). In two of 30 patients with unknown cause of death after autopsy (6.7%), interrogation revealed ventricular tachycardia as potential reason for decease (1 ICD, 1 PM). Postmortem CIED interrogation additionally allowed to make a statement regarding the day of death in 36 patients (51%; 13 ICD, 23 PM). This was in accordance with clinical data or the results of autopsy in nine patients (25%; 3 ICD, 6 PM) or could even clarify the time of death in six patients (16.7%; 4 ICD, 2 PM). CONCLUSION: Interrogation of CIED revealed potentially lethal ventricular arrhythmias in 9 of 70 patients investigated and enabled valid estimation of the day of death in 15 patients. We therefore conclude that routinely performed postmortem CIED interrogation may clarify time and cause of death.

CD34+ circulating cells display signs of immune activation in patients with acute coronary syndrome.

Bone marrow-derived endothelial progenitor cells (EPC) are released into the peripheral blood in situations of vascular repair/angiogenesis. Regulation of vascular repair and angiogenesis by EPC depends not only on the number of circulating EPC but also on their functionality. As endothelial cells can act as antigen-presenting cells in coronary artery disease (CAD), we postulated that EPC can be immune activated here as well. CD34+-EPC were isolated from peripheral blood of patients with ST-elevation myocardial infarction (STEMI, n = 12), non-STEMI/unstable angina (UA, n = 15), and stable CAD (SA, n = 18). Expression of HLA-DR, adhesion and costimulatory molecules by isolated CD34+-EPC were compared with levels in healthy controls (n = 18). There were no significant differences in VCAM-1 and CD80 expression by peripheral circulating CD34+-EPC between the four groups, yet expression of CD86 was highest in UA (p < 0.05). ICAM-1 expression was lowest in SA (p < 0.01). CD34+-EPC constitutively expressed HLA-DR across all groups. Of note, patients pretreated with HMG-CoA reductase inhibitors exhibited lower expression of VCAM-1 by CD34+-EPC throughout all patient groups; furthermore, statins significantly limited ex vivo-induced upregulation of ICAM-1 by TNF-alpha. To the best of our knowledge, this is the first study to examine the expression of immune markers in peripheral circulating CD34+-EPC ex vivo. We demonstrate that CD34+-EPC display different patterns of adhesion and costimulatory molecules in various states of CAD. Expression levels were affected by pretreatment with statins. Hence, immune activity of peripheral circulating CD34+ cells might play a pathophysiologic role in evolution of CAD.

Catheter Ablation of Atrial Fibrillation in Patients with Previous Lobectomy or Partial Lung Resection: Long-Term Results of an International Multicenter Study.

INTRODUCTION: Data regarding the efficacy of catheter ablation in patients with atrial fibrillation (AF) and patients' previous history of pulmonary lobectomy/pneumonectomy are scanty. We sought to evaluate the efficacy and long-term follow-up of catheter ablation in this highly selected group of patients. MATERIAL AND METHODS: Twenty consecutive patients (8 females, 40%; median age 65.2 years old) with a history of pneumonectomy/lobectomy and paroxysmal or persistent AF, treated by means of pulmonary vein isolation (PVI) at ten participating centers were included. Procedural success, intra-procedural complications, and AF recurrences were considered. RESULTS: Fifteen patients had a previous lobectomy and five patients had a complete pneumonectomy. A large proportion (65%) of PV stumps were electrically active and represented a source of firing in 20% of cases. PVI was performed by radiofrequency ablation in 13 patients (65%) and by cryoablation in the remaining 7 cases. Over a median follow up of 29.7 months, a total of 7 (33%) AF recurrences were recorded with neither a difference between patients treated with cryoablation or radiofrequency ablation or between the two genders. CONCLUSIONS: Catheter ablation by radiofrequency ablation or cryoablation in patients with pulmonary stumps is feasible and safe. Long-term outcomes are favorable, and a similar efficacy of catheter ablation has been noticed in both males and females.

Apixaban versus PhenpRocoumon: Oral AntiCoagulation plus antiplatelet tHerapy in patients with Acute Coronary Syndrome and Atrial Fibrillation (APPROACH-ACS-AF): Rationale and design of the prospective randomized parallel-group, open-label, blinded-endpoint, superiority, multicenter-trial of a triple therapy versus a dual therapy in patients with Atrial Fibrillation and Acute Coronary Syndrome undergoing coronary stenting.

BACKGROUND: A regimen of dual (DAT) vs. triple (TAT) antithrombotic therapy reduces bleeding in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, recent evidence suggests that DAT may be associated with an increased ischemic risk. This raises the question whether DAT rather than TAT should be recommended to AF patients that undergo PCI for acute coronary syndrome (ACS), carrying a particularly high risk of both bleeding and ischemic events, studied only as subgroups of previous trials. METHODS AND DESIGN: The APPROACH-ACS-AF-(DZHK-7) trial is a multicenter prospective, randomized, open-label, blinded endpoint (PROBE) trial which will include patients presenting with an ACS managed by PCI and requiring oral anticoagulation (OAC) due to AF. The trial will test, whether a DAT-regimen comprising clopidogrel plus the non-Vitamin-K-antagonist oral anticoagulant (NOAC) apixaban is superior to a TAT-regimen of vitamin-K-antagonist (VKA) plus dual anti-platelet therapy (APT) with respect to bleeding. A total of 400 patients will be randomized 1:1 to a control-arm with guideline-recommended TAT with VKA plus clopidogrel and acetylsalicylic-acid and a study arm receiving DAT comprising apixaban plus clopidogrel. Patients will be followed-up for 6 months. The primary endpoint of the study is the cumulative incidence of BARC type ≥2 bleeding, secondary endpoints include a composite clinical ischemic outcome and net clinical outcome. CONCLUSIONS: APPROACH-ACS-AF is the first trial dedicated to ACS patients, testing whether in terms of bleeding a DAT with NOAC is superior to a TAT regimen with VKA in high-risk ACS patients with AF.

3D matrix-embedding inhibits cycloheximide-mediated sensitization to TNF-alpha-induced apoptosis of human endothelial cells.

The programmed form of cell death (apoptosis) is essential for normal development of multicellular organisms. Dysregulation of apoptosis has been linked with embryonal death and is involved in the pathophysiology of various diseases. Others and we previously demonstrated endothelial biology being intertwined with biochemical and structural composition of the subendothelial basement membrane. We now demonstrate that a three-dimensional growing environment significantly shields endothelial cells from cytokine-induced apoptosis. Detailed analysis reveals differences in intracellular signaling pathways in naive endothelial cells and cytokine-stimulated endothelial cells when cells are grown within a three-dimensional collagen-based matrix compared to cells grown on two-dimensional tissue culture plates. Main findings are significantly reduced p53 expression and level of p38-phosphorylation in three-dimensional grown endothelial cells. Despite similar concentrations of focal adhesion kinase, three-dimensional matrix-embedded endothelial cells express significantly less tyrosine-phosphorylated focal adhesion kinase. Pretreatment with antibodies against integrin αv ß3 partially reversed the protective effect of three-dimensional matrix-embedding on endothelial apoptosis. Our findings provide detailed insights into the mechanisms of endothelial apoptosis with respect to the spatial matrix environment. These results enhance our understanding of endothelial biology and may otherwise help in the design of tissue-engineered materials. Furthermore, findings on focal adhesion kinase phosphorylation might enhance our understanding of clinical studies with tyrosine kinase inhibitors.

Impairment of Quality of Life among Patients with Wearable Cardioverter Defibrillator Therapy (LifeVest®): A Preliminary Study.

BACKGROUND: Wearable cardioverter defibrillator (WCD) therapy is feasible and safe in patients as a transient protection against sudden cardiac death (SCD). However, the impact of WCD therapy on quality of life (QoL) has not been studied. METHODS: In our single-centre study, 109 consecutive patients with a prescription of WCD were retrospectively analysed. Quality of life has been assessed by a standardized questionnaire (EQ-5D-3L, modified). Additionally, clinical baseline and follow-up data and recorded arrhythmic episodes were evaluated. RESULTS: Mean WCD therapy time was 56.2 (± 42.4) days, with a daily wear time of 19.7 (± 5) hours. A total of 3441 arrhythmia episodes were detected. Of these, 27 (1%) were adequate but did not require shock therapy. Likewise, no inadequate shock therapy occurred. WCD therapy negatively affected quality of life: 43% of patients reported mental health issues. 37% reported pain or discomfort. Self-care, usual activities, and mobility were restricted in 17%, 48%, and 36%, respectively. 29% were afraid of receiving shock therapy, and 48% suffered from sleep disturbance. However, 64% indicated having felt safe during WCD therapy. Accordingly, average quality of life was rated 70/100 points. CONCLUSION: In our cohort, no SCD was prevented by WCD therapy. In contrast, in this preliminary study quality of life was reduced. Thus, careful recommendation of WCD therapy for high risk patients should be considered.

Initial single centre experience with the novel Rhythmia© high density mapping system in an all comer collective of 400 electrophysiological patients.

BACKGROUND: A novel, automatically annotating ultra-high density mapping system (Rhythmia©, Boston Scientific) collects a high number and quality of electrograms (EGMs). So far, data on general use in the electrophysiological laboratory are sparse. METHODS: We retrospectively analyzed all our ablations using Rhythmia and recorded patient clinical data, procedural parameters, and mapping parameters including the count of EGMs, mapping time, and mapping volume. Where appropriate, procedural parameters were compared over time to assess a learning curve. RESULTS: 400 patients underwent ablation of atrial fibrillation (n = 202), typical (n = 16) or atypical atrial flutter (n = 49), VT (n = 48), PVC (n = 35), accessory pathways (n = 14), AVNRT (n = 4), and focal atrial tachycardia (n = 32). System use was feasible, as no procedure had to be stopped for technical reasons and no ablation had to be withheld because of mapping failure, and safe, with an overall complication rate of 2.25%. Initial restrictions in manoeuvrability of the mapping catheter were overcome rapidly, as indicated by a significant decrease of fluoroscopy time (20 vs. 14 min, p = 0.02), use of contrast agent (50 vs. 40 ml; p < 0.01), and (not significant) lower procedure times (194 vs. 170 min; p = 0.12; comparing the first with the last third of patients undergoing pulmonary vein isolation only procedure). Ablation of complex left atrial, focal and ventricular tachycardias benefited from the reliable automatic annotation of a high number of EGMs. CONCLUSION: The use of the Rhythmia is feasible and safe. Initial restrictions in manoeuvrability of the Orion mapping catheter were overcome rapidly. The procedures that benefit the most from ultra-high density mapping are complex left atrial tachycardias, focal tachycardias, and ventricular tachycardias.