Pulmonary vein reconnection and repeat ablation characteristics following cryoballoon-compared to radiofrequency-based pulmonary vein isolation.

BACKGROUND: Despite advances in efficacy and safety of pulmonary vein isolation (PVI), atrial fibrillation (AF) recurrence after PVI remains common. PV-reconnection is the main finding during repeat PVI procedures performed to treat recurrent AF. OBJECTIVE: To analyze pulmonary vein (PV) reconnection patterns during repeat ablation procedures in a large cohort of consecutive patients undergoing radio frequency or cryoballoon-based PVI. METHODS: Retrospective analysis of PV-reconnection patterns and analysis of re-ablation strategies in consecutive index RF- and CB-based PVI and their respective re-ablation procedures during concomitant usage of both energy sources at a single high-volume center in Germany. RESULTS: A total of 610 first (06/2015-10/2022) and 133 s (01/2016-11/2022) repeat ablation procedures after 363 (60%) RF- and 247 (40%) CB-based index PVIs between 01/2015 and 12/2021 were analyzed. PV-reconnection was found in 509/610 (83%) patients at first and 74/133 (56%) patients at second repeat procedure. 465 of 968 (48%) initially via CB isolated PVs were reconnected at first re-ablation but 796 of 1422 initially RF-isolated PV (56%) were reconnected (OR: 0.73 [95% CI: 0.62-0.86]; p < .001). This was driven by fewer reconnections of the left PVs (LSPV: OR: 0.60 [95% CI: 0.42-0.86]; p = .005 and LSPV: 0.67 [0.47-0.95]; p = .026). PV-reconnection was more likely after longer, RF-based index PVI and in older females. Repeat procedures were shorter after CB-compared to after RF-PVI. CONCLUSIONS: Reconnection remains the most common reason for repeat AF ablation procedures after PVI. Our data suggest to preferentially use of the cryoballoon during index PVI, especially in older women.

10-year follow-up of interventional electrophysiology: updated German survey during the COVID-19 pandemic.

INTRODUCTION: This study provides an update of survey-based data providing an overview of interventional electrophysiology over the last decade. Overall infrastructure, procedures, and training opportunities in Germany were assessed. METHODS: By analyzing mandatory quality reports, German cardiology centres performing electrophysiological studies were identified to repeat a questionnaire from 2010 and 2015. RESULTS: A complete questionnaire was returned by 192 centers performing about 75% of all ablations in Germany in 2020. In the presence of the COVID-19 pandemic, a total of 76.304 procedures including 68.407 ablations were reported representing a 38% increase compared to 2015. The median number of ablations increased from 180 in 2010 to 377 in 2020. AF was the most common arrhythmia ablated (51 vs. 35% in 2010). PVI with radiofrequency point-by-point ablation (64%) and cryo-balloon ablation (34%) were the preferred strategies. Less than 50 (75) PVI were performed by 31% (36%) of all centres. Only 25 and 24% of participating centres fulfilled EHRA and national requirements for training centre accreditation, respectively. There was a high number of EP centres with no fellows (38%). The proportion of female fellows in EP increased from 26% in 2010 to 33% in 2020. CONCLUSION: Comparing 2020, 2010 and 2015, an increasing number of EP centres and procedures were registered. In 2020, more than every second ablation was for therapy of AF. In the presence of an increasing number of procedures, training opportunities were still limited, and most centres did not fulfill recommended EHRA or national requirements for accreditation.

Spatial correction improves accuracy of catheter positioning during ablation of premature ventricular contractions: differences between ventricular outflow tracts and other localizations.

BACKGROUND: Hybrid activation mapping is a novel tool to correct for spatial displacement of the mapping catheter due to asymmetrical contraction of myocardium during premature ventricular contractions (PVC). The aim of this study is to describe and improve our understanding of spatial displacement during PVC mapping as well as options for correction using hybrid activation mapping. METHODS AND RESULTS: We analyzed 5798 hybrid mapping points in 40 acquired hybrid maps of 22 consecutive patients (age 63 ± 16 years, 45% female) treated for premature ventricular contractions (PVCs). Median PVC-coupling interval was 552 ms (IQR 83 ms). Spatial displacement was determined by measuring the dislocation of the catheter tip during PVC compared to the preceding sinus beat. Mean spatial displacement was 3.8 ± 1.5 mm for all maps. The displacement was 1.3 ± 0.4 mm larger for PVCs with non-outflow-tract origin compared to PVCs originating from the ventricular outflow tracts (RVOT/LVOT; p = 0.045). Demographic parameters, PVC-coupling-interval and chamber of origin had no significant influence on the extent of spatial displacement. CONCLUSION: Ectopic activation of the ventricular myocardium during PVCs results in spatial displacement of mapping points that is significantly larger for PVCs with non-outflow-tract origin. The correction for spatial displacement may improve accuracy of radiofrequency current (RFC)-application in catheter ablation of PVCs.

A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2-/- phenotype.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α-androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

[New strategies and technologies for ablation of atrial fibrillation : Where do we go?] / Neue Strategien und Technologien für die Ablation von Vorhofflimmern : "Where do we go?".

Catheter-based ablation is an established treatment option for patients with symptomatic atrial fibrillation (AF). Pulmonary vein isolation is the established cornerstone of all ablation strategies. However, the rate of electrical reconduction of previously isolated pulmonary veins is high and associated with recurrence of AF. Novel and innovative mapping and ablation systems are being developed or are under clinical evaluation aiming for higher durability of pulmonary vein isolation. Additional ablation strategies for patients with recurrence of AF despite persistent isolation of the pulmonary veins are under evaluation. These ablation strategies include ablation of complex fractionated atrial electrograms, linear lesions, rotors or drivers, fibrotic areas or ablation of extrapulmonary triggers. The true clinical benefit of these additional ablation strategies can only be assessed if the pulmonary veins are persistently isolated.

[Radiofrequency current or cryoballoon for ablation of atrial fibrillation? : Hot or cold?] / Hochfrequenzstrom oder Cryoballon für die Ablation von Vorhofflimmern? : "Hot or cold?".

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. The aim of therapy in symptomatic patients is the establishment of a stable sinus rhythm (SR). Catheter ablation with isolation of the pulmonary veins is the essential component of all forms of ablation therapy and provides the most effective treatment option. The most frequently used technologies for pulmonary vein isolation (PVI) are radiofrequency current (RFC)-based and cryoballoon (CB)-guided ablation. Irrespective of the simplification of PVI, CB ablation is characterized by a short learning curve and short procedural times and demonstrated non-inferiority with respect to safety and efficacy when directly compared to RFC ablation for the treatment of patients with paroxysmal AF; however, the clinical outcome in patients with persistent AF is often insufficient when performing pulmonary vein isolation (PVI) alone for stabilization of SR. Differentiated RFC ablation is the treatment of choice when performing additional ablation strategies beyond PVI in order to improve clinical results with freedom from arrhythmia recurrence.

What have we learned of ablation procedures for atrial fibrillation?

Atrial fibrillation is a widespread disease of growing clinical, economic and social importance. Interventional therapy for atrial fibrillation offers encouraging results, with pulmonary vein isolation (PVI) as the established cornerstone. Yet, the challenge to create durable transmural lesions remains, leading to recurrence of atrial fibrillation in long-term follow-up even after multiple ablation procedures in 20% of patients with paroxysmal atrial fibrillation and approximately 50% with persistent atrial fibrillation. To overcome these limitations, innovative tools such as the cryoballoon and contact force catheters have been introduced and have demonstrated their potential for safe and effective PVI. Furthermore, advanced pharmacological and pacing manoeuvres enhance evaluation of conduction block in PVI.

[ESC guidelines 2015 for ventricular arrhythmias and prevention of sudden cardiac death. What is new?]. / ESC-Leitlinien 2015 zu ventrikulären Arrhythmien und zur Prävention des plötzlichen Herztodes. Was ist neu?

The new European Society of Cardiology (ESC) guidelines for the management of patients with ventricular arrhythmia and the prevention of sudden cardiac death, recently published at the annual ESC meeting in London, contain an extensive update of the recommendations for the diagnostics, drug therapy, interventional and device therapy of ventricular arrhythmia. The new recommendations for implantable cardioverter defibrillator (ICD) treatment for primary and secondary prophylaxis of sudden cardiac death can be seen as a focused update of the previously published guidelines. Pre-existing recommendations for catheter ablation of ventricular arrhythmias have been partly extensively expanded with respect to the results of recent clinical trials. The guideline committee also adapted their recommendations regarding the hereditary arrhythmia syndromes to the 2013 consensus report of the American Heart Association (AHA), the European Heart Rhythm Association (EHRA) and the Asia Pacific Heart Rhythm Society (APHRS).

[Innovative techniques in atrial fibrillation therapy]. / Innovative Verfahren der Vorhofflimmertherapie.

Pulmonary vein isolation (PVI) is the established cornerstone in most catheter-based ablation treatment strategies for atrial fibrillation (AF); however, it is still a challenge to create contiguous, transmural and permanent ablation lesions using radiofrequency current in combination with three-dimensional mapping systems. To overcome these limitations, innovative spiral mapping and ablation catheters as well as balloon-based ablation catheters incorporating alternative energy sources, such as cryoenergy and laser were developed and evaluated and have proved their potential for safe and clinically effective PVI. In addition, novel ablation strategies, such as identification and ablation of AF-inducing foci and/or AF-perpetuating rotors using either endocardial or epicardial mapping systems were introduced and are currently under clinical evaluation. The identification and modulation of atrial ganglionic plexi (GP) and, therefore, of the autonomous nervous system is another additive ablation approach which requires further clinical evaluation.

Reduced proliferation of CD34(+) cells from patients with acute myeloid leukemia after gene transfer of INPP5D.

Acute myeloid leukemia (AML) is a malignant disease characterized by deregulated proliferation of immature myeloid cells. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently detected in approximately 50-70% of AML patients. The gene INPP5D encodes the SH2-containing inositol 5-phosphatase 1 (SHIP1), which is a negative regulator of PI3K/AKT signaling. After lentiviral-mediated gene transfer of INPP5D into CD34(+) cells derived from AML patients (n=12) the granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent proliferation was reduced in all samples analyzed (average 86%; range 72-93%). An enzymatically inactive form of SHIP1 (D672A) had no effect. In addition, SHIP1 reduced the autonomous proliferation of CD34(+) cells from a patient with a secondary AML who had a very high peripheral blast count (300 x 10(9) l(-1)). These data show that SHIP1 can effectively block GM-CSF-dependent and autonomous proliferation of AML cells.

Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations.

Juvenile myelomonocytic leukemia (JMML) is a malignant disease of early childhood characterized by a hypersensitivity to granulocyte/macrophage colony-stimulating factor (GM-CSF). Mutations in RAS or PTPN11 are frequently detected in JMML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP-1) is a negative regulator of GM-CSF signaling, and inactivation of SHIP-1 in mice results in a myeloproliferative disease. Here, we report the effects of SHIP-1 expression on GM-CSF-dependent proliferation and colony formation of human hematopoietic cells. After retroviral-mediated transduction of SHIP-1 into CD34+ cells from cord blood of healthy newborns or peripheral blood of JMML patients carrying mutations in KRAS2 or PTPN11, we observed a reduction in GM-CSF-dependent proliferation and colony formation. An enzymatically inactive form of SHIP-1 (D672A) had no effect. These data indicate that SHIP-1 can effectively block GM-CSF hypersensitivity in JMML progenitor cells with mutations in KRAS2 or PTPN11 and may be a useful approach for the treatment of JMML patients.

[Including pulsed Doppler ultrasound study in the obstetric management of at-risk pregnancies]. / Die Einbeziehung der gepulsten Doppler-Ultraschall-Untersuchung in das geburtshilfliche Management bei Risikoschwangerschaften.

Using the results of 2,130 assessments with pulsed wave Doppler-ultrasound we established an indication catalogue which reflect the availability in cases of high specificity of the method. The paper shows the modus of fetal monitoring by inclusion of the other obstetrical investigations in consequence of the Doppler-assessment and the frequency of repetition of it.

[Evaluation of the central hemodynamics of the fetus using pulsed Doppler ultrasound]. / Die Beurteilung der zentralen Hämodynamik des Feten mittels gepulstem Doppler-Ultraschall.

Using pulsed Doppler, blood flow in the cerebral arteries was measured to assess the fetal central circulation. The Pulsatility-Index (PI) was calculated as a qualitative parameter of flow velocity waveforms. In 418 normal singleton pregnancies we performed 558 measurements between the 27th and 40th week of gestation to get normal range values of the PI. The curve shows a small decrease in the observed interval. In cases of an intrauterine hypoxia the resistance of the central vessels decrease to render the distribution of the fetal blood volume. The result of this is a centralisation of the fetal circulation. 131 high risk pregnancies were investigated and in 21 cases such a centralisation was registered. The fetal outcome of these fetuses was significantly worse compared with fetuses having a normal central flow resistance. We found for example a higher rate of caesarean sections because of fetal distress when the Pulsatility-Index was below the 5th percentile. The sensitivity of the method in prediction caesarean section for fetal distress was 59.3%, the specifity 95.3%.

[Assessment of uteroplacental circulation in uncomplicated pregnancies using pulsed Doppler ultrasound]. / Erfassung der uteroplazentaren Durchblutung ungestörter Schwangerschaften mittels gepulstem Doppler Ultraschall.

The Doppler sonography enable as a new non-invasive procedure the assessment of the uteroplacental circulation. 209 blood flow measurements (pulsed wave Doppler) were recorded between the 20th and 40th weeks of gestation from the arcuate arteries in 130 women with uncomplicated pregnancy. The S/D Ratio, the Resistance Index (RI) and the Pulsatility Index (PI) were calculated. These Indices show throughout the observation time persisting low values which reflect the optimal uteroplacental circulation in a system with low downstream impedance. We found that the S/D Ratio and the RI are appropriate parameters in the qualitative analysis of the uteroplacental perfusion. On the other side we could demonstrate that the PI depends on the maternal heart rate which explains the high variability of the values. Therefore is the PI not appropriate for the impedance measurements in uteroplacental vessels.

[Contribution to the pathogenesis of carcinoma after laryngeal epithelial dysplasia (author's transl)]. / Untersuchungen zur Entstehung eines Karzinoms aus einer Epitheldysplasie der Kehlkopfschleimhaut.

Between 1967 and 1980 laryngeal leukoplakia was clinically diagnosed in 86 patients. Histology revealed a true invasive carcinoma in 18 patients. Epithelial dysplasia grade I was found in 32 patients, grade II in 25 and grade III (carcinoma in situ) in 9 patients. 8 patients (14%) with dysplasia grade I and II subsequently developed carcinoma in situ or true invasive carcinoma. The average time lapse between first biopsy and histologically verified carcinogenesis was 5.1 years. No correlations was found to the histological grading.