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Aims: Mosaic loss of Y chromosome (LOY) in blood cells is the most common acquired mutation, increases with age, and is related to cardiovascular disease. Loss of Y chromosome induces cardiac fibrosis in murine experiments mimicking the consequences of aortic valve stenosis, the prototypical age-related disease. Cardiac fibrosis is the major determinant of mortality even after transcatheter aortic valve replacement (TAVR). It was hypothesized that LOY affects long-term outcome in men undergoing TAVR., Methods and Results: Using digital PCR in DNA of peripheral blood cells, LOY (Y/X ratio) was assessed by targeting a 6 bp sequence difference between AMELX and AMELY genes using TaqMan. The genetic signature of monocytes lacking the Y chromosome was deciphered by scRNAseq. In 362 men with advanced aortic valve stenosis undergoing successful TAVR, LOY ranged from -4% to 83.4%, and was >10% in 48% of patients. Three-year mortality increased with LOY. Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off of LOY >17% to predict mortality. In multivariate analysis, LOY remained a significant (P < 0.001) independent predictor of death during follow-up. scRNAseq disclosed a pro-fibrotic gene signature with LOY monocytes displaying increased expression of transforming growth factor (TGF) β-associated signaling, while expression of TGFβ-inhibiting pathways was down-regulated., Conclusion: This is the first study to demonstrate that LOY in blood cells is associated with profoundly impaired long-term survival even after successful TAVR. Mechanistically, the pro-fibrotic gene signature sensitizing the patient-derived circulating LOY monocytes for the TGFβ signaling pathways supports a prominent role of cardiac fibrosis in contributing to the effects of LOY observed in men undergoing TAVR., Competing Interests: Conflict of interest A.M.Z. is scientific advisor for NovoNordisk, AstraZeneca, Boehringer Ingelheim, and Sanofi and reports lecture honoraria for NovoNordisk, AstraZeneca, Boehringer Ingelheim, Sanofi, Pfizer, Bayer Healthcare, Lilly, and Daichi., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF., Methods and Results: We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF >0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF < 0.5%), 29% with only one DNMT3A- or TET2-CH-driver mutations above the respective cut-off level and 42% in patients harbouring both DNMT3A- and TET2-CH-driver mutations above the respective cut-off levels. In carriers of a DNMT3A mutation with VAF ≥ 1.15%, 5-year mortality was 31%, compared with 18% mortality in those with VAF < 1.15% (P = 0.048). Likewise, in patients with TET2 mutations, 5-year mortality was 32% with VAF ≥ 0.73%, compared with 19% mortality with VAF < 0.73% (P = 0.029)., Conclusion: The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Predictors of atrial arrhythmia recurrence have not been described in a long-term follow-up study of patients undergoing pulmonary vein isolation (PVI) using the cryoballoon technique. We aimed to evaluate the efficacy of a second-generation cryoballoon and identify pre-procedural predictors of 3-year outcome after PVI., Methods and Results: For this observational cohort study, we enrolled 440 patients ablated at our institution with a second-generation cryoballoon. The endpoint was the first documented recurrence (>30 s) of atrial fibrillation (AF), atrial flutter, or atrial tachycardia after a 3-month blanking period. The impact of several pre-existing variables on clinical outcome was evaluated by univariate and multivariate analyses using the Cox proportional hazards regression model. The PLAAF (persistent AF, left atrial area, abnormal PV anatomy, AF history, female gender) score was defined to predict outcome. After a median follow-up of 36 months (interquartile range 25/75-27/42), the endpoint was achieved in 95 of 440 (21.6%) patients. Cox regression analysis showed that persistent AF, left atrial (LA) area, abnormal PV anatomy, AF history, and female gender independently predicted recurrence. The calculated optimal cut-offs for LA area and AF history were 21 cm2 and 3 years, respectively. Patients with a PLAAF score of 0 showed the best outcome, with an arrhythmia-free survival of 86.7%., Conclusion: PVI using the cryoballoon technique shows acceptable long-term results depending on predictors described by the new PLAAF score, which may facilitate patient selection for PVI.

Aims: There is no objective, early indicator of occlusion quality, and efficacy of cryoballoon pulmonary vein isolation. As previous experience suggests that the initial cooling rate correlates with these parameters, we investigated the slope of the initial temperature drop as an objective measure., Methods and Results: A systematic evaluation of 523 cryoapplications in 105 patients using a serial ROC-AUC analysis was performed. We found the slope of a linear regression of the temperature-time function to be a good predictor (PPV 0.9, specificity 0.72, sensitivity 0.71, and ROC-AUC 0.75) of acute isolation. It also correlated with nadir temperatures (P< 0.001, adjusted R2= 0.43), predicted very low nadir temperatures, and varied according to visual occlusion grades (ANOVA P< 0.001)., Conclusions: About 25 s after freeze initiation, the temperature-time slope predicts important key characteristics of a cryoablation, such as nadir temperature. The slope is the only reported predictor to actually precede acute isolation and thus to support decisions about pull-down manoeuvres or aborting a cryoablation early on. It is also predictive of very low nadir temperatures and phrenic nerve palsy and thus may add to patient safety., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: Although the generation of linear lesions by ablation improves success rates in patients with persistent atrial fibrillation (AF), the procedure has been considered unsuitable for cryoablation balloon catheter technologies. We developed a technique for linear ablations, using second-generation cryoballoon technology., Methods and Results: This was a single-arm, prospective study in 76 patients with persistent AF treated consecutively at our centre. Cryoablation was performed using a 28 mm second-generation cryoballoon. The first cryoenergy application was performed in close proximity to the position during isolation of the left superior pulmonary vein (PV). Sequential overlapping freezes were applied along the left atrial (LA) roof by slight clockwise rotation of the sheath in combination with slight retraction of the sheath and incremental advancement of the cryoballoon, until reaching the original position for right superior PV isolation. The acute endpoint was the creation of a roofline, defined as complete conduction block across the LA roof >120 ms and ascending activation across the posterior LA wall. Acute success in roofline generation was achieved in 88% of patients, applying on average five (median 4-6) freezes with nadir temperature of -40°C (-36 to -44°C). In five patients, conduction block could not be achieved. No phrenic nerve injuries occurred during roofline generation., Conclusion: Generation of linear roofline lesions is possible with the second-generation cryoballoon. The technique can be used in combination with PV isolation to treat persistent AF with good acute success rates, short procedure times, and acceptable safety concerns. If validated by further studies, the method would be an appealing alternative to radiofrequency ablation techniques., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: Extracorporeal life support (ECLS) has shown encouraging survival rates in patients with in-hospital cardiac arrest; however, its routine use is still controversial. We compared the survival of patients with in-hospital cardiac arrest receiving conventional cardiopulmonary resuscitation (CCPR) to that of patients with ECLS as an adjunct to cardiopulmonary resuscitation (ECPR)., Methods: A total of 353 patients with in-hospital cardiac arrest (272 CCPR and 52 ECPR) were included in this retrospective, propensity score-adjusted (1:1 matched), single-centre study. Primary endpoints were survival at 30 days, long-term survival and neurological outcome defined by the cerebral performance categories score., Results: In the unmatched groups patients undergoing ECPR initially had significantly higher APACHE II scores ( P=0.03), increased norepinephrine dosages ( P=0.03) and elevated levels of creatine kinase ( P<0.0001), creatinine ( P=0.04) and lactate ( P=0.02) before cardiopulmonary resuscitation compared with those undergoing CCPR. After equalising these parameters significant differences were observed in short and long-term survival, favouring ECPR over CCPR (27% vs. 17%; P=0.01 (short-term) and 23.1% vs. 11.5%; P=0.008 (long-term); median follow-up duration after discharge 1136 days (interquartile range 823-1416)). There was no significant difference in the incidence of a cerebral performance categories score of 1 or 2 between the matched groups (CCPR 66.7% vs. ECPR 83.3%; P=0.77). ECLS implantation was the only significant and independent predictor of mortality in multivariate Cox regression analysis (hazard ratio 0.57, 95% confidence interval 0.35-0.90; P=0.02)., Conclusion: In our cohort of cardiovascular patients ECPR was associated with better short- and long-term survival over CCPR, with a good neurological outcome in the majority of the patients with refractory in-hospital cardiac arrest.

Background: Acute kidney injury (AKI) is a complication after major cardiac surgery that is associated with higher rates of morbidity and mortality. MicroRNA-21 (miR-21) has been described as an early biomarker for AKI. We investigated whether miR-21 is predictive of AKI and long-term mortality after cardiac surgery., Methods: Consecutive patients (n = 115) undergoing major cardiac surgery were included. Serum creatinine was measured prior to, 4 h after, and 1, 4 and 7 days after extracorporeal circulation. Diagnosis of post-operative AKI was made in accordance with the international Kidney Disease: Improving Global Outcomes definition of AKI. Serum cystatin C and miR-21 were measured prior to and 4 h after surgery. miR-21 was determined by quantitative RT-PCR and was normalized to miRNA-39 from Caenorhabditis elegans. The median follow-up time was 2.9 years., Results: AKI occurred in 36.5% (n = 42) of all patients. Baseline miR-21 was significantly lower in patients developing cardiac surgery-associated AKI (CSA-AKI) than in patients without CSA-AKI [0.27 (interquartile range, IQR, 0.14-0.30) versus 0.44 (IQR 0.25-0.75); P < 0.01]. Baseline miR-21 predicted CSA-AKI Stage 2/3 with an area under the curve of 0.701 [95% confidence interval (CI) 0.59-0.82; P = 0.007]. Baseline miR-21 <0.31 showed a hazard ratio of 3.11 (95% CI: 1.33-11.26) for CSA-AKI Stage 2/3. Patients with AKI Stage 2/3 had a significantly higher mortality (50 versus 10%; P = 0.0001) and dialysis rate (27 versus 11%; P = 0.038) within the 2.9-year follow-up., Conclusions: Our results indicate that miR-21 has the potential to identify patients at higher risk for CSA-AKI. This predictive value might be helpful in pre-procedural risk assessment and peri-procedural diagnosis and treatment., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Aims: ECVUE™ technology, a novel, three-dimensional, non-invasive mapping system, offers a unique arrhythmia characterization and localization. We sought to evaluate the clinical impact of this system in routine clinical mapping and ablation of ventricular arrhythmias (VAs)., Methods and Results: Patients with monomorphic premature ventricular contractions with or without monomorphic ventricular tachycardia were enrolled prospectively and randomized into two groups: ventricular ectopy localization using either 12-lead electrocardiogram (ECG) algorithms or with ECVUE™, followed by conventional guided ablation. Forty-two patients were enrolled in the study. The ECVUE™ system accurately identified both the chamber and sub-localized the VA origin in 20 of 21 (95.2%) patients. In contrast, using 12-lead ECG algorithms, the chamber was accurately diagnosed in 16 of 21 (76.2%) patients, while the arrhythmia origin in only 8 of 21 (38.1%), (P = 0.001 vs. ECVUE™). Acute success in ablation was achieved in all patients. Regarding the number of radiofrequency-energy applications (in total 2 vs. 4, P = 0.005) in the ECVUE™ arm, ablation was more precise than the ECG group which used standard of care activation and pace mapping-guided ablation. Three months success in ablation was 95.2% for the ECVUE™ and 100% for the ECG group (P = ns). Time to ablation was 35.3 min in the conventional arm and 24.4 min in ECVUE Group, (P = 0.035). The X-ray radiation exposure was 3.21 vs. 0.39 mSv, P = 0.001 for the ECVUE™ group and ECG group., Conclusion: ECVUE™ technology offers a clinically useful tool to map VAs with high accuracy and more targeted ablations superior to the body surface ECG but had significantly higher radiation exposure due to computed tomography scan., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Long-term efficacy following cryoballoon (CB) ablation of atrial fibrillation (AF) remains unknown. This study describes 5 years follow-up results and predictors of success of CB ablation in patients with paroxysmal atrial fibrillation (PAF)., Methods and Results: In total, 163 patients were enrolled with symptomatic, drug refractory PAF. Pulmonary vein isolation (PVI) with CB technique was performed. Primary endpoint of this consecutive single-centre study was first electrocardiogram-documented recurrence of AF, atrial tachycardia or atrial flutter (AFLAT). Five years success rate after single CB ablation was 53%. In 70% of the patients acute complete PVI was achieved with a single 28 mm balloon. The univariate predictors of AFLAT recurrence were (1) size of left atrium, with normalized left atrium (NLA) ≥10.25 [hazard ratios (HR) of 1.81, 95% confidence interval (CI): 1.28-2.56] when compared with NLA <10.25 (35% vs. 53%, P = 0.0001) and (2) renal function, with impaired glomerular filtration rate (GFR) <80 ml/min (HR of 1.26, 95% CI: 1.02-1.57) when compared with GFR ≥80 ml/min (45% vs. 53%, P = 0.041). Normalized left atrium ≥10.25 was the sole independent predictor for outcome (HR 2.11; 95% CI: 1.34-3.31; P = 0.0001)., Conclusions: Sinus rhythm can be maintained in a substantial proportion of patients with PAF even 5 years after circumferential PVI using CB ablation. The rate of decline in freedom from AFLAT was highest within the first 12 months after the index procedure. The patients with enlarged left atrium and/or impaired renal function have lower outcome.

Aims: Cerebral embolism is a possible serious complication during catheter ablation of atrial fibrillation (AF). The purpose of this prospective pilot study was to analyse the incidence and possible impact of cryo ablation on cerebral lesions and possible differences to radiofrequency (RF) ablation during pulmonary vein isolation (PVI)., Methods and Results: Pulmonary vein isolation was performed in 89 patients, either with the cryoballoon technique (n = 45) or with RF ablation (n = 44). Phenprocoumon was stopped 3 days before intervention and replaced by subcutaneous low-molecular-weight heparin. During the catheter procedure, an infusion of unfractionated heparin was maintained to achieve an activated clotting time (ACT) of > 300 s. Cerebral magnetic resonance imaging scans were performed 1 day before and after PVI, and at 3-month follow-up. Chronic lesions were observed in 11 patients (12.3%) before PVI without statistically significant difference between the two groups. None of the patients had neurological symptoms during or following the procedure. Seven patients (7.9%) developed acute lesions 1 day after PVI, without statistically significant difference between the group treated by cryoenergy (8.9%) and RF ablation (6.8%). Patients with acute lesions were significantly older compared with those without acute cerebral lesions. No additional cerebral lesions during follow-up were observed., Conclusion: A considerable portion of patients with AF but without any neurological symptoms had chronic cerebral lesions before PVI. Additional acute lesions could be added after the procedure. Both ablation techniques showed additional cerebral acute lesions with no neurological symptoms after PVI.

The objective of this study was to identify electrocardiographic (ECG) and further predictors for atrioventricular (AV) block with a need for pacemaker (PM) implantation after transcatheter aortic valve implantation (TAVI). Pre- and post-procedural ECGs of patients with severe aortic stenosis and ongoing TAVI were investigated in a prospective study. From 50 consecutive patients enrolled in the study (mean age 80 +/- 6 years, 46% men), 17 (34%) experienced an AV block with subsequent requirement of a permanent PM [16 of 36 (44.4%) with CoreValve System and 1 of 14 (7.1%) with Edwards Sapiens System]. In patients with right bundle branch block (RBBB), PM implantation had to be performed more frequently [6 of 6 (100%) with CoreValve System and none with Edwards Sapiens System], P = 0.005. An AV block (Mobitz II second degree and third degree) occurred mostly within the first 24 h (range: Days 0-13) after the index procedure. No recovery of AV conduction with a change in PM indication occurred in a mean follow-up time of 13 +/- 6 days. Our data demonstrate that patients with pre-operative RBBB and those receiving CoreValve prosthesis are at a significantly higher risk for PM implantation after TAVI. Therefore, patients with the presence of RBBB before TAVI may be at lower risk for PM implantation using the Edwards Sapiens System.

We described a case of a 58-year-old man with organic changes consistent with right ventricular cardiomyopathy. He also had a loss-of-function mutation in the cardiac sodium channel gene SCN5A, described in Brugada syndrome. He first presented with non-sustained ventricular tachycardia and was implanted with an implantable cardioverter defibrillator. He remained asymptomatic for 8 years until he developed recurrent episodes of ventricular tachyarrhythmias, which required multiple shocks. The patient was treated with a combination of quinidine and verapamil and since then remained free of arrhythmias.

Aims: The purpose of this study was to determine the occurrence of asymptomatic episodes of atrial fibrillation (AF) and wrong AF perception after pulmonary vein isolation (PVI). We evaluated the success of ablation by using the following measurements: (i) clinical symptoms and duration of symptoms noticed by patients and (ii) synchronous event recording (ER)., Methods and Results: Eighty patients with paroxysmal AF underwent PVI and were provided repeatedly with a portable ER upon discharge and every 3 months for a year. The ER automatically detects arrhythmias by a detection algorithm and can also be manually triggered by the patient. In 46/80 patients (57.5%), episodes of AF were documented. Asymptomatic AF was detected in 21.3%. In 9/80 patients (11.3%), who reported clinical AF recurrence, no AF could be shown by ER. We compared patients' perception to have suffered AF episodes with the ERs and found a sensitivity of 75% and a specificity of 92%., Conclusion: Reliance on perception of AF by patients after PVI results in an underestimation of recurrence of the arrhythmia. We observed a maximal occurrence of silent AF or wrong perception of AF in 26/80 (32.6%) patients.