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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.

Background Mutations in the clonal hematopoiesis of indeterminate potential (CHIP)-driver genes DNMT3A and TET2 have been previously shown to be associated with short-term prognosis in patients undergoing TAVR for aortic valve stenosis. We aimed to extend and characterize these findings on long-term outcome in a large cohort. Methods A total of 453 consecutive patients undergoing TAVR were included in an up to 4-year follow-up study. Next-generation sequencing was used to identify DNMT3A- and/or TET2-CHIP-driver mutations. Primary endpoint was all-cause mortality. Since CHIP-driver mutations appear to be closely related to DNA methylation, results were also assessed in patients who never smoked, a factor known to interfere with DNA methylation. Results DNMT3A-/TET2-CHIP-driver mutations were present in 32.4% of patients (DNMT3A n = 92, TET2 n = 71), and were more frequent in women (52.4% vs. 38.9%, p = 0.007) and older participants (83.3 vs. 82.2 years, p = 0.011), while clinical characteristics or blood-derived parameters did not differ. CHIP-driver mutations were associated with a significantly higher mortality up to 4 years after TAVR in both univariate (p = 0.031) and multivariate analyses (HR 1.429, 95%CI 1.014–2.013, p = 0.041). The difference was even more pronounced (p = 0.011) in never smokers. Compared to TET2 mutation carriers, patients with DNMT3A mutations had significantly less frequently concomitant coronary and peripheral artery disease. Conclusion DNMT3A- and TET2-CHIP-driver mutations are associated with long-term mortality in patients with aortic valve stenosis even after a successful TAVR. The association is also present in never smokers, in whom no biasing effect from smoking on DNA methylation is to be expected. Graphical Abstract

Aims Clonal hematopoiesis (CH), defined as the presence of an expanded somatic blood cell clone due to acquired mutations in leukemia driver genes, was shown to be associated with increased mortality in patients with chronic ischemic heart failure with reduced ejection fraction (HFrEF). Mechanistically, circulating monocytes of mutation carriers display increased expression of proinflammatory genes involved in inflammasome and IL-6 signaling. Inherited single nucleotide variants (SNPs) in the IL-6 pathway are well known to affect inflammatory activation. Therefore, we investigated whether known SNPs in genes encoding for components of the inflammasome/IL-6 signaling pathway modulate fatal outcomes in HFrEF patients with CH. Methods and results In a total of 446 patients with chronic HFrEF, peripheral blood or bone marrow mononuclear cells were analyzed for the CH driver mutations DNMT3A and TET2 as well as 40 preselected SNPs affecting genes in the NLRP3 inflammasome/IL-6 signaling pathway. The 103 patients carrying a CH driver mutation demonstrated significantly increased mortality compared to the 343 patients without CH mutations (25,24% vs 13.99% at five years; p=0.0064). We identified three commonly occurring variants known to disrupt IL-6 signaling (rs2228145, rs4129267 and rs4537545) which are in strong linkage disequilibrium and present in more than 50% of CH carriers. As illustrated in Figure 1A, harboring one of those SNPs abrogated the increased mortality risk in patients with HFrEF and CH (p≤0.05 for each SNP). On the contrary, three different SNPs namely rs2250417, which is associated with increased IL-18 levels as well as rs4722172 and rs4845625, which are known to activate IL-6 signaling, were identified to mediate fatal outcomes in patients with HFrEF and CH (p Conclusion Among CHIP carriers with HFrEF, inherited variants in loci encoding for genes involved in inflammatory signaling associate with mortality. These data not only provide mechanistic insights into inflammatory mechanisms contributing to fatal outcome of HFrEF in CH carriers but may also inform trials evaluating precision-targeted anti-inflammatory therapy in patients with DNMT3A and TET2 mutations and chronic HFrEF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Center of Cardiovascular Research;Cardiopulmonary Institute, Frankfurt, Germany

Aims SARS-CoV-2 infection is associated with adverse outcomes in patients with cardiovascular disease. Here, we analyzed whether specific biomarkers predict the clinical course of COVID-19 in patients with cardiovascular comorbidities. Methods and results We enrolled 2147 patients with SARS-CoV-2 infection which were included in the Lean European Open Survey on SARS-CoV‑2 (LEOSS)-registry from March to June 2020. Clinical data and laboratory values were collected and compared between patients with and without cardiovascular comorbidities in different clinical stages of the disease. Predictors for mortality were calculated using multivariate regression analysis. We show that patients with cardiovascular comorbidities display significantly higher markers of myocardial injury and thrombo-inflammatory activation already in the uncomplicated phase of COVID-19. In multivariate analysis, elevated levels of troponin [OR 1.54; (95% CI 1.22–1.96), p p p Conclusion Patients with cardiovascular comorbidities show elevated markers of thrombo-inflammatory activation and myocardial injury, which predict mortality, already in the uncomplicated phase of COVID-19. Starting targeted anti-inflammatory therapy and aggressive anticoagulation already in the uncomplicated phase of the disease might improve outcomes after SARS-CoV-2 infection in patients with cardiovascular comorbidities. Graphic abstract Elevated markers of thrombo-inflammatory activation predict outcome in patients with cardiovascular comorbidities and COVID-19 disease: insights from the LEOSS registry

Background: The aim of this study was to identify pre-operative parameters able to predict length of stay (LoS) based on clinical data and patient-reported outcome measures (PROMs) from a scorecard database in patients with significant aortic stenosis who underwent TAVI (transfemoral aortic valve implantation). Methods: 302 participants (51.7% males, age range 78.2–84.2 years.) were prospectively recruited. After computing the median LoS value (=6 days, range = 5–8 days), we implemented a decision tree algorithm by setting dichotomized values at median LoS as the dependent variable and assessed baseline clinical variables and PROMs (Clinical Frailty Scale (CFS), EuroQol-5 Dimension-5 Levels (EQ-5D) and Kansas City Cardiomyopathy Questionnaire (KCCQ)) as potential predictors. Results: Among clinical parameters, only peripheral arterial disease (p = 0.029, HR = 1.826) and glomerular filtration rate (GFR, cut-off < 33 mL/min/1.73 m2, p = 0.003, HR = 2.252) were predictive of LoS. Additionally, two PROMs (CFS; cut-off = 3, p < 0.001, HR = 1.324 and KCCQ; cut-off = 30, p = 0.003, HR = 2.274) were strong predictors. Further, a risk score for LoS (RS_LoS) was calculated based on these predictors. Patients with RS_LoS = 0 had a median LoS of 5 days; patients RS_LoS ≥ 3 had a median LoS of 8 days. Conclusions: based on the pre-operative values of the above four predictors, a personalized prediction of LoS after TAVI can be achieved.

Inflammatory activation of leukocytes may limit prognosis of patients (pts) with severe aortic valve stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Leukocyte telomere length (LTL) is a marker of proliferative capacity and inflammatory responsiveness but the impact of LTL on the prognosis in AS remains elusive. The aim of this study was to analyse the association of LTL with inflammatory markers and prognosis of pts undergoing TAVR.LTL was analysed using quantitative real-time PCR in 285 consecutive pts (median age 82 years) undergoing TAVR and correlated with 18-month all-cause mortality. C-reactive protein was significantly elevated in pts with the longest LTL (Longer LTL is associated with increased mortality after TAVR. This might be explained by enhanced proliferative capacity of cells resulting in myeloid and systemic inflammation. Our findings suggest that targeting the specific inflammation pathways could present a novel strategy to augment survival in selected patients with degenerative aortic stenosis.

The aim of this study was to identify pre-operative parameters able to predict length of stay (LoS) based on clinical data and patient-reported outcome measures (PROMs) from a scorecard database in patients with significant aortic stenosis who underwent TAVI (transfemoral aortic valve implantation).302 participants (51.7% males, age range 78.2-84.2 years.) were prospectively recruited. After computing the median LoS value (=6 days, range = 5-8 days), we implemented a decision tree algorithm by setting dichotomized values at median LoS as the dependent variable and assessed baseline clinical variables and PROMs (Clinical Frailty Scale (CFS), EuroQol-5 Dimension-5 Levels (EQ-5D) and Kansas City Cardiomyopathy Questionnaire (KCCQ)) as potential predictors.Among clinical parameters, only peripheral arterial disease (based on the pre-operative values of the above four predictors, a personalized prediction of LoS after TAVI can be achieved.

Background and Objectives: We tested if a novel combination of predictors could improve the accuracy of outcome prediction after transfemoral transcatheter aortic valve implantation (TAVI). Materials and Methods: This prospective study recruited 169 participants (49% female; median age 81 years). The primary endpoint was midterm mortality; secondary endpoints were acute Valve Academic Research Consortium (VARC)-3 complication rate and post-TAVI in-hospital length of stay (LoS). EuroSCORE II (ESII), comorbidities (e.g., coronary artery disease), eGFR (estimated glomerular filtration rate; based on cystatin C), hemoglobin, creatinine, N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels and patient-reported outcome measures (PROMs, namely EuroQol-5-Dimension-5-Levels, EQ5D5L; Kansas City Cardiomyopathy Questionnaire, KCCQ; clinical frailty scale, CFS) at baseline were tested as predictors. Regression (uni- and multi-variate Cox; linear; binary logistic) and receiver operating characteristic (ROC)-curve analysis were applied. Results: Within a median follow-up of 439 (318–585) days, 12 participants died (7.1%). Independent predictors of mortality using multivariate Cox regression were baseline eGFR (p = 0.001) and KCCQ (p = 0.037). Based on these predictors, a Linear Prediction Score (LPS1) was calculated. The LPS1-area under the curve (AUC)-value (0.761) was significantly higher than the ESII-AUC value (0.597; p = 0.035). Independent predictors for LoS > 6 days (the median LoS) were eGFR (p = 0.028), NTproBNP (p = 0.034), and EQ5D5L values (p = 0.002); a respective calculated LPS2 provided an AUC value of 0.677 (p < 0.001). Eighty participants (47.3%) experienced complications. Male sex predicted complications only in the univariate analysis. Conclusions: The combination of KCCQ and eGFR can better predict midterm mortality than ES II alone. Combining eGFR, NTproBNP, and EQ5D5L can reliably predict LoS after TAVI. This novel method improves personalized TAVI risk stratification and hence may help reduce post-TAVI risk.

Background Presence of several comorbidities in patients with atrial fibrillation is well known, but impact of them on outcome after pulmonary vein isolation with cryo-balloon is not enough investigated. First aim of the study was analysis of the impact of comorbidities on long term outcome after PVI with cryo-balloon new generation (CBA) and secondary goal was evaluation of the impact of additional posterior roof ablation (PRA) in these patients. Methods Patients with non-paroxysmal AF ablated with CBA in our institution since May 2012 and completed follow up >3 months were enrolled in the study. The history of AF, cardiac comorbidities (CAD, Non ischemic-cardiomyopathy, heart insufficiency, right ventricular dysfunction) diabetes mellitus, and renal failure were assessed at admission, all patients received echocardiographic examination and blood test. After a single trans-septal access and PV angiography PVI was performed using a 28-mm CBA. Mapping of PV signals before, during, and after each cryo application was performed with a 3F lasso catheter. The procedural endpoint after PVI was defined as complete elimination of all fragmented signals at the PV antrum with verification of entrance and exit block. In some patients PRA was performed additionally to PVI at discretion of physician. The primary endpoint of this study was the first documented recurrence of atrial tachyarrhythmia (>30 sec.), hospitalization due to cardio-vascular cause, re-do procedure or re-administration of anti-arrhythmic drugs. Results Among 560 patients 78 (13.9%) had no comorbidity and 299 (53.4%) were lasted with >1 comorbidity. A total of 260 (46.4%) recurrences were obtained within median follow up of 28 (12–57) months. Female gender, long time from first diagnosis >12 months and cardiac comorbidity were revealed to be independent predictors for long term recurrences whereas additional PRA performed in 176 pts independently improved outcome (61.9% vs 49.7%). Conclusion Cardiac comorbidities increased probability of post ablation recurrences, but performing of additional posterior roof ablation improved outcome in our cohort. These results should be confirmed in multi-center randomized study Funding Acknowledgement Type of funding sources: None.

It is unknown whether left atrial (LA) roof ablation combined with pulmonary vein isolation (PVI) using a second-generation cryoballoon provides additional benefit beyond that of PVI alone in patients with persistent atrial fibrillation (AF). The aim of this study was to compare arrhythmia recurrence rates after PVI alone versus PVI plus LA roof ablation. In this observational study, we analyzed 399 symptomatic patients with persistent AF treated with cryoballoon ablation. After univariate and multivariate analyses of the entire cohort, propensity score matching resulted in two groups of 86 patients each: (1) PVI plus LA roof ablation (PVI-plus group) and (2) PVI alone (PVI-only group). The primary endpoint was the first documented > 30-s arrhythmia recurrence after a 3-month blanking period. PVI was successful in all patients. A bidirectional conduction block across the LA roof was verified in 91.9% of patients in the PVI-plus group. During a median mid-term follow-up of 33 months, 21 patients (24.4%) in the PVI-plus group and 37 patients (43.0%) in the PVI-only group (P = 0.01) reached the primary endpoint. Multivariate analysis revealed AF history > 2 years (hazard ratio [HR] = 2.04, P 21 cm2 (HR = 2.36, P

Introduction There are no data concerning clinical outcome and left atrial (LA) function after LA roof ablation using a second-generation cryoballoon (CB) for treatment of persistent atrial fibrillation (AF). Here, we report the first follow-up results after pulmonary vein isolation (PVI) plus LA roof ablation with the CB technique in patients with symptomatic persistent AF. Methods and results We enrolled 107 consecutive patients who underwent CB ablation at our institution with the aim of PVI and bidirectional conduction block across the LA roof. Clinical success was defined as freedom from >30-s recurrence of AF, atrial flutter, or atrial tachycardia after a 3-month blanking period. Follow-up data were collected during outpatient clinic visits. LA volume, LA emptying fraction, and LA expansion index (parameters of LA function) were evaluated by echocardiography before and 3 months after ablation. PVI was achieved in all patients, and bidirectional conduction block was verified in 91.6%. Median follow-up duration was 31 (interquartile range 11/44) months. PVI plus LA roof ablation was sufficient to restore and maintain sinus rhythm in 72.9% ( n = 78) of patients. The overall complication rate was 1.8%. LA volumes decreased significantly after ablation ( P P = 0.25) and LA expansion index ( P = 0.32) were preserved within the 3-month follow-up. Conclusions LA roof ablation combined with PVI using the CB technique is a safe and effective adjuvant treatment with a promising midterm outcome and preserved LA function 3 months after ablation.

Background: Transcatheter aortic valve replacement (TAVR) is increasingly being used for treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement (SAVR). Currently, real-world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated TAVR with those undergoing SAVR are scarce. Methods: We compared clinical characteristics and outcomes of patients with intermediate surgical risk (Society of Thoracic Surgeons score 4%–8%) who underwent isolated TAVR or conventional SAVR within the prospective, all-comers German Aortic Valve Registry. Results: A total of 7613 patients at intermediate surgical risk underwent isolated TAVR (n=6469) or SAVR (n=1144) at 92 sites in Germany between 2012 and 2014. Patients treated by TAVR were significantly older (82.5±5.0 versus 76.6±6.7 years, P P P P P =0.976), whereas unadjusted 1-year mortality was significantly higher in patients after TAVR (17.5% versus 10.8%, P P =0.59). Conclusions: Patients at intermediate risk undergoing TAVR differ significantly from those treated with SAVR with regard to age and baseline characteristics. Isolated TAVR and SAVR were associated with an in-hospital mortality rate of 3.6%. In the propensity score analysis, there was no significant difference in 1-year mortality between patients with TAVR and SAVR.

Aims Somatic mutations in haematopoietic stem cells can lead to the clonal expansion of mutated blood cells, known as clonal haematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF) ≥ 2% have been associated with atherosclerosis and chronic heart failure of ischemic origin (CHF). However, the effects of mutations in other driver genes for CH with low VAF (

Introduction Previous studies have shown that presence of diabetes (DM) worsens outcome of patients after transfemoral aortic valve (TAVR). DM has been associated with pathological T-lymphocyte (T-cell) polarization, marked by decreased anti-inflammatory Th2 cells and increased pro-inflammatory Th1 cells. However, the risk-modulatory impact of T-cell polarization in diabetic patients with severe aortic stenosis has not been shown thus far. In this study we assessed the role of T-cell subsets in diabetic patients undergoing TAVR. Methods and results A total of 129 patients (76% male, median age [IQR]: 83 years [79–86]) admitted for TAVR at the University Clinic Frankfurt were enrolled. The patients were evaluated using classical risk scores and the Th1/Th2 T-cell polarization was assessed using flow cytometry. The endpoint of the study was all-cause death. Kaplan-Meier survival, ROC curve analysis and Mann-Whitney-U-Test were used in statistical analysis. The differences were considered significant by error probability p0.7. Diabetes was revealed to be significantly associated with mortality in patients with and without DM (15/48 (31%) vs. 11/81 (14%), respectively, P=0.019). There were no significant differences in the counts of Th-cell subsets between diabetic and non-diabetic patients (Th1 (90.95 (62.41–154.22) vs 76.36 (53.16–100.49), P=0.072); Th2 (29.18 (20.13–43.77) vs 24.74 (20.27- 35.11), p=0.245), for DM and non-DM respectively). However, the survival rate in patients with DM and Th2 cell counts higher than or equal to the calculated optimal cut-off of 24.3 cells/μl was comparable with patients without DM (25/28 (89%) vs. 36/38 (95%), p=0.453). In contrast, diabetic patients with reduced Th2 cells ( Conclusion Our results show for the first time a risk-modulatory impact of T-cell immunity in diabetic patients with severe degenerative aortic stenosis. Reduced Th2 cells are strongly associated with mortality in patients considered for TAVR and significantly deteriorate prognosis in patients with concomitant diabetes. Funding Acknowledgement Type of funding source: None

Aims Systemic inflammatory response, identified by increased total leucocyte counts, was shown to be a strong predictor of mortality after transcatheter aortic valve implantation (TAVI). Yet the mechanisms of inflammation‐associated poor outcome after TAVI are unclear. Therefore, the present study aimed at investigating individual inflammatory signatures and functional heterogeneity of circulating myeloid and T‐lymphocyte subsets and their impact on 1 year survival in a single‐centre cohort of patients with severe aortic stenosis undergoing TAVI. Methods and results One hundred twenty‐nine consecutive patients with severe symptomatic aortic stenosis admitted for transfemoral TAVI were included. Blood samples were obtained at baseline, immediately after, and 24 h and 3 days after TAVI, and these were analysed for inflammatory and cardiac biomarkers. Myeloid and T‐lymphocyte subsets were measured using flow cytometry. The inflammatory parameters were first analysed as continuous variables; and in case of association with outcome and area under receiver operating characteristic (ROC) curve (AUC) ≥ 0.6, the values were dichotomized using optimal cut‐off points. Several baseline inflammatory parameters, including high‐sensitivity C‐reactive protein (hsCRP; HR = 1.37, 95% CI: 1.15–1.63; P

Background It is well known that prevalence of atrial fibrillation correlates with age, however the data on ablation of atrial fibrillation in elderly patients is poor. Aim of this study was analysis of outcome and prediction of recurrence after cryo-balloon ablation (CBA) in elderly patients based on available data in our registry. Methods The history of AF was assessed at admission. Additionally, all patients received echocardiographic examination and blood test. After a single trans-septal access and PV angiography PVI was performed using a 28-mm CBA. Mapping of PV signals before, during, and after each cryo application was performed with a 3F lasso catheter. The procedural endpoint after PVI was defined as complete elimination of all fragmented signals at the PV antrum with verification of entrance and exit block. Primary endpoint was first documented recurrence of AF, atrial tachycardia or atrial flutter (>30 sec.). All patients received a follow-up every 3 month within 1st year, once yearly thereafter and in case of symptoms. Seven days Holter ECG was recorded by every follow up. Results A total of 44 (39%) of enrolled patients were male, 48 (43%) suffered non- paroxysmal AF(nPAF), 93 (82%) had hypertension, CAD was diagnosed by 27 (24%), 28 (25%) had DM (Hb1AC > 6), Stroke/TIA was observed in 11 (10%). Median Age in elderly was 76 (75-78) y, BMI 25.77 (23.51-28.69), time since 1st diagnosis 40 (6-50) month, LA area index 11.36 (9.77-13.20), TAPSE 23 (19-26), GFR 74 (66-83) mL/min, LVEF 60 (57-62). A total of 44 patients (39%) reached endpoint within follow up of 20 (12-38) months. Univariate association with outcome was found by follows parameter: Time from 1st diagnosis > 3 y (HR = 3.22 (1.66-6.27), p=.001); LA area index (HR = 1.17 (1.03-1.32), p=.013); DM (HR = 1.89 (1.02-3.55), p=.042); nPAF (HR = 1.90 (1.04-3.47), p=.036). After multivariate analysis only time from 1st diagnosis > 3 y, (HR= 3.17 (1.62-6.16), p=.001 and nPAF (HR = 1.84 (1.01-3.36)), p=.048 were revealed to be predictive. The area under probability score calculated for these predictors was .731 (.638-8.25), p=.001. Follows complications were observed: 2 (2%) - pericard tamponades, 4 (4%) phrenicus nerve injury. Conclusion. PVI with cryo-balloon is effective for elderly patients providing freedom of arrhythmic events in 61% of patients. Longer history of AF over 3 years since 1st diagnosis was main predictor for post ablation recurrence. In elderly patients with shorter history of AF efficiency and safety of CBA is comparable with general population.

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 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.

Introduction Data on long-term outcomes of cryoballoon (CB) ablation for treatment of persistent atrial fibrillation (AF) are sparse. Here, we report the first 3-year follow-up results and predictors of success for catheter ablation using the second-generation CB in patients with persistent AF. Methods and results For this prospective observational study, we enrolled 101 patients ablated with the second-generation CB at our institution. The endpoint was the first documented recurrence (> 30 seconds) of AF, atrial flutter, or atrial tachycardia after a 3-month blanking period. Follow-up data were collected during outpatient clinic visits and included Holter-ECG recordings. The impact of several variables on recurrence was evaluated by means of univariate and multivariate analyses and Cox proportional hazards regression models. After a median follow-up of 37 (31 of 42) months, recurrence was documented in 30 patients (29.7%). The median procedure and fluoroscopy times were 120 (102 of 147) and 20 (16 of 27) minutes, respectively. Phrenic nerve palsy occurred in 2.0% of the patients. Among the 30 patients who experienced recurrence, 16 underwent repeat ablation in radiofrequency technique. Cox regression analysis showed that left atrial area > 21 cm2 and AF history duration > 2 years independently predicted recurrence. Conclusions Sinus rhythm was maintained in a substantial proportion of patients even 3 years after CB ablation. Patients with a nonenlarged left atrium and short AF history had the best outcome.

There is evidence for a lower mortality in female patients after transcatheter aortic valve implantation (TAVI), but the underlying reasons for the gender-specific differences in prognosis are not well understood. In particular, the role of left ventricular dysfunction is unclear. In this study, we addressed the question of whether differences in left ventricular ejection fraction (LVEF) could account for the gender benefit for female TAVI patients.From January 2011 to December 2013, a total of 15,616 patients treated with TAVI were prospectively enrolled in the German Aortic Valve Registry (GARY). For the present analysis, female TAVI patients (N=8,456) were compared with male TAVI patients (N=7,160) with a particular focus on LVEF. Mortality at one year was 18.1% in women and 22.6% in men (p0.001). Multivariate analysis also revealed that female gender was associated with a lower one-year mortality (adjusted hazard ratio [HR] 0.88 [0.81-0.95]). There was no difference in gender-specific mortality in patients with baseline LVEF50% (women: 16.4%; men 17.6%, p=0.268), but in patients with LVEF 30%-50% (21.0% versus 25.7%, p0.001) and30% (26.2% versus 37.6%, p0.001) one-year mortality was significantly lower in women than in men.The survival benefit for women over men after TAVI was only observed in patients with a preprocedural LVEF ≤50%.

Somatic mutations in hematopoietic stem cells can lead to the expansion of mutated blood cells, known as clonal hematopoiesis (CH). Mutations in the most prevalent genes DNMT3A and TET2 with a variant allele frequency (VAF)≥2% (CHIP) have been associated with atherosclerosis and chronic heart failure (CHF). However, the mutational landscape in CHF and the effects in CH-driver genes other than DNMT3A and TET2 with low VAF≤2% on CHF are still unknown. Therefore we analyzed bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality (3.95 years median follow-up). We detected 1113 mutations with a VAF≥0.5% in 347 patients (87%). Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A and TET2, mutations in the genes CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A and SRSF2 were associated with increased death compared to the average death rate of all patients (20%). To avoid confounding effects caused by the presence of DNMT3A and TET2 CHIP mutations, we excluded patients with CHIP-related mutations (VAF≥2%) for further analyses. Kaplan-Meier survival analyses revealed a significantly higher mortality in patients with mutations in the seven genes (53 patients), combined as the CH risk gene set for CHF. These patients showed no significant differences in any parameter including patient age, confounding diseases or blood parameters except for a reduced number of platelets. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (HR, 3.1; 95% CI, 1.8-5.4; p Somatic mutations with low VAF in these risk genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome, potentially providing a novel tool for risk assessment in CHF.

Background Systemic inflammatory response syndrome (SIRS) was shown to be a strong predictor of mortality in patients undergoing transcatheter aortic valve implantation (TAVI). However, given the rather non-specific nature of the SIRS criteria and their limited applicability in the modern era of TAVI, including lower periprocedural complication rates and shorter hospitalization periods in experienced competence centers, there is a need for defining novel prognostic inflammatory signatures for improved patient risk stratification. Thus, the objective of the present study was to characterize and assess the prognostic relevance of circulating leukocyte subsets, including phenotypical heterogeneity of monocytes and effector T cells, before and at various times after transfemoral TAVI. Methods and results 129 consecutive patients (59% male, mean age 82.3±5.6 years) with severe symptomatic aortic stenosis (Pmean 44.2±17mmHg), and high or prohibitive operative risk (mean EuroSCORE II 5.9; STS score 4.1) admitted to our clinic for TAVI were included into the study. Peripheral blood samples were obtained pre-procedurally (baseline, BL), directly after the intervention, and at 24h and 3 days after TAVI, and analyzed for inflammatory and cardiac biomarkers, including hs-CRP, IL-6, hs-TropT, and NT-proBNP. Differential myeloid and T-cell subset (Th1, Th2, Th17, Th1/Th17, Th22, Tregs) distribution and kinetics were analyzed using multiparameter flow cytometry. Neutrophil (P0.05 for all cell subsets). Univariate analysis showed that elevated levels of NT-proBNP (HR: 3.4, 95% CI: 1.7–6.8; P=0.0005), hsCRP (HR: 1.4, 95% CI: 1.2–1.7; P=0.0003), and IL-6 (HR: 1.0, 95% CI: 1.0–1.03; P=0.0007), lower counts of Th2 cells (HR: 0.94, 95% CI: 0.90–0.94; P=0.0045), as well as increased percentages of Th17 cells (HR: 1.2, 95% CI: 1.0–1.4; P=0.023), and of non-classical monocytes (HR=1.019, 95% CI: 1.001–1.039; P=0.049) were independently associated with 12-month all-cause mortality. When included in the regression model with STS score, these inflammatory biomarkers provided higher area under ROC curve and category-free net reclassification improvementof 59% at 1 year (P=0.0001). ROC curves inflammation markers add STS Conclusions Our findings demonstrate for the first time an association of inflammatory leukocyte phenotypes with increased mortality after TAVI. Specific monocytic and T-cell signatures might therefore provide novel additive biomarkers to improve individual risk stratification in patients with severe aortic stenosis.

Transcatheter aortic valve replacement (TAVR) is increasingly being used for treatment of severe aortic valve stenosis in patients at intermediate risk for surgical aortic valve replacement (SAVR). Currently, real-world data comparing indications and clinical outcomes of patients at intermediate surgical risk undergoing isolated TAVR with those undergoing SAVR are scarce.We compared clinical characteristics and outcomes of patients with intermediate surgical risk (Society of Thoracic Surgeons score 4%-8%) who underwent isolated TAVR or conventional SAVR within the prospective, all-comers German Aortic Valve Registry.A total of 7613 patients at intermediate surgical risk underwent isolated TAVR (n=6469) or SAVR (n=1144) at 92 sites in Germany between 2012 and 2014. Patients treated by TAVR were significantly older (82.5±5.0 versus 76.6±6.7 years, P0.001) and had higher risk scores (logistic EuroSCORE [European System for Cardiac Operative Risk Evaluation]: 21.2±12.3% versus 14.2±9.5%, P0.001; Society of Thoracic Surgeons score: 5.6±1.1 versus 5.2±1.0, P0.001). Multivariable analyses revealed that advanced age, coronary artery disease, New York Heart Association class III/IV, pulmonary hypertension, prior cardiac decompensation, elective procedure, arterial occlusive disease, no diabetes mellitus, and a smaller aortic valve area were associated with performing TAVR instead of SAVR (all P0.001). Unadjusted in-hospital mortality rates were equal for TAVR and SAVR (3.6% versus 3.6%, P=0.976), whereas unadjusted 1-year mortality was significantly higher in patients after TAVR (17.5% versus 10.8%, P0.001). After propensity score matching, the difference in 1-year mortality between patients with TAVR and SAVR was no longer significant (17.1% versus 15.7%, P=0.59).Patients at intermediate risk undergoing TAVR differ significantly from those treated with SAVR with regard to age and baseline characteristics. Isolated TAVR and SAVR were associated with an in-hospital mortality rate of 3.6%. In the propensity score analysis, there was no significant difference in 1-year mortality between patients with TAVR and SAVR.

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 R 2= 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.

Lesion formation is a critical determinant of technical and clinical success of pulmonary vein isolation. Different catheter designs aim to enhance tissue contact during ablation to enable optimized lesion formation. We analyzed procedural characteristics and predictors of clinical success in patients ablated with three different contemporary ablation catheters. Two hundred sixty-eight sequentially included patients receiving pulmonary vein isolation (PVI) with conventional (n = 122), contact-force (n = 96) and flexible-tip (n = 60) catheters were followed for a median of 14.1 months with 7d-Holter-monitoring and TTE at 3, 6, 12, and 24 months. Baseline characteristics and follow-up times were homogeneous across all groups. Multivariable Cox proportional hazard regression for arrhythmia recurrence demonstrated a favorable hazard ratio for contact-force and flexible-tip catheters vs. conventional open irrigation catheters. Procedure time and fluoroscopy time were shorter for contact-force and flexible-tip catheters versus conventional catheters, but equal between. Linear lesions were applied in 58 % of contact-force and 66 % of flexible-tip cases, and CFAEs were targeted in 26 % of either. Our non-randomized prospectively collected data do not show a difference in observed procedure characteristics and in clinical outcome for flexible-tip versus contact-force catheter designs, while both display improved performance against conventional open irrigated-tip catheters. Linear lesions and CFAEs ablation were not associated with improved arrhythmia-free survival.

INTRODUCTION We analyzed the procedural experience and clinical outcome after pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF) gained over 5 years using the second-generation cryoballoon (CB-Adv). METHODS AND RESULTS For this retrospective study, we enrolled 281 patients undergoing PVI at our institution between 2012 and 2016. The analyzed period was divided into 5 calendar years. Follow-up data, including Holter electrocardiography recordings, were collected during outpatient clinic visits. The impact of several variables on outcome was evaluated by means of univariate and multivariate analyses and Cox proportional hazards regression models. The median procedure and fluoroscopy times over the years were 90 (72 of 114) and 15 (11 of 21) minutes, respectively. A continuous decline in complication rates and fluoroscopy and procedure times was observed in each subsequent year. During mid-term follow-up (33 [25 of 48] months), 178 (63.3%) patients were AF, atrial flutter, or atrial tachycardia free. Multivariate analysis revealed left atrial area (hazard ratio [HR] = 1.05; P

Background Hemodynamic assessment during exercise may unmask an impaired functional reserve of the right ventricle and the pulmonary vasculature in patients with connective tissue disease. We assessed the effect of intravenous sildenafil on the hemodynamic response to exercise in patients with connective tissue disease. Methods In this proof-of-concept study, patients with connective tissue disease and mean pulmonary arterial pressure (mPAP) >20 mm Hg were subjected to a supine exercise hemodynamic evaluation before and after administration of intravenous sildenafil 10 mg. Results Ten patients (four with moderately elevated mPAP 21–24 mm Hg; six with mPAP >25 mm Hg) underwent hemodynamic assessment. All of them showed markedly abnormal exercise hemodynamics. Intravenous sildenafil was well tolerated and had significant hemodynamic effects at rest and during exercise, although without pulmonary selectivity. Sildenafil reduced median total pulmonary resistance during exercise from 6.22 (IQR 4.61–8.54) to 5.24 (3.95–6.96) mm Hg·min·L-1 (p = 0.005) and increased median pulmonary arterial capacitance during exercise from 1.59 (0.93–2.28) to 1.74 (1.12–2.69) mL/mm Hg (p = 0.005). Conclusions In patients with connective tissue disease who have an abnormal hemodynamic response to exercise, intravenous sildenafil improved adaption of the right ventricular-pulmonary vascular unit to exercise independent of resting mPAP. The impact of acute pharmacological interventions on exercise hemodynamics in patients with pulmonary vascular disease warrants further investigation. Trial registration Clinicaltrials.gov NCT01889966.

Aims In this observational study, we examine the significance of the left atrial (LA) surface area and compare the clinical usage of the Arctic Front Advance (CBA) versus Arctic Front (CB) cryoballoon with the intent to investigate the impact of each in terms of long-term freedom from atrial fibrillation (AF) for patients with nonvalvular AF. Methods Pulmonary vein isolation (PVI) was performed while using a cryoballoon ablation catheter in conjunction with an intraluminal circular diagnostic mapping catheter, Achieve. The consecutive patients ablated with CBA were matched with patients previously ablated with CB, using propensity score matching. The primary endpoint of this observational single-center retrospective study was the first observation of electrocardiogram-documented recurrence of atrial arrhythmias lasting >30 seconds. Results The patient demographic data were similar in the CBA- and CB-group (N = 188 patients each group). In all patients in the CBA-group and in 95% of the patients in the CB group, acute procedural PVI of all veins was achieved with the single usage of a 28-mm cryoballoon. The one-year freedom from atrial arrhythmias was significantly better in the CBA- versus the CB-group of patients, 90% versus 64%, respectively. During 15-month clinical follow-up in CBA group, patients with LA area above 23 cm2 were more likely to experience recurrence of AF (23%) than patients with LA area below 23 cm2 (7%). Conclusions Comparing one-year outcomes, the CBA is superior to the CB with regards to maintenance of normal sinus rhythm. When using the CBA catheter, an enlarged LA is associated with a higher recurrence of arrhythmia.

Background Transcatheter aortic valve replacement (TAVR) has evolved into a routine procedure with good outcomes in high-risk patients. Objectives TAVR complication rates were evaluated based on prospective data from the German Aortic Valve Registry (GARY). Methods From 2011 to 2013, a total of 15,964 TAVR procedures were registered. We evaluated the total cohort for severe vital complications (SVCs), including the following: death on the day of intervention, conversion to sternotomy, low cardiac output that required mechanical support, aortic dissection, and annular rupture; technical complications of the procedures (TCOs), such as repositioning or retrieval of the valve prosthesis and embolization of the prosthesis; and other complications. Results Mean patient age was 81 ± 6 years, 54% of the patients were women, the median logistic Euroscore I was 18.3, the German aortic valve score was 5.6, and the Society of Thoracic Surgeons score was 5.0. Overall in-hospital mortality was 5.2%, whereas SVCs occurred in 5.0% of the population. Independent predictors for SVCs were female sex, pre-operative New York Heart Association functional class IV, ejection fraction

Background: Relation between pre-procedural selection of patients and the success rate after a single cryoballoon ablation (CAB) procedure is unknown. Methods: CAB was performed in 378 (65% male, median age 58 years, 85% paroxysmal atrial fibrillation [AF]) consecutive patients with symptomatic and drug refractory AF. The combined ALARMEc (Atrial fibrillation type, Left Atrium size, Renal insufficiency, Metabolic syndrome, cardiomyopathy) risk score was calculated for each individual patient. The end-point of the study was the first AF, atrial flutter or atrial tachycardia recurrence after the 3-month blanking period in the 1-year follow-up since the index procedure, in the absence of anti-arrhythmic (class I and III) therapy. Results: Single and multi-catheter approach was used in 79% and 21% of patients, respec­tively. The acute success rate with single and multi-catheter approach was 79% and 99%, respectively. The overall 1-year success rate after a single CAB procedure was 70%. The 1-year outcome was: 83%, 70%, 60%, 40% and 29% in patients with ALARMEc risk score: 0, 1, 2, 3 and 5, respectively. Total rate of complications was 11%, including transient phrenic nerve palsy in 9.5% of cases. Conclusions: Multi-catheter approach was needed in 21% of patients to achieve acute pulmo­nary vein isolation. Patients with low (≤ 1) ALARMEc risk score, preferably young individuals with sole paroxysmal AF (ALARMEc = 0), are best candidates for CBA procedure. Performing CBA in patients with higher (> 2) ALARMEc risk score should be avoided. Phrenic nerve palsy was a transient complication.

Introduction Antiarrhythmic drug (AAD) therapy of patients with atrial fibrillation (AF) has limitations. We investigated the 2-year outcome and pre-procedural predictors of recurrence for first-line catheter ablation using the second-generation cryoballoon (CB-Adv) in a large cohort of patients with symptomatic AF. Methods and results For this prospective observational study, we enrolled 457 patients with symptomatic AF (278 paroxysmal, 179 persistent) who had no history of AAD use and who underwent pulmonary vein isolation (PVI) with the CB-Adv at our institution. Follow-up data, including Holter-ECGs, were collected during outpatient clinic visits. The impact of several variables on outcome was evaluated in univariate and multivariate analyses and Cox proportional hazards regression models. Median follow-up duration was 28 (interquartile range 15/42) months. PVI was sufficient in restoring and maintaining sinus rhythm in 79.2% ( n =362) of patients. The median procedure and fluoroscopy times were 90 (72/120) and 16 (12/21) min, respectively. Phrenic nerve injury occurred in 16 (3.5%) patients, persisting until hospital discharge in 6 (1.3%) patients; phrenic nerve function recovered in all patients during follow-up. Seven patients developed groin hematomas (1.5%). Cox regression analysis showed that left atrial area >21cm 2 independently predicted recurrence. Conclusion This is the first demonstration that PVI with CB-Adv is safe and effective as a first-line treatment of symptomatic AF. Sinus rhythm persisted in 79.2% of patients even 2years after ablation. The success rate was lower in patients with enlarged left atria.

Background N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) levels correlate with higher peri-procedural mortality after transcatheter aortic valve replacement (TAVR). The long-term prognostic value of NT-proBNP within the first days after TAVR, however, remains unclear. This study examined early changes in NT-proBNP prior to and within 6 days after TAVR, the diagnostic value of this biomarker regarding aortic regurgitation (AR), and its prognostic value regarding one-year mortality. Methods and results NT-proBNP concentrations were measured in 504 consecutive patients undergoing transapical (TA) or transfemoral (TF) TAVR before and directly after TAVR as well as 4 h and 1, 2, 3, and 6 days after TAVR. The follow-up period was 1 year. NT-proBNP was elevated in all patients at baseline (median 2141 ng/L [IQR 1021–5319 ng/L]). NT-proBNP changes in the first 6 days after TAVR showed significant differences depending on the approach, with a greater and more prolonged rise evident in TA-TAVR patients. NT-proBNP was an independent predictor of mortality in TA patients with AR, with an AUC of 0.794 (95% CI 0.663–0.925; P = 0.003) when measured on day 3 after TAVR. For TF patients with AR and reduced left ventricular systolic function, the AUC for prediction of mortality was 0.897 (95% CI 0.778–1.0; P = 0.004) on day 2. Conclusions The prognostic information of early post-procedural NT-proBNP concentrations is superior to pre-procedural values regarding all-cause mortality within 1 year. Post-procedural NT-proBNP must be interpreted in relation to the TAVR approach. NT-proBNP predicts mortality in TF-TAVR patients with AR and reduced left ventricular function.

Approximately every fifth patient undergoing transcatheter aortic valve implantation (TAVI) requires a permanent pacemaker (PPM) after the procedure. The aim of this study was to analyse predictors of atrioventricular block III° (AVBIII) persistence with concurrent PPM dependency after TAVI. Between 2010 and 2015 a total of 1198 patients underwent TAVI at the Kerckhoff Heart and Thorax Center, Germany. After exclusion of patients with prior PPM (n = 173) 14.7% (n = 176) of the patients underwent PPM implantation after the procedure. Independent predictors of PPM implantation were pre-existing right bundle branch block (RBBB, p

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.

The aim of this observational study was to compare the postprocedural incidence of bleeding and thromboembolic complications associated with novel oral anticoagulants (NOACs) with that of interrupted and continuous phenprocoumon after pulmonary vein isolation (PVI) using a purse-string suture (PSS) closure of the puncture site.Consecutive patients who had undergone PVI via cryoballoon ablation were divided into the following groups: (1) interrupted phenprocoumon with heparin bridging (n=101), (2) continuous phenprocoumon targeting an internationally normalized ratio2 (n=70), and (3) NOACs without bridging that were restarted 2-4h after the procedure (n=185). Protamine was not administered after venous closure with PSS at the end of the procedure. The total complication rate was significantly lower in group 3 than in groups 1 and 2 (1.62% vs. 6.93% vs. 7.14%, p=0.04). The hospital costs were lower and the hospital stay length was significantly shorter (4484±3742 vs. 6082±4044 Euro vs. 4908±2925, p=0.03; 1.94±1.67 vs. 2.70±1.80 vs. 2.19±1.30days, p0.01). No thromboembolic event occurred. Vascular complications were the most common complications noted (80%). The occurrence of any complication led to a significantly longer hospital stay (5 vs. 2days, p0.01) and higher costs (10,052±6241 Euro vs. 4747±3447, p0.01). The vascular complication rate after PSS was independent of intraprocedural heparin dosage and activated clotting time.NOACs have a lower complication rate and appear to be safer in this setting than phenprocoumon. The hospital costs and hospital stay length after PVI was significantly reduced in patients treated with NOACs compared with phenprocoumon.