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Katleen Nobbe,1 Melanie Erices-Leclercq,1 Frank Foerster,2,3 Robert Förster,4 Stephan E Baldus,5 Christian Rudlowski,1,6 Lars Schröder,7 Sabine Lubig1 1Breast Unit, Lutheran Hospital Bergisch Gladbach, Bergisch Gladbach, Germany; 2Department of Economical Sciences, University of Applied Sciences, Zwickau, Germany; 3Outpatient Department of Gynaecological Oncology and Palliative Care, Chemnitz, Germany; 4Institute for Radiation Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland; 5Institute for Pathology, Cytology and Molecular Pathology, Bergisch Gladbach, Germany; 6Department of Gynecology, University Hospital Bonn, Bonn, Germany; 7Department of Gynaecology and Obstetrics, Ketteler Krankenhaus, Offenbach, GermanyCorrespondence: Christian Rudlowski, Breast Unit, Lutheran Hospital Bergisch Gladbach, Ferrenbergstrasse 24, Bergisch Gladbach, 51465, Germany, Email c.rudlowski@evk.dePurpose: The introduction of HER2-targeting antibody drug conjugates (ADCs) offers new treatment options for female breast cancer patients (FBC) expressing low levels of HER2 (HER2 low). No evidence was found that HER2 low describes a new FBC subtype. There is a lack of studies determining the impact of HER2 low in male breast cancer (MBC). In this study, we evaluate the prevalence of HER2 low in primary MBC and correlate the results with patient characteristics.Patients and Methods: In this study, histological specimens were obtained from 120 male patients diagnosed and treated for primary invasive breast cancer from 1995 to 2022 at Breast Cancer Units in Bergisch Gladbach, Chemnitz, and Zwickau, Germany. HER2 immunostaining and in situ hybridization were performed by central pathology and evaluated based on the ASCO/CAP guidelines. The correlation of expression of HER2 low with tumor biological characteristics and patient outcomes was investigated.Results: Out of all cases, four patients (3.3%) showed HER2 positivity (3+), 39 (32.5%) patients were classified as HER2 low, 7 (5.

Background: Mitral transcatheter edge-to-edge repair (M-TEER) is a guideline-recommended treatment option for patients with severe symptomatic mitral regurgitation (MR). Outcomes with the PASCAL system in a post-market setting have not been established. Objectives: The authors report 30-day and 1-year outcomes from the MiCLASP (Transcatheter Repair of Mitral Regurgitation with Edwards PASCAL Transcatheter Valve Repair System) European post-market clinical follow-up study. Methods: Patients with symptomatic, clinically significant MR were prospectively enrolled. The primary safety endpoint was clinical events committee–adjudicated 30-day composite major adverse event rate and the primary effectiveness endpoint was echocardiographic core laboratory–assessed MR severity at discharge compared with baseline. Clinical, echocardiographic, functional, and quality-of-life outcomes were assessed at 1 year. Results: A total of 544 patients were enrolled (59% functional MR, 30% degenerative MR). The 30-day composite major adverse event rate was 6.8%. MR reduction was significant from baseline to discharge and sustained at 1 year with 98% of patients achieving MR ≤2+ and 82.6% MR ≤1+ (all P < 0.001 vs baseline). One-year Kaplan-Meier estimate for survival was 87.3%, and freedom from heart failure hospitalization was 84.3%. Significant functional and quality-of-life improvements were observed at 1 year, including 71.6% in NYHA functional class I/II, 14.4-point increase in Kansas City Cardiomyopathy Questionnaire score, and 24.2-m improvement in 6-minute walk distance (all P < 0.001 vs baseline). Conclusions: One-year outcomes of this large cohort from the MiCLASP study demonstrate continued safety and effectiveness of M-TEER with the PASCAL system in a post-market setting. Results demonstrate high survival and freedom from heart failure hospitalization, significant and sustained MR reduction, and improvements in symptoms, functional capacity, and quality of life.

Background Transcatheter aortic valve replacement (TAVR) has become an established alternative to surgical aortic valve replacement (AVR) for higher risk patients. Periprocedural TAVR complications decreased with a growing expertise of implanters. Yet, TAVR can be accompanied by life-threatening adverse events such as intraprocedural cardiopulmonary resuscitation (CPR). This study retrospectively analyzed predictors and outcomes in a cohort of patients from a high-volume center undergoing periprocedural CPR during TAVR. Methods A total of 729 patients undergoing TAVR, including 59 with intraprocedural CPR, were analyzed with respect to peri- and postprocedural outcomes. Results Patients undergoing CPR showed a significantly lower left ventricular ejection fraction (LVEF) and lower baseline transvalvular mean and peak pressure gradients. The systolic blood pressure measured directly preoperatively was significantly lower in the CPR cohort. CPR patients were in a higher need for intraprocedural defibrillation, heart-lung circulatory support, and conversion to open heart surgery. Further, they showed a higher incidence of atrioventricular block grade III , valve malpositioning, and pericardial tamponade. The in-hospital mortality was significantly higher after intraprocedural CPR, accompanied by a higher incidence of disabling stroke, new pacemaker implantation, more red blood cell transfusion, and longer stay in intensive care unit. Conclusion Impaired preoperative LVEF and instable hemodynamics before valve deployment are independent risk factors for CPR and are associated with compromised outcomes. Heart rhythm disturbances, malpositioning of the prosthesis, and pericardial tamponade are main causes of the high mortality of 17% reported in the CPR group. Nevertheless, mechanical circulatory support and conversion to open heart surgery reduce mortality rates of CPR patients.

Background Despite major advances, transcatheter aortic valve replacement (TAVR) is still associated with procedure-specific complications. Although previous studies reported lower bleeding rates in patients receiving protamine for heparin reversal, the optimal protamine-to-heparin dosing ratio is unknown. Hypothesis The aim of this study was a comparison of two different heparin antagonization regimens for the prevention of bleeding complications after TAVR. Methods The study included 1446 patients undergoing TAVR, of whom 623 received partial and 823 full heparin antagonization. The primary endpoint was a composite of 30-day mortality, life-threatening, and major bleeding. Safety endpoints included stroke and myocardial infarction at 30 days. Results Full antagonization of heparin resulted in lower rates of the primary endpoint as compared to partial heparin reversal (5.6% vs. 10.4%, p < .01), which was mainly driven by lower rates of life-threatening (0.5% vs. 1.6%, p = .05) and major bleeding (3.2% vs. 7.5%, p < .01). Moreover, the incidence of major vascular complications was significantly lower in patients with full heparin reversal (3.5% vs. 7.5%, p < .01). The need for red-blood-cell transfusion was lower in patients receiving full as compared to partial heparin antagonization (10.4% vs. 15.9%, p < .01). No differences were observed in the incidence of stroke and myocardial infarction between patients with full and partial heparin reversal (2.2% vs. 2.6%, p = .73 and 0.2% vs. 0.4%, p = .64, respectively). Conclusions Full heparin antagonization resulted in significantly lower rates of life-threatening and major bleeding after TAVR as compared to partial heparin reversal. The occurrence of stroke and myocardial infarction was low and comparable between both groups.

Aims This network meta-analysis aimed to assess the effect of early coronary angiography (CAG) compared with selective CAG (late and no CAG) for patients after out-of-hospital cardiac arrest without ST-elevation myocardial infarction (NSTE-OHCA). Methods and results A systematic literature search was performed using the EMBASE, MEDLINE and Web of Science databases without restrictions on publication date. The last search was performed on 15 July 2022. Randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing the effect of early CAG to selective CAG after NSTE-OHCA on survival and/or neurological outcomes were included. Meta-analyses were performed based on a DerSimonian-Laird random effects model. A total of 18 studies were identified by the literature search. After the exclusion of two studies due to high risk of bias, 16 studies (six RCTs, ten NRS) were included in the final analyses. Meta-analyses showed a statistically significant increase in survival after early CAG compared with selective CAG in the overall analysis [OR: 1.40, 95% confidence interval (CI): (1.12-1.76), P < 0.01, I-2 = 68%]. This effect was lost in the subgroup analysis of RCTs [OR: 0.89, 95% CI: (0.73-1.10), P = 0.29, I-2 = 0%]. Random effects model network meta-analysis of NRS based on a Bayesian method showed statistically significant increased survival after late compared with early CAG [OR: 4.20, 95% CI: (1.22, 20.91)]. Conclusion The previously reported superiority of early CAG after NSTE-OHCA is based on NRS at high risk of selection and survivorship bias. The meta-analysis of RCTs does not support routinely performing early CAG after NSTE-OHCA.

Policy makers in academic medicine, the educational and research sectors, and industry all agree: clinician scientists, physicians engaged in research, are the key to translating and implementing innovative therapeutic concepts into clinical practice. To this end, research on cardiovascular diseases, which cause most cases of death in the world, must be prioritized. Following internal group discussions and surveying physicians working in university hospitals and affiliated research institutes, the German Cardiac Society thoroughly analyzed the current and future situation and role of clinician scientists in cardiovascular medicine. Modern cardiology at university hospitals is characterized by higher workloads with more patients, shorter hospital stays, and increasingly more complex interventions, making it difficult for physicians and department heads to combine their research interests and activities with their clinical duties and training. This position paper discusses possibilities to improve working conditions and career perspectives for clinician scientists in cardiovascular medicine.

Background: The optimal timing to perform percutaneous coronary interventions (PCI) in transcatheter aortic valve implantation (TAVI) patients remains unknown. Aims: We sought to compare different PCI timing strategies in TAVI patients. Methods: The REVASC-TAVI registry is an international registry including patients undergoing TAVI with significant, stable coronary artery disease (CAD) at preprocedural workup. In this analysis, patients scheduled to undergo PCI before, after or concomitantly with TAVI were included. The main endpoints were all-cause death and a composite of all-cause death, stroke, myocardial infarction (MI) or rehospitalisation for congestive heart failure (CHF) at 2 years. Outcomes were adjusted using the inverse probability treatment weighting (IPTW) method. Results: A total of 1,603 patients were included. PCI was performed before, after or concomitantly with TAVI in 65.6% (n=1,052), 9.8% (n=157) or 24.6% (n=394), respectively. At 2 years, all-cause death was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (6.8% vs 20.1% vs 20.6%; p<0.001). Likewise, the composite endpoint was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (17.4% vs 30.4% vs 30.0%; p=0.003). Results were confirmed at landmark analyses considering events from 0 to 30 days and from 31 to 720 days. Conclusions: In patients with severe aortic stenosis and stable coronary artery disease scheduled for TAVI, performance of PCI after TAVI seems to be associated with improved 2-year clinical outcomes compared with other revascularisation timing strategies. These results need to be confirmed in randomised clinical trials.

Background: The deployment process of the largest self-expandable device (STHV-34) during transcatheter aortic valve implantation (TAVI) might be challenging due to stabilization issues. Whether the use of different TAVI-guidewires impact the procedural success and outcome is not well-known. Therefore, we sought to evaluate the impact of non-Lunderquist (NLu) vs. the Lunderquist (Lu) guidewires during TAVI using the STHV-34 on the procedural and 30-day outcomes. Methods: The primary study endpoint was defined as the final implantation depth (ID) depending on the selected guidewire strategy. Key secondary endpoints included VARC-3-defined complications. Results: The study cohort included 398 patients of four tertiary care institutions, of whom 79.6% (317/398) had undergone TAVI using NLu and 20.4% (81/398) using Lu guidewires. Baseline characteristics did not substantially differ between NLu and Lu patients. The average ID was higher in the Lu cohort (NLu vs. Lu: −5.2 [−7.0–(−3.5)] vs. −4.5 [−6.0–(−3.0)]; p = 0.022*). The optimal ID was reached in 45.0% of patients according to former and only in 20.1% according to nowadays best practice recommendations. There was no impact of the guidewire use on the 30-day outcomes, including conduction disturbances and pacemaker need (NLu vs. Lu: 15.1 vs. 18.5%; p = 0.706). Conclusion: The use of the LunderquistTM guidewire was associated with a higher ID during TAVI with the STHV-34 without measurable benefits in the 30-day course concerning conduction disturbances and associated pacemaker need. Whether using different guidewires might impact the outcome in challenging anatomies should be further investigated in randomized studies under standardized conditions.

Aims The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 x 10(-08)) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 x 10(-16)), GATA4 (P = 1.61 x 10(-09)), and TEX41 (P = 7.68 x 10(-04)). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and similar to 20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

Aims The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 x 10(-08)) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 x 10(-16)), GATA4 (P = 1.61 x 10(-09)), and TEX41 (P = 7.68 x 10(-04)). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and similar to 20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

Background: The optimal timing to perform percutaneous coronary interventions (PCI) in transcatheter aortic valve implantation (TAVI) patients remains unknown. Aims: We sought to compare different PCI timing strategies in TAVI patients. Methods: The REVASC-TAVI registry is an international registry including patients undergoing TAVI with significant, stable coronary artery disease (CAD) at preprocedural workup. In this analysis, patients scheduled to undergo PCI before, after or concomitantly with TAVI were included. The main endpoints were all-cause death and a composite of all-cause death, stroke, myocardial infarction (MI) or rehospitalisation for congestive heart failure (CHF) at 2 years. Outcomes were adjusted using the inverse probability treatment weighting (IPTW) method. Results: A total of 1,603 patients were included. PCI was performed before, after or concomitantly with TAVI in 65.6% (n=1,052), 9.8% (n=157) or 24.6% (n=394), respectively. At 2 years, all-cause death was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (6.8% vs 20.1% vs 20.6%; p<0.001). Likewise, the composite endpoint was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI., Background: The optimal timing to perform percutaneous coronary interventions (PCI) in transcatheter aortic valve implantation (TAVI) patients remains unknown. Aims: We sought to compare different PCI timing strategies in TAVI patients. Methods: The REVASC-TAVI registry is an international registry including patients undergoing TAVI with significant, stable coronary artery disease (CAD) at preprocedural workup. In this analysis, patients scheduled to undergo PCI before, after or concomitantly with TAVI were included. The main endpoints were all-cause death and a composite of all-cause death, stroke, myocardial infarction (MI) or rehospitalisation for congestive heart failure (CHF) at 2 years. Outcomes were adjusted using the inverse probability treatment weighting (IPTW) method. Results: A total of 1,603 patients were included. PCI was performed before, after or concomitantly with TAVI in 65.6% (n=1,052), 9.8% (n=157) or 24.6% (n=394), respectively. At 2 years, all-cause death was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (6.8% vs 20.1% vs 20.6%; p<0.001). Likewise, the composite endpoint was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (17.4% vs 30.4% vs 30.0%; p=0.003). Results were confirmed at landmark analyses considering events from 0 to 30 days and from 31 to 720 days. Conclusions: In patients with severe aortic stenosis and stable coronary artery disease scheduled for TAVI, performance of PCI after TAVI seems to be associated with improved 2-year clinical outcomes compared with other revascularisation timing strategies. These results need to be confirmed in randomised clinical trials.

Objectives To test if the early kinetics of neurofilament light (NFL) in blood adds to the absolute values of NFL in the prediction of outcome, and to evaluate if NFL can discriminate individuals with severe hypoxic-ischemic brain injury (sHIBI) from those with other causes of poor outcome after out-of-hospital cardiac arrest (OHCA). Design and setting Monocentric retrospective study involving individuals following non-traumatic OHCA between April 2014 and April 2016. NFL concentrations were determined on a SiMoA HD-1 device using NF-Light Advantage Kits. Participants Of 73 patients screened, 53 had serum samples available for NFL measurement at three timepoints (after 3, 24, and 48 h of admission). Of these 53 individuals, 43.4% had poor neurologic outcome at discharge as assessed by Glasgow-Pittsburgh cerebral performance categories, and, according to a current prognostication algorithm, poor outcome due to sHIBI in 20.7%. Main outcome measure Blood NFL and its early kinetics for prognostication of outcome and prediction of sHIBI after OHCA. Results An absolute NFL > 508.6 pg/ml 48 h after admission, or a change in NFL > 494 pg/ml compared with an early baseline value predicted outcome, and discriminated severe sHIBI from other causes of unfavorable outcome after OHCA with high sensitivity (100%, 95%CI 70.0-100%) and specificity (91.7%, 95%CI 62.5-100%). Conclusions Not only absolute values of NFL, but also early changes in NFL predict the outcome following OHCA, and may differentiate sHIBI from other causes of poor outcome after OHCA with high sensitivity and specificity. Our study adds to published data, overall corroborating that NFL measured in blood should be implemented in prognostication algorithms used in clinical routine.

Background Liver dysfunction is associated with an increased risk of mortality after cardiac interventions. The Fibrosis-4 (FIB-4 index), a marker of hepatic fibrosis, has been associated with a worse prognosis in heart failure. The prognostic relevance of the index in patients undergoing transcatheter aortic valve replacement (TAVR) is unknown. The aim of this study was to evaluate the clinical implications associated with the FIB-4 index in patients undergoing TAVR. Methods Between May 2012 and June 2019, 941 patients undergoing TAVR were stratified into a low or high FIB-4 index group, based on a cutoff value that was determined according to a receiver operating characteristic curve predicting 1-year all-cause mortality. Results Patients with a high FIB-4 index (n = 480), based on the cutoff value of 1.82, showed higher rates of pulmonary hypertension (43.8% vs. 31.8%, p < 0.01), right-ventricular systolic dysfunction (29.5% vs. 19.2%, p < 0.01) and larger inferior vena cava diameter (1.6 +/- 0.6 cm vs. 1.3 +/- 0.6 cm, p < 0.01) than patients with a low FIB-4 index (n = 461). Furthermore, a high FIB-4 index was associated with a significantly higher cumulative 1-year all-cause mortality (17.5% vs. 10.2%, p < 0.01) and non-cardiovascular mortality (12.1% vs. 2.5%, p < 0.01), compared to a low FIB-4 index. Multivariable analysis revealed that a high FIB-4 index was independently associated with all-cause mortality (HR: 1.75 [95% CI: 1.18-2.59], p < 0.01). Conclusions A high FIB-4 index is associated with right-sided heart overload and an increased risk of mortality in patients undergoing TAVR. The FIB-4 index may be useful as an additional predictor of outcomes in these patients.

Objective A sizeable proportion of patients with secondary mitral regurgitation (SMR) do not receive guideline-directed medical therapy (GDMT) for heart failure (HF). We investigated the association between the use of GDMT and mortality in patients with SMR who underwent transcatheter edge-to-edge repair (TEER). Methods We retrospectively analysed patients with SMR and a left ventricular ejection fraction of <50% who underwent TEER at three centres. According to current HF guidelines, GDMT was defined as triple therapy consisting of beta-blockers, renin-angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists (MRAs). Patients were divided into two groups: GDMT and non-GDMT groups. We calculated the propensity scores and carried out inverse probability of treatment weighting (IPTW) analyses to compare 2-year mortality between the two groups. Results Of 463 patients, 228 (49.2%) were treated with GDMT upon discharge. IPTW-adjusted Kaplan-Meier curve showed patients with GDMT had a lower incidence of mortality than those without GDMT (19.8% vs 31.1%, p=0.011). In IPTW-adjusted Cox proportional hazards analysis, GDMT was associated with a reduced risk of 2-year mortality (HR: 0.58; 95% CI: 0.35 to 0.95; p=0.030), which was consistent among clinical subgroups. Moreover, patients with GDMT had a higher rate of left ventricular reverse remodelling at 1 year after TEER than those without GDMT. Conclusion GDMT, defined as triple therapy consisting of beta-blockers, RAS inhibitors and MRAs, was associated with a reduced risk of 2-year mortality after TEER for SMR. Optimisation of medical therapy is crucial to improve clinical outcomes in patients undergoing TEER for SMR.

Objective Periinterventional stroke is one of the most feared potential complication, among patients treated with transcatheter aortic valve implantation (TAVI). The purpose of this review was to investigate the incidence of cerebrovascular events and the influence of postinterventional neurologic check-up in patients undergoing TAVI. Methods A systematic review and meta-analysis were conducted according to the PRISMA guideline. Three separate electronic searches of the public domains Medline and Clinicaltrials.gov were performed to identify the 30-day incidence of stroke within randomized controlled trials (RCTs) and registries for patients undergoing a TAVI procedure. A meta-analysis was conducted to evaluate the 30-day incidence of stroke within RCTs. Furthermore, we pooled the RCTs in which a scheduled neurological check-up was conducted or not to investigate the effect of this intervention. Results Twenty-three studies including 399,532,491 TAVI patients were included, 6370 from RCTs, 857,833 from cerebral-embolic protection device RCTs and 392,288 were adopted from registries. The mean 30-day incidence of stroke among all reviewed studies was 2.33%. In RCTs evaluating TAVI the pooled stroke incidence was 3.86%, among RCTs focused CEP the incidence was 6.4436% and in registries the incidence was 2.29%. Ten RCTs conducted scheduled neurological check-ups, the incidence in these was 4.03% and among the remaining RCTs it was 2.47%. In the meta-analysis, the pooled 30-day stroke incidence was 3.61% (95% CI 2.57-4.79%). Conclusion This systematic review demonstrates that the stroke incidences following TAVI differ strongly according to the study design and neurological follow-up. Intense neurological testing increases the incidence of a stroke after TAVI. [GRAPHICS] .

Background: In terms of pathophysiology, tricuspid regurgitation (TR) and right ventricular (RV) function are linked to each other. Aims: This study sought to evaluate RV-pulmonary artery (PA) coupling and its impact on clinical out-comes of TR in patients undergoing mitral transcatheter edge-to-edge repair (TEER). Methods: We calculated RV-PA coupling ratios in patients undergoing mitral TEER from August 2010 to March 2019 by dividing the tricuspid annular plane systolic excursion (TAPSE) by the echocardiographic estimated PA systolic pressure (PASP). TR was graded as none/trace, mild, moderate, or severe. The pri-mary outcome was all-cause mortality or rehospitalisation within 12 months. Results: Among 744 patients analysed, severe TR was documented in 22.3% of patients and the mean TAPSE/PASP was 0.43 +/- 0.25. Technical success of TEER was achieved in 97.2% of participants. Severe TR vs TR <= moderate (adjusted HR 1.92, 95% CI: 1.39-2.66) and TAPSE/PASP (adjusted HR 0.45, 95% CI: 0.22-0.93) were associated with the outcome. Patients were divided according to the TAPSE/PASP ter -tile. Compared to patients with TR <= moderate, patients with severe TR had a higher event rate (TAPSE/ PASP <0.30: 32.9% vs 45.1%; 0.30 <= TAPSE/PASP <0.44: 27.8% vs 41.8%; TAPSE/PASP <0.44: 16.0% vs 40.4%), whereas the prognostic significance of TR was attenuated in patients with reduced TAPSE/PASP (i.e., RV-PA uncoupling; interaction term p=0.03). The trends were consistent in the multivariable regres-sion models, spline curves, and sensitivity analysis using post-interventional parameters. Conclusions: RV-PA coupling affects the outcome correlation of TR in patients undergoing mitral TEER. The prognostic impact of TR is attenuated in patients with RV-PA uncoupling.

Background: In patients with severe mitral regurgitation (MR) who are scheduled for transcatheter mitral valve repair (TMVR), risk stratification is predominantly based on surgical risk scores. Aims: We sought to characterise and define stages of right heart remodelling in patients undergoing TMVR and evaluate the impact of this staging classification on survival. Methods: According to echocardiographic parameters, 929 patients undergoing MitraClip treatment were classified into three stages: severe MR without right heart damage (stage 0), with moderate-to-severe tricuspid regurgitation (TR) (stage 1), with right ventricular dysfunction defined as a reduced fractional area change <35% and a tricuspid annular plane systolic excursion <17 mm, or with increased right atrial area >25 cm2 and/or indexed right ventricular volume >30 ml/m2 (stage 2). We compared clinical outcomes and performed a multivariate analysis to evaluate the predictive value of the extent of cardiac damage. Results: Rates of one-year all-cause mortality increased with more advanced stages of right heart remodelling (stage 0: 8% vs stage 1: 9.7% vs stage 2: 18.1%; p<0.001). In the multivariate analysis, advanced cardiac damage was an independent predictor of one-year all-cause mortality (stage 2: p=0.007). Conclusions: A simple staging classification objectively characterises the extent of right heart remodelling caused by MR and allows risk prediction in patients undergoing a MitraClip procedure.

Aims Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellutar signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS. Methods and results Eight-week-old MFS (Fbn1(C1041G+)) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of etastin fragmentation by matrix metattoproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2 -OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1(C1041G/+) mice challenged with Angiotensin II. Conclusion NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-m

With the Collaborative Research Center TRR259 Aortic disease a research association on aortic diseases has been established for the first time worldwide and combines the expertise from three university hospitals. The aim of the research consortium is to elucidate the molecular and cellular pathomechanisms involved in the development of different aortic diseases. The main focus of the research program lies on diseases of the aortic valve, in particular calcific aortic valve stenosis and aortic aneurysms.

Staphylococcus aureus (SA) and Streptococcus species (SS) show different clinical manifestations in infective endocarditis (IE), but the impact on the complexity of surgical treatment remains unclear. All patients with surgically treated IE due to SA or SS between July 2013 and December 2016 were extracted from a prospectively collected, single-center registry. Data on patient characteristics, surgical procedures, and postprocedural outcomes were collected. SA-IE was more common with prosthetic valves (26.3% vs. 7.3%, p = 0.04), cardiac devices (14.3% vs. 0%, p = 0.03), previous cardiac surgery (28.6% vs. 9.8%, p = 0.03), intravenous drug abuse (14.3% vs. 0%, p = 0.03), and embolic events (57.1% vs. 26.8%, p = 0.007). Preoperative CRP was significantly higher in SA-IE (median 96.1 mg/L vs. 42.4 mg/L, p = 0.002). Otherwise, SS-IE affected more cusps/leaflets (mean 2.4 vs. 1.8, p = 0.03) and led to more valve dysfunction (83.8% vs. 54.3%, p = 0.007). Surgery times did not differ between the groups, though patients with SA spent more time in the intensive care unit (median 7 vs. 4.5 days, p = 0.04). Hospital mortality did not differ, but patients with SA-IE had unfavorable long-term survival (p = 0.001). Future studies need to be larger and focus on the mechanism behind the reduced long-term survival to mitigate the deleterious effect of SA in surgically treated patients with IE.

Background Appropriate and timely anticoagulant therapy with vitamin K antagonists (VKAs) or non-vitamin K oral antagonists (NOACs) is essential for stroke prevention in non-valvular atrial fibrillation (NVAF). Comparative data regarding effectiveness and safety for edoxaban vs phenprocoumon, the predominant VKA in Germany, are scarce. Objectives The study evaluates effectiveness and safety of edoxaban vs phenprocoumon in NVAF patients in a German real-world setting. Methods German statutory health insurance claims data of the Institute for Applied Health Research Berlin (InGef) Research Database from 2014 until 2019 were analyzed. In NVAF patients, new users of edoxaban and phenprocoumon were compared to assess effectiveness (stroke/systemic embolism (SE)) and safety (bleeding) during therapy. Hazard ratios (HR) were estimated through multiple outcome-specific cox proportional hazard models adjusting for baseline characteristics. Outcomes of geriatric patients were analyzed in subgroup analyses. Results Between 2015 and 2018, 7,975 and 13,319 NVAF patients newly initiated treatment with edoxaban or phenprocoumon. After adjusting for baseline confounders, the risk of stroke/SE (HR: 0.85, 95% CI: 0.70-1.02) was numerically but not significantly lower, while the risk of major bleeding (HR: 0.69, 95% CI: 0.58-0.81) was significantly lower for edoxaban. In the geriatric subgroups, homogenous results compared to the main analysis were obtained. Conclusion The results of this real-world analysis indicated better effectiveness and safety outcomes in patients with NVAF initiating edoxaban treatment compared to phenprocoumon. The findings confirm that the beneficial effects observed in the pivotal ENGAGE AF-TMI 48 trial can also be achieved in real-world use of edoxaban.

Aims Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Vascular remodelling of pulmonary arteries, characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a hallmark of PAH. Here, we aimed to systematically characterize coagulation-independent effects of key coagulation proteases thrombin and Factor Xa (FXa) and their designated receptors, protease-activated receptor (PAR)-1 and -2, on PASMCs in vitro and experimental PAH in vivo. Methods and results In human and murine PASMCs, both thrombin and FXa were identified as potent mitogens, and chemoattractants. FXa mediated its responses via PAR-1 and PAR-2, whereas thrombin signalled through PAR-1. Extracellular-signal regulated kinases 1/2, protein kinase B (AKT), and sphingosine kinase 1 were identified as downstream mediators of PAR-1 and PAR-2. Inhibition of FXa or thrombin blunted cellular responses in vitro, but unexpectedly failed to protect against hypoxia-induced PAH in vivo. However, pharmacological inhibition as well as genetic deficiency of both PAR-1 and PAR-2 significantly reduced vascular muscularization of small pulmonary arteries, diminished right ventricular systolic pressure, and right ventricular hypertrophy upon chronic hypoxia compared to wild-type controls. Conclusion Our findings indicate a coagulation-independent pathogenic potential of thrombin and FXa for pulmonary vascular remodelling via acting through PAR-1 and PAR-2, respectively. While inhibition of single coagulation proteases was ineffective in preventing experimental PAH, our results propose a crucial role for PAR-1 and PAR-2 in its pathobiology, thus identifying PARs but not their dedicated activators FXa and thrombin as suitable targets for the treatment of PAH.

Purpose: Baroreflex activation therapy has favorable effects in heart failure patients. We report the results of a single-center study of baroreflex activation therapy in heart failure with reduced ejection fraction including cardiopulmonary exercise testing for the first time to show the effect on exercise capacity. Methods: A total of 17 patients were treated with baroreflex activation therapy. Eligibility criteria were the New York Heart Association class >= III and ejection fraction <= 35% on guideline-directed medical and device therapy. The New York Heart Association class, quality of life, and 6-min hall walk distance were assessed in all patients. Twelve patients underwent cardiopulmonary exercise testing before and 8.9 +/- 6.4 months after initiation of baroreflex activation therapy. Results: The New York Heart Association class and 6-min hall walk distance improved after baroreflex activation therapy, while quality of life remained stable. Weight-adapted peak oxygen uptake increased significantly from 10.1 (8.2-12.9) ml/min/kg to 12.1 (10.4-14.61 ml/min/kg (p=0.041). Maximal heart rate was stable. Maximal oxygen pulse increased from 9.7 (5.5-11.31 to 9.9 (7.1-12.1)ml/heartbeat (p= 0.0471 in 10 patients with low maximal oxygen pulse at baseline (<16.5 ml/heartbeat). There was no significant change in maximal oxygen pulse in the whole cohort. Ventilatory efficiency remained stable. Conclusion: Weight-adapted peak oxygen uptake improved after baroreflex activation therapy, pointing to an enhanced exercise capacity. Ventilatory efficiency and heart rate did not change, while oxygen pulse increased in patients with low oxygen pulse at baseline, indicating an improvement in circulatory efficiency, that is, a beneficial effect on stroke volume and peripheral oxygen extraction.

Objectives This study aimed to investigate early haemodynamic and clinical performance of the SAPIEN 3 Ultra (S3 Ultra) transcatheter heart valve (THV) system in comparison to its precursor, the SAPIEN 3 (S3). Previous studies have indicated potential haemodynamic differences between the S3 Ultra and S3. Such differences may impact clinical outcome after transcatheter aortic valve implantation (TAVI). Methods Postprocedural haemodynamic performance and 30-day clinical outcome were compared in patients who underwent TAVI receiving either the S3 or the new S3 Ultra prostheses. Multivariable analysis and propensity score matching (PSM) were used to identify factors associated with higher mean transvalvular gradients. Results We included 697 patients (S3 Ultra: n=314, S3: n=383) from the multicentre RhineHeart TAVI Registry. Patients receiving the S3 Ultra prosthesis showed significantly higher postprocedural mean transvalvular gradients (14.2 +/- 4.8 vs 10.2 +/- 4.4 mm Hg; p<0.01). Multivariable logistic regression analyses and additional PSM revealed the use of the S3 Ultra to be associated with higher postprocedural mean transvalvular gradients (p<0.01). 30-day clinical outcomes, such as mortality, myocardial infarction, permanent pacemaker implantation and vascular complications were comparable between the groups. Conclusions The new S3 Ultra THV was associated with a higher postprocedural mean transvalvular gradient compared with the S3 system, while there was no difference in mortality or adverse clinical outcomes at 30 days. These echocardiographic differences will require long-term studies to assess the clinical relevance of this

Objectives This study aimed to compare hemodynamic characteristics of different self-expanding (SE) and balloon-expandable (BE) transcatheter heart valves (THV) in relation to native aortic annulus anatomy. Background A patient centered THV selection becomes increasingly important as indications for transcatheter aortic valve replacement (TAVR) are extended towards lower risk populations. Methods Hemodynamic parameters including mean gradient (MG), effective orifice area (EOA), Doppler velocity index (DVI), degree of paravalvular regurgitation (PVR) and patient-prosthesis mismatch (PPM) were compared by valve type, label size and in relation to quintiles of native aortic annulus area. Results 2609 patients were treated at 3 centers in Germany with SAPIEN 3 (n = 1146), ACURATE Neo (n = 649), Evolut R (n = 546) or Evolut Pro (n = 268) THV. SE THVs provided superior hemodynamics in terms of larger EOA, higher DVI and lower MG compared to BE THV, especially in patients with small aortic annuli. Severe PPM was less frequent in SE treated patients. The rate of PVR >= moderate was comparable for SE and BE devices in smaller annular dimensions, but remarkably lower for BE TAVR in large aortic annular dimensions (> 547.64 mm(2)) (2% BE THV vs. > 10% for SE THV; p < 0.001). Conclusions Patients with small aortic annular dimensions may benefit hemodynamically from SE THV. With increasing annulus size, BE THV may have advantages since PVR >= moderate occurs less frequently.

BackgroundTranscatheter tricuspid valve repair (TTVr) is routinely performed under general anesthesia (GA). This study aimed to investigate whether TTVr procedures can be performed effectively and safely without GA but using deep sedation (DS). MethodsWe performed a retrospective analysis of 104 patients from three centers who underwent TTVr between 2020 and 2021. The primary performance endpoints were technical success and severity of TR assessed at the time of discharge. The safety outcome was a composite of in-hospital complications, including occurrence of death, conversion to surgery, major adverse cardiac and cerebrovascular events, major vascular complications, or occurrence of pneumonia. ResultsSixty-four procedures were performed in GA and 40 procedures were performed in DS. The groups did not differ in age, EuroScore II, TR severity, ventricular function, or hemodynamic parameters. Technical success was achieved in 92.5% of the patients in the DS group and in 93.6% of the patients in the GA group (p = 0.805). In none of the patients intraprocedural conversion from DS to GA was required. There was no difference in total duration of the procedure, and number of devices implanted. The degree of TR was <= 2+ in 77.5% of the patients in the DS group and in 74.2% of the patients in the GA group (p = 0.705). The composite safety endpoint did not differ between the groups (2.5 vs. 6.3%, p = 0.384). The total duration of hospital stay was shorter in patients who underwent TTVr in DS compared to those who underwent TTVr in GA (6 [5, 9] days vs. 8 [6, 11] days; p = 0.011). ConclusionPerforming TTVr in DS was effective with similar procedural results, and was safe with similar low complication rates compared to GA.

The prevalence of left ventricular (LV) thrombus formation following percutaneous mitral valve edge-to-edge repair (TMVR) with the MitraClip system is unclear. Decreased total stroke volume and perfusion of the LV apex after mitral valve repair may facilitate thrombus formation especially in the context of reduced LV function. LV thrombus may cause disabling stroke or other thromboembolic events in this elderly and multimorbid patient cohort. Analyses of the prevalence of and risk factors for left ventricular thrombus formation in patients treated with the MitraClip system due to severe mitral valve regurgitation. All discharge and follow-up transthoracic echocardiographic examinations up to 6 months of 453 consecutive patients treated with the MitraClip system were screened for the presence of LV thrombus. Prevalence of LV thrombus formation was 1.1% (5/453). Importantly, LV thrombi were exclusively found in patients with severely depressed left ventricular systolic function (LV-EF < 30%), comprising a prevalence of 4.4% in this subgroup (5/113). Importantly, two of these patients were under active DOAC therapy with Rivaroxaban and Apixaban, respectively. Apart from LV-EF, we did not identify other factors that might have facilitated LV thrombus formation. LV thrombus formation following percutaneous mitral valve repair occurred exclusively in patients with severely depressed LV-EF. As two patients developed LV thrombus despite of DOAC therapy, anticoagulation with a Vitamin K antagonist should be considered in patients with an indication for oral anticoagulation following TMVR.

Aims This study sought to investigate current anticoagulatory treatment patterns and clinical outcome in patients undergoing transcatheter mitral valve repair (MitraClip). Methods and results In a retrospective study of a German claims database (InGef research database), anticoagulatory treatment regimens were assessed using any drug prescription post discharge within the first 90 days after MitraClip procedure. Clinical events between 30 days and 6 months were examined by treatment regime. The study population comprised 1342 patients undergoing MitraClip procedure between 2014 and 2018. 22.4% received antiplatelet monotherapy, 20.8% oral anticoagulation (OAC) plus antiplatelet therapy, 19.4% OAC monotherapy, 11.7% dual antiplatelet therapy, 2.8% triple therapy and 21.0% did not receive any anticoagulatory drugs. 63% of patients with OAC received non-vitamin-K antagonist oral anticoagulants (NOAC). A total of 168 patients were newly prescribed OAC after MitraClip, of whom 12 patients (7.1%) had no diagnosis of atrial fibrillation or venous thromboembolism. 40% of patients with OAC prior to MitraClip did not have any OAC after MitraClip. The adjusted risk of all-cause mortality was significantly increased in patients with no anticoagulatory treatment (HR 3.84, 95% CI 2.33-6.33, p < 0.0001) when compared to antiplatelet monotherapy whereas the other regimes were not significantly different. Conclusions This large real-world data analysis demonstrates a heterogeneous spectrum of prescriptions for anticoagulant therapies after MitraClip. Considering relevant differences in clinical outcome across treatment groups, major effort is warranted for controlled trials in order to establish evidence-based recommendations on anticoagulatory treatment after percutaneous mitral valve repair. [GRAPHICS] .

Background: Computed tomography derived Fractional Flow Reserve (CT-FFR) has been shown to decrease the referral rate for invasive coronary angiography (ICA). The purpose of the study was to evaluate the diagnostic performance of CT-FFR compared to hyperemia-free index Resting Full-cycle Ratio (RFR) in patients with relevant aortic stenosis (AS) and intermediate coronary stenosis. Methods: 41 patients with 46 coronary lesions underwent ICA with quantitative coronary angiography (QCA), pressure wire assessment and routine pre-transcatheter aortic valve replacement (TAVR) computed tomography (CT). CT-FFR analysis was performed using prototype on-site software. Results: RFR showed a significant correlation with CT-FFR (Pearson's correlation, r = 0.632, p < 0.001). On a per-lesion basis, diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CT-FFR were 82.6% (95% CI 68.6-92.2), 69.6% (95% CI 47.1-86.8), 95.7% (95% CI 78.1-99.9), 94.1% (95% CI 69.8-99.1), and 75.9% (95% CI 62.7-85.4), respectively. The optimal cutoff value of the CT-FFR for RFR <= 0.89 prediction was 0.815. The area under the receiver curve showed a larger area under the curve for CT-FFR (0.87; 95% CI 0.75-0.98) compared with CTA stenosis of >= 50% (0.54, 95% CI 0.38-0.71), CTA >= 70% (0.72, 95% CI 0.57-0.87) and QCA >= 50% (0.67, 95% CI 0.52-0.83). Conclusions: CT-FFR assessed by routine pre-TAVR CT is safe and feasible and shows a significant correlation with RFR in patients with AS. CT-FFR is superior to QCA >= 50%, CT >= 50% and CT >= 70% in assessing the hemodynamic relevance of intermediate coronary lesions. Thus, CT-FFR has the potential to guide revascularization in patients with AS.

Chronic kidney disease's prevalence rises globally. Whereas dialysis treatment replaces the kidney's filtering function and prolongs life, dreaded consequences in remote organs develop inevitably over time. Even milder reductions in kidney function not requiring replacement therapy associate with bacterial infections, cardiovascular and heart valve disease, which markedly limit prognosis in these patients. The array of complications is diverse and engages a wide gamut of cellular and molecular mechanisms. The innate immune system is profoundly and systemically altered in chronic kidney disease and, as a unifying element, partakes in many of the disease's complications. As such, a derailed immune system fuels cardiovascular disease progression but also elevates the propensity for serious bacterial infections. Recent data further point towards a role in developing calcific aortic valve stenosis. Here, we delineate the current state of knowledge on how chronic kidney disease affects innate immunity in cardiovascular organs and on a systemic level. We review the role of circulating myeloid cells, monocytes and neutrophils, resident macrophages, dendritic cells, ligands, and cellular pathways that are activated or suppressed when renal function is chronically impaired. Finally, we discuss myeloid cells' varying responses to uremia from a systems immunology perspective.

Aims Transcatheter mitral valve implantation (TMVI) represents a novel treatment option for patients with mitral regurgitation (MR) unsuitable for established therapies. The CHOICE-MI registry aimed to investigate outcomes of patients undergoing screening for TMVI. Methods and results From May 2014 to March 2021, patients with MR considered suboptimal candidates for transcatheter edge-to-edge repair (TEER) and at high risk for mitral valve surgery underwent TMVI screening at 26 centres. Characteristics and outcomes were investigated for patients undergoing TMVI and for TMVI-ineligible patients referred to bailout-TEER, high-risk surgery or medical therapy (MT). The primary composite endpoint was all-cause mortality or heart failure hospitalization after 1 year. Among 746 patients included (78.5 years, interquartile range [IQR] 72.0-83.0, EuroSCORE II 4.7% [IQR 2.7-9.7]), 229 patients (30.7%) underwent TMVI with 10 different dedicated devices. At 1 year, residual MR <= 1+ was present in 95.2% and the primary endpoint occurred in 39.2% of patients treated with TMVI. In TMVI-ineligible patients (n = 517, 69.3%), rates of residual MR <= 1+ were 37.2%, 100.0% and 2.4% after bailout-TEER, high-risk surgery and MT, respectively. The primary endpoint at 1 year occurred in 28.8% of patients referred to bailout-TEER, in 42.9% of patients undergoing high-risk surgery and in 47.9% of patients remaining on MT. Conclusion This registry included the largest number of patients treated with TMVI to date. TMVI with 10 dedicated devices resulted in predictable MR elimination and sustained functional improvement at 1 year. In TMVI-ineligible patients, bailout-TEER and high-risk surgery represented reasonable alternatives, while MT was associated with poor clinical and functional outcomes.

Aims Transcatheter mitral valve implantation (TMVI) is a new treatment option for patients with symptomatic mitral valve (MV) disease. Real-world data have not yet been reported. This study aimed to assess procedural and 30-day outcomes of TMVI in a real-world patient cohort. Method and results All consecutive patients undergoing implantation of a transapically delivered self-expanding valve at 26 European centres from January 2020 to April 2021 were included in this retrospective observational registry. Among 108 surgical high-risk patients included (43% female, mean age 75 +/- 7 years, mean STS-PROM 7.2 +/- 5.3%), 25% was treated for an off-label indication (e.g. previous MV intervention or surgery, mitral stenosis, mitral annular calcification). Patients were highly symptomatic (New York Heart Association [NYHA] functional class III/IV in 86%) and mitral regurgitation (MR) was graded 3+/4+ in 95% (38% primary, 37% secondary, and 25% mixed aetiology). Technical success rate was 96%, and MR reduction to <= 1+ was achieved in all patients with successful implantation. There were two procedural deaths and 30-day all-cause mortality was 12%. At early clinical follow-up, MR reduction was sustained and there were significant reductions of pulmonary pressure (systolic pulmonary artery pressure 52 vs. 42 mmHg, p < 0.001), and tricuspid regurgitation severity (p = 0.013). Heart failure symptoms improved significantly (73% in NYHA class I/II, p < 0.001). Procedural success rate according to MVARC criteria was 80% and was not different in patients treated for an off-label indication (74% vs. 81% for off- vs. on-label, p = 0.41). Conclusion In a real-world patient population, TMVI has a high technical and procedural success rate with efficient and durable MR reduction and symptomatic improvement.

Background:The best management of stable coronary artery disease (CAD) in patients undergoing transcatheter aortic valve implantation (TAVI) is still unclear due to the marked inconsistency of the available evidence. Methods:The REVASC-TAVI registry (Management of Myocardial Revascularization in Patients Undergoing Transcatheter Aortic Valve Implantation With Coronary Artery Disease) collected data from 30 centers worldwide on patients undergoing TAVI who had significant, stable CAD at preprocedural work-up. For the purposes of this analysis, patients with either complete or incomplete myocardial revascularization were compared in a propensity score matched analysis, to take into account of baseline confounders. The primary and co-primary outcomes were all-cause death and the composite of all-cause death, stroke, myocardial infarction, and rehospitalization for heart failure, respectively, at 2 years. Results:Among 2407 patients enrolled, 675 pairs of patients achieving complete or incomplete myocardial revascularization were matched. The primary (21.6% versus 18.2%, hazard ratio, 0.88 [95% CI, 0.66-1.18]; P=0.38) and co-primary composite (29.0% versus 27.1%, hazard ratio, 0.97 [95% CI, 0.76-1.24]; P=0.83) outcome did not differ between patients achieving complete or incomplete myocardial revascularization, respectively. These results were consistent across different prespecified subgroups of patients (< or >75 years of age, Society of Thoracic Surgeons score > or <4%, angina at baseline, diabetes, left ventricular ejection fraction > or <40%, New York Heart Association class I/II or III/IV, renal failure, proximal CAD, multivessel CAD, and left main/proximal anterior descending artery CAD; all P values for interaction >0.10). Conclusions:The present analysis of the REVASC-TAVI registry showed that, among TAVI patients with significant stable CAD found during the TAVI work-up, completeness of myocardial revascularization achieved either staged or concomitantly with

Background Midterm data comparing clinical outcomes after successful implantation of self-expanding and balloon-expandable transcatheter heart valves (THV) are limited. We aimed to compare 2-year outcomes after successful transcatheter aortic valve implantation (TAVI) with the Edwards balloon-expandable or the Medtronic self-expanding THV. Methods Two-year outcomes were analyzed according to the implanted THV in the GALILEO trial. Major adverse cardiac and cerebrovascular events (MACCE) was a composite of all-cause death or thromboembolic events including stroke, myocardial infarction, symptomatic valve thrombosis, systemic embolism, deep-vein thrombosis, or pulmonary embolism. Results Among 1644 patients recruited in 136 centers across 16 countries between 2015 and 2018, 499 received a self-expanding and 757 patients received a balloon-expandable THV. Patients treated with a self-expanding THV were more likely to be female, and had higher surgical risk, lower hemoglobin levels, and more frequent valve-in-valve procedures than those with a balloon-expandable THV. After multivariable adjustment, there were no significant differences in major clinical outcomes between self-expanding versus balloon-expandable THV: MACCE (17.0% vs. 13.4%, adjusted-hazard ratios [HR] 1.18, 95% confidence intervals [CI]: 0.82-1.69); all-cause death (11.4% vs. 9.3%, adjusted-HR 1.26; 95% CI: 0.78-2.05); cardiovascular death (8.5% vs. 4.0%, adjusted-HR 1.53; 95% CI: 0.82-2.86), any stroke (5.1% vs. 3.7%, adjusted-HR 0.86; 95% CI: 0.43-1.73); major or life-threatening bleeding (5.9% vs. 6.8%, adjusted-HR 0.93; 95% CI: 0.53-1.63). Clinical Trial Registration: . NCT02556203. Conclusions Two-year follow-up data from the GALILEO trial indicate that successful TAVI either with self-expanding or balloon-expandable THVs according to physician discretion did not show difference in rates of MACCE.

Aims Guideline-directed medical therapy (GDMT), based on the combination of beta-blockers (BB), renin-angiotensin system inhibitors (RASI), and mineralocorticoid receptor antagonists (MRA), is known to have a major impact on the outcome of patients with heart failure with reduced ejection fraction (HFrEF). Although GDMT is recommended prior to mitral valve transcatheter edge-to-edge repair (M-TEER), not all patients tolerate it. We studied the association of GDMT prescription with survival in HFrEF patients undergoing M-TEER for secondary mitral regurgitation (SMR). Methods and results EuroSMR, a European multicentre registry, included SMR patients with left ventricular ejection fraction <50%. The outcome was 2-year all-cause mortality. Of 1344 patients, BB, RASI, and MRA were prescribed in 1169 (87%), 1012 (75%), and 765 (57%) patients at the time of M-TEER, respectively. Triple GDMT prescription was associated with a lower 2-year all-cause mortality compared to non-triple GDMT (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.60-0.91). The association persisted in patients with glomerular filtration rate <30 ml/min, ischaemic aetiology, or right ventricular dysfunction. Further, a positive impact of triple GDMT prescription on survival was observed in patients with residual mitral regurgitation of >= 2+ (HR 0.62; 95% CI 0.44-0.86), but not in patients with residual mitral regurgitation of <= 1+ (HR 0.83; 95% CI 0.64-1.08). Conclusion Triple GDMT prescription is associated with higher 2-year survival after M-TEER in HFrEF patients with SMR. This association was consistent also in patients with major comorbidities or non-optimal results after M-TEER. [GRAPHICS] .

In the majority of cases patients with high-grade tricuspid valve insufficiency (TI) represent a high-risk population and the treatment is particularly complex. Therefore, selection of an appropriate therapeutic pathway for affected individuals first requires precise characterization of the genesis of the vitium. This includes transthoracic and transesophageal echocardiography, right heart and left heart catheterization and additional imaging by CT and MRI as needed. Treatment requires interdisciplinary discussion, including optimization of drug treatment for left heart failure, discussion of antiarrhythmic treatment procedures for atrial genesis of TI, exclusion of pathologies of the heart requiring surgical treatment, and exclusion of indications for targeted therapy for pulmonary arterial hypertension (PAH). Interventional treatment now has an important place, particularly because of the very frequent comorbidity of patients. The 2021 ESC guidelines recommended catheter-based reconstruction for the first time. The still limited experience with this complex form of treatment, the lack of randomized prospective studies on its effectiveness, and challenges in periprocedural imaging have prompted the DGK to formulate these recommendations in anticipation of concrete criteria for future center certification when providing a program for interventional treatment of tricuspid regurgitation. This paper is intended to contribute to the provision of this important treatment to patients in Germany under the premise of the best possible quality.

OBJECTIVES: The aim of this study was to analyse the outcome of patients between 50 and 69 years of age undergoing biological or mechanical aortic valve replacement. METHODS: Data were collected from the German Aortic Valve Registry. Data were analysed regarding baseline characteristics and outcome parameters such as 5-year survival, stroke and reintervention. RESULTS: In tota1,3046 patients undergoing isolated surgical aortic valve replacement between 2011 and 2012 were investigated and a propensity score matching was performed. Within this period, 2239 patients received a biological prostheses, while 807 patients received a mechanical prosthesis. Mean age in the biological group was 63.07 (+/- 5.11) and 57.34 (+/- 4.67) in the mechanical group (standardized mean difference 1.172). In the overall cohort, there were more female patients in the biological group (32.7% vs 28.4%) and log EuroSCORE I was higher (5.41% vs 4.26%). After propensity matching (610 pairs), there was no difference in the mortality at 5-year followup (12.1% biological vs 9.2% mechanical P= 0.05) nor for reoperation/reintervention (2.5% biological vs 2.0% mechanical, P = 0.546). Patients undergoing mechanical aortic valve replacement suffered from a higher stroke rate 3.3% vs 1.5% (P= 0.04) at 5-year follow-up. CONCLUSIONS: Aortic valve replacement with biological or mechanical prostheses showed similar 5-year outcomes for survival and reoperation in a propensity-matched cohort, but significantly increased stroke rate after mechanical aortic valve replacement. This could influence the choice of a mechanical valve in younger patients.

BACKGROUND Among patients with severe functional mitral regurgitation (FMR), atrial functional mitral regurgitation (aFMR) represents an underrecognized entity. Data regarding outcomes after mitral valve transcatheter edge-to-edge repair (M-TEER) in aFMR remain scarce. OBJECTIVES The objective of this study was to analyze the outcome of aFMR patients undergoing M-TEER. METHODS Using patients from the international EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry undergoing M-TEER for FMR, the authors analyzed baseline characteristics and 2-year outcomes in aFMR in comparison to non-aFMR and ventricular FMR. Additionally, the impact of right ventricular dysfunction (RVD) (defined as right ventricular to pulmonary artery uncoupling) on outcome after M-TEER was assessed. RESULTS Among 1,608 FMR patients treated by M-TEER, 126 (7.8%) were categorized as aFMR. All 126 aFMR patients had preserved left ventricular function without regional wall motion abnormalities, left arterial dilatation and Carpentier leaflet motion type I. Procedural success (defined as mitral regurgitation #2thorn at discharge) was 87.2% (P < 0.001) and New York Heart Association (NYHA) functional class significantly improved during follow-up (NYHA functional class III/IV: 86.5% at baseline to 36.6% at follow-up; P< 0.001). The estimated 2-year survival rate in aFMR patients was 70.4%. Twoyear survival did not differ significantly between aFMR, non-aFMR, and ventricular FMR. Besides NYHA functional class IV, RVD was identified as a strong independent predictor for 2-year survival (HR: 2.82 [95% CI: 1.24-6.45]; P = 0.014). CONCLUSIONS aFMR is a frequent cause of FMR and can be effectively treated with M-TEER to improve symptoms at follow-up. Advanced heart failure symptoms and RVD were identified as important risk factors for survival in aFMR patients. (J Am Coll Cardiol Img 2022;15:1843-1851) (c) 2022 by the American College of Cardiology Foundation.

The ESC/EACTS guidelines for the management of valvular heart disease, as published by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, underwent renewal in 2021. The current guidelines focus on early surgical treatment in patients with asymptomatic valvular heart disease, in particular aortic stenosis, aortic regurgitation and primary mitral regurgitation. Furthermore they specify the indications for transcatheter aortic valve implantation and upgrade leaflet-based transvenous reconstruction in patients with secondary mitral regurgitation. For the first time they name transcatheter repair for tricuspid regurgitation. In addition, the guidelines renewed the recommendations for anticoagulation following valvular repair and replacement. In the following, the German Society of Cardiology and the German Society for Thoracic and Cardiovascular Surgery comment on the new decisions.

Aims To investigate the role of left atrial volume index (LAVi) in patients with secondary mitral regurgitation (SMR) undergoing transcatheter edge-to-edge mitral valve repair (TEER). Methods and results Outcomes were evaluated in SMR patients of a European multicentre registry according to baseline LAVi. Main analysis was performed for all-cause mortality; residual mitral regurgitation (MR) and New York Heart Association (NYHA) class improvement were analysed for patients available. A total of 1074 patients were included with a median LAVi (interquartile range) of 58 ml/m(2) (46-73). Postprocedural reduction of MR grade to <= 2+ was similar across LAVi quintiles, ranging 91%-96% (p = 0.26). Symptomatic benefit (>= 1 NYHA class improvement) also did not differ by LAVi quintiles (61%-68% of patients) (p = 0.66). The risk of mortality increased by 23%-42% in the four upper quintiles compared to the bottom quintile (LAVi <42 ml/m(2)). The hazard ratio (HR) of mortality was 1.35 (95% confidence interval [CI] 1.02-1.78, p = 0.035) associated with a LAVi >42 ml/m(2), which was attenuated after multivariable adjustment (HR 1.18, 95% CI 0.83-1.67, p = 0.36). A significant interaction was found for MR severity and pulmonary hypertension, with an increased risk of death associated with enlarged LAVi in patients with inframedian effective regurgitant orifice area (HR 1.99, 95% CI 1.06-3.74, p = 0.032) and in patients with systolic pulmonary pressure <= 50 mmHg (HR 1.67, 95% CI 1.02-2.75, p = 0.042) in multivariable analysis. Conclusion Procedural success and symptomatic benefit were high throughout the whole range of LAVi. The prognostic impact of left atrial enlargement was relevant in patients with less severe SMR and without pulmonary hypertension, reinforcing the need to identify patients in the early course of backward congestion to achieve good long-term outcome after TEER.

The ESC/EACTS guidelines for the management of valvular heart disease, as published by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, underwent renewal in 2021. The current guidelines focus on early surgical treatment in patients with asymptomatic valvular heart disease, in particular aortic stenosis, aortic regurgitation and primary mitral regurgitation. Furthermore they specify the indications for transcatheter aortic valve implantation and upgrade leaflet-based transvenous reconstruction in patients with secondary mitral regurgitation. For the first time they name transcatheter repair for tricuspid regurgitation. In addition, the guidelines renewed the recommendations for anticoagulation following valvular repair and replacement. In the following, the German Society of Cardiology and the German Society for Thoracic and Cardiovascular Surgery comment on the new decisions.

Background Severe tricuspid regurgitation (TR) is independently associated with increased morbidity and mortality. Percutaneous transcatheter approaches may offer an alternative for patients not amenable to surgery. Methods TriCLASP is a prospective, single-arm, multicenter European post-market clinical follow-up study (NCT04614402) to evaluate the safety and performance of the PASCAL system (Edwards Lifesciences) in patients with severe or greater TR. At 30 days, a composite of major adverse events (MAEs) adjudicated by a clinical events committee, echocardiographic parameters adjudicated by core laboratory, and clinical, functional, and quality-of-life measures were evaluated. Results Mean age of the 74 enrolled patients was 80.3 years, with 58.1% female, 90.5% systemic hypertension, and 77.0% in New York Heart Association (NYHA) class III/IV. Mean Society for Thoracic Surgeons score (MV repair) was 9.0%. TR severity was significantly reduced at discharge (p < 0.001) and sustained at 30 days (p < 0.001), and 90.0% of patients achieved <= moderate TR. The composite MAE rate at 30 days was 3.0%, including 4 events in 2 patients: cardiovascular mortality 1.5%, stroke 1.5%, renal complications requiring unplanned dialysis or renal replacement therapy 1.5%, and severe bleeding 1.5%. There were no nonelective tricuspid valve reinterventions, major access site and vascular complications, major cardiac structural complications, or device embolizations. NYHA class I/II was achieved in 55.8%, 6-minute walk distance improved by 38.2 m (p < 0.001), and Kansas City cardiomyopathy questionnaire scores improved by 13.4 points (p < 0.001). Conclusion Experience with the PASCAL transcatheter valve repair system in a European post-market setting confirms favorable safety and effectiveness at 30 days. TR significantly reduced, and clinical, functional, and quality-of-life outcomes significantly improved. This study is ongoing. Clinical Trial Registration: The study is ongoing and re

OBJECTIVES This study aimed to improve echocardiographic assessment of pulmonary hypertension (PH) in patients presenting with severe tricuspid regurgitation (TR). BACKGROUND Echocardiographic assessment of PH in patients with severe TR carries several pitfalls for underestimation, hence concealing the true severity of PH in very sick patients in particular, and ultimately obscuring the impact of PH on survival after transcatheter tricuspid valve intervention (TTVI). METHODS All patients in this study underwent TTVI for severe TR between 2016 and 2020. To predict the mean pulmonary artery pressure (mPAP) solely based on echocardiographic parameters, we trained an extreme gradient boosting (XGB) algorithm. The derivation cohort was constituted by 116 out of 162 patients with both echocardiography and right heart catheterization data, preprocedurally obtained, from a bicentric registry. Moreover, 142 patients from an independent institution served for external validation. RESULTS Systolic pulmonary artery pressure was consistently underestimated by echocardiography in comparison to right heart catheterization (40.3 +/- 15.9 mm Hg vs 44.1 +/- 12.9 mm Hg; P = 0.0066), and the assessment was most discrepant among patients with severe defects of the tricuspid valve and impaired right ventricular systolic function. Using 9 echocardiographic parameters as input variables, an XGB algorithm could reliably predict mPAP levels (R = 0.96, P < 2.2 x 10(-16)). Moreover, patients with elevations in predicted mPAP levels >= 29.9 mm Hg showed significantly reduced 2-year survival after TTVI (58.3% [95% CI: 41.7%-81.6%] vs 78.8% [95% CI: 68.7%-90.5%]; P = 0.026). Importantly, the poor prognosis associated with elevation in predicted mPAP levels was externally confirmed (HR for 2-year mortality: 2.9 [95% CI: 1.5-5.7]; P = 0.002). CONCLUSIONS PH in patients with severe TR can be reliably assessed based on echocardiographic parameters in conjunction with an XGB algorithm, and elevations

Background: Recurrent mitral regurgitation (MR) following MitraClip has not been thoroughly investigated. We aimed to examine the predictive factors, morphology, and long-term outcome of recurrent MR after MitraClip. Methods: We assessed data from the Heart Failure Network Rhineland registry from August 2010 to October 2018. Competing risk analyses were performed using the Fine and Gray model to assess the risk of recurrent MR. Results: Among 685 MitraClip patients with a reduction in MR to <= 2+, 61 patients developed recurrent MR within the first 12 months. Flail leaflet (hazard ratio, 3.68; P=0.002) and residual MR (MR grade 2+ versus <= 1+: hazard ratio, 2.56; P=0.03) were the predictors of recurrent MR in primary MR patients, while left atrial volume (per 10 mL increase: hazard ratio, 1.11; P<0.001) and residual MR (hazard ratio, 2.45; P=0.01) were independently associated with recurrent MR in secondary MR patients. In primary MR patients, loss of leaflet insertion or leaflet tear were the predominant morphologies with recurrent MR. In secondary MR patients, more than half of the patients with recurrent MR did not show any disorder of the clip or leaflets. Patients with recurrent MR were more likely to experience unplanned heart failure hospitalization or heart failure symptom with New York Heart Association scale III/IV (54.1% versus 37.8%; P=0.018) and undergo a repeat mitral valve intervention (9.8% versus 2.2%; P=0.005) during the follow-up. In the landmark survival analysis, patients with recurrent MR tended to have lower long-term survival (58.7% versus 83.9%; P=0.08) than patients without recurrent MR. Conclusions: Flail leaflet and residual MR were the predictors of recurrent MR in primary MR patients, while a larger left atrial volume and residual MR were associated with recurrent MR in secondary MR patients, which may be associated with long-term clinical outcomes of patients after MitraClip.

Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and morphology in disease progression are lacking. Therefore, we refined an acute murine AS model to closely mimic human disease characteristics and developed a high-resolution magnetic resonance imaging (MRI) approach for simultaneous in-depth analysis of valvular, myocardial as well as aortic morphology/pathophysiology to identify early changes in tissue texture and critical transition points in the adaptive process to AS. AS was induced by wire injury of the aortic valve. Four weeks after surgery, cine loops, velocity, and relaxometry maps were acquired at 9.4 T to monitor structural/functional alterations in valve, aorta, and left ventricle (LV). In vivo MRI data were subsequently validated by histology and compared to echocardiography. AS mice exhibited impaired valve opening accompanied by significant valve thickening due to fibrotic remodelling. While control mice showed bell-shaped flow profiles, AS resulted not only in higher peak flow velocities, but also in fragmented turbulent flow patterns associated with enhanced circumferential strain and an increase in wall thickness of the aortic root. AS mice presented with a mild hypertrophy but unaffected global LV function. Cardiac MR relaxometry revealed reduced values for both T1 and T2 in AS reflecting subtle myocardial tissue remodelling with early alterations in mitochondrial function in response to the enhanced afterload. Concomitantly, incipient impairments of coronary flow reserve and myocardial tissue integrity get apparent accompanied by early troponin release. With this, we identified a premature transition point with still compensated cardiac function but beginning textural changes. This will allow interventional studies to explore early disease pathophysiology and novel therapeutic targets.