Search

Myocardial infarction causes unrecoverable loss of cardiomyocytes. Engineered heart tissue (EHT) is an in vitro model of three-dimensional, force generating cardiomyocyte network with morphological and functional similarity to native heart tissue. In this study we transplanted EHTs from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) on cryo-injured guinea pig hearts and investigated whether hiPSC-CM-EHTs support left ventricular function.Human iPSC were generated by retroviral reprogramming of dermal fibroblasts. Cardiac differentiation of hiPSC was performed by an embryoid body-based three-stage differentiation protocol. EHTs were created from hiPS-CM (5*10^6 cardiomyocytes and 2*10^6 GFP+-HUVECs per EHT) and cultivated for 3 weeks under auxotonic stretch between flexible silicone posts. Development of contractile force was monitored prior to transplantation. Left ventricular myocardial cryo-injury was induced in adult guinea pigs (n=21). 7 days after injury EHTs (2 per animal, n=12) or cell-free constructs (n=9) were implanted. Animals received ciclosporin and methylprednisolon for immunosuppression. Functional parameters were examined by echocardiography and histology at baseline, before and 28 days after transplantation.The cardiac differentiation protocol resulted in a cell population with ~50% cardiomyocytes, which was further enriched by lactate-based selection to >90% purity and directly used for EHT generation. HiPSC-CM-EHTs developed contractile force and displayed morphological properties of native heart tissue. Cryo-injury resulted in large transmural scars (~30% of ventricular wall) which were verified histologically. Immunohistochemical staining for dystrophin and MLC2v showed the formation of large islets of cross-striated muscle tissue in the scar. The human origin was demonstrated by fluorescent-in-situ-hybridization. The new myocardium was vascularized with endothelium partly being of human origin. Animals receiving cell-free constructs showed left ventricular dilatation 28 days after transplantation. The EHT-group showed less dilatation (8.12 mm ± 0.21 basal, 8.18 mm ± 0.23 7d post cryo-injury, 8.87 mm ± 0.41 28d EHT vs. 9.74 mm ± 0.72 28d control) and significantly better fractional area shortening (42.20% ± 1.92 basal, 26.07% ± 2.13 7d post cryo-injury, 41.98% ± 4.48 28d EHT vs. 23.00% ± 3.24 28d control).Transplantation of hiPSC-derived EHTs in a guinea pig cryo-injury model provides early evidence that human EHTs survive after transplantation and support cardiac function. [ABSTRACT FROM AUTHOR]

Objectives: Engineered Heart Tissue (EHT) is a promising tool to repair heart muscle defects and can additionally be used for drug testing. Due to the absence of an in vitro vascularization, EHT geometry crucially impacts nutrient and oxygen supply by diffusion capacity. We analyzed cardiomyocyte survival in different EHT geometries., Methods: Different geometries with varying surface-area-to-volume-ratios were calculated (structure A (Ring) AS/V = 58.47 mm 2 /440 μL 3 , structure B (Infinity) 25.86 mm 2 /440 μL 3 ). EHTs were generated from hiPSC-derived cardiomyocytes (4 × 10 6 ) and a fibrin/thrombin hydrogel. Cell viability was evaluated by RT-PCR, cytometric studies, and Bioluminescence imaging., Results: Using 3D-printed casting molds, spontaneously beating EHTs can be generated in various geometric forms. At day 7, the RT-PCR analyses showed a significantly higher Troponin-T value in ring EHTs, compared to infinity EHTs. In cytometric studies, we evaluated 15% more Troponin-T positive cells in ring (73% ± 12%), compared to infinity EHTs (58% ± 11%, p = 0.04). BLI visualized significantly higher cell survival in ring EHTs (ROI = A: 1.14 × 10 6 p/s and B: 8.47 × 10 5 p/s, p < 0.001) compared to infinity EHTs during longitudinal cultivation process., Conclusion: Use of 3D-printing allows the creation of EHTs in all desired geometric shapes. The geometry with an optimized surface-area-to-volume-ratio (ring EHT) demonstrated a significantly higher cell survival measured by RT-PCR, Bioluminescence imaging, and cytometric studies using FACS analysis., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Objective: Closure of the left atrial appendage (LAA) is a routine part of atrial fibrillation ablation surgery and significantly reduces stroke rates. Different LAA-closure techniques are used in cardiac surgery with variable results reported. We therefore evaluated the efficacy of 4 different LAA-closure techniques in patients undergoing cardiac surgery., Methods: In total, 149 patients who underwent concomitant LAA closure during cardiac surgery between 2015 and 2019 were included in this retrospective transesophageal echocardiography study. Four different LAA-closure techniques were evaluated: LAA clipping (n = 62), suture ligation (n = 28), stapler resection (n = 30), and surgical LAA excision (n = 29). Successful LAA closure was defined as absence of LAA perfusion and absence of a stump greater than 10 mm., Results: The mean patients age was 68.7 ± 9.4 years; 61.7% were male. No complications related to LAA closure were observed. Mean follow-up was 36.5 ± 8 months. Transesophageal echocardiography follow-up showed the following LAA closure success rates: LAA clip 98.4%, surgical excision 93.1%, stapler resection 76.6%, and suture ligation 39.2%. Suture ligation resulted in a high rate of recanalization (50%) and residual stumps (10.8%), whereas stapler resection resulted in a high rate of residual stumps (23.4%). Overall, 4 patients (2.7%) had a stroke during follow-up. In detail, 2 of 27 (7.4%) patients with unsuccessful LAA closure had a stroke, whereas 2 of the 122 (1.6%) patients with successful LAA closure had a stroke., Conclusions: In our study, LAA clipping and surgical LAA excision proved to be both successful LAA-closure methods. External LAA ligation and stapler resection resulted in low rates of successful LAA closure and should be avoided., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Objectives: Patients with atrial fibrillation (AF) have lower left atrial (LA) strain, which is a predictor for LA function. Here, we evaluated the prognostic value of LA strain to predict the rhythm outcome in patients with persistent AF undergoing LA cryoablation concomitant to minimally invasive mitral valve repair., Methods: Between 01/2016 and 12/2020, 72 patients with persistent AF underwent LA cryoablation during minimally invasive mitral valve surgery. All patients received a complete LA lesion set and left atrial appendage (LAA) closure with a clip. All patients received preoperative transthoracic echocardiography (TTE) with LA and left ventricular strain measurements. Preoperative LA and LV strain analysis was correlated with postoperative rhythm outcome., Results: The mean age of the patients was 66.9 ± 7.2 years, of whom 42 (58%) were male patients. No major ablation-related complications occurred in any of the patients. Successful LAA closure was confirmed by intraoperative echocardiography in all patients. The 1-year survival rate was 97%. Freedom from AF at 12 months was 72% and 68% off antiarrhythmic drugs. Preoperative LA strain values were statistically significantly higher in patients with freedom from AF at 12 months of follow-up (12.7% ± 6.9% vs. 4.9% ± 4.1%, p  = 0.006). Preoperative LV strain value was not associated with postoperative rhythm outcome. In multivariate logistic regression analysis, LA strain ( p  < 0.001) and AF duration ( p  = 0.017) were predictors for freedom from AF at 12 months of follow-up., Conclusions: In our study, LA strain analysis predicted the rhythm outcome in patients with persistent AF undergoing concomitant surgical AF ablation. In the future, LA strain might be a useful tool to guide decision-making on ablation strategies in patients with persistent AF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Yildirim, Yildirim, Petersen, Alassar, Sarwari, Sinning, Blankenberg, Reichenspurner and Pecha.)

Prosthetic materials are a source of bacterial infections, with significant morbidity and mortality. Utilizing the bionic "Lotus effect," we generated superhydrophobic vascular prostheses by nanocoating and investigated their resistance to bacterial colonization. Nanoparticles were generated from silicon dioxide (SiO 2 ), and coated vascular prostheses developed a nanoscale roughness with superhydrophobic characteristics. Coated grafts and untreated controls were incubated with different bacterial solutions including heparinized blood under mechanical stress and during artificial perfusion and were analyzed. Bioviability- and toxicity analyses of SiO 2 nanoparticles were performed. Diameters of SiO 2 nanoparticles ranged between 20 and 180 nm. Coated prostheses showed a water contact angle of > 150° (mean 154 ± 3°) and a mean water roll-off angle of 9° ± 2°. Toxicity and viability experiments demonstrated no toxic effects of SiO 2 nanoparticles on human induced pluripotent stem cell-derived cardiomyocytes endothelial cells, fibroblasts, and HEK239T cells. After artificial perfusion with a bacterial solution (Luciferase + Escherichia coli ), bioluminescence imaging measurements showed a significant reduction of bacterial colonization of superhydrophobic material-coated prostheses compared to that of untreated controls. At the final measurement ( t = 60 min), a 97% reduction of bacterial colonization was observed with superhydrophobic material-coated prostheses. Superhydrophobic vascular prostheses tremendously reduced bacterial growth. During artificial perfusion, the protective superhydrophobic effects of the vascular grafts could be confirmed using bioluminescence imaging.

Background: Previous reports suggest septal hypertrophy with an interventricular septum depth (IVSD) ≥ 14 mm may adversely affect outcomes after transcatheter aortic valve implantation (TAVI) due to suboptimal valve placement, valve migration, or residual increased LVOT pressure gradients., Aims: This analysis investigates the impact of interventricular septal hypertrophy on acute outcomes after TAVI., Methods: Between 2009 and 2021, 1033 consecutive patients (55.8% male, 80.5 ± 6.7 years, EuroSCORE II 6.3 ± 6.5%) with documented IVSD underwent TAVI at our center and were included for analysis. Baseline, periprocedural, and 30-day outcome parameters of patients with normal IVSD (< 14 mm; group 1) and increased IVSD (≥ 14 mm; group 2) were compared. Data were retrospectively analyzed according to updated Valve Academic Research Consortium-3 (VARC-3) definitions. Comparison of outcome parameters was adjusted for baseline differences between groups using logistic and linear regression analyses., Results: Of 1033 patients, 585 and 448 patients were allocated to groups 1 and 2, respectively. There was no significant difference between groups regarding transfemoral access rate (82.6% (n = 478) vs. 86.0% (n = 381), p = 0.157). Postprocedural mean transvalvular pressure gradient was significantly increased in group 2 (group 1, 7.8 ± 4.1 mmHg, vs. group 2, 8.9 ± 4.9 mmHg, p = 0.046). Despite this finding, there was no significant difference between groups regarding the rates of VARC-3 adjudicated composite endpoint device success (90.0% (n = 522) vs. 87.6% (n = 388), p = 0.538) or technical success (92.6% (n = 542) vs. 92.6% (n = 415), p = 0.639). Moreover, the groups showed no significant differences regarding the rates of paravalvular leakage ≥ moderate (3.1% (n = 14) vs. 2.6% (n = 9), p = 0.993), postprocedural permanent pacemaker implantation (13.4% (n = 77) vs. 13.8% (n = 61), p = 0.778), or 30-day mortality (5.1% (n = 30) vs. 4.5% (n = 20), p = 0.758)., Conclusion: Although transvalvular mean pressure gradients were significantly higher in patients with increased IVSD after TAVI, acute outcomes were comparable between groups suggesting no early impact of adverse hemodynamics due to elevated IVSD. However, how these differences in hemodynamic findings may affect mid- and long-term outcomes, especially in terms of valve durability, needs to be evaluated in further investigations., (© 2024. The Author(s).)

Introduction: In CIED infections, all device material needs to be removed. But, especially in pacemaker-dependent patients it is often not possible to realize a device-free interval for infection remediation. In those patients, different treatment options are available, however the ideal solution needs still to be defined., Methods: This retrospective analysis includes 190 patients undergoing CIED extractions due to infection. Three different treatment algorithms were analyzed: Group 1 included 89 patients with system removal only (System removal group). In Group 2, 28 patients received an epicardial electrode during extraction procedure (Epicardial lead group) while 78 patients in group 3 (contralateral reimplantation group) received implantation of a new system contralaterally during extraction procedure. We analyzed peri- and postoperative data as well as 1-year outcomes of the three groups., Results: Patients in the system removal and epicardial lead groups were significantly older, had more comorbidities, and suffered more frequently from systemic infections than those in contralateral reimplantation group. Lead extraction procedures had comparable success rates: 95.5%, 96.4%, and 93.2% of complete lead removal in the System removal, Epicardial Lead, Contralateral re-implantation group respectively. Device reimplantation was performed in all patients in Epicardial lead and Contralateral reimplantation group, whereas only 49.4% in System removal group received device re-implantation. At 1-year follow-up, freedom from infection and absence of pocket irritation were comparable for all groups (94.7% Contralateral reimplantation group and Epicardial lead group, 100% System removal group). No procedure-related mortality was observed, whereas 1-year mortality was 3.4% in System removal group, 4.1% in Contralateral re-implantation group and 21.4% in Epicardial lead group ( p  < 0.001)., Conclusion: In patients with CIED infection, systems should be removed completely and reimplanted after infection remediation. In pacemaker-dependent patients, simultaneous contralateral CIED re-implantation or epicardial lead placement may be performed, depending on route, severity and location of infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Burger, Strauß, Chung, Richter, Ziegelhöffer, Hakmi, Reichenspurner, Choi and Pecha.)

Objectives: Transcatheter aortic valve implantation (TAVI) using balloon-expandable (BE) transcatheter heart valves (THV) in aortic annuli above 29 mm includes particular procedural steps, mainly involving overfilling of the deployment balloon. Data on overfilling strategies in clinical daily practice is scarce. We herein aimed for a retrospective description of utilized overfilling strategies in those patients., Methods: Between January 2016 and December 2022, 45 patients (100% male, 76.9 ± 6.1 years) received TAVI in aortic annuli above 29 mm using a BE THV. Overfilling volumina of the deployment balloon were left to operators' discretion. Clinical and multislice computed tomography data were retrospectively collected. Clinical endpoints were adjudicated in accordance with the updated standardized VARC-3 definitions., Results: Profound overfilling (+4/5 mL) was used in patients with a mild calcium burden (˂750 mm³) even in aortic annuli of 29.0-30.0 mm. Nominal/slight overfilling (+1 mL) was used in aortic annuli up to 32.5 mm but an intermediate to severe calcific burden (>750-3200 mm³). Accordingly, a low calcification group (˂750 mm³, n = 17) compared to a significant calcification group (≥750 mm³, n = 28), presented with higher overfilling volumina (2.1 ± 1.4 vs. 0.8 ± 1.0; p ˂ 0.001), although aortic annulus diameter was not different (29.8 ± 0.8 vs. 29.9 ± 0.9 mm; p = 0.7). All-cause 30-day mortality was 0%. Device success was 97.8%. Transvalvular mean pressure gradient at discharge was 9.5 ± 3.6 mmHg. No case of PVL >mild was documented., Conclusion: Extent of overfilling of the deployment balloon largely depends on calcification burden in addition to aortic annulus diameter with significant and profound overfilling particularly in patients with a calcification burden of the aortic valve complex ˂750 mm³., (© 2023 Wiley Periodicals LLC.)

Background: The prevalence of young patients with cardiac implantable electronic devices (CIED) is steadily increasing, accompanied by a rise in the occurrence of complications related to CIEDs. Consequently, transvenous lead extraction (TLE) has become a crucial treatment approach for such individuals., Objective: The purpose of this study was to examine the characteristics and procedural outcomes of young patients who undergo TLE, with a specific focus on identifying independent risk factors associated with adverse events., Methods: All patients in the GALLERY (GermAn Laser Lead Extraction RegistrY) were categorized into two groups based on their age at the time of enrollment: 45 years or younger, and over 45 years. A subgroup analysis was conducted specifically for the younger population. In this analysis, predictor variables for all-cause mortality, procedural complications, and procedural failure were evaluated using multivariable analyses., Results: We identified 160 patients aged 45 years or younger with a mean age of 35.3 ± 7.6 years and 42.5% ( n  = 68) female patients. Leading extraction indication was lead dysfunction in 51.3% of cases, followed by local infections in 20.6% and systemic infections in 16.9%. The most common device to be extracted were implantable cardioverter-defibrillators (ICD) with 52.5%. Mean number of leads per patient was 2.2 ± 1.0. Median age of the oldest indwelling lead was 91.5 [54.75-137.5] months. Overall complication rate was 3.8% with 1.9% minor and 1.9% major complications. Complete procedural success was achieved in 90.6% of cases. Clinical procedural success rate was 98.1%. Procedure-related mortality was 0.0%. The all-cause in-hospital mortality rate was 2.5%, with septic shock identified as the primary cause of mortality. Multivariable analysis revealed CKD (OR: 19.0; 95% CI: 1.84-194.9; p  = 0.018) and systemic infection (OR: 12.7; 95% CI: 1.14-142.8; p  = 0.039) as independent predictor for all-cause mortality. Lead age ≥ 10 years (OR: 14.58, 95% CI: 1.36-156.2; p  = 0.027) was identified as sole independent risk factor for procedural complication., Conclusion: TLE in young patients is safe and effective with a procedure-related mortality rate of 0.0%. CKD and systemic infection are predictors for all-cause mortality, whereas lead age ≥ 10 years was identified as independent risk factor for procedural complications in young patients undergoing TLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Rexha, Chung, Burger, Ghaffari, Madej, Ziaukas, Hassan, Reichenspurner, Gessler, Willems, Butter, Pecha and Hakmi.)

Introduction: In an aging population with cardiac implantable electronic devices, an increasing number of octo- and even nonagenarians present for lead extraction procedures. Those patients are considered at increased risk for surgical procedures including lead extraction. Here, we investigated safety and efficacy of transvenous lead extraction in a large patient cohort of octo- and nonagenarians., Methods and Results: A subgroup analysis of all patients aged ≥80 years (n = 499) in the German Laser Lead Extraction Registry (GALLERY) was performed. Outcomes were compared to the nonoctogenarians from the registry. Primary extraction method was Laser lead extraction, with additional use of mechanical rotational sheaths or femoral snares, if necessary. An analysis of patient- and device characteristics, as well as an assessment of predictors for adverse events via multivariate analyses was conducted. Mean patients age was 84.3 ± 3.7 years in the octogenarians group and 64.1 ± 12.4 years in the nonoctogenarians group. The median lead dwell time was 118.0 months (78; 167) and 92.0 months [60; 133], p < .001 in the octogenarians and nonoctogenarians group, respectively. Clinical procedural success rate was achieved in 97.6% of the cases in octogenarians and 97.9% in nonoctogenarians (p = .70). Overall complication rate was 4.4% in octogenarians and 4.3% in nonoctogenarians (0.91). In octogenarians procedure-related mortality was 0.8% and all-cause in-hospital mortality was 5.4%, while in nonoctogenarians, procedure related and all-cause in-hospital mortality were 0.5% and 3.1%, respectively. A body mass index (BMI) <20 kg/m 2 , was the only statistically significant predictor for procedure-related complications in octogenarians, while systemic infection, BMI ≤20 kg/m 2 , procedural complications and chronic kidney disease were predictors for in-hospital mortality., Conclusions: Laser lead extraction in octo- and nonagenarians is safe and effective. BMI ≤20 kg/m 2 was the only statistically significant predictor for procedural complications. According to our data, advanced age should not be considered as contraindication for laser lead extraction., (© 2023 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Background: Valve-in-valve (ViV) transfemoral transcatheter aortic valve implantation (TAVI) for failing aortic surgical bioprostheses or transcatheter heart valves (THV) has demonstrated a reasonable clinical and hemodynamic efficacy. Traditionally, self-expanding (SE) supra-annular THV are considered to result in superior hemodynamics compared with balloon-expandable intra-annular THV after ViV. However, so far no data are found on latest-generation intra-annular SE THV for aortic ViV procedures which might be superior with regard to coronary access or subsequent valve reintervention., Aim: We herein aim to evaluate a latest-generation SE intra-annular THV for aortic ViV procedures., Materials and Methods: Between May 2022 and November 2022, five consecutive patients (4/5 female with mean age of 76.2 years and mean Society of Thoracic Surgeons predicted risk of mortality score of 2.9%) received ViV TAVI using the Navitor system (Abbott, Chicago, IL, USA) for treatment of failing surgical bioprostheses or THV. Data were retrospectively analyzed according to updated Valve Academic Research Consortium 3 (VARC-3) definitions., Results: At 30 days, absence of mortality and VARC-3 adjudicated clinical endpoints were documented. Echocardiography at 30 days revealed complete absence of paravalvular leakage and single-digit mean transvalvular gradients (mean of 6.0 mmHg) in all patients., Conclusion: The investigated intra-annular SE THV results in excellent 30-day outcomes for aortic ViV procedures for failing surgical bioprostheses or THV. Despite the intra-annular design, hemodynamic results were excellent, even in small bioprostheses. Ease of use of this valve platform is reflected by only two cycles of resheathing in five ViV procedures with hemodynamic stability during all steps of valve deployment., Competing Interests: AS received speaker honoraria from Abbott. LC is an advisory board member for Abbott, Medtronic, JenaValve, and MicroPort and has received honoraria from Edwards Lifesciences, Boston Scientific, Neovasc, Highlife, PiCardia, and MicroInterventions. MS received speaker honoraria from Abbott Vascular, Abiomed, Amgen, AstraZeneca, Boston Scientific, BMS/Pfizer, Daiichi Sankyo, Edwards Lifesciences, Inari, Medtronic, Philips, Shockwave Medical, and Siemens. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Schaefer, Demal, Bhadra, Grundmann, Voigtläender, Waldschmidt, Schirmer, Pecha, Schneeberger, Schofer, Sörensen, Blankenberg, Reichenspurner, Seiffert and Conradi.)

Background: Device complications, such as infection or lead dysfunction necessitating transvenous lead extraction (TLE) are continuously rising amongst patients with transvenous implantable-cardioverter-defibrillator (ICD)., Objectives: Aim of this study was to characterize the procedural outcome and risk-factors of patients with indwelling 1- and 2-chamber ICD undergoing TLE., Methods: We conducted a subgroup analysis of all ICD patients in the GALLERY (GermAn Laser Lead Extraction RegistrY) database. Predictors for procedural failure and all-cause mortality were assessed., Results: We identified 842 patients with an ICD undergoing TLE with the mean age of 62.8 ± 13.8 years. A total number of 1610 leads were treated with lead dysfunction (48.5%) as leading indication for extraction, followed by device-related infection (45.4%). Lead-per-patient ratio was 1.91 ± 0.88 and 60.0% of patients had dual-coil defibrillator leads. Additional extraction tools, such as mechanical rotating dilator sheaths and snares were utilized in 6.5% of cases. Overall procedural complications occurred in 4.3% with 2.0% major complications and a procedure-related mortality of 0.8%. Clinical success rate was 97.9%. All-cause in-hospital mortality was 3.4%, with sepsis being the leading cause for mortality. Multivariate analysis revealed lead-age ≥10 years (OR:5.82, 95%CI:2.1-16.6; p = .001) as independent predictor for procedural failure. Systemic infection (OR:9.57, 95%CI:2.2-42.4; p < .001) and procedural complications (OR:8.0, 95%CI:2.8-23.3; p < .001) were identified as risk factors for all-cause mortality., Conclusions: TLE is safe and efficacious in patients with 1- and 2-chamber ICD. Although lead dysfunction is the leading indication for extraction, systemic device-related infection is the main driver of all-cause mortality for ICD patients undergoing TLE., (© 2023 Wiley Periodicals LLC.)

Aims: Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients., Methods and Results: mRNA, protein levels, and localization of PDE8A and PDE8B isoforms were measured by RT-qPCR, western blot, co-immunoprecipitation and immunofluorescence. PDE8 function was assessed by FRET, patch-clamp and sharp-electrode recordings. PDE8A gene and protein levels were higher in paroxysmal AF (pAF) vs. sinus rhythm (SR) patients, whereas PDE8B was upregulated in cAF only. Cytosolic abundance of PDE8A was higher in atrial pAF myocytes, whereas PDE8B tended to be more abundant at the plasmalemma in cAF myocytes. In co-immunoprecipitation, only PDE8B2 showed binding to Cav1.2α1C subunit which was strongly increased in cAF. Accordingly, Cav1.2α1C showed a lower phosphorylation at Ser1928 in association with decreased ICa,L in cAF. Selective PDE8 inhibition increased Ser1928 phosphorylation of Cav1.2α1C, enhanced cAMP at the subsarcolemma and rescued the lower ICa,L in cAF, which was accompanied by a prolongation of action potential duration at 50% of repolarization., Conclusion: Both PDE8A and PDE8B are expressed in human heart. Upregulation of PDE8B isoforms in cAF reduces ICa,L via direct interaction of PDE8B2 with the Cav1.2α1C subunit. Thus, upregulated PDE8B2 might serve as a novel molecular mechanism of the proarrhythmic reduction of ICa,L in cAF., Competing Interests: Conflict of interest The authors have no competing interests. R.B.S. reports grants from European Union Horizon 2020, the German Ministry of Research and Education, ERACOSysMed3 and personal fees from BMS/Pfizer, outside this work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The incidence of cardiac implantable electronic device (CIED)-related complications, as well as the prevalence of obesity, is rising worldwide. Transvenous laser lead extraction (LLE) has grown into a crucial therapeutic option for patients with CIED-related complications but the impact of obesity on LLE is not well understood., Methods and Results: All patients ( n = 2524) from the GermAn Laser Lead Extraction RegistrY (GALLERY) were stratified into five groups according to their body mass index (BMI, <18.5; 18.5-24.9; 25-29.9; 30-34.9; ≥35 kg/m 2 ). Patients with a BMI ≥ 35.0 kg/m 2 had the highest prevalence of arterial hypertension (84.2%, p < 0.001), chronic kidney disease (36.8%, p = 0.020) and diabetes mellitus (51.1%, p < 0.001). The rates for procedural minor ( p = 0.684) and major complications ( p = 0.498), as well as procedural success ( p = 0.437), procedure-related ( p = 0.533) and all-cause mortality ( p = 0.333) were not different between groups. In obese patients (BMI ≥ 30 kg/m 2 ), lead age ≥10 years was identified as a predictor of procedural failure (OR: 2.99; 95% CI: 1.06-8.45; p = 0.038). Lead age ≥10 years (OR: 3.25; 95% CI: 1,31-8.10; p = 0.011) and abandoned leads (OR: 3.08; 95% CI: 1.03-9.22; p = 0.044) were predictors of procedural complications, while patient age ≥75 years seemed protective (OR: 0.27; 95% CI: 0.08-0.93; p = 0.039). Systemic infection was the only predictor for all-cause mortality (OR: 17.68; 95% CI: 4.03-77.49; p < 0.001)., Conclusions: LLE in obese patients is as safe and effective as in other weight classes, if performed in experienced high-volume centers. Systemic infection remains the main cause of in-hospital mortality in obese patients.

Objectives: Implantation of implantable cardioverter defibrillators (ICD) reduces the risk of all-cause mortality in symptomatic heart failure (HF) patients with severe left ventricular (LV) dysfunction. Nevertheless, the prognostic impact of ICD therapy in continuous flow left ventricular assist device (LVAD) recipients remains controversial., Methods: 162 consecutive HF patients, who underwent LVAD implantation at our institution between 2010 and 2019, were categorized according to the presence ( n  = 94, ICD-group ) or absence ( n  = 68, Control-group) of ICDs. Apart from clinical baseline and follow-up parameters, adverse events (AEs) related to ICD therapy and overall survival rates were retrospectively analyzed., Results: Out of 162 consecutive LVAD recipients 79 patients (48.8%) were preoperatively categorized as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile ≤2. The prevalence of severe HF symptoms and preoperative use of short-term circulatory support devices (54.4% vs. 13.8%, p  < 0.001) was higher within the Control-group, although baseline severity of LV and RV dysfunction was similar. Apart from an increased prevalence of perioperative right heart failure (RHF) within the Control-group (45.6% vs. 17.0%; p  < 0.001), procedural characteristics and perioperative outcome were similar. Overall-survival during a median follow-up of 14 (3.0-36.5) months was similar within both groups ( p  = 0.46). During the first 2 years after LVAD implantation 53 ICD-related AEs occurred within the ICD-group. Thereof, lead-dysfunction occurred in 19 patients and unplanned ICD-reintervention in 11 patients. Furthermore, in 18 patients appropriate shocks without loss of consciousness occurred, whereas inappropriate shocks occurred in 5 patients., Conclusion: ICD therapy in LVAD recipients was not associated with a survival benefit or reduced morbidity after LVAD implantation. Conservative ICD-programming seems to be justified to avoid ICD-related complications and "awake shocks" after LVAD implantation., Competing Interests: TT declared consulting activity for Medtronic and Boston Scientific, as well as speaker honorarium from Medtronic. YY and SP declared consulting activity for Medtronic and Philips Medical. HR declared travel grants and speaker honoraria from Abbott and Abiomed. AB declared consulting activity for Abiomed, as well as travel grants and speaker honoraria from Abbott and Abiomed., (© 2023 Pausch, Mersmann, Bhadra, Barten, Tönnis, Yildirim, Pecha, Reichenspurner and Bernhardt.)

Objective: At the tissue level, disruption of the extracellular matrix network leads to irreversible cardiac fibrosis, which contributes to myocardial dysfunction. At the myocyte level, downregulation of beta-adrenoceptors (beta-AR) reduces adaptation to increased workload. The aim of our study was to analyse the correlation between myocardial fibrosis and beta-AR sensitivity in patients with aortic valve (AV) disease. Methods: A total of 92 consecutive patients who underwent elective AV surgery between 2017-2019 were included in our study (51 with aortic regurgitation (AR-group); 41 with aortic stenosis (AS-group) and left ventricular (LV) biopsies were obtained intraoperatively. In vitro force contractility testing was performed by measuring beta-AR sensitivity (-log EC 50 [ISO]). In parallel, a quantitative analysis of myocardial fibrosis burden was performed. Results: Mean age at the time of AV surgery was not statistically different in both groups (AR: 53.3 ± 15.3 years vs. AS: 58.7 ± 17.0 years; p = 0.116). The LV end-diastolic diameter was significantly enlarged in the AR-group when compared to the AS-group (59.4 ± 15.6 vs. 39.7 ± 21.2; p < 0.001). Analysis of beta-AR sensitivity (AR: -6.769 vs. AS: -6.659; p = 0.316) and myocardial fibrosis (AR: 8.9% vs. AS: 11.3%; p = 0.284) showed no significant differences between patients with AS and AR. There was no correlation between myocardial fibrosis and beta-AR sensitivity in the whole study cohort (R = 0.1987; p = 0.100) or in the AS-subgroup (R = 0.009; p = 0.960). However, significant correlation of fibrosis and beta-AR sensitivity was seen in AR-patients (R = 0.363; p = 0.023). Conclusion: More severe myocardial fibrosis was associated with reduced beta-AR sensitivity in patients presenting with AR but not with AS. Therefore, our results suggest that in patients with AR, cellular myocardial dysfunction is present and correlates with the extent of myocardial fibrosis in the myocardium.

Background: Atrial fibrillation (AF) is common in patients with heart failure resulting in a high prevalence of AF in patients receiving Cardiac Resynchronization Therapy (CRT) implantation. In patients, unsuitable for transvenous left ventricular (LV)-lead implantation, epicardial LV-lead implantation represents a valuable alternative. Epicardial LV-lead placement can be achieved totally thoracoscopical or via minimally invasive left lateral thoracotomy. In patients with atrial fibrillation, concomitant left atrial appendage (LAA) clipping is feasible via the same access. Therefore, the aim of our study was the analysis of safety and efficacy of epicardial LV lead implantation and concomitant LAA clipping via minimally invasive left-lateral thoracotomy., Methods: Between December 2019 and March 2022, 8 patients received minimally invasive left atrial LV-lead implantation with concomitant LAA closure using the AtriClip. Transesophageal echocardiography (TEE) was performed to intraoperatively guide and control LAA closure., Results: Mean patients age was 64 ± 11.2 years, 67% were male patients. Minimally invasive left-lateral thoracotomy was used in 6 patients while a totally thoracoscopic approach was performed in 2 cases. Epicardial lead implantation was successfully performed in all patients with good pacing threshold (mean 0.8 ± 0.2 V) and sensing values (10.1 ± 2.3 mV). Posterolateral position of the LV lead was achieved in all patients. Furthermore, successful LAA closure was confirmed during TEE in all patients. No procedure-related complications occurred in any of the patients. Two patients additionally received simultaneous laser lead extraction during the same procedure. Complete lead extraction was achieved in both patients. All patients were extubated in the OR and had an uneventful postoperative course., Conclusion: Our study highlights a novel treatment approach for patients with atrial fibrillation and the necessity of epicardial LV leads. Placement of a posterolateral LV lead position with concomitant occlusion of the left atrial appendage via a minimally-invasive left-lateral thoracotomy or even a totally thoracoscopic approach is safe and feasible with superior cosmetic result and complete occlusion of the left atrial appendage., Competing Interests: SP is a consultant for Philips Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Petersen, Alassar, Yildirim, Tönnis, Reichenspurner and Pecha.)

Aims: The incidence of atrial fibrillation (AF) increases with age. Women have a lower risk. Little is known on the impact of age, sex and clinical variables on action potentials (AP) recorded in right atrial tissue obtained during open heart surgery from patients in sinus rhythm (SR) and in longstanding AF. We here investigated whether age or sex have an impact on the shape of AP recorded in vitro from right atrial tissue., Methods: We performed multivariable analysis of individual AP data from trabeculae obtained during heart surgery of patients in SR (n = 320) or in longstanding AF (n = 201). AP were recorded by sharp microelectrodes at 37 °C at 1 Hz. Impact of clinical variables were modeled using a multivariable mixed model regression., Results: In SR, AP duration at 90% repolarization (APD 90 ) increased with age. Lower ejection fraction and higher body mass index were associated with smaller action potential amplitude (APA) and maximum upstroke velocity (V max ). The use of beta-blockers was associated with larger APD 90 . In tissues from women, resting membrane potential was less negative and APA as well as V max were smaller. Besides shorter APD 20 in elderly patients, effects of age and sex on atrial AP were lost in AF., Conclusion: The higher probability to develop AF at advanced age cannot be explained by a shortening in APD 90 . Less negative RMP and lower upstroke velocity might contribute to lower incidence of AF in women, which may be of clinical relevance., Competing Interests: Declaration of Competing Interest SP has received lecture fees and advisory board fees from Medtronic and Philips Healthcare outside this work. RBS has received lecture fees and advisory board fees from BMS/Pfizer outside this work., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Transvenous lead extraction (TLE) has evolved as one of the most crucial treatment options for patients with cardiac device-related systemic infection (CDRSI)., Objective: The aim of this study was to characterize the procedural outcome and risk factors of patients with CDRSI undergoing TLE., Methods: A subgroup analysis of patients with CDRSI of the GALLERY (GermAn Laser Lead Extraction RegistrY) database was performed. Predictors for complications, procedural failure, and all-cause mortality were evaluated., Results: A total of 722 patients (28.6%) in the GALLERY had "systemic infection" as extraction indication. Patients with CDRSI were older (70.1 ± 12.2 years vs 67.3 ± 14.3 years; P < .001) and had more comorbidities than patients with local infections or noninfectious extraction indications. There were no differences in complete procedural success (90.6% vs 91.7%; P = .328) or major complications (2.5% vs 1.9%; P = .416) but increased procedure-related (1.4% vs 0.3%; P = .003) and all-cause in-hospital mortality (11.1% vs 0.6%; P < .001) for patients with CDRSI. Multivariate analyses revealed lead age ≥10 years as a predictor for procedural complications (odds ratio [OR] 3.23; 95% confidence interval [CI] 1.58-6.60; P = .001). Lead age ≥10 years (OR 2.57; 95% CI 1.03-6.46; P = .04) was also a predictor for procedural failure. We identified left ventricular ejection fraction <30% (OR 1.70; 95% CI 1.00-2.99; P = .049), age ≥75 years (OR 2.1; 95% CI 1.27-3.48; P = .004), chronic kidney disease (OR 1.92; 95% CI 1.17-3.14; P = .01), and overall procedural complications (OR 5.15; 95% CI 2.44-10.84; P < .001) as predictors for all-cause mortality., Conclusion: Patients with CDRSI undergoing TLE demonstrate an increased rate of all-cause in-hospital, as well as procedure-related mortality, despite having comparable procedural success rates. Given these data, it seems paramount to develop preventive strategies to detect and treat CDRSI in its earliest stages., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation is the most common arrhythmia and has been described as driver of cardiovascular morbidity and risk factor for cardiac device-related complications, as well as in transvenous lead extraction (TLE). Objectives: Aim of this study was to characterize the procedural outcome and risk-factors of patients with atrial fibrillation (AF) undergoing TLE. Methods: We performed a subgroup analysis of all AF patients in the GALLERY (GermAn Laser Lead Extraction RegistrY) database. Predictors for all-cause mortality were assessed. Results: A total number of 510 patients with AF were identified with a mean age of 74.0 ± 10.3 years. Systemic infection (38.4%) was the leading cause for TLE, followed by local infection (37.5%) and lead dysfunction (20.4%). Most of the patients (45.9%) presented with pacemaker systems to be extracted. The total number of leads was 1181 with a 2.3 ± 0.96 leads/patient. Clinical procedural success was achieved in 97.1%. Occurrence of major complications was 1.8% with a procedure-related mortality of 1.0%. All-cause mortality was high with 5.9% and septic shock being the most common cause. Systemic device infection (OR: 49.73; 95% CI: 6.56−377.09, p < 0.001), chronic kidney disease (CKD; OR: 2.67; 95% CI: 1.01−7.03, p = 0.048) and a body mass index < 21 kg/m2 (OR: 6.6; 95% CI: 1.68−25.87, p = 0.007) were identified as independent predictors for all-cause mortality. Conclusions: TLE in AF patients is effective and safe, but in patients with systemic infection the mortality due to septic shock is high. Systemic infection, CKD and body mass index <21 kg/m2 are risk factors for death in patient with AF undergoing TLE.

Background and Objectives : In patients with paroxysmal atrial fibrillation (AF) undergoing CABG or aortic valve surgery, many surgeons are not willing to open the left atrium to perform a complete left-sided Cox-Maze lesion set. Pulmonary vein isolation (PVI) is often favored in those patients. We investigated the outcome of patients with isolated pulmonary vein isolation compared to those receiving an extended left atrial (LA) lesion set. Materials and Methods : Between 2003 and 2016, 817 patients received concomitant surgical AF ablation in our institution. A total of 268 patients with paroxysmal AF were treated by surgical ablation concomitant to AVR or CABG. Of those, 86 patients underwent a complete left-sided lesion set, while 182 patients were treated with an isolated pulmonary vein isolation. The primary endpoint was freedom from atrial fibrillation at 12 months' follow-up. Results: There were no statistically significant differences regarding baseline characteristics. No major ablation-related complications were observed in any of the groups. In the PVI group, three patients (1.6%) had an intraoperative stroke, while two (2.3%) patients experienced a stroke in the LA ablation group ( p = 0.98). In-hospital mortality was 3.4% in the PVI group, and 2.8% in the extended LA group ( p = 0.33). Freedom from AF at 12 months' follow-up was 76% in the extended LA ablation group and 70% in the PVI group, showing no statistically significant difference ( p = 0.32). Conclusion: Surgical AF ablation concomitant to CABG or AVR in patients with paroxysmal AF is safe and effective. There was no statistically significant difference between the compared lesion sets in terms of freedom from AF, survival or stroke rate after 12 months.

Aims: The GermAn Laser Lead Extraction RegistrY: GALLERY is a retrospective, national multicentre registry, investigating the safety and efficacy of laser lead extraction procedures in Germany., Methods and Results: Twenty-four German centres that are performing laser lead extraction have participated in the registry. All patients, treated with a laser lead extraction procedure between January 2013 and March 2017, were consecutively enrolled. Safety and efficacy of laser lead extraction were investigated. A total number of 2524 consecutive patients with 6117 leads were included into the registry. 5499 leads with a median lead dwell time of 96 (62-141) months were treated. The mean number of treated leads per patient was 2.18 ± 1.02. The clinical procedural success rate was 97.86% and the complete lead removal was observed in 94.85%. Additional extraction tools were used in 6.65% of cases. The rate of procedural failure was 2.14% with lead age  ≥10 years being its only predictor. The overall complication rate was 4.32%, including 2.06% major and 2.26% minor complications. Procedure-related mortality was 0.55%. Female sex and the presence of abandoned leads were predictors for procedure-related complications. The all-cause in-hospital mortality was 3.56% with systemic infection being the strongest predictor, followed by age ≥75 years and chronic kidney disease., Conclusion: In the GALLERY, a high success- and low procedure-related complication rates have been demonstrated. In multivariate analysis, female sex and the presence of abandoned leads were predictors for procedure-related complications, while the presence of systemic infection, age ≥75 years, and chronic kidney disease were independent predictors for all-cause mortality., Competing Interests: Conflict of interest: S.P. reports grants and personal fees from Philips/Spectranetics, Medtronic, and AtriCure. H.B. reports grants and personal fees from Philips/Spectranetics, Cook Medical, Zoll Medical, Braun Medical, Abbott, Sorin Group/LivaNova, Impulse Dynamics, Biotronik, and Medtronic. B.O. reports grants and personal fees from Philips/Spectranetics and Medtronic. H.E. reports personal fees from Philips/Spectranetics. N.G. reports grants and personal fees from Boston Scientific, Medtronic, and Bayer Vital. M.K. reports grants and personal fees from Philips/Spectranetics, Zoll Medical, Sorin Group/LivaNova, Medtronic, Boston Scientific, and CVRx. H.R. reports personal fees from Medtronic. S.W. reports grants and personal fees from Abbott, Boston Scientific, Medtronic, Boehringer Ingelheim, Bristol Myers Squibb, Bayer Vital, Acutus, and Daiichi Sankyo. S.H. reports grants and personal fees from Boston Scientific, Edwards Lifesciences, Medtronic, Meril, Philips/Spectranetics, and Zoll Medical. All other authors have no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Minimally-invasive (MIS) mitral valve (MV) surgery has become standard therapy in many cardiac surgery centers. While femoral arterial perfusion is the preferred cannulation strategy in MIS mitral valve surgery, retrograde arterial perfusion is known to be associated with an increased risk for cerebral atheroembolism, particularly in atherosclerosis patients. Therefore, antegrade perfusion may be beneficial in such cases. This analysis aimed to compare outcomes of antegrade axillary vs. retrograde femoral perfusion in the MIS mitral valve surgery., Methods: This analysis includes 50 consecutive patients who underwent MIS between 2016 and 2020 using arterial cannulation of right axillary artery (Group A) due to severe aortic arteriosclerosis. Perioperative outcomes of the study group were compared with a historical control group of retrograde femoral perfusion (Group F) which was adjusted for age and gender ( n = 50). Primary endpoint of the study was in-hospital mortality and perioperative cerebrovascular events., Results: Patients in group A had a significantly higher perioperative risk as compared to Group F (EuroSCORE II: 3.9 ± 2.5 vs. 1.6 ± 1.5; p = 0.001; STS-Score: 2.1 ± 1.4 vs. 1.3 ± 0.6; p = 0.023). Cardiopulmonary bypass time (group A: 172 ± 46; group F: 178 ± 51 min; p = 0.627) and duration of surgery (group A: 260 ± 65; group F: 257 ± 69 min; p = 0.870) were similar. However, aortic cross clamp time was significantly shorter in group A as compared to group F (86 ± 20 vs. 111 ± 29 min, p < 0.001). There was no perioperative stroke in either groups. In-hospital mortality was similar in both groups (group A: 1 patient; group F: 0 patients; p = 0.289). In group A, one patient required central aortic repair due to intraoperative aortic dissection. No further cardiovascular events occurred in Group A patients., Conclusion: Selective use of antegrade axillary artery perfusion in patients with systemic atherosclerosis shows similar in-hospital outcomes as compared to lower risk patients undergoing retrograde femoral perfusion. Patients with higher perioperative risk and severe atherosclerosis can be safely treated via the minimally invasive approach with antegrade axillary perfusion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Petersen, Naito, Kloth, Pecha, Zipfel, Alassar, Detter, Conradi, Reichenspurner and Girdauskas.)

The treatment of valvular endocarditis in patients with cardiac implantable electrophysiological device (CIED) includes valvular surgery and lead extraction. This can be challenging in patients with severely reduced left ventricular ejection fraction (LVEF). Reduced LVEF in combination with sepsis and cardioplegic cardiac arrest can make weaning from cardiopulmonary bypass difficult. Some of these patients require venoarterial extracorporeal membrane oxygenation (VA-ECMO) for postcardiotomy syndrome. Lead extraction by manual traction is often not possible in cases with a long lead dwell time. Therefore, a lead extraction procedure with powered sheaths is required during the VA-ECMO support. We describe our technique for laser lead extraction during VA-ECMO support in a 64-year-old patient with triple valve endocarditis and lead vegetations.

Background and Aims: The relationship between postoperative atrial fibrillation (POAF) and 25-hydroxyvitamin D [25(OH)D] concentration as well as vitamin D supplementation has been discussed controversially. The relation of pre-operative vitamin D status and POAF remains unclear., Methods and Results: We analysed the risk of POAF in a prospective, observational cohort study of n = 201 patients undergoing coronary artery bypass graft surgery (CABG) with 25(OH)D concentration. The median age was 66.6 years, 15.4% were women. The median (25th/75th percentile) vitamin D concentration at baseline was 17.7 (12.6/23.7) ng/ml. During follow-up we observed 48 cases of POAF. In age, sex, and creatinine-adjusted analyses, 25(OH)D was associated with an increased risk of POAF, though with borderline statistical significance [odds ratio (OR) 1.85, 95% confidence interval (CI) 0.87-3.92, p-value 0.107], in further risk factor-adjusted analyses the results remained stable (OR 1.99, 95% CI 0.90-4.39, p-value 0.087). The subgroup with vitamin D supplementation at baseline showed an increased risk of POAF (OR 5.03, 95% CI 1.13-22.33, p-value 0.034)., Conclusion: In our contemporary mid-European cohort, higher 25(OH)D concentration did not show a benefit for POAF in CABG patients and may even be harmful, though with borderline statistical significance. Our data are in line with a recent randomised study in community-based adults and call for further research to determine both, the clinical impact of elevated 25(OH)D concentration and vitamin D supplementation as well as the possible underlying pathophysiological mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ohlrogge, Brederecke, Ojeda, Pecha, Börschel, Conradi, Rimkus, Blankenberg, Zeller and Schnabel.)

Abstract: In human hearts, muscarinic receptors (M-R) are expressed in ventricular and atrial tissue, but the acetylcholine-activated potassium current (IK,ACh) is expressed mainly in the atrium. M-R activation decreases force and increases electrical stability in human atrium, but the impact of IK,ACh to both effects remains unclear. We used a new selective blocker of IK,ACh to elaborate the contribution of IK,ACh to M-R activation-mediated effects in human atrium. Force and action potentials were measured in rat atria and in human right atrial trabeculae. Cumulative concentration-effect curves for norepinephrine-induced force and arrhythmias were measured in the presence of carbachol (CCh; 1 µM) or CCh together with the IK,ACh -blocker XAF-1407 (1 µM) or in time-matched controls. To investigate the vulnerability to arrhythmias, we performed some experiments also in the presence of cilostamide (0.3 µM) and rolipram (1 µM), inhibiting PDE3 and PDE4. In rat atria and human right atrial trabeculae, CCh shortened the action potential duration persistently. However, the direct negative inotropy of CCh was only transient in human, but stable in rat atria. In rat and human atria, the negative inotropic effect was insensitive to blockage of IK,ACh by XAF-1407. In the presence of cilostamide and rolipram about 40% of trabeculae developed arrhythmias when exposed to norepinephrine. CCh prevented these concentration-dependent norepinephrine-induced arrhythmias, again insensitive to XAF-1407. Maximum catecholamine-induced force was not depressed by CCh. In human atrium, the direct and the indirect negative inotropic effect of CCh are independent of IK,ACh. The same applies to the CCh-mediated suppression of norepinephrine/PDE-inhibition-induced arrhythmias., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Transcatheter aortic valve implantation (TAVI) is routinely performed in patients with severe aortic stenosis (AS). For patients with pure non-calcified aortic regurgitation (AR) who are not suitable for open heart surgery no clear recommendations exist and use of TAVI has been largely off-label. We herein report a series of patients treated with the self-expandable AcurateNeo and Neo2 (Boston Scientific Co., Marlborough, MS, USA) transcatheter heart valve (THV) for pure AR. Methods: Between 05/2017 and 03/2021, 9 patients (88.8% female, 74.4 ± 7.1 years, logEuroSCORE II 5.5 ± 3.6%, STS PROM 6.2 ± 3.0%) received transfemoral (TF) TAVI for pure non-calcified AR following an adjusted valve sizing algorithm. Data were retrospectively analyzed according to updated Valve Academic Research Consortium (VARC-2) definitions. Results: Device success was 100%. Early safety was 77.7% (7/10), due to two (22.2%) cases of acute kidney injury. Thirty-day mortality was 0%, in seven (77.7%) patients no or trace paravalvular leakage (PVL) was seen and mild PVL in two (22.2%) patients at 30-day follow-up. No permanent pacemaker (PPM) was required during 30-day follow-up. Conclusion: In this series of selected patients using the Acurate neo THV for pure non-calcified AR, safety and efficacy were demonstrated. Thirty-day mortality as well as PPM implantation and PVL rates showed excellent results in this high-risk patient cohort. These results will have to be confirmed in larger patient cohorts., Competing Interests: MS reports lecture fees and travel expenses from Boston Scientific. LC is advisory board member for Boston Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schneeberger, Seiffert, Schaefer, Bhadra, Schofer, Pecha, Westermann, Blankenberg, Reichenspurner and Conradi.)

Bacterial membrane vesicles (BMVs) are cupped-shaped structures formed by bacteria in response to environmental stress, genetic alteration, antibiotic exposure, and others. Due to the structural similarities shared with the producer organism, they can retain certain characteristics like stimulating immune responses. They are also able to carry molecules for long distances, without changes in the concentration and integrity of the molecule. Bacteria originally secrete membrane vesicles for gene transfer, excretion, cell to cell interaction, pathogenesis, and protection against phages. These functions are unique and have several innovative applications in the pharmaceutical industry that have attracted both scientific and commercial interest.This led to the development of efficient methods to artificially stimulate vesicle production, purification, and manipulation in the lab at nanoscales. Also, for specific applications, engineering methods to impart pathogen antigens against specific diseases or customization as cargo vehicles to deliver payloads to specific cells have been reported. Many applications of BMVs are in cancer drugs, vaccines, and adjuvant development with several candidates in clinical trials showing promising results. Despite this, applications in therapy and commercialization stay timid probably due to some challenges one of which is the poor understanding of biogenesis mechanisms. Nevertheless, so far, BMVs seem to be a reliable and cost-efficient technology with several therapeutic applications. Research toward characterizing more membrane vesicles, genetic engineering, and nanotechnology will enable the scope of applications to widen. This might include solutions to other currently faced medical and healthcare-related challenges., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to assess the clinical outcome of the bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary obstruction (BASILICA) technique in a single-center patient cohort considered at high or prohibitive risk of transcatheter aortic valve implantation (TAVI)-induced coronary obstruction., Methods: Between October 2019 and January 2021, a total of 15 consecutive patients (age 81.0 [78.1, 84.4] years; 53.3% female; EuroSCORE II 10.6 [6.3, 14.8] %) underwent BASILICA procedure prior to TAVI at our institution. Indications for TAVI were degeneration of stented (n = 12, 80.0%) or stentless (n = 1, 6.7%) bioprosthetic aortic valves, or calcific stenosis of native aortic valves (n = 2, 13.3%), respectively. Individual risk of TAVI-induced coronary obstruction was assessed by pre-procedural computed tomography analysis. Procedural and 30-day outcomes were documented in accordance with Valve Academic Research Consortium (VARC)-2 criteria., Results: BASILICA was attempted for single left coronary cusp in 12 patients (80.0%), for single right coronary cusp in 2 patients (13.3%), and for both cusps in 1 patient (6.7%), respectively. The procedure was feasible in 13 patients (86.7%) resulting in effective prevention of coronary obstruction, whilst TAVI was performed without prior successful bioprosthetic leaflet laceration in two patients (13.3%). In one of these patients (6.7%), additional chimney stenting immediately after TAVI was performed. No all-cause deaths or strokes were documented after 30 days., Conclusion: The BASILICA technique appears to be a feasible, safe and effective concept to avoid iatrogenic coronary artery obstruction during TAVI in both native and bioprosthetic valves of patients at high or prohibitive risk. ClinicalTrials.gov Identifier: NCT04227002 (Hamburg AoRtic Valve cOhoRt)., (© 2021. The Author(s).)

Background: The number of patients requiring lead extraction has been increasing in recent years. Despite significant advances in operator experience and technique, unexpected complications may occur. Prophylactic placement of femoral sheaths allows for immediate endovascular access for emergency procedures and may shorten response time in the event of complications., Objective: The purpose of this study was to assess the benefits of routine prophylactic femoral access in patients undergoing transvenous lead extraction (TLE) and to evaluate the methods, frequency, and efficacy of the emergency measures used in those patients., Methods: We conducted a retrospective analysis of patients who underwent TLE from January 2012 to February 2019. The data were analyzed with regard to procedural complications and deployment of emergency measures via femoral access., Results: Two hundred eighty-five patients (mean age 65.3 ± 15.5 years) were included in the study. Median lead dwell time was 84 months (interquartile range 58-144). Overall complication rate was 4.2% (n = 12), with 1.8% major complications (n = 5). Clinical success rate was 97.2%. Procedure-related mortality was 1.1% (n = 3). Femoral sheaths were actively engaged in 9.1% (n = 26) of cases. Deployment of snares was the most common intervention (n = 10), followed by prophylactic (n = 6) or emergency placement (n = 1) of occlusion balloons, temporary pacing (n = 3), venous angioplasty (n = 3), diagnostic venography (n = 3), and extracorporeal membrane oxygenation (n = 1). We did not observe any femoral vascular complications due to prophylactic sheath placement., Conclusion: Routine prophylactic placement of femoral sheaths shortens response time and quickly establishes control in the event of various complications that may occur during TLE procedures., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Human engineered heart tissue (EHT) transplantation represents a potential regenerative strategy for patients with heart failure and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices, and determination of the effective dose., Methods: Cardiomyocytes were differentiated from 3 different human induced pluripotent stem cell lines including one reprogrammed under good manufacturing practice conditions. Protocols for human induced pluripotent stem cell expansion, cardiomyocyte differentiation, and EHT generation were adapted to substances available in good manufacturing practice quality. EHT geometry was modified to generate patches suitable for transplantation in a small-animal model and perspectively humans. Repair efficacy was evaluated at 3 doses in a cryo-injury guinea pig model. Human-scale patches were epicardially transplanted onto healthy hearts in pigs to assess technical feasibility., Results: We created mesh-structured tissue patches for transplantation in guinea pigs (1.5×2.5 cm, 9-15×10 6 cardiomyocytes) and pigs (5×7 cm, 450×10 6 cardiomyocytes). EHT patches coherently beat in culture and developed high force (mean 4.6 mN). Cardiomyocytes matured, aligned along the force lines, and demonstrated advanced sarcomeric structure and action potential characteristics closely resembling human ventricular tissue. EHT patches containing ≈4.5, 8.5, 12×10 6 , or no cells were transplanted 7 days after cryo-injury (n=18-19 per group). EHT transplantation resulted in a dose-dependent remuscularization (graft size: 0%-12% of the scar). Only high-dose patches improved left ventricular function (+8% absolute, +24% relative increase). The grafts showed time-dependent cardiomyocyte proliferation. Although standard EHT patches did not withstand transplantation in pigs, the human-scale patch enabled successful patch transplantation., Conclusions: EHT patch transplantation resulted in a partial remuscularization of the injured heart and improved left ventricular function in a dose-dependent manner in a guinea pig injury model. Human-scale patches were successfully transplanted in pigs in a proof-of-principle study.

Objective: The incidence of atrial fibrillation increases with age, and therefore many elderly patients presenting for cardiac surgery have atrial fibrillation. In recent publications, increasing age has been recognized as a predictor for ablation failure. Furthermore, many surgeons are reluctant to perform a surgical ablation in elderly patients. We investigated the safety and efficacy of concomitant surgical atrial fibrillation ablation in elderly patients., Methods: Between 2003 and 2013, 556 patients underwent concomitant surgical atrial fibrillation ablation at the University Heart Center Hamburg and served as our primary study cohort. During follow-up, rhythm monitoring was established by 24-hour Holter electrocardiogram (70.5%) or an implantable loop recorder (29.5%) at 3, 6, and 12 months postoperatively. The primary end point of the study was freedom from atrial fibrillation at 12 months follow-up and the detection of deviations from a linear association between age and risk of atrial fibrillation recurrence. A multiple logistic regression model including age as a linear term was used to identify predictors for rhythm outcome., Results: Mean patients' age was 68.4 ± 9.07 years, and 67.3% of the patients were male. Mean duration of atrial fibrillation was 3.5 ± 3.3 years, and mean left atrium diameters were enlarged with 50.5 ± 8.8 mm. There were no major ablation-related complications. The 30-day and 1-year survivals were 97.7% and 95.8%, respectively. The overall rate of freedom from atrial fibrillation ranged from 62% to 72% and was independent of age. The age-dependent risk of atrial fibrillation at 12 months was significantly increased in elderly patients undergoing a concomitant coronary artery bypass grafting surgery. Multiple logistic regression model revealed double valve procedures (odds ratio, 3.48; P = .020), preoperative persistent atrial fibrillation (odds ratio, 2.43; P = .001), and coronary artery bypass grafting surgery in elderly patients (odds ratio, 2.03; P = .009) as risk factors for recurrence of atrial fibrillation. Sinus rhythm at discharge (odds ratio, 0.39; P < .001) and bipolar ablation (odds ratio, 0.32; P < .001) were significant predictors for successful ablation., Conclusions: Surgical atrial fibrillation ablation was safe and effective independently of age. Sinus rhythm at discharge and bipolar ablation were significant predictors for successful ablation, whereas double valve procedures, preoperative persistent atrial fibrillation, and coronary artery bypass grafting surgery in elderly patients were risk factors for recurrence of atrial fibrillation., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Transvenous lead extraction using mechanical rotational- or laser sheaths is an established procedure. Lead dwell time has been recognized as a risk factor for extraction failure and procedure-related complications. We therefore investigated the safety and efficacy of transvenous extraction of leads with an implant duration of more than 10 years., Methods: Between January 2013 and March 2017, a total of 403 patients underwent lead extraction in 2 high-volume lead extraction centres. One hundred and fifty-four patients with extraction of at least 1 lead aged over 10 years were included in this analysis. Laser lead extraction was the primary extraction method, with additional use of mechanical rotational sheaths or femoral snares, if necessary. All procedural- and patient-based data were collected into a database and retrospectively analysed., Results: Mean patient's age was 65.8 ± 15.8 years, 68.2% were male. Three hundred and sixty-two leads had to be extracted. The mean lead dwell time of treated leads was 14.0 ± 6.1 years. Complete procedural success was achieved in 91.6% of cases, while clinical success was achieved in 96.8%. Failure of extraction occurred in 3.2%. Leads that could not be completely removed had a significantly longer lead dwell time (18.2 vs 13.2 years; P = 0.016). Additional mechanical rotational sheaths or femoral snares were used in 26 (16.9%) patients. Overall complication rate was 4.6%, including 5 (3.3%) major and 2 (1.3%) minor complications. There was no procedure-related mortality., Conclusions: Transvenous lead extraction in leads aged over 10 years is safe and effective when performed in specialized centres and with use of multiple tools and techniques. Leads that could not be completely extracted had a statistically significant longer lead dwell time., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Due to high rates of transcatheter mitral valve replacement (TMVR) screening failure, a substantial proportion of patients with severe mitral regurgitation (MR) remains on optimal medical treatment (OMT) only. Data on outcomes of these patients ineligible for mitral interventions are scarce. This study aimed to assess characteristics and outcomes of severe MR patients treated medically following TMVR screening failure., Methods: From 2016-2020, a total of 111 patients with severe MR underwent screening for TMVR. Screening failure occurred in 66 cases. Among these, 30 patients were treated with OMT only. Characteristics of these patients were analyzed, Kaplan-Meier estimates calculated, and univariate regression analysis performed. Median follow-up time was 2.26 years (95% confidence interval, 1.24-3.25)., Results: Anatomical reasons for screening failure in the study cohort (n = 30) were left ventricular (LV) restraints, risk of LV outflow tract obstruction, mitral annulus calcification, and sizing issues. Median ejection fraction was 56.0% (interquartile range, 38.8%-60.0%). Concomitant tricuspid regurgitation and severe pulmonary hypertension were present in 36.7% and 46.2%, respectively. Intercommissural diameters ranged from 22.5-52.0 mm. Mortality was 23.6% after 6 months and 35.7% after 1 year. Factors associated with mortality were female sex, MR severity, ischemic MR, high N-terminal pro-brain natriuretic peptide levels, and small annulus diameters., Conclusions: Despite growing experience with TMVR, the subset of MR patients anatomically eligible for TMVR is small and many patients are treated medically. Mortality in these patients remains high, underlining an unmet need for adequate therapeutic alternatives. TMVR devices adapting to broader annular size ranges with smaller ventricular profiles might fill this gap.

Background: In the aging population equipped with cardiac implantable electronic devices, an increasing number of octogenarians require lead extractions. This patient population is often considered as a high-risk group for surgical procedures. We, therefore, investigated the safety and efficacy of transvenous lead extraction in octogenarians using powered extraction sheaths., Methods: Between January 2013 and March 2017, 403 patients underwent lead extraction at two high-volume lead extraction centers. A total of 71 octogenarians were treated with laser lead extraction and were included in this analysis. Primary extraction method was laser lead extraction, with additional use of mechanical rotational sheaths or femoral snares, if necessary. Patient-based and procedural data were collected and analyzed retrospectively., Results: Mean age was 83.5 ± 3.3 years, 64.7% were males. A total of 152 leads were extracted. The mean lead dwell time of treated leads was 10.2 ± 5.2 years. Complete procedural success rate was 92.9%, while clinical success was achieved in 98.6%. Failure of extraction occurred in one patient (1.4%). In six (7.7%) patients, additional mechanical rotational sheaths or femoral snares were used. Overall complication rate was 4.2%, including one (1.4%) major (RA perforation) and two (2.8%) minor complications. No procedure-related mortality was observed in any of the patients., Conclusion: Transvenous lead extraction in octogenarians with old leads is safe and effective when performed in experienced centers. Patient's age should therefore not be considered as contraindication for lead extraction using powered extraction sheaths., (© 2021 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

Aim: There is an increasing awareness of the impact of age and sex on cardiovascular diseases (CVDs). Differences in physiology are suspected. Beta-adrenoceptors (beta-ARs) are an important drug target in CVD and potential differences might have significant impact on the treatment of many patients. To investigate whether age and sex affects beta-AR function, we analysed a large data set on beta-AR-induced inotropy in human atrial trabeculae., Methods: We performed multivariable analysis of individual atrial contractility data from trabeculae obtained during heart surgery of patients in sinus rhythm (535 trabeculae from 165 patients). Noradrenaline or adrenaline were used in the presence of the beta 2 -selective antagonist (ICI 118 551, 50 nmol/L) or the beta 1 -selective antagonist (CGP 20712A, 300 nmol/L) to stimulate beta 1 -AR or beta 2 -AR respectively. Agonist concentration required to achieve half-maximum inotropic effects (EC 50 ) was taken as a measure of beta-AR sensitivity., Results: Impact of clinical variables was modelled using multivariable mixed model regression. As previously reported, chronic treatment with beta-blockers sensitized beta-AR. However, there was no significant interaction between basal force, maximum force and beta-AR sensitivity when age and sex were modelled continuously. In addition, there was no statistically significant effect of body mass index or diabetes on atrial contractility., Conclusion: Our large, multivariable analysis shows that neither age nor sex affects beta-AR-mediated inotropy or catecholamine sensitivity in human atrial trabeculae. These findings may have important clinical implications because beta-ARs, as a common drug target in CVD and heart failure, do not behave differently in women and men across age decades., (© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)