Publications by authors named "Hermann Reichenspurner"

394 Publications

Human Engineered Heart Tissue Patches Remuscularize the Injured Heart in a Dose-Dependent Manner.

Circulation 2021 Mar 2. Epub 2021 Mar 2.

Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Germany; German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.

Human engineered heart tissue (EHT) transplantation represents a potential regenerative strategy for heart failure patients and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices (GMP) and determination of the effective dose. Cardiomyocytes were differentiated from three different human induced pluripotent stem cell (hiPSC) lines including one reprogrammed under GMP conditions. Protocols for hiPSC expansion, cardiomyocyte differentiation and EHT generation were adapted to substances available in GMP 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. We created mesh structured tissue patches for transplantation in guinea pigs (1.5x2.5 cm, 9-15x10 cardiomyocytes) and pigs (5x7 cm, 450 x10 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, 12x10 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. While standard EHT patches did not withstand transplantation in pigs, the human-scale patch enabled successful patch transplantation. 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047904DOI Listing
March 2021

Mapping genetic changes in the cAMP-signaling cascade in human atria.

J Mol Cell Cardiol 2021 Feb 22. Epub 2021 Feb 22.

Université Paris-Saclay, Inserm, UMR-S 1180, Châtenay-Malabry, France; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.

Aim: To obtain a quantitative expression profile of the main genes involved in the cAMP-signaling cascade in human control atria and in different cardiac pathologies.

Methods And Results: Expression of 48 target genes playing a relevant role in the cAMP-signaling cascade was assessed by RT-qPCR. 113 samples were obtained from right atrial appendages (RAA) of patients in sinus rhythm (SR) with or without atrium dilation, paroxysmal atrial fibrillation (AF), persistent AF or heart failure (HF); and left atrial appendages (LAA) from patients in SR or with AF. Our results show that right and left atrial appendages in donor hearts or from SR patients have similar expression values except for AC7 and PDE2A. Despite the enormous chamber-dependent variability in the gene-expression changes between pathologies, several distinguishable patterns could be identified. PDE8A, PKI3G and EPAC2 were upregulated in AF. Different phosphodiesterase (PDE) families showed specific pathology-dependent changes.

Conclusion: By comparing mRNA-expression patterns of the cAMP-signaling cascade related genes in right and left atrial appendages of human hearts and across different pathologies, we show that 1) gene expression is not significantly affected by cardioplegic solution content, 2) it is appropriate to use SR atrial samples as controls, and 3) many genes in the cAMP-signaling cascade are affected in AF and HF but only few of them appear to be chamber (right or left) specific.

Topic: AC, AKAP, PDE, Epac, PKA, CaMKII TRANSLATIONAL PERSPECTIVE: The cyclic AMP signaling pathway is important for atrial function. However, expression patterns of the genes involved in the atria of healthy and diseased hearts are still unclear. We give here a general overview of how different pathologies affect the expression of key genes in the cAMP signaling pathway in human right and left atria appendages. Our study may help identifying new genes of interest as potential therapeutic targets or clinical biomarkers for these pathologies and could serve as a guide in future gene therapy studies.
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http://dx.doi.org/10.1016/j.yjmcc.2021.02.006DOI Listing
February 2021

Blunted beta-adrenoceptor-mediated inotropy in valvular cardiomyopathy: another piece of the puzzle in human aortic valve disease.

Eur J Cardiothorac Surg 2021 Feb 23. Epub 2021 Feb 23.

Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany.

Objectives: Heart failure induced by valvular cardiomyopathy occurs in a substantial proportion of patients undergoing heart valve surgery. We aimed (i) to quantify beta-adrenoceptor (beta-AR) function by measuring the inotropic effect of isoprenaline in left ventricular (LV) tissue and (ii) to correlate beta-AR-mediated inotropy with clinical markers of heart failure.

Methods: A total of 179 LV myocardial samples were obtained from 104 consecutive patients who underwent aortic valve (AV) surgery between 2017 and 2019. Beta-ARs were stimulated by increasing the concentrations of isoprenaline, followed by a single high concentration of forskolin and calcium. Beta-AR sensitivity was estimated as the concentration to achieve half maximum effects (EC50). Maximum effect size was calculated as the relative beta-AR-mediated inotropic response compared to the force in the presence of high calcium [FISO/Ca (%)]. In vitro data were correlated with the clinical indicators of LV disease.

Results: FISO/Ca was independent of age and sex and amounted to 79.6 ± 20.5%. In a multivariate regression model, we found a significant inverse association between FISO/Ca and preoperative left ventricular end-diastolic diameter increase per 10 mm (OR -9.24, 95% CI -16.66 to -1.82; P = 0.015). Furthermore, patients with end-stage heart failure showed a strong tendency towards more severe reduction of max beta-AR response, as indicated by reduced FISO/Ca in a multivariate model (OR -29.60, 95% CI -61.92 to 2.72; P = 0.055).

Conclusions: Our study indicates that in vitro myocardial contractility testing can quantify beta-AR dysfunction in patients with AV disease. We found a significant association between reduced beta-AR sensitivity and increased LV diameter, which may indicate a role of beta-AR dysfunction in the development of heart failure in patients with AV disease.
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http://dx.doi.org/10.1093/ejcts/ezab004DOI Listing
February 2021

Characteristics and Outcomes of Patients Ineligible for Transcatheter Mitral Valve Replacement (TMVR): Implications for Future Device Innovation.

J Invasive Cardiol 2021 Feb 18. Epub 2021 Feb 18.

Department of Cardiology, University Heart and Vascular Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.

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.
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February 2021

Safety and efficacy of transvenous lead extraction in octogenarians using powered extraction sheaths.

Pacing Clin Electrophysiol 2021 Feb 16. Epub 2021 Feb 16.

Department of Cardiovascular Surgery, University Heart and Vascular Center, Hamburg, Germany.

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.
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http://dx.doi.org/10.1111/pace.14195DOI Listing
February 2021

The benefits of routine prophylactic femoral access during transvenous lead extraction.

Heart Rhythm 2021 Feb 9. Epub 2021 Feb 9.

Department of Cardiology & Critical Care Medicine, Asklepios Klinik St. Georg, Hamburg, Germany.

Background: The number of patients with necessity for lead extraction has been rising in recent years. Despite significant advances in operator experience and technique, unexpected complications may occur. The prophylactic placement of femoral sheaths allows for immediate endovascular access for emergency procedures and may shorten response time in face of complications.

Objectives: The aim of this study was to assess the benefits of routine prophylactic femoral access in patients undergoing TLE and to evaluate methods, frequency and efficacy of the deployed emergency measures in those patients.

Methods: We conducted a retrospective analysis of patients who underwent TLE from January 2012 until February 2019. The data was analyzed in regards to procedural complications and deployment of emergency measures via femoral access.

Results: 285 patients with a mean age of 65.3±15.5 years were included. Median lead dwell time was 84 [IQR: 58 - 144] months. 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, with deployment of snares being the most common intervention (n=10), followed by prophylactic- (n=6) or emergent placement (n=1) of occlusion balloons, temporary pacing (n=3), venous angioplasty (n=3), diagnostic venography (n=3) or implantation of an ECMO (n=1). We did not observe any femoral vascular complications due to prophylactic sheath placement.

Conclusion: The routine prophylactic placement of femoral sheaths enables to shorten response time and quickly establish control in face of various complications that may be encountered during TLE procedures.
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http://dx.doi.org/10.1016/j.hrthm.2021.02.004DOI Listing
February 2021

Non-immune risk predictors of cardiac allograft vasculopathy: Results from the U.S. organ procurement and transplantation network.

Int J Cardiol 2021 Feb 8. Epub 2021 Feb 8.

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Germany.

Background: Cardiac allograft vasculopathy (CAV) remains a major long-term complication in heart transplant (HT) recipients related to increased mortality. We aimed to identify non-immune recipient- and donor-related risk factors for the development of CAV in HT patients.

Methods: 40,647 recipients, prospectively enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed after exclusion of pediatric patients, those with missing information on CAV, and re-transplantation. Multivariable-adjusted Cox regression analyses were performed to identify recipient- and donor-related risk factors for CAV. 5-year population attributable risk for classical cardiovascular risk factors was calculated to estimate the recipients' CAV risk. Analyses were based on OPTN data (June 30, 2019).

Results: Of 40,647 post-transplant patients, 14,698 (36.2%) developed CAV with a higher incidence in males (37.3%) than in females (32.6%) (p < 0.001). The mean follow-up time was 68.2 months. In recipients, male sex, African American and Asian ethnicity, ischemic cardiomyopathy, body mass index and smoking were associated with CAV occurrence. In donors, older age, male sex, smoking, diabetes and arterial hypertension were related to CAV. Results remained fairly stable after analysis of different time periods. 5-year attributable CAV risk for classical cardiovascular risk factors was 9.1%.

Conclusions: In this large registry with known limitations concerning data completeness, CAV incidence was higher in males than in females. Next to male sex and donor age, the classical cardiovascular risk factors were related to incident CAV. Classical cardiovascular risk factors played only a minor role for the 5-year attributable CAV risk.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.002DOI Listing
February 2021

Addendum to: Publication Performance in German Academic Heart Surgery.

Thorac Cardiovasc Surg 2021 Jan 29;69(1):e1. Epub 2021 Jan 29.

Herz- und Gefäßzentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1055/s-0041-1724138DOI Listing
January 2021

Predicting clinical outcome by indexed mitral valve tenting in functional mitral valve regurgitation.

Open Heart 2021 Jan;8(1)

Cardiovascular Surgery, University Hospital Hamburg Eppendorf University Heart Centre, Hamburg, Germany.

Objectives: Mitral valve (MV) tenting parameters are indicators of left ventricular remodelling severity and may predict outcome in functional mitral regurgitation (FMR). We hypothesised that indexing of MV tenting area to body surface area (BSA), to mitral annulus diameter or gender-adjusted analysis of tenting parameters may improve their prognostic value.

Methods: We identified retrospectively 240 patients with consecutive FMR (mean age 68±10 years; men=135) from our institutional database who underwent isolated MV annuloplasty during a period of 7 years (2010-2016). Using preoperative two-dimensional transthoracic echocardiographic images, MV tenting parameters including tenting area, tenting height and annulus diameter were systematically assessed. Follow-up protocol consisted of chart review and structured clinical questionnaire. Primary study endpoint was the composite of death and adverse cardiac events (ie, MV reoperation, cardiac resynchronisation therapy implantation, ventricular assist device implantation or heart transplantation).

Results: BSA-indexed MV tenting area was identified as independent predictor of primary study endpoint (HR 1.9; 95% CI 1.1 to 3.5; p=0.02). After cut-off point analysis, BSA-indexed MV tenting area >1.35 cm/m was significantly associated with primary study outcome (HR 2.3; 95% CI 1.3 to 4.0; p=0.003). Annulus-indexed MV tenting area showed only a tendency towards primary study endpoint prediction (HR 2.8; 95% CI 0.6 to 12.6; p=0.17). Between female and male patients, BSA-indexed MV tenting area was similar (1.42±0.4 cm/m vs 1.45±0.4cm/cm; p=0.6) and gender was not associated with primary study outcome (HR 0.8; 95% CI 0.5 to 1.4; p=0.5).

Conclusion: In our FMR cohort, BSA-indexed MV tenting area showed the strongest association with negative outcomes following isolated MV annuloplasty. Patients with BSA-indexed MV tenting area >1.35cm/m could potentially benefit from additional surgical maneuvers addressing left ventricular remodelling.
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http://dx.doi.org/10.1136/openhrt-2020-001483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839912PMC
January 2021

Ablation of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy: Treatment Strategy, Characteristics of Consecutive Atrial Tachycardia and Long-Term Outcome.

J Am Heart Assoc 2021 Feb 17;10(3):e017451. Epub 2021 Jan 17.

Department of Cardiology University Heart and Vascular Center HamburgUniversity Medical Center Hamburg-Eppendorf Hamburg Germany.

Background Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and is associated with a deterioration of clinical status. Ablation of symptomatic AF is an established therapy, but in HCM, the characteristics of recurrent atrial arrhythmias and the long-term outcome are uncertain. Methods and Results Sixty-five patients with HCM (aged 64.5±9.9 years, 42 [64.6%] men) underwent AF ablation. The ablation strategy included pulmonary vein isolation in all patients and ablation of complex fractionated atrial electrograms or subsequent atrial tachycardias (AT) if appropriate. Paroxysmal, persistent AF, and a primary AT was present in 13 (20.0%), 51 (78.5%), and 1 (1.5%) patients, respectively. Twenty-five (38.4%) patients developed AT with a total number of 54 ATs. Stable AT was observed in 15 (23.1%) and unstable AT in 10 (15.3%) patients. The mechanism was characterized as a macroreentry in 37 (68.5%), as a localized reentry in 12 (22.2%), a focal mechanism in 1 (1.9%), and not classified in 4 (7.4%) ATs. After 1.9±1.2 ablation procedures and a follow-up of 48.1±32.5 months, freedom of AF/AT recurrences was demonstrated in 60.0% of patients. No recurrences occurred in 84.6% and 52.9% of patients with paroxysmal and persistent AF, respectively (<0.01). Antiarrhythmic drug therapy was maintained in 24 (36.9%) patients. Conclusions AF ablation in patients with HCM is effective for long-term rhythm control, and especially patients with paroxysmal AF undergoing pulmonary vein isolation have a good clinical outcome. ATs after AF ablation are frequently observed in HCM. Freedom of atrial arrhythmia is achieved by persistent AF ablation in a reasonable number of patients even though the use of antiarrhythmic drug therapy remains high.
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http://dx.doi.org/10.1161/JAHA.120.017451DOI Listing
February 2021

Performance and outcome of the subcutaneous implantable cardioverter-defibrillator after transvenous lead extraction.

Pacing Clin Electrophysiol 2021 Feb 12;44(2):247-257. Epub 2021 Jan 12.

Department of Cardiology & Critical Care Medicine, Asklepios Klinik St. Georg, Hamburg, Germany.

Aims: The subcutaneous cardioverter-defibrillator (S-ICD) may be a valuable option in patients after successful transvenous lead extraction (TLE) without indication for pacemaker therapy and persistent risk of sudden cardiac death. The aim of this study was to evaluate device performance, postoperative outcome, and safety in patients who received a S-ICD after TLE compared to patients who underwent de-novo S-ICD implantation.

Methods: A retrospective analysis of all patients included into our institution's S-ICD database between September 2010 and May 2019 was conducted.The patients were divided in two groups, depending on whether they had received their S-ICD after TLE (n = 31) or de-novo (n = 113).

Results: The TLE group was significantly older with a mean age of 54.3 ± 15.7 versus 46.7 ± 14.4 years; p = .007. Leading S-ICD indication in the TLE group was previous infection (50%), whereas in the de-novo group the S-ICD was primarily chosen due to young patient age (74.6%). Median duration of follow-up was 527.0 versus 472.5 days, respectively; p = .576. Most common complication during follow-up was inappropriate ICD therapy (12.9% vs. 13.3%); p = 1.000. Pocket erosion/infection occurred in 3.2% versus 3.5% with no reported cases of systemic (re-)infection in either group; p = 1.000. All-cause mortality was low (6.2% vs. 2.7%) and entirely unrelated to S-ICD implantation or the device itself; p = .293.

Conclusion: The S-ICD is a safe and effective alternative for patients after TLE with very similar results regarding device performance and postoperative outcome, when compared to patients who underwent de-novo S-ICD implantation.
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http://dx.doi.org/10.1111/pace.14157DOI Listing
February 2021

Changes in transvalvular flow patterns after aortic valve repair: comparison of symmetric versus asymmetric aortic valve geometry.

Eur J Cardiothorac Surg 2020 Dec 7. Epub 2020 Dec 7.

Department of Cardiovascular Surgery, University Heart and Vascular Center Hamburg, UKE, Hamburg, Germany.

Objectives: The aim of this study was to compare the effect of asymmetric versus symmetric bicuspid aortic valve (BAV) repair on transvalvular flow patterns and aortic wall shear stress (WSS).

Methods: Four-dimensional flow magnetic resonance imaging was prospectively and consecutively performed in patients with congenital aortic valve (AV) disease before and after AV repair. The following MRI-based parameters were assessed: (i) flow eccentricity index, (ii) backward flow across the AV, (iii) grading of vortical and helical flow, and (iv) WSS (N/m2) in the proximal aorta. MRI-derived flow parameters were compared between patients who underwent 'asymmetric BAV repair' (n = 13) and 'symmetric BAV repair' (n = 7).

Results: A total of 20 patients (39 ± 12 years, 80% male), who underwent BAV repair, were included. In the asymmetric BAV repair group, circumferential WSS reduction was found at the level of the aortic arch (P = 0.015). In the symmetric BAV repair group, postoperative circumferential WSS was significantly reduced compared to baseline at all levels of the proximal aorta (all P < 0.05). Postoperative circumferential WSS was significantly higher in the asymmetric versus symmetric BAV repair group at the level of the sinotubular junction (0.45 ± 0.15 vs 0.30 ± 0.09 N/m2; P = 0.028), ascending aorta (0.59 ± 0.19 vs 0.44 ± 0.08 N/m2; P = 0.021) and aortic arch (0.59 ± 0.25 vs 0.40 ± 0.08 N/m2; P = 0.017). Segmental WSS analysis showed significantly higher postoperative WSS after asymmetric versus symmetric BAV repair, especially in the anterior aortic segment (P = 0.004).

Conclusions: Symmetric BAV repair results in more physiological flow patterns and significantly reduces WSS, as compared to asymmetric BAV repair. From a haemodynamic point of view, symmetric AV geometry should be attempted in every congenital AV repair.
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http://dx.doi.org/10.1093/ejcts/ezaa445DOI Listing
December 2020

Feasibility, safety, and resource utilisation of active mobilisation of patients on extracorporeal life support: a prospective observational study.

Ann Intensive Care 2020 Dec 1;10(1):161. Epub 2020 Dec 1.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: There is scarce evidence on the feasibility, safety and resource utilisation of active mobilisation in critically ill patients on extracorporeal life support (ECLS).

Methods: This prospective observational single-centre study included all consecutive critically ill patients on ECLS admitted to an academic centre in Germany over a time period of one year. The level of mobilisation was categorised according to the ICU Mobility Scale (IMS). Primary outcome was complications during mobilisation.

Results: During the study period, active mobilisation with an activity level on the IMS of ≥ 3 was performed at least on one occasion in 43 out of 115 patients (37.4%). A total of 332 mobilisations with IMS ≥ 3 were performed during 1242 ECLS days (26.7%). ECLS configurations applied were va-ECMO (n = 63), vv-ECMO (n = 26), vv-ECCOR (n = 12), av-ECCOR (n = 10), and RVAD (n = 4). Femoral cannulation had been in place in 108 patients (93.9%). The median duration of all mobilisation activities with IMS ≥ 3 was 130 min (IQR 44-215). All mobilisations were undertaken by a multi-professional ECLS team with a median number of 3 team members involved (IQR 3-4). Bleeding from cannulation site requiring transfusion and/or surgery occurred in 6.9% of actively mobilised patients and in 15.3% of non-mobilised patients. During one mobilisation episode, accidental femoral cannula displacement occurred with immediate and effective recannulation. Sedation was the major reason for non-mobilisation.

Conclusions: Active mobilisation (IMS ≥ 3) of ECLS patients undertaken by an experienced multi-professional team was feasible, and complications were infrequent and managed successfully. Larger prospective multicentre studies are needed to further evaluate early goal directed sedation and mobilisation bundles in patients on ECLS.
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http://dx.doi.org/10.1186/s13613-020-00776-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708587PMC
December 2020

Safety and efficacy of transvenous lead extraction of very old leads.

Interact Cardiovasc Thorac Surg 2020 Nov 30. Epub 2020 Nov 30.

Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.

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.
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http://dx.doi.org/10.1093/icvts/ivaa278DOI Listing
November 2020

Prognostic value of the H FPEF score in patients undergoing transcatheter aortic valve implantation.

ESC Heart Fail 2021 Feb 20;8(1):461-470. Epub 2020 Nov 20.

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Aims: The aim of this study was to assess the prognostic value of the H FPEF score in patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) and preserved left ventricular ejection fraction (EF).

Methods And Results: In this multicentre study, a total of 832 patients from two German high-volume centres, who received TAVI for severe AS and preserved EF (≥50%), were identified for calculation of the H FPEF score. Patients were dichotomized according to low (0-5 points; n = 570) and high (6-9 points; n = 262) H FPEF scores. Kaplan-Meier and Cox regression analyses were applied to assess the prognostic impact of the H FPEF score. We observed a decrease in stroke volume index (-2.04 mL/m /point) and mean transvalvular gradients (-1.14 mmHg/point) with increasing H FPEF score translating into a higher prevalence of paradoxical low-flow, low-gradient AS among patients with high H FPEF score. One year after TAVI, the rates of all-cause (low vs. high H FPEF score: 8.0% vs. 19.4%, P < 0.0001) and cardiovascular (CV) mortality (1.9% vs. 9.0%, P < 0.0001) as well as the rate of CV mortality or rehospitalization for congestive heart failure (6.4% vs. 23.2%, P < 0.0001) were higher in patients with high H FPEF score compared with those with low H FPEF score. After multivariable analysis, a high H FPEF score remained independently predictive of all-cause mortality [hazard ratio 1.59 (1.28-2.35), P = 0.018] and CV mortality or rehospitalization for congestive heart failure [hazard ratio 2.92 (1.65-5.15), P < 0.001]. Among the H FPEF score variables, atrial fibrillation, pulmonary hypertension, and elevated left ventricular filling pressure were the strongest outcome predictors.

Conclusions: The H FPEF score serves as an independent predictor of adverse CV and heart failure outcome among TAVI patients with preserved EF. A high H FPEF score is associated with the presence of paradoxical low-flow, low-gradient AS, the HFpEF in patients with AS. By identifying patients in advanced stages of HFpEF, the H FPEF score might be useful as a risk prediction tool in patients with preserved EF scheduled for TAVI.
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http://dx.doi.org/10.1002/ehf2.13096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835574PMC
February 2021

qSOFA Score Is Useful to Assess Disease Severity in Patients With Heart Failure in the Setting of a Heart Failure Unit (HFU).

Front Cardiovasc Med 2020 28;7:574768. Epub 2020 Oct 28.

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany.

There is no gold standard to predict outcome in acute decompensated heart failure (ADHF). Several scores for mortality prediction of patients with ADHF have been developed and mostly consist of complex regression models. None of these models has been widely adopted by clinicians. The quick SOFA score (qSOFA) is a simple score including three parameters (systolic blood pressure ≤ 100 mmHg, respiratory rate ≥22 breathes/min, and GCS <15) and is validated for discrimination of mortality risk in septic patients. Here, we adapted qSOFA score to patients admitted to a Heart Failure Unit (HFU) and assessed the prognostic accuracy. qSOFA, SOFA score, and SIRS criteria were assessed at admission. Clinical, laboratory, and echocardiographic parameters were recorded. A follow-up was performed 30 days after discharge. Primary outcome was all-cause mortality or readmission to hospital due do worsening of heart failure symptoms. Of 240 patients (73% male, 16-93 years), 25 patients (10%) had a qSOFA ≥2 points and 126 patients (53%) fulfilled none of qSOFA criteria. Within 30 days, the primary endpoint occurred in 46 patients (19%). Seventeen patients (7%) died and 34 patients (14%) were readmitted to hospital due to worsening heart failure. Patients with qSOFA ≥2 reached this endpoint more frequently (48 vs. 19%, = 0.002), had more often dyspnea NYHA III-IV (OR 2.4, = 0.005) and a higher risk for multi organ failure during hospital stay (28 vs. 9%, = 0.005). qSOFA is useful to identify patients with heart failure at high risk for worse outcome and to operationalize severity of decompensation.
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http://dx.doi.org/10.3389/fcvm.2020.574768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655543PMC
October 2020

Clinical outcomes of complete versus incomplete revascularization in patients treated with coronary artery bypass grafting: insights from the TiCAB trial.

Eur J Cardiothorac Surg 2020 Nov 14. Epub 2020 Nov 14.

Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

Objectives: In this post hoc analysis of the Ticagrelor in coronary artery bypass grafting (CABG) trial, we aimed to analyse patients treated with CABG receiving either complete revascularization (CR) or incomplete revascularization (ICR) independent from random allocation to either ticagrelor or aspirin.

Methods: Of 1859 patients enrolled in the Ticagrelor in CABG trial, 1550 patients (83.4%) received CR and 309 patients (16.6%) ICR. Outcomes were evaluated regarding all-cause mortality, cardiovascular death, myocardial infarction (MI), repeat revascularization, stroke and bleeding within 12 months after CABG.

Results: Baseline parameters revealed significant differences regarding clinical presentation (stable angina pectoris: CR 68.9% vs ICR 71.2%, instable angina pectoris: 14.1% vs 7.8%, non-ST elevation MI: 17.0% vs 21.0%, P ˂ 0.01), lesion characteristics (chronic total occlusion: CR 91.3% vs ICR 96.8%, P ˂ 0.01), operative technique [off-pump coronary artery bypass surgery (OPCAB): CR 3.0% vs ICR 6.1%, P ˂ 0.01] and number of utilized grafts (total number of grafts: 2.69/patient vs 2.49/patient, P ˂ 0.001). ICR patients displayed a significantly increased risk of repeat revascularization [hazard ratio (HR) 1.91, 95% confidence interval (CI) 1.16-3.16; P < 0.01] and percutaneous coronary intervention (HR 1.95, 95% CI 1.13-3.35; P < 0.05) within 12 months after CABG. Higher risk for repeat revascularization in ICR patients was independent from random allocation to either ticagrelor or aspirin and persisted after adjustment for baseline imbalances.

Conclusions: Patients with ICR presented more stable at the time of admission, but received less grafts, highly likely due to a higher rate of chronic total occlusion lesions and performed OPCAB. Although mortality presented no difference between groups, our results suggest that patients benefit from CR with regard to prevention of repeat revascularization.
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http://dx.doi.org/10.1093/ejcts/ezaa330DOI Listing
November 2020

Bicuspid aortopathy - molecular involvement of microRNAs and MMP-TIMP.

Biomarkers 2020 Dec 9;25(8):711-718. Epub 2020 Nov 9.

Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany.

Objectives: We aimed to elucidate the correlation between expression patterns of aortic tissue microRNAs and the aortopathy formation in bicuspid aortic valve (BAV) disease.

Methods: All 65 patients who underwent elective aortic valve repair/replacement +/- proximal aortic replacement due to BAV disease with or without concomitant aortic aneurysm were identified from our BAV registry. Aortic tissue was collected intraoperatively from the ascending aorta at the greater and lesser curvature. Aortic tissue microRNAs analysis included 11 microRNAs (). Furthermore, analysis of MMP2, TIMP1/2 mRNA and the protein expression was subsequently performed. The primary study endpoint was the correlation between microRNAs and MMP2, TIMP1/2 mRNA/protein expression.

Results: We found a significant association between miR-133a and TIMP1 mRNA ( = 0.870,  < 0.001), an inverse correlation between miR-143a and MMP2 protein expression (= -0.614,  = 0.044) and a positive correlation between miR-133a and TIMP-2 protein expression ( = 0.583,  = 0.036) at the greater curvature.

Conclusion: Our findings indicate that aortic tissue microRNAs may reflect remodelling processes of the proximal aorta in BAV aortopathy. Specific aortic tissue microRNAs may exert their regulatory effects on the aortopathy through their impact on MMPs/TIMPs homeostasis at the level of the greater curvature.
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http://dx.doi.org/10.1080/1354750X.2020.1841297DOI Listing
December 2020

Left Ventricular Unloading Is Associated With Lower Mortality in Patients With Cardiogenic Shock Treated With Venoarterial Extracorporeal Membrane Oxygenation: Results From an International, Multicenter Cohort Study.

Circulation 2020 Dec 9;142(22):2095-2106. Epub 2020 Oct 9.

German Center for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, Germany (B.S., P.M.B., A.B., S. Blankenberg, S.D., M.E., I.E., D.F., N.F., T.G., P.K., C.N., D.W.).

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality.

Methods: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort.

Results: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63-0.98]; =0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site-related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%).

Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688081PMC
December 2020

No impact of sex and age on beta-adrenoceptor-mediated inotropy in human right atrial trabeculae.

Acta Physiol (Oxf) 2021 Mar 29;231(3):e13564. Epub 2020 Oct 29.

Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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 -selective antagonist (ICI 118 551, 50 nmol/L) or the beta -selective antagonist (CGP 20712A, 300 nmol/L) to stimulate beta -AR or beta -AR respectively. Agonist concentration required to achieve half-maximum inotropic effects (EC ) 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.
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http://dx.doi.org/10.1111/apha.13564DOI Listing
March 2021

Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation.

Naunyn Schmiedebergs Arch Pharmacol 2021 Feb 19;394(2):291-298. Epub 2020 Sep 19.

DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.

Atrial fibrillation (AF)-associated remodeling includes contractile dysfunction whose reasons are only partially resolved. Serotonin (5-HT) increases contractile force and causes arrhythmias in atrial trabeculae from patients in sinus rhythm (SR). In persistent atrial fibrillation (peAF), the force responses to 5-HT are blunted and arrhythmic effects are abolished. Since force but not arrhythmic responses to 5-HT in peAF could be restored by PDE3 + PDE4 inhibition, we sought to perform real-time measurements of cAMP to understand whether peAF alters PDE3 + PDE4-mediated compartmentation of 5-HT receptor-cAMP responses. Isolated human atrial myocytes from patients in SR, with paroxysmal AF (paAF) or peAF, were adenovirally transduced to express the FRET-based cAMP sensor Epac1-camps. Forty-eight hours later, cAMP responses to 5-HT (100 μM) were measured in the absence or concomitant presence of the PDE3 inhibitor cilostamide (0.3 μM) and the PDE4 inhibitor rolipram (1 μM). We successfully established real-time cAMP imaging in AF myocytes. 5-HT increased cAMP in SR, paAF, and peAF, but in line with previous findings on contractility, this increase was considerably smaller in peAF than in SR or paAF. The maximal cAMP response to forskolin (10 μM) was preserved in all groups. The diminished cAMP response to 5-HT in peAF was recovered by preincubation with cilostamide + rolipram. We uncovered a significantly diminished cAMP response to 5-HT receptor stimulation which may explain the blunted 5-HT inotropic responses observed in peAF. Since both cAMP and force responses but not arrhythmic responses were recovered after concomitant inhibition of PDE3 + PDE4, they might be regulated in different subcellular microdomains.
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http://dx.doi.org/10.1007/s00210-020-01968-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835186PMC
February 2021

Publication Performance in German Academic Heart Surgery.

Thorac Cardiovasc Surg 2021 Jan 8;69(1):19-25. Epub 2020 Sep 8.

Herz- und Gefäßzentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background:  This study was designed to evaluate the publication performance of management teams consisting of chief and senior physicians in German university cardiac surgery units over a 10-year period and to facilitate benchmarking.

Methods:  The cutoff date for consideration of staffing from the unit Web site and publications was July 1, 2017. The literature search was based on an evaluation of the PubMed database. The 5-year impact factor (IF) from 2016 was assigned to each journal.

Results:  Two thousand five hundred thirty-five publications (average IF 3.02) were registered, published in 323 journals. Of a total of 341 management team members, 235 (68.9%) published as first or last author over the 10-year period. The number of publications from the units divided into quintiles varied considerably with the first six units contributing 39.0% of all publications and the last nine units 9.4%. With a cumulative IF total of 3265, the publications of the first six units accounted for 42.7% of the cumulative IF, the last unit quintile amounted to 621 (8.1%) of the cumulative IF. When considering publications per managing member, the first quintile averaged 11.9 publications (29.6 IF) per managing member, the last quintile 3.3 publications (8.0 IF) per member.

Conclusions:  The six units of the first quintile published on average 3.6 times more per managing member than the nine units in the last quintile and the average cumulative IF per member in the first quintile was almost five times higher. Further investigation must show whether this considerable difference in publication activity between the university units is also observed in other operative fields.
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http://dx.doi.org/10.1055/s-0040-1715599DOI Listing
January 2021

Left Ventricular Assist Device Implantation and Concomitant Dor Procedure: a Single Center Experience.

Braz J Cardiovasc Surg 2020 08 1;35(4):477-483. Epub 2020 Aug 1.

Department of Cardiovascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Objective: Left ventricular assist device (LVAD) implantation with concomitant Dor plasty is only reported anecdotally. We herein aimed to describe our experience with LVAD and concomitant Dor procedures and describe long-term outcomes of this special subset of heart failure patients.

Methods: Between January/2010 and December/2018, 144 patients received LVAD therapy at our institution. Of those, five patients (80% male, 60.4±7.2 years) presented with an apical aneurysm and received concomitant Dor plasty. Apical aneurysms presented diameter between 75 and 98 mm, with one impending rupture.

Results: Procedural success was achieved in all patients. No unplanned right ventricular assist device implantation occurred. Furthermore, no acute 30-day mortality was seen. In follow-up, one patient was lost due to intentional disconnection of the driveline. One patient underwent heart transplantation on postoperative day 630. The remaining three patients are still on device with sufficient flow; pump thromboses were successfully managed by lysis therapy in one patient.

Conclusion: LVAD implantation with concomitant Dor procedure is feasible, safe, and occasionally performed in patients with ischemic cardiomyopathy. Major advantages are prevention of thromboembolism and facilitation of LVAD placement by improving pump stability and warranting midventricular, coaxial alignment of the inflow cannula. In long-term follow-up, no adverse event associated with Dor plasty was observed.
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http://dx.doi.org/10.21470/1678-9741-2019-0349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454606PMC
August 2020

Spontaneous echo contrast, left atrial appendage thrombus and stroke in patients undergoing transcatheter aortic valve implantation.

EuroIntervention 2021 Jan;16(13):1114-1122

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Aims: The relevance of spontaneous echo contrast (SEC) and left atrial appendage thrombus (LAAT) in patients undergoing transcatheter aortic valve implantation (TAVI) remains unclear. In this study, we aimed to assess the prevalence of SEC and LAAT and evaluate the impact on periprocedural outcome after TAVI.

Methods And Results: A total of 2,549 consecutive patients underwent TAVI between 2008 and 2017. After exclusion of cases with insufficient imaging, concomitant procedures or severe intraprocedural complications, 1,558 cases were analysed. Three groups were defined according to (pre)thrombotic formations - moderate or severe SEC (n=89), LAAT (n=53), and reference (n=1,416). The primary outcome was disabling ischaemic stroke within 24 hours. The prevalence was 4.4% for LAAT and 5.4% for moderate/severe SEC. The primary outcome occurred more frequently in patients with moderate/severe SEC (6.8%) compared to the reference (2.1%) and LAAT (1.9%) groups (p=0.020). SEC was identified as an independent risk factor for the primary outcome (OR 3.54 [95% CI: 1.30-9.61], p=0.013). LAAT was associated with an impaired unadjusted one-year survival (43.4%) compared to the SEC (27.3%) and reference groups (18.7%, p<0.001).

Conclusions: SEC and LAAT were detected in a relevant number of patients undergoing TAVI. SEC may represent an important risk factor for intraprocedural stroke; increased mortality was observed in patients with LAAT. Visual summary. Left atrial appendage thrombus or (pre)thrombotic formations were observed in a relevant number of patients undergoing TAVI. An increased risk for periprocedural cerebrovascular events was observed if moderate or severe spontaneous echo contrast was present. The unadjusted all-cause mortality was higher in patients with left atrial appendage thrombus.
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http://dx.doi.org/10.4244/EIJ-D-20-00743DOI Listing
January 2021

Focus on a rare clinical entity: unicuspid aortic valve disease.

Expert Rev Cardiovasc Ther 2020 Sep 31;18(9):625-633. Epub 2020 Aug 31.

Department of Cardiovascular Surgery, University Heart and Vascular Center Hamburg , Hamburg, Germany.

Introduction: While the understanding of the pathophysiology and clinical implication of bicuspid aortic valves evolves rapidly, the natural history of unicuspid aortic valves is still poorly understood. Hence, a universally accepted diagnostic work-up process and therapy recommendations for UAV still have to be established.

Areas Covered: This article aims to give an overview on the most recent literature addressing the pathophysiology, the diagnostic tools and appropriate surgical therapy options of unicuspid aortic valve. Due to the rare prevalence, the understanding of pathophysiology is still missing. Further, symptomatic aortic valve disease are seen much earlier life stage in this cohorts. Thus, it highlights the several surgical treatment options with pro and contra especially for the young adult cohorts.

Expert Opinion: Large scale prospective observational studies using standardized diagnostic criteria are needed to reveal the clinical course. Further appropriate treatment strategies of unicuspid aortic valve patients is demanded.
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http://dx.doi.org/10.1080/14779072.2020.1811685DOI Listing
September 2020

Clinical characteristics and outcomes of patients with adult congenital heart disease listed for heart and heart‒lung transplantation in the Eurotransplant region.

J Heart Lung Transplant 2020 Jul 25. Epub 2020 Jul 25.

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany; Partner Site Hamburg/Kiel/Lübeck, German Center of Cardiovascular Research (DZHK), Berlin, Germany.

Background: The therapeutic success in patients with congenital heart disease (CHD) leads to a growing number of adults with CHD (adult CHD [ACHD]) who develop end-stage heart failure. We aimed to determine patient characteristics and outcomes of ACHD listed for heart transplantation.

Methods: Using data from all the patients with ACHD in 20 transplant centers in the Eurotransplant region from 1999 to 2015, we analyzed patient characteristics, waiting list, and post-transplantation outcomes.

Results: A total of 204 patients with ACHD were listed during the study period. The median age was 38 years, and 62.3% of the patients were listed in high urgency (HU), and 37.7% of the patients were in transplantable (T)-listing status. A total of 23.5% of the patients died or were delisted owing to clinical worsening, and 75% of the patients underwent transplantation. Median waiting time for patients with HU-listing status was 4.18 months and with T-listing status 9.07 months. There was no difference in crude mortality or delisting between patients who were HU status listed and T status listed (p = 0.65). In multivariable regression analysis, markers for respiratory failure (mechanical ventilation, hazard ratio [HR]: 1.41, 95% CI: 1.11-1.81, p = 0.006) and arrhythmias (anti-arrhythmic medication, HR: 1.42, 95% CI: 1.01-2.01, p = 0.044) were associated with a higher risk of death or delisting. In the overall cohort, post-transplantation mortality was 26.8% after 1 year and 33.4% after 5 years.

Conclusions: Listed patients are at high risk of death without differences in the urgency of listing. Respiratory failure requiring invasive ventilation and possibly arrhythmias requiring anti-arrhythmic medication indicate worse outcomes on waiting list.
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http://dx.doi.org/10.1016/j.healun.2020.07.012DOI Listing
July 2020

Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation.

Circ Res 2020 Sep 30;127(8):1036-1055. Epub 2020 Jul 30.

Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (J.H., A.P.M., T.V., C.E.M., M.T., I.H.A.-T., M.G., S.N., D.D.).

Rationale: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.

Objective: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.

Methods And Results: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca]-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca-release events and L-type Ca-current alternans occurred more frequently. CaMKII (Ca/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca-content was unchanged in POAF despite greater SR Ca-leak, with a trend towards increased SR Ca-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca-uptake are sufficient to reproduce the Ca-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β.

Conclusions: Preexisting Ca-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604886PMC
September 2020

The H-Y Antigen in Embryonic Stem Cells Causes Rejection in Syngeneic Female Recipients.

Stem Cells Dev 2020 09 25;29(18):1179-1189. Epub 2020 Aug 25.

Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.

Pluripotent stem cells are promising candidates for cell-based regenerative therapies. To avoid rejection of transplanted cells, several approaches are being pursued to reduce immunogenicity of the cells or modulate the recipient's immune response. These include gene editing to reduce the antigenicity of cell products, immunosuppression of the host, or using major histocompatibility complex-matched cells from cell banks. In this context, we have investigated the antigenicity of H-Y antigens, a class of minor histocompatibility antigens encoded by the Y chromosome, to assess whether the gender of the donor affects the cell's antigenicity. In a murine transplant model, we show that the H-Y antigen in undifferentiated embryonic stem cells (ESCs), as well as ESC-derived endothelial cells, provokes T- and B cell responses in female recipients.
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http://dx.doi.org/10.1089/scd.2019.0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482111PMC
September 2020

Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3.

EBioMedicine 2020 Jul 4;57:102862. Epub 2020 Jul 4.

Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address:

Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG).

Methods: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133 bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions.

Findings: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical:SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3.

Validation: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature.

Interpretation: Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response.

Funding: German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274.
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http://dx.doi.org/10.1016/j.ebiom.2020.102862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339012PMC
July 2020

Left ventricular reverse remodeling after successful subannular mitral valve repair in end-stage heart failure: a case report.

Eur Heart J Case Rep 2020 Jun 27;4(3):1-5. Epub 2020 Apr 27.

Department of Cardiovascular Surgery, University Heart and Vascular Center Hamburg, Martinistraße 52, D-20246 Hamburg, Germany.

Background: Due to ongoing left ventricular (LV) remodeling and consecutive geometric displacement of both papillary muscles, end-stage heart failure is frequently associated with relevant functional mitral regurgitation (FMR) Type IIIb. Treatment strategies of FMR and their prognostic impact are still controversial.

Case Summary: We present a case of an 80-year-old patient who suffered from recurrent symptoms of congestive heart failure due to dilated cardiomyopathy and concomitant severe FMR. To specifically address severe tethering of both mitral leaflets heart team decision was to perform minimally invasive mitral valve repair (MVR) including a subannular LV remodeling procedure, instead of an interventional edge-to-edge repair (MitraClip procedure). In addition to mitral valve ring annuloplasty, standardized relocation of both papillary muscles was performed successfully, leading to a complete resolution of mitral leaflet tethering. There were no procedural complications and the patient was discharged with an excellent functional result without residual mitral regurgitation. Furthermore, after 12 and 24 months, he reported an increase of his functional exercise capacity and a remarkable reverse LV remodeling could be demonstrated.

Discussion: Novel subannular repair techniques, especially the relocation of both papillary muscles, specifically address severe leaflet tethering in FMR and have an obvious potential to improve long-term competence of MVR. Therefore, they could be considered as a viable therapeutic option even in elderly patients presenting with end-stage cardiomyopathy and severe leaflet tenting.
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http://dx.doi.org/10.1093/ehjcr/ytaa087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319855PMC
June 2020