Engineered heart muscle allografts for heart repair in primates and humans.

Cardiomyocytes can be implanted to remuscularize the failing heart. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques.

Genetically encoded mechano-sensors with versatile readouts and compact size.

Mechanical forces are critical for virtually all fundamental biological processes, yet quantification of mechanical forces at the molecular scale remains challenging. Here, we present a new strategy using calibrated coiled-coils as genetically encoded, compact, tunable, and modular mechano-sensors to substantially simplify force measurement , via diverse readouts (luminescence, fluorescence and analytical biochemistry) and instrumentation readily available in biology labs. We demonstrate the broad applicability and ease-of-use of these coiled-coil mechano-sensors by measuring forces during cytokinesis (formin Cdc12) and endocytosis (epsin Ent1) in yeast, force distributions in nematode axons (β-spectrin UNC-70), and forces transmitted to the nucleus (mini-nesprin-2G) and within focal adhesions (vinculin) in mammalian cells.

Fast Fission Yeast Genome Editing by CRISPR/Cas9 Using Gap Repair and Fluoride Selection.

We present a protocol to perform CRISPR/Cas9-mediated genome editing in the fission yeast Schizosaccharomyces pombe that does not require cloning and uses the fluoride exporter channel Fex1 as the selection marker. Transformation is typically carried out on the same day of PCR primer arrival and successfully edited strains are selected 5 days after transformation. We expect the adoption of this protocol to further accelerate the throughput of genome editing in S.

Cross-regulations of two connected domains form a mechanical circuit for steady force transmission during clathrin-mediated endocytosis.

Mechanical forces are transmitted from the actin cytoskeleton to the membrane during clathrin-mediated endocytosis (CME) in the fission yeast Schizosaccharomyces pombe. End4p directly transmits force in CME by binding to both the membrane (through the AP180 N-terminal homology [ANTH] domain) and F-actin (through the talin-HIP1/R/Sla2p actin-tethering C-terminal homology [THATCH] domain). We show that 7 pN force is required for stable binding between THATCH and F-actin.

Comparison of Two Generations of Self-Expandable Transcatheter Heart Valves in Nine Surgical Valves: An In Vitro Study.

(1) Background: This study aimed to analyse the hydrodynamic performance of two generations of self-expanding transcatheter heart valves (THV) as a valve-in-valve (ViV) in different surgical aortic valve (SAV) models under standardised conditions. The nitinol-based Evolut R valve is frequently used in ViV procedures. It is unclear whether its successor, the Evolut PRO, is superior in ViV procedures, particularly considering the previously implanted SAV model.

Characteristic calcification behavior of five surgical aortic valve bioprostheses models: An in vitro study.

Background And Aims: The durability of surgical aortic valve bioprostheses (SAV) is limited by the calcification of the leaflets, which results in degeneration. In clinical routine, there seems to be substantial variability in the degeneration of specific SAV models. Our study aims to establish an in vitro calcification model for prosthetic valves, characterizing the calcification behavior of different SAVs.

Impact of Different Valve-in-Valve Positions on Functional Results of the New Generation of Balloon-Expandable Transcatheter Heart Valve.

Objectives:  Very precise positioning of the transcatheter heart valve (THV) inside the degenerated SAV is a crucial factor for valve-in-valve (ViV) procedure to achieve optimal hemodynamic results. Therefore, our study aimed to investigate the impact of implantation depth on functional results after ViV procedures in a standardized in vitro setting.

Methods:  THV (SAPIEN 3 Ultra 23-mm size) and three SAV models (Magna Ease, Trifecta, and Hancock II-all 21-mm size) were tested at different circulatory conditions in five different positions of the THV (2-6 mm) inside the SAV.

Ex vivo evaluation of 3 different right ventricular outflow tract substitutes.

Objectives: The Ross procedure represents an excellent treatment option in younger patients with aortic stenosis but is limited by poor availability of homografts. In this study, we investigated the hydrodynamic performance of 3 different types of right ventricular outflow tract replacement with pericardium or synthetic material.

Methods: Three different types of valved conduits were constructed using pericardium and/or synthetic material (Group PEPE: pericardial cusps and pericardial conduit, Group PEPR: pericardial cusps and Dacron conduit, Group PRPR: expanded polytetrafluoroethylene cusps and Dacron conduit).

Force redistribution in clathrin-mediated endocytosis revealed by coiled-coil force sensors.

Forces are central to countless cellular processes, yet in vivo force measurement at the molecular scale remains difficult if not impossible. During clathrin-mediated endocytosis, forces produced by the actin cytoskeleton are transmitted to the plasma membrane by a multiprotein coat for membrane deformation. However, the magnitudes of these forces remain unknown.

Impact of heart rate, aortic compliance and stroke volume on the aortic regurgitation fraction studied in an ex vivo pig model.

Introduction: Drug therapy to reduce the regurgitation fraction (RF) of high-grade aortic regurgitation (AR) by increasing heart rate (HR) is generally recommended. However, chronic HR reduction in HFREF patients can significantly improve aortic compliance and thereby potentially decrease RF. To clarify these contrasts, we examined the influence of HR, aortic compliance and stroke volume (SV) on RF in an ex vivo porcine model of severe AR.

A Novel Model to Predict 1-Year Mortality in Elective Transfemoral Aortic Valve Replacement: The TAVR-Risk Score.

Objectives: We aimed to develop and validate an effective prediction model for 1-year mortality risk in elective transfemoral transcatheter aortic valve replacement (TAVR), ie, the TAVR-Risk (TARI) model.

Background: TAVR is the primary treatment for patients with symptomatic severe aortic valve stenosis; however, risk assessment tools for longer-term outcomes after TAVR remain scarce.

Methods: This retrospective cohort study used logistic regression to test univariate and multivariate associations.

Impact of high-pressure balloon aortic valvuloplasty on the hydrodynamic result after a transcatheter valve-in-valve procedure.

Objectives: The aim of this study was to investigate the degree of functional improvement of a transcatheter heart valve (THV) for valve-in-valve after bioprosthetic valve fracture (BVF) of three small surgical aortic valve bioprostheses (SAVBP) using high-pressure balloon aortic valvuloplasty (HP-BAV) under standardized ex-vivo-conditions.

Methods: A THV 26 mm (Evolut R) and SAVBP 21 mm (Perimount Magna Ease, Trifecta, and Epic supra [n = 4] were used. Mean pressure gradient (MPG), effective orifice area (EOA), geometric orifice area (GOA), minimal internal diameter (MID), and pinwheeling index (PWI) were analyzed before and after HP-BAV of the SAVBP using a noncompliant balloon.

Functional performance of 8 small surgical aortic valve bioprostheses: an in vitro study.

Objectives: Selection of a surgical aortic valve (SAV) bioprosthesis model for the treatment of aortic valve disease remains controversial. The aim of this study was to characterize the functional performance of 8 SAV models in a standardized in vitro setting.

Methods: The hydrodynamic performance of 8 SAVs with labelled size 21 mm (Avalus™, Hancock® II, Mosaic® Ultra™, Perimount®, Perimount® Magna Ease, Epic™ Supra, Trifecta™ GT; Freestyle®), was investigated in a pulse duplicator.

Ex vivo evaluation of the Ozaki procedure in comparison with the native aortic valve and prosthetic valves.

Objectives: We investigated the hydrodynamic performance and cusp kinematics of the Ozaki neocuspidized aortic valve in comparison with the native aortic and prosthetic valves in an ex vivo study.

Methods: Native aortic valves of swine hearts were replaced by aortic valve substitutes, and their hydrodynamic performance (effective orifice area and mean pressure gradient) was evaluated in a mock circulation under defined conditions. The following aortic valve substitutes were investigated: native aortic valve, Ozaki valve, Perimount Magna Ease, Trifecta and St.

Elucidation of the genetic causes of bicuspid aortic valve disease.

Aims: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect.

Methods And Results: We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29.

Surgical aortic valve replacement in patients aged 50-69 years-insights from the German Aortic Valve Registry (GARY).

Objectives: The aim of this study was to analyse the outcome of patients between 50 and 69 years of age undergoing biological or mechanical aortic valve replacement.

Methods: Data were collected from the German Aortic Valve Registry. Data were analysed regarding baseline characteristics and outcome parameters such as 5-year survival, stroke and reintervention.

The figure-of-8 aortic valve suturing technique optimizes the effective orifice area of a small aortic annulus-an ex vivo study.

Objectives: Surgical aortic valve replacement (SAVR) in small annuli carries an elevated risk for the patient-prosthesis mismatch. In this study, we systematically investigated the influence of different implantation techniques including annular enlargement (AE) on the functional result after SAVR in small annuli using a standardized ex vivo model.

Methods: SAVR using the PERIMOUNT Magna Ease® (PME) 21 mm was performed in small porcine aortic roots using 4 implantation techniques: non-everting pledgeted (NE) suture, single interrupted (SI) suture, continuous suture (CS), figure-of-8 (F8) suture, as well as the PME 23 mm after AE using the Nunez method and the NE suture technique (PME23 AE).

Impact of different valve-in-valve positions on the hydrodynamic performance of the newest-generation self-expanding transcatheter heart valve.

Objectives: Transcatheter aortic valve-in-valve (ViV) procedures are increasingly performed for the treatment of degenerated surgical aortic valves with a high risk for a redo operation. For an optimal functional result, precise positioning of the transcatheter heart valve (THV) inside the SHV is crucial. The aim of this study was to systematically investigate the impact of implantation depth on the functional result after a ViV procedure in a standardized in vitro setting.

State-of-the-art: Insights from the Ross Registry.

The treatment of aortic valve disease in young patients is still a major clinical challenge, as the pre-eminent emphasis is on durability and long-term outcomes beyond 10 to 15 years, sometimes >20 to 30 years. The Ross procedure uses the autologous pulmonary valve as an aortic valve substitute and aims to improve valve durability while avoiding anticoagulation and therefore achieve a sustained long-term result with regard to survival, valve functionality, and quality of life. However, this procedure is technically demanding and only performed at a low frequency.

Chalcone-Supported Cardiac Mesoderm Induction in Human Pluripotent Stem Cells for Heart Muscle Engineering.

Human pluripotent stem cells (hPSCs) hold great promise for applications in cell therapy and drug screening in the cardiovascular field. Bone morphogenetic protein 4 (BMP4) is key for early cardiac mesoderm induction in hPSC and subsequent cardiomyocyte derivation. Small-molecular BMP4 mimetics may help to standardize cardiomyocyte derivation from hPSCs.

An ex vivo evaluation of two different suture techniques for the Ozaki aortic neocuspidization procedure.

Objectives: We investigated the Ozaki procedure using a single interrupted suture technique (SST) and compared this with the standard continuous suture technique (CST) with regard to hydrodynamic valve performance. In addition, both techniques were compared with the native aortic valve (NAV).

Methods: Effective orifice area, mean pressure gradient and leakage volume were evaluated in the NAV as well as after an Ozaki procedure using SST or CST in fresh swine aortic roots using a mock circulation loop.

Five-year outcome in 18 010 patients from the German Aortic Valve Registry.

Objectives: To determine the 5-year outcome in patients treated by isolated transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (sAVR)-a prospective observational cohort study.

Methods: A total of 18 010 patients were included (n = 8942 TAVI and n = 9068 sAVR) in the German Aortic Valve Registry (GARY) who were treated in 2011 and 2012 at 92 sites in central Germany. Eligible patients with TAVI and sAVR were matched using propensity scores in a nearest-neighbour approach.

Long-Term Outcomes of Patients Undergoing the Ross Procedure.

Background: Treatment of aortic-valve disease in young patients still poses challenges. The Ross procedure offers several potential advantages that may translate to improved long-term outcomes.

Objectives: This study reports long-term outcomes after the Ross procedure.