[Show abstract][Hide abstract] ABSTRACT: The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
[Show abstract][Hide abstract] ABSTRACT: To investigate if the extent of aortic valve calcification is associated with postprocedural prosthesis eccentricity and paravalvular regurgitation (PAR) in patients undergoing transcatheter aortic valve implantation (TAVI).
Cardiac computed tomography angiography (CCTA) was performed before and 3 months after TAVI in 46 patients who received the self-expanding CoreValve and in 22 patients who underwent balloon-expandable Edwards Sapien XT implantation. Aortic annulus calcification was measured with CCTA prior to TAVI and prosthesis eccentricity was assessed with post-TAVI CCTA. Standard echocardiography was also performed in all patients at 3-month follow-up exam.
Annulus eccentricity was reduced during TAVI using both implantation systems (from 0.23 ± 0.06 to 0.18 ± 0.07 using CoreValve and from 0.20 ± 0.07 to 0.05 ± 0.03 using Edwards Sapien XT; P<.001 for both). With Edwards Sapien XT, eccentricity reduction at the level of the aortic annulus was significantly higher compared with CoreValve (P<.001). Annulus eccentricity after CoreValve use was significantly related to absolute valve calcification and to valve calcification indexed to body surface area (BSA) (r = 0.48 and 0.50, respectively; P<.001 for both). Furthermore, a significant association was observed between aortic valve calcification and PAR (P<.01 by ANOVA) in patients who received CoreValve. Using ROC analysis, a cut-off value over 913 mm² aortic valve calcification predicted the occurrence of moderate or severe PAR with a sensitivity of 92% and a specificity of 63% (area under the curve = 0.75). Furthermore, multivariable analysis showed that aortic valve calcification was a robust predictor of postprocedural eccentricity and PAR, independent of the aortic annulus size and native valve eccentricity and of CoreValve prosthesis size (adjusted r = 0.46 and 0.50, respectively; P<.01 for both). Such associations were not present with the Edwards Sapien XT system.
The extent of native aortic annulus calcification is predictive for postprocedural prosthesis eccentricity and PAR, which is an important marker for long-term mortality in patients undergoing TAVI. This observation applies for the CoreValve, but not for the Edwards Sapien XT valve.
The Journal of invasive cardiology 03/2015; 27(3):172-80. · 0.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Consistent protocols for the assessment of diastolic and systolic cardiac function to assure the comparability of existing data on preclinical models are missing. Calcineurin transgene (CN) mice are a preclinical model for hypertrophic and failing hearts. We aimed at evaluating left and right ventricular structural and functional remodeling in CN hearts with an optimized phenotyping protocol. We developed a protocol using techniques and indices comparable to those from human diagnostics for comprehensive in vivo cardiac screening using high-frequency echocardiography, Doppler, electrocardiography and cardiac magnetic resonance (CMR) techniques. We measured left and right ventricular dimensions and function, pulmonary and mitral flow pattern and the hearts electrophysiology non-invasively in <1 h per mouse. We found severe biventricular dilation and a drastic decline in performance in accordance with a condition of heart failure (HF), diastolic dysfunction and defects in electrical conduction in 8-week-old calcineurin transgenic mice. Echocardiography of the left ventricle was performed with and without anesthesia. In all cases absolute values on echocardiography compared with CMR were smaller for LV dimension and wall thickness, resulting in higher fractional shorting and ejection fraction. The study protocol described here opens opportunities to assess the added value of combined echocardiography, Doppler, CMR and ECG recording techniques for the diagnosis of biventricular cardiac pathologies i.e. of HF and to study symptom occurrence and disease progression non-invasively in high-throughput. Phenotyping CN hearts revealed new symptom occurrence and allowed insights into the diverse phenotype of hypertrophic failing hearts.
The international journal of cardiovascular imaging 01/2015; 31(4). DOI:10.1007/s10554-015-0596-z · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.
PLoS ONE 12/2014; 9(12):e114918. DOI:10.1371/journal.pone.0114918 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The transcription factor Zscan10 had been attributed a role as a pluripotency factor in embryonic stem cells based on its interaction with Oct4 and Sox2 in in vitro assays. Here we suggest a potential role of Zscan10 in controlling progenitor cell populations in vivo. Mice homozygous for a Zscan10 mutation exhibit reduced weight, mild hypoplasia in the spleen, heart and long bones and phenocopy an eye malformation previously described for Sox2 hypomorphs. Phenotypic abnormalities are supported by the nature of Zscan10 expression in midgestation embryos and adults suggesting a role for Zscan10 in either maintaining progenitor cell subpopulation or impacting on fate choice decisions thereof.
PLoS ONE 08/2014; 9(8). DOI:10.1371/journal.pone.0104568 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inducible gene targeting in mice using the Cre/LoxP system has become a valuable tool to analyze the roles of specific genes in the adult heart. However, the commonly used Myh6-MerCreMer system requires time-consuming breeding schedules and is potentially associated with cardiac side effects, which may result in transient cardiac dysfunction. The aim of our study was to establish a rapid and simple system for cardiac gene inactivation in conditional knockout mice by gene transfer of a Cre recombinase gene using adeno-associated viral vectors of serotype 9 (AAV9).
Cardiovascular Research 07/2014; 104(1). DOI:10.1093/cvr/cvu174 · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed.
JAMA The Journal of the American Medical Association 07/2014; 312(2):162-70. DOI:10.1001/jama.2014.7246 · 30.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims
This analysis from the German Mitral Valve Registry investigates the impact of the learning curve with the MitraClip® technique on procedural success and complications.
Methods and results
Consecutive patients treated since 2009 in centers that performed more than 50 transcatheter mitral repairs were included. Results of the first half of the patients were compared to those of the second. Altogether 496 patients from 10 centers were included. Patients treated later had less common severe heart failure symptoms (patients with NYHA IV: 22.1 vs. 14.5 %, p
Clinical Research in Cardiology 06/2014; 103(11). DOI:10.1007/s00392-014-0734-y · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mice with genetic alterations are used in heart research as model systems of human diseases. In the last decade there was a marked increase in the recognition of genetic diversity within inbred mouse strains. Increasing numbers of inbred mouse strains and substrains and analytical variation of cardiac phenotyping methods require reproducible, high-throughput methods to standardize murine cardiovascular physiology. We describe methods for non-invasive, reliable, easy and fast to perform echocardiography and electrocardiography on awake mice. This method can be used for primary screening of the murine cardiovascular system in large-scale analysis. We provide insights into the physiological divergence of C57BL/6N, C57BL/6J, C3HeB/FeJ and 129P2/OlaHsd mouse hearts and define the expected normal values. Our report highlights that compared to the other three strains tested C57BL/6N hearts reveal features of heart failure such as hypertrophy and reduced contractile function. We found several features of the mouse ECG to be under genetic control and obtained several strain-specific differences in cardiac structure and function.
Journal of Comparative Physiology B 05/2014; 184(6). DOI:10.1007/s00360-014-0830-3 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We intended to show feasibility of sheathless transfemoral aortic valve implantation in patients with small access vessel diameters.
Transcatheter aortic valve implantation (TAVI) has emerged as a valid treatment option in patients with aortic valve stenosis who are poor candidates for surgical aortic valve replacement. Few patients, who cannot undergo transfemoral or transsubclavian aortic valve implantation due to small access vessel diameters, are not suitable for transapical or direct aortic valve implantation, either.
In more than 700 transcatheter aortic valve implantations since 2008 we identified 17 patients who had to be excluded from transfemoral valve implantation due to vessel diameters <6 mm and who were no candidates for transapical or direct aortic implantation. We performed CoreValve™ implantations in these patients without the required 18F sheath to cross the vessels despite their small size (4.6-5.9 mm).
Sixteen sheathless implantations were successful. In all 17 patients, bleeding during the procedure due to the smaller delivery catheter was minimal. Sixteen patients had a successful access site closure at the end of the procedure.
Sheathless implantation of a self-expanding aortic valve can be safely considered in selected patients with access vessel diameters below 6 mm, if transapical or direct aortic implantation is not suitable.
Clinical Research in Cardiology 04/2014; 103(10). DOI:10.1007/s00392-014-0713-3 · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims: We assessed feasibility, efficacy and safety of a suture-mediated closure device, Perclose Proglide® (Abbott Vascular Devices, Santa Clara, CA, USA), for closure of the femoral vein access after percutaneous MitraClip® (Abbott Vascular Devices) implantation. Methods and results: Venous access of 80 consecutive patients undergoing percutaneous mitral valve repair using the MitraClip device was managed either by manual compression, "figure eight" suture and compression bandage for 12 hours, or by applying the Proglide device for haemostasis after the procedure (40 patients each group). Patients with Proglide closure showed complete immediate haemostasis in 92.5% (37/40) and were immobilised with a compression bandage for only four hours. In the Proglide group, one arteriovenous fistula was observed and had to be treated by vascular surgery. The overall duration of stay on an intensive care unit was significantly reduced in the Proglide group (59.4±48.9 hours vs. 84.6±59.5 hours, p<0.005). Conclusions: Using a suture-mediated closure device for the femoral vein after percutaneous MitraClip implantation is feasible and safe. This allows earlier patient mobilisation and may reduce post-interventional duration of stay on an intensive care unit.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 04/2014; 10(11). DOI:10.4244/EIJV10I11A231 · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transcatheter aortic valve implantation has become an established treatment for severe aortic stenosis in patients with high surgical risk. Due to its specific design, the self-expanding 31 mm CoreValve prosthesis can be technically challenging. This is especially true for patients with large annuli above 27.5 mm for which the CoreValve 31 mm device is the only option.
To evaluate procedural results and short-term outcome with the 31 mm CoreValve device in patients with large annuli.
We retrospectively analyzed 54 patients in whom we implanted a 31 mm self-expanding CoreValve bioprosthesis and compared them to 50 consecutive patients implanted with the smaller 29 mm device within the same period of time.
Patients with the 31 mm prosthesis had significantly higher rates of postinterventional pacemaker implantations (35% vs. 20%; P = 0.036) despite similar implantation depths (6.5 ± 4 vs. 7.5 ± 4; P = 0.34). However, the number of deep implantations (>8 mm) was significantly higher (P = 0.045). No significant difference could be observed with respect to cases with ≥Grade 2 postinterventional aortic regurgitation (8% vs. 12.9%; P = 0.5294). Major vascular complications (4% vs. 3.7%; P = ns), 30-day mortality (8% vs. 7.7%; P = ns), and major stroke (3.8% vs. 2%; P = ns) were not different between the 2 groups.
Despite the technical challenges, procedural results with the 31 mm self-expanding CoreValve prosthesis in large anatomies were similar to those with the smaller sized 29 mm version of the device. However, postinterventional pacemaker rates were significantly higher in the 31 mm cohort despite comparable implantation depths, which might be the result of the specific design of the device.
[Show abstract][Hide abstract] ABSTRACT: Elevated concentrations of troponin T have prognostic impact in patients with various cardiovascular diseases including those with severe aortic stenosis. Transcatheter aortic valve implantation (TAVI) has improved prognosis for patients without a surgical option. Whether this affects the prognostic value of preinterventional troponin T remains unclear.
We therefore conducted a prospective study in 198 consecutive patients with subsequent, successful transfemoral TAVI and analyzed cardiac troponin T (cTnT) levels with a new generation, high-sensitive troponin T assay before and after TAVI, as well as their prognostic value after 12 months.
Patients with severe aortic stenosis (AS) showed significant elevation of preinterventional cTnT levels. Postinterventional cTnT levels significantly rose further about sevenfold after transfemoral TAVI and peaked at day three until they steadily declined thereafter. Baseline renal function (P = 0.011), the duration of intraprocedural rapid pacing (P = 0.0012), and baseline cTnT (P = 0.0001) values predicted the magnitude of postinterventional cTnT elevations. Interestingly, Kaplan-Meier curve analysis revealed, that although cTnT levels were not predictive for short-term mortality, preinterventional as well as postinterventional peak cTnT showed prognostic value for 1-year mortality, regardless of successful TAVI.
Pre- and postinterventional hscTnT levels signal adverse 1-year mortality in patients with severe AS independent of successful aortic valve replacement.
Clinical Research in Cardiology 10/2013; 103(1). DOI:10.1007/s00392-013-0624-8 · 4.56 Impact Factor