[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.
[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).
[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. · 29.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This analysis from the German Mitral Valve Registry investigates the impact of the learning curve with the MitraClip(®) technique on procedural success and complications.
Clinical research in cardiology : official journal of the German Cardiac Society. 06/2014;
[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; · 2.02 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; · 3.67 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; · 3.17 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.
Journal of Interventional Cardiology 01/2014; · 1.50 Impact Factor
[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; · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.
The Journal of clinical investigation 07/2013; · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: So far, the role of mutations in the δ-sarcogylcan (Sgcd) gene in causing autosomal dominant dilated cardiomyopathy (DCM) remains inconclusive. A p.S151A missense mutation in exon 6 of the Sgcd gene was reported to cause severe isolated autosomal dominant DCM without affecting skeletal muscle. This is controversial to our previous findings in a large consanguineous family where this p.S151A mutation showed no relevance for cardiac disease. In this study, the potential of the p.S151A mutation to cause DCM was investigated by using two different approaches: (1) engineering and characterization of heterozygous knock-in (S151A-) mice carrying the p.S151A mutation and (2) evaluation of the potential of adeno-associated virus (AAV) 9-based cardiac-specific transfer of p.S151A-mutated Sgcd cDNA to rescue the cardiac phenotype in Sgcd-deficient (Sgcd-null) mice as it has been demonstrated for intact, wild-type Sgcd cDNA. Heterozygous S151A knock-in mice developed a rather mild phenotype of cardiomyopathy. Increased heart to body weight suggests cardiac enlargement in 1-year-old S151A knock-in mice. However, at this age cardiac function, assessed by echocardiography, is maintained and histopathology completely absent. Myocardial expression of p.S151A cDNA, similar to intact Sgcd cDNA, restores cardiac function, although not being able to prevent myocardial histopathology in Sgcd-null mice completely. Our results suggest that the p.S151A mutation causes a mild, subclinical phenotype of cardiomyopathy, which is prone to be overseen in patients carrying such sequence variants. Furthermore, this study shows the suitability of an AAV-mediated cardiac gene transfer approach to analyze whether a sequence variant is a disease-causing mutation.European Journal of Human Genetics advance online publication, 22 May 2013; doi:10.1038/ejhg.2013.97.
European journal of human genetics: EJHG 05/2013; · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims: The influence of age on baseline demographics and outcomes of patients selected for MitraClip® has not been previously investigated. Methods and results: Baseline demographics and acute outcomes in 1,064 patients from the German TRAMI registry were stratified by age (525 patients ≥76 years and 539 patients <76 years). In elderly patients, logistic EuroSCORE was higher (25[15-40]% vs. 18[10-31]%, p<0.0001) and the proportion of women was greater (47.2% vs. 29.3%, p<0.0001). Elderly patients were more likely to have preserved left ventricular ejection fraction >50% (40.1% vs. 21.8%, p<0.0001) and degenerative mitral regurgitation (DMR, 35.3% vs. 25.6%, p<0.01). Age was the most frequent reason for non-surgical treatment in the elderly (69.4% vs. 36.1%, p<0.0001). The intrahospital MACCE (death, myocardial infarction, stroke) was low in both groups (3.5% vs. 3.4%, p=0.93) and the proportion of non-severe mitral regurgitation at discharge was similar (95.8% vs. 96.4%, p=0.73). A logistic regression model did not reveal any significant impact of age on acute efficacy and safety of MitraClip therapy. In both groups, the majority of patients were discharged home (81.8% vs. 86.2%, p=0.06). Conclusion: Elderly and younger patients have similar benefits from MitraClip therapy. Age was the most frequent cause for denying surgery in elderly patients.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 04/2013; · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIMS: The aim of the present study was to investigate 1 year clinical and functional efficacy of percutaneous mitral valve (MV) repair using MitraClip™ in high-risk surgical patients with symptomatic severe MV regurgitation (MR) and reduced LVEF. METHODS AND RESULTS: Between September 2009 and November 2011, 59 patients with reduced EF and severe MR received endovascular MV repair using MitraClip™. Patients were characterized after 1 and 12 months using echocardiography, 6 min walk test distance, and cardiac biomarkers. The predicted 30-day surgical perioperative mortality rate was 11.4 ±2.2% using the Society of Thoracic Surgeons' score. Complete 1-year clinical follow-up was achieved in 70% of the patients (n = 41; EF 33 ±3%). Percutaneous MV repair resulted in significantly reduced MR and improved NYHA functional class, translating into significantly increased 6 min walk test distance, while high-sensitive troponin T (P < 0.05) and NT-proBNP (non-significant) were reduced. Echocardiography revealed structural reverse remodelling with significantly reduced left atrial volume and LV end-systolic diameter, as well as significantly increased LVEF. These results were consistent in a subgroup of patients with severely reduced LVEF (EF 23 ±2%; n = 25). Thirty-day mortality was 2.9%. CONCLUSION: Percutaneous MV repair using MitraClip™ is a safe technique in high-risk surgical patients, causing significant 1 year reduction of MR which results in structural cardiac reverse remodelling and an increased LVEF. The present data encourage percutaneous MV repair in heart failure patients.
European Journal of Heart Failure 03/2013; · 5.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Percutaneous edge-to-edge mitral valve repair using the MitraClip device has evolved as a new tool for the treatment of severe mitral valve regurgitation. This technique has been evaluated in both surgical low- and high-risk patients. The aim of this study was to assess the feasibility and efficacy of MitraClip implantation in critically ill, unstable patients with severe mitral regurgitation who would persistently need inotropes or who could not be weaned from a ventilator. Six patients with the above-mentioned criteria were identified among the 87 patients that were treated with MitraClip implantation between October 2009 and January 2012 at our institution. All patients were considered as surgical high-risk patients with a Society of Thoracic Surgeons (STS) score between 8.0% and 56.9%. In all patients, MitraClip implantation was successfully achieved without relevant complications. More importantly, all patients showed rapid clinical improvement within a few days, allowing discontinuation of inotropes and/or weaning from a respirator and finally a transfer to a regular ward or discharge home. These data emphasize the safety profile of the MitraClip system in multimorbid, high-risk patients. In addition, it demonstrates the applicability of this treatment in unstable and critically ill conditions as a tool for acute stabilization.
The Journal of invasive cardiology 02/2013; 25(2):69-72. · 1.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aortic valve stenosis is the most prevalent, clinically significant valvular disorder in adult patients. Surgical valve replacement is the standard therapy for patients with symptomatic and severe aortic stenosis; however, many patients are suboptimal candidates for surgery due to age and co-morbidities. The development of transcatheter aortic valve implantation (TAVI) has broadened the therapeutic options, especially in high-risk patients. The first randomized study comparing surgical valve replacement with TAVI in operable high-risk patients show similar mortality and reduction in symptoms after a 2-year follow-up. These data support the use of this technique in high-risk patients with severe aortic stenosis.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Transcatheter aortic valve-in-valve (VIV) implantation is an emerging therapeutic alternative for patients with failed surgical bioprosthesis and may obviate the need for reoperation. We evaluated the clinical results of this technique using a large, worldwide registry. METHODS AND RESULTS: The Global Valve-in-Valve Registry included 202 patients with degenerated bioprosthetic valves (age 77.7 ± 10.4 years; 52.5% men) from 38 cardiac centers. Bioprosthesis mode of failure was stenosis (n=85, 42%), regurgitation (n=68, 34%) or combined stenosis and regurgitation (n=49, 24%). Implanted devices included CoreValve (n=124) and Edwards SAPIEN (n=78). Procedural success was achieved in 93.1% of cases. Adverse procedural outcomes included initial device malposition in 15.3% of cases and ostial coronary obstruction in 3.5%. Post-procedure, valve maximum / mean gradients were 28.4 ± 14.1 mmHg / 15.9 ± 8.6 mmHg and 95% of patients had ≤ +1 degree of aortic regurgitation. At 30 days' follow-up, all-cause mortality was 8.4% and 83.7% of patients were at New York Heart Association functional class I/II. One-year follow-up was obtained in 87 patients, with 85.8% survival of treated patients. CONCLUSIONS: The VIV procedure is clinically effective in the vast majority of patients with degenerated stenotic or regurgitant bioprosthetic valves. Safety and efficacy concerns include device malposition, ostial coronary obstruction, and high gradients after the procedure.