12‐Month outcomes of transcatheter tricuspid valve repair with the PASCAL system for severe tricuspid regurgitation

2021

Objectives We investigated the durability of tricuspid regurgitation (TR) reduction and the clinical outcomes through 12 months after transcatheter tricuspid valve repair (TTVr) with the PASCAL Transcatheter Valve Repair System. Background TTVr has rapidly developed and demonstrated favorable acute outcomes, but longer follow-up data are needed. Methods Overall, 30 patients (age 77 ± 6 years; 57% female) received PASCAL implantation from September 2017 to May 2019 and completed a clinical follow-up at 12 months. Results The TR etiology was functional in 25 patients (83%), degenerative in three (10%), and mixed in two (7%). All patients had TR severe or greater (massive or torrential in 80%)…

Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

2020

Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we perfor…

SLC20A1 Is Involved in Urinary Tract and Urorectal Development

2020

Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exs…

Impact of Proportionality of Secondary Mitral Regurgitation on Outcome After Transcatheter Mitral Valve Repair

2020

The purpose of this paper was to evaluate the impact of proportionality of secondary mitral regurgitation (SMR) in a large real-world registry of transcatheter edge-to-edge mitral valve repair (TMVr) BACKGROUND: Differences in the outcomes of recent randomized trials of TMVr for SMR may be explained by the proportionality of SMR severity to left ventricular (LV) volume.The ratio of pre-procedural effective regurgitant orifice area (EROA) to LV end-diastolic volume (LVEDV) was retrospectively assessed in patients undergoing TMVr for severe SMR between 2008 and 2019 from the EuroSMR registry. A recently proposed SMR proportionality scheme was adapted to stratify patients according to EROA/LVE…

Incidence, determinants and prognostic relevance of dyspnea at admission in patients with Takotsubo syndrome: results from the international multicen…

2020

AbstractClinical presentation of Takotsubo syndrome (TTS) may range from acute chest pain to dyspnea: the prognostic role of clinical onset is still controversial. Aim of this study was therefore to investigate the prognostic relevance of dyspnea at presentation in patients with TTS. We analyzed 1,071 TTS patients (median age 72 years, 90% female) enrolled in the international multicenter GEIST registry. Patients were divided according to the presence or absence of dyspnea at hospital admission, as clinically assessed by the accepting physician. The primary endpoint was occurrence of in-hospital complications defined as a composite of pulmonary edema, cardiogenic shock and death. Overall, 3…

Mutation ofPOC1Bin a Severe Syndromic Retinal Ciliopathy

2014

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next-generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in …

Organization of intensive cardiac care units in Europe: Results of a multinational survey

2020

Background: The present survey aims to describe the intensive cardiac care unit organization and admission policies in Europe. Methods: A total of 228 hospitals (61% academic) from 27 countries participated in this survey. In addition to the organizational aspects of the intensive cardiac care units, including classification of the intensive cardiac care unit levels, data on the admission diagnoses were gathered from consecutive patients who were admitted during a two-day period. Admission policies were evaluated by comparing illness severity with the intensive cardiac care unit level. Gross national income was used to differentiate high-income countries (n=13) from middle-income countries…

Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer

2019

Background The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Methods A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the …

Impact of Right Ventricular Dysfunction on Outcomes After Transcatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation

2021

OBJECTIVES This study sought to assess the impact of right ventricular dysfunction (RVD) as defined by impaired right ventricular-to-pulmonary artery (RV-PA) coupling, on survival after edge-to-edge transcatheter mitral valve repair (TMVR) for severe secondary mitral regurgitation (SMR). BACKGROUND Conflicting data exist regarding the benefit of TMVR in severe SMR. A possible explanation could be differences in RVD. METHODS Using data from the EuroSMR (European Registry on Outcomes in Secondary Mitral Regurgitation) registry, this study compared the characteristics and outcomes of SMR patients undergoing TMVR, according to their RV-PA coupling, assessed by tricuspid annular plane systolic e…

Sex-Related Clinical Characteristics and Outcomes of Patients Undergoing Transcatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation.

2021

OBJECTIVES The authors sought to assess sex-based differences in characteristics and outcomes of patients undergoing transcatheter edge-to-edge mitral valve repair (TMVR) for secondary mitral regurgitation (SMR). BACKGROUND Subgroup analysis from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart��Failure Patients with Functional Mitral Regurgitation) trial indicated potential sex-related differences in outcomes after TMVR. The impact of sex on results after TMVR in a real-world setting is unknown. METHODS The authors assessed clinical outcomes and echocardiographic parameters in women and men undergoing TMVR for SMR between 2008 and 2018 who were …

Gender differences in takotsubo syndrome

2022

Background: Male sex in takotsubo syndrome (TTS) has a low incidence and it is still not well characterized. Objectives: The aim of the present study is to describe TTS sex differences. Methods: TTS patients enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry were analyzed. Comparisons between sexes were performed within the overall cohort and using an adjusted analysis with 1:1 propensity score matching for age, comorbidities, and kind of trigger. Results: In total, 286 (11%) of 2,492 TTS patients were men. Male patients were younger (age 69 ± 13 years vs 71 ± 11 years; P = 0.005), with higher prevalence of comorbid conditions (diabetes mellitus 25% …

Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women

2013

<b><i>Objective:</i></b> The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution. <b><i>Method:</i></b> We genotyped and measured the serum leptin levels of the NP-Y rs16147 polymorphism in 1,097 Caucasian subjects in the context of a pop…

Right ventricular strain assessment by cardiovascular magnetic resonance myocardial feature tracking allows optimized risk stratification in Takotsub…

2018

Background A substantial number of patients with Takotsubo syndrome (TTS) exhibit right ventricular (RV) dysfunction which has been associated with adverse outcome. The aim of this study was to assess the clinical and prognostic value of RV myocardial strain in TTS using cardiovascular magnetic resonance myocardial feature tracking (CMR-FT). Methods CMR-FT was performed in a core laboratory to determine RV longitudinal strain in 134 TTS patients undergoing CMR in median 2 days after admission to 2 experienced centers. For comparison, RV involvement was evaluated by sole visual assessment concerning RV contraction abnormalities. Both approaches were analyzed regarding their long-term prognos…

Incidence and Clinical Impact of Recurrent Takotsubo Syndrome: Results From the GEIST Registry

2019

Background Current literature only reports variable information from single‐center studies on the recurrence rate, the complications, and the outcome of patients with Takotsubo syndrome ( TTS) experiencing recurrent TTS . Therefore, a detailed description of clinical characteristics, predictors, and the prognostic impact of patients with TTS and recurrences in a multicenter registry is needed. Methods and Results We analyzed 749 patients with TTS from 9 European centers being part of the international, multicenter GEIST (German Italian Stress Cardiomyopathy) Registry. Patients were divided into the recurrence group and the nonrecurrence group. The recurrence rate at a median follow‐up of 8…

Cardiopulmonary Hemodynamic Profile Predicts Mortality After Transcatheter Tricuspid Valve Repair in Chronic Heart Failure.

2020

This study was designed to assess hemodynamic changes in response to transcatheter tricuspid valve edge-to-edge repair (TTVR) and to identify hemodynamic predictors associated with mortality.Severe tricuspid regurgitation (TR) is associated with high mortality. TTVR effectively alleviates heart failure symptoms, but comprehensive hemodynamic characterization of patients undergoing TTVR is currently lacking.This international, multicenter study included 236 patients undergoing TTVR. Data from clinical assessment, echocardiography, intraprocedural right heart catheterization, and noninvasive cardiac output measurement were analyzed. Hemodynamic predictors for mortality were identified using l…

Correction: The genomic and clinical landscape of fetal akinesia

2020

Abstract An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prevalence, management, and outcome of adverse rhythm disorders in takotsubo syndrome: insights from the international multicenter GEIST registry

2019

One important complication related to takotsubo syndrome (TTS) is adverse rhythm disorders. Our study was conducted to determine the incidence and management of adverse rhythm disorders in TTS and its long-term prognostic impact. We analyzed 906 TTS patients from 9 European centers. Patients were divided into the adverse rhythm disorders group (encompassing ventricular tachycardia, ventricular fibrillation, torsade de pointes, and asystole or complete atrioventricular block) and non-adverse rhythm disorders group. In our study cohort, we identified 67 (7.4%) patients with presence of adverse rhythm disorders. TTS patients were followed up over a period of 2.8 years. In the adverse rhythm di…

Compassionate Use of the PASCAL Transcatheter Valve Repair System for Severe Tricuspid Regurgitation

2019

Abstract Objectives The purpose of this observational first-in-human experience was to investigate the feasibility and safety of the PASCAL transcatheter valve repair system and its impact on short-term clinical outcomes in patients with severe tricuspid regurgitation (TR). Background Transcatheter repair of severe TR is a promising treatment option for patients at prohibitive surgical risk. Large leaflet coaptation gaps and tethering represent common features that challenge the application of transcatheter repair techniques. Methods Twenty-eight patients with severe TR were treated with the PASCAL system in a compassionate use experience at 6 sites. All patients had heart failure due to se…

PEX6 is Expressed in Photoreceptor Cilia and Mutated in Deafblindness with Enamel Dysplasia and Microcephaly

2015

Deafblindness is part of several genetic disorders. We investigated a consanguineous Egyptian family with two siblings affected by congenital hearing loss and retinal degeneration, initially diagnosed as Usher syndrome type 1. At teenage, severe enamel dysplasia, developmental delay, and microcephaly became apparent. Genome-wide homozygosity mapping and whole-exome sequencing detected a homozygous missense mutation, c.1238G>T (p.Gly413Val), affecting a highly conserved residue of peroxisomal biogenesis factor 6, PEX6. Biochemical profiling of the siblings revealed abnormal and borderline plasma phytanic acid concentration, and cerebral imaging revealed white matter disease in both. We show …

Prognostic Value of Microvascular Obstruction and Infarct Size, as Measured by CMR in STEMI Patients

2014

The aim of this study was to evaluate the value of microvascular obstruction (MO) and infarct size as a percentage of left ventricular mass (15%LV), as measured by contrast-enhanced cardiac magnetic resonance, in predicting major cardiovascular adverse events (MACE) at 2 years in patients with ST-segment elevation myocardial infarction reperfused by primary percutaneous coronary intervention. Individual data from 1,025 patients were entered into the pooled analysis. MO was associated with the occurrence of MACE, defined as a composite of cardiac death, congestive heart failure, and myocardial re-infarction (adjusted hazard ratio: 3.74; 95% confidence interval: 2.21 to 6.34). IS% LV >= 25% w…

TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

2015

Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse p…

The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser sti…

2010

Background: Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase ( COMT) have been suggested to affect clinical and experimental pain-related phenotypes including regional μ-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography). The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been…

Prevalence and Prognostic Impact of Diabetes in Takotsubo Syndrome: Insights From the International, Multicenter GEIST Registry

2017

OBJECTIVE In view of low prevalence rates, diabetes is discussed as a protective factor for the occurrence of Takotsubo syndrome (TTS). Furthermore, it was associated with improved outcome in a small single-center analysis. Therefore, this study assessed the prevalence and prognostic relevance of concomitant diabetes in TTS. RESEARCH DESIGN AND METHODS A total of 826 patients with TTS were enrolled in an international, multicenter, registry-based study (eight centers in Italy and Germany). All-cause mortality was compared between patients with diabetes and patients without diabetes, and the independent predictive value of diabetes was evaluated in multivariate regression analysis. RESULTS …

S3-Leitlinie „Einsatz der intraaortalen Ballongegenpulsation in der Herzchirurgie“

2015

Although intra-aortic balloon pumping (IABP) is the most frequently used mechanical cardiac assist device in cardiothoracic surgery, there are only guidelines for substantive sections of aortic counterpulsation including prophylactic and postoperative use. In contrast, evidence-based recommendations are still lacking concerning intraoperative use, management, contraindication and other relevant issues. According to international surveys, important aspects of IABP usage show a wide variation in clinical practice. The results of a national questionnaire performed before initiation of this guideline confirmed these findings and demonstrated a clear need for the development of a consensus-based…

Incidence and Clinical Impact of Right Ventricular Involvement (Biventricular Ballooning) in Takotsubo Syndrome

2021

Background The short- and long-term prognosis of Takotsubo syndrome (TTS) presenting with right ventricular (RV) involvement remains poorly understood. Research Question What is the incidence and clinical outcome of RV involvement in TTS? Study Design and Methods This study analyzed 839 consecutive patients with TTS (758 female subjects and 81 male subjects) in a multicenter registry. RV involvement was defined as wall motion abnormality of the RV free wall, with or without apical involvement. The median long-term follow-up was 2.1 years (interquartile range, 0.3-4.5 years). The primary outcome was in-hospital and out-of-hospital all-cause mortality. The secondary end point was a composite …

Lack of association of a functional catechol-O-methyltransferase gene polymorphism with risk of tobacco smoking: results from a multicenter case-cont…

2013

Background The catechol-O-methyltransferase (COMT) modulates dopaminergic neurotransmission in the prefrontal cortex as well as in the mesolimbic reward system. Since the reward system mediates addictive behavior, the COMT gene is a strong candidate gene regarding the pathophysiology of tobacco dependence and smoking behavior. Because of rather conflicting results in previous studies, the purpose of the present study was to test for association between a functional genetic variant in the COMT gene (single nucleotide polymorphism [SNP] rs4680) and tobacco smoking behavior. Methods In a population-based case-control multicenter study designed for tobacco addiction research, a total of 551 cur…

Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large…

2016

PLoS one 11(4), e0152984 (2016). doi:10.1371/journal.pone.0152984

Author response: TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

2015

The genomic and clinical landscape of fetal akinesia

2020

International audience; Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood.Methods: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA).Results: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1…

Impact of Residual Mitral Regurgitation on Survival After Transcatheter Edge-to-Edge Repair for Secondary Mitral Regurgitation.

2021

OBJECTIVES The aim of this study was to assess the impact of residual mitral regurgitation (resMR) on mortality with respect to left ventricular dilatation (LV-Dil) or right ventricular dysfunction (RV-Dys) in patients with secondary mitral regurgitation (SMR) who underwent mitral valve transcatheter edge-to-edge repair (TEER). BACKGROUND The presence of LV-Dil and RV-Dys correlates with advanced stages of heart failure in SMR patients, which may impact the outcome after TEER. METHODS SMR patients in a European multicenter registry were evaluated. Investigated outcomes were 2-year all-cause mortality and improvement in New York Heart Association functional class with respect to MR reduction…

Outcomes of transcatheter tricuspid valve intervention by right ventricular function: a multicentre propensity-matched analysis

2021

BACKGROUND Tricuspid regurgitation (TR) has a poor prognosis and limited treatment options and is frequently accompanied by right ventricular (RV) dysfunction. Transcatheter tricuspid valve interventions (TTVI) to reduce TR have been shown to be safe and feasible with encouraging early results. Patient selection for TTVI remains challenging, with the role of right ventricular (RV) function being unknown. AIMS The aims of this study were 1) to investigate survival in a TTVI-treated patient population and a conservatively treated TR population, and 2) to evaluate the outcome of TTVI as compared to conservative treatment stratified according to the degree of RV function. METHODS We studied 684…

Impact of intra-aortic balloon counterpulsation on all-cause mortality among patients with Takotsubo syndrome complicated by cardiogenic shock: resul…

2023

Abstract Aims Takotsubo syndrome (TTS) is an acute and reversible left ventricular dysfunction and can be complicated by cardiogenic shock (CS). However, few data are available on optimal care in TTS complicated by CS. Aim of this study was to evaluate short- and long-term impact of intra-aortic balloon pumping (IABP) on mortality in this setting. Methods and results In a multi-centre, international registry on TTS, 2248 consecutive patients were enrolled from 38 centres from Germany, Italy, and Spain. Of the 2248 patients, 212 (9.4%) experienced CS. Patients with CS had a higher prevalence of diabetes (27% vs. 19%), male sex (25% vs. 10%), and right ventricular involvement (10% vs. 5%) (P …

Esophageal Atresia with or without Tracheoesophageal Fistula (EA/TEF): Association of Different EA/TEF Subtypes with Specific Co-occurring Congenital…

2017

Background Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) represents the most common developmental malformation of the upper digestive tract. It is classified into six subtypes according to the classification of Vogt, depending on anatomical variation of this malformation. Around 50% of the patients with EA/TEF present additional anomalies, which often influence, next to the EA/TEF subtype, the overall prognosis of EA/TEF newborns. Here, we investigated the association of the different EA/TEF subtypes with co-occurring congenital anomalies in EA/TEF patients and demonstrate their implications for postnatal diagnostic workup. Materials and Methods We investigated 333 …

Assessment of the German and Italian Stress Cardiomyopathy Score for Risk Stratification for In-hospital Complications in Patients With Takotsubo Syn…

2019

IMPORTANCE Takotsubo syndrome (TTS) is an acute, reversible heart failure syndrome featured by significant rates of in-hospital complications. There is a lack of data for risk stratification during hospitalization. OBJECTIVE To derive a simple clinical score for risk prediction of in-hospital complications among patients with TTS. DESIGN, SETTING, AND PARTICIPANTS In this prognostic study, 1007 consecutive patients were enrolled in the German and Italian Stress Cardiomyopathy (GEIST) registry from July 1, 2007, through December 31, 2017, and identified as the derivation cohort; 946 patients were enrolled in the Spanish Registry for Takotsubo Cardiomyopathy (RETAKO) as the external score val…

P3691Intra-aortic balloon counterpulsation in takotsubo syndrome complicated by cardiogenic shock: short- and long-term results from a cohort of 2250…

2019

Abstract Background Takotsubo syndrome (TTS) is featured by an acute and reversible left ventricular dysfunction and can be complicated by cardiogenic shock. Intra-aortic balloon pumping (IABP) use in this setting is controversial, and few data are available from large populations. Aim of this study was therefore to evaluate short- and long-term impact of IABP on mortality in TTS complicated by cardiogenic shock. Methods The GEIST registry is a multicenter, international registry on TTS involving 38 centers from Germany, Italy and Spain. Between 2006 and 2017, 2250 consecutive patients with TTS were enrolled. Results Of the 2250 patients, 211 (9%) experienced cardiogenic shock during hospit…

2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

2020

2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

Additional file 1: of Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian can…

2019

Table S1. Inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) for BRCA1 and BRCA2 germline testing. Table S2. Genotype, phenotype and cancer family history of familial BC index patients carrying heterozygous germline loss-of-function (LoF) variants in the BARD1 gene (transcript NM_000465.3). Table S3. Prevalence of heterozygous germline LoF variants identified in the BARD1 gene (transcript NM_000465.3). Table S4. Potentially damaging rare missense variants identified in the BARD1 gene (transcript NM_000465.3). (DOCX 76 kb)