Publications by authors named "Holger Thiele"

801 Publications

Cardiac Output States in Patients with Severe Functional Tricuspid Regurgitation - Impact on Treatment Success and Prognosis.

Eur J Heart Fail 2021 Jul 16. Epub 2021 Jul 16.

Dept. of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany.

Aims: To investigate whether there is evidence for distinct cardiac output (CO) based phenotypes in patients with chronic right heart failure associated with severe tricuspid regurgitation (TR) and to characterize their impact on TR treatment and outcome.

Methods And Results: A total of 132 patients underwent isolated transcatheter tricuspid valve repair (TTVR) for functional TR at two centers. Patients were clustered according to k-means clustering into low (C-1: CI<1.7 l/min/m ), intermediate (C-2: CI=1.7-2.6 l/min/m ) and high CO (C-3: CI>2.6 l/min/m ) clusters. All-cause mortality and clinical characteristics during follow-up were compared among different CO-clusters. Mortality rates were highest for patients in a low - (24%) and high CO state (42%, log-rank p<0.001). High CO patients were characterized by larger vena cava inferior diameters (p=0.003), reduced liver function, higher incidence of ascites (p=0.006) and markedly reduced systemic vascular resistance (p<0.001) as compared to TTVR patients in other CO states. Despite comparable procedural success rates, the extent of changes in right atrial pressures (p=0.01) and right ventricular dimensions (p<0.001) per decrease in regurgitant volume following TTVR was less pronounced in high CO patients as compared to other CO states. Successful TTVR was associated with the smallest prognostic benefit among low- and high CO patients.

Conclusions: Patients with chronic right heart failure and severe TR display distinct CO states. The high CO state is characterized by advanced congestive hepatopathy, a substantial decrease in peripheral vascular tone, a lack of response of central venous pressures to TR reduction, and worse prognosis. These data are relevant to the pathophysiological understanding and management of this important clinical syndrome.
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http://dx.doi.org/10.1002/ejhf.2307DOI Listing
July 2021

A 24-generation-old founder mutation impairs splicing of RBBP8 in Pakistani families affected with Jawad syndrome.

Clin Genet 2021 Jul 16. Epub 2021 Jul 16.

Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Jawad syndrome is a multiple congenital anomaly and intellectual disability syndrome with mutation in RBBP8 reported only in two families. Here, we report on two new families from Pakistan and identified a previously reported variant in RBBP8, NM_002894.3:c.1808-1809delTA. We could show that this mutation impairs splicing resulting in two different abnormal transcripts. Finally, we could verify a shared haplotype among all four families and estimate the founder event to have occurred some 24 generations ago.
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http://dx.doi.org/10.1111/cge.14028DOI Listing
July 2021

Manta versus Perclose ProGlide vascular closure device after transcatheter aortic valve implantation: Initial experience from a large European center.

Cardiovasc Revasc Med 2021 Jul 3. Epub 2021 Jul 3.

Department of Structural Heart Disease/Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany. Electronic address:

Background: Vascular and bleeding complications are common after transcatheter aortic valve implantation (TAVI) and are associated with worse outcomes. The plug-based Manta (M) vascular closure device (VCD) is a novel option to achieve haemostasis for large-bore arterial access sites.

Objective: We aimed to compare vascular and bleeding complications between the M-VCD and the established suture-based Perclose ProGlide (P)-VCD.

Methods: From February to September 2019 a total of 578 patients underwent transfemoral TAVI at a single high-volume centre. Access site closure was performed using M-VCD in 195 patients (33.7%) and P-VCD in 383 patients (66.3%). We assessed vascular and access site-related complications as well as bleeding events according to the Valve Academic Research Consortium-2 definition.

Results: Overall vascular complications occurred less frequently in the M-VCD group (10.7% vs. 19.0%, p = 0.011) driven by a significantly lower rate of major vascular events (2.0% vs. 6.5%, p = 0.025). Access site-related complications were significantly less frequent in the M-VCD cohort (10.7% vs. 16.6%, p = 0.048). The M-VCD was associated with significantly lower rates of major (0.5% vs. 4.4%, p = 0.009) and life-threatening bleeding (0% vs. 2.3%, p = 0.032). In multivariable analysis, the use of M-VCD was the only independent predictor of vascular complications (odds ratio 0.54, 95% confidence interval 0.32-0.91, p = 0.022).

Conclusions: The M-VCD was associated with a reduction of vascular and access-site complications as well as severe bleeding after transfemoral TAVI compared to the P-VCD in this observational study.
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http://dx.doi.org/10.1016/j.carrev.2021.06.134DOI Listing
July 2021

Profile of urinary amino acids and their post-translational modifications (PTM) including advanced glycation end-products (AGEs) of lysine, arginine and cysteine in lean and obese ZSF1 rats.

Amino Acids 2021 Jul 11. Epub 2021 Jul 11.

Institute of Toxicology, Hannover Medical School, Core Unit Proteomics, Carl-Neuberg-Strasse 1, 30623, Hannover, Germany.

Heart failure with preserved ejection fraction (HFpEF) is associated with high mortality and has an increasing prevalence associated with the demographic change and limited therapeutic options. Underlying mechanisms are largely elusive and need to be explored to identify specific biomarkers and new targets, which mirror disease progression and intervention success. Obese ZSF1 (O-ZSF1) rats are a useful animal model, as they spontaneously develop hypertension, hyperlipidemia and glucose intolerance and finally HFpEF. The urinary profile of amino acids and their metabolites of post-translational modifications (PTM), including the advanced glycation end-products (AGEs) of lysine, arginine and cysteine, are poorly investigated in HFpEF and ZSF1 rats. The aim of the present study was to characterize the status of free amino acids and their metabolites of PTM and glycation in lean ZSF1 (L-ZSF1) and O-ZSF1 rats in urine aiming to find possible effects of glucose on the excretion of native and modified amino acids. In the urine of twelve L-ZSF1 and twelve O-ZFS1 rats collected at the age of 20 weeks, we measured the concentration of native and modified amino acids by reliable previously validated stable-isotope dilution gas chromatography-mass spectrometry (GC-MS) approaches. Serum glucose was 1.39-fold higher in the O-ZSF1 rats, while urinary creatinine concentration was 2.5-fold lower in the O-ZSF1 rats. We observed many differences in urinary amino acids excretion between L-ZSF1 and O-ZSF1 rats. The creatinine-corrected homoarginine excretion was twofold lower in the O-ZSF1 rats. We also observed distinct associations between the concentrations of serum glucose and urinary amino acids including their PTM and AGE metabolites in the L-ZSF1 and O-ZSF1 rats. Our study shows that PTM metabolites and AGEs are consistently lower in the L-ZSF1 than in the O-ZSF1 rats. Serum malondialdehyde (MDA) concentration was higher in the O-ZSF1 rats. These results suggest that hyperglycemia, hyperlipidemia and elevated oxidative stress in the O-ZSF1 rats favor PTM methylation of arginine and lysine and the glycation of lysine and cysteine. The area under the receiver operation characteristic (ROC) curve values were 0.996 for serum glucose, 0.951 for urinary creatinine, 0.939 for serum MDA, 0.885 for N-carboxyethyl-lysine, 0.830 for carboxyethyl-cysteine, and 0.792 for monomethyl-lysine. Non-invasive measurement of methylation and glycation products of arginine, lysine and cysteine residues in proteins in urine of L-ZSF1 and O-ZSF1 rats may be useful in studying pathophysiology and pharmacology of HFpEF.
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http://dx.doi.org/10.1007/s00726-021-03042-3DOI Listing
July 2021

Optimising clinical trials in acute myocardial infarction complicated by cardiogenic shock: a statement from the 2020 Critical Care Clinical Trialists Workshop.

Lancet Respir Med 2021 Jul 7. Epub 2021 Jul 7.

Department of Anesthesia, Burn and Critical Care Medicine, AP-HP, Hôpitaux Universitaires Saint-Louis-Lariboisière, FHU PROMICE, INI-CRCT, and Université de Paris, MASCOT, INSERM, Paris, France. Electronic address:

Acute myocardial infarction complicated by cardiogenic shock (AMICS) is a critical syndrome with a high risk of morbidity and mortality. Current management consists of coronary revascularisation, vasoactive drugs, and circulatory and ventilatory support, which are tailored to patients mainly on the basis of clinicians' experience rather than evidence-based recommendations. For many therapeutic interventions in AMICS, randomised clinical trials have not shown a meaningful survival benefit, and a disproportionately high rate of neutral and negative results has been reported. In this context, an accurate definition of the AMICS syndrome for appropriate patient selection and optimisation of study design are warranted to achieve meaningful results and pave the way for new, evidence-based therapeutic options. In this Position Paper, we provide a statement of priorities and recommendations agreed by a multidisciplinary group of experts at the Critical Care Clinical Trialists Workshop in February, 2020, for the optimisation and harmonisation of clinical trials in AMICS. Implementation of proposed criteria to define the AMICS population-moving beyond a cardio-centric definition to that of a systemic disease-and steps to improve the design of clinical trials could lead to improved outcomes for patients with this life-threatening syndrome.
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http://dx.doi.org/10.1016/S2213-2600(21)00172-7DOI Listing
July 2021

Proteomics to improve phenotyping in obese patients with heart failure with preserved ejection fraction.

Eur J Heart Fail 2021 Jul 7. Epub 2021 Jul 7.

Department of Cardiology, Heart Center Leipzig at University Leipzig, Leipzig, Germany.

Aims: Recent evidence points towards a distinct obese phenotype among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes.

Methods And Results: From the LIFE-Heart study, 999 patients with HFpEF and 999 patients without heart failure (no-HF) were selected and 92 circulating serum biomarkers were measured using a proximity extension assay. Elevation of identified biomarkers was validated in 220 patients from the Aldo-DHF trial with diagnosed HFpEF. HFpEF patients were older and had more comorbidities including coronary artery disease and type 2 diabetes as compared to no-HF patients (P < 0.05 for all). After adjusting for covariates, adrenomedullin (ADM), galectin-9 (Gal-9), thrombospondin-2 (THBS-2), CD4, and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) were significantly higher in obese HFpEF patients [body mass index (BMI) ≥30 kg/m , n = 464] as compared to lean HFpEF (BMI <30 kg/m , n = 535) and obese no-HF patients (BMI ≥30 kg/m , n = 387) (P < 0.001 for both); these findings were verified in the Aldo-DHF validation cohort (P < 0.001). Except for CD4 these proteins were associated with increased estimates of left atrial pressure in a linear fashion. Importantly, ADM and CD4 were associated with increased mortality in obese HFpEF patients after adjusting for covariates.

Conclusion: Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS-2) and systemic inflammation (Gal-9, CD4) compared to obese non-HFpEF or lean HFpEF patients. These findings support the clinical definition of a distinct obese HFpEF phenotype and might merit further investigation.
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http://dx.doi.org/10.1002/ejhf.2291DOI Listing
July 2021

ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants.

Neurogenetics 2021 Jul 3. Epub 2021 Jul 3.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.
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http://dx.doi.org/10.1007/s10048-021-00655-4DOI Listing
July 2021

[Cardiovascular side effects in patients undergoing androgen deprivation therapy: superiority of gonadotropin-releasing hormone antagonists? An update].

Urologe A 2021 Jul 2. Epub 2021 Jul 2.

Klinik für Urologie, Universitätsklinikum Schleswig-Holstein, Lübeck, Deutschland.

Background: Androgen deprivation therapy (ADT) plays a crucial role in treatment of advanced prostate cancer (PCa). The additional application of new drugs results in prolonged overall survival, both in the hormone sensitive and castration resistant state. Consequently, the long-term use of ADT moves potential side effects into the focus of interest. In this context special consideration must be given to cardiovascular events.

Objectives: Review of current evidence on potential differences regarding the cardiovascular risk profile of gonadotropin-releasing hormone (GnRH) agonists compared to GnRH antagonists.

Methods: Narrative review based on an expert consensus supported by a literature search in PubMed (MEDLINE) and the abstract databases of ASCO and ESMO was conducted for publications published between January 2015 and January 2021. Significant meta-analyses, randomized controlled trials (RCTs) and real-world data (RWD) revealing relevant results for clinical practice were taken into account. Selection of studies was performed based on the clinical relevance for everyday practice.

Results: The search yielded three relevant meta-analyses, two prospective RCTs as well as three RWD publications that are of importance for clinical practice. Overall, a decreased incidence of cardiovascular events was reported for GnRH antagonists compared to GnRH agonists. Only one RWD publication described comparable rates of complications for both drug classes.

Conclusion: GnRH antagonists have a lower risk of treatment related cardiovascular events compared to GnRH agonists. Risks should be minimized by taking known cardiovascular risk factors into account before initiating therapy.
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http://dx.doi.org/10.1007/s00120-021-01583-9DOI Listing
July 2021

NT-proANP levels in peripheral and cardiac circulation.

J Interv Card Electrophysiol 2021 Jun 25. Epub 2021 Jun 25.

School of Medicine - Cardiovascular Medicine, Boston University, 72 E Concord St, Boston, MA, 02118, USA.

Background: Recent studies have reported an association between N-terminal atrial natriuretic peptide (NT-proANP) and the progression of atrial fibrillation (AF). However, NT-proANP levels in peripheral and cardiac circulation in AF patients and in non-AF individuals need to be defined. The aims of the current study are (1) to analyze NT-proANP levels in peripheral and cardiac circulation in AF patients and (2) to compare NT-proANP levels in individuals with and without AF.

Methods: We recruited AF patients who were undergoing their first AF catheter ablation and non-AF individuals. Blood plasma samples taken from the femoral vein and the left atrium (LA) were collected before AF ablation in the AF patients and from the cubital vein in the non-AF controls. Low voltage areas (LVAs) were determined using high-density maps during catheter ablation and defined as < 0.5 mV.

Results: The study included 189 AF patients (64 ± 10 years, 59% male, 61% persistent AF, 30% LVAs) and 26 non-AF individuals (58 ± 10 years, 50% male). Patients with AF were significantly older and had larger LA (p < 0.05). Compared to non-AF controls, peripheral and cardiac NT-proANP levels were significantly higher in AF patients without and with LVAs (median 5.4, 10.5, 14.8 ng/ml, respectively, p < 0.001). In multivariable analysis, NT-proANP (OR 1.238, 95% CI 1.007-1.521, p = 0.043) remained significantly different between non-AF individuals and AF patients. In AF, NT-proANP levels were significantly higher in the cardiac blood samples than in the peripheral blood (median 13.0 versus 11.4 ng/ml, p = 0.003). The ability to predict LVAs was modest when using cardiac NT-proANP (AUC 0.661) and peripheral NT-proANP (AUC 0.635), without statistical difference (p = 0.937).

Conclusions: NT-proANP levels are higher in individuals with AF than in controls and are more pronounced in progressed AF. Elevated cardiac and peripheral NT-proANP levels similarly predict LVAs.
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http://dx.doi.org/10.1007/s10840-021-01020-zDOI Listing
June 2021

Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials.

Eur J Heart Fail 2021 Jun 17. Epub 2021 Jun 17.

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

Aims: Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCT). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials.

Methods And Results: Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility.

Conclusion: The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ejhf.2274DOI Listing
June 2021

An identical-by-descent novel splice-donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families.

Ann Hum Genet 2021 Jun 10. Epub 2021 Jun 10.

Institut du Cerveau, INSERM U1127, CNRS UMR7225, Sorbonne Université, Paris, France.

PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop-gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole-exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice-donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in-frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1-related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice-site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction.
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http://dx.doi.org/10.1111/ahg.12437DOI Listing
June 2021

Sex-Specific Molecular Signatures of Fibrocalcific Aortic Valve Disease: Leveraging the Power of Artificial Intelligence?

JACC Basic Transl Sci 2021 May 24;6(5):413-415. Epub 2021 May 24.

Department of Internal Medicine/Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany.

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http://dx.doi.org/10.1016/j.jacbts.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165124PMC
May 2021

Modifier Genes in Microcephaly: A Report on , , and Variants Exacerbating Disease Caused by Biallelic Mutations of and .

Genes (Basel) 2021 May 13;12(5). Epub 2021 May 13.

Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic-microcephaly primary hereditary (MCPH)-and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH ( = 3) or Seckel syndrome ( = 2). In addition to homozygous causal variants in or , we discovered additional heterozygous modifier variants in and -genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional variant. We show that the missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.
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http://dx.doi.org/10.3390/genes12050731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153008PMC
May 2021

Joint EAPCI/ACVC expert consensus document on percutaneous ventricular assist devices.

Eur Heart J Acute Cardiovasc Care 2021 Jun;10(5):570-583

Department of Adult Intensive Care Unit, Royal Brompton and Harefield NHS Foundation Trust, Royal Brompton Hospital, Sydney Street, SW3 6NP London, UK.

There has been a significant increase in the use of short-term percutaneous ventricular assist devices (pVADs) as acute circulatory support in cardiogenic shock and to provide haemodynamic support during interventional procedures, including high-risk percutaneous coronary interventions. Although frequently considered together, pVADs differ in their haemodynamic effects, management, indications, insertion techniques, and monitoring requirements. This consensus document summarizes the views of an expert panel by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and the Association for Acute Cardiovascular Care (ACVC) and appraises the value of short-term pVAD. It reviews the pathophysiological context and possible indications for pVAD in different clinical settings and provides guidance regarding the management of pVAD based on existing evidence and best current practice.
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http://dx.doi.org/10.1093/ehjacc/zuab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245145PMC
June 2021

Joint EAPCI/ACVC expert consensus document on percutaneous ventricular assist devices.

EuroIntervention 2021 Jul 20;17(4):e274-e286. Epub 2021 Jul 20.

Interventional Cardiology Unit San Raffaele Scientific Institute - Milan, Italy.

There has been a significant increase in the use of short-term percutaneous ventricular assist devices (pVADs) as acute circulatory support in cardiogenic shock and to provide haemodynamic support during interventional procedures, including high-risk percutaneous coronary interventions. Although frequently considered together, pVADs differ in their haemodynamic effects, management, indications, insertion techniques, and monitoring requirements. This consensus document summarizes the views of an expert panel by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and the Association for Acute Cardiovascular Care (ACVC) and appraises the value of short-term pVAD. It reviews the pathophysiological context and possible indications for pVAD in different clinical settings and provides guidance regarding the management of pVAD based on existing evidence and best current practice.
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http://dx.doi.org/10.4244/EIJY21M05_01DOI Listing
July 2021

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

Genet Med 2021 May 30. Epub 2021 May 30.

Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.

Purpose: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development.

Methods: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b.

Results: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye.

Conclusion: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
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http://dx.doi.org/10.1038/s41436-021-01196-9DOI Listing
May 2021

Incidence and Clinical Impact of Right Ventricular Involvement (Biventricular Ballooning) in Takotsubo Syndrome: Results From the GEIST Registry.

Chest 2021 May 27. Epub 2021 May 27.

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany; DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany.

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 of in-hospital death, thromboembolic events, cardiogenic shock, pulmonary edema, and malignant arrhythmias.

Results: The incidence of RV involvement in TTS was 11% (n = 93). More often patients with RV involvement were male compared with patients without RV involvement (P = .02). There was a slight difference in the left ventricular ejection fraction measured in patients with RV involvement vs those patients with isolated left ventricular TTS (38 ± 10% vs 40 ± 10%; P = .03). No major differences in terms of comorbidities were observed between groups except regarding a history of cancer, which was significantly more prevalent in patients with TTS presenting with RV involvement (P = .03). Physical stressors were more prevalent in the RV group (P < .01), whereas emotional stressors were less prevalent (P < .01). Patients with RV involvement had a higher incidence of in-hospital cardiogenic shock (P = .02). The primary outcome (in- and out-of-hospital all-cause mortality) was observed in 12.8% of patients without RV involvement compared with 29% of patients with RV involvement. Although the in-hospital mortality rate was similar in both groups, a higher out-of-hospital all-cause mortality rate (log-rank test, P = .008) was observed in the RV involvement group. The Cox multivariable regression analysis showed that physical triggers were independent predictors of RV involvement.

Interpretation: RV involvement defines a high-risk cohort of patients with TTS.

Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04361994; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.04.072DOI Listing
May 2021

Dissecting Calcific Aortic Valve Disease-The Role, Etiology, and Drivers of Valvular Fibrosis.

Front Cardiovasc Med 2021 10;8:660797. Epub 2021 May 10.

Department of Internal Medicine/Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany.

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.
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http://dx.doi.org/10.3389/fcvm.2021.660797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143377PMC
May 2021

Outcomes of Valve-in-Valve Transcatheter Aortic Valve Implantation with and without Bioprosthetic Valve Fracture.

EuroIntervention 2021 05 25. Epub 2021 May 25.

MVZ Department Structural Heart Disease, Asklepios St. Georg, Hamburg, Germany.

Background: Bioprosthetic valve fracture (BVF) is a technique to reduce gradients in valve-in-valve transcatheter aortic valve implantation (VIV-TAVI) procedures. Outcome of VIV-TAVI with BVF has not been compared with VIV-TAVI without BVF.

Aims: To evaluate the outcome of VIV-TAVI with BVF compared to VIV-TAVI without BVF.

Methods: In total, 81 cases of BVF-VIV-TAVI (BVF-group) from 14 centres were compared to 79 cases of VIV-TAVI without BVF (control-group).

Results: VARC-2 defined device success was 93% in the BVF- and 68.4% in the control-group (p<0.001). The mean transvalvular gradient decreased from 37 ± 13mmHg to 10.8 ± 5.9mmHg (p<0.001) in the BVF- and from 35 ± 16mmHg to 15.8 ± 6.8mmHg (p<0.001) in the control-group with a significantly higher final gradient in control (p<0.001). The transvalvular gradients did not significantly change over time. In-hospital major adverse events occurred in 3.7% in BVF- and 7.6% in control-group (p=0.325). A linear mixed model identified BVF, self-expanding transcatheter heart valves (THVs) and other surgical aortic valve (SAV) types other than Mitroflow as predictors for lower transvalvular gradients.

Conclusions: Compared to VIV-TAVI alone, VIV-TAVI with BVF resulted in a significantly lower transvalvular gradient acutely and at follow-up. Independent predictors for lower gradients were the use of self-expanding THVs and the treatment of SAVs other than Mitroflow, irrespective of BVF-performance. BVF significantly reduced the gradient independently from transcatheter or surgical valve type.
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http://dx.doi.org/10.4244/EIJ-D-21-00254DOI Listing
May 2021

Left Ventricular Support for the Management of Cardiogenic Shock: Sooner May Be Better.

JACC Cardiovasc Interv 2021 May;14(10):1120-1122

Heart Center Leipzig at University of Leipzig, Leipzig, Germany.

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http://dx.doi.org/10.1016/j.jcin.2021.04.016DOI Listing
May 2021

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry.

Clin Res Cardiol 2021 May 19. Epub 2021 May 19.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.

Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.

Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.

Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.

Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621.
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http://dx.doi.org/10.1007/s00392-021-01857-4DOI Listing
May 2021

Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling.

Kidney Int Rep 2021 May 29;6(5):1368-1378. Epub 2021 Jan 29.

Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Introduction: Disease-causing mutations in the protocadherin have been recently described both in patients with a glomerulotubular nephropathy and in patients with a syndromic nephropathy.

Methods: We identified 4 patients with -associated disease, performed clinical and genetic characterization, and compared our findings to the previously published patients. Patient-derived primary urinary epithelial cells were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblotting to identify possible alterations in Hippo signaling.

Results: Here we expand the spectrum of -associated disease with the identification of novel mutations in 4 patients from 3 families (homozygous truncating variants in 3, compound heterozygous missense variants in 1 patient). All patients show an ophthalmologic phenotype together with heterogeneous renal phenotypes ranging from normal renal function to early-onset end-stage kidney failure. Molecular analysis of primary urine-derived urinary renal epithelial cells revealed alterations in the Hippo signaling cascade with a decreased phosphorylation of both the core kinase MST and the downstream effector YAP. Consistently, we found a transcriptional upregulation of YAP target genes.

Conclusion: A comprehensive review of the here identified patients and those previously published indicates a highly diverse phenotype in patients with missense mutations but a more uniform and better recognizable phenotype in the patients with truncating mutations. Altered Hippo signaling and de-repressed YAP activity might be novel contributing factors to the pathomechanism in -associated renal disease.
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http://dx.doi.org/10.1016/j.ekir.2021.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116753PMC
May 2021

Clopidogrel vs. prasugrel vs. ticagrelor in patients with acute myocardial infarction complicated by cardiogenic shock: a pooled IABP-SHOCK II and CULPRIT-SHOCK trial sub-analysis.

Clin Res Cardiol 2021 May 17. Epub 2021 May 17.

Department of Medicine I, University Hospital, Ludwig-Maximilians-University, Munich, Germany.

Aims: The aim of this pooled sub-analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated either with clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor.

Methods And Results: For the current analysis the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. 856 patients were eligible for analysis. Of these, 507 patients (59.2%) received clopidogrel, 178 patients (20.8%) prasugrel and 171 patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ significantly between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60-1.09, p = 0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65-1.15, p = 0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20 -0.69, p = 0.002) and not significantly different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43 -1.24, p = 0.24).

Conclusion: This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that acute therapy with either clopidogrel, prasugrel or ticagrelor is no independent predictor of 1-year mortality. Treatment with ticagrelor seems independently associated with less in-hospital moderate and severe bleeding events compared to clopidogrel. This finding might be due to selection bias and should be interpreted with caution.
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http://dx.doi.org/10.1007/s00392-021-01866-3DOI Listing
May 2021

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

JACC Cardiovasc Interv 2021 Jun 12;14(11):1243-1253. Epub 2021 May 12.

Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany; Munich Heart Alliance, Partner Site German Center for Cardiovascular Disease, Munich, Germany. Electronic address:

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, LV-Dil (defined as LV end-diastolic volume ≥159 ml), and RV-Dys (defined as tricuspid annular plane systolic excursion-to-systolic pulmonary artery pressure ratio of <0.274 mm/mm Hg).

Results: Among 809 included patients, resMR ≤1+ was achieved in 546 (67%) patients. Overall estimated 2-year mortality rate was 32%. Post-procedural resMR was significantly associated with mortality (p = 0.031). Although the improvement in New York Heart Association functional class persisted regardless of either LV-Dil or RV-Dys, the beneficial treatment effect of resMR ≤1+ on 2-year mortality was observed only in patients without LV-Dil and RV-Dys (hazard ratio: 1.75; 95% confidence interval: 1.03 to 3.00).

Conclusions: Achieving optimal MR reduction by TEER is associated with improved survival in SMR patients, especially if the progress in heart failure is not too advanced. In SMR patients with advanced stages of heart failure, as evidenced by LV-Dil or RV-Dys, the treatment effect of TEER on symptomatic improvement is maintained, but the survival benefit appears to be reduced.
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http://dx.doi.org/10.1016/j.jcin.2021.03.050DOI Listing
June 2021

Bioprosthetic valve fracture: Predictors of outcome and follow-up. Results from a multicenter study.

Catheter Cardiovasc Interv 2021 May 15. Epub 2021 May 15.

MVZ Department Structural Heart Disease, Asklepios St. Georg, Hamburg, Germany.

Objectives: To evaluate outcome and its predictors of bioprosthetic valve fracture (BVF) in patients undergoing valve-in-valve transcatheter aortic valve replacement (VIV-TAVR).

Background: BVF is feasible and reduces transvalvular gradients in VIV-TAVR-procedures, but follow-up-data and information on factors influencing the outcome are missing.

Methods: The 81 cases of BVF-VIV-TAVR were collected from 14 international centers.

Results: Predominantly transcatheter heart valve (THV) was implanted first, followed by BVF. VARC-2 defined device success was 93%, most failures were attributed to residual high gradients. Mean gradients decreased from 37 ± 13 mmHg to 10.8 ± 5.9 mmHg (p < 0.001). BVF reduced the gradient by 16 mmHg. During follow-up (FU, 281 ± 164 days) mean gradient remained stable (10.8 ± 5.9 mmHg at discharge, 12.4 ± 6.3 mmHg at FU, p = ns). In-hospital major adverse events occurred in 3.7%. Event-free survival at 276 ± 237.6 days was 95.4%. The linear mixed model identified balloon-expandable valves (BEV), Mitroflow surgical valve, stenotic surgical bioprostheses and balloon only 1 mm larger than the true internal diameter of the surgical valve as predictors for higher gradients.

Conclusions: BVF is safe and can significantly reduce gradients, which remain stable at FU. BEV, Mitroflow surgical valve, stenotic bioprostheses and balloon larger than the true internal diameter of the surgical valve of only 1 mm are predictors for higher final gradients.
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http://dx.doi.org/10.1002/ccd.29755DOI Listing
May 2021

A novel remitting leukodystrophy associated with a variant in .

Brain Commun 2021 11;3(2):fcab036. Epub 2021 Mar 11.

Department of Pediatrics and Pediatric Neurology, University Medical Center Göttingen, Georg August University, 37075 Göttingen, Germany.

Leukodystrophies are genetic disorders of cerebral white matter that almost exclusively have a progressive disease course. We became aware of three members of a family with a disorder characterized by a sudden loss of all previously acquired abilities around 1 year of age followed by almost complete recovery within 2 years. Cerebral MRI and myelin sensitive imaging showed a pronounced demyelination that progressed for several months despite signs of clinical improvement and was followed by remyelination. Exome sequencing did not-identify any mutations in known leukodystrophy genes but revealed a heterozygous variant in the gene, c.343G>A, p. Val115Met, shared by the affected family members. Cerebral MRI of other family members demonstrated similar white matter abnormalities in all carriers of the variant in . The gene codes for muscle fructose 1,6-bisphosphatase, an enzyme involved in gluconeogenesis that is highly expressed in brain tissue. Biochemical analysis showed that the variant has a dominant negative effect on enzymatic activity, substrate affinity, cooperativity and thermal stability. Moreover, it also affects the non-canonical functions of muscle fructose 1,6-bisphosphatase involved in mitochondrial protection and regulation of several nuclear processes. In patients' fibroblasts, muscle fructose 1,6-bisphosphatase shows no colocalization with mitochondria and nuclei leading to increased reactive oxygen species production and a disturbed mitochondrial network. In conclusion, the results of this study indicate that the variant in disturbs cerebral energy metabolism and is associated with a novel remitting leukodystrophy.
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http://dx.doi.org/10.1093/braincomms/fcab036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097510PMC
March 2021