Iatrogenic atrial septal defects after transseptal puncture for percutaneous left atrial appendage occlusion and their hemodynamic effects

Background Percutaneous left atrial appendage occlusion(LAAO)requires puncture of the interatrial septum.The immediate hemodynamic effects of iatrogenic atrial septal defects(iASD)after LAAO have not been examined so far.We aimed at evaluat-ing these effects through invasive measurements of pressure and oxygen saturation.Moreover,we assessed the incidence of per-sistent iASD at three months.METHODS Forty-eight patients scheduled for percutaneous LAAO were prospectively included in the study.Pressure and oxygen saturation were measured(1)in the right atrium(RA)before transseptal puncture,(2)in the left atrium(LA)through the transseptal sheath after transseptal puncture,(3)in the LA after removal of introducer sheath,and(4)in the RA after removal of introducer sheath.Transesophageal echocardiography was performed at three months to detect iASD.RESULTS Pressure in the RA increased significantly after removing the introducer sheath(P=0.034),whereas no difference was found in oxygen saturation in the RA(P=0.623).Pressure measurement in the LA showed no significant difference after re-moving the introducer sheath(P=0.718).Oxygen saturation in the LA also showed no significant difference(P=0.129).Follow-up transesophageal echocardiogram at 3 months revealed a persistent iASD in 4 patients(8.5%).CONCLUSIONS Our study suggests that iASD after percutaneous LAAO does not result in significant shunts directly after the procedure,although a significant increase of mean right atrial pressure can be observed.Persistent iASDs after percutaneous LAAO seem to be relatively rare at three months.

Non-human primate pluripotent stem cells for the preclinical testing of regenerative therapies

Non-human primates play a key role in the preclinical validation of pluripotent stem cell-based cell replacement therapies.Pluripotent stem cells used as advanced therapy medical products boost the possibility to regenerate tissues and organs affected by degenerative diseases.Therefore,the methods to derive human induced pluripotent stem cell and embryonic stem cell lines following clinical standards have quickly developed in the last 15 years.For the preclinical validation of cell replacement therapies in non-human primates,it is necessary to generate non-human primate pluripotent stem cell with a homologous quality to their human counterparts.However,pluripotent stem cell technologies have developed at a slower pace in non-human primates in comparison with human cell systems.In recent years,however,relevant progress has also been made with non-human primate pluripotent stem cells.This review provides a systematic overview of the progress and remaining challenges for the generation of non-human primate induced pluripotent stem cells/embryonic stem cells for the preclinical testing and validation of cell replacement therapies.We focus on the critical domains of(1)reprogramming and embryonic stem cell line derivation,(2)cell line maintenance and characterization and,(3)application of non-human primate pluripotent stem cells in the context of selected preclinical studies to treat cardiovascular and neurodegenerative disorders performed in non-human primates.

Novel heart valve leaflet designs with stiff polymeric materials and biomimetic kinematics

Despite continuous efforts to improve the robustness of cardiac valve implants,neither bioprosthetic nor mechanical valves fulfill both hemodynamic and durability requirements.This study discussed novel flexible leaflet designs,focusing on polymeric materials with proven hemocompatibility,such as polyether ether ketone,of much higher stiffness than native tissue,aiming at optimal valve implants.A biomimetic valve with a single-curvature belly-curve(B-C)was used as a reference for new design variants with a double-curvature B-C with varying radii.Soft(13.2 MPa)and stiff(2.4 GPa)leaflet materials and different thicknesses were studied using lean simulations and in vitro experiments under physiologic hemodynamic conditions.The performance was assessed using opening pressure(OP)and orifice area(OA).The latter was determined by a newly developed automatized image processing tool.Experimental trends are in agreement with simulations and demonstrated that a buckling-inspired double-curvature leaflet design significantly enhances the trileaflet valve opening behavior,which is particularly advantageous for stiffer leaflet materials.Compared to the reference,the best-performing variant showed an OP improvement of 47%and 44%based on simulations and experiments,respectively.In contrast,the achieved mean pressure differential was directly comparable to state-of-the-art bioprosthetic valves.The OA was slightly reduced for new variants but still in the satisfying range.

Diagnostic and prognostic value of circulating micro RNAs in heart failure with preserved and reduced ejection fraction

micro RNAs(mi RNAs) are powerful regulators of posttranscriptional gene expression and play an important role in pathophysiological processes. Circulating mi RNAs can be quantified in body liquids and are promising biomarkers in numerous diseases. In cardiovascular disease mi RNAs have been proven to be reliable diagnostic biomarkers for different disease entities. In cardiac fibrosis(CF) and heart failure(HF) dysregulated circulating mi RNAs have been identified,indicating their promising applicability as diagnostic biomarkers. Some mi RNAs were successfully tested in risk stratification of HF implementing their potential use as prognostic biomarkers. In this respect mi RNAs might soon be implemented in diagnostic clinical routine. In the young field of mi RNA based research advances have been made in identifying mi RNAs as potential targets for the treatment of experimental CF and HF. Promising study results suggest their potential future application as therapeutic agents in treatment of cardiovascular disease. This article summarizes the current state of the various aspects of mi RNA research in the field of CF and HF with reduced ejection fraction as well as preserved ejection fraction. The review provides an overview of the application of circulating mi RNAs as biomarkers in CF and HF and current approaches to therapeutically utilize mi RNAs in this field of cardiovascular disease.

Challenges in the conduct of randomised controlled trials in cardiogenic shock complicating acute myocardial infarction

Cardiogenic shock(CS)following acute myocardial infarction(AMI)is a major challenge in cardiovascular care.Mortality remains high with 40%-50%after thirty days.Randomised controlled trials(RCTs)play a key role to generate evidence on optimal care in this field.However,the number of completed or ongoing RCTs is still relatively low compared to the gaps in evidence.Challenges in the conduct of these trials are in particular the selection of patients and ethical issues in the informed consent process.When determining eligibility criteria,special attention should be paid to the severity of CS,to the inclusion of patients with cardiac arrest and to potential age limits.Median age of AMI-CS patients is increasing.Age limits are therefore controversial as it is important to include elderly patients in RCTs in order to make the results generalisable and to address the special needs of this group.As patients with AMI-CS are in most cases unable to provide informed consent themselves,a step-wise approach with acute consent by a legal representative or independent physicians and later informed consent by the patient if possible might be established depending on regularities of the respective ethical review board and country legislation.Multicenter studies should be sought to generate adequate power.

Clinical and echocardiographic analysis of patients suffering from recurrent takotsubo cardiomyopathy

Background Recurrence of takotsubo cardiomyopathy （TTC） is a well-known complication. However, current literature lists only a few isolated cases. We aimed to determine the incidence and clinical significance of recurrent TTC. Methods ＆ Results Our institutional database constituted a collective of 114 patients diagnosed with TTC since 2003. Close follow-up of these patients revealed a recurrence of TTC in seven of these （6.1%）. The time interval between the index event and its recurrence varied between six months and six years. Arterial hypertension was more revealed in the recurrence group of TTC compared to non-recurrence group, （P = 0.02）. Chronic obstructive pulmo- nary disease and/or asthma was more diagnosed in the recurrence group, （P = 0.04）. Clinical events like fight ventficular involvement, TTC related complications such as life-threatening arrhythmias, pulmonary congestion and in hospital death were observed more frequently in the recurrent episode. Over a mean follow-up of one year the mortality rate was similar in both groups. Conclusions Recurrence of TTC within six years after index event is not an uncommon phenomenon. In the event of right ventricular involvement in the relapse phase, it might be associated with a higher complication rate. TTC recurrence should be the first differential diagnosis in patients with a past history of TTC.

Instantaneous wave-free ratio(iFR) to determine hemodynamically significant coronary stenosis: A comprehensive review

Coronary angiography is considered to be the gold standard in the morphological evaluation of coronary artery stenosis. The morphological assessment of the severity of a coronary lesion is very subjective. Thus, the invasive fractional flow reserve(FFR) measurement represents the current standard for estimation of the hemodynamic significance of coronary artery stenosis. The FFR-guided revascularization strategy was initially classified as a Class-IA-recommendation in the 2014 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines on myocardial revascularization. Both the Deferral vs Performance of Percutaneous Coronary Intervention of Functionally Non-Significant Coronary Stenosis and Flow Reserve vs Angiography for Multivessel Evaluation studies showed no treatment advantage for hemodynamically insignificant stenoses. With the help of FFR(and targeted interventions), clinical results could be improved; however, the use in clinical practice is still limited due to the need of adenosine administration and a significant prolongation of the length of the procedure. Instantaneous wave-free ratio(iFR~) is a new innovative approach for the determination of the hemodynamic significance of coronary stenosis, which can be obtained at rest without the use of vasodilators. Regarding the periprocedural complications as well as prognosis, iFR~ showed non-inferiority to FFR in the SWEDEHEART and DEFINE-FLAIR trials. Furthermore, iFR~, enhanced by iFR~-pullback, provides the possibility to display the iFR~-change over the course of the vessel to create a hemodynamic map.

Age-related outcomes in patients with cardiogenic shock stratified by etiology

BACKGROUND As a result of improved and novel treatment strategies,the spectrum of patients with cardiovascular disease is consistently changing.Overall,those patients are typically older and characterized by increased burden with comorbidities.Limited data on the prognostic impact of age in cardiogenic shock(CS)is available.Therefore,this study investigates the prognostic impact of age in patients with CS.METHODS From 2019 to 2021,consecutive patients with CS of any cause were included.The prognostic value of age(i.e.,60-80 years and>80 years)was investigated for 30-day all-cause mortality.Spearman’s correlations,Kaplan-Meier analyses,as well as multivariable Cox proportional regression analyses were performed for statistics.Subsequent risk assessment was performed based on the presence or absence of CS related to acute myocardial infarction(AMI).RESULTS 223 CS patients were included with a median age of 77 years(interquartile range:69-82 years).No significant difference in 30-day all-cause mortality was observed for both age-groups(54.6%vs.63.4%,log-rank P=0.169;HR=1.273,95%CI:0.886-1.831,P=0.192).In contrast,when analyzing subgroups stratified by CS-etiology,AMI-related CS patients of the group>80 years showed an increased risk of 30-day all-cause mortality(78.1%vs.60.0%,log-rank P=0.032;HR=1.635,95%CI:1.000-2.673,P=0.050),which was still evident after multivariable adjustment(HR=2.072,95%CI:1.174-3.656,P=0.012).CONCLUSIONS Age was not associated with 30-day all-cause mortality in patients with CS of mixed etiology.However,increasing age was shown to be a significant predictor of increased mortality-risk in the subgroup of patients presenting with AMI-CS.

Membrane-destabilizing ionizable phospholipids: Novel components for organ-selective mRNA delivery and CRISPR-Cas gene editing

In a new study published in Nature Materials,Liu et al.1 report a novel design of lipid nanoparticles(LNPs)in which multi-tailed ionizable phospholipids(iPhos)constitute the active component,and which facilitates endosomal escape and thus improves delivery of mRNA and/or single-guide(sg)RNA for in vivo gene editing.LNPs composed of the best-performing iPhos and different helper lipids_zwitterionic lipids,ionizable cationic lipids and permanently cationic lipids-achieved selective organ targeting(SORT)and organ-specific CRISPR-Cas9 gene editing in spleen,liver,and lungs of mice,respectively.

Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases

Excessive release of neutrophil extracellular traps(NETs)is associated with disease severity and contributes to tissue injury,followed by severe organ damage.Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models,indicating that NETs are potential therapeutic targets.Here,we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody(tACPA)has broad therapeutic potential.Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology,including inflammatory arthritis(IA),pulmonary fibrosis,inflammatory bowel disease and sepsis.We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention,whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects.Because citrullinated histones are generated during NET release,we investigated the ability of tACPA to inhibit NET formation.tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli.Moreover,tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo,which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA.To our knowledge,we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases,as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.

Long noncoding RNA MALAT1-derived mascRNA is involved in cardiovascular innate immunity

Dear Editor,Next-generation sequencing revealed that the majority of the human genome is transcribed but has no coding function.It is estimated that.30000 long noncoding RNAs(lncRNAs)are expressed in humans,but their functions are largely unknown(Suckau et al.,2009;Rinn and Chang,2012;Poller et al.,2013).Consideration of noncoding genomic elements in pathogenetic studies is warranted and enabled by technological advances allowing comprehensive transcriptome mapping of protein-coding genes as well as small and long ncRNAs.

Cardiovascular Involvement in Chronic Hepatitis C Virus Infections - Insight from Novel Antiviral Therapies

Whereas statistical association of hepatitis C virus(HCV)infection with cardiomyopathy is long known,establishment of a causal relationship has not been achieved so far.Patients with advanced heart failure(HF)are mostly unable to tolerate interferon(IFN)-based treatment,resulting in limited experi-ence regarding the possible pathogenic role of HCV in this patient group.HCV infection often triggers disease in a broad spectrum of extrahepatic organs,with innate immune and autoimmune pathogenic processes involved.The fact that worldwide more than 70 million patients are chronically infected with HCV illustrates the possible clinical impact arising if cardiomyopathies were induced or aggravated by HCV,resulting in progressive HF or severe arrhythmias.A novel path has been opened to finally resolve the long-standing question of cause-effect relationship between HCV infection and cardiac dysfunction,by the recent development of IFN-free,highly efficient,and well tolerable anti-HCV regimens.The new direct-acting antiviral(DAA)agents are highly virus-specific and lack unspecific side-effects upon cardiac function which have always confounded the interpret-tation of IFN treatment data.The actual frequency of un-explained HF in chronic HCV infection will be determined from a planned large-scale study.Whereas such patients probably constitute a rather small fraction of all those harboring HCV,they have major clinical relevance.It is not yet known which fraction of these patients will significantly benefit from HCV eradication,but this issue will be addressed now in a prospective study.

Fire up the pyre:inosine thermogenic signaling for obesity therapy

In a recent study published in Nature,Niemann et al.may have discovered a metabolite signaling pathway that could pave the way to new weight loss drugs1(Fig.1).Obesity and its comorbidities are a major threat to public health,but efficient therapeutics are still scarce.

Starving out brain tumors: a reprogrammed lysine catabolism serves as a novel target for glioblastoma treatment

In their recent study published in Nature,Yuan and colleagues enlighten the role of histone lysine crotonylation(Kcr)in brain tumor biology.They report a novel lysine-dependent mechanism through which glioblastoma stem cells modulate type I interferon(IFNα/IFNβ)signaling to create an immunosuppressive environment.

Breaking barriers:noncanonical inflammasome executes blood–brain barrier disruption

In a landmark study recently published in Nature,1 Wei and colleagues demonstrate that the activation of GSDMD by the cytosolic lipopolysaccharide(LPS)sensor caspase-11 triggers blood–brain barrier(BBB)breakdown upon LPS challenge independent of TLR4-induced cytokine release.Their work identifies the noncanonical inflammasome and GSDMD pore formation as a potential target for treating central nervous system(CNS)disorders associated with inflammatory BBB dysfunction.

Long noncoding RNA in cardiac aging and disease

Cardiovascular diseases(CVDs)are the main cause of morbidity and mortality in Western society and present an important agerelated risk.With the constant rise in life expectancy,prevalence ofCVD in the population will likely increase further.New therapies,especially in the elderly,are needed to combat CVD.This review is focused on the role of long noncoding RNA(IncRNA)in CVD.RNA sequencing experiments in the past decade showed that most RNA does not code for protein,but many RNAs function as ncRNA.Here,we summarize the recent findings of IncRNA regulation in the diseased heart.The potential use of these RNAs as biomarkers of cardiac disease prediction is also discussed.

A novel long non-coding RNA Myolinc regulates myogenesis through TDP-43 and Filip1

Myogenesis is a complex process required for skeletal muscle formation during embryonic development and for regeneration and growth of myofibers in adults. Accumulating evidence suggests that long non-coding RNAs （IncRNAs） play key roles in regulating cell fate decision and function in various tissues. However, the role of IncRNAs in the regulation of myogenesis remains poorly understood. In this study, we identifed a novel muscle-enriched IncRNA called ＇Myolinc （AK142388）＇, which we functionally characterized in the C2C12 myoblast cell line. Myolinc is predominately localized in the nucleus, and its levels increase upon induction of the differ-entiation. Knockdown of Myolinc impairs the expression of myogenic regulatory factors and formation of multi-nucleated myotubes in cultured myoblasts. Myolinc also regulates the expression of Filipl in a cis-manner. Similar to MyoUnc, knockdown of FiUpl inhi-bits myogenic differentiation. Furthermore, Myolinc binds to TAR DNA-binding protein 43 （TDP-43）, a DNA/RNA-binding protein that regulates the expression of muscle genes （e.g. Actal and MyoD）. Knockdown of TDP-43 inhibits myogenic differentiation. We also show that Myolinc-TDP-43 interaction is essential for the binding of TDP-43 to the promoter regions of muscle marker genes. Finally, we show that silencing of Myolinc inhibits skeletal muscle regeneration in adult mice. Altogether, our study identifies a novel IncRNA that controls key regulatory networks of myogenesis.

Electrolyser design controls position-divergent C–H carboxylation

In recent years,molecular electrochemistry has undergone a remarkable renaissance to surface as a sustainable strategy for organic synthesis and catalysis,gaining considerable momentum by the use of renewable forms of energy[1,2].Modern organic electrochemistry has the unique power to control chemo-,regio-,and position-selectivities through the judicious choice of the electrode material,the applied potential or an additional catalyst,among others[1,2].Despite the major advances in molecular electrochemistry,these approaches continue to predominantly rely on non-renewable fossil resources.

SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy

Alternative mRNA splicing is a fundamental process to increase the versatility of the genome.In humans,cardiac mRNA splicing is involved in the pathophysiology of heart failure.Mutations in the splicing factor RNA binding motif protein 20(RBM20) cause severe forms of cardiomyopathy.To identify novel cardiomyopathy-associated splicing factors,RNA-seq and tissue-enrichment analyses were performed,which identified up-regulated expression of Sam68-Like mammalian protein 2(SLM2) in the left ventricle of dilated cardiomyopathy(DCM) patients.In the human heart,SLM2 binds to important transcripts of sarcomere constituents,such as those encoding myosin light chain2(MYL2),troponin 13(TNNI3),troponin T2(TNNT2),tropomyosin 1/2(TPM1/2),and titin(TTN).Mechanistically,SLM2 mediates intron retention,prevents exon exclusion,and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-,glutamate-,valine-,and lysine-rich(PEVK) domain and another part of the I-band region of titin.In summary,SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin.

Comparison of Cox Model Methods in A Low-dimensional Setting with Few Events

Prognostic models based on survival data frequently make use of the Cox proportional hazards model. Developing reliable Cox models with few events relative to the number of predictors can be challenging, even in low-dimensional datasets, with a much larger number of observations than variables. In such a setting we examined the performance of methods used to estimate a Cox model, including （i） full model using all available predictors and estimated by standard techniques, （ii） backward elimination （BE）, （iii） ridge regression, （iv） least absolute shrinkage and selection operator （lasso）, and （v） elastic net. Based on a prospective cohort of patients with manifest coronary artery disease （CAD）, we performed a simulation study to compare the predictive accuracy, calibration, and discrimination of these approaches, Candidate predictors for incident cardiovascular events we used included clinical variables, biomarkers, and a selection of genetic variants associated with CAD. The penalized methods, i.e., ridge, lasso, and elastic net, showed a comparable performance, in terms of predictive accuracy, calibration, and discrimination, and outperformed BE and the full model. Excessive shrinkage was observed in some cases for the penalized methods, mostly on the simulation scenarios having the lowest ratio of a number of events to the number of variables. We conclude that in similar settings, these three penalized methods can be used interchangeably. The full model and backward elimination are not recommended in rare event scenarios.