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.

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.

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

takotsubo 心肌症(TTC ) 的复发是著名复杂并发症。然而，当前的文学列出仅仅一些孤立的盒子。我们试图决定发生和周期性的 TTC.Methods 与组成的 ResultsOur 机构的数据库的临床的意义一自从 2003，与 TTC 诊断的 114 个病人集体。这些病人的靠近的后续在这些中的七个揭示了 TTC 的复发(6.1%) 。在索引事件和它的复发之间的时间间隔在六个月和六年之间变化了。动脉的高血压是与非复发组相比在 TTC 的复发组揭示的更多，(P = 0.02 ) 。长期的妨碍的肺的疾病或气喘是在复发组诊断的更多，(P = 0.04 ) 。临床的事件喜欢恰好室的参与， TTC 相关复杂并发症象威胁生活的心律不齐那样，肺的拥挤并且在医院里，死亡在周期性的事件更经常被观察。在索引事件不是不平常的现象以后，在一年的吝啬的后续上，死亡率在在六年以内的 TTC 的两 groups.ConclusionsRecurrence 是类似的。万一在恶化阶段的恰好室的参与，它可能与更高的复杂并发症率被联系。TTC 复发应该是在有 TTC 的过去的历史的病人的第一微分诊断。

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.

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.

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.

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.

Retinal microvascular signs and recurrent vascular events in patients with TIA or minor stroke

Background and purpose Retinal pathologies are an independent risk factor for ischaemic stroke,but research on the predictive value of retinal abnormalities for recurrent vascular events in patients with prior stroke is inconclusive.We investigated the association of retinal pathologies with subsequent vascular events.Methods In a substudy of the Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients(INSPiRE-TMS)trial,we enrolled patients with recent transient ischaemic attack(TIA)or minor stroke with at least one modifiable risk factor.Primary outcome was the composite of subsequent vascular events.Retinal photographs were taken at baseline and categorised into three different fundus groups by a telemedically linked ophthalmologist.Results 722 patients participated in the current study and 109 major vascular events occurred.After multivariable adjustments,we did not find a significant association between fundus categories and risk for subsequent vascular events(HRs for moderate vascular retinopathy and vascular retinopathy with vessel rarefaction in comparison to no vascular retinopathy 1.03(95%CI 0.64 to 1.67),p=0.905 and 1.17(95%CI 0.62 to 2.20),p=0.626).In a selective post hoc analysis in patients with diabetes mellitus and hypertension,patients with vascular retinopathy with vessel rarefaction had a higher risk for recurrent stroke(HR 24.14(95%CI 2.74 to 212.50),p=0.004).Conclusions Retinal changes did not predict major subsequent vascular events in patients with recent TIA or minor stroke.Further studies are needed to examine the utility of fundus photography in assessing the risk of stroke recurrence in patients with diabetes mellitus and hypertension.

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.

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.

Time's up:mutation rate and lifespan

In a recent study published in Nature,Alex Cagan,Adrian Baez-Ortega and colleagues found that many mammalian species present a similar somatic mutational load at the end of life.The mutational burden is independent of lifetime and body mass,only varying by a relatively small fold change among species.1These data may suggest that mutational burden predicts mortality.