Volume 46, Issue 35

European Heart Journal, Issue at a Glance, Volume 46, Issue 35. Focus Issue, Arrhythmias and Genetics, by Editor-in-Chief Professor Filippo Crea. Read to you by Morgan Bryan. genes, long non-coding RNAs and nucleic acid-base therapies. Our genetics is changing the present and future of cardiovascular diseases.

This focus issue on arrhythmias and genetics contains a state-of-the-art review article entitled Physiological Pacing, Mechanisms, Clinical Indications and Perspectives by Zachary Winnett and colleagues from Imperial College London in the United Kingdom in which the authors review the evolving field of physiological pacing. Normal cardiac function depends on a highly efficient cardiac conduction system.

Conduction system disease impairs cardiac function which can reduce exercise capacity, force symptoms such as breathlessness and fatigue and, if severe, result in syncope and death. Pacemakers were originally developed to treat profound bradycardia caused by complete heart block. However, pacing the right ventricle leads to non-physiological activation of the ventricular myocardium.

reducing global cardiac performance. Early developments in physiological pacing focused on promoting intrinsic activation, delivering more physiological heart rate responses during exercise,

and coordinating atrial and ventricular activation. More recently, the focus has shifted to delivering pacing which preserves or restores normal ventricular activation patterns including atrio biventricular pacing, conduction system pacing by his bundle pacing, left bundle branch pacing, left septal pacing, and Bachmann's bundle pacing.

Adoption of these more physiological approaches might reduce the adverse effects of pacing as well as expanding pacing indications to treatment of other forms of conduction system disease.

Advancements in gene editing technology hold the promise of revolutionising the management of cardiovascular and metabolic disorders by targeting the genetically regulated pathways underlying these diseases.

In a state-of-the-art review article entitled Gene Therapy and Genome Editing for Lipoprotein Disorders, Chen Gurevich and colleagues from the Icahn School of Medicine at Mount Sinai in New York, New York, USA, revisit major monogenic and polygenic disorders of lipoprotein metabolism, including familial hypercholesterolemia, elevated lipoprotein, and familial chylomicronemia syndrome.

and discuss the genetic-based therapies for management. Genetic factors play a critical role in the development of lipoprotein disorders. which significantly contribute to atherosclerotic cardiovascular disease or ASCVD. Traditional management of these conditions has relied on lipid lowering therapies. which require lifelong adherence. Recent advancements in gene addition and editing technologies offer novel and potential transformative approaches for treating lipoprotein disorders

by targeting the relevant genetic pathways for each disease. RNA based, gene addition and gene editing therapies including clustered regularly interspaced short palindromic repeats or

CRISPR-based editing and interventions are highlighted for their potential to provide durable treatments which overcome the adherence challenge. Integration of machine learning for risk prediction and the use of polygenic risk scores to enhance risk stratification further demonstrate the promise of personalized approaches and overall potential for gene-based treatments

to revolutionize ASCVD prevention and management. Though it's hypothesized that only a proportion of long non-coding RNAs or LNC RNAs are functional, it is definitively established that several are essential in cardiac homeostasis or as mediators of cardiovascular complications. In a viewpoint article entitled Missing LNCs. How insufficient scrutiny can lead to misrepresentation of long non-coding RNAs, LNC RNAs, and their function in cardiovascular disease.

Matthew Bennett, Igor Ulitsky, and Andrew Baker from the University of Edinburgh in the United Kingdom and Wiseman Institute of Science in Rehoboth, Israel, provide a critical perspective

that will help cardiovascular reviewers and editors navigate the complexities involved in lncRNA research. A typical lncRNA is expressed only in particular cell types or states, with a lower expression, a lower conservation level across species and a more complex set of possible transcript variants or isoforms when compared with a typical protein coding gene.

Many lncRNAs are also expressed as genome regions with overlapping genes and other functionality. For instance, they may overlap regulatory DNA elements bound by transcription factors, e.g. enhancers that boost nearby gene transcription, or be processed into small RNAs including microRNAs. Further advances in protein coding gene annotation methods have indicated that some lncRNAs produce small functional peptides and thus require reclassification as protein coding genes.

The combination of these features presents a substantial challenge for gene annotation and experimental study, e.g., which isoforms are relevant, which may produce a small RNA, Do answers to these questions vary across cell types? Which techniques are appropriate to assess this? How will this affect interpretation of experimental data?

Some answers to these questions can be sought in easily accessible genomic resources and by scrutinizing the lncRNA gene locus in a genome browser. However, relying solely on broad brush approaches may downplay their complexity in many cases.

It's a progressive disease associated with a high incidence of heart failure and arrhythmias and has a poor prognosis. Cardiac amyloidosis is often advanced at the time of diagnosis. Therefore, its early diagnosis will have a significant prognostic effect on life expectancy. In a clinical research article entitled Atrial Amyloidosis

identified by biopsy in atrial fibrillation, prevalence and clinical presentation. Kodai Shinzato and colleagues from the Saga University in Japan aim to assess the prevalence of CA in patients with non-valvular atrial fibrillation or AF and to test the hypothesis that early stage CA can be identified through atrial biopsy.

atrial biopsy was performed on 578 patients during af ablation the amyloid type was assessed using immunohistochemistry Patients were classified into groups of atrial biopsy detected CA or ABIOCA and non-CA with an additional 58 patients clinically diagnosed with CA comprising the clinical CA group. Amyloid deposits were identified in atrial samples from 40 patients, or 7%, including 25 amyloid transthyretin, or ATTR, types.

Prevalence increased to 20-40% with advancing age, left ventricular or LV hypertrophy and the presence of low voltage areas in the left atrium. The ABIOCA group exhibited a thinner LV posterior wall, P being less than 0.001, compared with the clinical CA group. The ABIOCA group displayed a thicker LV posterior wall, P being less than 0.001 and a higher frequency of low voltage areas defined as less than 0.5 millivolts P being less than 0.001 compared with the non-CA group.

The authors conclude that atrial biopsy reveals amyloid deposits in 7% of patients undergoing AF ablation, identifying early stage CA. The manuscript is accompanied by an editorial. by Arnella Salgic, Alicia Niskala and Tomas Jespertsson from the University of Copenhagen in Denmark. The authors underscore that the findings of Shinzato et al.

suggests that atrial biopsies may serve as a promising prognostic marker for identifying early-stage CA. Biopsies can, without increased risk, be harvested during AF ablation, catheter, and open chest procedures. As patients with CA commonly present with AF and increased risk of stroke and HF, there appears to be a causal link between the comorbidities

rather than them existing as separate co-occurring conditions. Early intervention and detection are vital to better understand how CA contributes to these conditions. In combination with current imaging modalities, echocardiography stroke magnetic resonance imaging, or MRI, and histological confirmation of amyloid deposits from atrial and ventricular biopsies, Initiation of early therapeutic treatments can affect patient outcomes and lead to longer survival times.

or SCD, during childhood and adolescence, occurs with an estimated frequency of 1 to 3 in 100,000 person years. Inherited primary arrhythmia syndrome, such as long QT syndrome, or LQTS, might be the underlying cause of such tragic events. Long QT syndrome is a genetic disorder, altering cardiomyocyte action potential and is associated with an increased risk.

for life-threatening rhythm disturbances. In a clinical research article entitled Long QT Syndrome in Children and Adolescents Risk Factors and Outcomes in a Large German Cohort Leah Lippert and colleagues from the Technical University of Munich in Germany describe outcomes in a large contemporary national cohort of children and adolescents with LQTS.

The authors carried out data analysis of 548 paediatric LQTS patients at 12 German tertiary care centres. The primary outcome... was the occurrence of a major arrhythmic event, or MAE, defined as SCD, aborted cardiac arrest, or ACA, and appropriate implantable cardioverted defibrillator, or... ICD therapy before the age of 18 years. Patients 49% male presented at a median age of 6.3 years with incidental findings 27%

symptoms 31% and for cascade screening 42%. The primary outcome occurred in 10.6% of patients, SCD in 1.3%, ACA in 7.3%, and appropriate ICD therapy in 2% with an overall event rate of 1.0 per 100 patient years at risk. During follow-up before 18 years of age, 92% of patients received cardiac medications. An ICD was implanted in 13.3% of whom 34% received appropriate therapy.

In multivariable analysis the likelihood of experiencing an MAE was greater in patients with LQTS hazard ratio or HR 2.5 P equaling 0.03 syncope hr 3.0 p being less than 0.01 absence of cardiac medication hr 9.5 p being less than 0.01 and QTC greater than or equal to 500 milliseconds HR 2.9 P being less than 0.01 The authors conclude that pediatric LQTS patients are at risk for life-threatening arrhythmias at less than 18 years of age and require a meticulous personalized clinical approach.

The manuscript is accompanied by an editorial by Peter Schwarz and Carla Spazzolini from the Instituto Auxologico Italiano e ArcGIS in Milan, Italy. The authors note that Lippert et al. have the merit of having provided relevant information on the very important population below the age of 18. There are not many reports, especially recent ones, on this subset of LQTS patients of any genotype.

Their study is a welcome contribution to the field, as on the one hand, it provides a reliable picture of what is likely to happen to young Germans affected by LQTS. and on the other hand offers a rather unique comparison with their management elsewhere. This comparison offers the possibility of an unabashed and frank analysis of what occurs in different countries and in different centres.

which might lead some of them to consider changing their management strategies for the benefit of LQTS patients elsewhere.

Atrial fibrosis represents a critical determinant of AF pathogenesis. Although endothelial dysfunction is a hallmark feature of AF, the precise mechanisms by which endothelial cells or ECs contribute to atrial fibrosis, remain incompletely understood. In a translational science article entitled, Endothelial Plasticity...

in atrial fibrosis by integrating single cell sequencing and genetic lineage tracing. Jiwei Zhang from the Peking Union Medical School in Beijing, China provide novel insights into the pathophysiology of atrial fibrosis. to analyse intercellular communication networks in atrial tissues from both sinus rhythm, or SR, and AF patients. were generated to track endothelial plasticity following transverse aortic constriction or TAC.

Cell-cell interaction were investigated using isolated human primary atrial ECs and fibroblasts in vitro. To elucidate the regulatory role of endothelial-derived transforming growth factor β1, or TGFβ1, on FB function, endothelial-specific TGFβ1 knockout mice were generated. SCRNA-seq analysis identified ECs as predominant signal sending cells with extensive FB connectivity in both SR and AF atrial tissues.

During progression of fibrosis, ECs displayed significant mesenchymal activation at the transcriptional level. However, immunofluorescence and high content screening revealed minimal complete endothelial to FB transition. Cell-cell communication analysis and in vitro studies identified a TGFb1 as the key mediator through which mesenchymal-activated ECs, or endo-MA, promoted FB proliferation and collagen production. Notably, endothelial-specific TGF-beta-1 deletion

attenuated TAC-induced atrial fibrosis and reduced AF susceptibility. The authors conclude that the findings demonstrated that endo-MA-derived TGF-beta-1 critically regulates FB function and drives progression of atrial fibrosis. Targeting endothelial specific pathways represents a promising therapeutic strategy for attenuating atrial fibrosis in af pathogenesis the manuscript is accompanied by an editorial by guillermo luxan and samuel sosala from the goethe university frankfurt in germany

and Justus Liebig University Gießen in Germany. The authors note that it is undisputed that fibrosis is one of the key players in the pathophysiology of AF, and it is, of course, closely linked to and influences electrical remodeling. Despite its clinical significance, no specific therapies currently target atrial fibrosis directly.

An urgent gap highlighted by the DCAF2 trial, which demonstrated that MRI-guided fibrosis ablation did not significantly reduce AF recurrence compared with conventional ablation. This indeed underscores the crucial need for a deeper understanding of the underlying pathophysiology as the foundation for developing innovative fibrosis-targeted treatments.

a perspective that is also increasingly emphasized from a clinical standpoint regarding therapeutic implementation. The potential implementation of such a therapeutic approach remains unclear at present. as early intervention will probably be required, ideally before significant fibrosis and fibrosis-dependent AF occur. Consequently, future discussions and research will probably focus on concepts

such as treating patients at risk and preventative strategies in the context of such approaches. In conclusion, a deeper understanding of the pathophysiology of AF particularly the roles of endothelial plasticity and fibrosis, is essential for advancing treatment strategies.

Familial ST depression, or FSTD syndrome, is a recently identified inherited cardiac disease associated with arrhythmias and systolic dysfunction. The underlying genetic etiology has remained elusive. In a translational science article entitled, Gain-of-function enhancer variant near KCNB1 causes familial ST depression syndrome. Alex Holby Christensen and colleagues from the Copenhagen University Hospital Rijkshospitalet in Denmark characterize a non-coding variant near KCNB1

as the cause of the dominantly inherited FSTD syndrome. A total of 67 FSTD patients, 20 families, were studied. Linkage analysis and whole genome sequencing or WGS were initially performed. An identified non-coding variant was functionally characterized in AC16 human cardiomyocytes, muscle tissues and human myocardium. In silico analyses, luciferase and DCAS9 activator stroke repressor assays, protein DNA experiments, chromosome confirmation capture, or 4C,

and RNA sequencing were also performed. The electrocardiographic, or ECG, phenotype was inherited in an autosomal dominant manner in all families. Linkage analysis revealed a single peak on chromosome 20 and WGS identified a single rare non-coding variant located 18 kilobase downstream of KCNB1 on chromosome 20. in all affected individuals. Perfect co-segregation with ECG phenotype was observed together with full penetrance in all families. The variant creates an MEF2 binding site.

and the presence of the variant allele or MEF2 co-expression enhanced transcriptional activity. DCAS9 activator stroke repressor assays showed that KCNB1 was the only gene consistently regulated by the locus, and 4C experiments in AC16 cells and human muscle tissue confirmed the locus-KCNB1 promoter interaction. Expression analysis in human endocardial tissue did not document any change in gene expression, probably explained by expressional heterogeneity.

The authors conclude that a gain-of-function enhancer variant creates a hyperactive regulatory locus that interacts with the KCNB1 promoter and causes FSTD. This is the first time that KCNB1 has been implicated in human cardiac electrophysiology and arrhythmogenesis. The manuscript is accompanied by an editorial. from the University of Oslo in Norway and Karolinska University Hospital in Stockholm, Sweden. The authors highlight that the genetic era has shown us multiple times

that previously unseen and unknown syndromes suddenly become visible, explainable and in many cases even treatable with risk-reducing agents. However, you see only what you look for. Due to the eye-opening studies from our colleagues, we will probably find these patients in every centre and region. Should we regard the new entity as a typical ion channel disease? Probably not.

A significant number of patients with FSTD syndrome had concomitant and progressive LV dysfunction, indicating the overlap between ion channel and functional dysfunction. Interestingly, The ECGST depressions were also slowly progressive over time, which is not seen in other ion channelopathies. These findings add to previous reports showing that altered ion channel function

is associated with subtle or overt changes in cardiac function and structure. These findings add to previous reports showing that altered ion channel function is associated with subtle or overt changes in cardiac function and structure, exemplified by Brugada syndrome and the LQTS. The impressive work from this group has covered the chain from clinical presentation to definition to inheritance pattern and they have now in this translational work demonstrated the genetic causative variant.

The issue is also complemented by two discussion forum contributions. In a commentary entitled, Gender-Specific Associations and Circulating Proteins in Myocardial Infarction. potential causal relationships. and Shuzhou Medical University in China, comment on the recently published paper entitled Plasma Proteome and Incident Myocardial Infarction Sex Specific Differences by Olga Titova et al from Uppsala University in Sweden. Titova and colleagues reply in a separate contribution.

The editors hope that this issue of the European Heart Journal will be of interest to its listeners.