A multi-omic atlas of human embryonic skeletal development.

Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception.

An organotypic atlas of human vascular cells.

The human vascular system, comprising endothelial cells (ECs) and mural cells, covers a vast surface area in the body, providing a critical interface between blood and tissue environments. Functional differences exist across specific vascular beds, but their molecular determinants across tissues remain largely unknown. In this study, we integrated single-cell transcriptomics data from 19 human organs and tissues and defined 42 vascular cell states from approximately 67,000 cells (62 donors), including angiotypic transitional signatures along the arterial endothelial axis from large to small caliber vessels.

Multidimensional Analysis of the Adult Human Heart in Health and Disease Using Hierarchical Phase-Contrast Tomography.

Background Current clinical imaging modalities such as CT and MRI provide resolution adequate to diagnose cardiovascular diseases but cannot depict detailed structural features in the heart across length scales. Hierarchical phase-contrast tomography (HiP-CT) uses fourth-generation synchrotron sources with improved x-ray brilliance and high energies to provide micron-resolution imaging of intact adult organs with unprecedented detail. Purpose To evaluate the capability of HiP-CT to depict the macro- to microanatomy of structurally normal and abnormal adult human hearts ex vivo.

Biallelic variants in cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy.

encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of in mice results in sinus pauses and bradycardia and morpholino knockdown of zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy.

Multidimensional Analysis of the Adult Human Heart in Health and Disease using Hierarchical Phase-Contrast Tomography (HiP-CT).

Cardiovascular diseases (CVDs) are a leading cause of death worldwide. Current clinical imaging modalities provide resolution adequate for diagnosis but are unable to provide detail of structural changes in the heart, across length-scales, necessary for understanding underlying pathophysiology of disease. Hierarchical Phase-Contrast Tomography (HiP-CT), using new (4) generation synchrotron sources, potentially overcomes this limitation, allowing micron resolution imaging of intact adult organs with unprecedented detail.

Spatially resolved multiomics of human cardiac niches.

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations.

The Ycx1 protein encoded by the yeast YDL206W gene plays a role in calcium and calcineurin signaling.

Calcium is ubiquitously present in all living cells and plays important regulatory roles in a wide variety of biological processes. In yeast, many effects of calcium are mediated via the action of calcineurin, a calcium/calmodulin-dependent protein phosphatase. Proper signaling of calcium and calcineurin is important in yeast, and the calcineurin pathway has emerged as a valuable target for developing novel antifungal drugs.

A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity.

Re-activating quiescent adult epicardium represents a potential therapeutic approach for human cardiac regeneration. However, the exact molecular differences between inactive adult and active fetal epicardium are not known. In this study, we combined fetal and adult human hearts using single-cell and single-nuclei RNA sequencing and compared epicardial cells from both stages.

Erratum: Author Correction: A single-cell comparison of adult and fetal human epicardium defines the age-associated changes in epicardial activity.

[This corrects the article DOI: 10.1038/s44161-022-00183-w.].

Single-cell transcriptomics for the assessment of cardiac disease.

Cardiovascular disease is the leading cause of death globally. An advanced understanding of cardiovascular disease mechanisms is required to improve therapeutic strategies and patient risk stratification. State-of-the-art, large-scale, single-cell and single-nucleus transcriptomics facilitate the exploration of the cardiac cellular landscape at an unprecedented level, beyond its descriptive features, and can further our understanding of the mechanisms of disease and guide functional studies.

Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies.

Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states.

Impact of COVID-19 pandemic on cardiac rhythm management services: Views from the United Kingdom.

Background: Effects of the COVID-19 pandemic on cardiac rhythm management (CRM) services remain poorly quantified.

Objective: To describe the impact of COVID-19 on specialist CRM centers in the United Kingdom (UK).

Methods: Two-center study involving the Liverpool Heart and Chest Hospital NHS Foundation Trust and Royal Papworth Hospital NHS Foundation Trust.

Pulsed Levosimendan in advanced heart failure due to congenital heart disease: a case series.

Background: Levosimendan is a non-adrenergic calcium-sensitizing agent with positive inotropic and vasodilatory effects. Its use in acute decompensation of heart failure is established. Good evidence now exists for repetitive infusions of Levosimendan to improve symptoms and reduce hospitalization in advanced heart failure (AdHF) populations.

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.

Catastrophic antiphospholipid syndrome causing ST-segment elevation myocardial infarction with non-obstructive coronary arteries.

A 51-year-old woman with known primary antiphospholipid syndrome presented with a 4-day history of chest and abdominal pain, inferior ST-segment elevation on a 12-lead ECG and a subtherapeutic international normalised ratio. In view of a significantly raised high-sensitivity troponin I assay, inferior wall hypokinesis on transthoracic echocardiography and despite unobstructed epicardial vessels on emergency coronary angiography, a diagnosis of myocardial infarction was made. Furthermore, the patient also developed both bilateral adrenal haemorrhages leading to acute adrenal insufficiency and microvascular thrombotic renal disease concurrently.

Clinical outcomes of bioresorbable vascular scaffolds implanted with routine versus selective optical coherence tomography guidance: results from a single-centre experience.

Aims: We aimed to investigate the effects of an initial learning period with mandatory optical coherence tomography (OCT) guidance for the implantation of everolimus-eluting bioresorbable vascular scaffolds (BVS).

Methods And Results: We analysed procedural and clinical outcomes of all BVS implantations at a single centre where OCT guidance was mandatory in the initial rollout (OCT-mandatory) phase. We compared these data with the later phase where use of OCT was at operator discretion (OCT-selective or angiography).

Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β) murine hearts.

Introduction: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors.

Materials And Methods: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA.

Results And Discussion: Young and aged Pgc-1β showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT.

The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: implications for neural control of cardiac excitability.

The autonomic phenotype of congestive cardiac failure is characterised by high sympathetic drive and impaired vagal tone, which are independent predictors of mortality. We hypothesize that impaired bradycardia to peripheral vagal stimulation following high-level sympathetic drive is due to sympatho-vagal crosstalk by the adrenergic co-transmitters galanin and neuropeptide-Y (NPY). Moreover we hypothesize that galanin acts similarly to NPY by reducing vagal acetylcholine release via a receptor mediated, protein kinase-dependent pathway.

Growth factor staining patterns in the pig retina following retinal laser photocoagulation.

Aim: To identify changes in growth factor expression in miniature pig retinas following retinal laser photocoagulation.

Methods: Pigs were sacrificed at different times (15 minutes to 42 days) post-laser and the retinas were immunolabelled for basic fibroblast growth factor, insulin-like growth factor I, transforming growth factor beta, epidermal growth factor, transforming growth factor alpha, platelet derived growth factor, vascular endothelial growth factor, and epidermal growth factor receptor. Total mRNA levels were also determined.