Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses.

Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that drive electrical conduction disorders and AF (i.e.

Quaking regulates circular RNA production in cardiomyocytes.

Circular RNAs (circRNAs) are a class of non-coding RNA molecules that are gaining increasing attention for their roles in various pathophysiological processes. The RNA-binding protein quaking (QKI) has been identified as a regulator of circRNA formation. In this study, we investigate the role of QKI in the formation of circRNAs in the heart by performing RNA-sequencing on Qki-knockout mice.

Splicing factors in the heart: Uncovering shared and unique targets.

Alternative splicing generates specialized protein isoforms that allow the heart to adapt during development and disease. The recent discovery that mutations in the splicing factor RNA-binding protein 20 (RBM20) cause a severe form of familial dilated cardiomyopathy has sparked a great interest in alternative splicing in the field of cardiology. Since then, identification of splicing factors controlling alternative splicing in the heart has grown at a rapid pace.

The RNA-binding protein QKI governs a muscle-specific alternative splicing program that shapes the contractile function of cardiomyocytes.

Aims: In the heart, splicing factors orchestrate the functional properties of cardiomyocytes by regulating the alternative splicing of multiple genes. Work in embryonic stem cells has shown that the splicing factor Quaking (QKI) regulates alternative splicing during cardiomyocyte differentiation. However, the relevance and function of QKI in adult cardiomyocytes remains unknown.

Inhibition of minor intron splicing reduces Na+ and Ca2+ channel expression and function in cardiomyocytes.

Eukaryotic genomes contain a tiny subset of 'minor class' introns with unique sequence elements that require their own splicing machinery. These minor introns are present in certain gene families with specific functions, such as voltage-gated Na+ and voltage-gated Ca2+ channels. Removal of minor introns by the minor spliceosome has been proposed as a post-transcriptional regulatory layer, which remains unexplored in the heart.

Extracellular matrix remodeling in animal models of anthracycline-induced cardiomyopathy: a meta-analysis.

As in other cardiomyopathies, extracellular matrix (ECM) remodeling plays an important role in anthracycline-induced cardiomyopathy. To understand the pattern and timing of ECM remodeling pathways, we conducted a systematic review in which we describe protein and mRNA markers for ECM remodeling that are differentially expressed in the hearts of animals with anthracycline-induced cardiomyopathy. We included 68 studies in mice, rats, rabbits, and pigs with follow-up of 0.

Dietary restriction in the long-chain acyl-CoA dehydrogenase knockout mouse.

Patients with a disorder of mitochondrial long-chain fatty acid β-oxidation (FAO) have reduced fasting tolerance and may present with hypoketotic hypoglycemia, hepatomegaly, (cardio)myopathy and rhabdomyolysis. Patients should avoid a catabolic state because it increases reliance on FAO as energy source. It is currently unclear whether weight loss through a reduction of caloric intake is safe in patients with a FAO disorder.

Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes.

Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues.

Low miR-19b-1-5p Expression Is Related to Aspirin Resistance and Major Adverse Cardio- Cerebrovascular Events in Patients With Acute Coronary Syndrome.

Background Because of a nonresponse to aspirin (aspirin resistance), patients with acute coronary syndrome (ACS) are at increased risk of developing recurrent event. The in vitro platelet function tests have potential limitations, making them unsuitable for the detection of aspirin resistance. We investigated whether miR-19b-1-5p could be utilized as a biomarker for aspirin resistance and future major adverse cardio-cerebrovascular (MACCE) events in patients with ACS.

Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice.

Aims: SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms.

MiR-223-3p and miR-122-5p as circulating biomarkers for plaque instability.

Background: In this study, we discovered and validated candidate microRNA (miRNA) biomarkers for coronary artery disease (CAD).

Method: Candidate tissue-derived miRNAs from atherosclerotic plaque material in patients with stable coronary artery disease (SCAD) (n=14) and unstable coronary artery disease (UCAD) (n=25) were discovered by qPCR-based arrays. We validated differentially expressed miRNAs, along with seven promising CAD-associated miRNAs from the literature, in the serum of two large cohorts (n=395 and n=1000) of patients with SCAD and UCAD and subclinical atherosclerosis (SubA) and controls, respectively.

circRNAprofiler: an R-based computational framework for the downstream analysis of circular RNAs.

Background: Circular RNAs (circRNAs) are a newly appreciated class of non-coding RNA molecules. Numerous tools have been developed for the detection of circRNAs, however computational tools to perform downstream functional analysis of circRNAs are scarce.

Results: We present circRNAprofiler, an R-based computational framework that runs after circRNAs have been identified.

Loss-of-function variants in myocardin cause congenital megabladder in humans and mice.

Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants.

Conserved NPPB+ Border Zone Switches From MEF2- to AP-1-Driven Gene Program.

Background: Surviving cells in the postinfarction border zone are subjected to intense fluctuations of their microenvironment. Recently, border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here, we defined their unique transcriptional and regulatory properties, and comprehensively validated new molecular markers, including Nppb, encoding B-type natriuretic peptide, after infarction.

Circular RNAs open a new chapter in cardiovascular biology.

Circular RNAs (circRNAs) are emerging as a new class of non-coding RNA molecules. This unusual class of RNA species is generated by a back-splicing event of one or two exons, resulting in a covalently closed circRNA molecule. Owing to their circular form, circRNAs are protected from degradation by exonucleases and have greater stability than linear RNA.

Circular RNAs in the cardiovascular system.

Until recently considered as rare, circular RNAs (circRNAs) are emerging as important regulators of gene expression. They are ubiquitously expressed and represent a novel branch of the family of non-coding RNAs. Recent investigations showed that circRNAs are regulated in the cardiovascular system and participate in its physiological and pathological development.

AAV9-mediated Rbm24 overexpression induces fibrosis in the mouse heart.

The RNA-binding protein Rbm24 has recently been identified as a pivotal splicing factor in the developing heart. Loss of Rbm24 in mice disrupts cardiac development by governing a large number of muscle-specific splicing events. Since Rbm24 knockout mice are embryonically lethal, the role of Rbm24 in the adult heart remained unexplored.

Study Design and qPCR Data Analysis Guidelines for Reliable Circulating miRNA Biomarker Experiments: A Review.

Background: In the past decade, the search for circulating microRNA (miRNA) biomarkers has yielded numerous associations between miRNAs and different types of disease. However, many of these relations could not be replicated in subsequent studies under similar experimental conditions. Although this lack of replicability may be explained by the variation in experimental design and analysis methods, guidelines on the most appropriate design and analysis methods to study circulating miRNAs are scarce.

Nur77 protects against adverse cardiac remodelling by limiting neuropeptide Y signalling in the sympathoadrenal-cardiac axis.

Aims: Cardiac remodelling and heart failure are promoted by persistent sympathetic activity. We recently reported that nuclear receptor Nur77 may protect against sympathetic agonist-induced cardiac remodelling in mice. The sympathetic co-transmitter neuropeptide Y (NPY) is co-released with catecholamines and is a known cardiac modulator and predictor of heart failure mortality.

A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy.

Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. Here, we investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy.

Methods And Results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation-negative relatives.

RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling.

Background: Mutations in RBM20 (RNA-binding motif protein 20) cause a clinically aggressive form of dilated cardiomyopathy, with an increased risk of malignant ventricular arrhythmias. RBM20 is a splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and CAMK2D (calcium/calmodulin-dependent kinase II delta). Aberrant TTN splicing is thought to be the main determinant of RBM20-induced dilated cardiomyopathy, but is not likely to explain the increased risk of arrhythmias.

Cardiac circRNAs arise mainly from constitutive exons rather than alternatively spliced exons.

Circular RNAs (circRNAs) are a relatively new class of RNA molecules, and knowledge about their biogenesis and function is still in its infancy. It was recently shown that alternative splicing underlies the formation of circular RNAs (circRNA) arising from the Titin gene. Since the main mechanism by which circRNAs are formed is still unclear, we hypothesized that alternative splicing, and in particular exon skipping, is a major driver of circRNA production.