A novel tsRNA-5008a promotes ferroptosis in cardiomyocytes that causes atrial structural remodeling predisposed to atrial fibrillation.

Atrial fibrillation (AF) is an extremely common clinical arrhythmia disease, but whether its mechanism is associated with ferroptosis remains unclear. The tRNA-derived small RNAs (tsRNAs) are involved in a variety of cardiovascular diseases, however, their role and mechanism in atrial remodeling in AF have not been studied. We aimed to explore whether tsRNAs mediate ferroptosis in AF progression. The AF models were constructed to detect ferroptosis-related indicators, and Ferrostatin-1 (Fer-1) was introduced to clarify the relationship between ferroptosis and AF. Atrial myocardial tissue was used for small RNA sequencing to screen potential tsRNAs. tsRNA functioned on ferroptosis and AF was explored. Atrial fibrosis and changes in the cellular structures and arrangement were observed in AF mice model, and these alterations were accompanied by ferroptosis occurrence, exhibited by the accumulation of Fe2+ and MDA levels and the decrease of expression of FTH1, GPX4, and SLC7A11. Blocking above ferroptosis activation with Fer-1 resulted in a significant improvement for AF. A total of 7 tsRNAs were upregulated (including tsRNA-5008a) and 2 tsRNAs were downregulated in atrial myocardial tissue in the AF group compared with the sham group. We constructed a tsRNA-mRNA regulated network, which showed tsRNA-5008a targeted 16 ferroptosis-related genes. Knockdown of tsRNA-5008a significantly suppressed ferroptosis through targeting SLC7A11 and diminished myocardial fibrosis both in vitro and in vivo. On the contrary, tsRNA-5008a mimics promoted ferroptosis in cardiomyocytes. Collectively, tsRNA-5008a involved in AF through ferroptosis. Our study provides novel insights into the role of tsRNA-5008a mediated ferroptosis in AF progression.

Impact of rs1805127 and rs55742440 Variants on Atrial Remodeling in Hypertrophic Cardiomyopathy Patients with Atrial Fibrillation: A Romanian Cohort Study.

Atrial fibrillation (AFib) is characterized by a complex genetic component. We aimed to investigate the association between variations in genes related to cardiac ion handling and AFib in a cohort of Romanian patients with hypertrophic cardiomyopathy (HCM). Forty-five unrelated probands with HCM were genotyped by targeted next-generation sequencing (NGS) for 24 genes associated with cardiac ion homeostasis. Subsequently, the study cohort was divided into two groups based on the presence (AFib+) or absence (AFiB-) of AFib detected during ECG monitoring. We identified two polymorphisms (rs1805127 located in KCNE1 and rs55742440 located in SCN1B) linked to AFib susceptibility. In AFib+, rs1805127 was associated with increased indexed left atrial (LA) maximal volume (LAVmax) (58.42 ± 21 mL/m2 vs. 32.54 ± 6.47 mL/m2, p < 0.001) and impaired LA strain reservoir (LASr) (13.3 ± 7.5% vs. 24.4 ± 6.8%, p < 0.05) compared to those without respective variants. The rs55742440 allele was less frequent in patients with AFib+ (12 out of 25, 48%) compared to those without arrhythmia (15 out of 20, 75%, p = 0.05). Also, AFib+ rs55742440 carriers had significantly lower LAVmax compared to those who were genotype negative. Among patients with HCM and AFib+, the rs1805127 variant was accompanied by pronounced LA remodeling, whereas rs55742440's presence was related to a milder LA enlargement.

A novel therapeutic strategy for alleviating atrial remodeling by targeting exosomal miRNAs in atrial fibrillation.

Atrial fibrillation (AF) is one of the most frequent cardiac arrhythmias, and atrial remodeling is related to the progression of AF. Although several therapeutic approaches have been presented in recent years, the continuously increasing mortality rate suggests that more advanced strategies for treatment are urgently needed. Exosomes regulate pathological processes through intercellular communication mediated by microribonucleic acid (miRNA) in various cardiovascular diseases (CVDs). Exosomal miRNAs associated with signaling pathways have added more complexity to an already complex direct cell-to-cell interaction. Exosome delivery of miRNAs is involved in cardiac regeneration and cardiac protection. Recent studies have found that exosomes play a critical role in the diagnosis and treatment of cardiac fibrosis. By improving exosome stability and modifying surface epitopes, specific pharmaceutical agents can be supplied to improve tropism and targeting to cells and tissues in vivo. Exosomes harboring miRNAs may have clinical utility in cell-free therapeutic approaches and may serve as prognostic and diagnostic biomarkers for AF. Currently, limitations challenge pharmaceutic design, therapeutic utility and in vivo targeted delivery to patients. The aim of this article is to review the developmental features of AF associated with exosomal miRNAs and relate them to underlying mechanisms.

Spatial multi-omic map of human myocardial infarction.

Myocardial infarction is a leading cause of death worldwide1. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality2. Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

Study on the role and mechanism of lncRNA in the remodeling of atrial energy metabolism in rabbits with atrial fibrillation based on nano sensor technology.

The purpose is to reveal the role and mechanism of long non-coding ribonucleic acid (lncRNA) in atrial fibrillation (AF) and atrial energy metabolism remodeling. The healthy adult New Zealand rabbit was chosen as the experimental animal, and the AF rabbit models were built. Besides, the lncRNA sequencing method based on nano sensor technology was employed to detect the differentially expressed lncRNAs, and the target lncRNA and its target genes were determined through bioinformatics analysis. Subsequently, TCONS_00016478 dysfunction experiment was performed. The gene level and protein level of TCONS_00016478, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), and its downstream genes were detected. The results show that after sequencing, 99,755 new lncRNAs transcripts are found in total, of which 1,215 are significantly differentially expressed, 974 are down-regulated, and 241 are up-regulated. A new transcript TCONS_00016478 associated with the remodeling of atrial energy metabolism is further screened. Silencing TCONS_00016478 can significantly reduce PGC1-α, PPARγ, GLUT4, and CPT1 expression levels (P < 0.05). Thereby, TCONS_00016478 can affect the atrial energy metabolism remodeling and atrial fibrillation in experimental rabbits by regulating the PGC1-α/PPARγ signaling pathway.

Molecular mechanism of atrial remodeling in patients with aging atrial fibrillation under the expression of microRNA-1 and microRNA-21.

We investigated the expression levels of microRNA-1 (miRNA-1) and microRNA-21 (miRNA-21) in the atrial tissues of patients with atrial fibrillation (AF) and the molecular mechanism of action in atrial remodeling. Patients with valvular heart disease were selected as the subjects. The ultrastructure, degree of myocardial fibrosis, apoptosis index (AI), expression of microRNA-1, expression of microRNA-21, and mRNA of TIMP-1, MMP-9, BCL-2, and Bax of patients were compared and analyzed in each group. The results showed that the degree of myocardial fibrosis and AI in patients with AF of the same age were extremely higher than those of patients with sinus rhythm (SR) (P < 0.01). Patients with AF showed much higher messenger RNA (mRNA) levels of mini-mental Parkinson 9 (MMP9) and Bax and obvious lover mRNA levels of tissue inhibitors of metalloproteinase 1 (TIMP-1) and Bcl-2 compared with patients with sinus rhythm (SR) (P < 0.05). It indicated that the expression of miRNA-1 in the AF patients was markedly down-regulated, and that miRNA-21 was up-regulated. This showed that microRNA-1 and microRNA-21 were involved in the molecular remodeling of aging AF through the regulation of primers, which would provide a critical basis for diagnosis and treatment of aging AF.

Urocortin Role in Ischemia Cardioprotection and the Adverse Cardiac Remodeling.

Despite the considerable progress in strategies of myocardial protection, ischemic heart diseases (IHD) and consequent heart failure (HF) remain the main cause of mortality worldwide. Several procedures are used routinely to guarantee the prompt and successful reestablishment of blood flow to preserve the myocardial viability of infarcted hearts from ischemia injuries. However, ischemic heart reperfusion/revascularization triggers additional damages that occur when oxygen-rich blood re-enters the vulnerable myocardial tissue, which is a phenomenon known as ischemia and reperfusion (I/R) syndrome. Complications of I/R injuries provoke the adverse cardiac remodeling, involving inflammation, mishandling of Ca2+ homeostasis, apoptotic genes activation, cardiac myocytes loss, etc., which often progress toward HF. Therefore, there is an urgent need to develop new cardioprotective therapies for IHD and HF. Compelling evidence from animal studies and pilot clinical trials in HF patients suggest that urocortin (Ucn) isoforms, which are peptides associated with stress and belonging to the corticotropin releasing factor family, have promising potential to improve cardiovascular functions by targeting many signaling pathways at different molecular levels. This review highlights the current knowledge on the role of urocortin isoforms in cardioprotection, focusing on its acute and long-term effects.

Changes in ion channel expression and function associated with cardiac arrhythmogenic remodeling by Sorbs2.

The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is an important component of cardiomyocyte sarcomere. It has been recently reported that loss of Sorbs2 is causally associated with arrhythmogenic cardiomyopathy in human. However, the ionic mechanisms leading to cardiac arrhythmogenesis by Sorbs2 deficiency are unknown. In this study, we hypothesized that Sorbs2 plays an important role in regulating cardiac ion channel expression and function. Using electrophysiological and molecular biological approaches, we found that the Sorbs2 knockout (KO) mice progressively developed cardiac structural and electrical remodeling as early as 1 to 2 months of age and died prematurely at 5 to 7 months of age. Electrocardiographic recordings showed that Sorbs2 KO mice had conduction delays, spontaneous ventricular extrasystoles and polymorphic ventricular tachyarrhythmia. Intracellular recordings revealed abnormal action potentials with depolarized resting potential, reduced upstroke velocity, prolonged repolarization, and effective refractory period in the ventricular preparations of Sorbs2 KO mice. Patch clamp experiments demonstrated that Sorbs2 KO mice displayed distinct abnormalities in the expression and function of cardiac ion channels, including those of the voltage-gated Na+ channels, L-type Ca2+ channels, the voltage-gated K+ channels and the inward-rectifier K+ channels. Moreover, Sorbs2 physically interacted with the RNAs and/or proteins of important cardiac ion channels and directly regulated their expression in vitro. Our results indicate that Sorbs2 plays a pivotal role in the regulation of cardiac channel physiology. Loss of Sorbs2 promotes cardiac ion channelopathies and life-threatening arrhythmias.

Serum extracellular vesicles containing MIAT induces atrial fibrosis, inflammation and oxidative stress to promote atrial remodeling and atrial fibrillation via blockade of miR-485-5p-mediated CXCL10 inhibition.

BACKGROUND: Atrial fibrillation (AF), a supraventricular arrhythmia that impairs cardiac function, is a main source of morbidity and mortality. Serum-derived extracellular vesicles (EVs) have been identified to carry potential biomarker or target for the diagnosis and treatment of AF. We intended to dissect out the role of lncRNA MIAT enriched in serum-derived EVs in AF. METHODS: MIAT expression was quantified in EVs isolated from serum samples of AF patients. Mouse and cell models of AF were developed after angiotensin II (Ang II) induction. Relationship between MIAT, miR-485-5p, and CXCL10 was identified. Ectopic expression and depletion assays were implemented in Ang II-treated mice or HL-1 cells, or those co-cultured with serum-derived EVs to explore the roles of EV-carried MIAT. RESULTS: MIAT was upregulated in EVs from serum samples of AF patients. Further analysis indicated that MIAT enriched in serum-derived EVs promoted atrial fibrosis, inflammation and oxidative stress, and aggravated the atrial remodeling and resultant AF. Mechanistically, MIAT bound to miR-485-5p and weakened its inhibitory role on the target CXCL10, which was responsible for the role of serum-derived EV containing MIAT in cellular fibrosis, oxidative stress and inflammation, and atrial remodeling in vivo. CONCLUSIONS: In conclusion, serum-derived EV containing MIAT facilitates atrial remodeling and exacerbates the AF by abolishing the miR-485-5p-mediated CXCL10 inhibition. This finding aids in the deeper understanding about the pathophysiology of AF.

Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models.

Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives.

Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Piezo1 and BKCa channels in human atrial fibroblasts: Interplay and remodelling in atrial fibrillation.

AIMS: Atrial Fibrillation (AF) is an arrhythmia of increasing prevalence in the aging populations of developed countries. One of the important indicators of AF is sustained atrial dilatation, highlighting the importance of mechanical overload in the pathophysiology of AF. The mechanisms by which atrial cells, including fibroblasts, sense and react to changing mechanical forces, are not fully elucidated. Here, we characterise stretch-activated ion channels (SAC) in human atrial fibroblasts and changes in SAC- presence and activity associated with AF. METHODS AND RESULTS: Using primary cultures of human atrial fibroblasts, isolated from patients in sinus rhythm or sustained AF, we combine electrophysiological, molecular and pharmacological tools to identify SAC. Two electrophysiological SAC- signatures were detected, indicative of cation-nonselective and potassium-selective channels. Using siRNA-mediated knockdown, we identified the cation-nonselective SAC as Piezo1. Biophysical properties of the potassium-selective channel, its sensitivity to calcium, paxilline or iberiotoxin (blockers), and NS11021 (activator), indicated presence of calcium-dependent 'big potassium channels' (BKCa). In cells from AF patients, Piezo1 activity and mRNA expression levels were higher than in cells from sinus rhythm patients, while BKCa activity (but not expression) was downregulated. Both Piezo1-knockdown and removal of extracellular calcium from the patch pipette resulted in a significant reduction of BKCa current during stretch. No co-immunoprecipitation of Piezo1 and BKCa was detected. CONCLUSIONS: Human atrial fibroblasts contain at least two types of ion channels that are activated during stretch: Piezo1 and BKCa. While Piezo1 is directly stretch-activated, the increase in BKCa activity during mechanical stimulation appears to be mainly secondary to calcium influx via SAC such as Piezo1. During sustained AF, Piezo1 is increased, while BKCa activity is reduced, highlighting differential regulation of both channels. Our data support the presence and interplay of Piezo1 and BKCa in human atrial fibroblasts in the absence of physical links between the two channel proteins.

Myocardial transcription of inflammatory and remodeling markers in cats with hypertrophic cardiomyopathy and systemic diseases associated with an inflammatory phenotype.

Feline hypertrophic cardiomyopathy (HCM) is characterized by macrophage-driven myocardial remodeling processes in a pro-inflammatory environment. To further investigate the mechanisms behind these processes, the myocardial transcription of cytokines and remodeling enzymes was comparatively assessed in cats with HCM and cats without cardiac diseases. Sixty-seven cats were included, 17 cats with HCM (including 5 with atrial thrombus; AT), and 50 cats without cardiac diseases. The latter comprised 10 control cats (no cardiac or relevant systemic disease), 34 cats with diseases suspected to be associated with a systemic inflammatory state of which 18 suffered from feline infectious peritonitis (FIP), and 6 cats with multicentric lymphoma. Samples from atria, ventricular free walls and interventricular septum were examined using quantitative reverse transcriptase PCR. The overall highest myocardial marker transcriptions were observed in cats with multicentric lymphoma, FIP and HCM, followed by diseases likely associated with a systemic inflammatory state, and control cats. Inflammatory marker transcription predominated in the myocardium of cats with systemic inflammatory diseases, whereas in HCM the transcription of remodeling enzymes prevailed. Sex significantly influenced the myocardial transcription of several remodeling enzymes. These results suggest a versatile myocardial response depending on the disease and illustrates the relevance of sex for the cardiac response to cardiac and systemic disease in cats. A systemic inflammatory state appears to elicit an inflammatory phenotype in the myocardium, whereas in HCM, the myocardium mediates its own remodeling. In HCM, the identified markers might be involved in the ongoing remodeling processes causing structural and functional changes.

The association between impairment of HDL cholesterol efflux capacity and atrial remodeling in atrial fibrillation.

This cross-sectional study enrolled 202 patients with atrial fibrillation (AF) who had undergone catheter ablation and evaluated the association between high-density lipoprotein (HDL) functionality, cholesterol efflux capacity (CEC) of HDL, and the pathophysiology of left atrial structural remodeling. Participants were divided into two groups, based on their left atrial volume index (LAVI) (< 34 mL/m2, n = 60 vs. LAVI ≥ 34 mL/m2, n = 142). We quantified three types of HDL CECs by the presence or absence of cyclic-AMP, as entire, and CEC dependent or not dependent on ATP binding cassette transporter A1 (ABCA1) and termed them Global CEC, ABCA1 CEC, and Non-ABCA1 CEC, respectively. Consequently, Global and Non-ABCA1 CECs were significantly impaired in patients with an enlarged LA (Global CEC: p = 0.039, Non-ABCA1 CEC: p = 0.022). Logistic regression analyses demonstrated that Non-ABCA1 CEC was significantly associated with an enlarged LA after adjusting for the conventional risk factors of AF. Furthermore, the association of higher Non-ABCA1 CEC with an enlarged LA was independent of serum levels of HDL cholesterol and serum myeloperoxidase (Odds ratio of 1 standard deviation higher: 0.64, 95% confidence interval: 0.43-0.95, p = 0.027). The findings of this study indicate the potential contribution of reduced Non-ABCA1 CEC in HDL to the pathophysiology in left atrial structural remodeling of patients with AF.

Cadherin-11 deficiency mitigates high-fat diet-induced inflammatory atrial remodeling and vulnerability to atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia nowadays. The occurrence of AF is closely associated with obesity. Cadherin-11 (Cad-11), as a member of the cadherin family, can make a contribution to diet-induced obesity and it will be informative to know whether Cad-11 exerts its effects on atrial remodeling and AF vulnerability in a diet-induced obesity model. In this study, we demonstrated that the expression of Cad-11 was significantly upregulated in the left atrium of AF patients with obesity and mice following 16 weeks of high-fat diet (HFD) feeding. Further confirmed that Cad-11 could regulate the activity of atrial fibroblasts by participating in inducing proinflammatory cytokines production. At animal levels, we found that although there was a lack of statistical difference in body weight, Cad-11-/- mice could markedly improve impaired glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, inflammation, and fibrosis provoked by HFD feeding were mitigated in Cad-11-/- mice. Mechanistically, Cad-11 activated mitogen-activated protein kinases and nuclear factor-κB for interleukin-6 production in atrial fibroblasts that may contribute to the atrial fibrosis process in obesity-related AF, suggesting Cad-11 might be a new therapeutic target for obesity-related AF.

The potential regulatory role of hsa_circ_0004104 in the persistency of atrial fibrillation by promoting cardiac fibrosis via TGF-ß pathway.

INTRODUCTION: The progression of paroxysmal AF (PAF) to persistent AF (PsAF) worsens the prognosis of AF, but its underlying mechanisms remain elusive. Recently, circular RNAs (circRNAs) were reported to be associated with cardiac fibrosis. In case of the vital role of cardiac fibrosis in AF persistency, we hypothesis that circRNAs may be potential regulators in the process of AF progression. MATERIALS AND METHODS: 6 persistent and 6 paroxysmal AF patients were enrolled as derivation cohort. Plasma circRNAs expressions were determined by microarray and validated by RT-PCR. Fibrosis level, manifested by serum TGF-ß, was determined by ELISA. Pathways and related non-coding RNAs involving in the progression of AF regulated were predicted by in silico analysis. RESULTS: PsAF patients showed a distinct circRNAs expression profile with 92 circRNAs significantly dysregulated (fold change ≥ 2, p < 0.05), compared with PAF patients. The validity of the expression patterns was subsequently validated by RT-PCR in another 60 AF patients (30 PsAF and PAF, respectively). In addition, all the 5 up and down regulated circRNAs were clustered in MAPK and TGF-beta signaling pathway by KEGG pathway analysis. Among the 5 circRNAs, hsa_circ_0004104 was consistently downregulated in PsAF group (0.6 ± 0.33 vs 1.46 ± 0.41, p < 0.001) and predicted to target several AF and/or cardiac fibrosis related miRNAs reported by previous studies. In addition, TGF-ß1 level was significantly higher in the PsAF group (5560.23 ± 1833.64 vs 2236.66 ± 914.89, p < 0.001), and hsa_circ_0004104 showed a significant negative correlation with TGF-ß1 level (r = - 0.797, p < 0.001). CONCLUSION: CircRNAs dysregulation plays vital roles in AF persistency. hsa_circ_0004104 could be a potential regulator and biomarker in AF persistency by promoting cardiac fibrosis via targeting MAPK and TGF-beta pathways.

An Investigation of Fibulin-2 in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease, with a prevalence of at least 1 in 500 in the general population. The disease is pleiotropic and is characterized by an increased stiffness of the myocardium, partly due to changes in the extracellular matrix (ECM), with elevated levels of interstitial fibrosis. Myocardial fibrosis is linked to impaired diastolic function and possibly phenotypic heterogeneity of HCM. The ECM consists of a very large number of proteins, which actively interact with each other as well as with myocardial cells. The role of other multiple components of the ECM in HCM has not been defined. Fibulin-2 is a glycoprotein component of the ECM, which plays an important role during embryogenesis of the heart; however, its role in adult myocardium has not been adequately studied. We here describe, for the first time, abnormal expression of fibulin-2 in the myocardium in patients with HCM as compared to normal controls. This abnormal expression was localized in the cytoplasm of myocardial cells and in the interstitial fibroblasts. In addition, fibulin-2 levels, measured by ELISA, were significantly elevated in the serum of patients with HCM as compared to normal controls.

Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure.

Hypertrophic cardiomyopathy (HCM) is a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to physiological or pathological stress, prolonged hypertrophy can lead to heart failure. Here we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N-methyltransferase factors (Ehmts) act together to reduce expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of the pro-hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Our study demonstrates that Prdm16 protects the heart against age-dependent cardiac hypertrophy and heart failure.

Long noncoding RNA TCONS-00106987 promotes atrial electrical remodelling during atrial fibrillation by sponging miR-26 to regulate KCNJ2.

Long noncoding RNAs (lncRNAs) have been suggested to play indispensable roles in multiple heart diseases. However, the correlations between lncRNAs and atrial fibrillation (AF) are unclear. In this study, we performed comprehensive lncRNA profiling via high-throughput RNA sequencing analysis using non-AF and AF rabbit models. Based on a series of filtering pipelines and bioinformatics analyses, TCONS-00106987 was selected for further research. TCONS-00106987 levels were increased in the atria during AF. Moreover, the atrial effective refractory period was shortened and the AF inducibility was increased in vivo in response to lentiviral-mediated up-regulation of TCONS-00106987. TCONS-00106987 repression resulted in the opposite effects. Further studies indicated that TCONS-00106987 expression was positively correlated with the expression of the protein-coding gene KCNJ2. Luciferase reporter assays and whole-cell patch-clamp recording confirmed that TCONS-00106987 promoted electrical remodelling via endogenous competition with microRNA-26 (miR-26) to induce transcription of its target gene KCNJ2, thereby increasing inward-rectifier K+ current (IK1 ). In conclusion, our study reveals a pathogenic lncRNA-miRNA regulatory network specific to atrial electrical remodelling that offers potential therapeutic targets for AF.

Relations between plasma microRNAs, echocardiographic markers of atrial remodeling, and atrial fibrillation: Data from the Framingham Offspring study.

BACKGROUND: Circulating microRNAs may reflect or influence pathological cardiac remodeling and contribute to atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to identify candidate plasma microRNAs that are associated with echocardiographic phenotypes of atrial remodeling, and incident and prevalent AF in a community-based cohort. METHODS: We analyzed left atrial function index (LAFI) of 1788 Framingham Offspring 8 participants. We quantified expression of 339 plasma microRNAs. We examined associations between microRNA levels with LAFI and prevalent and incident AF. We constructed pathway analysis of microRNAs' predicted gene targets to identify molecular processes involved in adverse atrial remodeling in AF. RESULTS: The mean age of the participants was 66 ± 9 years, and 54% were women. Five percent of participants had prevalent AF at the initial examination and 9% (n = 157) developed AF over a median 8.6 years of follow-up (IQR 8.1-9.2 years). Plasma microRNAs were associated with LAFI (N = 73, p<0.0001). Six of these plasma microRNAs were significantly associated with incident AF, including 4 also associated with prevalent AF (microRNAs 106b, 26a-5p, 484, 20a-5p). These microRNAs are predicted to regulate genes involved in cardiac hypertrophy, inflammation, and myocardial fibrosis. CONCLUSIONS: Circulating microRNAs 106b, 26a-5p, 484, 20a-5p are associated with atrial remodeling and AF.