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.     

Efficacy and safety of atrial fibrillation ablation in heart failure patients with left ventricular ejection fraction less than 50%

IntroductionThe efficacy of catheter ablation in patients with low cardiac function has been previously reported; however, only a few studies have included mid-range ejection fraction (mrEF). This study aimed to evaluate the efficacy and safety of atrial fibrillation (AF) ablation in patients with left ventricular ejection fraction (LVEF) < 50%.MethodsThis study retrospectively analyzed 79 patients (reduced ejection fraction [rEF]/mrEF, 38/41; paroxysmal/persistent, 37/42; heart failure hospitalizations within one year before ablation, 36 [45.6%]) who underwent the first ablation procedure at our hospital from April 2017 to December 2021. Radiofrequency ablation and cryoablation were performed for 69 and 10 patients, respectively.ResultsComplications included pacemaker implantation for postoperative sick sinus syndrome in one patient and inguinal hematoma in one patient. Regarding efficacy, there were significant postoperative improvements in echocardiographic data, blood test values, and diuretic use. After a mean follow-up of 60 months, 86.1% patients had no AF recurrence. There were 9 heart failure hospitalizations (11.4%) and 5 all-cause deaths (6.3%); no significant differences were found between the rEF and mrEF groups. No significant predictors of AF recurrence were found in preoperative patient characteristics.ConclusionAF ablation in patients with LVEF <50% significantly improved cardiac and renal functions with few complications, resulting in a high non-recurrence rate and reduced heart failure.     

Coronary Artery-Bypass-Graft Surgery Increases the Plasma Concentration of Exosomes Carrying a Cargo of Cardiac MicroRNAs: An Example of Exosome Trafficking Out of the Human Heart with Potential for Cardiac Biomarker Discovery

IntroductionExosome nanoparticles carry a composite cargo, including microRNAs (miRs). Cultured cardiovascular cells release miR-containing exosomes. The exosomal trafficking of miRNAs from the heart is largely unexplored. Working on clinical samples from coronary-artery by-pass graft (CABG) surgery, we investigated if: 1) exosomes containing cardiac miRs and hence putatively released by cardiac cells increase in the circulation after surgery; 2) circulating exosomes and exosomal cardiac miRs correlate with cardiac troponin (cTn), the current “gold standard” surrogate biomarker of myocardial damage.ConclusionsThe plasma concentrations of exosomes and their cargo of cardiac miRs increased in patients undergoing CABG and were positively correlated with hs-cTnI. These data provide evidence that CABG induces the trafficking of exosomes from the heart to the peripheral circulation. Future studies are necessary to investigate the potential of circulating exosomes as clinical biomarkers in cardiac patients.     

Cardiac complications in a geriatric population hospitalized with COVID-19: The OCTA-COVID cohort

PurposeThe geriatric population is especially vulnerable to coronavirus disease (COVID-19) and its potential complications. We sought to analyze the incidence of cardiological complications in an elderly population hospitalized for COVID-19.MethodsA prospective observational longitudinal that included patients ≥75 years of age with diagnosis of COVID-19 admitted to the Geriatric Department from March to May 2020. Epidemiological, geriatric, clinical and laboratory test variables were collected. Cardiovascular events, including de novo atrial fibrillation (AF), acute coronary syndrome (ACS), congestive heart failure (CHF), pulmonary embolism and in-hospital death, were documented. A follow-up was carried out at 12 months through a telephone interview as well as using electronic medical records, collecting cardiac events and mortality.Results305 patients were included; 190 (62.3%) were female, with median age of 87 years (interquartile range (82–91)). More than half of the patients had a history of cardiac disease, with AF being the most common and affecting 85 (27.9%) patients. During hospitalization, 112 (36.7%) patients died. Eighty-nine (29.2%) patients presented cardiac complications. Acute heart failure was the most prevalent (46; 15.1%), followed by new-onset AF (20; 6.5%), pulmonary embolism (17; 5.6%), and ACS (5; 1.6%). Patients with cardiac complications had a longer hospital stay (p < 0.001). During follow-up, 29 (15.1%) died, and 40 (20.8%) patients had a cardiovascular event being CHF the most prevalent complication (16.7%).ConclusionThe incidence of cardiovascular complications in geriatric patients is high and is associated with a longer hospital stay. CHF was the most frequent event, followed by AF.     

miR-29b ameliorates atrial fibrosis in rats with atrial fibrillation by targeting TGFβRΙ and inhibiting the activation of Smad-2/3 pathway

Objective

Atrial fibrillation (AF) is a major cause of stroke with lifetime risks. microRNAs (miRNAs) are associated with AF attenuation, yet the mechanism remains unknown. This study investigated the functional mechanism of miR-29b in atrial fibrosis in AF.

Methods

The AF rat model was established by a 7-day intravenous injection of Ach-CaCl₂ mixture. AF rats were injected with adeno-associated virus (AAv)-miR-29b and TGFβRΙ overexpression plasmid. AF duration was recorded by electrocardiogram. Atrial fibrosis was observed by Masson staining. Expressions of COL1A1, COL3A1, TGFβRΙ, TGFβΙ, miR-29b and Smad-2/3 pathway-related proteins in atrial tissues were detected by RT-qPCR and Western blot. Binding sites of miR-29b and TGFβRΙ were predicted and their target relationship was verified by dual-luciferase reporter assay.

Results

miR-29b was poorly expressed and expressions of COL1A1, COL3A1, TGFβRΙ, and TGFβ1 were increased in atrial tissues of AF rats. miR-29b overexpression alleviated atrial fibrosis, reduced expressions of COL1A1, COL3A1, and TGFβ1, and shortened AF duration in AF rats. TGFβRΙ was highly expressed in atrial tissues of AF rats. miR-29b targeted TGFβRΙ. TGFβRΙ overexpression overcame the improving effect of miR-29b overexpression on AF. miR-29b overexpression decreased ratios of p-Smad-2/3 and Smad-2/3 and inhibited the Smad-2/3 pathway.

Conclusion

miR-29b might mitigate atrial fibrosis in AF rats by targeting TGFβRΙ and inhibiting the Smad-2/3 pathway.

     

A comparison of clinical outcomes following atrial fibrillation ablation for heart failure patients with preserved or reduced left ventricular function: A systematic review and meta-analysis

BackgroundThis review aims to determine if patients who undergo atrial fibrillation (AF) ablation with heart failure with preserved ejection fraction (HFpEF) do better, or worse or the same compared to patients with heart failure with reduced ejection fraction (HFrEF).MethodsA search of MEDLINE and EMBASE was performed using the search terms: “atrial fibrillation”, “ablation” and terms related to HFpEF and HFrEF in order to identify studies that evaluated one or more of i) AF recurrence, ii) periprocedural complications and iii) adverse outcomes at follow up for patients with HFpEF and HFrEF who underwent AF ablation. Data was extracted from included studies and statistically pooled to evaluate adverse events and AF recurrence.Results5 studies were included in this review and the sample size of the studies ranged from 91 to 521 patients with heart failure. There was no significant difference in the pooled rate for no AF or symptom recurrence after AF ablation comparing patients with HFpEF vs HFrEF (RR 1.07 95%CI 0.86–1.33, p = 0.15). The most common complications were access site complications/haematoma/bleeding which occurred in similar proportion in each group; HFpEF (3.1%) and HFrEF (3.1%). In terms of repeat ablations, two studies were pooled to yield a rate of 78/455 (17.1%) for HFpEF vs 24/279 (8.6%) for HFrEF (p = 0.001.ConclusionsHeart failure patients with preserved or reduced ejection fraction have similar risk of AF or symptom recurrence after AF ablation but two studies suggest that patients with HFpEF are more likely to have repeat ablations.     

Intermittent fasting attenuates obesity-related atrial fibrillation via SIRT3-mediated insulin resistance mitigation

ObjectiveAtrial fibrillation (AF) is the most common tachyarrhythmia in urgent need of therapeutic optimization. Obesity engenders AF, and its pathogenesis is closely intertwined with insulin resistance (IR), but mechanism-based management is still underinvestigated. Intermittent fasting (IF) is a novel lifestyle intervention that mitigates IR, a potential AF driver, yet whether IF can prevent obesity-related AF remains elusive. Here, we aimed to evaluate the impacts of short-term IF on AF and to uncover the underlying mechanism.MethodsWe subjected obese mice (high-fat diet for 8-week) to IF (alternative-day fasting for another 5-week) for AF vulnerability and substrate formation assessment, and similarly treated neonatal atrial cardiomyocytes (NRCMs) and fibroblasts (NRCFs) (palmitate, 200 μM) with IF (alternative-day short-term starvation for 8-day) for mechanism investigation.ResultsObese mice were prone to AF and atrial remodeling. IF reduced AF inducibility, duration, and reversed atrial remodeling including channel disturbance, left atrial dilation, cardiac hypertrophy and fibrosis in obese mice independent of weight loss. Mechanistically, IF up-regulated the SIRT3 protein level both in vivo and in vitro, and pharmacologic inhibition (3-(1H-1,2,3-Triazol-4-yl) pyridine, 50 μM) and genetic suppression of SIRT3 could attenuate the IF-mediated benefits against hypertrophy and fibrosis. Furthermore, IF activated AMPK and Akt signaling, two positive downstream targets of SIRT3, and inactivated HIF1α signaling, a negative downstream target of SIRT3 in both obese mice atria and palmitate-treated cells, while inhibition of SIRT3 reversed these effects.ConclusionIF prevents obesity-related AF via SIRT3-mediated IR mitigation, thus representing a feasible lifestyle intervention to improve AF management.     

Effects of Thyroid Dysfunction and the Thyroid-Stimulating Hormone Levels on the Risk of Atrial Fibrillation: A Systematic Review and Dose-Response Meta-Analysis from Cohort Studies

ObjectiveTo explore the relationship between thyroid dysfunction, thyroid-stimulating hormone (TSH) levels, and risks of atrial fibrillation (AF) in studies and conduct a dose-response meta-analysis on the correlation between the TSH levels and risk of AF.MethodsThirteen studies from 5 databases with 649 293 subjects (mean age, 65.1 years) were included. The dose-response meta-analysis was conducted by comparing the risk ratios (RRs) and 95% confidence intervals (CIs) for incident AF associated with different levels of TSH (vs TSH level of 0 mU/L) across studies. Data were collected until October 25, 2021.ResultsSubclinical hyperthyroidism, subclinical hypothyroidism, and clinical hyperthyroidism were associated with an increased risk of AF (RR, 1.70; 95% CI, 1.11-2.62; RR, 1.23; 95% CI, 1.05-1.44; and RR, 2.35; 95% CI, 1.07-5.16, respectively), whereas clinical hypothyroidism was not associated with the significantly increased risk of AF (RR, 1.20; 95% CI, 0.72-1.99). A nonlinear relationship was observed in 2 models (crude model, P_nonlinear < .001; adjusted model, P_nonlinear = .0391) between the TSH levels and risks of AF.ConclusionsOur study indicated that subclinical hyperthyroidism, subclinical hypothyroidism, clinical hyperthyroidism were associated with the risk of AF, and the results for the TSH levels and risk of AF were mixed, which showed a U-shaped relationship.     

Intra-individual variation of miRNA expression levels in human plasma samples

Background: Circulating miRNAs as potential non-invasive biomarkers for disease risk assessment and cancer early diagnosis have attracted increasing interest. Little information, however, is available regarding the intra-individual variation of circulating miRNA levels.

Methods: We measured expression levels of a panel of 800 miRNAs in repeated plasma samples from 51 healthy individuals that were collected 6 to 12?months apart and evaluated the intra-individual variation by the intra-class correlation coefficient (ICC).

Results: After background correction, a total of 185 miRNAs were detected in at least 10% of the plasma samples, with 69 and 28 miRNAs being detected in 50% and 90% of samples, respectively. The median ICC was 0.46 for these 185 miRNAs. Among them, 41% (75 miRNAs) had an ICC?≥?0.5, and 23% (42 miRNAs) had an ICC?≥?0.6. The ICC is higher for miRNAs with higher expression levels or higher detection rates, when compared to those with lower expression levels or lower detection rates.

Conclusions: These results suggest that common circulating miRNAs are stable over a relatively long period and can serve as reliable biomarkers for epidemiological and clinical research.     

Polysomnography in AF patients without prior diagnosis of obstructive sleep apnea reveals significant sleep abnormality: A strong case for screening in all patients with atrial fibrillation?

BackgroundObstructive sleep apnea (OSA) and atrial fibrillation (AF) are known to often coexist together. However, whether all patients with AF should be screened for sleep abnormalities is not clear. No previous study has examined the association of asymptomatic OSA with AF.ObjectiveThis study sought to determine the prevalence of asymptomatic OSA in patients with persistent AF and whether asymptomatic OSA is an independent risk factor for atrial fibrillation.MethodPatients with persistent AF without a prior diagnosis of OSA and asymptomatic for sleep abnormalities were prospectively enrolled over 12 months. All patients underwent polysomnography after informed consent. Patients without AF or OSA who underwent polysomnography during the same period served as controls.ResultsA total of 97 patients were studied; 50 were in the case group (patients with persistent AF) and 47 were in the control group (patients in sinus rhythm). Asymptomatic OSA was diagnosed on polysomnography in 72% of patients in the AF group and 17% of the control population. Multivariable analysis of factors including diabetes, hypertension, coronary artery disease, hypothyroidism, prior MI, and asymptomatic OSA, suggested asymptomatic OSA as an independent factor associated with AF.ConclusionA significant proportion (72%) of patients with persistent AF have underlying asymptomatic OSA. Sleep abnormality thus has a strong association with AF even in patients who are asymptomatic for OSA. Screening for OSA may be advised for all patients with AF, as this may have significant implications for management.     

Cardinal roles of miRNA in cardiac development and disease

MicroRNAs (miRNAs) are small noncoding RNAs that are emerging as pivotal modulators in virtually all aspects of cardiac biology, from cardiac development to cardiomyocyte survival and hypertrophy. The miRNA profiling, following gain- and loss-of-function studies using in vitro and in vivo models, has identified wide-ranging functions for miRNAs in the heart, providing new perspectives on their contributions to cardiac pathogenesis, and revealing potential therapeutic targets and diagnostic biomarkers. This review summarizes current progress in regulation of miRNAs in heart development and disease.     

Can baseline serum microRNAs predict response to TNF-alpha inhibitors in rheumatoid arthritis?

BackgroundIn rheumatoid arthritis, prediction of response to TNF-alpha inhibitor (TNFi) treatment would be of clinical value. This study aims to discover miRNAs that predict response and aims to replicate results of two previous studies addressing this topic.MethodsFrom the observational BiOCURA cohort, 40 adalimumab- (ADA) and 40 etanercept- (ETN) treated patients were selected to enter the discovery cohort and baseline serum profiling on 758 miRNAs was performed. The added value of univariately selected miRNAs (p < 0.05) over clinical parameters in prediction of response was determined by means of the area under the receiver operating characteristic curve (AUC-ROC). Validation was performed by TaqMan single qPCR assays in 40 new patients.ResultsExpression of miR-99a and miR-143 predicted response to ADA, and miR-23a and miR-197 predicted response to ETN. The addition of miRNAs increased the AUC-ROC of a model containing only clinical parameters for ADA (0.75 to 0.97) and ETN (0.68 to 0.78). In validation, none of the selected miRNAs significantly predicted response. miR-23a was the only overlapping miRNA compared to the two previous studies, however inversely related with response in one of these studies. The reasons for the inability to replicate previously proposed miRNAs predicting response to TNFi and replicate those from the discovery cohort were investigated and discussed.ConclusionsTo date, no miRNA consistently predicting response to TNFi therapy in RA has been identified. Future studies on this topic should meet a minimum of standards in design that are addressed in this study, in order to increase the reproducibility.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-016-1085-z) contains supplementary material, which is available to authorized users.     

The Benefit of Atrioventricular Junction Ablation for Permanent Atrial Fibrillation and Heart Failure Patients Receiving Cardiac Resynchronization Therapy: An Updated Systematic Review and Meta-analysis

BackgroundAtrial fibrillation (AF) is correlated with a poor biventricular pacing and inadequate response to cardiac resynchronization therapy (CRT). Biventricular pacing improvement can be achieved by conducting the atrioventricular junction ablation (AVJA). We aimed to investigate the benefit of AVJA for permanent AF and heart failure with reduced ejection fraction (HFrEF) patients receiving CRT.MethodsIn August 2020, a systematic review and meta-analysis study comparing CRT plus AVJA versus CRT for permanent AF and HFrEF patients was conducted. Relevant articles were identified through the electronic scientific database such as ClinicalTrials.gov, ProQuest, ScienceDirect, PubMed, and Cochrane. The pooled risk ratio (RR) and pooled mean difference (MD) were estimated.ResultsA total of 3199 patients from 14 cohort studies were involved in this study. Additional AVJA reduced cardiovascular mortality (RR = 0.75, 95% confidence interval [CI] = 0.61 to 0.93, P < 0.01) in permanent AF and HFrEF patients receiving CRT. Biventricular pacing rate was higher in CRT plus AVJA group (MD = 8.65%, 95% CI = 5.62 to 11.67, P < 0.01) than in CRT alone group. The reverse remodeling characterized by the reduction of left ventricular end-diastolic diameter (LVEDD) was greater in the CRT plus AVJA group (MD = ?2.11 mm, 95% CI = ?3.79 to ?0.42, P = 0.01).ConclusionIn permanent AF and HFrEF patients receiving CRT, AVJA effectively increased the biventricular pacing rate. Adequate biventricular pacing rate provided a better response to the CRT marked by the greater ventricular reverse remodeling and survival from cardiovascular mortality.     

Serum Galectin-3 level and recurrence of atrial fibrillation post-ablation – Systematic review and meta-analysis

BackgroundSerum galectin-3, a circulating biomarker of fibrosis, has been associated with atrial remodelling. Recent studies investigating serum galectin-3 and AF recurrence post-ablation have shown mixed results. We aimed to analyze the latest evidence on the association between serum galectin-3 and AF recurrence after catheter ablation.MethodsWe performed a comprehensive search on topics that assesses serum galectin-3 and AF recurrence post-ablation up until August 2019.ResultsThere were 597 patients from seven studies. The mean difference of serum galectin-3 was similar in both AF recurrence and non AF recurrence group (mean difference 0.78 ng/mL [-0.56, 2.13]; p = 0.25; I²: 69%. Upon removal of a study in sensitivity analysis, the serum galectin-3 became higher in AF recurrence group (mean difference 1.41 ng/mL [0.47, 2.34], p = 0.003; I²: 17%). Serum galectin-3 was associated with a higher risk for AF recurrence (HR 1.25 [1.01, 1.55]; p = 0.04; I²: 76%). Upon removal of a study in sensitivity analysis, HR became 1.45 [1.07, 1.96], p = 0.02; I²: 47%. Meta-analysis of adjusted HR demonstrated that high serum galectin-3 independently predicts AF recurrence (HR 1.15 [1.02, 1.29], p < 0.02; I²: 57%, p = 0.10)ConclusionSerum galectin-3 is associated with an increased risk of AF recurrence post-ablation. Further studies are required, especially emphasis on the cut-off point should be given, before integrating it in routine risk stratification for AF ablation.     

MicroRNAs expression profiles as diagnostic biomarkers of gastric cancer: a systematic literature review

Objective: The early identification of gastric cancer (GC) represents a major clinical challenge. We conducted a systematic review of studies evaluating the miRNA expression profiling as a diagnostic tool in GC.

Methods: We performed a search of PubMed, ISI Web of Science and SCOPUS databases for studies on diagnostic miRNAs and GC, published in English up to October 2017. Eligibility criteria included case-control studies evaluating blood or tissue-based miRNA expression profiles, and incorporating at least two detection phases (screening and validation).

Results: We included 27 eligible studies, that reported on 97 deregulated miRNAs either in blood or tissue, out of which 30 were reported in at least two studies. Among 22 studies on tissue-diagnostic miRNAs, 13 consistently upregulated miRNAs (miR-214, miR-21, miR-103, miR-107, miR-196a, miR-196b, miR-7, miR-135b, miR-222, miR-23b, miR-25, miR-92 and miR-93), and six consistently downregulated miRNAs (miR-148a, miR-375, miR-133b, miR-30a, miR-193a and miR-204) were reported. Ten miRNAs with inconsistent direction of expression in tissues were identified. Among the five studies performed on blood samples, only one miRNA was consistently upregulated (miR-20a).

Conclusions: This review shows that some tissue or blood miRNAs may be considered as potential biomarkers for GC diagnosis, that urgently needs to be confirmed from large prospective studies.