Background —Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The "NACHT, LRR and PYD domain containing protein 3" (NLRP3)-inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells, but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3-inflammasome in AF. Methods —NLRP3-inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal (pAF) or long-standing persistent (chronic) AF (cAF). To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knock-in mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electrical activation pattern, Ca 2+ spark frequency (CaSF), atrial effective refractory period (AERP), and morphology of atria were evaluated in CM-KI mice and WT littermates. Results —NLRP3-inflammasome activity was increased in atrial CMs of pAF and cAF patients. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3-inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic-reticulum Ca 2+ -release, AERP shortening and atrial hypertrophy. Adeno-associated virus subtype-9 mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. Conclusions —Our study establishes a novel pathophysiological role for CM NLRP3-inflammasome signaling with a mechanistic link to the pathogenesis of AF, and establishes inhibition of NLRP3 as a potential novel AF-therapy approach.

Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation.

Galectin-3 is a member of the galectin family, which are β‑galactoside‑binding lectins with ≥1 evolutionary conserved carbohydrate‑recognition domain. It binds proteins in a carbohydrate‑dependent and ‑independent manner. Galectin‑3 is predominantly located in the cytoplasm; however, it shuttles into the nucleus and is secreted onto the cell surface and into biological fluids including serum and urine. It serves important functions in numerous biological activities including cell growth, apoptosis, pre‑mRNA splicing, differentiation, transformation, angiogenesis, inflammation, fibrosis and host defense. Numerous previous studies have indicated that galectin‑3 may be used as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and cancer. With emerging evidence to support the function and application of galectin‑3, the current review aims to summarize the latest literature regarding the biomarker characteristics and potential therapeutic application of galectin‑3 in associated diseases.

/pdf/galectin-3-as-a-novel-biomarker-for-disease-diagnosis-and-a-5ci70sx8cb.pdf

Galectin-3 as a novel biomarker for disease diagnosis and a target for therapy (Review)

Myocardial fibrosis is the result of excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation. It causes cardiac dysfunction, arrhythmias, and ischaemia, and thereby determines the clinical course and outcome of cardiac patients even when adequately treated. Therefore, further research is needed to identify and better understand the factors that trigger and maintain the myocardial fibrotic response against different injuries in a variety of cardiac diseases. Here, we will focus on the following major areas of research: molecules that stimulate the differentiation of fibroblasts into myofibroblasts and subsequently alter collagen turnover (e.g. cardiotrophin‐1, galectin‐3, NADPH oxidases, and neutrophil gelatinase‐associated lipocalin), microRNA‐induced alterations of collagen gene expression, and matricellular protein‐ and lysyl oxidase‐mediated alterations of collagen cross‐linking and deposition.

Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential (vol 17, pg 764, 2015)

Background Left atrial (LA) strain imaging enables the quantitative assessment of LA function. The clinical relevance of these measurements is dependent on the provision of information incremental to the left ventricular (LV) evaluation. The aim of this study was to test the hypothesis that LA pump function but not reservoir function is independent of measurement of LV mechanics. Methods Echocardiography was undertaken in a community-based study of 576 participants ≥65 years of age with one or more risk factors (e.g., hypertension, diabetes mellitus, obesity). Strain analysis was conducted using a dedicated software package, using R-R gating. LV function was classified as normal in the presence of global longitudinal strain (GLS) (≤−18%) or global circumferential strain (GCS) (≤−22%). The associations between GLS or GCS and LA reservoir, conduit, and pump strain were assessed using univariate and multivariate linear regression. Results Patients (mean age 71 ± 5 years, 54% women) with reduced GLS had higher blood pressure and rates of diabetes and obesity ( P P  = .004] and 18.7 ± 5.7% vs 20.5 ± 5.1% [ P P  = .72). GLS was independently associated with LA reservoir and conduit strain ( P P  = .91). Reduced GCS was associated with a larger body mass index, male sex, and diabetes ( P P  > .05). Conclusions The application of LA strain is specific to the component measured. LA pump strain is independent of LV mechanics.

Association of the Active and Passive Components of Left Atrial Deformation with Left Ventricular Function.

Galectin-3 and incidence of atrial fibrillation: The Atherosclerosis Risk in Communities (ARIC) study.

New onset atrial fibrillation is associated with elevated galectin-3 levels

Age and sexual dimorphism contribute to the differential cardiometabolic dysfunctions associated with diet-induced obesity. However, the underlying mechanisms remain elusive. RNA modifications via RNA m6A methylation, is an emerging mediator of RNA stability, translation and localisation responsible for regulation of multiple biological functions. In this study, we aim to determine differential RNA methylation changes within the heart in a diet-induced cardiomyopathy mouse model, stratified according to age and sex. 

Mechanism(s) for Age-Related Sex Differences in Diet-Induced Cardiomyopathy: Role of RNA Methylation

Doxorubicin (DOX) is among the most used anticancer drugs with associated cardiotoxicity. Follistatin-like 3 (FSTL3), a secreted member of the follistatins family that can selectively bind to members of the TGF-β superfamily, is involved in regulation of cardiac hypertrophy and heart failure. FSTL3 is also upregulated in breast and colorectal cancer tumours, is also an unfavourable prognostic indicator for various cancers. We aim to determine the dual role of FSTL3 in prevention of DOX-induced cardiotoxicity and synergistic anti-cancer effects. 

Doxorubicin-Induced Upregulation of Follistatin-Like 3 (FSTL3): A New Therapeutic Target


 
 
 Obesity and metabolic dysregulation are closely associated with the pathophysiology of multiple cardiovascular diseases (CVD). To date, the pathophysiological mechanism(s) of obesity and its link with cardiovascular systems remain largely unknown. Adipose tissue inflammation as a result of excessive fat expansion in obesity, leading to increased systemic production of growth factors and recruitment of inflammatory cells have been postulated to be a major factor. Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is linked with obesity and metabolic regulation and has been indicated to affect cardiovascular functions. Currently, the role of circulating SFRP5 levels as a biomarker for cardiovascular diseases are poorly understood, with studies yielding discordant results.
 
 
 
 This study aims to evaluate the relationship between circulating SFRP5 and cardiovascular functions in a cohort of patients with established CVD.
 
 
 
 Patients (n=262, 148 male (56.5%), age (68±11 yrs)) presenting to the cardiology unit for cardiovascular investigations were recruited into the study. Plasma SFRP5 levels were measured via enzyme-linked immunosorbent assay (ELISA). Associations between plasma SFRP5 levels, cardiovascular functions, and patients' co-morbidities were analysed using univariate and multivariate analyses.
 
 
 
 Plasma SFRP5 levels were significantly lower in patients presenting with: heart failure (HF) vs non-HF (median; (10.7 vs 31.0; p<0.001); coronary artery disease (CAD) vs non-CAD; (11.0 vs 33.8; p<0.001); and atrial fibrillation (AF) vs non-AF; (11.2 vs 23.2; p=0.001). On univariate analyses, SFRP5 levels also significantly positively correlated with left ventricular ejection fraction (LVEF) (r=0.52, p<0.001), estimated glomerular filtration rate (eGFR) (r=0.16, p=0.02), total cholesterol levels and triglycerides (r=0.29, p<0.001; r=0.17, p<0.01 respectively). Low SFRP5 levels were correlated with high C-reactive protein (CRP) and E/E' (r=−0.29, p<0.001, r=−0.30, p<0.001, respectively). Patients with HF, CAD, statin use, low LVEF, low triglycerides, high CRP and high eGFR were associated with lower SFRP5 levels independent of age, BMI or diabetes on multivariate analysis (overall model r=0.729, SE=0.638).
 
 
 
 Our results show that low plasma SFRP5 levels are independently associated with HF, CAD, and impaired systolic and diastolic functions. These results suggest that SFRP5 may regulate cardiovascular functions independent of obesity and metabolic regulations.
 
 
 
 Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Heart Foundation of Australia Future Leader FellowshipsNSW Ministry of Health EMC FellowshipHeart Foundation of Australia Future Leader Fellowship


/pdf/heart-failure-is-associated-with-low-circulating-levels-of-2n2m9nra.pdf

Heart failure is associated with low circulating levels of secreted frizzled receptor protein 5 (Sfrp5)

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New onset atrial fibrillation is associated with elevated galectin-3 levels

Mechanism(s) for Age-Related Sex Differences in Diet-Induced Cardiomyopathy: Role of RNA Methylation

Doxorubicin-Induced Upregulation of Follistatin-Like 3 (FSTL3): A New Therapeutic Target

Heart failure is associated with low circulating levels of secreted frizzled receptor protein 5 (Sfrp5)