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)

The hallmark symptom of chronic heart failure (HF) is severe exercise intolerance. Impaired perfusive and diffusive O2 transport are two of the major determinants of reduced physical capacity and l...

Exercise limitations in heart failure with reduced and preserved ejection fraction.

Inorganic nitrite and nitrate in cardiovascular therapy: A better alternative to organic nitrates as nitric oxide donors?

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

AIMS Takotsubo syndrome (TTS) episodes are primarily initiated by 'pulse' release of catecholamines inducing neutrophil infiltration and myocardial inflammation in susceptible individuals (largely ageing women) Evidence of myocardial inflammation and associated energetic impairment persists for ≥ 3 months post-acute TTS episodes, suggesting the existence of additional 'perpetuating' mechanisms The effects of B-type natriuretic peptide (BNP) in suppressing superoxide (O2- ) release from neutrophils are transiently impaired in acute heart failure We also evaluated the extent and duration of BNP-induced suppression of O2- release post-TTS METHODS AND RESULTS TTS patients were studied acutely (n = 34) and 3 months thereafter (n = 13) and compared with control subjects (n = 25) O2- generation from neutrophils, triggered by N-formyl-methionyl-leucyl-phenylalanine and phorbol myristate acetate, and its suppression by BNP, were measured in vitro Determinants of variability in BNP effect were sought via univariate and multivariate analyses Relative to control subjects, in TTS patients, BNP suppression of both phorbol myristate acetate and N-formyl-methionyl-leucyl-phenylalanine-induced O2- release was impaired acutely (P < 005 for both); this did not improve over the 3-month recovery period, despite treatment with conventional anti-failure medication in 85% of patients No significant correlates of BNP effect (other than TTS) were identified CONCLUSIONS (1) While TTS is associated with marked and prolonged release of BNP, there is virtually total loss of the ability of BNP to suppress neutrophil O2- release and its impact on tissue inflammation (2) BNP responses do not recover for at least 3 months post-attacks, suggesting that this might contribute to perpetuation of myocardial inflammation in TTS patients

/pdf/prolonged-suppression-of-the-anti-oxidant-anti-inflammatory-57t9n7rygr.pdf

Prolonged suppression of the anti-oxidant/anti-inflammatory effects of BNP post-Takotsubo syndrome.

Tako-tsubo cardiomyopathy is associated with loss of anti-inflammatory effect of released B-type natriuretic peptide

Diabetes is Associated with Paradoxically Low Plasma Concentrations of Asymmetric Dimethylarginine (ADMA)

/pdf/644-vascular-responses-to-gtn-but-not-salbutamol-decline-2gj6edlqb1.pdf

644 Vascular responses to GTN but not salbutamol decline with age

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