Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease.

AIMS: Right heart disease (RHD), characterized by right ventricular (RV) and atrial (RA) hypertrophy, and cardiomyocytes' (CM) dysfunctions have been described to be associated with the incidence of atrial fibrillation (AF). Right heart disease and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. We hypothesized that right heart disease generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility. METHODS AND RESULTS: Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275 g) to provoke an RHD. Twenty-one days (D21) post-surgery, all rats underwent echocardiography and electrophysiological studies (EPS). Optical mapping was performed in situ, on Langendorff-perfused hearts. The contractility of freshly isolated CM was evaluated and recorded during 1 Hz pacing in vitro. Histological analyses were performed on formalin-fixed RA to assess myocardial fibrosis, connexin-43 levels, and CM morphology. Right atrial levels of selected genes and proteins were obtained by qPCR and Western blot, respectively. Pulmonary artery banding induced severe RHD identified by RV and RA hypertrophy. Pulmonary artery banding rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated and hypercontractile. Right atrial CM from PAB animals showed significant augmentation of mRNA and protein levels of pro-inflammatory interleukin (IL)-6 and IL1ß. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) and junctophilin-2 were decreased in RA CM from PAB compared to sham rats. CONCLUSIONS: Right heart disease-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF.

The role of cellular senescence in profibrillatory atrial remodeling associated with cardiac pathology.

AIMS: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to: 1) Evaluate AF-susceptibility and senescence-marker expression in rat models of aging and myocardial infarction (MI); 2) Study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI-rats; 3) Assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS: AF-susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital-PCR or RT-qPCR (mRNA). A previously-validated senolytic combination, dasatinib and quercetin (D + Q), (or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment-assignment. Burst pacing-induced AF was seen in 100% of aged rats, 87.5% of young MI-rats and 10% of young-control rats (P≤0.001 vs. each). Conduction velocity was slower in aged (both left atrium, LA and right atrium, RA) and young-MI (LA) rats versus young-control rats (P≤0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young-MI (LA) versus young-control rats (P < 0.05 for each). Senolytic therapy reduced AF-inducibility in MI-rats (from 8/9 rats, 89% in MI-vehicle, to 0/9 rats, 0% in MI-D + Q, P < 0.001) and attenuated LA-fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence-markers were upregulated in older (≥ 70 years) and longstanding-AF patients versus individuals ≤ 60 and sinus-rhythm controls respectively. CONCLUSIONS: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.

An inflammation resolution-promoting intervention prevents atrial fibrillation due to left-ventricular dysfunction.

AIMS: Recent studies suggest that bioactive mediators called resolvins promote active resolution of inflammation. Inflammatory signaling is involved in development of the substrate for atrial fibrillation (AF). To evaluate effects of resolvin-D1 on atrial arrhythmogenic remodeling resulting from left-ventricular dysfunction induced by myocardial infarction (MI) in rats. METHODS AND RESULTS: MI was produced by left anterior descending coronary-artery ligation. Intervention-groups received daily intraperitoneal resolvin-D1, beginning before MI-surgery (early-RvD1) or day-7 post-MI (late-RvD1) and continued until day-21 post-MI. AF-vulnerability was evaluated by electrophysiological study. Atrial conduction was analyzed by optical mapping. Fibrosis was quantified by Masson's trichrome staining; gene-expression by qPCR and RNA-sequencing. Investigators were blinded to group identity.Early-RvD1 significantly reduced MI-size (17 ± 6%, vs. 39 ± 6% in vehicle-MI) and preserved left-ventricular ejection fraction; these were unaffected by late-RvD1. Transesophageal pacing induced atrial tachyarrhythmia in 2/18 (11%) sham-operated rats, vs. 18/18 (100%) MI-only rats, 5/18 (28%, P < 0.001 vs. MI) early-RvD1 MI-rats and 7/12 (58%, P < 0.01) late-RvD1 MI rats. Atrial conduction velocity significantly decreased post-MI; an effect suppressed by RvD1-treatment. Both early- and late-RvD1 limited MI-induced atrial fibrosis and prevented MI-induced increases in atrial expression of inflammation- and fibrosis-related biomarkers and pathways. CONCLUSIONS: RvD1 suppressed MI-related atrial arrhythmogenic remodeling. Early-RvD1 had MI-sparing and atrial-remodeling suppressant effects, whereas late-RvD1 attenuated atrial remodeling and AF-promotion without ventricular protection, revealing atrial-protective actions unrelated to ventricular-function changes. These results point to inflammation-resolution promoting compounds as novel cardioprotective interventions with particular interest in attenuating AF-substrate development.

Pollutants, including Organophosphorus and Organochloride Pesticides, May Increase the Risk of Cardiac Remodeling and Atrial Fibrillation: A Narrative Review.

Atrial fibrillation (AF) is the most common type of cardiac rhythm disorder. Recent clinical and experimental studies reveal that environmental pollutants, including organophosphorus-organochloride pesticides and air pollution, may contribute to the development of cardiac arrhythmias including AF. Here, we discussed the unifying cascade of events that may explain the role of pollutant exposure in the development of AF. Following ingestion and inhalation of pollution-promoting toxic compounds, damage-associated molecular pattern (DAMP) stimuli activate the inflammatory response and oxidative stress that may negatively affect the respiratory, cognitive, digestive, and cardiac systems. Although the detailed mechanisms underlying the association between pollutant exposure and the incidence of AF are not completely elucidated, some clinical reports and fundamental research data support the idea that pollutant poisoning can provoke perturbed ion channel function, myocardial electrical abnormalities, decreased action potential duration, slowed conduction, contractile dysfunction, cardiac fibrosis, and arrhythmias including AF.

Inhibition of transglutaminase 2 (TG2) ameliorates ventricular fibrosis in isoproterenol-induced heart failure in rats.

AIMS: Transglutaminase (TG) inhibitors represent promising therapeutic interventions in cardiac fibrosis and related dysfunctions. However, it remains unknown how TG inhibition, TG2 in particular, affects the signaling systems that drive pathological fibrosis. This study aimed to examine the effect TG inhibition by cystamine on the progression of isoproterenol (ISO)-induced cardiac fibrosis and dysfunction in rats. MATERIALS AND METHODS: Cardiac fibrosis was established by intraperitoneal injection of ISO to rats (ISO group), followed by 6 weeks of cystamine injection (ISO + Cys group). The control groups were administered normal saline alone or with cystamine. Hemodynamics, lipid profile, liver enzymes, urea, and creatinine were assessed in conjunction with heart failure markers (serum NT-proANP and cTnI). Left ventricular (LV) and atrial (LA) fibrosis, total collagen content, and mRNA expression of profibrotic markers including TG2 were quantified by Masson's trichrome staining, LC-MS/MS and quantitative PCR, respectively. KEY FINDINGS: Cystamine administration to ISO rats significantly decreased diastolic and mean arterial pressures, total cholesterol, triglycerides, LDL, liver enzymes, urea, and creatinine levels, while increasing HDL. NT-proANP and cTnI serum levels remained unchanged. In LV tissues, significant reductions in ISO-induced fibrosis and elevated total collagen content were achieved after cystamine treatment, together with a reduction in TG2 concentration. Reduced mRNA expression of several profibrotic genes (COL1A1, FN1, MMP-2, CTGF, periostin, CX43) was also evidenced in LV tissues of ISO rats upon cystamine administration, whereas TGF-ß1 expression was depressed in LA tissues. Cystamine decreased TG2 mRNA expression in the LV of control rats, while LV expression of TG2 was relatively low in ISO rats irrespective of cystamine treatment. SIGNIFICANCE: TG2 inhibition by cystamine in vivo exerted cardioprotective effects against ISO-induced cardiac fibrosis in rats decreasing the LV abundance of several profibrotic markers and the content of TG2 and collagen, suggesting that TG2 pharmacological inhibition could be beneficial to alleviate cardiac fibrosis.

Involvement and possible role of transglutaminases 1 and 2 in mediating fibrotic signalling, collagen cross-linking and cell proliferation in neonatal rat ventricular fibroblasts.

Transglutaminase (TG) isoforms control diverse normal and pathophysiologic processes through their capacity to cross-link extracellular matrix (ECM) proteins. Their functional and signalling roles in cardiac fibrosis remain poorly understood, despite some evidence of TG2 involvement in abnormal ECM remodelling in heart diseases. In this study, we investigated the role of TG1 and TG2 in mediating fibrotic signalling, collagen cross-linking, and cell proliferation in healthy fibroblasts by siRNA-mediated knockdown. siRNA for TG1, TG2 or negative control was transfected into cultured neonatal rat ventricular fibroblasts and cardiomyocytes. mRNA expression of TGs and profibrotic, proliferation and apoptotic markers was assessed by qPCR. Cell proliferation and soluble and insoluble collagen were determined by ELISA and LC-MS/MS, respectively. TG1 and TG2 were both expressed in neonatal rat cardiomyocytes and fibroblasts before transfection. Other TGs were not detected before and after transfection. TG2 was predominantly expressed and more effectively silenced than TG1. Knocking down TG1 or TG2 significantly modified profibrotic markers mRNA expression in fibroblasts, decreasing connective tissue growth factor (CTGF) and increasing transforming growth factor-ß1 compared to the negative siRNA control. Reduced expression of collagen 3A1 was found upon TG1 knockdown, while TG2 knockdown raised α-smooth muscle actin expression. TG2 knockdown further increased fibroblast proliferation and the expression of proliferation marker cyclin D1. Lower insoluble collagen content and collagen cross-linking were evidenced upon silencing TG1 or TG2. Transcript levels of collagen 1A1, fibronectin 1, matrix metalloproteinase-2, cyclin E2, and BCL-2-associated X protein/B-cell lymphoma 2 ratio were strongly correlated with TG1 mRNA expression, whereas TG2 expression correlated strongly with CTGF mRNA abundance. These findings support a functional and signalling role for TG1 and TG2 from fibroblasts in regulating key processes underlying myocardial ECM homeostasis and dysregulation, suggesting that these isoforms could be potential and promising targets for the development of cardiac fibrosis therapies.

Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology.

Inflammation has been implicated in atrial fibrillation (AF), a very common and clinically significant cardiac rhythm disturbance, but its precise role remains poorly understood. Work performed over the past 5 years suggests that atrial cardiomyocytes have inflammatory signalling machinery - in particular, components of the NLRP3 (NACHT-, LRR- and pyrin domain-containing 3) inflammasome - that is activated in animal models and patients with AF. Furthermore, work in animal models suggests that NLRP3 inflammasome activation in atrial cardiomyocytes might be a sufficient and necessary condition for AF occurrence. In this Review, we evaluate the evidence for the role and pathophysiological significance of cardiomyocyte NLRP3 signalling in AF. We first summarize the evidence for a role of inflammation in AF and review the biochemical properties of the NLRP3 inflammasome, as defined primarily in studies of classic inflammation. We then briefly consider the broader evidence for a role of inflammatory signalling in heart disease, particularly conditions that predispose individuals to develop AF. We provide a detailed discussion of the available information about atrial cardiomyocyte NLRP3 inflammasome signalling in AF and related conditions and evaluate the possibility that similar signalling might be important in non-myocyte cardiac cells. We then review the evidence on the role of active resolution of inflammation and its potential importance in suppressing AF-related inflammatory signalling. Finally, we consider the therapeutic potential and broader implications of this new knowledge and highlight crucial questions to be addressed in future research.

Mechanisms and Management of Thyroid Disease and Atrial Fibrillation: Impact of Atrial Electrical Remodeling and Cardiac Fibrosis.

Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with increased cardiovascular morbidity and mortality. The pathophysiology of AF is characterized by electrical and structural remodeling occurring in the atrial myocardium. As a source of production of various hormones such as angiotensin-2, calcitonin, and atrial natriuretic peptide, the atria are a target for endocrine regulation. Studies have shown that disorders associated with endocrine dysregulation are potential underlying causes of AF. The thyroid gland is an endocrine organ that secretes three hormones: triiodothyronine (T3), thyroxine (T4) and calcitonin. Thyroid dysregulation affects the cardiovascular system. Although there is a well-established relationship between thyroid disease (especially hyperthyroidism) and AF, the underlying biochemical mechanisms leading to atrial fibrosis and atrial arrhythmias are poorly understood in thyrotoxicosis. Various animal models and cellular studies demonstrated that thyroid hormones are involved in promoting AF substrate. This review explores the recent clinical and experimental evidence of the association between thyroid disease and AF. We highlight the current knowledge on the potential mechanisms underlying the pathophysiological impact of thyroid hormones T3 and T4 dysregulation, in the development of the atrial arrhythmogenic substrate. Finally, we review the available therapeutic strategies to treat AF in the context of thyroid disease.

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling.

BACKGROUND: Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. METHODS: Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. RESULTS: High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. CONCLUSION: DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Evidence of Failed Resolution Mechanisms in Arrhythmogenic Inflammation, Fibrosis and Right Heart Disease.

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can lead to chronic inflammatory disorders due to aggravation of structural damages, development of a fibrous area, and loss of function. Various human conditions show a typical unresolved inflammatory profile. Inflammatory diseases include cancer, neurodegenerative disease, asthma, right heart disease, atherosclerosis, myocardial infarction, or atrial fibrillation. New evidence has started to emerge on the role, including pro-resolution involvement of chemical mediators in the acute phase of inflammation. Although flourishing knowledge is available about the role of specialized pro-resolving mediators in neurodegenerative diseases, atherosclerosis, obesity, or hepatic fibrosis, little is known about their efficacy to combat inflammation-associated arrhythmogenic cardiac disorders. It has been shown that resolvins, including RvD1, RvE1, or Mar1, are bioactive mediators of resolution. Resolvins can stop neutrophil activation and infiltration, stimulate monocytes polarization into anti-inflammatory-M2-macrophages, and activate macrophage phagocytosis of inflammation-debris and neutrophils to promote efferocytosis and clearance. This review aims to discuss the paradigm of failed-resolution mechanisms (FRM) potentially promoting arrhythmogenicity in right heart disease-induced inflammatory status.

Implications of enigmatic transglutaminase 2 (TG2) in cardiac diseases and therapeutic developments.

Cardiac diseases are the leading cause of mortality and morbidity worldwide. Mounting evidence suggests that transglutaminases (TGs), tissue TG (TG2) in particular, are involved in numerous molecular responses underlying the pathogenesis of cardiac diseases. The TG family has several intra- and extracellular functions in the human body, including collagen cross-linking, angiogenesis, cell growth, differentiation, migration, adhesion as well as survival. TGs are thiol- and calcium-dependent acyl transferases that catalyze the formation of a covalent bond between the γ-carboxamide group of a glutamine residue and an amine group, thus increasing the stability, rigidity, and stiffness of the myocardial extracellular matrix (ECM). Excessive accumulation of cross-linked collagen leads to increase myocardial stiffness and fibrosis. Beyond TG2 extracellular protein cross-linking action, increasing evidence suggests that this pleiotropic TG isozyme may also promote fibrotic diseases through cell survival and profibrotic pathway activation at the signaling, transcriptional and translational levels. Due to its multiple functions and localizations, TG2 fulfils critical yet incompletely understood roles in myocardial fibrosis and associated heart diseases, such as cardiac hypertrophy, heart failure, and age-related myocardial stiffness under several conditions. This review summarizes current knowledge and existing gaps regarding the ECM-dependent and ECM-independent roles of TG2 and highlights the therapeutic prospects of targeting TG2 to treat cardiac diseases.

Resolution-promoting autacoids demonstrate promising cardioprotective effects against heart diseases.

Chronic heart diseases have in common an unresolved inflammatory status. In atherosclerosis, myocarditis, myocardial infarction, or atrial fibrillation, mounting evidence suggests that unresolved inflammation contributes to the chronicity, aggravation, and morbidity of the disease. Following cardiac injury or infection, acute inflammation is a normal and required process to repair damaged tissues or eliminate pathogens and promote restoration of normal functions and structures. However, if acute inflammation is not followed by resolution, a chronic and deleterious inflammatory status may occur, characterized by the persistence of inflammatory biomarkers, promoting aggravation of myocardial pathogenesis, abnormal structural remodeling, development of cardiac fibrosis, and loss of function. Although traditional antiinflammatory strategies, including the use of COX-inhibitors, to inhibit the production of inflammation promotors failed to promote homeostasis, mounting evidence suggests that activation of specific endogenous autacoids may promote resolution and perpetuate cardioprotective effects. The recent discovery of the active mechanism of resolution suggests that proresolving signals and cellular processes may help to terminate inflammation and combat the development of its chronic profile in cardiac diseases. This review discussed (I) the preclinical and clinical evidence of inflammation-resolution in cardiac disorders including atrial fibrillation; (II) how and why many traditional antiinflammatory treatments failed to prevent or cure cardiac inflammation and fibrosis; and (III) whether new therapeutic strategies may interact with the resolution machinery to have cardioprotective effects. RvD D-series resolving, RvE E-series resolving, LXA4 lipoxin A4, MaR1 maresin-1.

Pulmonary Disease, Pulmonary Hypertension and Atrial Fibrillation.

Atrial fibrillation is associated with aging, obesity, heart disease, diabetes, and/or hypertension. Recent evidence suggests that parenchymal and vascular lung diseases increase atrial fibrillation risk. We review the epidemiology, clinical features, pathophysiologic mechanisms, and treatment implications of atrial fibrillation associated with diseases of the lungs and their vasculature, especially pulmonary hypertension. We also consider other features of pulmonary disease-associated atrial fibrillation. A key mediator of these conditions is right heart disease and right atrial remodeling. We pay particular attention to the pathophysiology and treatment challenges in atrial fibrillation associated with right heart disease induced by pulmonary diseases, including pulmonary hypertension.

Role of atrial arrhythmia and ventricular response in atrial fibrillation induced atrial remodelling.

AIMS: No studies have assessed the specific contributions of atrial fibrillation (AF)-related atrial vs. associated ventricular arrhythmia to remodelling. This study assessed the roles of atrial arrhythmia vs. high ventricular rate in AF-associated remodelling. METHODS AND RESULTS: Four primary dog-groups (12/group) were subjected to 3-week pacing: 600-b.p.m. atrial tachypacing maintaining AF [AF w/o- atrioventricular block (AVB)]; atrial tachypacing with atrioventricular-node ablation (AF+AVB) and ventricular-demand pacing (80 b.p.m.); 160-b.p.m. ventricular-tachypacing (V160) reproducing the response rate during AF; and sinus rhythm with AVB/ventricular-pacing at 80-b.p.m. (control group). At terminal study, left-atrial (LA) effective refractory period (ERP) was reduced equally in both AF groups (w/o-AVB and AF+AVB). AF-inducibility was increased strongly in AF groups (w/o-AVB and AF+AVB) and modestly in V160. AF duration was significantly increased in AF w/o-AVB but not in AF+AVB or V160. Conduction velocity was decreased in AF w/o-AVB, to a greater extent than in AF+AVB and V160. Atrial fibrous-tissue content was increased in AF w/o-AVB, AF+AVB and V160, with collagen-gene up-regulation only in AF w/o-AVB. Connexin43 gene expression was reduced only in AF w/o-AVB. An additional group of 240-b.p.m. ventricular tachypacing dogs (VTP240; to induce heart failure) was studied: vs. other tachypaced groups, VTP240 caused greater fibrosis, but no change in LA-ERP or AF-inducibility. VTP240 also increased AF duration, strongly decreased left ventricular ejection fraction, and was the only group with LA natriuretic-peptide activation. CONCLUSION: The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodelling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodelling and novel considerations for ventricular rate-control.

The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease.

AIMS: Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD. METHODS AND RESULTS: Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1ß, TGFß3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. CONCLUSION: The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

Current knowledge into the role of the peptidylarginine deiminase (PAD) enzyme family in cardiovascular disease.

Peptidylarginine deiminase (PAD) family members have a vital role in maintaining the stability of the extracellular matrix (ECM) during remodelling in several heart diseases. PAD-mediated deamination, or citrullination, has been studied in different physiological and pathological conditions in the body. However, the role of PAD isoforms has not been fully studied in cardiovascular system. Citrullination is a post-translational modification that involves conversion of peptidyl-based arginine to peptidyl-based citrulline by PAD family members in a calcium-dependent manner. Upregulation of PADs have been observed in various cardiovascular diseases, including venous thrombosis, cardiac fibrosis, heart failure, atherosclerosis, coronary heart disease and acute inflammation. In this review, experimental aspects of in vivo and in vitro studies related to the roles PAD isoforms in cardiovascular diseases including mechanisms, pathophysiological and therapeutic properties are discussed. Pharmacological strategies for targeting PAD family proteins in cardiac diseases have not yet been studied. Furthermore, the role played by PAD family members in the remodelling process during the progression of cardiovascular diseases is not fully understood.

Comparison of Atrial Remodeling Caused by Sustained Atrial Flutter Versus Atrial Fibrillation.

BACKGROUND: Atrial flutter (AFL) and atrial fibrillation (AF) are associated with AF-promoting atrial remodeling, but no experimental studies have addressed remodeling with sustained AFL. OBJECTIVES: This study aimed to define the atrial remodeling caused by sustained atrial flutter (AFL) and/or atrial fibrillation (AF). METHODS: Intercaval radiofrequency lesions created a substrate for sustained isthmus-dependent AFL, confirmed by endocavity mapping. Four groups (6 dogs per group) were followed for 3 weeks: sustained AFL; sustained AF (600 beats/min atrial tachypacing); AF superimposed on an AFL substrate (AF+AFLs); sinus rhythm (SR) with an AFL substrate (SR+AFLs; control group). All dogs had atrioventricular-node ablation and ventricular pacemakers at 80 beats/min to control ventricular rate. RESULTS: Monitoring confirmed spontaneous AFL maintenance >99% of the time in dogs with AFL. At terminal open-chest study, left-atrial (LA) effective refractory period was reduced similarly with AFL, AF+AFLs and AF, while AF vulnerability to extrastimuli increased in parallel. Induced AF duration increased significantly in AF+AFLs and AF, but not AFL. Dogs with AF+AFLs had shorter cycle lengths and substantial irregularity versus dogs with AFL. LA volume increased in AF+AFLs and AF, but not dogs with AFL, versus SR+AFLs. Optical mapping showed significant conduction slowing in AF+AFLs and AF but not AFL, paralleling atrial fibrosis and collagen-gene upregulation. Left-ventricular function did not change in any group. Transcriptomic analysis revealed substantial dysregulation of inflammatory and extracellular matrix-signaling pathways with AF and AF+ALs but not AFL. CONCLUSIONS: Sustained AFL causes atrial repolarization changes like those in AF but, unlike AF or AF+AFLs, does not induce structural remodeling. These results provide novel insights into AFL-induced remodeling and suggest that early intervention may be important to prevent irreversible fibrosis when AF intervenes in a patient with AFL.