Pathophysiology and clinical relevance of atrial myopathy.

Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies.

Right Atrial Remodeling and Outcome in Patients with Secondary Tricuspid Regurgitation.

BACKGROUND: In patients with secondary tricuspid regurgitation (STR), right atrial remodeling (RAR) is a proven marker of disease progression. However, the prognostic value of RAR, assessed by indexed right atrial volume (RAVi) and reservoir strain (RAS), remains to be clarified. Accordingly, the aim of our study is to investigate the association with outcome of RAR in patients with STR. METHODS: We enrolled 397 patients (44% men, 72.7 ± 13 years old) with mild to severe STR. Complete two-dimensional and speckle-tracking echocardiography analysis of right atrial and right ventricular (RV) size and function were obtained in all patients. The primary end point was the composite of death from any cause and heart failure hospitalization. RESULTS: After a median follow-up of 15 months (interquartile range, 6-23), the end point was reached by 158 patients (39%). Patients with RAS <13% and RAVi >48 mL/m2 had significantly lower survival rates compared to patients with RAS ≥13% and RAVi ≤48 mL/m2 (log-rank P < .001). On multivariable analysis, RAS <13% (hazard ratio, 2.11; 95% CI, 1.43-3.11; P < .001) and RAVi > 48 mL/m2 (hazard ratio, 1.49; 95% CI, 1.01-2.18; P = .04) remained associated with the combined end point, even after adjusting for RV free-wall longitudinal strain, significant chronic kidney disease, and New York Heart Association class. Secondary tricuspid regurgitation excess mortality increased exponentially with values of 18.2% and 51.3 mL/m2 for RAS and RAVi, respectively. In nested models, the addition of RAS and RAVi provided incremental prognostic value over clinical, conventional echocardiographic parameters of RV size and function and RV free-wall longitudinal strain. CONCLUSIONS: In patients with STR, RAR was independently associated with mortality and heart failure hospitalization. Assessment of RAR could improve risk stratification of patients with STR, potentially identifying those who may benefit from optimization of medical therapy and a closer follow-up.

Underlying mechanism of atrial fibrillation-associated Nppa-I137T mutation and cardiac effect of potential drug therapy.

BACKGROUND: More than a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved. OBJECTIVE: This study aimed to investigate the mechanism and potential treatment of NPPA mutation-associated AF. METHODS: Nppa knock-in (KI, p.I137T) rats were generated, and cardiac function was evaluated. Blood pressure was recorded using a tail-cuff system. The expression levels were measured using real-time polymerase chain reaction, enzyme-linked immunosorbent assay or Western blot analysis, and RNA-sequence analysis. Programmed electrical stimulation, patch clamp, and multielectrode array were used to record the electrophysical characteristics. RESULTS: Mutant rats displayed downregulated expression of atrial natriuretic peptide but elevated blood pressure and enlarged left atrial end-diastolic diameter. Further, gene topology analysis suggested that the majority of differently expressed genes in Nppa KI rats were related to inflammation, electrical remodeling, and structural remodeling. The expression levels of C-C chemokine ligand 5 and galectin-3 involved in remodeling were higher, while there were declined levels of Nav1.5, Cav1.2, and connexin 40. AF was more easily induced in KI rats. Electrical remodeling included abbreviated action potentials, effective refractory period, increased late sodium current, and reduced calcium current, giving rise to conduction abnormalities. These electrophysiological changes could be reversed by the late sodium current blocker ranolazine and the Nav1.8 blocker A-803467. CONCLUSION: Our findings suggest that structural remodeling related to inflammation and fibrosis and electrical remodeling involved in late sodium current underly the major effects of the Nppa (p.I137T) variant to induce AF, which can be attenuated by the late sodium current blocker and Nav1.8 blocker.

Colchicine attenuates the electrical remodeling of post-operative atrial fibrillation through inhibited expression of immune-related hub genes and stabilization of microtubules.

Rationale: Acute inflammation is a major risk factor for post-operative atrial fibrillation (POAF), and epicardial adipose tissue (EAT) is considered as a source of inflammatory mediators. However, underlying mechanisms and pharmacological targets of POAF are poorly understood. Methods: Integrative analysis of array data from EAT and right atrial appendage (RAA) samples was conducted to identify potential hub genes. Lipopolysaccharide (LPS)-stimulated inflammatory models in mice and in induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) were used to examine the exact mechanism underlying POAF. Electrophysiological analysis, multi-electrode array, and Ca2+ imaging was employed to explore the alterations of electrophysiology and Ca2+ homeostasis under inflammation. Flow cytometry analysis, histology and immunochemistry were performed to investigate immunological alterations. Results: We observed electrical remodeling, enhanced atrial fibrillation (AF) susceptibility, immune cell activation, inflammatory infiltration, and fibrosis in LPS-stimulated mice. LPS-stimulated iPSC-aCMs showed arrhythmias, abnormal Ca2+ signaling, reduced cell viability, disrupted microtubule network and increased α-tubulin degradation. VEGFA, EGFR, MMP9 and CCL2 were identified as hub genes simultaneously targeted in the EAT and RAA of POAF patients. Notably, treatment of colchicine in LPS-stimulated mice resulted in a U-shape dose-response curve, where greatly improved survival rates were observed only at doses between 0.10-0.40 mg/kg. At this therapeutic dose level, colchicine inhibited the expression of all the identified hub genes and effectively rescued the pathogenic phenotypes observed in LPS-stimulated mice and iPSC-aCM models. Conclusions: Acute inflammation promotes α-tubulin degradation, induces electrical remodeling, and both recruits and facilitates the infiltration of circulating myeloid cells. A certain dose of colchicine attenuates electrical remodeling and decreases the recurrence of AF.

Mecanismos de adaptação do coração em atletas de elite do sexo feminino: comparação com indivíduos sadios e tempo de treinamento / Heart adaptation mechanisms in elite female athletes: comparison with healthy individuals and time of training

Fundamento: O exercício intenso e continuado em atletas provoca fenótipos de remodelamento adaptativo, cujos parâmetros podem ser avaliados pela ecocardiografia convencional, e de deformação miocárdica. Assim, foi comparado o remodelamento miocárdico em atletas do sexo feminino (grupo atletas) com mulheres sedentárias da mesma faixa etária (grupo-controle) e entre atletas com maior e menor tempo de treinamento. Métodos: Foram selecionadas 57 futebolistas femininas (grupo atletas) e 25 mulheres sadias sedentárias (grupocontrole). As atletas foram divididas em dois grupos: grupo principal, com 32 atletas, e grupo sub-17, com 25 atletas. Foram determinadas, através de ecocardiografia, as dimensões, a função sistólica e diastólica das câmaras cardíacas e a deformação miocárdica (strain longitudinal, circunferencial, radial e mecânica rotacional), utilizando a estatística Z com significância de p < 0,05. Resultados: A idade dos grupos atletas, controle, principal e sub-17 foi de 22,1±6,3; 21,2±5,0; 26,5±5,1; e 16,5±0,6, respectivamente. O peso, o índice de massa corporal e a frequência cardíaca foram menores no grupo atletas. A espessura das paredes, o índice de massa do ventrículo esquerdo (VE), o volume do átrio esquerdo (AE), a fração de ejeção e as dimensões do ventrículo direito (VD) foram maiores no grupo atletas, mas dentro de valores normais. A deformação miocárdica mostrou diminuição do strain radial, da rotação basal, da rotação apical e do twist, sugerindo mecanismo de reserva contrátil. Esses parâmetros foram menores no grupo principal, que também apresentava maior espessura das paredes, maior volume do AE e maior tamanho do VD, sugerindo que o aumento da reserva contrátil se relaciona com maior tempo de treinamento. Conclusões: As atletas do sexo feminino com treinamento intenso de longa duração apresentam remodelamento adaptativo das câmaras cardíacas e aumento da reserva contrátil observada em repouso, com esses parâmetros mais acentuados nas atletas com maior tempo de treinamento.(AU)

Background: Intense continuous exercise provokes adaptive remodeling phenotypes in athletes, the parameters of which can be evaluated through conventional echocardiography and myocardial deformation. We compared myocardial remodeling in female athletes (athlete group) with sedentary women of the same age range (control group) and between older and younger athletes. Methods: A total of 57 female soccer players and 25 healthy sedentary women were selected. The athlete group was subdivided into a main group and those under 17 years of age (< 17 group). The dimensions and systolic and diastolic function of the cardiac chambers and myocardial deformation (longitudinal and circumferential, as well as radial strain and rotational mechanics) was determined through echocardiography, using the Z statistic with a significance level of p< 0.05. Results: The mean age of the athlete, control, main, and < 17 groups was 22.1 (SD, 6.3); 21.2 (SD, 5.0); 26.5 (SD, 5.1); 16.5 (SD, 0.6) years, respectively. Weight, body mass index and heart rate were lower in the athlete group. Wall thickness, left ventricular mass index, left atrial (LA) volume, ejection fraction, and right ventricular dimensions were higher in athlete group, but remained within normal ranges. Regarding myocardial deformation, there was decreased radial strain, basal rotation, apical rotation, and twisting in the athlete group, suggesting a contractile reserve mechanism. These parameters were lesser in the main athlete group, who also had greater wall thickness, greater volume in the left atrium (LA) and larger size in the right ventricle (RV), suggesting that increased contractile reserve is related to longer time spent in the sport. Conclusions: In female athletes who had undergone intense long-term training, we observed adaptive remodeling of the cardiac chambers and increased contractile reserve (at rest), and these changes were more pronounced in those with longer involvement in the sport.(AU)

High-phosphate diet causes atrial remodeling and increases atrial fibrillation vulnerability via STAT3/NF-κB signaling and oxidative stress.

AIM: Hyperphosphatemia is associated with adverse cardiovascular outcomes in both the general population and patients with end-stage renal disease. We evaluated whether high inorganic phosphate (Pi) intake causes atrial remodeling and increased atrial fibrillation (AF) risk. METHODS: The 5/6 nephrectomized chronic kidney disease (CKD) mice were fed a high-Pi (2%) diet for 10 weeks. AF vulnerability was evaluated through transesophageal burst atrial pacing. Phosphoproteomic, Western blotting, and immunohistochemistry were used to evaluate the effects of high Pi in atrial fibroblasts, atrial myocytes, and HL-1 myocytes. RESULTS: CKD and sham mice fed a high-Pi diet exhibited increased AF vulnerability, atrial fibrosis, and oxidative stress compared with mice fed a normal diet. Compared with normal (1 mM) Pi, high (2 mM) Pi significantly increased the activity of atrial fibroblasts and mitochondrial oxidative stress. Phosphoproteomic analysis revealed that compared with normal Pi, high Pi considerably increased the phosphorylation of intracellular proteins in atrial fibroblasts, including proteins related to NF-κB signaling and STAT3. Inhibition of NF-κB, STAT3, and Nox4 by small interfering RNA reduced the high-Pi-induced expression of collagen. In HL-1 myocytes, the high Pi induced the degradation of myofibril proteins and hyperphosphorylation of RyR2, which was abolished by Nox4 and CaMKII inhibition. Switching back to a normal-Pi diet improved the atrial abnormalities induced by high-Pi diet. CONCLUSIONS: High-Pi intake causes atrial structural and electrical remodeling and increases AF vulnerability, which is mediated through STAT3/NF-κB signaling and oxidative stress. High dietary Pi intake can exert detrimental effects on atria and may increase AF risk.

Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes.

An aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of INa,Late in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca2+ imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca2+ release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased INa,Late and were significantly mediated by treatment with the INa,Late blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased INa,Late and subsequent aberrant myocyte excitability, which were abolished by INa,Late inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic INa,Late. These results indicate that PI3K/Akt signaling is critical for regulating INa,Late and electrical remodeling, supporting the use of PI3K/Akt-mediated INa,Late as a therapeutic target for AF.

Alpha-lipoic acid prevents atrial electrical and structural remodeling via inhibition of NADPH oxidase in a rabbit rapid atrial pacing model.

BACKGROUND: Alpha-lipoic acid (ALA) is a natural compound, one of the natural antioxidants with high activity. In the NADPH oxidase family, NADPH oxidase 4 (NOX4) is an important subunit participating in the production of ROS. NADPH oxidase 2 (NOX2) can form active NADPH oxidase complexes when binding to several other subunits in the cytoplasm, and NOX2 is its major functional subunit. Rapid atrial pacing (RAP) model was constructed to study the effects of ALA on electrical and structural remodeling in rabbits. METHODS: Thirty rabbits were divided into SHAM group, RAP group and ALA+RAP group. Their right atriums were paced at a speed of 600 beats/min for 12 h in the RAP and ALA+RAP groups, and the atrial effective refractory period (AERP) and AERP frequency adaptability were determined during the pace. In ALA+RAP group, ALA (30 mg/kg) was administered intraperitoneally daily to the rabbits for 3 days before RAP. Atrial tissue was collected from each group to detect malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen species (ROS) to observe the effect of oxidative stress. The pathological structure of the atrial tissue was observed through hematoxylin-eosin (HE) staining. Ultrastructural changes in the atrial myocytes were observed by transmission electron microscopy (TEM), and the expression levels of Nox2 and Nox4 were detected by immunohistochemistry, western blot and ELISA. RESULTS: AERP gradually shortened, while ALA injection could remarkably delay this process. HE staining showed that the most of the nuclei appeared normal, the myocardial fibers did not show ruptures, and their arrangement was slightly ordered, and myofilament dissolution and mitochondrial swelling and deformation were rarely observed by TEM in the ALA+RAP group. Compared with the RAP group, the contents of MDA and ROS were reduced, SOD activity was enhanced, and the expression of NOX2 and NOX4 was decreased in the ALA+RAP group. DISCUSSION: ALA can inhibit atrial electrical remodeling and structural remodeling, and its mechanism may be related to inhibiting the activity of NADPH oxidase.

Left atrial myocardial intrinsic function remodeling response to repair of primary mitral regurgitation.

Severe mitral regurgitation (MR) is a common valve disease which is associated with high mortality, if only managed medically. MR produces chronic and progressive volume overload with left atrial (LA) and left ventricular (LV) dilatation and dysfunction, atrial fibrillation (AF) and eventually myocardial fibrosis, irrespective of ejection fraction (EF). Surgical correction (mitral valve repair) of MR removes the volume overload, hence unmasks pre-operative LV structure and function disturbances, including reduced EF and global longitudinal and circumferential strain, as well as LA volume and strain. This review aims at describing LA remodeling before and after surgical repair.

Improving effects of eplerenone on atrial remodeling induced by chronic intermittent hypoxia in rats.

OBJECTIVE: Atrial fibrillation (AF) is closely associated with the overactivation of the renin-angiotensin-aldosterone system. Large cohort studies and recent meta-analyses have shown that the utilization of mineralocorticoid receptor antagonists has positive effects on the prevention and development of AF. This study aimed to investigate the effects of eplerenone on atrial remodeling in AF model rats and elucidate its intrinsic mechanism. METHODS: Ninety male Sprague-Dawley rats were randomly divided into the control group, chronic intermittent hypoxia (CIH) group, and CIH-eplerenone intervention (CIH-E) group. Rats in the CIH and CIH-E groups received CIH for 6 weeks, and rats in the CIH-E group were additionally administered eplerenone gavage (10 mg/kg/d). After modeling, the baseline parameters of each group were examined. Histopathology, molecular biology, isolated electrophysiology, and patch clamp experiments were performed after sampling. RESULTS: Compared with the control group, rats in the CIH group showed atrial enlargement, significant aggravated fibrosis, upregulated JAK/STAT3 pathway, shortened effective refractory period (ERP), increased AF inducibility, and decreased peak current density of characteristic voltage-gated ion channels in atrial myocytes. After eplerenone intervention, rats in the CIH-E group had a smaller atrial diameter than those in the CIH group. Furthermore, downregulated JAK/STAT3 pathway, prolonged ERP, decreased AF inducibility, and increased peak current density of characteristic ion channels were also observed in the CIH-E group. CONCLUSIONS: CIH induced significant atrial remodeling in rats and eplerenone significantly ameliorated the atrial remodeling caused by CIH. This could be attributed to the downregulation of the JAK/STAT3 pathway and the increase in the characteristic ion current density of atrial myocytes.

Inflammation and remodeling pathways and risk of cardiovascular events in patients with ischemic heart failure and reduced ejection fraction.

Patients with heart failure (HF) and coronary artery disease (CAD) have a high risk for cardiovascular (CV) events including HF hospitalization, stroke, myocardial infarction (MI) and sudden cardiac death (SCD). The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case-control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR < 0.001 (NT-proBNP, BNP, T-cell immunoglobulin and mucin domain containing 4 (TIMD4), fibroblast growth factor 23 (FGF-23), growth differentiation factor-15 (GDF-15), pulmonary surfactant-associated protein D (PSP-D) and Spondin-1 (SPON1)). No significant interactions were identified between the type of clinical event (MI/stroke, SCD or HFH) and specific biomarkers (all interaction FDR > 0.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033-0.082), p < 0.0001 and the net reclassification index was 54.9 (42.5 to 67.3), p < 0.0001. In patients with HFrEF and CAD following HF hospitalization, we found that NT-proBNP, BNP, TIMD4, FGF-23, GDF-15, PSP-D and SPON1, biomarkers broadly associated with inflammation and remodeling mechanistic pathways, were strong but indiscriminate predictors of a variety of individual CV events.

Ameliorative Impact of Liraglutide on Chronic Intermittent Hypoxia-Induced Atrial Remodeling.

Atrial fibrillation (AF) is the most frequent form of clinical cardiac arrhythmias. Previous evidence proved that atrial anatomical remodeling (AAR) and atrial electrical remodeling (AER) are crucial for the progression and maintenance of AF. This study is aimed at investigating the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist, Liraglutide (Lir), on atrial remodeling (AR) mouse model induced by chronic intermittent hypoxia (CIH). C57BL/6 mice were categorized randomly into the control, Lir, CIH, and CIH+Lir groups. CIH was performed in CIH and CIH+Lir groups for 12 weeks. Lir (0.3 mg/kg/day, s.c) was administered to the Lir and CIH+Lir groups for four weeks, beginning from the ninth week of CIH. Meanwhile, echocardiography and right atrial endocardial electrophysiology via jugular vein, as well as induction rate and duration of AF, were evaluated. Masson and Sirius red staining assays were utilized to assess the extent of fibrosis in the atrial tissue of the mice. Immunohistochemical staining, RT-qPCR, and Western blotting were performed to evaluate the marker levels of AAR and AER and the expression of genes and proteins of the miR-21/PTEN/PI3K/AKT signaling pathway, respectively. ELISA was also performed to evaluate the changes of serum inflammatory factor levels. The CIH group exhibited significant AR, increased atrial fibrosis, and a higher incidence rate of AF compared to the control group. Lir could significantly downregulate the protein expression level in the PI3K/p-AKT pathway and upregulated that of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Moreover, Lir downregulated the expression of miR-21. However, the protein expressions of CACNA1C and KCNA5 in atrial tissue were not changed significantly. In addition, Lir significantly attenuated the levels of markers of inflammation (TNF-α and IL-6) in the serum. In the mouse model of CIH, Lir treatment could ameliorate AR by the miR-21/PTEN/PI3K/AKT signaling pathway and modulation of inflammatory responses.

Distinct atrial remodeling in patients with subclinical atrial fibrillation: Lessons from computed tomographic images.

AIMS: Cardiac implanted electronic devices (CIEDs) can detect atrial high-rate episodes (AHREs) and challenge current management of subclinical atrial fibrillation (AF). METHODS: To characterize the anatomic and functional remodeling of cardiac structures between patients with subclinical AF (SCAF) and clinical AF. The predictors for AHREs ≥6 min were also investigated. RESULTS: We compared the atrial volume, dynamic function, and peri-atrial fat between 104 CIEDs (AHREs = 0, n = 12; SCAF, n = 66; CIEDs with AF, n = 26) and 40 paroxysmal AF patients who were planning for catheter ablation (AF for ablation) using 256-slice multidetector computed tomography for the duration of the AHREs. The maximal volume of the left atrium (LA) and LA appendage (LAA) were significantly smaller; the total emptying fraction (EF) and active EF of the LA and LAA were significantly better in the patients with SCAF than in those with clinical AF. Less peri-atrial fat (p < 0.001) and a greater LAA/ascending aorta (AA) Hounsfield unit (HU) ratio (p < 0.05) were noted in the patients with SCAF. Significantly increased volume reduced the total EF of LA and LAA and a reduced LAA/AA HU ratio (0.91 ± 0.18 vs 0.98 ± 0.03 vs 0.97 ± 0.05, p < 0.05) were demonstrated in patients with AHREs ≥6 min compared to those with AHREs <6 min and without AHRE. Multivariate analysis showed the reduced LAA/AA HU ratio is an independent predictor for the development of AHREs ≥6 min. CONCLUSION: As compared to clinical AF, patients with SCAF show a more favorable LA remodeling process. Among the patients with device-detected AHREs, worse LA remodeling and a reduced LAA/AA HU ratio were associated with the occurrence of AHREs ≥6 min. These findings may provide an incremental value for understanding SCAF.

[Effects of chronic intermittent hypoxia on atrial electrical remodeling in rats].

OBJECTIVE: The aim of this study was to investigate the effects of chronic intermittent hypoxia (CIH) on atrial electrical remodeling in Sprague-Dawley (SD) rats, which provide the explication for the mechanisms of CIH promoting atrial fibrillation (AF). METHODS: Eighty SD rats were randomly divided into 2 groups: control group and CIH group (n=40). CIH rats were subjected to CIH 8 h/d for 30 days. After the echocardiography and hemodynamics examination, cardiac electrophysiological experiments, histological experiments, and molecular biological experiments were executed. AF susceptibility was measured by isolated heart electrophysiological experiments. Masson's trichrome stain was used to assess the degree of atrial fibrosis. The protein expression levels of sodium voltage-gated channel alpha subunit 5 (SCN5A/Nav1.5), calcium voltage-gated channel subunit alpha1 C (CACNA1C/Cav1.2) and potassium voltage-gated channel subfamily D member 3 (KCND3/Kv4.3) were measured by Western blot. In whole-cell patch clamp experiments, current clamp mode was used to record AP, and APD90 and APD50 were analyzed and compared between the two groups. In voltage clamp mode, INa, ICa-L, Ito and their kinetic parameters were recorded and compared between the two groups. RESULTS: Compared to the control rats, atrial interstitial collagen deposition (P＜0.01) and AF inducibility (P＜0.05) were increased in CIH rats, whereas the expression levels of Nav1.5, Cav1.2 and Kv4.3 were decreased (P＜0.05). APD90 and APD50 in CIH rats' atrial myocytes were longer than those of control rats, and CIH rats showed decreased current density of INa, ICa-L(P＜0.01) and Ito(P＜0.01). CONCLUSION: CIH-induced changes in the protein expression levels of ion channel subunits, current intensity, APD, and AF susceptibility, which may be the mechanisms of CIH promoting AF.

Connexin 43 participates in atrial electrical remodelling through colocalization with calcium channels in atrial myocytes.

Atrial fibrillation (AF) is associated with atrial conduction disturbances caused by electrical and/or structural remodelling. In the present study, we hypothesized that connexin might interact with the calcium channel through forming a protein complex and, then, participates in the pathogenesis of AF. Western blot and whole-cell patch clamp showed that protein levels of Cav1.2 and connexin 43 (Cx43) and basal ICa,L were decreased in AF subjects compared to sinus rhythm (SR) controls. In cultured atrium-derived myocytes (HL-1 cells), knocking-down of Cx43 or incubation with 30 mmol/L glycyrrhetinic acid significantly inhibited protein levels of Cav1.2 and Cav3.1 and the current density of ICa,L and ICa,T . Incubation with nifedipine or mibefradil decreased the protein level of Cx43 in HL-1 cells. Moreover, Cx43 was colocalized with Cav1.2 and Cav3.1 in atrial myocytes. Therefore, Cx43 might regulate the ICa,L and ICa,T through colocalization with calcium channel subunits in atrial myocytes, representing a potential pathogenic mechanism in AF.

EGCG prevents pressure overload­induced myocardial remodeling by downregulating overexpression of HDAC5 in mice.

Myocardial remodeling is a complex pathological process and its mechanism is unclear. The present study investigated whether epigallocatechin gallate (EGCG) prevents myocardial remodeling by regulating histone acetylation and explored the mechanisms underlying this effect in the heart of a mouse model of transverse aortic constriction (TAC). A TAC mouse model was created by partial thoracic aortic banding (TAB). Subsequently, TAC mice were injected with EGCG at a dose of 50 mg/kg/day for 12 weeks. The hearts of mice were collected for analysis 4, 8 and 12 weeks after TAC. Histopathological changes in the heart were observed by hematoxylin and eosin, Masson trichrome and wheat germ agglutinin staining. Protein expression levels were investigated using western blotting. Cardiac function of mice was detected by echocardiography. The level of histone acetylated lysine 27 on histone H3 (H3K27ac) first increased and then decreased in the hearts of mice at 4, 8 and 12 weeks after TAC. The expression levels of two genes associated with pathological myocardial remodeling, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), also increased initially but then decreased. The expression levels of histone deacetylase 5 (HDAC5) gradually increased in the hearts of mice at 4, 8 and 12 weeks after TAC. Furthermore, EGCG increased acetylation of H3K27ac by inhibiting HDAC5 in the heart of TAC mice treated with EGCG for 12 weeks. EGCG normalized the transcriptional activity of heart nuclear transcription factor myocyte enhancer factor 2A in TAC mice treated for 12 weeks. The low expression levels of myocardial remodeling­associated genes (ANP and BNP) were reversed by EGCG treatment for 12 weeks in TAC mice. In addition, EGCG reversed cardiac enlargement and improved cardiac function and survival in TAC mice when treated with EGCG for 12 weeks. Modification of the HDAC5­mediated imbalance in histone H3K27ac served a key role in pathological myocardial remodeling. The present results show that EGCG prevented and delayed myocardial remodeling in TAC mice by inhibiting HDAC5.

Plasticity of the bony carotid canal and its clinical use for assessing negative remodeling of the internal carotid artery.

BACKGROUND AND OBJECTIVE: It has long been believed that the bony carotid canal has no plasticity and that a small canal represents a hypoplastic internal carotid artery. We aimed to show whether the carotid canal can narrow according to morphological changes in the internal carotid artery. MATERIALS AND METHODS: The carotid canal diameter was longitudinally measured in seven individuals who underwent carotid artery ligation. As moyamoya disease is known to be associated with negative remodeling of the internal carotid artery, the carotid canal diameter was measured in 106 patients with moyamoya disease, and an association with the outer diameter of the internal carotid artery or a correlation with the disease stage was investigated. The carotid canal was measured by computed tomography (106 patients), and the outer diameter of the artery was measured by high-resolution magnetic resonance imaging (63 patients). The carotid canal area was calculated by the product of the maximum axial diameter and its perpendicular diameter. RESULTS: All seven patients who underwent carotid artery ligation showed narrowing of the carotid canal, and the carotid canal area decreased by 12.2%-28.9% during a mean follow-up period of 4.2 years. In patients with moyamoya disease, the carotid canal area showed a linear correlation with the outer area of the internal carotid artery (r = 0.657, p < 0.001), and a negative correlation with the disease stage (ρ = -0.283, p < 0.001). CONCLUSION: The bony carotid canal has plasticity, and its area reflects the outer area of the internal carotid artery, therefore, it can be used to assess the remodeling of the carotid artery. A narrow carotid canal may not necessarily indicate hypoplastic internal carotid artery.

A Potential Novel Indication for Preventing Thromboembolism in Patients with Atrial Arrhythmias: Remodeling of the Left Atrium.

OBJECTIVE: Thrombosis in patients with atrial arrhythmias might be associated with remodeling of the left atrium (LA). We aimed to describe this relationship and identify a novel factor, in addition to the CHA2DS2-VASc score, to guide therapeutic strategies for preventing thromboembolism in the hope of improving the prognosis for such patients. METHODS: Patients diagnosed with atrial arrhythmias and who met our inclusion criteria were enrolled in this study. Various clinical parameters were recorded; diameters reflecting remodeling of the LA were measured and thrombosis was diagnosed by enhanced CT. RESULTS: Totally, 192 patients were enrolled in the study. The overall prevalence of left atrial thrombosis was 8.3%. Patients with persistent atrial fibrillation exhibited the highest anteroposterior diameter of the LA (45.1±7.2 mm) and prevalence of thrombosis (15.6%). An anteroposterior LA diameter of ≥50 mm was a strong independent impact risk factor for thrombosis (OR=10.1, 95%CI: 2.8-36.9, P<0.001). The prevalence of LA thrombosis in patients with and without anteroposterior LA diameter of ≥50 mm was 25.8% and 5.0%, respectively. CONCLUSION: Marked remodeling of the LA characterized by an anteroposterior LA diameter of ≥50 mm is a strong independent risk factor of thrombosis, and should be considered for the prevention of thromboembolism through various strategies.

Atrial Cardiomyopathy: Pathophysiology and Clinical Consequences.

Around the world there are 33.5 million patients suffering from atrial fibrillation (AF) with an annual increase of 5 million cases. Most AF patients have an established form of an atrial cardiomyopathy. The concept of atrial cardiomyopathy was introduced in 2016. Thus, therapy of underlying diseases and atrial tissue changes appear as a cornerstone of AF therapy. Furthermore, therapy or prevention of atrial endocardial changes has the potential to reduce atrial thrombogenesis and thereby cerebral stroke. The present manuscript will summarize the underlying pathophysiology and remodeling processes observed in the development of an atrial cardiomyopathy, thrombogenesis, and atrial fibrillation. In particular, the impact of oxidative stress, inflammation, diabetes, and obesity will be addressed.

Impact of left atrial geometric remodeling on late atrial fibrillation recurrence after catheter ablation.

AIMS: To quantitatively investigate the impact of left atrial geometric remodeling on atrial fibrillation recurrence after catheter ablation. METHODS: A retrospective analysis of 105 patients with atrial fibrillation who underwent coronary computed tomographic angiography before catheter ablation. Risk factors for atrial fibrillation recurrence were identified by multivariable logistic regression analysis and used to create a nomogram. RESULTS: After at least 12 months of follow-up, 30 patients (29%) developed recurrent atrial fibrillation. Patients with recurrence had higher left atrial volume, left atrial sphericity, and lower left atrial ejection fraction (LAEF) (P < 0.05). There was no significant difference in asymmetry index between the two groups (P = 0.121). Multivariable regression analysis showed that left atrial minimal volume index (LAVImin) [odds ratio (OR): 1.026, 95% confidence interval (CI): 1.002-1.050, P = 0.034], left atrial sphericity (OR: 1.222, 95% CI: 1.040-1.435, P = 0.015) and CHADS2 score (OR: 1.511, 95% CI: 1.024-2.229, P = 0.038) were independent predictors of atrial fibrillation recurrence. The combined model of the left atrial sphericity to the LAVImin substantially increased the predictive power for atrial fibrillation recurrence [area under the curve (AUC) = 0.736, 95% CI: 0.627-0.844, P < 0.001], with a sensitivity of 80% and a specificity of 61%. A nomogram was generated based on the contribution weights of the risk factors; the AUC was 0.772 (95% CI: 0.670-0.875) and had good internal validity. CONCLUSION: The CHADS2 score, left atrial sphericity, and LAVImin were significant and independent predictors of atrial fibrillation recurrence after catheter ablation. Furthermore, the nomogram had a better predictive capacity for atrial fibrillation recurrence.