Berberine ameliorates chronic intermittent hypoxia-induced cardiac remodelling by preserving mitochondrial function, role of SIRT6 signalling.

Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH-induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH-induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno-associated virus 9 (AAV9) carrying SIRT6 or SIRT6-specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK-FOXO3a signalling. BBR dose-dependently ameliorated cardiac injury in CIH-induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6-specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6-AMPK-FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1-Parkin-mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH-induced cardiac dysfunction. BBR attenuates CIH-induced myocardial injury by improving mitochondrial biogenesis and PINK1-Parkin-dependent mitophagy via the SIRT6-AMPK-FOXO3a signalling pathway.

Circulating neuropeptide Y as a biomarker in postoperative atrial fibrillation cases administered off-pump coronary bypass Graft surgery.

Background and aims: Postoperative atrial fibrillation (POAF) is considered the most prevalent irregular heart rhythm after heart surgery. The cardiac autonomic nervous system significantly affects POAF, and neuropeptide Y (NPY), an abundant neuropeptide in the cardiovascular system, is involved in this autonomic regulation. The current work aimed to examine the potential association of NPY with POAF in individuals administered isolated off-pump coronary artery bypass grafting. Methods: From January 1 to May 31, 2020, we examined consecutive cases administered successful isolated off-pump coronary artery bypass grafting with no previously diagnosed atrial fibrillation (AF). Clinical characteristics and plasma samples were collected before surgery. NPY was quantified by enzyme-linked immunosorbent assay (ELISA) in peripheral blood, and POAF cases were identified through a 7-day Holter monitoring. Results: Among 120 cases with no previously diagnosed AF, 33 (27.5 %) developed POAF during hospitalization. Median NPY levels were markedly elevated in the POAF group in comparison with the sinus rhythm group (31.72 vs. 27.95, P = 0.014). Multivariable logistic regression analysis revealed age (OR = 1.135, 95%CI 1.054-1.223; P = 0.001), left atrial size (OR = 1.136, 95%CI 1.004-1.285; P = 0.043), and NPY levels in peripheral blood (OR = 1.055, 95%CI 1.002-1.111; p = 0.041) independently predicted POAF. Additionally, NPY levels were positively correlated with high-frequency (HF) (r = 0.2774, P = 0.0022) and low-frequency (LF) (r = 0.2095, P = 0.0217) components of heart rate variability. Conclusion: In summary, this study demonstrates an association between elevated NPY levels in peripheral blood before surgery and POAF occurrence.

Robust Artificial Intelligence Tool for Atrial Fibrillation Diagnosis: Novel Development Approach Incorporating Both Atrial Electrograms and Surface ECG and Evaluation by Head-to-Head Comparison With Hospital-Based Physician ECG Readers.

BACKGROUND: Atrial fibrillation (AF) increases risk of embolic stroke, and in postoperative patients, increases cost of care. Consequently, ECG screening for AF in high-risk patients is important but labor-intensive. Artificial intelligence (AI) may reduce AF detection workload, but AI development presents challenges. METHODS AND RESULTS: We used a novel approach to AI development for AF detection using both surface ECG recordings and atrial epicardial electrograms obtained in postoperative cardiac patients. Atrial electrograms were used only to facilitate establishing true AF for AI development; this permitted the establishment of an AI-based tool for subsequent AF detection using ECG records alone. A total of 5 million 30-second epochs from 329 patients were annotated as AF or non-AF by expert ECG readers for AI training and validation, while 5 million 30-second epochs from 330 different patients were used for AI testing. AI performance was assessed at the epoch level as well as AF burden at the patient level. AI achieved an area under the receiver operating characteristic curve of 0.932 on validation and 0.953 on testing. At the epoch level, testing results showed means of AF detection sensitivity, specificity, negative predictive value, positive predictive value, and F1 (harmonic mean of positive predictive value and sensitivity) as 0.970, 0.814, 0.976, 0.776, and 0.862, respectively, while the intraclass correlation coefficient for AF burden detection was 0.952. At the patient level, AF burden sensitivity and positive predictivity were 96.2% and 94.5%, respectively. CONCLUSIONS: Use of both atrial electrograms and surface ECG permitted development of a robust AI-based approach to postoperative AF recognition and AF burden assessment. This novel tool may enhance detection and management of AF, particularly in patients following operative cardiac surgery.

Branched-chain amino acid catabolic defect in vascular smooth muscle cells drives thoracic aortic dissection via mTOR hyperactivation.

Metabolic reprogramming of vascular smooth muscle cell (VSMC) plays a critical role in the pathogenesis of thoracic aortic dissection (TAD). Previous researches have mainly focused on dysregulation of fatty acid or glucose metabolism, while the impact of amino acids catabolic disorder in VSMCs during the development of TAD remains elusive. Here, we identified branched-chain amino acid (BCAA) catabolic defect as a metabolic hallmark of TAD. The bioinformatics analysis and data from human aorta revealed impaired BCAA catabolism in TAD individuals. This was accompanied by upregulated branched-chain α-ketoacid dehydrogenase kinase (BCKDK) expression and BCKD E1 subunit alpha (BCKDHA) phosphorylation, enhanced vascular inflammation, and hyperactivation of mTOR signaling. Further in vivo experiments demonstrated that inhibition of BCKDK with BT2 (a BCKDK allosteric inhibitor) treatment dephosphorylated BCKDHA and re-activated BCAA catabolism, attenuated VSMCs phenotypic switching, alleviated aortic remodeling, mitochondrial reactive oxygen species (ROS) damage and vascular inflammation. Additionally, the beneficial actions of BT2 were validated in a TNF-α challenged murine VSMC cell line. Meanwhile, rapamycin conferred similar beneficial effects against VSMC phenotypic switching, cellular ROS damage as well as inflammatory response. However, co-treatment with MHY1485 (a classic mTOR activator) reversed the beneficial effects of BT2 by reactivating mTOR signaling. Taken together, the in vivo and in vitro evidence showed that impairment of BCAA catabolism resulted in aortic accumulation of BCAA and further caused VSMC phenotypic switching, mitochondrial ROS damage and inflammatory response via mTOR hyperactivation. BCKDK and mTOR signaling may serve as the potential drug targets for the prevention and treatment of TAD.

Gut Microbiota in Patients with Postoperative Atrial Fibrillation Undergoing Off-Pump Coronary Bypass Graft Surgery.

BACKGROUND: Post-operative atrial fibrillation (POAF) is one of the most common complications of cardiac surgery. However, the underlying mechanism is not well understood. Alterations in the gut microbiota are associated with the development of atrial fibrillation (AF). The aim of this study was to explore the relationship between gut microbiota and POAF. METHODS: Fecal samples were collected before surgery from 45 patients who underwent coronary artery bypass grafting with POAF and 90 matched patients without POAF (1:2). 16S rRNA sequencing was used to detect the microbiome profiles of 45 POAF patients and 89 matched patients (one sample in the no-POAF group was deleted owing to low quality after sequencing). Plasma 25-hydroxy vitamin D level was measured by ELISA. RESULTS: Compared to the patients without POAF, gut microbiota composition was remarkably changed in the patients with POAF, with an increase in Lachnospira, Acinetobacter, Veillonella and Aeromonas, and a decrease in Escherichia-Shigella, Klebsiella, Streptococcus, Brevundimonas and Citrobacter. Furthermore, plasma 25-hydroxy vitamin D levels were decreased in POAF patients and negatively correlated with an abundance of Lachnospira. CONCLUSIONS: The gut microbiota composition between patients with and without POAF is significantly different, implying that gut microbiota may play a role in the pathogenesis of POAF. Further studies are needed to fully clarify the role of gut microbiota in the initiation of AF.

Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1.

Ferroptosis contributes to the pathogenesis of atrial fibrillation (AF), although the mechanisms are still largely uncovered. The current study was designed to explore the pharmacological effects of icariin against ethanol-induced atrial remodeling, if any, and the mechanisms involved with a focus on SIRT1 signaling. Excessive ethanol-treated animals were administered with Ferrostatin-1, Erastin or icariin to evaluate the potential effects of icariin or ferroptosis. Then, the underling mechanisms was further explored in the in vitro experiments using HL-1 atrial myocytes. Excessive ethanol administration caused significant atrial damage as evidenced by increased susceptibility to AF, altered atrial conduction pattern, atrial enlargement, and enhanced fibrotic markers. These detrimental effects were reversed by Ferrostatin-1 or icariin treatment, while Erastin co-administration markedly abolished the beneficial actions conferred by icariin. Mechanistically, ethanol-treated atria exhibited markedly up-regulated pro-ferroptotic protein (PTGS2, ACSL4, P53) and suppressed anti-ferroptotic molecules (GPX4, FTH1). Icariin treatment inhibited ethanol-induced atrial ferroptosis by reducing atrial mitochondrial damage, ROS accumulation and iron overload. Interestingly, the in vivo and in vitro data showed that icariin activated atrial SIRT1-Nrf-2-HO-1 signaling pathway, while EX527 not only reversed these effects, but also abolished the therapeutic effects of icariin. Moreover, the stimulatory effects on GPX4, SLC7A11 and the suppressive effects on ACSL4, P53 conferred by icariin were blunted by EX527 treatment. These data demonstrate that ferroptosis plays a causative role in the pathogenesis of ethanol-induced atrial remodeling and susceptibility to AF. Icariin protects against atrial damage by inhibiting ferroptosis via SIRT1 signaling. Its role as a prophylactic/therapeutic drug deserves further clinical study.

Impact of proinflammatory epicardial adipose tissue and differentially enhanced autonomic remodeling on human atrial fibrillation.

OBJECTIVES: The mechanisms underlying atrial fibrillation are yet to be elucidated. We sought to investigate the interactions among autonomic remodeling, epicardial adipose tissue, inflammation, and atrial fibrillation. METHODS: Myocardium and adjacent epicardial adipose tissue of the left atrial appendage, right atrial appendage, and pulmonary vein muscle sleeves were obtained from 61 consecutive patients (35 with atrial fibrillation, 26 with no atrial fibrillation) during mitral valve surgeries. Patients were divided into the atrial fibrillation group and no atrial fibrillation group according to the history and Holter monitoring before surgery. Sympathetic and parasympathetic innervation were evaluated by tyrosine hydroxylase and choline acetyltransferase staining, respectively. Atrial fibrosis as well as cytokines/adipokines and related inflammatory proteins and signaling pathways in the epicardial adipose tissue were examined. RESULTS: Immunohistochemical studies revealed significantly increased tyrosine hydroxylase (+) and choline acetyltransferase (+) neural elements in the left atrial appendage and pulmonary vein muscle sleeve myocardium, as well as adjacent epicardial adipose tissue in the atrial fibrillation group, particularly the pulmonary vein muscle sleeve sites. The receiver operating curve identified a threshold ratio (tyrosine hydroxylase/choline acetyltransferase) of 0.8986 in the epicardial adipose tissue (sensitivity = 82.86%; specificity = 80.77%; area under the curve = 0.85, 95% confidence interval = 0.76-0.95, P < .0001). More patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio (≥0.8986) had atrial fibrillation. Expression levels of the genes and related proteins of the ß1 adrenergic, mitogen-activated protein kinase, and nuclear factor kappa B signaling pathways were higher in patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio. The tyrosine hydroxylase/choline acetyltransferase ratio also correlated with fibrosis. CONCLUSIONS: Differentially enhanced autonomic remodeling and proinflammatory and profibrotic cytokines/adipokines in the epicardial adipose tissue adjacent to the pulmonary vein muscle sleeve site may work synergistically to promote atrial fibrillation.

Macrophage Rmp Ameliorates Myocardial Infarction by Modulating Macrophage Polarization in Mice.

Background: Inflammation plays important roles during myocardial infarction (MI). Macrophage polarization is a major factor that drives the inflammatory process. Our previous study found that RNA polymerase II subunit 5-mediating protein (RMP) knockout in cardiomyocytes caused heart failure by impairing mitochondrial structure and function. However, whether macrophage RMP plays a role in MI has not been investigated. Methods: Macrophage RMP-knockout in combination with a mouse model of MI was used to study the function of macrophage RMP in MI. Next, we modified bone marrow-derived macrophages (BMDMs) by plasmid transfection, and the BMDMs were administered to LysM-Cre/DTR mice by tail vein injection. Immunoblotting and immunofluorescence were used to detect macrophage polarization, fibrosis, angiogenesis, and the p38 signaling pathway in each group. Results: Macrophage RMP deficiency aggravates cardiac dysfunction, promotes M1 polarization, and inhibits angiogenesis after MI. However, RMP overexpression in macrophages promotes M2 polarization and angiogenesis after MI. Mechanistically, we found that RMP regulates macrophage polarization through the heat shock protein 90- (HSP90-) p38 signaling pathway. Conclusions: Macrophage RMP plays a significant role in MI, likely by regulating macrophage polarization via the HSP90-p38 signaling pathway.

Preventive Effect of Berberine on Postoperative Atrial Fibrillation.

BACKGROUND: Postoperative atrial fibrillation (POAF) is one of the most common complications of cardiac surgery, but the underlying factors governing POAF are not well understood. The aim of this study was to investigate the efficacy of berberine administration on POAF. METHODS: We conducted a randomized, double-blind, placebo-controlled trial with patients who underwent isolated coronary artery bypass grafting in China to study the impact of oral berberine on the incidence of POAF. A total of 200 patients who underwent coronary artery bypass grafting were randomized into the berberine group (n=100) and the placebo group (n=100). All patients underwent 7-day continuous telemetry and Holter monitoring. RESULTS: The primary outcome was the incidence of POAF at 7 days. Secondary outcomes included clinical outcomes, POAF burden, intestinal endotoxin, and serum inflammatory biomarker levels. The POAF incidence was reduced from 35% to 20% under berberine treatment (hazard ratio, 0.5 [95% CI, 0.29-0.78]; P=0.0143). Perioperative mortality and morbidity did not differ between the 2 groups. POAF burden and the dose of amiodarone were significantly reduced in the berberine group. Oral berberine significantly decreased lipopolysaccharide, CRP (C-reactive protein), and IL (interleukin)-6 levels. Elevated lipopolysaccharide after surgery has been associated with POAF. CONCLUSIONS: Our results showed that administration of berberine may be effective for reducing the occurrence of POAF after coronary artery bypass grafting. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2000028839.

Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling.

Excessive alcohol consumption has long been identified as a risk factor for adverse atrial remodeling and atrial fibrillation (AF). Icariin is a principal active component from traditional Chinese medicine Herba Epimedii and has been demonstrated to exert potential antiarrhythmic effect. The present study was designed to evaluate the effect of icariin against alcohol-induced atrial remodeling and disruption of mitochondrial dynamics and furthermore, to elucidate the underlying mechanisms. Excessive alcohol-treated C57BL/6 J mice were infected with serotype 9 adeno-associated virus (AAV9) carrying mouse SIRT3 gene or negative control virus. Meanwhile, icariin (50 mg/kg/d) was administered to the animals in the presence or absence of AAV9 carrying SIRT3 shRNA. We noted that 8 weeks of icariin treatment effectively attenuated alcohol consumption-induced atrial structural and electrical remodeling as evidenced by reduced AF inducibility and reversed atrial electrical conduction pattern as well as atrial enlargement. Furthermore, icariin-treated group exhibited significantly enhanced atrial SIRT3-AMPK signaling, decreased atrial mitoSOX fluorescence and mitochondrial fission markers, elevated mitochondrial fusion markers (MFN1, MFN2) as well as NRF-1-Tfam-mediated mitochondrial biogenesis. Importantly, these beneficial effects were mimicked by SIRT3 overexpression while abolished by SIRT3 knockdown. These data revealed that targeting atrial SIRT3-AMPK signaling and preserving mitochondrial dynamics might serve as the novel therapeutic strategy against alcohol-induced AF genesis. Additionally, icariin ameliorated atrial remodeling and mitochondrial dysfunction by activating SIRT3-AMPK signaling, highlighting the use of icariin as a promising antiarrhythmic agent in this circumstance.

Polydatin attenuates chronic alcohol consumption-induced cardiomyopathy through a SIRT6-dependent mechanism.

Polydatin has attracted much attention as a potential cardioprotective agent against ischemic heart disease and diabetic cardiomyopathy. However, the effect and mechanism of polydatin supplementation on alcoholic cardiomyopathy (ACM) are still unknown. This study aimed to determine the therapeutic effect of polydatin against ACM and to explore the molecular mechanisms with a focus on SIRT6-AMP-activated protein kinase (AMPK) signaling and mitochondrial function. The ACM model was established by feeding C57/BL6 mice with an ethanol Lieber-DeCarli diet for 12 weeks. The mice received polydatin (20 mg kg-1) or vehicle treatment. We showed that polydatin treatment not only improved cardiac function but also reduced myocardial fibrosis and dynamin-related protein 1 (Drp-1)-mediated mitochondrial fission, and enhanced PTEN-induced putative kinase 1 (PINK1)-Parkin-dependent mitophagy in alcohol-treated myocardium. Importantly, these beneficial effects were mimicked by SIRT6 overexpression but abolished by the infection of recombinant serotype 9 adeno-associated virus (AAV9) carrying SIRT6-specific small hairpin RNA. Mechanistically, alcohol consumption induced a gradual decrease in the myocardial SIRT6 level, while polydatin effectively activated SIRT6-AMPK signaling and modulated mitochondrial dynamics and mitophagy, thus reducing oxidative stress damage and preserving mitochondrial function. In summary, these data present new information regarding the therapeutic actions of polydatin, suggesting that the activation of SIRT6 signaling may represent a new approach for tackling ACM-related cardiac dysfunction.

The systemic-immune-inflammation index predicts the recurrence of atrial fibrillation after cryomaze concomitant with mitral valve surgery.

BACKGROUND AND AIMS: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). The systemic inflammation indexes are easily evaluated and predict AF development. However, it's role in prediction of recurrence of AF is unknown. We aim to explore the association between the systemic inflammation indexes and recurrence of AF in patients underwent cryoablation (CryoMaze) concomitant with mitral valve surgery. METHODS: We examined systemic inflammation indexes during perioperative period in 122 patients between 2015 and 2018. Systemic inflammation indexes were developed by systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocytes to monocytes ratio. Univariate and multivariate analyses were performed to examine the association of each markers with recurrence of AF. RESULTS: Of the 122 patients included in this study, 22 patients (18%) experienced AF recurrence after CryoMaze concomitant with mitral valve surgery. There is no significant difference between each systemic inflammation indexes before surgery and recurrence of AF. In univariate analysis, MLR after surgery 3 days, PLR, MPLR, NLR, SII after surgery 7 days were able to predict recurrence of AF. In multivariate analyses, SII ≥ 1696 independently predicted recurrence (OR, 3.719; 95% CI, 1.417-9.760). Interestingly, baseline SII showed no significant in prediction of recurrence. It was sharply elevated after surgery and dropped slowly. In patients of recurrence, SII after 7 days of surgery increased again. CONCLUSIONS: The raised SII again was associated with an increased risk of the postoperative recurrence of AF and independently predicted the late recurrence of AF after CryoMaze concomitant with mitral valve surgery.

Comparison of CryoMaze With Cut-and-Sew Maze Concomitant With Mitral Valve Surgery: A Randomized Noninferiority Trial.

In this trial, we sought to evaluate the efficacy and safety of the addition of the Maze performed by cryoablation (CryoMaze) to the mitral valve surgeries. The trial is a randomized, single-center trial to determine whether CryoMaze was noninferior to cut-and-sew maze procedure (CSM) in patients with persistent or long-standing persistent atrial fibrillation (AF), with a 15% margin to establish noninferiority. The primary endpoint was freedom from AF off antiarrhythmic drugs (AADs) at 12 months. Secondary endpoints included freedom from AF off AADs at 3 and 6 months, and a composite of serious adverse events. Two hundred patients were randomized to either CryoMaze (n = 100) or CSM (n = 100). Freedom from AF was achieved in 85 % (95% confidence interval, 0.76-0.91) in the CryoMaze group and 88% (95% confidence interval, 0.80-0.94) in the CSM group, showing that CryoMaze was noninferior to CSM at 12 months (P value for noninferiority = 0.0065). There was no significant difference in serious adverse effects (n = 12 in CryoMaze; n = 17 in CSM; P = 0.315). Perioperative bleeding and the length of surgery, ICU stay, postoperative hospital stay; and the need for temporary pacing decreased significantly in the CryoMaze group. CryoMaze was noninferior to CSM for efficacy and safety for patients with persistent or long-standing persistent AF undergoing mitral valve surgeries. CryoMaze significantly decreased bleeding, the length of surgery, ICU and hospital stay, as well the need for temporary pacing. (Chinese Clinical Trial Register number, ChiCTR-IOR-16008112.).

Left Atrial Mechanical Function Predicts Postoperative AF in Patients with Rheumatic Mitral Valve Disease Who Underwent Mitral Valve Surgery.

OBJECTIVE: Postoperative atrial fibrillation (PoAF) is a common complication after surgical mitral valve replacement. Late PoAF is independently associated with long-term mortality. This study aimed to test the utility of preoperative left atrial mechanical function as a predictor of early and late PoAF in clinical practice. METHODS: Patients (N = 150) with a rheumatic mitral valve who underwent mitral valve replacement with or without tricuspid valvuloplasty and who were in stable sinus rhythm were included. Baseline characteristics and transthoracic echocardiographic assessment information on the day before surgery were collected. Em, Em´, and Ei´ indicate early diastolic peak velocity of the mitral valve, early diastolic velocity at the lateral wall of the mitral annulus, and early diastolic velocity at the interventricular septal annulus, respectively. RESULTS: Early PoAF was present in 59 of 150 patients (39.3%), and 32 of 150 patients (21.3%) developed late PoAF within 1 year after surgery. Among all of the variables examined, age, diabetes, early mitral filling velocity (Mitral E), left atrial mechanical function (Mitral A), Em/Em´, Em/Ei´, and mitral transvalvular gradient showed a significant correlation with PoAF. Only age, Mitral A, and mitral transvalvular gradient showed strong, significant correlations with the occurrence of late PoAF. In a multivariate analysis, predictors of late PoAF recurrence included early PoAF and Mitral A. CONCLUSION: Routine evaluation of Mitral A is feasible and useful to predict early and late PoAF in patients with a rheumatic mitral valve undergoing surgical mitral valve replacement.

Efficacy of Cut-and-Sew Surgical Ablation for Atrial Fibrillation in Patients With Giant Left Atria Undergoing Mitral Valve Surgery: A Propensity-Matched Analysis.

Surgical management for patients with long-standing persistent (LSP) AF and giant left atria (GLA) associated with mitral valve diseases remains a challenge. We aimed to assess the efficacy of the cut-and-sew maze procedure (CSM) in this subgroup of patients, in terms of maintenance of sinus rhythm (SR), atrial function, and to identify the operative risks of this procedure. A total of 229 patients with LSP-AF underwent CSM at our institution from December 2013 to October 2017. Patients were divided into 2 groups based on LA diameter: NGLA group (<65 mm, n = 171), GLA group (≥65 mm, n = 58). Patients with GLA were propensity score matched to patients without GLA resulting in 45 pairs of patients. Early death occurred in 1 (2.2%) in GLA group and no deaths in NGLA group (P = 0.315). Early complications did not differ significantly between the 2 groups. The GLA group showed similar rates of SR on and off antiarrhythmic drugs compared with NGLA group at 2 years (86.36% vs 93.9%, P = 0.338; 81.82% vs 90.91%, P = 0.322). At 2 years, LA contraction was comparable between patients with and without GLA (81.81% vs 90.9%, P = 0.322). Right atrial contraction recovery rate was 96% in NGLA group, and 86.36% in GLA group (P = 0.138). Concomitant CSM is effective and feasible for restoration of SR and atrial contraction, for patients with LSP-AF and GLA associated with mitral valve diseases with acceptable operative risks.

A prospective randomized trial of the cut-and-sew Maze procedure in patients undergoing surgery for rheumatic mitral valve disease.

OBJECTIVE: To evaluate the safety and efficacy of the addition of the cut-and-sew Maze III procedure (CSM) for mitral valve replacement (MVR) in patients with atrial fibrillation (AF) associated with rheumatic mitral valve disease (RMVD). METHODS: A total of 130 patients with persistent or long-standing persistent AF associated with RMVD were assigned at random to either the CSM plus MVR (Maze III) group or MVR alone (non-Maze) group. The primary endpoint was a composite of freedom from stroke and death at 1 year. RESULTS: There were no significant differences between the Maze III and non-Maze groups in terms of major complications and in-hospital mortality. One-year freedom from stroke or death was better in the Maze III group compared with the non-Maze group (P = .0028; hazard ratio, 0.2653; 95% confidence interval, 0.1122 to 0.6270). The risk of AF recurrence in the Maze III group was 0.002-fold that in non-Maze group (P = .000). CONCLUSIONS: Addition of the CSM to an MVR procedure can decrease the risk of stroke or death and high sinus rhythm at 1 year without increasing the operative risk. CSM is a safe and effective approach to treating AF associated with RMVD.

Effect of left atrial enlargement on expression of the angiotensinⅡ, signal transducers and activators of transcription 3 and Rac GTPase activating protein 1 signaling pathways in patients with persistent atrial fibrillation and rheumatic heart disease / 中国胸心血管外科临床杂志

@#Objective To evaluate the effect of left atrial enlargement on atrial myocardial fibrosis degree and levels of the angiotensinⅡ (AngⅡ)/Rac GTPase activating protein 1 (Rac1)/signal transducersand activators of transcription 3 (STAT3) signaling pathways expressing in patients with persistent atrial fibrillation and rheumatic heart disease (RHD). Methods From March to December 2011, 30 patients with RHD who underwent prosthetic valve replacement in our hospital were enrolled, including 16 males and 14 females, aged 42-70 (56.9±6.8) years. Twenty RHD patients with persistent atrial fibrillation as a research group and ten RHD patients with sinus rhythm as a control group (group A) underwent transthoracic echocardiography and right atrial appendage (RAA) tissue samples were obtained from these patients during mitral/aortic valve replacement operation. The research group according to left atrial diameter (LAD) was divided into two groups, ten patients in each group: a group B with LAD of 50–65 mm and a group C with LAD of LAD>65 mm. For each sample, histological examination was performed by hematoxylin-eosin and Masson’s trichrome staining. Light-microscopic pictures of atrial tissues samples were stained and tissue fibrosis degree in each group was analyzed. AngⅡ concentration was measured by enzyme linked immunosorbent assay. Rac1 and STAT3 were measured by western blotting. Results LAD was significantly greater in AF patients with RHD than in the control group. Hematoxylin-eosin staining demonstrated highly organized arrangement of atrial muscles in the control group and significant derangement in both group B and group C with reduced cell density and increased cell size. Moreover, Masson’s trichrome staining showed that atrial myocytes were surrounded by large trunks of collagen fibers in both group B and group C, but not in the group A. There was a positive correlation between atrial tissue fibrosis and LAD. AngⅡ content was positively correlated with LAD. Similarly, Rac1 and STAT3 protein levels were found considerably higher in the group C and group B than in the group A with excellent correlation to LAD. Conclusion In patients with RHD complicated with persistent atrial fibrillation, the degree of atrial fibrosis and the expression level of AngⅡ/Rac1/STAT3 signaling pathways significantly increase with the left atrialenlargement.

Gender differences in fibrosis remodeling in patients with long-standing persistent atrial fibrillation.

The success rate of catheter ablation in atrial fibrillation (AF) is known to be lower in females than in males. However, while the exact mechanism for this phenomenon remains to be elucidated, tissue fibrosis may play an important role in this regard. It has been shown that fibrosis promotes AF and its recurrence, thereby substantially reducing the efficacy of catheter ablation in AF patients. Thus, we hypothesized that fibrosis may contribute to gender differences in the outcomes of AF catheter ablation. Here we systematically assessed pulmonary vein sleeves obtained from 166 patients with and without long-standing persistent-AF (LSP-AF) in order to identify gender-specific mechanistic differences in fibrosis remodeling of AF patients. Histological analysis revealed that the female LSP-AF group, rather than its male counterpart, had a higher degree of fibrosis when compared to the NON-AF group. Further analysis using microarray, immunohistochemistry and Western Blot displayed that gender differences in fibrosis remodeling of LSP-AF were mainly due to the inherent differential expression of fibrosis-related genes (n=32) and proteins (n=6). Especially, those related to the TGFß/Smad3 pathway appeared to be up-regulated in the female LSP-AF group thus promoting an aggravation of fibrosis remodeling. In summary, our data suggest that the aggravation of fibrosis remodeling in women may be an important reason for the low success rate of AF catheter ablation when compared to men. Therefore, inhibiting the TGFß/Smad3 pathway-mediated fibrosis could represent an interesting target for future therapeutic concepts to improve the success rate of AF catheter ablation in women.

A safety evaluation of profound hypothermia-induced suspended animation for delayed resuscitation at 90 or 120 min.

BACKGROUND: The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia-induced suspended animation for delayed resuscitation (SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest (CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals. METHODS: Sixteen male BAMA minipigs were randomized into two groups: CA90 group (90 min, n = 8) and CA120 group (120 min, n = 8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution (OPS), cardioplegia and profound hypothermia (15 °C) were induced. After CA, cardiopumonary bypass (CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CR), lactic dehydrogenase (LDH) and troponin T (TnT)] and survival were observed from pre-operation to 7 days post-operation. RESULTS: Fifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation (ALT 84.43 ± 18.65 U/L; AST 88.99 ± 23.19 U/L; Cr 87.90 ± 24.49 µmol/L; LDH 1894.13 ± 322.26 U/L; TnT 0.849 ± 0.135 ng/ml) but decreased to normal or almost normal levels at 7 days post-operation (ALT 52.48 ± 9.04 U/L; AST 75.23 ± 21.46 U/L; Cr 82.69 ± 18.41 µmol/L; LDH 944.67 ± 834.32 U/L; TnT 0.336 ± 0.076 ng/ml). CONCLUSIONS: Profound hypothermia-induced SADR is an effective method for inducing cardiac arrest. Our results indicate that inducing CA for 90 min (at 15 °C) is safer than doing so for 120 min. Our results indicate that 120 min of CA at 15 °C is dangerous and can result in high mortality and severe neurological complications. Further experimentation is needed to determine whether 120 min of CA at temperatures lower than 15 °C can lead to safe recovery.

The midterm results of radiofrequency ablation and vagal denervation in the surgical treatment of long-standing atrial fibrillation associated with rheumatic heart disease.

BACKGROUND: Though maze III procedure is an effective surgical treatment for atrial fibrillation (AF), the complexity and complications prevent its widespread application. Radiofrequency ablation (RA) has become an accepted therapy, but its chronic effects are still unclear. This retrospective clinical study describes our experience of RA and vagal denervation (VD) in surgical treatment of long-standing AF associated with rheumatic heart disease (RHD) during a 5-year follow-up. METHODS: Between June 2006 and December 2007, a total of 173 consecutive patients with long-standing AF-associated RHD underwent mitral valve replacement and ablation maze procedure. In total, 92 cases had RA alone and 81 had RA + VD. Patients were followed up with clinical examination and electrocardiography, and the data were analyzed by multivariable analysis with Cox hazard model. RESULTS: The average follow-up time was 5.0 ± 0.6 years. Multivariable analysis with Cox hazard model revealed that the duration of AF, the size of the left atrium, and tricuspid regurgitation are risk factors for AF recurrence. In addition, long-standing AF ≥ 7 years, left atrium diameter ≥ 58 mm, and severe tricuspid regurgitation may increase the risk of AF recurrence by 2.16-, 2.37-, and 2.67-fold, respectively. Although the freedom from AF during 2 to 5 postoperative years in the RA and RA + VD groups were similar, the percentage of antiarrhythmic drug therapy was higher in the RA group during the early postoperative period (4th month, 54.1 vs. 34.7%, p = 0.017; 5th month, 39.2 vs. 21.3%, p = 0.018; 6th month, 23.0 vs. 10.7%, p = 0.044). Furthermore, the percentage of those free from AF was lower during the 1st year (6th month, 82.2 vs 93.8%, p = 0.023; 1st year, 76.1 vs. 89.9%, p = 0.019). CONCLUSION: RA is effective for the surgical treatment of long-standing AF associated with rheumatic valve disease. Though vagal denervation helped to maintain a stable sinus rhythm at an early stage, there was no additional benefit after the 1st year of follow-up.