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.

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.

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.

Carvedilol for prevention of atrial fibrillation after cardiac surgery: a meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) remains the most common complication after cardiac surgery. Current guidelines recommend ß-blockers to prevent POAF. Carvedilol is a non-selective ß-adrenergic blocker with anti-inflammatory, antioxidant, and multiple cationic channel blocking properties. These unique properties of carvedilol have generated interest in its use as a prophylaxis for POAF. OBJECTIVE: To investigate the efficacy of carvedilol in preventing POAF. METHODS: PubMed from the inception to September 2013 was searched for studies assessing the effect of carvedilol on POAF occurrence. Pooled relative risk (RR) with 95% confidence interval (CI) was calculated using random- or fixed-effect models when appropriate. Six comparative trials (three randomized controlled trials and three nonrandomized controlled trials) including 765 participants met the inclusion criteria. RESULTS: Carvedilol was associated with a significant reduction in POAF (relative risk [RR] 0.49, 95% confidence interval [CI] 0.37 to 0.64, p<0.001). Subgroup analyses yielded similar results. In a subgroup analysis, carvedilol appeared to be superior to metoprolol for the prevention of POAF (RR 0.51, 95% CI 0.37 to 0.70, p<0.001). No evidence of heterogeneity was observed. CONCLUSIONS: In conclusion, carvedilol may effectively reduce the incidence of POAF in patients undergoing cardiac surgery. It appeared to be superior to metoprolol. A large-scale, well-designed randomized controlled trial is needed to conclusively answer the question regarding the utility of carvedilol in the prevention of POAF.

[Early and midterm outcomes of artificial chordae transplant in mitral valve repair].

OBJECTIVE: To summarize the early and midterm outcomes of artificial chordae transplant in mitral valve repair. METHODS: A total of 50 patients underwent mitral valve repair with artificial chordae transplant from January 2009 to January 2010 in General Hospital of Shenyang Military Command. Follow-up was conducted on 48 cases (96%) for 3-4 years. RESULTS: No early postoperative mortality occurred. All cases had cardiac function New York Heart Association (NYHA) grade I/II at discharge. Among 48 cases, one died of cerebral infarction after 13 months and the reminder survived and no one underwent reoperation. Among survivors, 45 cases were in cardiac function NYHA grade I and another 2 in grade II. Echocardiography showed that postoperative 3 years left atrial diameter, left ventricular end-diastolic dimension, left ventricular end-systolic dimension and the ratio of regurgitation beam area and left atrial area were significantly smaller than those preoperative ones (39.5% ± 9.7% vs 5.6% ± 0.1%, P < 0.01) and left ventricular ejection fraction increased markedly (0.55 ± 0.06 vs 0.67 ± 0.07, P < 0.01). There was no instance of artificial chordae rupture. CONCLUSION: Gore-Tex artificial chordae transplant is a safe and effective technique in mitral valve repair with excellent early and midterm operative outcomes.

Risk factors for midterm cardiac function deterioration after valve replacement surgery in patients with rheumatic mitral stenosis.

BACKGROUND: A symptomatic reduction in left ventricular ejection fraction (LVEF) is the main reason for postoperative heart failure after valve replacement surgery. However, postoperative heart failure occurs in patients with normal preoperative LVEF. Therefore, we examined clinical and echocardiographic data of patients with rheumatic heart disease to determine additional risk factors for low LVEF in the postoperative period. METHODS AND RESULTS: Ninety-seven patients with rheumatic heart disease (RHD) who underwent mitral valve replacement for severe mitral valve stenosis were included retrospectively in this study. All patients had normal LVEF before surgery. Patients were divided into 2 groups based on postoperative LVEF 6 months after surgery. Groups A had normal postoperative LVEF (82 cases, 84.5%), and group B had low postoperative LVEF (15 cases, 15.5%). Clinical and electrocardiographic data were collected to determine risk factors for deterioration in cardiac function. Multivariate analysis revealed that preoperative low systolic peak velocities at the lateral tricuspid annulus (St) and no or mild aortic stenosis were independent risk factors for cardiac deterioration in patients with normal preoperative LVEF. Individuals with preoperative St ≤ 4.8 cm/s were more likely to develop lower LVEF at follow-up (χ(2) = 7.54; P = .006; odds ratio 5.03, 95% confidence interval 1.31-20.82). All 15 patients who had normal preoperative LVEF but abnormal postoperative LVEF had no or only mild aortic valve stenosis. CONCLUSIONS: Decreased right ventricular function and no or mild aortic stenosis were independent risk factors for low LVEF at follow-up in patients with RHD who had normal preoperative LVEF. The velocity of the tricuspid valve ring should be included in preoperative evaluations to improve the accuracy of postsurgical prognosis and clinical decision making.

[Study of cardiopulmonary adaptation during exercise in patients after extracardiac conduit total cavopulmonary connection].

OBJECTIVE: To study cardiopulmonary physiology during exercise in patients after extracardiac total cavopulmonary connection (ECTCPC). METHODS: Twenty-six patients were studied after ECTCPC by exercise testing with bicycle treadmill protocol. Heart rate (HR), blood pressure (BP), respiratory frequency (RF) and pulse oxygen saturation (SpO(2)) were measured continuously; twenty-six patients suffered from Fallot 4 underwent biventricular repair were also studied as control group. RESULTS: In ECTCPC group, HR, BP, SpO(2) and RF all increased with exercise below 3 grade; when exceed 4 grade, BP, SpO(2) decreased and RF kept increasing. Compared with control group, HR, RF were higher (t = 2.13, P < 0.05; t = 2.31, P < 0.05), SpO(2) was lower (t = 2.46, P < 0.05) under the quiescent condition; When exceed 3 grade, HR, BP, SpO(2) decreased more significantly, but RF increased continuously. In fenestration group after ECTCPC, HR reached the top at 5 grades, but in group without fenestration it reached the top at 3 grades; In the whole process of exercising, RF kept higher and SpO(2) kept lower in fenestration group. CONCLUSIONS: The ECTCPC patients showed obviously exercise limitation. Totally bypass of sinoatrial node in this operation may have some adverse effects on the integer regulation of HR.

[The effects of inhaled nitric oxide on pulmonary vascular resistance in patients after total cavopulmonary connection].

OBJECTIVE: To study the effects of inhaled nitric oxide (NO) on pulmonary vascular resistance in patients after total cavopulmonary connection (TCPC). METHODS: Fifty-two patients after TCPC were evaluated, of them 24 patients were administered with inhaled nitric oxide in the early postoperative period. The cardiac index (CI) and pulmonary vascular resistance (PVR) were compared before and after inhaled NO. RESULTS: In experimental group, after inhaled NO, partial pressure of oxygen in artery/fraction of inspired oxygen increased from 161 +/- 17 to 193 +/- 23 (t = 2.75, P < 0.01); CI from (2.86 +/- 0.24) L.min(-1).m(-2) to (3.13 +/- 0.22) L.min(-1).m(-2) (t = 2.25, P < 0.05); PVR decreased from (4.2 +/- 0.5) U/m(2) to (3.8 +/- 1.4) U/m(2) (t = 2.29, P < 0.05); central venous pressure (CVP) from (17.0 +/- 1.8) mm Hg to (15.0 +/- 1.1) mm Hg, decreased 11.7%. Compared with the control group, respirator time decreased from (86 +/- 27) h to (54 +/- 18) h (t = 2.29, P < 0.05); ICU time from (6 +/- 2) d to (4 +/- 2) d (t = 2.32, P < 0.05); But hydrothorax drainage and length of stay had no significant difference. CONCLUSIONS: Though inhaled NO, there is no significant long-term effects in patients after TCPC, but it may play an important role in the management of low cardiac output syndrome and high cava pressure caused by reactive elevated pulmonary vascular resistance in the early postoperative period of TCPC.