SIRT3 regulates cardiolipin biosynthesis in pressure overload-induced cardiac remodeling by PPARγ-mediated mechanism.

Cardiac remodeling is the primary pathological feature of chronic heart failure (HF). Exploring the characteristics of cardiac remodeling in the very early stages of HF and identifying targets for intervention are essential for discovering novel mechanisms and therapeutic strategies. Silent mating type information regulation 2 homolog 3 (SIRT3), as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolism. However, whether SIRT3 plays a role in cardiac remodeling by regulating the biosynthesis of mitochondrial cardiolipin (CL) is unknown. In this study, we induced pressure overload in wild-type (WT) and SIRT3 knockout (SIRT3-/-) mice via transverse aortic constriction (TAC). Compared with WT mouse hearts, the hearts of SIRT3-/- mice exhibited more-pronounced cardiac remodeling and fibrosis, greater reactive oxygen species (ROS) production, decreased mitochondrial-membrane potential (ΔΨm), and abnormal mitochondrial morphology after TAC. Furthermore, SIRT3 deletion aggravated TAC-induced decrease in total CL content, which might be associated with the downregulation of the CL synthesis related enzymes cardiolipin synthase 1 (CRLS1) and phospholipid-lysophospholipid transacylase (TAFAZZIN). In our in vitro experiments, SIRT3 overexpression prevented angiotensin II (AngII)- induced aberrant mitochondrial function, CL biosynthesis disorder, and peroxisome proliferator-activated receptor gamma (PPARγ) downregulation in cardiomyocytes; meanwhile, SIRT3 knockdown exacerbated these effects. Moreover, the addition of GW9662, a PPARγ antagonist, partially counteracted the beneficial effects of SIRT3 overexpression. In conclusion, SIRT3 regulated PPARγ-mediated CL biosynthesis, maintained the structure and function of mitochondria, and thereby protected the myocardium against cardiac remodeling.

Comparative effectiveness and safety of DOACs vs. VKAs in treatment of left ventricular thrombus- a meta-analysis update.

BACKGROUND AND OBJECTIVE: Left ventricular thrombus (LVT) formation in patients with acute myocardial infarction (AMI) or cardiomyopathies is not uncommon. The optimal oral anticoagulation therapy for resolving LVT has been under intense debate. Vitamin K antagonists (VKAs) remain the anticoagulant of choice for this condition, according to practice guidelines. Evidence supporting the use of direct oral anticoagulants (DOACs) in the management of LVT continues to grow. We performed a systematic review and meta-analysis to compare the efficacy and safety of DOACs versus VKAs. METHODS: A comprehensive literature search was carried out in PubMed, Cochrane Library, Web of Science, Embase, and Scopus databases in July 2023. The efficacy outcomes of this study were thrombus resolution, ischemic stroke, systemic embolism, stroke/systemic embolism, all-cause mortality, and adverse cardiovascular events. The safety outcomes were any bleeding, major bleeding, and intracranial hemorrhage. A total of twenty-seven eligible studies were included in the meta-analysis. Data were analyzed utilizing Stata software version 15.1. RESULTS: There was no significant difference between DOACs and VKAs with regard to LVT resolution (RR = 1.00, 95% CI 0.95-1.05, P = 0.99). In the overall analysis, DOACs significantly reduced the risk of stroke (RR = 0.74, 95% CI 0.57-0.96, P = 0.021), all-cause mortality (RR = 0.70, 95% CI 0.57-0.86, P = 0.001), any bleeding (RR = 0.75, 95% CI 0.61-0.92, P = 0.006) and major bleeding (RR = 0.67, 95% CI 0.52-0.85, P = 0.001) when compared to VKAs. Meanwhile, in the sub-analysis examining randomized controlled trials (RCTs), the aforementioned outcomes no longer differed significantly between the DOACs and VKAs groups. The incidences of systemic embolism (RR = 0.81, 95% CI 0.54-1.22, P = 0.32), stroke/systemic embolism (RR = 0.85, 95% CI 0.72-1.00, P = 0.056), intracranial hemorrhage (RR = 0.59, 95% CI 0.23-1.54, P = 0.28), and adverse cardiovascular events (RR = 0.99, 95% CI 0.63-1.56, P = 0.92) were comparable between the DOACs and VKAs groups. A subgroup analysis showed that patients treated with rivaroxaban had a significantly lower risk of stroke (RR = 0.24, 95% CI 0.08-0.72, P = 0.011) than those in the VKAs group. CONCLUSION: With non-inferior efficacy and superior safety, DOACs are promising therapeutic alternatives to VKAs in the treatment of LVT. Further robust investigations are warranted to confirm our findings.

Direct Oral Anticoagulants versus Vitamin K Antagonists in Cirrhotic Patients with Atrial Fibrillation: Update of Systematic Review and Meta-Analysis.

BACKGROUND: Prevention of ischemic stroke is an essential part of managing atrial fibrillation (AF). In recent years, direct oral anticoagulants (DOACs) have emerged as an alternative to vitamin K antagonists (VKAs). Little is understood regarding the efficacy and safety of DOACs in AF patients with liver cirrhosis (LC). OBJECTIVE: This meta-analysis is designed to evaluate the benefits and risks of DOACs compared to VKAs in AF patients with concomitant LC. METHODS: A thorough search was conducted in PubMed, Cochrane Library, Web of Science, Embase, Scopus, and CNKI databases up to February 2023. A total of seven clinical studies including 7551 patients were analyzed in this meta-analysis. All data analyses were performed using Review Manager software version 5.3. RESULTS: Regarding efficacy outcomes, DOACs had comparable clinical benefit in reducing ischemic stroke/systemic thromboembolism (HR=0.79, 95% CI [0.59, 1.06], p = 0.12) to VKAs. The incidence of all-cause death was similar between the DOACs and VKAs group (HR 0.94, 95% CI [0.69, 1.28], p = 0.69). Regarding safety outcomes, DOACs were associated with a significantly lower risk of major bleeding (HR 0.61, 95% CI [0.50, 0.75], p < 0.00001), intracranial hemorrhage (HR 0.55, 95% CI [0.31, 0.98], p = 0.04) and major gastrointestinal bleeding (HR 0.66, 95% CI [0.51, 0.85], p = 0.001) than VKAs. Additional subgroup analysis of advanced cirrhosis revealed that DOACs were associated with a significantly lower risk of major bleeding (HR 0.59, 95% CI [0.39, 0.89], p = 0.01) than VKAs. There were no significant differences between the DOACs and VKAs group concerning the incidence of ischemic stroke/systemic thromboembolism (HR 1.38, 95% CI [0.75, 2.55], p = 0.31) and major gastrointestinal bleeding (HR 0.65, 95% CI [0.41, 1.04], p = 0.08). CONCLUSION: DOACs are associated with more favorable safety outcomes and may be a feasible option of oral anticoagulant for individuals with atrial fibrillation and cirrhosis. Pending validation by randomized prospective studies, the findings of this study should be interpreted with caution.

Combination of Intracardiac Echocardiography and Contact Force Sensing for Left Ventricular Papillary Muscle Arrhythmias.

OBJECTIVES: The catheter ablation of ventricular arrhythmias (VAs) arising from the left ventricular (LV) papillary muscles (PMs) is challenging. This study sought to address whether the combination of intracardiac echocardiography (ICE) and contact force sensing (CFS) can improve the acute and long-term ablation outcomes of left ventricular papillary muscle arrhythmias. METHODS AND RESULTS: From May 2015 to August 2022, a total of thirty-three patients underwent catheter ablation for LV PM arrhythmias: VAs were located in anterolateral PMs in 11 and posteromedial PMs in 22. A combination of intracardiac echocardiography (ICE) and contact force sensing (CFS) was used in 21 of the 33 procedures. A mean of 6.93 ± 4.91 for lesions was used per patient, comparable between the CFS/ICE and no ICE/CFS (4.90 ± 2.23 vs. 10.17 ± 5.89; p = 0.011). The mean CF achieved in the ICE/CFS group was 7.52 ± 3.31 g. Less X-ray time was used in the combination group (CFS/ICE: 165.67 ± 47.80 S vs. no ICE/CFS: 365.00 ± 183.73 S; p < 0.001). An acute success rate of 100% was achieved for the ICE/CFS group (n = 22) and 66.67% for the no ICE/CFS group (n = 8). VA recurrence at the 11.21 ± 7.21-month follow-up was 14.2% for the ICE/CFS group and 50% for the no ICE/CFS group (p = 0.04). No severe complications occurred in all patients. CONCLUSIONS: The combination of intracardiac echocardiography (ICE) and contact force sensing (CFS) could provide precise geometries of cardiac endocavitary structures and accurate contact information for the catheter during ablation, which improved acute and long-term ablation outcomes. The routine adoption of this strategy should be considered to improve the outcomes of LV PM VA ablation.

Efficacy and Safety of NOACs Compared With VKAs for Patients With Atrial Fibrillation After Transcatheter Aortic Valve Implantation: A System Review and Meta-Analysis.

Novel oral anticoagulants (NOACs) are preferentially recommended in patients with nonvalvular atrial fibrillation (AF) for stroke prevention over vitamin K antagonists (VKAs). However, the evidence regarding the efficacy and safety of NOACs versus VKAs after transcatheter aortic valve implantation (TAVI) in patients with AF is very rare. Pubmed, Embase, Web of science, and Cochrane Databases were searched for eligible studies published before May 19, 2022. A total of 11 studies were included in this meta-analysis involving 27 107 patients. Regarding primary outcomes, there were no differences between NOACs and VKAs in all-cause mortality (RR: 0.84, 95% CI: (0.69, 1.02)) and stroke (RR: 1.00, 95% CI: (0.85, 1.19)). With respect to secondary outcomes, NOACs were associated with reduced incidence of bleeding (RR: 0.77, 95% CI: (0.71, 0.83)) and intracranial bleeding (RR: 0.57, 95% CI: (0.39, 0.83)), whereas no significant differences were found in major or life-threatening bleeding (RR: 0.98, 95% CI: (0.82, 1.17)) and myocardial infarction (RR: 1.37, 95% CI: (0.83, 2.26)). Our meta-analysis revealed the safety and efficacy of NOACs may be superior to VKAs in AF patients undergoing TAVI.

Association of acetaldehyde dehydrogenase 2 rs671 polymorphism with the occurrence and progression of atrial fibrillation.

Background: Acetaldehyde dehydrogenase 2 (ALDH2) is an essential enzyme in alcohol metabolism, playing a vital function in resisting oxidative stress. Lots of gene variants have been associated with atrial fibrillation (AF), among which the association between ALDH2 rs671 polymorphism and AF is variable. This study aimed to investigate the relationship between ALDH2 rs671 polymorphism and AF occurrence or progression and AF recurrence after catheter ablation. Methods: A total of 924 subjects were enrolled in the study. The ALDH2 genotypes are composed of wild-type homozygotes (ALDH2*1/*1), heterozygotes (ALDH2*1/*2), and mutant homozygotes (ALDH2*2/*2), in which the genotypes ALDH2*1/*2 and ALDH2*2/*2 are combined into the ALDH2*2. Univariate and multivariate logistic regression analyses were performed to investigate the association between ALDH2*2 and AF occurrence and progression. COX regression analysis was used to explore the association of ALDH2*2 with AF recurrence after catheter ablation. Results: The prevalence of AF differed significantly between the ALDH2*2 group (102/251) and ALDH2*1/*1 group (330/673) (P = 0.023). For AF occurrence, in the univariate analysis, alcohol consumption was a risk factors (OR: 1.503, P = 0.003), whereas ALDH2*2 was a protective factor (OR: 0.712, P = 0.023). In the multivariate analysis, alcohol consumption (P = 0.156) and ALDH2*2 (P = 0.096) were no longer independent factors. ALDH2*2 with non-drinking was associated with a decreased AF occurrence (OR: 0.65, P = 0.021), whereas ALDH2*2 with drinking was not (P = 0.365). For AF progression, multivariate analysis revealed ALDH2*2 could promote persistent AF in female AF patients (OR: 2.643, P = 0.008). Cox regression analysis suggested that ALDH2*2 (P = 0.752) was not a risk factor for AF recurrence after catheter ablation during a median 6 months follow-up. Conclusion: While ALDH2*2 was not directly related to AF, ALDH2*2 with non-drinking was associated with a decreased incidence of AF. ALDH2*2 may accelerate AF progression in female patients, increasing the likelihood of developing persistent AF. Therefore, individuals with ALDH2*2 should refrain from consuming alcohol to decrease the onset and progression of AF.

Understanding the scope of intracardiac echocardiography in catheter ablation of ventricular arrhythmia.

Over the last few decades, catheter ablation has emerged as the first-line treatment for ventricular arrhythmias. However, detailed knowledge of cardiac anatomy during the surgery remains the prerequisite for successful ablation. Intracardiac echocardiography (ICE) is a unique imaging technique, which provides real-time visualization of cardiac structures, and is superior to other imaging modalities in terms of precise display of cardiac tissue characteristics as well as the orientation of anatomical landmarks. This article aimed to introduce the various advantages and limitations of ICE in the ablation of ventricular arrhythmias.

Case report: Double-chambered right ventricle diagnosed in a middle-aged female with hypertrophic cardiomyopathy and atrial flutter: A rare case.

Double-chambered right ventricle (DCRV) is a rare congenital heart defect in adults, manifesting with progressive right ventricular outflow tract obstruction. We describe the first case of DCRV coexisting with hypertrophic cardiomyopathy, which is complicated by atrial flutter. A middle-aged woman with recurrent symptomatic atrial flutter who had previously been diagnosed with biventricular hypertrophic cardiomyopathy was admitted to our department. Echocardiography and cardiac magnetic resonance revealed asymmetrical interventricular septal hypertrophy, and abnormal muscle bundles within the right ventricle, generating an obstructive gradient. Genetic testing detected a hypertrophic cardiomyopathy-associated mutation: MYH7, c.4135G > A, p. Ala1379Thr. A diagnosis of DCRV complicated by hypertrophic cardiomyopathy and atrial flutter was made. Surgical intervention was performed, which included radiofrequency ablation, removal of abnormal muscle bundles, and ventricular septal defect repair. Intraoperative transesophageal echocardiography demonstrated the well-corrected right ventricular outflow tract. Free of early postoperative complications, the patient was discharged in sinus rhythm on the 11th day after the surgery. Unfortunately, the patient died from a sudden death 38 days following the surgery. In conclusion, the coexistence of DCRV with hypertrophic cardiomyopathy in patients is an uncommon condition. The present case highlights the importance of diagnostic imaging in the management of this disorder.

Case Report: Acute Renal and Splenic Infarctions Secondary to Atrial Fibrillation.

Acute renal and splenic infarctions are an uncommon condition that can result from obstruction or decrease of renal and splenic arterial flow. We described a 73-year-old woman who presented with right flank pain and nocturnal dyspnea. The computed tomography (CT) scan with intravenous contrast showed multiple infarcts in both bilateral kidneys and spleen. Serum creatinine clearance was impaired. Further investigation by electrocardiogram (ECG) and 24-h Holter revealed that the patient had paroxysmal atrial fibrillation (PAF). Transthoracic and transesophageal echocardiographic findings were unremarkable except for severe spontaneous echo contrast (SEC) in the left atrial appendage. The development of thromboembolic renal and splenic infarction was attributed to embolism caused by atrial fibrillation. Anticoagulant therapy was initiated with low molecular weight heparin (LMWH) and followed by an oral anticoagulant. To manage PAF and prevent further embolism, the "One-stop" procedure, including atrial fibrillation catheter ablation and left atrial appendage occlusion (LAAO), was applied to this patient. Follow-up at 1 month showed normal sinus rhythm, improved renal function, and relieved renal and splenic infarction.

The role of alcohol consumption on echocardiographic and electrophysiologic changes in atrial fibrillation.

BACKGROUND: A wealth of evidence suggests that alcohol consumption is a risk factor for atrial fibrillation (AF); however, the mechanisms underlying this association are unclear. This makes it challenging to develop therapeutic strategies in patients with AF attributed to alcohol consumption. PURPOSE: To investigate the echocardiographic and electrophysiologic changes caused by alcohol consumption in patients with AF. METHODS: The study was registered in Chinese Clinical Trial Registry (Registration number ChiCTR2000041575). Data on 134 consecutive non-valvular AF patients who underwent radiofrequency catheter ablation in our center was collected from April 1, 2019 to June 30, 2020. Patients were divided into no-alcohol (72) and alcohol groups [categorized into light (34), moderate (11) and heavy (17) alcohol consumption]. All patients underwent echocardiographic and electrophysiologic examinations for the assessment of left atrial (LA) strain, inter-atrial conduction, intra-atrial conduction, and atrial effective refractory period (ERP). RESULTS: Overall, the mean age was 61 ± 11 years and 87 (65%) were males. Compared with the no-alcohol group, impaired peak LA longitudinal strain, obvious inter-atrial conduction delay and increasing ERP dispersion were observed in the alcohol group. Intra-atrial conduction delay and ERP dispersion increased with increasing amounts of alcohol consumption. CONCLUSION: Alcohol consumption was associated with substantial abnormal echocardiographic and electrophysiologic changes in AF patients. These changes may contribute to the occurrence and progression of AF attributed to alcohol consumption, which may help in the development of new strategies for the prevention and management of AF. However further investigation is required.

Can intracardiac echocardiography completely replace transesophageal echocardiography to guide left atrial appendage closure?-The comparisons of intracardiac echocardiography with transesophageal echocardiography.

Left atrial appendage closure (LAAC) is an effective means of preventing ischemic stroke in patients with nonvalvular atrial fibrillation. Transesophageal echocardiography (TEE) is the primary imaging technique to guide LAAC. Its shortcomings, namely the use of general anesthesia and tracheal intubation, inevitably increase procedural risks. Intracardiac echocardiography (ICE), a novel imaging modality for guiding LAAC, has proven more advantageous over TEE due to use of local anesthesia, shortened procedural time, and reduced radiation exposure. This review highlights the differences between ICE and TEE guided LAAC, aiming to provide a reference for clinical decision-making.

Correction: Mouse Sirt3 promotes autophagy in AngII-induced myocardial hypertrophy through the deacetylation of FoxO1.

[This corrects the article DOI: 10.18632/oncotarget.13429.].

SS31 Alleviates Pressure Overload-Induced Heart Failure Caused by Sirt3-Mediated Mitochondrial Fusion.

Heart failure caused by pressure overload is one of the leading causes of heart failure worldwide, but its pathological origin remains poorly understood. It remains critical to discover and find new improvements and treatments for pressure overload-induced heart failure. According to previous studies, mitochondrial dysfunction and myocardial interstitial fibrosis are important mechanisms for the development of heart failure. The oligopeptide Szeto-Schiller Compound 31 (SS31) can specifically interact with the inner mitochondrial membrane and affect the integrity of the inner mitochondrial membrane. Whether SS31 alleviates pressure overload-induced heart failure through the regulation of mitochondrial fusion has not yet been confirmed. We established a pressure-overloaded heart failure mouse model through TAC surgery and found that SS31 can significantly improve cardiac function, reduce myocardial interstitial fibrosis, and increase the expression of optic atrophy-associated protein 1 (OPA1), a key protein in mitochondrial fusion. Interestingly, the role of SS31 in improving heart failure and reducing fibrosis is inseparable from the presence of sirtuin3 (Sirt3). We found that in Sirt3KO mice and fibroblasts, the effects of SS31 on improving heart failure and improving fibroblast transdifferentiation were disappeared. Likewise, Sirt3 has direct interactions with proteins critical for mitochondrial fission and fusion. We found that SS31 failed to increase OPA1 expression in both Sirt3KO mice and fibroblasts. Thus, SS31 can alleviate pressure overload-induced heart failure through Sirt3-mediated mitochondrial fusion. This study provides new directions and drug options for the clinical treatment of heart failure caused by pressure overload.

Feasibility and safety of left atrial appendage occlusion guided by procedural fluoroscopy only: A pilot study.

BACKGROUND: Left atrial appendage occlusion (LAAO) is usually performed via the guidance of procedural transesophageal echocardiography (TEE) companied by general anesthesia (GA). OBJECTIVE: To investigate the feasibility and safety of LAAO guided by procedural fluoroscopy only. METHODS: The patients eligible for LAAO were enrolled into the current study and received implantation of either Watchman device or LAmbre device. The procedure was carried out with procedural fluoroscopy only and no companied GA; the position, shape, and leakage of the device were assessed by contrast angiography. TEE was performed after 3-month follow-up to evaluate the thrombosis, and leakage of device. RESULTS: Ninety-seven patients with atrial fibrillation (AF) with either Watchman device (n = 49) or LAmbre device (n = 48) were consecutively enrolled. Watchman device group was of lower CHA2 DS2 -VASc and HAS-BLED scores compared with LAmbre device groups (p < .05); the two groups had similar distributions of other baseline characteristics (p > .05), including procedural success rate (98.0% vs. 97.9%), mean procedure time, mean fluoroscopy time, total radiation dose, contrast medium dose, percentage of peri-device leakage. Pericardial effusions requiring intervention occurred in two of the Watchman group. TEE follow-up found no patient with residual leakage ≥5 mm at 3 months and no device related thrombosis (DRT). During the 22.0 ± 11.1 months follow-up, two patients experienced ischemic stroke. CONCLUSIONS: LAAO with the procedural imaging of fluoroscopy only exhibited the promising results of efficacy and safety. A prospective randomized multicenter study would be required to verify the observations in this study.

Ranolazine alleviates contrast-associated acute kidney injury through modulation of calcium independent oxidative stress and apoptosis.

This study investigates the role of ranolazine in contrast-associated acute kidney injury (CA-AKI) and potential mechanisms. For in vivo studies, mouse models of CA-AKI and control mice were treated with ranolazine or vehicle. Blood urea nitrogen (BUN) and serum creatinine were detected by spectrophotometry. Anti-T-cell immunoglobulin and mucin domain 1 (TIM 1) and anti-lipocalin 2 antibody (LCN2) were detected by immunofluorescence. Hemodynamic parameters were detected via invasive blood pressure measurement and renal artery color doppler ultrasound, capillary density was measured by CD31 immunofluorescence, vascular permeability assay was performed by Evans blue dye. The expressions of oxidative stress and apoptotic markers were measured and analyzed by immunofluorescence and western blotting. For in vitro studies, intracellular calcium concentration of HUVECs was measured with Fluo 3-AM under confocal microscopy. Results show that compared with control mice, serum BUN, creatinine, TIM 1 and LCN2 levels were elevated in CA-AKI mice, but this effect was alleviated by ranolazine-pretreatment. Safe doses of ranolazine (less than 64 mg/kg) had no significant effect on overall blood pressure, but substantially improved renal perfusion, reduced contrast-induced microcirculation disturbance, improved renal capillary density and attenuated renal vascular permeability in ranolazine-pretreated CA-AKI mice. Mechanistically, ranolazine markedly down-regulated oxidative stress and apoptosis markers compared to CA-AKI mice. Intracellularly, ranolazine attenuated calcium overload in HUVECs. These results indicate that ranolazine alleviates CA-AKI through modulation of calcium independent oxidative stress and apoptosis.

SIRT3 protects endothelial cells from high glucose-induced senescence and dysfunction via the p53 pathway.

Hyperglycemia induces endothelial cells (ECs) dysfunction and vascular complications by accelerating ECs senescence. It also induces downregulation of sirtuins (SIRTs). However, the molecular mechanism involved in the regulation of ECs senescence by SIRT3 remains unclear. Here, we showed that high glucose (HG) decreased the expression level of SIRT3 in human umbilical vein endothelial cells (HUVECs), increased the proportion of cells expressing senescence-associated galactosidase (SA-gal), and HG damaged the cell's ability to form tubule networks on Matrigel. However, transfection with adenoviral construct including SIRT3 significantly inhibited HG-induced SA-gal activity, decreased p53 acetylation level at the site Lys 320 (k320), and overexpression of SIRT3 antagonized high glucose-induced angiogenic dysfunction. Our results suggested a possible molecular mechanism involving HG-SIRT3-p53 in ECs senescence.

Thromboembolic Risk of Cessation of Oral Anticoagulation Post Catheter Ablation in Patients With and Without Atrial Fibrillation Recurrence.

Cessation of oral anticoagulation (OAC) is common after the first 3 months of catheter ablation of atrial fibrillation (AF); however, thromboembolic risk has not been defined in patients with and without AF recurrence (RAF vs NRAF) post ablation. We identified 796 patients who discontinued OAC at 3 months post AF ablation from January 2015 to May 2018 in our center. Regular follow-up was performed to detect RAF, collect medication management and thromboembolic and major bleeding events. CHA2DS2-VASc score was 1.79 ± 1.50; 547 (68.7%) patients were at intermediate and high risk (i.e., CHA2DS2-VASc score ≥1 in male patients, or ≥2 in female patients); 169 (21.2%) were RAF. During 29.2±12.2 months follow-up, the incidence rate of thromboembolism was 1.62 per 100 patient-year (7 in 431 years) in RAF, 0.33 per 100 patient-year (5 in 1,503 years) in NRAF. After adjusting for potential confounding factors, RAF was associated with more 3.5-fold higher rate of thromboembolism compared with NRAF (adjusting HR, 4.488; 95% CI, 1.381 to 14.586). Rate of thromboembolism was even higher in patients with intermediate and high risk (2.16 per 100 patient-year [7 in 323 years] vs 0.38 per 100 patient-year [4 in 1,043 years], aHR, 5.807; 95% CI, 1.631 to 20.671). In multivariate logistic regression analysis, RAF was the only independent predictor of thromboembolism (4.837 [1.498 to 15.621], p = 0.008). In conclusion, cessation of OAC in NRAF may be reasonable, especially for patients with the contraindications for continuing OAC; however, cessation of OAC appeared unsafe in RAF with a high-risk stroke profile because of high incidence rate of thromboembolism.

Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway.

Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms. Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2-10 µM) or SU and TMZ (40-120 µM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] - 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC50 4.07 µM) and inhibits the AMPK/mTOR/autophagy pathway (p < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP - 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (p < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo (p < 0.001) and in vitro (p < 0.05). Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.

Sirt3 promotes sensitivity to sunitinib-induced cardiotoxicity via inhibition of GTSP1/JNK/autophagy pathway in vivo and in vitro.

Sunitinib malate is a multi-targeted tyrosine kinase inhibitor used extensively for treatment of human tumors. However, cardiovascular adverse effects of sunitinib limit its clinical use. It is pivotal to elucidate molecular targets that mediate sunitinib-induced cardiotoxicity. Sirtuin 3 (Sirt3) is an effective mitochondrial deacetylase that has been reported to regulate sensitivity of different types of cells to chemotherapies, but roles of Sirt3 in sunitinib-induced cardiotoxicity have not been investigated. In the present study, we established wild type, Sirt3-knockout, and Sirt3-overexpressing mouse models of sunitinib (40 mg kg-1 day-1 for 28 days)-induced cardiotoxicity and examined cardiovascular functions and pathological changes. We further cultured wild type, Sirt3-knockout, and Sirt3-overexpressing primary mouse cardiac pericytes and analyzed sunitinib (10 µMol for 48 h)-induced alterations in cellular viability, cell death processes, and molecular pathways. Our results show that sunitinib predominantly induced hypertension, left ventricular systolic dysfunction, and cardiac pericyte death accompanied with upregulation of Sirt3 in cardiac pericytes, and these cardiotoxicities were significantly attenuated in Sirt3-knockout mice, but aggravated in Sirt3-overexpressing mice. Mechanistically, sunitinib induced cardiac pericyte death through inhibition of GSTP1/JNK/autophagy pathway and Sirt3 interacted with and inhibited GSTP1, further inhibiting the pathway and aggravating sunitinib-induced pericyte death. Conclusively, we demonstrate that Sirt3 promotes sensitivity to sunitinib-induced cardiotoxicity via GSTP1/JNK/autophagy pathway. Our results suggest Sirt3 might be a potential target for developing cardioprotective therapies for sunitinib-receiving patients.

Correlations of Serum Cyclophilin A and Melatonin Concentrations with Hypertension-induced Left Ventricular Hypertrophy.

BACKGROUND AND AIMS: Cyclophilin A (CyPA) is an abundantly expressed pro-inflammatory cytokine and a major secreted oxidative stress-induced factor (SOXF). Melatonin is an important chronobiological regulatory molecule that is mainly released from the pineal gland and exerts antioxidant effects by acting as a radical scavenger. Based on accumulating evidence, both CyPA and melatonin play important roles in cardiovascular diseases. However, further investigations are required to determine whether CyPA and melatonin are associated with hypertension-induced left ventricular hypertrophy (LVH). METHODS: A total of 135 patients with essential hypertension were divided into an LVH (+) group and an LVH (-) group according to Doppler echocardiography results. Clinical data of the two groups were evaluated. RESULTS: High CyPA levels and low melatonin levels are independent risk factors for LVH (p = 0.000). In addition, body mass index (BMI) and systolic blood pressure (SBP) are correlated with the risk of LVH (p = 0.000). However, other factors did not display statistically significant associations (p >0.05). The Pearson correlation and linear regression analyses show that BMI, SBP, and CyPA levels were positively correlated with left ventricular mass (LVM) and the left ventricular mass index (LVMI) (p <0.05), whereas melatonin levels were negatively correlated with LVM and the LVMI (p = 0.000). Furthermore, according to the results of the Pearson correlation analysis, CyPA levels were negatively correlated with melatonin levels (p <0.01) in subjects with LVH. CONCLUSIONS: Based on these results, both CyPA and melatonin are closely related to the pathogenesis of LVH. As CyPA was negatively correlated with melatonin in patients with LVH, additional studies are required to determine whether melatonin may partially protect the myocardium by decreasing CyPA levels.