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Background. Acute myocardial infarction (AMI) is a common cardiovascular disease with high disability and mortality. Circular RNAs (circRNAs) are implicated in the pathomechanism of multiple human diseases, including AMI. This study intended to explore the function and working mechanism of a novel circRNA circ_0023461 in hypoxia-induced cardiomyocytes. Methods. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were implemented to detect RNA and protein expression. Cell counting kit-8 (CCK8) assay and 5-ethynyl-2 ′ -deoxyuridine (Edu) assay were conducted to analyze cell viability and proliferation ability. Cell migration and apoptosis were assessed by Transwell assay and flow cytometry. Cell oxidative stress was analyzed using the commercial kits. Enzyme-linked immunosorbent assay (ELISA) was conducted to analyze cell inflammation. Cell glycolytic metabolism was evaluated using the commercial kits. Dual-luciferase reporter assay and RNA pull-down assay were conducted to verify the intermolecular interactions. Results. circ_0023461 expression was upregulated in AMI patients and hypoxia-induced AC16 cells. Hypoxia restrained the viability, proliferation, migration, and glycolysis and induced the apoptosis, oxidative stress, and inflammation of AC16 cells, and these effects were attenuated by the silence of circ_0023461. MicroRNA-370-3p (miR-370-3p) was verified as a target of circ_0023461, and circ_0023461 silencing-mediated protective effects in hypoxia-induced cardiomyocytes were partly alleviated by the knockdown of miR-370-3p. miR-370-3p interacted with the 3 ′ untranslated region (3 ′ UTR) of phosphodiesterase 4D (PDE4D), and PDE4D overexpression partly reversed miR-370-3p overexpression-induced protective effects in hypoxia-induced cardiomyocytes. circ_0023461 can upregulate PDE4D expression by acting as a molecular sponge for miR-370-3p in AC16 cells. Conclusion. circ_0023461 knockdown attenuated hypoxia-induced dysfunction in AC16 cells partly by targeting the miR-370-3p/PDE4D axis.

We report a 15-year-old boy with cat-eye syndrome (CES) without short stature or intellectual disorder. The boy was confirmed by cytogenetic and high-resolution chromosome microarray analysis (CMA). The G-banding karyotype confirmed the de novo of the patient. Also, the CMA result showed 1.76 Mb tetrasomy of proximal 22Q11.1 ⟶ 22Q11.21 consistent with CES {arr22q11.1q11.21 (16,888,899–18,644,241) X4}, a typical small type I CES chromosome. The patient has many of the basic characteristics of CES; however, he is taller than his peers instead of shorter. It is rarely reported in the past since short stature is a common feature of this syndrome. Furthermore, the boy has no intellectual disorder and attends a normal school since he was six-year-old. What bothered him most were recurrent respiratory infections, retromicrognathia, and heart defects.

As a pre-clinical assessment, the present study aimed to investigate the safety and effectiveness of a novel valved pulmonary arterial conduit constructed entirely from biomaterials by transplanting it in the outflow tract of the right ventricle in sheep. Under extracorporeal circulation, the valved pulmonary arterial conduit was used to replace the pulmonary artery of sheep with a beating heart. The performance was assessed at 30, 90 and 180 days post-surgery. Hemodynamic and structural changes were evaluated, and safety was assessed after 180 postoperative days. The hemodynamic effect and biosafety of the implant were further evaluated by observing the changes in various pressure indicators of the heart, echocardiographic results, anatomical and pathological examination results, liver and kidney functions, routine blood tests, a blood coagulation test, and other test results following implantation of the purely biotic valved conduit. The conduit was successfully implanted in 12 sheep and no mortality occurred postoperatively. During the 180-day follow-up, there was no obvious stenosis or regurgitation of the right ventricular outflow tract and pulmonary valve after valved conduit implantation. The findings of autopsy, pathology and laboratory examinations were unremarkable. The implantation of this biosynthetic vascular graft into animals meets the safety and effectiveness requirements for clinical application. This pulmonary arterial conduit has potential clinical application for children with complex congenital heart disease who require pulmonary artery reconstruction to achieve a radical cure.

Background Thoracic aortic aneurysm and dissection (TAAD) is a life‐threatening pathology that remains a challenge worldwide. Up to 40% of TAAD cases are hereditary with complex heterogeneous genetic backgrounds. The purposes of this study were to determine the diagnostic rate of patients with TAAD, investigate the molecular pathologic spectrum of TAAD by next‐generation sequencing (NGS), and explore the future preclinical prospects of genetic diagnosis in patients at high ‐risk of study. Methods NGS was used to screen 15 genes associated with genetic TAAD in 212 patients from northwestern China. Clinical data of patients were gathered by electrocardiography, transthoracic echocardiography, and computed tomography. Results Of the 212 patients, 67 (31.60%) tested positive for a (likely) pathogenic variant, 42 (19.81%) had a variant of uncertain significance (VUS), and 103 (48.58%) had no variant (likely benign/benign/negative). A total of 135 reportable variants were detected in our test, among which 77 (57.04%) are first reported in this paper. A genotype–phenotype correlation of FBN1 was assessed, and the data showed that the patients with truncating and splicing mutations are more prone to developing severe aortic dissection than those with missense mutations, especially frameshift mutations (82.76% vs. 42.86%). In this study, 43 (20.28%) patients had a family history of sudden death or TAAD, whereas 132 (62.26%) did not (the remaining 37 were not available), and the positive rate of genetic testing was higher in TAAD patients with family history than in those without (76.74% vs. 18.94%). Conclusion Our study concludes that genetic variation is an important consideration in the risk stratification of individualized prediction and disease diagnosis., NGS was used to screen 15 genes associated with genetic TAAD in 212 patients from northwestern China. Our study concludes that genetic variation is an important consideration in the risk stratification of individualized prediction and disease diagnosis.

The incidence of cardiovascular diseases was significantly increased in postmenopausal women. The protection of estrogen in the cardiovascular system has been further reported for decades. Although menopausal hormone therapy has been used in many clinical trials, the debatable results indicate that the studies for elucidating the precise molecular mechanism are urgently required. G protein–coupled estrogen receptor 30 (GPR30) is a membrane receptor of estrogen and displays protective roles in diverse cardiovascular diseases. Previous studies have revealed that ERK1/2-mediated MMP-9 signaling was involved in ischemic heart diseases. However, the role of ERK1/2-mediated MMP-9 signaling in the protection of GPR30 against cardiac hypertrophy in aged female mice has not been investigated. Our present study demonstrated that GPR30 overexpression and its agonist G1 co-administration reduced transverse aortic constriction–induced myocardial fibrosis and preserved cardiac function in aged female mice. MMP-9 expression was markedly increased via ERK1/2 phosphorylation in transverse aortic constriction–injured myocardium of aged female mice. Further results showed that GPR30/G1 activation decreased MMP-9 expression via ERK1/2 inhibition, which further reduced TGF-β1 expression. Inhibition of the ERK1/2 signaling pathway by its inhibitor PD98059 suppressed the induction of the cardiomyocyte MMP-9 level caused by the GRP30 antagonist G15 and inhibited TGF-β1 expression in cardiac fibroblast in vitro. In summary, our results from in vivo and in vitro studies indicated that GPR30 activation inhibited myocardial fibrosis and preserved cardiac function via inhibiting ERK-mediated MMP-9 expression. Thus, the present study may provide the novel drug targets for prevention and treatment of cardiac pathological hypertrophy in postmenopausal women.

Following hospital discharge, patients with type A acute aortic dissection (TA-AAD) may present an increase in mortality risk. However, little is known about specific biomarkers associated with post-discharge survival, and there is a paucity of prognostic markers associated with TA-AAD. Here, we identify nine candidate proteins specific for patietns with TA-AAD in a cross-sectional dataset by unbiased protein screening and in-depth bioinformatic analyses. In addition, we explore their association with short-term and long-term mortality in a derivation cohort of patients with TA-AAD, including an internal (n = 300) and external (n = 236) dataset. An elevated osteoprotegerin (OPG)/tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) ratio was the strongest predictor of overall, 30-day, post-30-day mortality in both datasets and was confirmed to be a strong predictor of mortality in an independent validation cohort (n = 400). Based on OPG/TRAIL ratio-guided risk stratification, patients at high risk (>33) had a higher 1-year mortality (55.6% vs. 4.3%; 68.2% vs. 2.6%) than patients at low risk (, Despite many therapeutic improvements, mortality risk in patients with type A acute aortic dissection remains high. Here the authors construct a biomarker-guided risk stratification tool to predict death, which could potentially contribute to treatment decision-making and improvement of the prognosis.

Background Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte injury, which induced by metabolic disorder. Nowadays, there is still a lack of drugs for the treatment of DCM. Growth differentiation factor 11 (GDF11) is a novel member of the transforming growth factor β superfamily that alleviates cardiac hypertrophy, myocardial infarction, and vascular injury by regulating oxidative stress, inflammation, and cell survival. However, the roles and underlying mechanisms of GDF11 in DCM remain largely unknown. Methods In this study, we sought to determine whether GDF11 could prevent DCM. The mouse model of diabetes was established by administering a high-fat diet and intraperitoneal injecting streptozotocin. After that, intramyocardial injection of an adeno-associated virus carrying GDF11 gene was used to achieve myocardium-specific overexpression. Results Our data showed that GDF11 overexpression remarkably improved cardiac dysfunction and interstitial fibrosis by reducing the levels of reactive oxygen species and protecting against cardiomyocyte loss. Mechanistically, decreased sirtuin 1 (SIRT1) expression was observed in diabetic mice, which was significantly increased after GDF11 overexpression. To further explore how SIRT1 mediates the role of GDF11, the selective inhibitor EX527 was used to block SIRT1 signaling pathway, which abolished the protective effects of GDF11 against DCM. In vitro studies confirmed that GDF11 protected against H9c2 cell injury in high glucose and palmitate by attenuating oxidative injury and apoptosis, and these effects were also eliminated by SIRT1 depletion. Conclusion Our results demonstrated for the first time that GDF11 protected against DCM by regulating SIRT1 signaling pathway, and GDF11 had the potential to become a novel target for reversing cardiac dysfunction in diabetic patients.

Objectives: To assess sex differences of clinical presentation and outcomes in propensity-matched patients with acute type A aortic dissection (AAAD). Methods: We collected the clinical data of patients with AAAD from a single heart center between January 2009 and July 2014. After propensity score matching, we compared differences in clinical presentation and outcomes of patients with AAAD between men and women. Results: There were 590 patients (295 men and 295 women) with AAAD through propensity matching on demographics and patients’ history. We found that the presentation and diagnosis of AAAD often were more delayed in women. Severe signs of congestive heart failure (9.8% vs. 5.1%, P = 0.017), cardiac tamponade/shock (9.1% vs. 4.1%, P < 0.001), and periaortic hematoma (26.4% vs. 21.7%, P < 0.001) were more commonly presented in women. Surgery was more commonly performed in men than in women (95.4% (281/295) vs. 91.5% (270/295), P = 0.045), indicating the association of sex with surgical decision. To investigate the association of sex with outcomes after surgery, patients who underwent surgical treatment were re-matched (262 men and 262 women) by propensity score. Women suffered from greater in-hospital mortality than men (8.4% vs. 3.4%, P < 0.001). Postoperative complications of congestive heart failure (9.1% vs. 3.8%, P < 0.001), visceral ischemia (6.8% vs. 1.1%, P < 0.001), and limb ischemia (7.6% vs. 1.5%, P < 0.001) were more frequent in women. For women, prolonged operative time may increase in-hospital mortality, especially after 12 hours from the start of surgery (30.0% vs. 14.3%, P < 0.001). Kaplan-Meier survival analysis indicated worse late outcomes in women in the matched surgery group (log-rank P = 0.012). Conclusions: Our analysis provides new insights into sex differences in clinical presentation and outcomes of AAAD.

SARS‐CoV‐2, the virus responsible for the global coronavirus disease (COVID‐19) pandemic, attacks multiple organs of the human body by binding to angiotensin‐converting enzyme 2 (ACE2) to enter cells. More than 20 million people have already been infected by the virus. ACE2 is not only a functional receptor of COVID‐19 but also an important endogenous antagonist of the renin‐angiotensin system (RAS). A large number of studies have shown that ACE2 can reverse myocardial injury in various cardiovascular diseases (CVDs) as well as is exert anti‐inflammatory, antioxidant, anti‐apoptotic and anticardiomyocyte fibrosis effects by regulating transforming growth factor beta, mitogen‐activated protein kinases, calcium ions in cells and other major pathways. The ACE2/angiotensin‐(1‐7)/Mas receptor axis plays a decisive role in the cardiovascular system to combat the negative effects of the ACE/angiotensin II/angiotensin II type 1 receptor axis. However, the underlying mechanism of ACE2 in cardiac protection remains unclear. Some approaches for enhancing ACE2 expression in CVDs have been suggested, which may provide targets for the development of novel clinical therapies. In this review, we aimed to identify and summarize the role of ACE2 in CVDs.

Background: Stroke is a common postoperative complication in patients with acute type A aortic dissection (ATAAD). We aimed to explore the preoperative imaging risk findings for postoperative new stroke in patients with ATAAD.Methods: From January 2015 to December 2018, 174 patients with ATAAD who underwent preoperative aortic computed tomography angiography (CTA) and cerebral diffusion-weighted imaging (DWI) as well as postoperative brain CT were included, and divided into DWI (+) and DWI (–) groups. Pre- and intraoperative variables were collected, and logistic regression analysis was used to determine the independent risk predictors of postoperative new stroke.Results: The incidence of postoperative new stroke was 18.4% (32/174) in patients with ATAAD. Postoperative stroke was detected in 13 (31.0%) patients in the DWI (+) group and in 19 (14.4%) patients in the DWI (–) group with significant difference (P = 0.016). In the DWI (+) group, the lesions of the cerebral infarction located in the unilateral cerebral hemisphere and distributed more than three lobes (P = 0.007) were an independent risk factor for postoperative new stroke. Hypotension (P = 0.002), retrograde ascending aorta dissection with thrombosis of the false lumen (P = 0.010), aortic arch entry (P = 0.035), and coronary artery involvement (P = 0.001) were independent risk factors for postoperative stroke in the DWI (–) cohort.Conclusions: Patients with ATAAD with cerebral infarction are more likely to develop postoperative new stroke; thus, a preoperative DWI examination may be necessary. DWI lesions distributed more than 3 lobes in the unilateral hemisphere suggest a high possibility of postoperative stroke. For patients with ATAAD with normal brain, particular attention should be given to the CTA findings of false lumen thrombosis, aortic arch entry, and coronary artery involvement to avoid postoperative stroke.

Melatonin functions as an endogenous protective molecule in multiple vascular diseases, whereas its effects on thoracic aortic aneurysm and dissection (TAAD) and underlying mechanisms have not been reported. In this study, TAAD mouse model was successfully induced by β-aminopropionitrile fumarate (BAPN). We found that melatonin treatment remarkably prevented the deterioration of TAAD, evidenced by decreased incidence, ameliorated aneurysmal dilation and vascular stiffness, improved aortic morphology, and inhibited elastin degradation, macrophage infiltration, and matrix metalloproteinase expression. Moreover, melatonin blunted oxidative stress damage and vascular smooth muscle cell (VSMC) loss. Notably, BAPN induced a decrease in SIRT1 expression and activity of mouse aorta, whereas melatonin treatment reversed it. Further mechanistic study demonstrated that blocking SIRT1 signaling partially inhibited these beneficial effects of melatonin on TAAD. Additionally, the melatonin receptor was involved in this phenomenon. Our study is the first to report that melatonin exerts therapeutic effects against TAAD by reducing oxidative stress and VSMC loss via activation of SIRT1 signaling in a receptor-dependent manner, thus suggesting a novel therapeutic strategy for TAAD.

Background Bone marrow mesenchymal stem cells (BMSCs) have been used as important cell-based tools for clinical applications. Oxidative stress-induced apoptosis causes a low survival rate after transplantation, and the underlying mechanisms remain unknown. The endoplasmic reticulum (ER) and mitochondria are vital organelles regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK), especially during oxidative stress injury. Melatonin exerts an antioxidant effect by scavenging free radicals. Here, we aimed to explore whether cytoprotective melatonin relieves ER stress-mediated mitochondrial dysfunction through AMPK in BMSCs after oxidative stress injury. Methods Mouse BMSCs were isolated and exposed to H2O2 in the absence or presence of melatonin. Thereafter, cell damage, oxidative stress levels, mitochondrial function, AMPK activity, ER stress-related proteins, and apoptotic markers were measured. Additionally, the involvement of AMPK and ER stress in the melatonin-mediated protection of BMSCs against H2O2-induced injury was investigated using pharmacologic agonists and inhibitors. Results Melatonin improved cell survival and restored mitochondrial function. Moreover, melatonin intimately regulated the phosphorylation of AMPK and molecules associated with ER stress pathways. AMPK activation and ER stress inhibition following melatonin administration improved the mitochondrial membrane potential (MMP), reduced mitochondria-initiated oxidative damage, and ultimately suppressed apoptotic signaling pathways in BMSCs. Cotreatment with N-acetyl-l-cysteine (NAC) significantly enhanced the antioxidant effect of melatonin. Importantly, pharmacological AMPK activation/ER stress inhibition promoted melatonin-induced cytoprotection, while pharmacological AMPK inactivation/ER stress induction conferred resistance to the effect of melatonin against H2O2 insult. Conclusions Our data also reveal a new, potentially therapeutic mechanism by which melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis, possibly by regulating the AMPK-ER stress pathway.

Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPRmt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPRmt activation mechanism. THC supplement partly upregulated UPRmt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPRmt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPRmt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPRmt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.

Objectives The aim of this study was to evaluate the safety and feasibility of total arch repair with open placement of a novel double-branched stent graft for acute Type A aortic dissection (TAAD). Methods We retrospectively analysed the effect of the double-branched stent graft for total aortic arch placement with acute TAAD from December 2013 to February 2015. The effectiveness of the open placement of the double-branched stent graft was estimated by complete thrombus obliteration of the false lumen surrounding it on computed tomography angiography. Follow-up was performed at 6 months postoperatively and annually thereafter. Results The double-branched stent graft was successfully placed into the true lumen of the descending aorta, aortic arch, left subclavian artery and left common carotid artery through the delivery system in 21 patients with acute TAAD. The mean cardiopulmonary bypass time was 210.2 ± 32.4 min, the mean aortic cross-clamp time was 94.9 ± 18.0 min, and the selective cerebral perfusion and deep hypothermia cardiopulmonary arrest time was 27.0 ± 10.4 min. The in-hospital mortality rate was 4.8%. The mean follow-up duration was 38.2 ± 12.5 months. No severe complications related to the surgery or residual dissection occurred during the follow-up. All survivors resumed normal activities. Conclusions The novel double-branched stent graft is proved to be safe and effective for total arch repair with acute TAAD in this study. It would be a new selective method for total arch repair in patients with acute TAAD. Clinical registration number Research on pathogenic risk factors or characteristic features and clinical treatment of aortic dissection in Chinese Population (20120216-4).

Background: To investigate the feasibility of combined computed tomography angiography (CTA) of the aorta and craniocervical artery in acute type A aortic dissection (ATAAD) and the value of incremental craniocervical information. Methods: Combined CTA of head, neck and aorta was performed in patients with suspected aortic dissection and 243 ATAAD patients were analyzed. The image quality and radiation dose were assessed. Valuable craniocervical CTA findings were determined for further surgical analysis. Results: The mean dose-length product (DLP) was 314.11±29.31 mGy.cm. The image quality of craniocervical arteries were 100% diagnostic. Intimal flap involving carotid arteries was detected in 47% of patients, and significant stenosis of true lumen was observed in 60% of common carotid arteries (CCAs). Hypodensity and hypoplasia/occlusion of carotid arteries were also detected and apprised surgeons. The tortuosity of carotid artery was found in 90.9% of patients. Bilateral antegrade selective cerebral perfusion (ASCP) was performed in 21.1% of aortic arch surgery based on 7 hemodynamic variation types of the circle of Willis (CW) determined by cranial CTA information. Conclusions: A combined CTA of head, neck and aorta is feasible with low radiation dose and diagnostic image quality. Incremental information on craniocervical pathology and anatomy may be useful for surgery repair of ATAAD.

Mulberry leaves are used in Chinese traditional medicine to prevent diabetes and the preventive and therapeutic effects of MLE have been seen in preclinical models. Herein, mulberry leaf extract (MLE) was analyzed to identify its active components. Ultra-performance liquid chromatography–mass spectrometry revealed that MLE contained 1-deoxynojirimycin (1-DNJ, 5.47%), chlorogenic acid (CA, 1.21%), resveratrol (RESV, 0.39%), scopoletin (Sco, 0.09%), and astragaloside (AS, 0.04%). Mice with induced diabetic cardiomyopathy were treated with MLE or each of its main components for 12 weeks. MLE and 1-DNJ significantly improved cardiac function, body weight, and glucose and lipid metabolism, while reducing myocardial fibrosis. Moreover, 1-DNJ reduced the levels of reactive oxygen species and oxidative stress, inhibited the TGF-β pathway, prevented the expression of α-SMA and Smad2/3, as well as collagen 1 and 3. Collectively, these findings suggest that1-DNJ is the main active component of MLE that protects the diabetic myocardium and regulates the TGF β–Smad2/3 pathway.

Total aortic-arch replacement (TAR) is one of the major cardiovascular surgeries, which is by far the most effective emergency treatment of Acute Aortic Dissection type-A (AADA). In TAR, cardiopulmonary bypass is established and the aortic arch is replaced and reconstructed. Though hypothermic circulatory arrest (HCA) and unilateral antegrade cerebral perfusion (uACP) are often used for brain protection, parts of the brain may still encounter insufficient blood supply. With prolonged HCA time, this insufficiency causes brain injuries. Currently, there lacks an effective, real-time cerebral imaging technique that can be used in cardiac surgeries. Electrical impedance tomography (EIT) is a low-cost, non-invasive imaging method, which is sensitive to the bio-electrical impedance of tissues. In this study, we are the first using electrical impedance tomography (EIT) intraoperatively to image and monitor the relative changes in cerebral blood volume (rc-CBV). A subject with AADA is monitored using EIT in TAR surgeries and EIT images during the HCA + uACP period are reconstructed and analyzed. A blood factorization model was proposed to estimate the relative changes in blood proportion using EIT images. We found that (1) EIT images are sensitive to the changes in the rate of cerebral perfusion. (2) During uACP, the right hemisphere is perfused directly via cannulation into the right subclavian artery and the circulation to the left cerebral is mainly compensated through the circle of Willis. EIT and rc-CBV images show relatively high impedance and low blood ratios in the left hemisphere, which indicates that the patient may have insufficient collateral circulation. (3) EIT has moderate spatial resolutions, which provides additional information regarding the pathological changes in different regions deep in the brain. We conclude that cerebral EIT is a promising imaging method and it may provide early warning signs regarding insufficient cerebral blood supply in TAR surgeries.

OBJECTIVES Acute ischaemic stroke (AIS) is a highly dreaded complication of acute type A aortic dissection (ATAAD). Knowledge about independent predictors of preoperative AIS in patients with ATAAD remains unclear. The aim of this study was to identify the risk factors for preoperative AIS in patients with ATAAD by computed tomography angiography (CTA) findings. METHODS Between October 2014 and March 2017, 281 (217 male; mean age, 50 years) patients with ATAAD underwent aortic CTA and diffusion-weighted magnetic resonance imaging of the brain was used to confirm the results. The clinical data and CTA findings were evaluated retrospectively. Patients were divided into 2 groups depending on the presence or absence of preoperative AIS. RESULTS Preoperative AIS was detected in 103 (36.7%) of the patients with ATAAD. Univariable analysis of the clinical characteristics and CTA findings revealed that age, aortic valve insufficiency (moderate or severe), the ratio of the diameter of the true lumen of the ascending aorta to the diameter of the involved ascending aorta, intimal flap plaque, dissection of the common carotid artery (CCA), the lower density of the unilateral internal carotid artery, the CCA originating from the false lumen and dissection of the subclavian artery were implicated in patients with ATAAD with AIS. Multivariable analysis further showed that aortic valve insufficiency (moderate or severe) [odds ratio (OR) 2.033, 95% confidence interval (CI) 1.052–3.931; P = 0.035], 2 CTA findings including the ratio of the diameters (OR 0.074, 95% CI 0.011–0.516; P = 0.009) and dissection of the CCA (OR 2.422, 95% CI 1.389–4.224; P = 0.002) were independent risk predictors for preoperative AIS in patients with ATAAD. The lower density in the false lumen, the same enhancement in the true and false lumen with re-entry and the stenosis of the true lumen without re-entry significantly increased the risk of preoperative AIS in CCA dissection. CONCLUSIONS Aortic valve insufficiency (moderate or severe), the ratio of the diameters of the true and false lumens and CCA dissection are independent predictors of preoperative AIS in patients with ATAAD. The specific carotid and aortic CTA findings may help to predict the risk factors for preoperative AIS in patients with ATAAD. Clinical registration number 20120216-4.

C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, which exerts protective function in ischemic or diabetic heart injury. However, the role of CTRP3 in cardiac hypertrophy remains unclear. The aim of this study was to investigate the pharmacological effects of CTRP3 on pathological cardiac hypertrophy induced by hypertension. Male C57BL/6 J wild-type (WT) mice, Ctrp3 knockout mice, and mice infected with lentivirus overexpressing mouse Ctrp3 underwent sham surgery or transverse aortic constriction (TAC) surgery. After 4 weeks, cardiac hypertrophy, fibrosis, and cardiac function were examined. Compared with WT mice, Ctrp3 deficiency substantially impaired contractile dysfunction, exacerbated the enlargement of cardiomyocytes and myocardial fibrosis, and reprogramed the expression of pathological genes after TAC. Conversely, CTRP3 overexpression played a role in restoring the left ventricular cardiac contractile function, alleviating cardiac hypertrophy and fibrosis, and inhibiting the expression of hypertrophic and fibrotic signaling in mice after TAC. Furthermore, CTRP3 regulated the expression of the p38/CREB pathway and of the primary modulating factors of the endoplasmic reticulum stress, i.e., GRP78 and the downstream molecules eukaryotic translation inhibition factor 2 submit α, C/EBP homologous protein, and inositol-requiring enzyme-1. Further, inhibition of p38 MAPK by SB203580 blunted the ER stress intensified by Ctrp3 deficiency. In vitro, CTRP3 protected neonatal rat cardiac myocytes against phenylephrine-induced cardiomyocyte hypertrophy. We conclude that CTRP3 protects the host against pathological cardiac remodeling and left ventricular dysfunction induced by pressure overload largely by inhibiting the p38/CREB pathway and alleviating p38-induced ER stress.

Headings aims Cardiac stem cells (CSCs)-transplanted therapy provides a promising therapy for the ischemic heart disease (IHD), especially in the epidemic of myocardial infarction (MI). The compound 2,3,5,4′-tetrahydroxystilbene-2-O-β- d -glucoside (THSG) can induce CSC proliferation in vitro based on our previous study, so we aimed to study the induce effect of THSG on CSCs-transplanted MI rat in vivo. Materials and methods Using a murine model of MI, this study was designed to evaluate the impact of THSG (30, 60, 120 mg/kg) on CSCs-based therapy for MI and the underlying mechanism in this process. Key finding The results showed that THSG on CSCs-transplanted therapy groups (THSG + CSCs groups) can significantly reduce S-T segment elevation, and increase heart rate compared with MI group. The left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS) were significantly reduced in THSG + CSCs groups compared to the MI group. The levels of enzyme expression (CK-MB, LDH), the heart weight index (HWI) and myocardial infarct size (IS) were all reduced in THSG + CSCs groups. Moreover, other changes noted during these 28 days post-MI, included pathologic changes, as well as increased stem cell antigen-1 (Sca-1) expression, or expression of Nkx2.5, GATA-4, and Connexin 43 in myocardial tissue, and reduced the Caspase-3 expression. Significance Our findings indicated that THSG facilitated CSCs-transplanted therapy in MI. These observations may be associated with the inducted of THSG on the proliferation of CSCs in vivo and also, with the subsequent differentiation of additional intrinsic neonatal cardiomyocytes to replace damaged heart tissue.

Recently, we demonstrated that melatonin reduced protein kinase RNA (PKR)-like ER kinase (PERK)-eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor-4 (ATF4)-mediated myocardial endoplasmic reticulum (ER) stress and apoptosis during myocardial ischemia-reperfusion (MI/R) injury. However, the underlying mechanisms are still not clear. Myocardial reperfusion injury salvage kinase (RISK) pathway as well as survivor activating factor enhancement (SAFE) pathway are two pivotal intrinsic pro-survival signaling cascades. In this study, we performed in vivo and in vitro experiment to investigate the ameliorative effect of melatonin on ER stress with a focus on RISK and SAFE pathways interaction. Male C57Bl/6 mice received melatonin (300 μg/25 g/day, 3 days before MI/R surgery; 300 μg/25 g, 25 min before the onset of ischemia) pre-treatment with or without the administration of LY294002 (a PI3K/Akt inhibitor), U0126 (an ERK1/2 inhibitor) or AG490 (a STAT3 pathway inhibitor). H9c2 cells were pre-treated with melatonin (100 μM, 8 h) in the presence or absence of LY294002, U0126 or AG490. Compared with the I/R-injured group, melatonin effectively reduced myocardial apoptosis, oxidative stress and improved cardiac function. In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3β, ERK1/2 and STAT3 and reduced PERK-eIF2α-ATF4-mediated ER stress. However, these effects were blocked by LY294002, U0126 or AG490. Additionally, either LY294002 or U0126 treatment could inhibit STAT3 phosphorylation, whereas AG490 administration also reduced both Akt and ERK1/2 phosphorylation, indicating an interplay exists between RISK and SAFE pathways in melatonin's cardioprotective effect. In summary, our study demonstrates that RISK and SAFE pathways mediate the cardioprotective effect of melatonin against MI/R injury. Melatonin pre-treatment attenuates PERK-eIF2α-ATF4-mediated ER stress and apoptosis during MI/R injury via RISK and SAFE pathways interaction.

Objective This study aimed to evaluate the safety and feasibility of total endovascular repair of the aortic arch using a novel designed stent-graft system (Yanger stent-graft system; Lifetech Scientific, Shenzhen, China) in vitro and in a canine model. Methods The Yanger stent-graft system is composed of a main stent-graft, branched stent-graft, and a delivery system. In an in vitro aortic arch simulation test bench, the system was tested, and the success rate of stent-graft releasing, anchoring, and positioning was recorded and analyzed. Meanwhile, in vivo implantation of the Yanger stent-graft system was carried out in 16 healthy adult crossbreed dogs. The feasibility of using these stent-grafts was evaluated with aortography, multislice computed tomography, and autopsy 6 months after the procedure. Results All stent-graft releasing and positioning were successful for in vitro test. In the canine model, the Yanger stent-graft system was placed successfully in the aortic arch in all 14 dogs with the exception of 2 mortalities. All dogs survived for at least 3 months with normal physiologic signs. Aortography, multislice computed tomography, and animal necropsy revealed good fixation in all cases. The ascending aorta, descending aorta, brachiocephalic trunk, and left subclavian artery were all covered without endoleak. There was no significant obstruction or stenosis in brachiocephalic branches at the 6-month follow-up. Conclusions Total endovascular repair of aortic arch with the novel designed Yanger stent-graft system is safe and feasible in preclinical studies. With a better understanding of preclinical knowledge, patient selection criteria and first-in-human studies will be addressed.

The effect of estrogen receptors on diabetes-induced vascular dysfunction is critical, but ambiguous. Individuals with diabetic vascular disease may require estrogen receptor-specific targeted therapy in the future. The G protein-coupled estrogen receptor (GPER) has beneficial effects on vascular function. However, its fundamental mechanisms are unclear. The RhoA/Rho-kinase pathway contributes to diabetic vascular complications, whereas estrogen can suppress Rho-kinase function. Thus, we assumed that GPER inhibits diabetes-mediated RhoA activation to prevent vascular dysfunction. We further investigated the underlying mechanisms involved in this process. Vascular endothelial cells and ex vivo cultured ovariectomized (OVX) C57BL/6 mouse aortae were treated with high glucose (HG) alone or in combination with GPER agonist (G1). G1 treatment was also administered to OVX db/db mice for 8 weeks. An ex-vivo isovolumic myograph was used to analyze the endothelium-dependent vasodilation and endothelium-independent contraction of mouse aortae. Apoptosis, oxidative stress, and inflammation were attenuated in G1-pretreated vascular endothelial cells. G1 significantly decreased the phosphorylation of inhibitory endothelial nitric oxide (NO) synthase residue threonine 495 (eNOS Thr495), inhibited RhoA expression, and increased NO production. Additionally, G1 rescued the impaired endothelium-dependent relaxation and inhibited RhoA activation in the thoracic aorta of OVX db/db mice and ex-vivo cultured OVX C57BL/6 mouse aortae treated with HG. Estrogens acting via GPER could protect vascular endothelium, and GPER activation might elicit ERα-independent effect to inhibit RhoA/Rho-kinase pathway. Additionally, GPER activation might reduce vascular smooth muscle contraction by inhibiting RhoA activation. Thus, the results of the present study suggest a new therapeutic paradigm for end-stage vascular dysfunction by inhibiting RhoA/Rho-kinase pathway via GPER activation.

Pterostilbene (PT), an analog of resveratrol, exerts a potent anti-inflammatory effect. However, the protective effects of PT against inflammation in endothelial cells have not been elucidated. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of endothelial cell inflammation. In this study, we explored the effect of PT on the tumor necrosis factor-α (TNF-α)-induced inflammatory response in human umbilical vein endothelial cells (HUVECs) and elaborated the role of ERS in this process. TNF-α treatment significantly upregulated the levels of inflammation-related molecules in cell culture media, increased the adhesion of monocytes to HUVECs, and enhanced the expression of the MMP9 and ICAM proteins in HUVECs. Additionally, TNF-α potently increased ERS-related protein levels, such as GRP78 and p-eIF2α. However, PT treatment reversed the increased production of inflammatory cytokines and the adhesion of monocytes to HUVECs, as well as reduced the TNF-α-induced effects exerted by ERS-related molecules. Furthermore, thapsigargin (THA), an ERS inducer, attenuated the protective effect of PT against TNF-α-induced inflammation and ERS in HUVECs. Additionally, the downregulation of ERS signaling using siRNA targeting eIF2α and IRE1 not only inhibited ERS-related molecules but also simulated the therapeutic effects of PT on TNF-α-induced inflammation. In summary, PT treatment potently attenuates inflammation in vascular endothelial cells, which at least partly depends on the reduction of ERS.

The aim of this study was to determine CT risk findings predictive of temporary neurological dysfunction (TND) and permanent neurological dysfunction (PND) after surgical repair for acute type A aortic dissection (ATAAD). A total of 255 patients (41 ± 16 years, 79% male) with ATAAD underwent aortic CT angiography (CTA) and surgical repair consecutively from January 2013 to June 2016. The CTA findings of the 255 patients for the thoracic aorta and carotid artery were analysed to identify risk factors predictive of TND and PND. Thirty-eight patients (15%) suffered TND, and 18 (7%) exhibited PND. Common carotid artery (CCA) dissection (OR = 4.63), lower enhancement of unilateral ICA (OR = 3.02) and aortic arch tears (OR = 2.83) were predictors of postoperative TND, while PND was best predicted by retrograde ascending aorta (aAO) dissection (OR = 5.62) and aortic arch tears (OR = 6.74). In CCA dissection, the extent of the entire CCA and proximal ICA (P = 0.014), a low-enhancement false lumen with re-entry (P = 0.000) and a severely narrowed true lumen without re-entry (P = 0.005) significantly increased the risk of postoperative TND. In patients with ATAAD, specific CT findings allow the individual risk of postoperative TND and PND to be identified and may guide subsequent surgical management.

Objective To explore the feasibility of using electrical impedance tomography (EIT) to provide noninvasive cerebral imaging and monitoring in total aortic arch replacement (TAAR). Design A prospective, observational study. Setting Department of cardiovascular surgery in a university hospital. Participants Forty-two patients undergoing TAAR using hypothermic circulatory arrest and unilateral antegrade cerebral perfusion. Interventions None. Measurements and Main Results Cerebral impedances of the patients were monitored intraoperatively by an EIT system. The prognostic information of the patients, including postoperative neurological dysfunction, was collected during their hospitalizations. Eight (19.0%) subjects had at least 1 postoperative neurological dysfunction complication. The results show that cerebral impedance was related negatively to perfusion flow, and the gradual increase in cerebral resistivity might reflect the evolving process of brain tissue caused by hypoxia. Maximum resistivity asymmetry index was extracted from the reconstructed images to quantify the pathological changes of the brain. The area under the receiver operating characteristic curve of maximum resistivity asymmetry index for postoperative neurological dysfunction was 0.864. In multivariate logistic regression, maximum resistivity asymmetry index was the strongest independent predictor of neurological dysfunction with an odds ratio of 24.3. Conclusion EIT is a promising technique to provide noninvasive cerebral imaging and monitoring in TAAR.

Reducing oxidative stress is a crucial therapeutic strategy for ameliorating diabetic myocardial ischemia/reperfusion (MI/R) injury. Honokiol (HKL) acts as an effective cardioprotective agent for its strong antioxidative activity. However, its roles and underlying mechanisms against MI/R injury in type 1 diabetes (T1D) remain unknown. Since SIRT1 and Nrf2 are pivotal regulators in diabetes mellitus patients suffering from MI/R injury, we hypothesized that HKL ameliorates diabetic MI/R injury via the SIRT1-Nrf2 signaling pathway. Streptozotocin-induced T1D rats and high-glucose-treated H9c2 cells were exposed to HKL, with or without administration of the SIRT1 inhibitor EX527, SIRT1 siRNA, or Nrf2 siRNA, and then subjected to I/R operation. We found that HKL markedly improved the postischemic cardiac function, decreased the infarct size, reduced the myocardial apoptosis, and diminished the reactive oxygen species generation. Intriguingly, HKL remarkably activated SIRT1 signaling, enhanced Nrf2 nuclear translocation, increased antioxidative signaling, and decreased apoptotic signaling. However, these effects were largely abolished by EX527 or SIRT1 siRNA. Additionally, our cellular experiments showed that Nrf2 siRNA blunted the cytoprotective effects of HKL, without affecting SIRT1 expression and activity. Collectively, these novel findings indicate that HKL abates MI/R injury in T1D by ameliorating myocardial oxidative damage and apoptosis via the SIRT1-Nrf2 signaling pathway.

Berberine (BBR) confers cardioprotective effect against myocardial ischemia reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also reduces MI/RI. We hypothesize that BBR may protect against MI/RI by modulating Notch1/Hes1-Phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signaling. In this study, male Sprague-Dawley rats were exposed to BBR treatment (200 mg/kg/d) for 2 weeks and then subjected to MI/RI. BBR significantly improved cardiac function recovery and decreased myocardial apoptosis, infarct size, serum creatine kinase and lactate dehydrogenase levels. Furthermore, in cultured H9c2 cardiomyocytes, BBR (50 μmol/L) attenuated simulated ischemia/reperfusion-induced myocardial apoptosis. Both in vivo and in vitro study showed that BBR treatment up-regulates Notch1 intracellular domain, Hes1, Bcl-2 expression and p-Akt/Akt ratio, down-regulates Bax Caspase-3 and cleaved Caspase-3 expression. However, the anti-apoptotic effect conferred by BBR was blocked by Notch1 siRNA, Hes1 siRNA or LY294002 (the specific inhibitor of Akt signaling) in the cultured cardiomyocytes. In summary, our results demonstrate that BBR treatment attenuates MI/RI by modulating Notch1/Hes1-PTEN/Akt signaling.

Objective To establish a systematic registry of aortic dissection in China, assess the clinical features of Chinese patients with acute aortic dissection (AAD), and compare our results with the data published by the International Registry of Acute Aortic Dissection (IRAD). Methods We established the first Registry of Aortic Dissection in China (Sino-RAD) in 2011. Then we evaluated 1003 patients with AAD in Sino-RAD and compared our results with those reported by IRAD. Results Compared with IRAD, the patients with AAD in Sino-RAD were significantly younger. Also, the ratio of male patients in Sino-RAD was significantly greater for the total cohort and the type A and B cohorts. The overall in-hospital mortality was 10.3% in Sino-RAD. For type A dissection, more patients in Sino-RAD received medical treatment and fewer received surgical treatment. The overall mortality, mortality of medical treatment, and mortality of surgical treatment was lower in Sino-RAD. In type B dissection, fewer patients in Sino-RAD received medical and surgical treatment and more received endovascular treatment. Conclusions The first Sino-RAD, including 15 large cardiovascular centers throughout China, was established. Our data were compared with those reported by IRAD. We found that, compared with Western populations, Chinese patients with AAD showed 6 differences, including earlier onset, more male patients, a low incidence of hypertension, a low incidence of chest pain, a high incidence of back pain, great differences in the choice of therapeutic strategies, and relatively low in-hospital mortality.

Objective To review the experiences in repairing the anomalous origin of one pulmonary artery in infants. Methods From March 2005 to May 2010, 11 infants diagnosed with anomalous origin of one pulmonary artery underwent surgical treatment. Their mean age was 12.7 months (two months to three years), and their mean body weight was 7.1 kg (4 to 13 kg). Seven patients had anomalous origin of the right pulmonary artery, and four patients had anomalous origin of the left pulmonary artery. All 11 patients had an intracardiac anomaly or vascular malformations as well as pulmonary hypertension. A median sternotomy and cardiopulmonary bypass (CPB) were used in all 11 patients. The mean follow-up was 20.5 months (6 to 60 months). Results The operation time was 169 to 293 min (231 ± 55 min), the CPB time was 87 to 210 min (138 ± 47 min), and the aortic cross-clamp time was 45 to 133 min (86 ± 28 min). There was one hospital death (mortality 9%) in a patient with tetralogy of Fallot who had low cardiac output after the operation. In all cases, there was no application of artificial or homologous grafts. All surviving patients had satisfactory early to midterm results except for one patient with mild pulmonary stenosis. Conclusion The surgical correction of anomalous origin of one pulmonary artery without artificial or homologous grafts has satisfactory early to midterm results in infants. doi: 10.1111/jocs.12456 (J Card Surg 2015;30:85–91)

Melatonin confers cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury by reducing oxidative stress. Activation of silent information regulator 1 (SIRT1) signaling also reduces MI/R injury. We hypothesize that melatonin may protect against MI/R injury by activating SIRT1 signaling. This study investigated the protective effect of melatonin treatment on MI/R heart and elucidated its potential mechanisms. Rats were exposed to melatonin treatment in the presence or the absence of the melatonin receptor antagonist luzindole or SIRT1 inhibitor EX527 and then subjected to MI/R operation. Melatonin conferred a cardioprotective effect by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase release, upregulating SIRT1, Bcl-2 expression and downregulating Bax, caspase-3 and cleaved caspase-3 expression. Melatonin treatment also resulted in reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde level, and increased myocardium superoxide dismutase (SOD) level, which indicate that the MI/R-induced oxidative stress was significantly attenuated. However, these protective effects were blocked by EX527 or luzindole, indicating that SIRT1 signaling and melatonin receptor may be specifically involved in these effects. In summary, our results demonstrate that melatonin treatment attenuates MI/R injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor-dependent manner.

Objectives The objective of this study was to evaluate the safety and efficacy of the surgical versus transcatheter approach to correct perimembranous ventricular septal defects (pmVSDs) in a prospective, randomized, controlled clinical trial. Background pmVSD is a common congenital heart disease in children. Surgical closure of pmVSD is a well-established therapy but requires open-heart surgery with cardiopulmonary bypass. Although the transcatheter approach is associated with significant incidence of complete atrioventricular block, it may provide a less invasive alternative. Critical comparison of the safety and efficacy of the 2 interventions necessitates a prospective, randomized, controlled trial. Methods Between January 2009 and July 2010, 229 children with pmVSD were randomly assigned to surgical or transcatheter intervention. Clinical, laboratory, procedural, and follow-up data over a 2-year period were compared. Results Neither group had mortality or major complications. However, statistical analysis of the 2 groups demonstrated significant differences (p Conclusions Transcatheter device closure and surgical repair are effective interventions with excellent midterm results for treating pmVSD in children. Transcatheter device closure has a lower incidence of myocardial injury, less blood transfused, faster recovery, shorter hospital stay, and lower medical expenses. (Transcatheter Closure Versus Surgery of Perimembranous Ventricular Septal Defects; NCT00890799 )

Ischemia reperfusion (IR) injury (IRI) is harmful to the cardiovascular system and causes mitochondrial oxidative stress. Silent information regulator 1 (SIRT1), a type of histone deacetylase, contributes to IRI. Curcumin (Cur) is a strong natural antioxidant and is the active component in Curcuma longa; Cur has protective effects against IRI and may regulate the activity of SIRT1. This study was designed to investigate the protective effect of Cur pretreatment on myocardial IRI and to elucidate this potential mechanism. Isolated and in vivo rat hearts and cultured neonatal rat cardiomyocytes were subjected to IR. Prior to this procedure, the hearts or cardiomyocytes were exposed to Cur in the absence or presence of the SIRT1 inhibitor sirtinol or SIRT1 siRNA. Cur conferred a cardioprotective effect, as shown by improved postischemic cardiac function, decreased myocardial infarct size, decreased myocardial apoptotic index, and several biochemical parameters, including the up-regulation of the antiapoptotic protein Bcl2 and the down-regulation of the proapoptotic protein Bax. Sirtinol and SIRT1 siRNA each blocked the Cur-mediated cardioprotection by inhibiting SIRT1 signaling. Cur also resulted in a well-preserved mitochondrial redox potential, significantly elevated mitochondrial superoxide dismutase activity, and decreased formation of mitochondrial hydrogen peroxide and malondialdehyde. These observations indicated that the IR-induced mitochondrial oxidative damage was remarkably attenuated. However, this Cur-elevated mitochondrial function was reversed by sirtinol or SIRT1 siRNA treatment. In summary, our results demonstrate that Cur pretreatment attenuates IRI by reducing IR-induced mitochondrial oxidative damage through the activation of SIRT1 signaling.

Ischemia/reperfusion injury (IRI) is harmful to the cardiovascular system and causes mitochondrial oxidative stress. Numerous data indicate that the JAK2/STAT3 signaling pathway is specifically involved in preventing myocardial IRI. Melatonin has potent activity against IRI and may regulate JAK2/STAT3 signaling. This study investigated the protective effect of melatonin pretreatment on myocardial IRI and elucidated its potential mechanism. Perfused isolated rat hearts and cultured neonatal rat cardiomyocytes were exposed to melatonin in the absence or presence of the JAK2/STAT3 inhibitor AG490 or JAK2 siRNA and then subjected to IR. Melatonin conferred a cardio-protective effect, as shown by improved postischemic cardiac function, decreased infarct size, reduced apoptotic index, diminished lactate dehydrogenase release, up-regulation of the anti-apoptotic protein Bcl2, and down-regulation of the pro-apoptotic protein Bax. AG490 or JAK2 siRNA blocked melatonin-mediated cardio-protection by inhibiting JAK2/STAT3 signaling. Melatonin exposure also resulted in a well-preserved mitochondrial redox potential, significantly elevated mitochondrial superoxide dismutase (SOD) activity, and decreased formation of mitochondrial hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA), which indicates that the IR-induced mitochondrial oxidative damage was significantly attenuated. However, this melatonin-induced effect on mitochondrial function was reversed by AG490 or JAK2 siRNA treatment. In summary, our results demonstrate that melatonin pretreatment can attenuate IRI by reducing IR-induced mitochondrial oxidative damage via the activation of the JAK2/STAT3 signaling pathway.

Previous studies have demonstrated that Notch signaling pathway plays a regulatory role in cellular oxidative stress injury (OSI). In this study, our aim was to explore the role of the Notch signaling pathway in hydrogen peroxide (H(2)O(2))-induced OSI and the protective effect of curcumin during (H(2)O(2))-induced injury in human umbilical vein endothelial cells (HUVECs). DAPT, a specific inhibitor of the Notch signaling pathway, and Notch1 siRNA were used to study Notch activity. Further, HUVECs were exposed to H(2)O(2) in the absence or presence of curcumin. DAPT and Notch1 siRNA significantly inhibited OSI and the expression of Notch1 and Hes1. Curcumin conferred a protective effect on the HUVECs against H(2)O(2), which was evidenced by improved cell viability, adhesive ability and migratory ability and a decreased apoptotic index, decreased production of reactive oxygen species (ROS) and a reduction in several biochemical parameters. Immunofluorescence and Western blotting analyses demonstrated that H(2)O(2) treatment upregulated the expression of Notch1, Hes1, Caspase3, Bax and cytochrome c downregulated the expression of Bcl2, and treatment with curcumin reversed these effects. We demonstrated for the first time that the inhibition of Notch signaling pathway imparts a protective effect against endothelial OSI. The protective effects of curcumin against OSI are at least in part dependent on Notch1 inhibition.

Enhancing mitochondrial biogenesis and reducing mitochondrial oxidative stress have emerged as crucial therapeutic strategies to ameliorate diabetic myocardial ischemia/reperfusion (MI/R) injury. Melatonin has been reported to be a safe and potent cardioprotective agent. However, its role on mitochondrial biogenesis or reactive oxygen species (ROS) production in type 1 diabetic myocardium and the underlying mechanisms remain unknown. We hypothesize that melatonin ameliorates MI/R injury in type 1 diabetic rats by preserving mitochondrial function via AMPK-PGC-1α-SIRT3 signaling pathway. Both our in vivo and in vitro data showed that melatonin reduced MI/R injury by improving cardiac function, enhancing mitochondrial SOD activity, ATP production and oxidative phosphorylation complex (II, III and IV), reducing myocardial apoptosis and mitochondrial MDA, H2O2 generation. Importantly, melatonin also activated AMPK-PGC-1α-SIRT3 signaling and increased SOD2, NRF1 and TFAM expressions. However, these effects were abolished by Compound C (a specific AMPK signaling blocker) administration. Additionally, our cellular experiment showed that SIRT3 siRNA inhibited the cytoprotective effect of melatonin without affecting p-AMPK/AMPK ratio and PGC-1α expression. Taken together, we concluded that melatonin preserves mitochondrial function by reducing mitochondrial oxidative stress and enhancing its biogenesis, thus ameliorating MI/R injury in type 1 diabetic state. AMPK-PGC1α-SIRT3 axis plays an essential role in this process.

We investigated the myocardial protective effect of a moderate-potassium cold blood cardioplegic solution (K+, 10 mmol/L) in pediatric cardiac surgery.Sixty-eight pediatric patients with congenital heart disease and undergoing open heart surgery with cardiopulmonary bypass were randomly allocated to the high potassium (HP [K+, 20 mmol/L, n=31]) cold blood cardioplegia group or the moderate potassium (MP [K+, 10 mmol/L, n=37]) cold blood cardioplegia group. Heart arresting time, rhythm recovery time, mechanical ventilation time, inotropic drug use in the intensive care unit, perioperative serum cardiac troponin I concentrations, morbidities, and mortalities were compared between the two groups.There were no differences in cardiopulmonary bypass time, aorta cross-clamping time, cardioplegia volume, lowest body temperature during cardiopulmonary bypass, total volume of cardioplegia delivered, hematocrit value, and fluid output during the operation between the two groups. However, there was a longer arresting time and a shorter rhythm recovery time in the MP group (35.6±2.4 s, and 30.8±3.1 s) when compared with that in the HP group (24.7±2.7 s, and 42.0±4.0 s, both p0.05). The total mediastinal drainage volume, the length of stay in the intensive care unit, the postoperative inotropic drug use, and the postoperative hospital time were similar between the two groups, but the number of patients with a long postoperative mechanical ventilation time (24 hours) in the MP group (6 of 36) was less than that in HP group (13 of 30; p0.05). At 1 hour, 3 hours, and 6 hours after myocardium reperfusion, the serum concentration of cardiac troponin I significantly decreased in the MP group (in ng/mL: 15.18±3.57, 24.83±4.91, and 19.62±3.93, respectively) when compared with that in the HP group (in ng/mL: 32.67±5.31, 39.26±7.43, and 30.52±5.17, respectively, p0.05).The present study demonstrated that the M (10 mmol/L) cold blood cardioplegia formula is associated with better myocardial protective effects when compared with conventional HP cardioplegia in pediatric patients.

The clinical profiles and outcomes of acute aortic dissection (AAD) have not been evaluated in China. We retrospectively analyzed, from January 1, 2008 to December 31, 2011, the data from 1,812 patients (mean age 51.1 ± 10.9 years; 77.5% men) with AAD (726 with type A and 1,086 with type B) from 19 large hospitals. Most patients had hypertension and presented with an abrupt onset of chest and/or back pain. Patients with type A AAD were more likely to present with typical symptoms and signs. Computed tomography was the most common initial imaging modality, used in 76.3% of patients with an AAD. The overall in-hospital mortality rate was 17.7%, with most of the deaths occurring within the first week. Surgery was used in 75.3% of patients with type A AAD. The mortality in this cohort was 33.8%. Endovascular treatment was performed in 76.1% of patients with type B AAD. The mortality rate was 2.2%. Multivariate analysis showed that hypertension (odds ratio 2.80, p

Heat shock protein (HSP) 70 plays a critical role in protecting the heart from various stressor-induced cell injuries; the mechanism remains to be further understood. The present study aims to elucidate the effect of a probiotics-derived protein, LGG-derived protein p75 (LGP), in alleviating the ischemia/reperfusion (I/R)-induced heart injury. We treated rats with the I/R with or without preadministration with LGP. The levels of HSP70 and carboxy terminus of HSP70-interacting protein (CHIP) in the heart tissue were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The effect of CHIP on suppression of HSP70 and the effect of LGP on suppression of CHIP were investigated with an I/R rat model and a cell culture model. The results showed that I/R-induced infarction in the heart could be alleviated by pretreatment with LGP. HSP70 was detected in naïve rat heart tissue extracts. I/R treatment significantly suppressed the level of HSP70 and increased the levels of CHIP in the heart. A complex of CHIP/HSP70 was detected in heart tissue extracts. The addition of recombinant CHIP to culture inhibited HSP70 in heart cells. LGP was bound CHIP in heart cells and prevented the CHIP from binding HSP70. In summary, I/R can suppress HSP70 and increase CHIP in heart cells. CHIP can suppress HSP70 that can be prevented by pretreatment with LGP. The results imply that CHIP may be a potential target in the prevention of I/R-induced heart cell injury.

Background and Aims Patients with diabetes show enhanced susceptibility to myocardial ischemia/reperfusion (MI/R) injury. Epidemiological studies indicated that consumption of α-linolenic acid (ALA) significantly reduces the risk of cardiac events in post-acute myocardial infarction patients. The present study attempted to investigate the effects of ALA intake on MI/R injury in normal and diabetic rats and its mechanisms. Methods The high-fat diet-fed streptozotocin (HFD-STZ) rat model was developed. Age-matched normal and HFD-STZ rats were randomly assigned to receive normal diet or ALA (oral gavage, 500 μg/kg per day). After 4 weeks of feeding, animals were subjected to 30 min of myocardial ischemia and 4 or 6 h of reperfusion. Results Compared with the normal control, HFD-STZ rats showed more severe myocardial functional impairment and injury. Although ALA intake for 4 weeks did not change myocardial function and injury in normal rats, it significantly improved the instantaneous first derivation of left ventricle pressure, reduced infarct size, plasma creatine kinase and lactate dehydrogenase activities, and apotosis at the end of reperfusion in HFD-STZ diabetic rats. Moreover, ALA intake not only significantly reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations but reduced the increase in superoxide production and malonaldialdehyde formation and simultaneously enhanced the antioxidant capacity in the diabetic hearts. Myocardial PI3K expression and Akt phosphorylation were increased by ALA intake in diabetic but not normal rats. Conclusions Chronic ALA intake confers cardioprotection in MI/R by exerting anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats, which is possibly through PI3K-Akt-dependent mechanism.

Aims The aim of this study was to evaluate the safety and efficacy of transcatheter closure for perimembranous ventricular septal defect (pmVSD) and its long-term results. The most common congenital heart condition is pmVSD. Transcatheter closure of pmVSD is a recently described technique with limited results for mid- to long-term follow-up. Methods and results Between June 2002 and June 2008, 848 patients with pmVSD were enrolled in our study and treated percutaneously with pmVSD occluders. All patients were followed up until December 2008, an average of 37 months. According to colour Doppler transthoracic echocardiography before the intervention and ventriculography, the average end-diastolic pmVSD size was 5.1 and 5.4 mm, respectively. Placement of the device was successful in 832 patients (98.1%) and the median device size was 8.6 mm. During follow-up, 103 adverse events (12.4%) were reported. Most adverse events were categorized as minor and there were nine major adverse events (8.7%), including two complete atrioventricular block requiring pacemaker implantation. Kaplan–Meier estimates showed >85% freedom from major or minor adverse events during a maximal follow-up of 79 months. Conclusions In experienced hands, transcatheter pmVSD closure can be performed safely and successfully with low morbidity and mortality. Long-term prognostic results are favourable, and the transcatheter approach provides a less-invasive alternative that may become the first choice in selected pmVSD patients. This trial is registered with ClinicalTrials.gov, number [NCT00890799][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00890799&atom=%2Fehj%2F31%2F18%2F2238.atom

The effects of sevoflurane inhalation during cardiopulmonary bypass (CPB) on postoperative courses and serum cardiac troponin I (cTnI) concentrations in pediatric patients undergoing cardiac surgery have not been extensively investigated. In this single-center, prospective, randomized trial, an anesthetic regimen containing 2% sevoflurane used throughout the CPB process was compared with a total intravenous anesthesia (TIVA) regimen. One hundred and three patients undergoing congenital heart defect repair with CPB were included in this prospective randomized controlled study. They were randomized into two groups: the sevoflurane group, who received 2% sevoflurane during CPB via an oxygenator, and the control group, who received only an oxygen-air mixture. The pre- and intra-operative parameters were comparable between the two groups. There was a slight but significant increase of arterial diastolic pressure in the sevoflurane group immediately after CPB compared with control patients (46.9 ± 9.3 mm Hg vs. 43.6 ± 8.9 mm Hg; p = 0.033). There was no death in either group. The postoperative ventilation time (in mean [95% confidence interval]) was shorter in the sevoflurane group than that in the control group (26.1 [19.2, 33.0] h vs. 37.7 [24.4, 50.9] h; p = 0.014). The postoperative ICU time, hospital days, and serial serum cTnI concentrations were not significantly different between the two groups. Inhalation of 2% sevoflurane during CPB is beneficial to the recovery of pediatric patients undergoing cardiac surgery but has no significant effect on postoperative cTnI release.