Exendin-4 alleviates myocardial ischemia reperfusion injury by enhancing autophagy through promoting nuclear translocation of TFEB.

Ischemia-reperfusion (I/R) injury (IRI) is a common clinical consequence of myocardial infarction. Exendin-4 is a glucagon-like peptide-1 (GLP-1) analog that has been demonstrated to alleviate myocardial IRI. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in myocardial IRI. However, whether exendin-4 exerts a protective effect on myocardial IRI by modulating autophagy remains elusive. Herein, we investigated the effect of exendin-4 on autophagic flux and explored the underlying molecular mechanisms. Our data revealed that the autophagic flux was blocked in the human ventricular cardiomyocyte cell lines (AC16) subjected to oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Exendin-4 pre-treatment markedly restored the blocked autophagic flux induced by OGD/R through promoting nuclear translocation of TFEB and transcription of genes involving autophagy initiation, the effect of which was reversed by TFEB knockdown. The restoration of autophagic flux contributed to multiple beneficial effects of exendin-4 in cardiomyocytes, including reduction of oxidative stress, preservation of mitochondrial network as well as inhibition of cytochrome c leakage from mitochondrial permeability transition pore (MPTP) and the resulting apoptosis. Moreover, the administration of exendin-4 reduced infarct size and preserved cardiac function through its anti-apoptosis and antioxidative effects in vivo. These results shed some light on understanding the novel mechanism of exendin-4 as a protective agent against myocardial IRI.

Kappa-Opioid Agonist U50,488H-Mediated Protection Against Heart Failure Following Myocardial Ischemia/Reperfusion: Dual Roles of Heme Oxygenase-1.

BACKGROUNDS/AIMS: The selective κ-opioid agonist U50,488H protects heart from myocardial ischemia-reperfusion (MI/R) injury. We examined whether U50,488H is also beneficial for MI/R induced heart failure. METHODS: Anesthetized male Sprague-Dawley rats were subjected to 30 min of myocardial ischemia via left anterior descending coronary artery (LAD) occlusion, followed by 4 weeks of reperfusion. Infarct size was examined by Evans blue/triphenyl tetrazolium chloride (TTC) staining. Cardiac function and remodeling were examined by echocardiography and histology. HO-1 gene transcription and expression were measured by RT-PCR and western blot. RESULTS: Compared to vehicle-treated MI/R rats, rats administered a single dose of U50,488H at the beginning of reperfusion exhibited reduced myocardial infarct size, oxidative stress, hypertrophy, and fibrosis, improved mechanical function, and greater neovascularization. U50,488H also increased myocardial heme oxygenase (HO)-1 gene transcription and expression, while pharmacological HO-1 inhibition reversed all protective effects of U50,488H. Furthermore, U50,488H protected control cultured cardiomyoctes against simulated I/R-induced apoptosis but not cultures subjected to shRNA-mediated HO-1 knockdown. Inhibition of HO-1 in the subacute phase of reperfusion reversed the U50,488H-induced increase in neovascularization and suppression of oxidative stress. Finally, U50,488H increased Akt phosphorylation and nuclear translocation of Nrf2, a key HO-1 transcription activator, while inhibition of PI3K-Akt signaling abolished U50,488H-induced Nrf2 nuclear translocation, HO-1 upregulation, and cardioprotection. CONCLUSION: Activation of HO-1 expression through the PI3K-Akt-Nrf2 pathway may mediate the acute and long-term protective effects of U50,488H against heart failure by enhancing cardiomyocyte survival and neoangiogenesis and by reducing oxidative stress.

Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury.

Acute traumatic brain injury (TBI) is associated with long-term cognitive and behavioral dysfunction. In vivo studies have shown histone deacetylase inhibitors (HDACis) to be neuroprotective following TBI in rodent models. HDACis are intriguing candidates because they are capable of provoking widespread genetic changes and modulation of protein function. By using known HDACis and a unique small-molecule pan-HDACi (LB-205), we investigated the effects and mechanisms associated with HDACi-induced neuroprotection following CNS injury in an astrocyte scratch assay in vitro and a rat TBI model in vivo. We demonstrate the preservation of sufficient expression of nerve growth factor (NGF) and activation of the neurotrophic tyrosine kinase receptor type 1 (TrkA) pathway following HDACi treatment to be crucial in stimulating the survival of CNS cells after TBI. HDACi treatment up-regulated the expression of NGF, phospho-TrkA, phospho-protein kinase B (p-AKT), NF-κB, and B-cell lymphoma 2 (Bcl-2) cell survival factors while down-regulating the expression of p75 neurotrophin receptor (NTR), phospho-JNK, and Bcl-2-associated X protein apoptosis factors. HDACi treatment also increased the expression of the stem cell biomarker nestin, and decreased the expression of reactive astrocyte biomarker GFAP within damaged tissue following TBI. These findings provide further insight into the mechanisms by which HDACi treatment after TBI is neuroprotective and support the continued study of HDACis following acute TBI.

Surgical repair of an aneurysm-like fistula connecting the left main coronary artery with the right atrium.

Coronary fistula is defined as an anomalous connection between a coronary artery and any of the four chambers of the heart or any of its great vessels. A coronary fistula connecting the left main coronary artery to the right atrium is the most uncommon. In the present study, we report the surgical management of a very uncommon case of an aneurysm-like fistula connecting the left main coronary artery to the right atrium in a 2-year-old boy.

FUNDC1 alleviates doxorubicin-induced cardiotoxicity by restoring mitochondrial-endoplasmic reticulum contacts and blocked autophagic flux.

Rationale: Autophagy dysregulation is known to be a mechanism of doxorubicin (DOX)-induced cardiotoxicity (DIC). Mitochondrial-Endoplasmic Reticulum Contacts (MERCs) are where autophagy initiates and autophagosomes form. However, the role of MERCs in autophagy dysregulation in DIC remains elusive. FUNDC1 is a tethering protein of MERCs. We aim to investigate the effect of DOX on MERCs in cardiomyocytes and explore whether it is involved in the dysregulated autophagy in DIC. Methods: We employed confocal microscopy and transmission electron microscopy to assess MERCs structure. Autophagic flux was analyzed using the mCherry-EGFP-LC3B fluorescence assay and western blotting for LC3BII. Mitophagy was studied through the mCherry-EGFP-FIS1 fluorescence assay and colocalization analysis between LC3B and mitochondria. A total dose of 18 mg/kg of doxorubicin was administrated in mice to construct a DIC model in vivo. Additionally, we used adeno-associated virus (AAV) to cardiac-specifically overexpress FUNDC1. Cardiac function and remodeling were evaluated by echocardiography and Masson's trichrome staining, respectively. Results: DOX blocked autophagic flux by inhibiting autophagosome biogenesis, which could be attributed to the downregulation of FUNDC1 and disruption of MERCs structures. FUNDC1 overexpression restored the blocked autophagosome biogenesis by maintaining MERCs structure and facilitating ATG5-ATG12/ATG16L1 complex formation without altering mitophagy. Furthermore, FUNDC1 alleviated DOX-induced oxidative stress and cardiomyocytes deaths in an autophagy-dependent manner. Notably, cardiac-specific overexpression of FUNDC1 protected DOX-treated mice against adverse cardiac remodeling and improved cardiac function. Conclusions: In summary, our study identified that FUNDC1-meditated MERCs exerted a cardioprotective effect against DIC by restoring the blocked autophagosome biogenesis. Importantly, this research reveals a novel role of FUNDC1 in enhancing macroautophagy via restoring MERCs structure and autophagosome biogenesis in the DIC model, beyond its previously known regulatory role as an mitophagy receptor.

NDRG2: a newly identified mediator of insulin cardioprotection against myocardial ischemia-reperfusion injury.

The N-myc downstream-regulated gene 2 (NDRG2) is involved in cell apoptosis and survival. Although reported to be highly expressed in the cardiac tissue, the biological function of NDRG2 in the heart remains to be established. Insulin exerts protective effects against myocardial ischemia/reperfusion (I/R) injury through the PI3K/Akt pathway. Here, we examined the changes in phosphorylation of NDRG2, a novel substrate and phosphoprotein of Akt, in insulin-induced protection against myocardial I/R. Rat hearts were subjected to 30 min regional ischemia followed by reperfusion with or without insulin at the onset of reperfusion. Reperfusion with insulin inhibited myocardial apoptosis and reduced infarct size, as well as significantly up-regulated myocardial Akt and NDRG2 phosphorylation levels compared with the I/R group. These effects of insulin were blocked by pretreatment with the PI3K inhibitor wortmannin or Akt inhibitor. To further ascertain the role of NDRG2 in insulin-induced cardioprotection, cardiomyocytes were transduced with a lentivirus encoding shRNA targeting NDRG2 (loss-of-function), which rendered the cells more susceptible to I/R injury and significantly blunted the anti-apoptotic effect of insulin. Moreover, the NDRG2 shRNA lentivirus was tested in vivo, and NDRG2 knockdown aggravated myocardial I/R injury and attenuated the insulin-mediated cardioprotection against I/R injury. Taken together, these results suggest a novel role of PI3K/Akt/NDRG2 signaling in the cardioprotective effect of insulin.

Development of a new thiol site-specific prosthetic group and its conjugation with [Cys(40)]-exendin-4 for in vivo targeting of insulinomas.

A new tracer, N-5-[(18)F]fluoropentylmaleimide ([(18)F]FPenM), for site-specific labeling of free thiol group in proteins and peptides was developed. The tracer was synthesized in three steps ((18)F displacement of the aliphatic tosylate, di-Boc removal by TFA to expose free amine, and incorporation of the free amine into a maleimide). The radiosynthesis was completed in 110 min with 11-17% radiochemical yield (uncorrected), and specific activity of 20-49 GBq/µmol. [(18)F]FPenM showed comparable labeling efficiency with N-[2-(4-[(18)F]fluorobenzamido)ethyl]maleimide ([(18)F]FBEM). Its application was demonstrated by conjugation with glucagon-like peptide type 1 (GLP-1) analogue [cys(40)]-exendin-4. The cell uptake, binding affinity, imaging properties, biodistribution, and metabolic stability of the radiolabeled [(18)F]FPenM-[cys(40)]-exendin-4 were studied using INS-1 tumor cells and INS-1 xenograft model. Positron emission tomography (PET) results showed that the new thiol-specific tracer, [(18)F]FPenM-[cys(40)]-exendin-4, had high tumor uptake (20.32 ± 4.36%ID/g at 60 min postinjection) and rapid liver and kidney clearance, which was comparable to the imaging results with [(18)F]FBEM-[cys(40)]-exendin-4 reported by our group.

Dual Function of a in vivo Albumin-Labeling Tracer for Assessment of Blood Perfusion and Vascular Permeability in Peripheral Arterial Disease by PET.

BACKGROUND: Peripheral arterial disease (PAD) leads to tissue ischemia in the extremities. Enhanced vascular permeability plays a critical role in targeted delivery of drugs for effective therapeutic angiogenesis and resultant blood perfusion recovery. However, optimal tracers for evaluating this process in PAD patients are lacking. At this time, we employed a novel in vivo albumin-labeling tracer of dual function, termed as 18F-NEB, to assess blood perfusion as well as vascular permeability by positron emission tomography (PET). METHODS AND RESULTS: After successful establishment of mouse hindlimb ischemia (HI) model, static PET imaging was performed 15 min and 2 h post injection (p.i.) of 18F-NEB at 1, 3, 5, 7, 10 and 14 days post-surgery respectively. Gradual recovery of blood supply was detected by PET scan 15 min p.i. and collaborated by serial Laser Doppler. In addition, the highest vascular permeability observed by high local uptake of 18F-NEB at 2 h p.i. was consistent with histological examinations. Furthermore, we quantitatively evaluated the effect of vascular endothelial growth factor (VEGF) stimulus on vascular permeability and blood perfusion by PET scan using 18F-NEB probe in HI model, which were also confirmed by immunohistological results. CONCLUSION: The application of 18F-NEB probe alone by PET can successfully achieve dual imaging of blood perfusion as well as vascular permeability at different time points p.i. and monitor their responses to therapy in PAD model. The simple labeling approach and multipurpose feature suggest the great promise of using this imaging probe in theranostic applications for treating ischemic disease.

Aortic Balloon Occlusion Technique Does Not Improve Peri-Operative Outcomes for Acute Type A Acute Aortic Dissection Patients With Lower Body Malperfusion.

Background: The management of malperfusion is vital to improve the outcomes of surgery for acute type A acute aortic dissection (ATAAD). Open arch repair under hypothermic circulatory arrest with selective antegrade cerebral perfusion (HCA/sACP) is safe and efficient but associated with inevitable hypothermia and ischemia-reperfusion injury. The aortic balloon occlusion (ABO) technique is shown to be organ protective by allowing higher temperature and shorter circulatory arrest time. In this study, we aimed to evaluate the safety and efficacy of this new technique for ATAAD patients with lower body malperfusion. Methods: Between January 2013 and November 2020, 355 ATAAD patients with lower body malperfusion who underwent arch repair in our institute were enrolled. The patients were divided into 2 groups: ABO group (n = 85) and HCA/sACP group (n = 271). Propensity score matching was performed to correct baseline differences. Results: Using the propensity score matching, 85 pairs were generated. Circulatory arrest time was significantly lower in the ABO group compared with the HCA/sACP group (median, 8 vs. 22 min; p < 0.001). The incidence of in-hospital mortality (10.6 vs. 12.9%; p = 0.812), stroke (7.1 vs. 7.1%; p = 1.000), dialysis (25.9 vs. 32.9%; p = 0.183), hepatic dysfunction (52.9 vs. 57.6%; p = 0.537), tracheostomy (4.7 vs. 2.4%; p = 0.682), paraplegia (1.2 vs. 4.7%; p = 0.368) were comparable between ABO and HCA/sACP groups. Other outcomes and major adverse events were comparable. The multivariable logistic analysis did not recognize ABO technique protective against any major adverse outcomes. Conclusions: For ATAAD patients with lower body malperfusion, the ABO technique allows the performance of arch repair with frozen elephant trunk (FET) under higher temperature and shorter circulatory arrest time. However, ABO technique did not improve perioperative outcomes. Future studies are warranted to evaluate the efficacy of this technique.

Coronary Malperfusion Secondary to Acute Type A Aortic Dissection: Surgical Management Based on a Modified Neri Classification.

Background: Coronary malperfusion (CM) secondary to acute type A aortic dissection (ATAAD) is considered rare but has a high mortality rate. This study examined the incidence, management, and outcomes of patients with CM secondary to ATAAD and proposes a modified Neri classification. Methods: Between 2015 and 2020, out of 1018 patients who underwent surgical repair for ATAAD, 137 presented with CM, including 68 (49.6%), 43 (31.3%), and 15 (10.9%) with Neri types A, B, and C, respectively, and 11 (8.0%) with coronary orifice intimal tear (COIT), which we consider a novel category. Results: The occurrence rate of CM was 13.4%. CM was associated with higher in-hospital mortality (18.2% vs. 7.8%, p < 0.001). For Neri type A (98.5%) and most type B lesions (72.1%), coronary repair was adequate. Coronary artery bypass grafting (CABG) was necessary for type B patients unsuited for repair (23.2%) and for all type C patients (100%). Repair of COIT was possible (45.5%). The in-hospital mortality rates differed significantly among the four lesion groups (p = 0.006). Conclusions: The occurrence of CM secondary to ATAAD may be more frequent than previously reported. Surgical management based on lesion classification achieved acceptable outcomes. Repair was adequate for Neri type A and most type B lesions. Other type B and type C lesions could be treated by CABG. Coronary orifice intimal tear is a unique set of lesions, for which orifice repair was also possible.

Right axillary artery cannulation in acute type A aortic dissection with involvement of the right axillary artery.

OBJECTIVE: The right axillary artery is currently recommended for arterial cannulation in surgery for acute type A aortic dissection. However, the feasibility of cannulation on a dissected right axillary artery remains undetermined. The objective was to examine the feasibility of cannulation on a dissected right axillary artery. METHODS: From 2016 to 2020, 835 patients who underwent acute type A aortic dissection repair were included in this study. Cannulation strategy and perioperative outcomes of patients who did and did not have right axillary artery dissection were compared. Propensity score matching and logistic regression were applied. RESULTS: A total of 124 patients had right axillary artery dissection, and 711 patients did not. Direct right axillary artery cannulation was used for cardiopulmonary bypass in the majority of patients, but with a lower rate in patients with right axillary artery dissection (n = 88 [71.0%] vs n = 579 [81.4%], P = .007). Right axillary artery cannulation failure (n = 3 [2.4%] vs n = 5 [0.7%], P = .102) and related complications (n = 1 [0.8%] vs n = 6 [0.8%], P = 1.000) were rare in both groups. In-hospital mortality (n = 18 [14.5%] vs n = 59 [8.3%], P = .027) and stroke (n = 14 [11.3%] vs n = 42 [5.9%], P = .027) were significantly higher in the right axillary artery dissection group, but after propensity score matching, in-hospital outcomes were comparable. Right axillary artery dissection was not a risk factor for mortality, stroke, right axillary artery cannulation not performed, or right axillary artery cannulation failure. CONCLUSIONS: Direct right axillary artery cannulation is feasible for most patients with acute type A aortic dissection with right axillary artery dissection.

Variation of NDRG2 and c-Myc expression in rat heart during the acute stage of ischemia/reperfusion injury.

N-Myc downstream regulated gene 2 (NDRG2), a Myc-repressed gene, is highly expressed in heart tissue. NDRG2 increases in response to hypoxia-induced stress and is involved in hypoxia-induced radioresistance. However, little is known about the expression changes and possible roles of NDRG2 in the heart under hypoxia condition. Here, the authors show that NDRG2, mainly localized in cardiomyocyte cytoplasm, was significantly reduced in myocardial tissue after acute ischemia/reperfusion (I/R) injury. Meanwhile, c-Myc was up-regulated following acute I/R injury, and the expression of c-Myc was significantly inversely correlated with that of NDRG2. In addition, overexpression of c-Myc in primary cultured cardiomyocyte repressed NDRG2 expression. Furthermore, the increase of cardiomyocyte apoptosis was correlated with the decrease of NDRG2 protein during the acute phase of reperfusion. These data suggested for the first time that I/R injury-induced up-regulation of pro-apoptotic c-Myc expression may contribute to the down-regulation of anti-apoptotic NDRG2. This stress response might be involved in the novel mechanism of myocardial apoptosis induced by I/R injury in rat.

Effects and mechanisms of ghrelin on cardiac microvascular endothelial cells in rats.

Ghrelin is thought to directly exert a protective effect on the cardiovascular system, specifically by promoting vascular endothelial cell function. Our study demonstrates the ability of ghrelin to promote rat CMEC (cardiac microvascular endothelial cell) proliferation, migration and NO (nitric oxide) secretion. CMECs were isolated from left ventricle of adult male Sprague-Dawley rat by enzyme digestion and maintained in endothelial cell medium. Dil-ac-LDL (1,1'-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine-labelled acetylated low-density lipoprotein) intake assays were used to identify CMECs. Cells were split into five groups and treated with varying concentrations of ghrelin as follows: one control non-treated group; three ghrelin dosage groups (1×10-9, 1×10-8, 1×10-7 mol/l) and one ghrelin+PI3K inhibitor group (1×10-7 mol/l ghrelin+20 µmol/l LY294002). After 24 h treatment, cell proliferation capability was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and Western blot for PCNA (proliferating cell nuclear antigen) protein expression. Migration of CMECs was detected by transwell assays, and NO secretion of CMECs was measured via nitrate reduction. Protein expression of AKT and phosphorylated AKT in CMECs was measured by Western blot after exposure to various concentrations of ghrelin and the PI3K inhibitor LY294002. Our results indicate that ghrelin significantly enhanced cell growth at concentrations of 10-8 mol/l (0.271±0.041 compared with 0.199±0.021, P = 0.03) and 10-7 mol/l (0.296±0.039 compared with 0.199±0.021, P<0.01). However, addition of the PI3K/AKT inhibitor LY294002 inhibited the ghrelin-mediated enhancement in cell proliferation (0.227±0.042 compared with 0.199±0.021, P = 0.15). At a concentration between 10-8 and 10-7 mol/l, ghrelin caused a significant increase in the number of migrated cells compared with the control group (126±9 compared with 98±7, P = 0.02; 142±6 compared with 98±7, P<0.01), whereas no such change could be observed in the presence of 20 µmol/l of the PI3K/Akt inhibitor LY294002 (103±7 compared with 98±7, P = 0.32). Ghrelin treatment significantly enhanced NO production in a dose-dependent fashion compared with the untreated control group [(39.93±2.12) µmol/l compared with (30.27±2.71) µmol/l, P = 0.02; (56.80±1.98) µmol/l compared with (30.27±2.71) µmol/l, P<0.01]. However, pretreatment with 20 µmol/l LY294002 inhibited the ghrelin-stimulated increase in NO secretion [(28.97±1.64) µmol/l compared with (30.27±2.71) µmol/l, P = 0.37]. In summary, we have found that ghrelin treatment promotes the proliferation, migration and NO secretion of CMECs through activation of PI3K/AKT signalling pathway.

Femoral artery cannulation as a safe alternative for aortic dissection arch repair in the era of axillary artery cannulation.

BACKGROUND: To evaluate the safety and efficacy of femoral artery cannulation as an alternative to axillary artery cannulation, we retrospectively compared outcomes between patients with axillary or femoral artery cannulation during open aortic arch repair for type A aortic dissection (TAAD). METHODS: Between January 2014 and January 2019, 646 patients underwent open aortic arch repair with circulatory arrest for TAAD using antegrade selective cerebral perfusion (SACP) and were divided into two groups according to the site of arterial cannulation: an axillary artery group (axillary group, n=558) or a femoral artery group (femoral group, n=88). The axillary artery was considered as the primary cannulation site, and the femoral artery was used as an alternative when axillary artery cannulation was deemed unsuitable or had failed. Propensity score matching was performed to correct baseline differences. RESULTS: After propensity score matching, the patients' characteristics were comparable between groups (n=85 in each). The incidence of in-hospital mortality (10.6% vs. 14.1%; P=0.642) and stroke (3.5% vs. 5.9%; P=0.720) were comparable between the axillary and femoral groups. The incidence of newly required dialysis was lower in the femoral group, but the difference was not statistically significant (34.1% vs. 20.0%; P=0.050). Other outcomes and major adverse events were comparable. CONCLUSIONS: Femoral artery cannulation produced similar perioperative outcomes to axillary cannulation after open arch repair for TAAD. The femoral artery can be used as a safe and effective alternative to the axillary artery for arterial cannulation in TAAD patients undergoing open arch repair.

Noninvasive monitoring of the development and treatment response of ischemic hindlimb by targeting matrix metalloproteinase-2 (MMP-2).

Critical limb ischemia (CLI) is a common cause of high vascular morbidity and mortality. Monitoring the development and treatment response of hindlimb ischemia (HI) in an animal model enables a better understanding of the pathological mechanisms underlying CLI, and evaluation of the efficacy of novel therapeutic approaches. Matrix metalloproteinase (MMP) activity is essential for remodeling of ischemic tissue including extracellular matrix degradation and angiogenesis. Herein, a mouse HI model is established and subjected to noninvasive optical imaging with a novel and ultra-sensitive MMP activatable probe, termed MMP-P12, for analyzing the development and treatment response of HI. Our results show that angiogenesis development during HI was well correlated with MMP-2 activity alteration as examined by western blot, histological staining and MMP-P12 fluorescence signal recovery. Moreover, vascular endothelial growth factor (VEGF) mediated HI treatment was also monitored by MMP-P12. Up-regulated MMP-2 expression and an enhancement of angiogenesis were observed after VEGF treatment, which peaked at 7 days after the treatment. Overall, our results showed that MMP-2 plays an important role in the monitoring of angiogenesis during HI development and therapy. Application of MMP-P12 to visualize MMP-2 activity alteration can serve as a promising noninvasive optical imaging strategy to monitor angiogenesis and its response to therapy in CLI.

ZP2495 Protects against Myocardial Ischemia/Reperfusion Injury in Diabetic Mice through Improvement of Cardiac Metabolism and Mitochondrial Function: The Possible Involvement of AMPK-FoxO3a Signal Pathway.

Coronary heart disease patients with type 2 diabetes were subject to higher vulnerability for cardiac ischemia-reperfusion (I/R) injury. This study was designed to evaluate the impact of ZP2495 (a glucagon-GLP-1 dual-agonist) on cardiac function and energy metabolism after myocardial I/R injury in db/db mice with a focus on mitochondrial function. C57BLKS/J-lepr+/lepr+ (BKS) and db/db mice received 4-week treatment of glucagon, ZP131 (GLP-1 receptor agonist), or ZP2495, followed by cardiac I/R injury. The results showed that cardiac function, cardiac glucose metabolism, cardiomyocyte apoptosis, cardiac mitochondrial morphology, and energetic transition were improved or ameliorated by ZP2495 to a greater extent than that of glucagon and ZP131. In vitro study showed that ZP2495, rather than glucagon, alleviated mitochondrial depolarization, cytochrome C release, and mitochondria ROS generation in neonatal rat ventricular myocytes subjected to high-glucose and simulated I/R injury conditions, the effects of which were weaker in the ZP131 group. Furthermore, the expressions of Akt, FoxO3a, and AMPK phosphorylation were elevated by ZP2495 to a greater extent than that of ZP131. In conclusion, ZP2495 may contribute to the improvement of cardiac function and energy metabolism in db/db mice after myocardial I/R injury by improving mitochondrial function possibly through Akt/FoxO3a and AMPK/FoxO3a signal pathways.

The effect of antegrade pulmonary blood flow following a late bidirectional Glenn procedure.

OBJECTIVES: The effect of antegrade pulmonary blood flow (APBF) has never been studied in the bidirectional Glenn (BDG) procedure performed late. METHODS: Records of 112 consecutive patients who had a BDG procedure during a 10-year period were reviewed retrospectively. The patients were divided into 2 groups based on whether APBF occurred following the BDG procedure (APBF group, n = 81) or not (non-APBF group, n = 31). The median age at the BDG procedure was 6.16 ± 3.93 years in the APBF group and 6.12 ± 4.40 years in the non-APBF group. RESULTS: Demographics and pre- and intraoperative variables were comparable for both groups. Follow-up data were obtained for patients at the BDG stage and for those who had undergone the Fontan completion. Both oxygen saturation levels (81.72 ± 1.976% vs 78.32 ± 2.344%, P < 0.01) and pulmonary pressure (13.59 ± 1.376 mmHg vs 12.90 ± 0.978 mmHg, P = 0.012) were higher in the APBF group immediately after the BDG procedure. Both the duration of chest tube drainage and the total length of stay were longer in the APBF group. The pre-Glenn measurements showed a mean McGoon ratio of 1.68 ± 0.114 in the APBF group and 1.67 ± 0.098 in the non-APBF group (P = 0.474). The McGoon ratios measured before the Fontan procedure were also comparable (1.669 ± 0.726 vs 1.685 ± 0.669, P = 0.576). At the pre-Fontan measurement, there was no significant difference in mean pulmonary artery pressures between the groups (13.72 ± 1.368 vs 13.50 ± 1.265, P = 0.653). Fifty-nine patients underwent the Fontan completion (43 from the APBF group and 16 from the non-APBF group) procedure with a median of 1.2 (APBF group) and 1.4 (non-APBF group) years after the BDG procedure. No significant differences between groups were observed in arterial oxygen saturation levels, incidence of systemic atrioventricular valve regurgitation or ventricular dysfunction in survivors at the last follow-up visit. CONCLUSIONS: The BDG procedure can be safely performed at a relatively older age (∼6 years). APBF increases oxygen saturation but also prolongs pleural effusion and hospital stay. Medium-term outcomes and the Fontan completion rate in the APBF and the non-APBF groups are comparable. Further large studies and long-term follow-up are needed to clarify the effect of APBF in patients who have the late BDG.

Concomitant surgical atrial fibrillation ablation is safe and efficacious in patients undergoing double valve replacement - A cohort study.

BACKGROUND: Current European Society of Cardiology Guidelines recommend concomitant atrial fibrillation (AF) ablation for all symptomatic patients undergoing other cardiac surgeries, but the safety and potential benefits of concomitant atrial fibrillation (AF) ablation at the time of double valve replacement (DVR: aortic and mitral valve replacement) remains unexamined. MATERIALS AND METHODS: We conducted a retrospective review of 238 patients with AF who underwent DVR with or without concomitant surgical ablation (Ablation group, n = 113; Non-ablation group, n = 125) at a single institute from April 2006 to September 2011. RESULTS: There were no significant group differences in early postoperative mortality and morbidity, late survival, and freedom from major cardiac and cerebrovascular events (MACCEs). However, the Ablation group exhibited higher rates of sinus rhythm restoration at discharge (86.7% vs. 5.6%, P < 0.01) and at last follow-up (71.2% vs. 8.5%, P < 0.01). Follow-up echocardiography demonstrated smaller left atrial dimension and higher ejection fraction in the Ablation group (both P < 0.01). CONCLUSION: Concomitant surgical ablation for AF did not increase perioperative mortality or morbidity in patients undergoing DVR, but significantly increased sinus rhythm restoration, improved heart function, and decreased oral anticoagulation requirements.

Bilateral versus unilateral antegrade cerebral perfusion in total arch replacement for type A aortic dissection.

BACKGROUND: Antegrade cerebral perfusion (ACP) is the most widely used cerebral protection strategy for complex aortic repair and includes unilateral (u-ACP) and bilateral (b-ACP) techniques. The superiority of b-ACP over u-ACP has been the subject of much debate. Focusing on type A aortic dissection requiring total arch replacement, we investigated the clinical effects of b-ACP versus u-ACP. METHODS: Between September 2006 and August 2014, 203 patients presenting with type A aortic dissection (median age, 51.0 ± 13 years; range, 17-72 years; 128 males) underwent total aortic arch replacement with hypothermic circulatory arrest. ACP was used in all patients, including u-ACP in 82 (40.3%) and b-ACP in 121 (59.7%). RESULTS: There was no significant difference between the u-ACP and b-ACP groups in terms of cardiopulmonary bypass (CPB) time, cross-clamp time, or circulatory arrest time. Overall 30-day mortality was comparable in the 2 groups (11.6% for b-ACP vs 20.7% for u-ACP; P = .075). The prevalence of postoperative permanent neurologic dysfunction (PND) was comparable as well (8.4% vs 16.9%; P = .091). Mean ventilation time was lower in the b-ACP group (95.5 ± 45.25 hours vs 147.0 ± 82 hours; P < .001). Mean lengths of stay in the intensive care unit and the hospital overall were comparable in the 2 groups (intensive care unit: 16 ± 17.75 days vs 17 ± 11.5 days, P = .454; hospital: 26.5 ± 20.6 days vs 24.8 ± 10.3 days, P = .434). The P values from logistic regression models indicated that in the 2 groups combined, CPB time and circulatory arrest time were independent risk factors for both mortality and PND. CONCLUSIONS: In this, the first published study focusing on the efficacy of u-ACP and b-ACP in total arch replacement for type A aortic dissection, the b-ACP group did not demonstrate significantly lower 30-day mortality or PND rate compared with the u-ACP group. Future large-sample studies are warranted to thoroughly examine this critical issue.

Endothelial deletion of mTORC1 protects against hindlimb ischemia in diabetic mice via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation.

Peripheral arterial disease (PAD) complicated with diabetes mellitus (DM) still remains a thorny issue due to lack of effective strategies. Our previous study has demonstrated that inhibition of mTORC1 protected adipose-derived stromal cells from hindlimb ischemic injury in PAD mice. However, whether inhibition of mTORC1 could protect against PAD in diabetes mellitus and the underlying mechanisms remained elusive. In this study, we employed endothelial-specific raptor (an essential component of the mTORC1 signaling complex) knockout (KO) mice (Tie2-mTORC1ko) to investigate whether and how mTORC1 downregulation could alleviate hindlimb ischemic injury in diabetic mice. Tie2-mTORC1ko mice and their wild-type littermates were intraperitoneally injected with streptozocin to induce type 1 diabetic model, after which the hyperglycemic mice were randomly allocated to sham operation or PAD operation (femoral artery ligation). The restoration of hindlimb blood perfusion and recovery of limb functions were improved in diabetic Tie2-mTORC1ko PAD mice with significant improvements of autophagy, angiogenesis and vascular integrity as well as attenuation of apoptosis, inflammation and oxidative stress. In vitro, high glucose combining with hypoxia/serum deprivation treatment (HG+H/SD) significantly triggered apoptosis, reactive oxygen species generation and inflammation while inhibited autophagy and tube formation in HUVECs. The effect could be accentuated and attenuated by mTORC1 over-expression (TSC2 siRNA) and mTORC1 silencing (raptor siRNA), respectively. Moreover, autophagy inhibitor 3-MA could simulate the effects of TSC2 siRNA while autophagy inducer rapamycin could mimic the effects of raptor siRNA, suggesting that the beneficial effects of mTORC1 deletion were associated with autophagy induction. In conclusion, our present study demonstrates that endothelial mTORC1 deletion protects against hindlimb ischemic injury in diabetic mice possibly via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation. Therapeutics targeting mTORC1 may therefore represents a promising strategy to rescue limb ischemia in diabetes mellitus.