Outcomes of surgery for acute type A dissection in octogenarians versus non-octogenarians: a systematic review and meta analysis.

INTRODUCTION: Acute Type A Aortic Dissection (ATAAD) is a cardiothoracic emergency that requires urgent intervention. Elderly status, particularly age over 80, is an independent risk factor for mortality and morbidity. The mid-term outcomes of this age group are also unknown. This systematic review and meta-analysis of observational studies was therefore performed to analyse short- and mid-term mortality and morbidity in octogenarians following surgery for ATAAD. METHODS: A systematic review was conducted for studies published since January 2000. The primary endpoint was short-term mortality, either reported as 30-day mortality or in-hospital mortality and medium-term (five year) survival. Secondary endpoints were rates of postoperative complications, namely stroke, acute renal failure (ARF), re-exploration and intensive care unit (ICU) length of stay (LOS). RESULTS: A total of 16 retrospective studies, with a total of 16, 641 patients were included in the systematic review and meta-analysis. Pooled analysis demonstrated that octogenarian cohorts are at significantly higher risk of short-term mortality than non-octogenarians (OR 1.93; 95% CI 1.33-2.81; P < 0.001). Actuarial survival was significantly lower in the octogenarian cohort, with a five-year survival in the octogenarian cohort of 54% compared to 76% in the non-octogenarian cohort (P < 0.001). There were no significant differences between the cohorts in terms of secondary outcomes: stroke, ARF, re-exploration or ICU LOS. CONCLUSION: Octogenarians are twice as likely to die in the short-term following surgery for ATAAD and demonstrate a significantly lower five-year actuarial survival. Patients and family members should be well informed of the risks of surgery and suitable octogenarians selected for surgery.

A Novel Knitted Polytetrafluoroethylene Patch for Cardiovascular Surgery.

Polytetrafluoroethylene (PTFE) is widely used in cardiovascular surgeries; however, postoperative complications such as thrombosis, calcification, and neointimal hyperplasia are yet to be resolved in patients. We developed two types of novel knitted PTFE patches and evaluated them using a swine model. Both patches were composed of knitted PTFE impregnated with micro-PTFE particles, and one of them was pressed after PTFE impregnation. Twenty micromini pigs were used in this study. After left lateral thoracotomy, the new patches (n = 8 for each type of patch) were implanted into the descending aorta and left atrium for the high- and low-pressure models, respectively. Clinically used expanded PTFE (ePTFE) patches were used as the control material (n = 4). The patches were explanted and histopathologically examined at 4, 12, and 24 weeks after implantation. A tensile test was also applied to the high-pressure model at 12 and 24 weeks. As a result, there was no significant difference noted in the tensile test, intimal hyperplasia thickness, or endothelialization among the three patches. In contrast, the degree of macrophage infiltration into the patches and the degree of macrophage, lymphocyte, and granulocyte infiltration outside the patches were lower in the new patches than in the control ePTFE. The degree of cellular infiltration outside new patches decreased over time. There were no significant differences between the two new patch types in these results. In conclusion, our novel knitted PTFE patch showed noninferiority in durability and intensity and less inflammatory responses than a clinically used ePTFE patch.

Impact of Complete Revascularization on Long-Term Outcomes After Coronary Artery Bypass Grafting in Patients With Left Ventricular Dysfunction.

BACKGROUND: The long-term outcomes of complete revascularization (CR) in patients with left ventricular (LV) dysfunction undergoing coronary artery bypass grafting (CABG) remain unclear. Methods and Results: We evaluated a consecutive series of 111 patients with LV ejection fraction ≤35% who underwent isolated first-time CABG: 63 underwent CR and 48 underwent incomplete revascularization (IR). At a median follow-up of 10.1 years, the rates of death from any cause, cardiac death, and major adverse cardiac and cerebrovascular events (MACCE) were significantly greater in the IR group. After adjusting for propensity score, no significant difference was found between the CR and IR groups regarding death from any cause (hazard ratio [HR], 1.45; 95% CI: 0.75-2.81; P=0.271) and cardiac death (HR, 1.45; 95% CI: 0.68-3.10; P=0.337). In contrast, IR increased the risk of MACCE (HR, 1.92; 95% CI: 1.08-3.41; P=0.027), which was principally attributed to an increased risk of repeat revascularization (HR, 3.92; 95% CI: 1.34-11.44; P=0.013). CONCLUSIONS: Although IR was not significantly associated with an increased risk of long-term mortality in patients with LV dysfunction who underwent CABG, CR might reduce the risks of repeat revascularization and subsequent MACCE.

Specific autophagy and ESCRT components participate in the unconventional secretion of CFTR.

The most common mutation in cystic fibrosis patients is a phenylalanine deletion at position 508 (ΔF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This mutation impairs cell-surface trafficking of CFTR. During cellular stress, core-glycosylated CFTRΔF508 is transported to the cell surface from the endoplasmic reticulum (ER) via an unconventional route that bypasses the Golgi. However, the mechanisms for this unconventional secretory pathway of CFTR are not well delineated. Here, we report that components of the macroautophagy/autophagy and ESCRT (endosomal sorting complex required for transport) pathways are involved in unconventional secretion of CFTR. In mammalian cells, we found that autophagic pathways were modulated by conditions that also stimulate unconventional secretion, namely ER stress and an ER-to-Golgi transport blockade. Additionally, we found that knockdown of early autophagy components, ATG5 and ATG7, and treatment with pharmacological autophagy inhibitors, wortmannin and 3-methyladenine, abolished the unconventional secretion of CFTR that had been stimulated by ER stress and an ER-to-Golgi blockade. Interestingly, immunoelectron microscopy revealed that GORASP2/GRASP55, which mediates unconventional CFTR trafficking, is present in multivesicular bodies (MVB) and autophagosomal structures under ER stress conditions. A custom small-interfering RNA screen of mammalian ESCRT proteins that mediate MVB biogenesis showed that silencing of some ESCRTs, including MVB12B, inhibited unconventional CFTRΔF508 secretion. Furthermore, MVB12B overexpression partially rescued cell-surface expression and Cl- channel function of CFTRΔF508. Taken together, these results suggest that components involved in early autophagosome formation and the ESCRT/MVB pathway play a key role in the stress-induced unconventional secretion of CFTR.

Effectiveness and long-term outcomes of surgical intervention for constrictive epicardium in constrictive pericarditis.

OBJECTIVE: Epicardial resection is considered effective in patients with constrictive pericarditis accompanied by epicardial constriction, but few publications have evaluated its long-term outcomes. The study objective was to evaluate early and late results of epicardial resection. METHODS: A total of 22 patients with pericardiectomy for constrictive pericarditis were treated at our institution between 1989 and 2016. They were stratified by the presence or absence of constrictive epicardium and the surgical intervention performed. Group A (n = 7) included those with constrictive epicardium and epicardial resection in addition to pericardiectomy. Group B (n = 5) included those with constrictive epicardium and single pericardiectomy. Group C (n = 10) included those without constrictive epicardium and with a single pericardiectomy. Postsurgical changes were evaluated by echocardiography. RESULTS: No significant differences were found in preoperative baseline characteristics, operative details, and operative mortality among the groups. The median postoperative follow-up was 80 months. Group A patients did not experience cardiac events, and left ventricular end-diastolic volume and stroke volume were significantly improved at late follow-up compared with before and soon after surgery. The early postsurgical parameters were significantly improved in Group C patients, but the improvements were attenuated on late follow-up. Group B patients had the highest occurrence of cardiac events and no improvement in echocardiographic parameters. CONCLUSION: Surgical intervention in constrictive epicardium improved echocardiographic parameters and was free of cardiac events during long-term follow-up.

Surgical Treatment of Coronary to Pulmonary Artery Fistulas in Adults.

Coronary to pulmonary artery fistulas (CPAFs) are abnormal communications between the coronary and pulmonary arteries. They are an uncommon congenital heart disease and usually remain asymptomatic until later in life. However, there is no consensus on their management. We present four adult patients who required surgery for coronary to pulmonary artery fistulas to illuminate this issue. The clinical presentations were variable depending on the anatomical features of coronary to pulmonary artery fistulas and the presence or absence of other cardiac diseases. We successfully performed surgical closure of the coronary to pulmonary artery fistulas in each of the cases. In this report, we describe our experience with these cases and outline the available therapeutic strategies and treatment options for coronary to pulmonary artery fistulas.

[Coronary-pulmonary Artery Fistula in a Hemodialysis Patient].

We report a case of coronary-pulmonary artery fistula in a hemodialysis patient treated surgically. A 47-year-old man was admitted with chest pain and exertional dyspnea that progressively worsened over the previous 2 months. He had a history of end-stage renal disease and has been on hemodialysis for 5 years. Coronary angiography and computed tomography revealed coronary-pulmonary artery fistula that originated from both the left anterior descending coronary artery and the right coronary artery. Under cardiopulmonary bypass, we opened the pulmonary artery and closed the fistula. The symptoms of the patient improved after the surgery, and he was discharged without major complications. Coronary-pulmonary artery fistulas in hemodialysis patients are rare. The presence of additional arteriovenous fistula used for dialysis in these patients increases the left-to-right shunt flow and might cause progression of heart failure. Even if the left-to-right shunt volume is small, surgical treatment is highly recommended at an early stage of the coronary-pulmonary artery fistula in hemodialysis patients.

[Unroofed Coronary Sinus in an Adult; Report of a Case].

Unroofed coronary sinus( UCS) is a rare cardiac anomaly and the most uncommon type of atrial septal defect. It is rarely diagnosed by only echocardiography prior to surgery. We herein report a case of UCS (partially unroofed terminal portion) without persistent left superior vena cava that was precisely diagnosed by cardiac multi-detector low computed tomography (MDCT). A 50-year-old asymptomatic man was admitted for cardiac evaluation. A transesophageal echocardiography showed a left to right shunt at the atrial level. MDCT clearly showed a defect in the coronary sinus and lower part of the interatrial septum. At the time of surgery, the defect was closed using a Gore-Tex patch, such that the coronary sinus drained entirely into the left atrium. The postoperative course was uneventful. Cardiac MDCT provides accurate anatomic details about defects as well as the associated anomalies of the heart and pulmonary vasculature.

O-GlcNAc modification is essential for the regulation of autophagy in Drosophila melanogaster.

O-GlcNAcylation is a dynamic post-translational modification that takes place on ser/thr residues of nucleocytoplasmic proteins. O-GlcNAcylation regulates almost all cellular events as a nutrient sensor, a transcriptional and translational regulator, and a disease-related factor. Although the role of O-GlcNAcylation in insulin signaling and metabolism are well established, the relationship between O-GlcNAcylation and autophagy is largely unknown. Here, we manipulated O-GlcNAcylation in Drosophila and found that it regulates autophagy through Akt/dFOXO signaling. We demonstrate that O-GlcNAcylation and the levels of O-GlcNAc transferase (OGT) are increased during starvation. Furthermore, Atg proteins and autolysosomes are increased in OGT-reduced flies without fasting. Atg proteins and autophagosomes are reduced in OGT-overexpressing flies. Our results suggest that not only autophagy gene expression but also autophagic structures are regulated by OGT through Akt and dFOXO. These data imply that O-GlcNAcylation is important in modulating autophagy as well as insulin signaling in Drosophila.

Coronary artery spasm following off-pump coronary artery bypass surgery.

Coronary artery spasm after coronary artery bypass surgery may result in life-threatening arrhythmias, circulatory collapse, or death. We report two cases of coronary artery spasm after coronary artery bypass surgery, one of which developed ventricular fibrillation requiring extracorporeal membrane oxygenation support. Both patients were discharged in good condition and are currently followed as outpatients. Unexpected sudden hemodynamic compromise could be due to coronary vasospasm, and this should be considered as one of the possible differential diagnoses. We were able to prevent the lethal consequences seen with coronary artery spasm by early diagnosis and management.

ERADication of EDEM1 occurs by selective autophagy and requires deglycosylation by cytoplasmic peptide N-glycanase.

ER degradation-enhancing α-mannosidase-like 1 protein (EDEM1) is involved in the routing of misfolded glycoproteins for degradation in the cytoplasm. Previously, we reported that EDEM1 leaves the endoplasmic reticulum via non-COPII vesicles (Zuber et al. in Proc Natl Acad Sci USA 104:4407-4412, 2007) and becomes degraded by basal autophagy (Le Fourn et al. in Cell Mol Life Sci 66:1434-1445, 2009). However, it is unknown which type of autophagy is involved. Likewise, how EDEM1 is targeted to autophagosomes remains elusive. We now show that EDEM1 is degraded by selective autophagy. It colocalizes with the selective autophagy cargo receptors p62/SQSTM1, neighbor of BRCA1 gene 1 (NBR1) and autophagy-linked FYVE (Alfy) protein, and becomes engulfed by autophagic isolation membranes. The interaction with p62/SQSTM1 and NBR1 is required for routing of EDEM1 to autophagosomes since it can be blocked by short inhibitory RNA knockdown of the cargo receptors. Furthermore, p62/SQSTM1 interacts only with deglycosylated EDEM1 that is also ubiquitinated. The deglycosylation of EDEM1 occurs by the cytosolic peptide N-glycanase and is a prerequisite for interaction and aggregate formation with p62/SQSTM1 as demonstrated by the effect of peptide N-glycanase inhibitors on the formation of protein aggregates. Conversely, aggregation of p62/SQSTM1 and EDEM1 occurs independent of cytoplasmic histone deacetylase. These data provide novel insight into the mechanism of autophagic degradation of the ER-associated protein degradation (ERAD) component EDEM1 and disclose hitherto unknown parallels with the clearance of cytoplasmic aggregates of misfolded proteins by selective autophagy.

Intraoperative assessment for mitral valve competency in a beating heart under retrograde coronary perfusion.

Intraoperative assessment of a repaired mitral valve is of paramount importance for reparative mitral surgery. From September 2010 through November 2012, 20 consecutive patients underwent mitral valve plasty for mitral regurgitation. The patients who underwent surgery after June 2012 received assessment of the repair with the heart beating (HB group, n = 10), and the patients who underwent the operation before May 2012 were assessed for the repair only under cardioplegic heart arrest (non-HB group, n = 10). Intermittent cold retrograde blood cardioplegia was used in all patients. In the HB-group, after completion of the procedures, pump blood without a crystalloid additive was delivered into the coronary sinus. The function of the mitral valve was assessed under beating conditions. There were no differences between the two groups in aortic cross clamp time and operation time, although operative and concomitant procedures were slightly more complicated in the HB group than in the non-HB group. Postoperative echocardiography revealed none or mild mitral regurgitation in all the patients in both groups. Reopening of the closed left atrium for additional repair was necessary only in one patient in the HB group and 3 patients in the non-HB group. In conclusion, the method of perfusing the myocardium retrogradely via the coronary sinus with warm blood is safe and effective for assessing the competency of the mitral valve in a beating heart.

Large protein complexes retained in the ER are dislocated by non-COPII vesicles and degraded by selective autophagy.

Multisubunit protein complexes are assembled in the endoplasmic reticulum (ER). Existing pools of single subunits and assembly intermediates ensure the efficient and rapid formation of complete complexes. While being kinetically beneficial, surplus components must be eliminated to prevent potentially harmful accumulation in the ER. Surplus single chains are cleared by the ubiquitin-proteasome system. However, the fate of not secreted assembly intermediates of multisubunit proteins remains elusive. Here we show by high-resolution double-label confocal immunofluorescence and immunogold electron microscopy that naturally occurring surplus fibrinogen Aα-γ assembly intermediates in HepG2 cells are dislocated together with EDEM1 from the ER to the cytoplasm in ER-derived vesicles not corresponding to COPII-coated vesicles originating from the transitional ER. This route corresponds to the novel ER exit path we have previously identified for EDEM1 (Zuber et al. Proc Natl Acad Sci USA 104:4407-4412, 2007). In the cytoplasm, detergent-insoluble aggregates of fibrinogen Aα-γ dimers develop that are targeted by the selective autophagy cargo receptors p62/SQSTM1 and NBR1. These aggregates are degraded by selective autophagy as directly demonstrated by high-resolution microscopy as well as biochemical analysis and inhibition of autophagy by siRNA and kinase inhibitors. Our findings demonstrate that different pathways exist in parallel for ER-to-cytoplasm dislocation and subsequent proteolytic degradation of large luminal protein complexes and of surplus luminal single-chain proteins. This implies that ER-associated protein degradation (ERAD) has a broader function in ER proteostasis and is not limited to the elimination of misfolded glycoproteins.

Effect of globular adiponectin on interleukin-6 and interleukin-8 expression in periodontal ligament and gingival fibroblasts.

PURPOSE: Globular adiponectin (gAd) is a type of adipocytokine, which is mainly produced by adipose tissue. It has been reported that gAd acts as a pro- as well as an anti-inflammatory factor. Interleukin (IL)-6 and IL-8 are pro-inflammatory cytokines. To investigate the role of gAd on periodontal tissues, the expression of adiponectin receptor 1 (AdipoR1) and the effect of gAd on the expression of IL-6 and IL-8 were investigated in periodontal ligament (PDL) and gingival fibroblasts. METHODS: PDL and gingival fibroblasts were cultured from human periodontal tissues. gAd derived from Escherichia coli and murine myeloma cells were used. The expression of AdipoR1 was estimated by reverse transcription-polymerase chain reaction and western blot. The expression of cytokines was measured by enzyme-linked immunosorbent assay. RESULTS: PDL and gingival fibroblasts expressed both mRNA and protein of AdipoR1. gAd derived from E. coli increased the production of IL-6 and IL-8, but polymyxin B, an inhibitor of lipopolysaccharide (LPS), inhibited IL-6 and IL-8 production induced by gAd in both types of cells. gAd derived from murine myeloma cells did not induce IL-6 and IL-8 production in those cells. gAd derived from E. coli contained higher levels of LPS than gAd derived from murine myeloma cells. LPS increased production of IL-6 and IL-8 in PDL and gingival fibroblasts, but pretreatment of cells with gAd derived from murine myeloma cells did not inhibit LPS-induced IL-6 and IL-8 expression. CONCLUSIONS: Our results suggest that PDL and gingival fibroblasts express AdipoR1 and that gAd does not act as a modulator of IL-6 and IL-8 expression in PDL and gingival fibroblasts.