Mid-term outcomes of surgical aortic valve replacement using a mosaic porcine bioprosthesis with concomitant mitral valve repair.

This study retrospectively evaluated the mid-term outcomes of surgical aortic valve replacement (SAVR) using a stented porcine aortic valve bioprosthesis (Mosaic; Medtronic Inc., Minneapolis, MN, USA) with concomitant mitral valve (MV) repair. From 1999 to 2014, 157 patients (median [interquartile range] age, 75 [70-79] years; 47% women) underwent SAVR with concomitant MV repair (SAVR + MV repair), and 1045 patients (median [interquartile range] age, 76 [70-80] years; 54% women) underwent SAVR only at 10 centers in Japan as part of the long-term multicenter Japan Mosaic valve (J-MOVE) study. The 5-year overall survival rate was 81.5% ± 4.1% in the SAVR + MV repair group and 85.1% ± 1.4% in the SAVR only group, and the 8-year overall survival rates were 75.2% ± 5.7% and 78.1% ± 2.1%, respectively. Cox proportional hazards analysis showed no significant difference in the survival rates between the two groups (hazard ratio, 0.87; 95% confidence interval, 0.54-1.40; P = 0.576). Among women with mild or moderate mitral regurgitation who were not receiving dialysis, those who underwent SAVR + MV repair, were aged > 75 years, and had a preoperative left ventricular ejection fraction of 30-75% tended to have a lower mortality risk. In conclusion, this subgroup analysis of the J-MOVE cohort showed relevant mid-term outcomes after SAVR + MV repair.

Prevalence of bleeding events in real-world Japanese registry for Percutaneous Ventricular Assist Device.

PURPOSE: Bleeding complication is a critical risk factor for outcomes of acute heart failure patients requiring mechanical circulatory support (MCS), including percutaneous catheter-type heart pumps (Impella). The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) is an ongoing, large-scale, real-world registry to characterize Japanese patients requiring Impella. Here we analyzed bleeding complication profiles in patients who received Impella. METHODS: All consecutive Japanese patients who received Impella from October 2017 to January 2020 were enrolled. The 30-day survival and bleeding complications were analyzed. RESULTS: A total of 1344 patients were included: 653 patients received Impella alone, 685 patients received a combination of veno-arterial extracorporeal membrane oxygenation and Impella (ECPELLA), and 6 patients had failed Impella delivery. Overall 30-day survival was 67.0%, with Impella alone at 81.9% and ECPELLA at 52.7%. Overall bleeding/hematoma adverse events with a relation or not-excluded relation to Impella was 6.92%. Among them, the rates of hematoma and bleeding from medical device access sites were 1.41% and 4.09%, respectively. There was no difference between etiologies for these events. CONCLUSION: This study represents the first 3-year survival and the safety profile focused on bleeding adverse events from the J-PVAD registry. The results show that the real-world frequency of bleeding adverse events for patients who received Impella was an expected range from previous reports, and future real-world studies should aim to expand this data set to improve outcomes and adverse events.

Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes.

Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition of desmosome proteins, disrupted intercalated disk structures in the myocardium. Induced pluripotent stem cells (iPSCs) were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). Both isogenic iPSCs were differentiated into cardiomyocytes [induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)]. Multielectrode array analysis detected abnormal excitation in R119X-iPSC-CMs but not in HDR-iPSC-CMs. Micro-force testing of three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. Notably, these phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and electron microscopic analysis confirmed that desmosomes were disrupted in these cells. Unexpectedly, the absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2 but no other desmosome proteins. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs. Our findings confirm the presence of a desmoglein-2-deficient cardiomyopathy among clinically diagnosed dilated cardiomyopathies. Recapitulation and correction of the disease phenotype using iPSC-CMs provide evidence to support the development of precision medicine and the proof of concept for gene replacement therapy for this cardiomyopathy.

Effectiveness of Proximal Landing Zone 1 and 2 Thoracic Endovascular Aortic Repair for Type B Aortic Dissection by Comparing Outcomes With Thoracic Arch Aneurysm.

PURPOSE: Hybrid thoracic endovascular aortic repair (TEVAR) for aortic arch aneurysms is a minimally invasive procedure with improved results. This study aimed to clarify the effectiveness and expand the possibilities of zone 1 and 2 landing TEVAR for type B aortic dissection (TBAD) using our treatment strategy. METHODS: This retrospective, single-center, observational cohort study included 213 patients (TBAD, n=69; thoracic arch aneurysm [TAA], n=144; median age, 72 years; median follow-up period, 6 years) from May 2008 to February 2020. The following conditions were satisfied before performing zone 1 and 2 landing TEVAR: TBAD; proximal landing zone (LZ): diameter <37 mm, length >15 mm, and nondissection area, proximal stent-graft: size ≤40 mm and oversizing rate: 10% to 20%, and TAA; proximal LZ: diameter ≤42 mm and length >15 mm, proximal stent-graft: size ≤46 mm and oversizing rate: 10% to 20%. Of the 69 patients in the TBAD group, 34 (49.3%) had patent false lumen (PFL), and 35 (50.7%) had false lumen partial thrombosis (FLPT), including ulcer-like projections. Emergency procedures were performed in 33 (15.5%) patients. RESULTS: There were no significant differences in the in-hospital mortality (TBAD: 1.5% vs TAA: 0.7%, p=0.544) or the in-hospital aortic complications (TBAD: n=1 vs TAA: n=5, p=0.666). Retrograde type A dissection was not observed in the TBAD group. The aortic event-free rates at 10 years were 89.7% (95% confidence interval [CI]: 78.7%-95.3%) and 87.9% (95% CI: 80.3%-92.8%) in the TBAD and TAA groups, respectively (log-rank p=0.636). In the TBAD group, the early and late outcomes were not significantly different between the PFL and FLPT groups. CONCLUSION: Satisfactory early and long-term results were obtained with zone 1 and 2 landing TEVAR. The TBAD cases had the same good results as the TAA cases. Using our strategy, we especially might reduce complications and be an effective treatment for acute complicated TBAD. CLINICAL IMPACT: This study aimed to clarify the effectiveness and expand the possibilities of zones 1 and 2 landing TEVAR for type B aortic dissection (TBAD) using our treatment strategy. Satisfactory early and long-term results in the TBAD and thoracic arch aneurysm (TAA) groups were obtained with zones 1 and 2 landing TEVAR. The TBAD cases had the same good results as the TAA cases. Using our strategy, we especially might reduce complications and be an effective treatment for acute complicated TBAD.

The Efficacy of Second-Stage Endovascular Repair Strategy for Acute Type A Aortic Dissection.

PURPOSE: To evaluate the usefulness of a hybrid treatment strategy for acute type A aortic dissection (AAAD). METHODS: We retrospectively evaluated the outcomes of 39 partial arch replacements (PAR; 26 male/13 female, mean age=67.9 years) in 62 patients with AAAD operated at our hospital from January 2019 to January 2023. The technique included PAR with graft-designed landing length and translocated the brachiocephalic artery inflow site during the initial surgery to minimize the invasiveness of the surgery. Thereafter, second-stage thoracic endovascular aortic repair (second TEVAR) for distal aortic events in the chronic phase was performed. RESULTS: There was 1 case of 30-day mortality (2.6%) and 2 cases of postprocedural cerebral infarction (5.1%). The cumulative survival rates were 97.4%/1 year and 97.4%/3 years. The cumulative freedom from aorta-related second-stage procedure for the distal aortic event after initial PAR, which was performed in 13 patients (33.3%), was 63.9%/1 year and 59.7%/3 years. All patients requiring re-intervention after initial PAR underwent a second TEVAR with a 100% success rate and no postoperative complications. CONCLUSION: Initial PAR for AAAD in anticipation of the second TEVAR is a valuable strategy for enabling minimally invasive additional treatment of aorta-related re-intervention for distal aortic events in the chronic phase. CLINICAL IMPACT: This study provides detailed information on the hybrid aortic repair strategy of the initial open partial arch repair and second staged endovascular repair for the acute type A aortic dissection. Based on this study, distal aortic re-intervention after initial open partial arch repair was necessary only in about 30% of cases, and no cases of SCI were observed in the initial treatment or in the second-stage endovascular repair and no cases of distal SINE were observed after the second staged endovascular repair. Overall, the results suggest that limiting the initial open partial arch repair can achieve good perioperative and early outcomes of initial surgery, and that second staged endovascular re-intervention for distal aortic events can be performed reliably, safely, and with minimal invasiveness.

Clinical and Economic Evaluation of Impella Treatment for Fulminant Myocarditis　- A Preliminary Retrospective Cohort Study in Japan.

BACKGROUND: Fulminant myocarditis (FM) is rare but has an extremely poor prognosis. Impella, a catheter-based heart pump, is a new therapeutic strategy, but reports regarding its health economics are lacking.Methods and Results: This retrospective cohort study compared Impella treatment (Group I) with existing treatments (Group E) using medical data collected from October 2017 to September 2021, with a 1-year analysis period. Cost-effectiveness indices were life-years (LY; effect index) and medical fee amount (cost index). Results were validated using probabilistic sensitivity analysis. The incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted LY (QALY) and medical costs. Each group included 7 patients, and more than half (57.1%) received combined Impella plus extracorporeal membrane oxygenation. There was no significant difference between Groups I and E in 1-year mortality rates (28.6% vs. 57.1%, respectively) or LY (mean [±SD] 163.1±128.3 vs. 107.8±127.3 days, respectively), but mortality risk was significantly lower in Group I than Group E (95% confidence interval 0.02-0.96; P<0.05). Compared with Group E, Group I had higher total costs (9,270,597±4,121,875 vs. 6,397,466±3,801,364 JPY/year; P=0.20) and higher cost-effectiveness (32,443,987±14,742,966 vs. 92,637,756±98,225,604 JPY/LY; P=0.74), which was confirmed in the sensitivity analysis. ICER probability distribution showed 23.2% and 51.5% reductions below 5 million and 10 million JPY/QALY, respectively. CONCLUSIONS: Impella treatment is more cost-effective than conventional FM treatments. Large-scale studies are needed to validate the added effects and increasing costs.

Prognosis of Patients With Heart Failure Receiving Autologous Myoblast Patches　- Comparison of Single-Arm Trial Data to Registry Data.

BACKGROUND: Clinical studies in regenerative medicine remain insufficient in Japan due to ethical concerns regarding the control group and a lack of statistical methodology to evaluate efficacy in a small treatment group. This study evaluated the efficacy of autologous myoblast patch (AMP) treatment for heart failure using restricted mean survival time (RMST) analysis by comparing data from a small single-arm trial to epidemiological data from a registry.Methods and Results: The clinical trial arm included 55 patients with advanced ischemic cardiomyopathy who received an AMP between 2010 and 2020. The registry-based control group comprised 937 participants with severely impaired left ventricular function who were hospitalized for heart failure during the study period. Due to the limited number of patients, RMST analysis was used to compare survival between the 2 groups. Cox regression analyses revealed non-significant differences in survival between the groups at 3, 3.5, and 4 years. In contrast, RMST analyses revealed significant differences in survival at 3 years (P=0.008) and 3.5 (P=0.024) years, but not at 4 years. CONCLUSIONS: This small single-arm trial using RMST analyses was able to detect the efficacy of AMP transplantation for advanced heart failure (compared with a registry-based control group), with better survival until 3.5 years. This approach may be useful for efficacy analyses in regenerative medicine, where traditional clinical trials are difficult.

Regenerative Effect of Umbilical Cord-Derived Mesenchymal Stromal Cells in a Rat Model of Established Limb Ischemia.

BACKGROUND: Although regenerative cell therapy is expected to be an alternative treatment for peripheral artery disease (PAD), many regenerative cell therapies have failed to show sufficient efficacy in clinical trials. Most preclinical studies have used acute ischemia models, despite PAD being a chronic disease. In addition, aging and atherosclerosis decrease the quality of a patient's stem cells. Therefore, using a non-acute ischemic preclinical model and stem cells with high regenerative potency are important for the development of effective regenerative therapy. In this study, we assessed the tissue regenerative potential of umbilical cord-derived mesenchymal stromal cells (UCMSCs), which could potentially be an ideal cell source, in a rat model of established ischemia.Methods and Results: The regenerative capacity of UCMSCs was analyzed in terms of angiogenesis and muscle regeneration. In vitro analysis showed that UCMSCs secrete high amounts of cytokines associated with angiogenesis and muscle regeneration. In vivo experiments in a rat non-acute ischemia model showed significant improvement in blood perfusion after intravenous injection of UCMSCs compared with injection of culture medium or saline. Histological analysis revealed UCMSCs injection enhanced angiogenesis, with an increased number of von Willebrand factor-positive microcapillaries, and improved muscle regeneration. CONCLUSIONS: These results suggest that intravenous administration of UCMSCs may be useful for treating patients with PAD.

Short-Term Outcomes of Impella Support in Japanese Patients With Cardiogenic Shock Due to Acute Myocardial Infarction　- Japanese Registry for Percutaneous Ventricular Assist Device (J-PVAD).

BACKGROUND: The Impella®percutaneous left ventricular assist device has been available in Japan since 2017. This is the first large-scale registry study to analyze the efficacy and safety of Impella in Japanese patients with acute myocardial infarction with cardiogenic shock (AMICS).Methods and Results: The Japanese registry for Percutaneous Ventricular Assist Device (J-PVAD) has registered all consecutive Japanese patients treated with Impella. We extracted data for 593 AMICS patients from J-PVAD and analyzed 30-day survival and safety profiles. Overall 30-day survival was 63.1%. The 30-day survival of the Impella alone and Impella plus venoarterial extracorporeal membrane oxygenation (ECPELLA) groups was 80.9% and 45.7%, respectively. The Impella alone group was older and had a lower rate of cardiac arrest, milder consciousness disturbance, less inotrope use, lower serum lactate concentrations, higher B-type natriuretic peptide concentrations, and higher left ventricular ejection fraction (LVEF) than the ECPELLA group. Cox regression analysis revealed that older age and comorbid renal disturbance were common risk factors affecting 30-day mortality in both groups. Major adverse events were hemolysis (10.8%), hemorrhage/hematoma (7.6%), peripheral ischemia (4.4%), stroke (1.3%), and thrombosis (0.7%). LVEF improved in both groups during support. CONCLUSIONS: AMICS treatment with Impella showed favorable 30-day survival and safety profiles. The survival rate of patients treated with Impella alone was particularly high. Further studies are needed to improve outcomes of patients with ECPELLA support.

Engineered clustered myoblast cell injection augments angiogenesis and muscle regeneration in peripheral artery disease.

The low survival rate of administered cells due to ischemic and inflammatory environments limits the efficacy of the current regenerative cell therapy in peripheral artery disease (PAD). This study aimed to develop a new method to enhance the efficacy of cell therapy in PAD using cell sheet technology. Clustered cells (CCs) from myoblast cell sheets obtained from C57/BL6 mice were administered into ischemic mouse muscles 7 days after induction of ischemia (defined as day 0). Control groups were administered with single myoblast cells (SCs) or saline. Cell survival, blood perfusion of the limb, angiogenesis, muscle regeneration, and inflammation status were evaluated. The survival of administered cells was markedly improved in CCs compared with SCs at days 7 and 28. CCs showed significantly improved blood perfusion, augmented angiogenesis with increased density of CD31+/α-smooth muscle actin+ arterioles, and accelerated muscle regeneration, along with the upregulation of associated genes. Additionally, inflammation status was well regulated by CCs administration. CCs administration increased the number of macrophages and then induced polarization into an anti-inflammatory phenotype (CD11c-/CD206+), along with the increased expression of genes associated with anti-inflammatory cytokines. Our findings suggest clinical potential of rescuing severely damaged limbs in PAD using CCs.

1-year outcomes of patients implanted with the Perceval sutureless valve: the Japanese post-marketing surveillance study.

Sutureless offers an alternative to standard valves in surgical aortic valve replacement (SAVR). We sought to confirm the efficacy and safety of the Perceval sutureless valve in Japanese patients. Prospective observational study of 204 patients who underwent SAVR with Perceval at 19 sites in Japan between March and December 2019. The primary outcomes were 30-day mortality and postoperative complications; the secondary outcome was all-cause mortality at 1 year. Efficacy outcomes were changed in New York Heart Association (NYHA) class, pressure gradients, effective orifice area (EOA), EOA indexed to body surface area (EOAi) and severity of aortic regurgitation. Mean age was 77.7 years, 62.7% were female. Procedural success rate was 99.0%. The median cross-clamp and cardiopulmonary bypass times were 68.0 and 108 min. Perceval size S and M were implanted in 95 (46.6%) and in 76 (37.3%) of patients, respectively. The 30-day and late mortality rate were 0.5% and 4.4%, while the new permanent pacemaker implantation rate was 4.4%. Mean pressure gradient was 13.0 mmHg at discharge, reaching 11.0 mmHg at 1 year; while the mean EOA was 1.5 cm2 at discharge remaining stable up to 1 year. No moderate or severe leakages were present at discharge or at 1 year. NYHA class improved by ≥ 1 level in 55.1% of the patients at discharge and in 69.4% of the patients at 1 year. 1-year outcomes of SAVR with the Perceval sutureless valve in Japanese patients were favorable. This valve offers a promising alternative to conventional biological AVR in this Japanese population.

Preoperative higher right ventricular stroke work index increases the risk of de novo aortic insufficiency after continuous-flow left ventricular assist device implantation.

During continuous-flow left ventricular assist device (CF-LVAD) support, hemodynamic shear stress causes a burden on aortic valve (AV) leaflets, leading to de novo aortic insufficiency (AI). This study investigated the influence of preoperative hemodynamic parameters on de novo AI in CF-LVAD recipients. We reviewed 125 patients who underwent CF-LVAD implantation without concomitant AV surgery between 2005 and 2018. De novo AI was defined as moderate or severe AI in those with none or trivial preoperative AI. During mean 30 ± 16 months of CF-LVAD support, de novo AI-free rate was 86% and 67% at 1 and 2 years, respectively. Multivariable analysis showed that higher right ventricular stroke work index (RVSWI) (hazard ratio, 1.12 /g/m2/beat; 95% confidence interval, 1.00-1.20; p = 0.047) and trivial grade AI (hazard ratio, 2.8; 95% confidence interval, 1.2-6.4; p = 0.020) were independent preoperative risk factors for de novo AI. The longitudinal analysis using generalized mixed effects model showed that higher RVSWI was associated with continuous AV closure after LVAD implantation (Odd ratio, 1.20/g/m2/beat; 95% confidence interval, 1.00-1.43 /g/m2/beat; p = 0.047). Right heart catheterization revealed that preoperative RVSWI was positively correlated with postoperative pump flow index in patients with continuously closed AV (r = 0.44, p = 0.04, n = 22). Preoperative higher RVSWI was a significant risk factor for de novo AI following CF-LVAD implantation. In patients with preserved right ventricular function, postoperative higher pump flow may affect AI development via hemodynamic stress on the AV.

Aortic thrombosis with visceral malperfusion during circulatory support with a combination of Impella and extracorporeal membrane oxygenation for postcardiotomy cardiogenic shock.

Although veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used to aid myocardial recovery in patients with postcardiotomy cardiogenic shock (PCCS), it has been associated with adverse effects. The combined use of VA-ECMO and Impella (ECPELLA) for PCCS, however, has been reported to be efficacious with few reports of thromboembolic events. We present a case of aortic thrombosis with visceral malperfusion during ECPELLA management for PCCS. We performed the Bentall procedure, mitral valve repair, tricuspid annuloplasty, and coronary artery bypass graft on a 73-year-old man admitted with congestive heart failure caused by annuloaortic ectasia, along with severe aortic and mitral regurgitation. VA-ECMO and Impella were required, since the cardiopulmonary bypass weaning was difficult. Impella was removed on postoperative day 4. On postoperative days 5 and 6, laboratory data showed worsening renal dysfunction, lactate levels, and acidosis. Contrast-enhanced computed tomography showed thrombosis in the celiac and superior mesenteric arteries. Aortic thrombectomy was performed. Hyperkalemia, caused by a reperfusion injury, resulted in ventricular fibrillation. Continuous hemodiafiltration improved the hyperkalemia. However, irreversible acidosis progressed, and the VA-ECMO flow rate could not be sustained. On postoperative day 7, the patient died. Perioperative use of Impella for PCCS may be effective in improving postoperative cardiac function. When sudden organ failure is observed after surgery, it is necessary to not only keep the exacerbation of cardiogenic shock in mind, but also the possibility of thrombosis.

Three-year experience of catheter-based micro-axial left ventricular assist device, Impella, in Japanese patients: the first interim analysis of Japan registry for percutaneous ventricular assist device (J-PVAD).

Catheter-based micro-axial ventricular assist device Impella® (Abiomed, Danvers, MA) has been used in Japanese patients with drug-refractory acute heart failure (AHF) since 2017. This is the first interim analysis of the ongoing Japan Registry for Percutaneous Ventricular Assist Device (J-PVAD) to investigate the safety and efficacy of Impella support. Between October 2017 and January 2020, 823 Japanese patients, who were treated with the Impella 2.5, CP, or 5.0 pump, were enrolled. The primary endpoints were safety profiles and cumulative 30-day survival. Among them, 44.8% of patients were acute myocardial infarction with cardiogenic shock. The Impella pumps were unable to implant in 4 patients. The Impella 2.5, CP, and 5.0 pumps were used in 72.4%, 6.2%, and 16.6%, respectively, and mean support duration was 8.1 ± 10.2 days. Combination use of Impella and venoarterial extracorporeal membrane oxygenation (VA-ECMO) was applied for 387 patients (47.3%). Pump stop occurred 22 patients (2.7%). Major adverse events included hemolysis (11.2%), hemorrhage/hematoma (6.1%), peripheral ischemia (1.6%), and stroke (1.6%). The overall 30-day survival was 62.2%. Survival of patients with single Impella support was significantly higher than patients with Impella combined with VA-ECMO support (81.1% vs 49.6%; p < 0.01), who had lower blood pressure, lower left ventricular ejection fraction, and higher degree of inotropic support. Results suggest that short-term outcome of Impella support for Japanese patients was favorable with acceptable safety profiles.

Postoperative cerebral infarction and arrhythmia after pulmonary lobectomy in Japan: a retrospective analysis of 77,060 cases in a national clinical database.

PURPOSE: To investigate the incidence of postoperative cerebral infarction after curative lobectomy, its association with the type of lobectomy, and how postoperative new-onset arrhythmia contributes to postoperative cerebral infarction. METHODS: The subjects of this analysis were 77,060 patients who underwent curative lobectomy for lung cancer between 2016 and 2018 according to the National Clinical Database. Incidences of postoperative cerebral infarction and postoperative new-onset arrhythmia were analyzed. Moreover, mediation analysis was performed to evaluate the causal pathway between postoperative new-onset arrhythmia and postoperative cerebral infarction. RESULTS: Postoperative cerebral infarction occurred in 110 (0.7%) patients after left upper lobectomy and in 85 (0.7%) patients after left lower lobectomy. Left upper lobectomy and left lower lobectomy were associated with a higher likelihood of postoperative cerebral infarction than right lower lobectomy. Left upper lobectomy was the strongest independent predictor of postoperative new-onset arrhythmia. However, in the mediation analysis, the odds ratio for cerebral infarction did not change after the addition of the factor of postoperative new-onset arrhythmia. CONCLUSION: Cerebral infarction occurred significantly more often not only after left upper lobectomy, but also after left lower lobectomy. Postoperative new-onset arrhythmia was less likely to be related to cerebral infarction after left upper lobectomy.

Yes-associated protein activation potentiates glycogen synthase kinase-3 inhibitor-induced proliferation of neonatal cardiomyocytes and iPS cell-derived cardiomyocytes.

Because mammalian cardiomyocytes largely cease to proliferate immediately after birth, the regenerative activity of the heart is limited. To date, much effort has been made to clarify the regulatory mechanism of cardiomyocyte proliferation because the amplification of cardiomyocytes could be a promising strategy for heart regenerative therapy. Recently, it was reported that the inhibition of glycogen synthase kinase (GSK)-3 promotes the proliferation of neonatal rat cardiomyocytes (NRCMs) and human iPS cell-derived cardiomyocytes (hiPSC-CMs). Additionally, Yes-associated protein (YAP) induces cardiomyocyte proliferation. The purpose of this study was to address the importance of YAP activity in cardiomyocyte proliferation induced by GSK-3 inhibitors (GSK-3Is) to develop a novel strategy for cardiomyocyte amplification. Immunofluorescent microscopic analysis using an anti-Ki-67 antibody demonstrated that the treatment of NRCMs with GSK-3Is, such as BIO and CHIR99021, increased the ratio of proliferative cardiomyocytes. YAP was localized in the nuclei of more than 95% of cardiomyocytes, either in the presence or absence of GSK-3Is, indicating that YAP was endogenously activated. GSK-3Is increased the expression of ß-catenin and promoted its translocation into the nucleus without influencing YAP activity. The knockdown of YAP using siRNA or pharmacological inhibition of YAP using verteporfin or CIL56 dramatically reduced GSK-3I-induced cardiomyocyte proliferation without suppressing ß-catenin activation. Interestingly, the inhibition of GSK-3 also induced the proliferation of hiPSC-CMs under sparse culture conditions, where YAP was constitutively activated. In contrast, under dense culture conditions, in which YAP activity was suppressed, the proliferative effects of GSK-3Is on hiPSC-CMs were not detected. Importantly, the activation of YAP by the knockdown of α-catenin restored the proproliferative activity of GSK-3Is. Collectively, YAP activation potentiates the GSK-3I-induced proliferation of cardiomyocytes. The blockade of GSK-3 in combination with YAP activation resulted in remarkable amplification of cardiomyocytes.

Comparison of the Outcomes of Total Endovascular Aortic Arch Repair Between Branched Endograft and Chimney Endograft Technique in Zone 0 Landing.

PURPOSE: Zone 0 landing in thoracic endovascular aortic repair (TEVAR) has recently gained increasing attention for the treatment of high-risk patients. The aim of this study was to compare the outcomes of total endovascular aortic arch repair between branched TEVAR (bTEVAR) and chimney TEVAR (cTEVAR) in the landing zone (LZ) 0. MATERIALS AND METHODS: This was a single-center, retrospective, and observational cohort study. From January 2010 to March 2020, 40 patients (bTEVAR, n=25; cTEVAR, n=15; median age: 79 years) were enrolled in this study, with a median follow-up period of 4.1 years. These patients were considered unsuitable for open surgical treatment. RESULTS: All procedures were successful and no cases of conversion to open repair were noted during the 30-day postoperative period. The 30-day mortality was 2.5% (n=1; bTEVAR [0 of 25, 0%] vs cTEVAR [1 of 15, 6.7%]; p=0.375), the perioperative stroke rate was 10.0% (n=4; bTEVAR [4 of 25, 16.0%] vs cTEVAR [0 of 15, 0%], p=0.278), and type 1a endoleak rate was 15.0% (n=6; bTEVAR [0 of 25, 0%] vs cTEVAR [6 of 15, 40.0%], p=0.001). The risk factor for stroke was atheroma grade of ≥2 in the brachiocephalic artery (p<0.001). The risk factor for type 1a endoleak was cTEVAR (p=0.001). The 8-year survival rate was 49.9%. The aorta-related death-free rate and aortic event-free rate at 8 years were 94.4% (bTEVAR: 95.5% vs cTEVAR: 93.3%, p=0.504) and 60.7% (bTEVAR: 70.7% vs cTEVAR: 40.0%, p=0.048), respectively. CONCLUSIONS: Total endovascular aortic arch repair using bTEVAR and cTEVAR is feasible for the treatment of aortic arch diseases in high-risk patients who are unsuitable for open surgery. However, as the rate of stroke is high, strict preoperative evaluation to prevent stroke is needed. No rupture of the aneurysm was observed in cTEVAR, but patients should be selected carefully because of the high incidence of type 1a endoleak.

Effectiveness of Proximal Landing Zones 0, 1, and 2 Hybrid Thoracic Endovascular Aortic Repair: A Single Centre 12 Year Experience.

OBJECTIVE: Hybrid thoracic endovascular aortic repair (TEVAR) is being accepted increasingly as a first line treatment for arch repair at the present authors' institution. This study aimed to clarify the effectiveness of zones 0, 1, and 2 landing hybrid TEVAR. METHODS: This was a retrospective single centre case series. From April 2008 to March 2020, 348 patients (median age 72 years; interquartile range [IQR] 65, 77 years) were enrolled, with a median follow up period of 5.6 years (IQR 2.6, 8.7 years). The procedures included zone 0 in 135 patients (38.8%), zone 1 in 82 patients (23.6%), and zone 2 proximal landing zone (LZ) hybrid TEVAR in 131 patients (37.6%). The pathologies consisted of dissecting aortic aneurysms in 123 (35.3%) patients. Emergency procedures were performed in 39 (11.2%) patients. RESULTS: The 30 day mortality (n = 2, 0.6%) and hospital deaths (n = 6, 1.7%) were registered. The stroke rate was 1.1% (n = 4), while early and late endoleak rates were 4.8% (n = 17) and 1.7% (n = 6), respectively. Type 1a endoleak and retrograde type A dissection occurred in seven (2.0%) and three (0.9%) patients, respectively. The cumulative survival, freedom from aorta related deaths, and freedom from aortic events in 10 years were 75.0%, 97.2%, and 84.1%, respectively. The freedom from aortic events in each landing zone in 10 years was 82.3%, 81.4%, and 87.9% for zones 0, 1, and 2, respectively. The 10 year survival rates were 82.5% and 73.6%; the 10 year aorta related death free rates were 94.9% and 98.6%, and the 10 year aortic event free rates were 82.3% and 85.5% in the zone 0 and zone 1 and 2 TEVAR, respectively. CONCLUSION: Satisfactory early and long term results of hybrid arch repair at zones 0, 1, and 2 were achieved. To avoid complications and aortic events, the treatment strategy of hybrid arch repair for aortic arch pathologies should be tailored using accurate pre-operative assessment of the ascending aorta and the aortic arch.

Effect of Diabetes Mellitus on Outcomes in Patients With Left Ventricular Assist Device　- Analysis of Data From a Japanese National Database.

BACKGROUND: The objective of this study is to investigate the effect of preoperative diabetes on all-cause mortality and major postoperative complications among patients with continuous-flow left ventricular assist device (LVAD) by using data from a national database.Methods and Results: The 545 study patients who underwent primary HeartMateII implantation between 2013 and 2019 were divided into 2 groups according to their diabetes mellitus (DM) status; patients with DM (n=116) and patients without DM (n=429). First, the on-device survival and incidence of adverse events were evaluated. Second, after adjusting for patients' backgrounds, the change of laboratory data in the 2 groups were compared. Overall, on-device survival at 1, 2, and 3 years was almost equivalent between the 2 groups; it was 95%, 94%, and 91% in patients without DM, and 93%, 91%m and 91% in patients with DM (P=0.468) The incidence of adverse events was similar between 2 groups of patients, except for driveline exit site infection in the adjusted cohort. Cox proportional hazards regression analysis revealed younger age (HR: 0.98 (95% confidence interval (CI): 0.97-0.99, P=0.001) and presence of DM (HR: 1.83 (95% CI: 1.14-2.88), P=0.016) as significant predictors of driveline infection. Laboratory findings revealed no differences between groups throughout the periods. CONCLUSIONS: The clinical results after LVAD implantation in DM patients were comparable with those in non-DM patients, except for the driveline exit site infection.

Long-Term Outcomes of the Mosaic Mitral Porcine Bioprosthesis in Japan　- Results From the Japan Mosaic Valve Long-Term Multicenter Study.

BACKGROUND: This study retrospectively evaluated the long-term patient outcomes and durability of the Mosaic mitral porcine bioprosthesis in the Japan Mosaic valve long-term multicenter study.Methods and Results:The medical records of 390 patients who underwent mitral valve replacement with the Mosaic bioprosthesis at 10 centers in Japan (1999-2014) were reviewed. Patient data were collected using the Research Electronic Data Capture software. Patient survival was determined using the Kaplan-Meier method. Freedom from structural valve deterioration (SVD) and valve-related reoperation and death were determined using actuarial methods. The median (interquartile range [IQR]) age of the cohort was 73 (69-77) years. The median (IQR) follow-up period was 4.83 (1.84-8.26) years. The longest follow-up period was 15.8 years. The 30-day mortality rate was 5.4%. The 12-year actuarial survival rate was 54.1±4.5%, and the freedom from valve-related death was 85.3±3.4%. The freedom from reoperation at 12 years was 74.3±5.7%. The freedom from SVD at 12 years was 81.4±6.6% for patients aged ≥65 years and 71.6±11.1% for those aged <65 years. The median (IQR) mean pressure gradient was 4.1 (3.0-6.0) and 5.6 (4.0-6.7) mmHg at 1 and 10 years, respectively. The median (IQR) effective orifice area was 1.7 (1.4-2.0) and 1.4 (1.2-1.6) cm2at 1 and 10 years, respectively. CONCLUSIONS: The Mosaic porcine bioprosthesis offered satisfactory long-term outcomes for up to 12 years.