Pre-Existing Left Bundle Branch Block and Clinical Outcomes After Transcatheter Aortic Valve Replacement.

Background: Few reports on pre-existing left bundle branch block (LBBB) in patients undergoing transcatheter aortic valve replacement (TAVR) are currently available. Further, no present studies compare patients with new onset LBBB with those with pre-existing LBBB. Objectives: This study aimed to investigate the association between pre-existing or new onset LBBB and clinical outcomes after TAVR. Methods: Using data from the Japanese multicenter registry, 5,996 patients who underwent TAVR between October 2013 and December 2019 were included. Patients were classified into 3 groups: no LBBB, pre-existing LBBB, and new onset LBBB. The 2-year clinical outcomes were compared between 3 groups using Cox proportional hazards models and propensity score analysis to adjust the differences in baseline characteristics. Results: Of 5,996 patients who underwent TAVR, 280 (4.6%) had pre-existing LBBB, while 1,658 (27.6%) experienced new onset LBBB. Compared with the no LBBB group, multivariable Cox regression analysis showed that pre-existing LBBB was associated not only with a higher 2-year all-cause (adjusted HR: 1.39; 95% CI: 1.06-1.82; P = 0.015) and cardiovascular (adjusted HR: 1.60; 95% CI: 1.04-2.48; P = 0.031) mortality, but also with higher all-cause (adjusted HR: 1.43, 95% CI: 1.07-1.91; P = 0.016) and cardiovascular (adjusted HR: 1.81, 95% CI:1.12-2.93; P = 0.014) mortality than the new onset LBBB group. Heart failure was the most common cause of cardiovascular death, with more heart failure deaths in the pre-existing LBBB group. Conclusions: Pre-existing LBBB was independently associated with poor clinical outcomes, reflecting an increased risk of cardiovascular mortality after TAVR. Patients with pre-existing LBBB should be carefully monitored.

Coronary Artery Bypass Grafting for a Young Female Patient With Chronic Active Epstein-Barr Virus Infection.

A 24-year-old woman with chronic active Epstein-Barr virus (CAEBV) infection successfully underwent coronary artery bypass grafting for triple coronary arteries with chronic total occlusion and aneurysms. This case underscores the importance of accurate assessment and treatment of coronary artery lesions in patients with CAEBV infection.

Alternative mechanisms of Notch activation by partitioning into distinct endosomal domains.

Different membrane microdomain compositions provide unique environments that can regulate signaling receptor function. We identify microdomains on the endosome membrane of Drosophila endosomes, enriched in lipid-raft or clathrin/ESCRT-0, which are associated with Notch activation by distinct, ligand-independent mechanisms. Transfer of Notch between microdomains is regulated by Deltex and Suppressor of deltex ubiquitin ligases and is limited by a gate-keeper role for ESCRT complexes. Ubiquitination of Notch by Deltex recruits it to the clathrin/ESCRT-0 microdomain and enhances Notch activation by an ADAM10-independent/TRPML-dependent mechanism. This requirement for Deltex is bypassed by the downregulation of ESCRT-III. In contrast, while ESCRT-I depletion also activates Notch, it does so by an ADAM10-dependent/TRPML-independent mechanism and Notch is retained in the lipid raft-like microdomain. In the absence of such endosomal perturbation, different activating Notch mutations also localize to different microdomains and are activated by different mechanisms. Our findings demonstrate the interplay between Notch regulators, endosomal trafficking components, and Notch genetics, which defines membrane locations and activation mechanisms.

Right Ventricular Dysfunction in Patients With Concomitant Tricuspid Regurgitation Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: This study investigated the impact and predictive factors of concomitant significant tricuspid regurgitation (TR) and evaluated the roles of right ventricle (RV) function and the etiology of TR in the clinical outcomes of patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI).Methods and Results: We assessed grading of TR severity, TR etiology, and RV function in pre- and post-TAVI transthoracic echocardiograms for 678 patients at Keio University School of Medicine. TR etiology was divided into 3 groups: primary TR, ventricular functional TR (FTR), and atrial FTR. The primary outcomes were all-cause and cardiovascular death. At baseline, moderate or greater TR was found in 55 (8%) patients and, after adjustment for comorbidities, was associated with increased all-cause death (hazard ratio [HR] 2.11; 95% confidence interval [CI] 1.19-3.77; P=0.011) and cardiovascular death (HR 2.29; 95% CI 1.06-4.99; P=0.036). RV dysfunction (RVD) also remained an independent predictor of cardiovascular death (HR 2.06; 95% CI 1.03-4.14; P=0.042). Among the TR etiology groups, patients with ventricular FTR had the lowest survival rate (P<0.001). Patients with persistent RVD after TAVI had a higher risk of cardiovascular death than those with a normal or recovered RV function (P<0.001). CONCLUSIONS: The etiology of TR and RV function play an important role in predicting outcomes in concomitant TR patients undergoing TAVI.

Safety and efficacy of aortic valvuloplasty for de novo aortic insufficiency in patients with a left-ventricular assist device.

OBJECTIVES: Progression of aortic insufficiency during left-ventricular assist device (LVAD) support is a crucial topic. One treatment option is aortic valvuloplasty (AVP); however, there is controversy regarding its safety and efficacy. We investigated the safety and efficacy of AVP using the coaptation stitch method (Park's stitch) performed for de novo aortic insufficiency. METHODS: Between 2013 and 2020, 175 consecutive patients underwent LVAD implantation, of which 7 patients [men, 2 (28.6%); median age, 55 years] underwent late-stage AVP. Two patients underwent AVP within 2 weeks, and the remaining six patients underwent AVP 3, 19, 24, 28, 42, and 49 months, respectively, after LVAD implantation. RESULTS: Preoperatively, the degree of aortic insufficiency was moderate in 6 (85.7%) patients and severe in 1 (14.3%) patient. AVP was technically successful in 6 (85.7%) patients, while one case of failed plasty was subsequently treated with bioprosthetic valve replacement. A 1-year post-AVP right heart catheterization study revealed a median pulmonary artery wedge pressure of 10.0 mmHg. No deaths or heart failure admissions occurred during the follow-up (median, 38.0 months). There was no aortic insufficiency in 2 (28.6%) patients; however, trivial AI was observed in 3 (42.8%) patients, and mild AI was observed in 1 (14.3%) patient 2 years postoperatively. However, at the 3-year follow-up, two patients developed an increase in AI grade from trivial to mild. CONCLUSIONS: AVP using Park's stitch was safe. It is critical to carefully observe the aortic valve during AVP surgery to ensure that AVP is appropriate.

Open Versus Zone 0/1 Endovascular Aortic Repair for Arch Aneurysm: A Propensity Score-Matched Study from the National Clinical Database in Japan.

BACKGROUND: Although open surgical repair (OSR) is the gold standard for treating arch aneurysms, thoracic endovascular aortic repair (TEVAR) may be a less invasive alternative. However, it remains unclear which of the 2 methods yields better outcomes. In this study, we compared the perioperative outcomes of both procedures for arch aneurysms using a nationwide surgical database. METHODS: Data of patients who underwent elective aortic repair for true arch aneurysms were extracted from the National Clinical Database of Japan. Patients who underwent OSR and Zone 0/1 TEVAR were matched in a 1:1 ratio using propensity scores and their mortality and morbidity rates were compared. RESULTS: A total of 2,815 and 1,125 patients underwent OSR and Zone 0/1 TEVAR, respectively. After propensity score matching, 1,058 patients were included in both groups. Compared with OSR, Zone 0/1 TEVAR was associated with a significantly higher incidence of stroke (5.8 vs. 10.0%, P < 0.001) and paraplegia/paraparesis (1.6 vs. 4.4%, P < 0.001). However, there were no significant differences in the 30-day and operative mortality rates between the 2 groups (2.2 vs. 2.7% and 4.5 vs. 5.4%, respectively). In the Zone 0/1 TEVAR group, postoperative computed tomography was performed in 92.4% of patients, and types I and III endoleaks were identified in 6.4% and 1.1% of patients, respectively. CONCLUSIONS: Zone 0/1 TEVAR has higher incidences of stroke and paraplegia/paraparesis than OSR, with a risk of postoperative endoleaks. Resolving these problems is the key for expanding the application of Zone 0/1 TEVAR and in the meantime OSR remains the gold standard for surgically fit patients.

Retinal ferroptosis as a critical mechanism for the induction of retinochoroiditis during ocular toxoplasmosis.

Toxoplasmosis is a major infectious disease, affecting approximately one-third of the world's population; its main clinical manifestation, ocular toxoplasmosis (OT), is a severe sight-threatening disease. Nevertheless, the diagnosis of OT is based on clinical findings, which needs improvement, even with biochemical tests, such as polymerase chain reaction and antibody detections. Furthermore, the efficacy of OT-targeted treatment is limited; thus, additional measures for diagnosis and treatments are needed. Here, we for the first time report a significantly reduced iron concentration in the vitreous humor (VH) of human patients infected with OT. To obtain further insights into molecular mechanisms, we established a mouse model of T. gondii infection, in which intravitreally injected tracer 57Fe, was accumulated in the neurosensory retina. T. gondii-infected eyes showed increased lipid peroxidation, reduction of glutathione peroxidase-4 expression and mitochondrial deformity in the photoreceptor as cristae loss. These findings strongly suggest the involvement of ferroptotic process in the photoreceptor of OT. In addition, deferiprone, an FDA-approved iron chelator, reduced the iron uptake but also ameliorated toxoplasma-induced retinochoroiditis by reducing retinal inflammation. In conclusion, the iron levels in the VH could serve as diagnostic markers and iron chelators as potential treatments for OT.

AATS 2023: Left ventricular restoration with scar exclusion in the surgical treatment for ischemic heart failure.

OBJECTIVE: Post-infarction myocardial scar as detected by cardiac magnetic resonance (CMR) is associated with adverse left ventricular (LV) remodeling and negatively affects the prognosis. We sought to analyze the impact of left ventricular restoration (LVR) with asynergic scar exclusion on long-term outcomes for patients with ischemic heart failure (IHF). METHODS: From January 2005, 134 consecutive patients with IHF underwent scar-exclusive LVR. Among the 131 survivors, 108 patients had paired late gadolinium enhancement (LGE)-CMR preoperatively and one year after, and represent the study population. Patients were divided into two groups according to whether their post-LVR residual percentage of scarred LV perimeter was <35% (%Scar <35; n = 55) or more (%Scar ≥35; n = 53). We compared the two groups, by looking at LGE-CMR outcomes, and at long-term survival and cardiac event (hospitalization for cardiac causes)-free survival. RESULTS: Postoperative LV end-systolic volume index decreased significantly and ejection fraction increased with significant increase in stroke volume index (P < 0.05 for both). LV diastolic function of the left atrial volume index was significantly improved in patients with residual %Scar <35 than in those with %Scar ≥35 (P interaction = 0.005). Median survival in patients with residual %Scar <35 and ≥ 35 were 8.3 (4.5-12.2) years and 6.8 (1.8-11.8) years respectively (P = 0.106). Median cardiac event-free survival in patients with %Scar <35 and ≥ 35 were 8.0 (3.9-12.1) years and 4.8 (0.8-8.8) years respectively (P < 0.001). CONCLUSIONS: Scar-exclusive LVR yielded sustainable improvement in LV function and favorable long-term survival regardless of the extent of residual scar. The LVR should be performed to attain scar exclusion in the surgical treatment for IHF, which in turn might protectively affect LV diastolic function and cardiac event-free survival.

Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.

Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.

Clinical outcomes of Najuta thoracic stent graft system for arch aneurysms.

Objectives: We aimed to elucidate the perioperative and short-term clinical outcomes of the Najuta thoracic stent graft system with fenestrations for supra-aortic vessels. Methods: We retrospectively investigated the perioperative and short-term clinical outcomes of 20 patients treated for arch or distal arch aneurysms using the Najuta thoracic stent graft system during the period from May 2019 to February 2023. Results: The technical success rate of the Najuta thoracic stent graft system was 95%. Of the 20 patients, 17 patients (85.0%) underwent concomitant extra-anatomical supra-aortic bypass. Postoperative CT revealed type Ia (n = 2) and type II (n = 3) endoleaks which disappeared on follow-up. The postoperative complications were stroke (n = 2, 10.0%), paraplegia (n = 1, 5.0%), and paraparesis (n = 1, 5.0%). In a very old patient, a blood transfusion was performed from the common iliac artery using the retroperitoneal approach. There were no aorta-related complications such as retrograde type A dissection or distal stent graft-induced new entry. Conclusions: We treated arch or distal arch thoracic aneurysms by inserting a tube-type stent graft as a scaffold on the peripheral site and placing the Najuta thoracic stent graft on the proximal site. By extending the landing zone to Zone 0 and using a low radial force, which is a feature of the Najuta thoracic stent graft system, postoperative bird-beak and aorta-related complications were avoided. The treatment of arch and distal arch aortic aneurysms using the Najuta thoracic stent graft system showed acceptable perioperative and short-term clinical outcomes. Thoracic endovascular aortic repair using the Najuta thoracic stent graft system may be a potential treatment option for arch and distal arch aortic aneurysms, warranting further studies.

Bayesian network enables interpretable and state-of-the-art prediction of immunotherapy responses in cancer patients.

Immune checkpoint inhibitors, especially PD-1/PD-L1 blockade, have revolutionized cancer treatment and brought tremendous benefits to patients who otherwise would have had a limited prognosis. Nonetheless, only a small fraction of patients respond to immunotherapy, and the costs and side effects of immune checkpoint inhibitors cannot be ignored. With the advent of machine and deep learning, clinical and genetic data have been used to stratify patient responses to immunotherapy. Unfortunately, these approaches have typically been "black-box" methods that are unable to explain their predictions, thereby hindering their responsible clinical application. Herein, we developed a "white-box" Bayesian network model that achieves accurate and interpretable predictions of immunotherapy responses against nonsmall cell lung cancer (NSCLC). This tree-augmented naïve Bayes (TAN) model accurately predicted durable clinical benefits and distinguished two clinically significant subgroups with distinct prognoses. Furthermore, our state-of-the-art white-box TAN approach achieved greater accuracy than previous methods. We hope that our model will guide clinicians in selecting NSCLC patients who truly require immunotherapy and expect our approach to be easily applied to other types of cancer.

FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation.

Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disorder caused by overnutrition and can lead to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The transcription factor Forkhead box K1 (FOXK1) is implicated in regulation of lipid metabolism downstream of mechanistic target of rapamycin complex 1 (mTORC1), but its role in NAFLD-NASH pathogenesis is understudied. Here, we show that FOXK1 mediates nutrient-dependent suppression of lipid catabolism in the liver. Hepatocyte-specific deletion of Foxk1 in mice fed a NASH-inducing diet ameliorates not only hepatic steatosis but also associated inflammation, fibrosis, and tumorigenesis, resulting in improved survival. Genome-wide transcriptomic and chromatin immunoprecipitation analyses identify several lipid metabolism-related genes, including Ppara, as direct targets of FOXK1 in the liver. Our results suggest that FOXK1 plays a key role in the regulation of hepatic lipid metabolism and that its inhibition is a promising therapeutic strategy for NAFLD-NASH, as well as for HCC.