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Migrasomes, the newly discovered cellular organelles that form large vesicle-like structures on the retraction fibers of migrating cells, are thought to be involved in communication between neighboring cells, cellular content transfer, unwanted material shedding, and information integration. Although their formation has been described previously, the molecular mechanisms of migrasome biogenesis are largely unknown. Here, we developed a cell line that overexpresses GFP-tetraspanin4, enabling observation of migrasomes. To identify compounds that regulate migrasome activity in retinal pigment epithelial (RPE) cells, we screened a fecal chemical library and identified cadaverine, a biogenic amine, as a potent migrasome formation inducer. Compared with normal migrating cells, those treated with cadaverine had significantly more migrasomes. Putrescine, another biogenic amine, also increased migrasome formation. Trace amine-associated receptor 8 (TAAR8) depletion inhibited migrasome increase in cadaverine-treated RPE cells, and cadaverine also inhibited protein kinase A phosphorylation. In RPE cells, cadaverine triggers migrasome formation via a TAAR8-mediated protein kinase A signaling pathway.

Abstract Background The operative outcomes of thoracoabdominal aortic aneurysms (TAAAs) are challenged by high operative mortality and disabling complications. This study aimed to explore the baseline clinical, anatomical, and procedural risk factors that impact early and late outcomes following open repair of TAAAs. Methods We reviewed the medical records of 290 patients who underwent open repair of TAAAs between 1992 and 2020 at a tertiary referral center. Determinants of early mortality (within 30 days or in hospital) were analyzed using multivariable logistic regression models, while those of overall follow-up mortality were explored using multivariable Cox proportional hazards models and landmark analyses. Results The rates of early mortality and spinal cord deficits were 13.1% and 11.0%, respectively, with Crawford extent II showing the highest rates. In the logistic regression models, older age (P 0.05). Conclusion There were differential temporal impacts of perioperative risk variables on mortality in open repair of TAAAs, with older age and low hemoglobin level having significant impacts throughout the postoperative period, and low surgical volume, high CPB time, and Crawford extent II having impacts in the early postoperative phase.

Background: This study compared the outcomes of surgical aortic valve replacement (AVR) in patients aged 50 to 70 years based on the type of prosthetic valve used. Methods: We compared patients who underwent mechanical AVR to those who underwent bioprosthetic AVR at our institution between January 2000 and March 2019. Competing risk analysis and the inverse probability of treatment weighting (IPTW) method based on propensity score were employed for comparisons. Results: A total of 1,580 patients (984 patients with mechanical AVR; 596 patients with bioprosthetic AVR) were enrolled. There was no significant difference in early mortality between the mechanical AVR and bioprosthetic AVR groups (0.9% vs. 1.7%, p=0.177). After IPTW adjustment, the risk of all-cause mortality was significantly higher in the bioprosthetic AVR group than in the mechanical AVR group (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.07–1.80; p=0.014). Competing risk analysis revealed lower risks of stroke (sub-distributional hazard ratio [sHR], 0.44; 95% CI, 0.28–0.67; p

Background This present study aimed to investigate the impact of left atrial appendage (LAA) isolation on adverse clinical outcomes, with a further stratified analysis by biatrial (BA) and left atrial lesion sets, in patients with atrial fibrillation (AF) undergoing surgical ablation (SA) concurrent with mitral valve (MV) surgery.Methods We evaluated 875 patients (aged 65.1±12.0 years) who underwent SA of AF concomitant to MV surgery, excluding those with mechanical prostheses requiring lifelong anticoagulation, between 2005 and 2017 in five tertiary cardiac centres in South Korea. Of these, 458 had isolated the LAA, whereas the remainder (n=417) had the LAA preserved. Comparative risk of stroke, mortality and AF recurrence was assessed between the groups, considering death as a competing event. Inverse-probability treatment weighting was used for baseline adjustment.Results During the median follow-up of 57.4 months (IQR, 32.5–92.4 months), the adjusted risk of long-term stroke was significantly lower in the patients who underwent LAA isolation compared with those who preserved the LAA (subdistribution HR (SHR), 0.28; 95% CI 0.15 to 0.51; p

ABSTRACTAutophagy plays a critical role in regulating the quality and quantity of cellular compartments; however, the mechanisms governing endoplasmic reticulum (ER) autophagy (ER-phagy) are still largely undefined. In this study, we identified several inhibitors of USP14, a ubiquitin-specific protease, including IU1 and b-AP15, as novel ER-phagy inducers through chemical library screening. While USP14 is known to act as an ER stress inducer, its precise role in ER-phagy remains unclear. Our findings demonstrate that treatment with either IU1 or b-AP15 induces ER-phagy by increasing ER stress in HepG2 cells. Similarly, depletion of USP14 augments ER-phagy and the ER stress response. The blockage of autophagy using an ULK1 inhibitor, SBI0206965, impedes ER-phagy. Moreover, inhibition of ER stress with tauroursodeoxycholic acid reverses ER-phagy by alleviating ER stress in HepG2 cells. We also found that suppression of the stress kinase JNK inhibited ER-phagy in IU1-treated cells. In conclusion, the results of this study suggest that the inhibition of USP14 accelerates ER-phagy by enhancing ER stress and JNK activation in HepG2 cells.

Objective: To investigate the association between false lumen (FL) dependency of segmental arteries (SAs) at T9-L3 levels and the risk of spinal cord injury (SCI) following total arch replacement and frozen elephant trunk (FET) implantation in the setting of acute DeBakey type I aortic dissection (AAD). Methods: The study involved consecutive patients with AAD who underwent total arch replacement and FET implantation between 2020 and 2022. Primary outcome was postoperative SCI. The inverse probability of treatment weighting (IPTW) method was employed to minimize the impact of no-randomization bias. Antegrade placement of FET was followed by end-to-end anastomosis of a 4-branch arch graft at the proximal landing site of FET. Results: A total of 146 patients were included (age, 50.5 ± 11.7 years, 115 male), of whom 35 (24%) had SAs at T9-L3 levels completely dependent on FL (FL-dependency group). There was no significant difference in early (30-day or in-hospital) mortality rates between FL-dependency (14.3%) and FL-independency (18.0%) groups (P = .80), however, the rate of SCI was significantly higher in the FL-Dependency group (34.3% vs 2.7%, P

Objective: Genetic aortopathy, if left untreated, leads to aortic catastrophe in most affected individuals. We sought to determine the genetic mutation patterns and detection rates in patients with aortopathy and their families with a systematic screening protocol. Methods: In 2016 to 2020, patients with aortic dissection or root aneurysm (Z score ≥2) and their first-degree relatives were enrolled in a prospective registry at a tertiary referral center. The individuals underwent systematic single- or multi-gene panel testing depending on clinical presentations. Results: Among 575 enrolled individuals (mean age, 46.6 ± 14.5 years; 203 women), 346 (60.2%) underwent genetic testing. Rates of relevant gene mutations identified were 39.4% (91/231), 27.1% (54/199) and 72.4% (n = 105) in aneurysm, dissection, and family screening groups, respectively (P

Background: The surgical threshold for bicuspid aortic valve (BAV)-related aortopathy is a matter of debate due to its uncertain etiology and prognosis. This study investigated the prognosis of unrepaired BAV aortopathy in patients undergoing surgical aortic valve replacement (SAVR). Methods: We retrospectively analyzed data from 720 patients (age, 60.8±11.5 years; 246 women) who underwent SAVR for BAV disease without aortic repair between 2005 and 2020 at Asan Medical Center. The clinical endpoints were defined as occurrences of sudden death, aortic dissection or rupture, and elective aortic repair. To estimate postoperative changes in the dimensions of the unrepaired aorta, the individual annual aortic expansion rate was calculated. Multiple linear regression models were used to evaluate the risk of aortic expansion. Results: The mean ascending aortic diameter was 39.5±4.6 mm, and 299 patients (41.5%) had a baseline ascending aorta diameter >40 mm. During 70.0±68.3 months of follow-up, the mean annual aortic expansion rate was 0.39±1.96 mm/yr, no aortic dissection or rupture was observed, and sudden deaths were reported in 12 patients (0.34% per person-year). Linear regression analysis revealed no significant correlation between the baseline ascending aortic diameter and postoperative aortic expansion (R2=0.004, β=-0.84, p=0.082). Conclusion: In selected patients undergoing SAVR for a BAV (45 mm, the study results need further validation by studies involving larger populations or randomized controlled trials.

Abstract The primary cilium, an antenna-like structure on the cell surface, acts as a mechanical and chemical sensory organelle. Primary cilia play critical roles in sensing the extracellular environment to coordinate various developmental and homeostatic signaling pathways. Here, we showed that the depletion of heat shock protein family A member 9 (HSPA9)/mortalin stimulates primary ciliogenesis in SH-SY5Y cells. The downregulation of HSPA9 enhances mitochondrial stress by increasing mitochondrial fragmentation and mitochondrial reactive oxygen species (mtROS) generation. Notably, the inhibition of either mtROS production or mitochondrial fission significantly suppressed the increase in primary ciliogenesis in HSPA9-depleted cells. In addition, enhanced primary ciliogenesis contributed to cell survival by activating AKT in SH-SY5Y cells. The abrogation of ciliogenesis through the depletion of IFT88 potentiated neurotoxicity in HSPA9-knockdown cells. Furthermore, both caspase-3 activation and cell death were increased by MK-2206, an AKT inhibitor, in HSPA9-depleted cells. Taken together, our results suggest that enhanced primary ciliogenesis plays an important role in preventing neurotoxicity caused by the loss of HSPA9 in SH-SY5Y cells.

A specialized membrane-bound organelle, named the melanosome, is central to the storage and transport of melanin as well as melanin synthesis in melanocytes. Although previous studies have linked melanosomal degradation to autophagy, the precise mechanisms remain elusive. Autophagy, a complex catabolic process involving autophagosomes and lysosomes, plays a vital role in cellular constituent degradation. In this study, the role of autophagy in melanosomal degradation was explored, employing a cell-based screening system designed to unveil key pathway regulators. We identified specific dipeptidyl peptidase-4 inhibitors, such as teneligliptin hydrobromide and retagliptin phosphate, as novel agents inducing melanophagy through a comprehensive screening of a ubiquitination-related chemical library. We found that treatment with teneligliptin hydrobromide or retagliptin phosphate not only diminishes melanin content elevated by alpha-melanocyte-stimulating hormone (α-MSH) but also triggers autophagy activation within B16F1 cells. In addition, the targeted inhibition of unc-51-like kinase (ULK1) significantly attenuated both the anti-pigmentation effects and autophagy induced by teneligliptin hydrobromide and retagliptin phosphate in α-MSH-treated cells. Collectively, our data demonstrate a new frontier in understanding melanosomal degradation, identifying teneligliptin hydrobromide and retagliptin phosphate as promising inducers of melanophagy via autophagy activation. This study contributes essential insights into cellular degradation mechanisms and offers potential therapeutic avenues in the regulation of pigmentation.

Background: In this study, we present recent trends in heart valve surgery in Korea through analyses of data from the Korea Heart Valve Surgery Registry (KHVSR). Methods: We enrolled 8,981 patients who were registered in the KHVSR from 2017 to 2020. Yearly trends in patients’ baseline characteristics, surgical profiles, and early mortality rates were explored. The observed/expected mortality ratio (O/E ratio), calculated from the actual mortality in the KHVSR and the predicted mortality estimated using the EuroSCORE II, was also analyzed. Results: The proportion of aortic valve surgery significantly increased from 56.8% in 2017 to 60.3% in 2020. The proportion of all combined procedures and minimally invasive surgery significantly increased over the 4-year study period. The operative mortality rate was 2.9% in the entire cohort, while mitral valve repair showed the lowest mortality risk (0.9%). The mortality rates of isolated aortic valve replacement (AVR) significantly decreased from 2.1% in 2017 to 0.8% in 2020 (p=0.016). Overall, the O/E ratio was 0.784 (95% confidence interval [CI], 0.677–0.902) demonstrating significantly lower actual mortality risks than expected based on the EuroSCORE II. In particular, the O/E ratios were as low as 0.364 (95% CI, 0.208–0.591) for isolated AVR. Conclusion: The recent data from the KHVSR showed increasing trends for complex procedures and minimally invasive surgery in heart valve surgery in Korea, and demonstrated remarkably low risks of operative mortality.

Autophagy is a pivotal biological process responsible for maintaining the homeostasis of intracellular organelles. Yet the molecular intricacies of peroxisomal autophagy (pexophagy) remain largely elusive. From a ubiquitin-related chemical library for screening, we identified several inhibitors of the Von Hippel–Lindau (VHL) E3 ligase, including VH298, thereby serving as potent inducers of pexophagy. In this study, we observed that VH298 stimulates peroxisomal degradation by ATG5 dependently and escalates the ubiquitination of the peroxisomal membrane protein ABCD3. Interestingly, the ablation of NBR1 is similar to the curtailed peroxisomal degradation in VH298-treated cells. We also found that the pexophagy induced by VH298 is impeded upon the suppression of gene expression by the translation inhibitor cycloheximide. Beyond VHL inhibition, we discovered that roxadustat, a direct inhibitor of HIF-α prolyl hydroxylase, is also a potent inducer of pexophagy. Furthermore, we found that VH298-mediated pexophagy is blocked by silencing HIF-1α. In conclusion, our findings suggest that VH298 promotes pexophagy by modulating VHL-mediated HIF-α transcriptional activity.

Abstract Aortic valve calcium scoring by cardiac computed tomographic (CT) has been recommended as an alternative to classify the AS (aortic stenosis) severity, but it is unclear that whether CT findings would have additional value to discriminate significant AS subtypes including high gradient severe AS, classic low-flow, low gradient (LF-LG) AS, paradoxical LF-LG AS, and moderate AS. In this study, we examined the preoperative clinical and cardiac CT findings of different subtypes of AS in patients with surgical aortic valve replacement (AVR) and evaluated the subtype classification as a factor affecting post-surgical outcomes. This study included 511 (66.9 ± 8.8 years, 55% men) consecutive patients with severe AS who underwent surgical AVR. Aortic valve area (AVA) was obtained by echocardiography (AVAecho) and by CT (AVACT) using each modalities measurement of the left ventricular outflow tract. Patients with AS were classified as (1) high-gradient severe (n = 438), (2) classic LF-LG (n = 18), and (3) paradoxical LF-LG (n = 55) based on echocardiography. In all patients, 455 (89.0%) patients were categorized as severe AS according to the AVACT. However, 56 patients were re-classified as moderate AS (43 [9.8%] high-gradient severe AS, 5 [27.8%] classic LF-LG AS, and 8 [14.5%] paradoxical LF-LG AS) by AVACT. The classic LF-LG AS group presented larger AVACT and aortic annulus than those in high-gradient severe AS group and one third of them had AVACT ≥ 1.2 cm2. After multivariable adjustment, old age (hazard ratio [HR], 1.04, P = 0.049), high B-type natriuretic peptide (BNP) (HR, 1.005; P

Background: While the use of bioprosthetic valves for mitral valve replacement (MVR) is increasing, very few studies have compared bovine pericardial and porcine valves in the mitral position to help guide bioprosthetic selection. Methods: In the present study, patients who underwent MVR using bovine pericardial valves were compared with those who underwent MVR with porcine bioprostheses between January 1996 and July 2018. Those with prior MVR, infective endocarditis, congenital mitral valve disease, or ischemic mitral regurgitation were excluded. The primary outcomes were structural valve deterioration (SVD) and mitral valve reoperation from any cause, and death was regarded as a competing risk. Competing risk analysis and propensity score-matching were used for comparisons. Results: Among the 388 patients enrolled, pericardial and porcine bioprostheses were implanted in 217 (55.9%) and 171 (44.1%), respectively. Propensity score-matching yielded 122 pairs of patients that were well-balanced for all baseline covariates. No significant differences were observed between the groups in unadjusted (p=0.09) and adjusted overall survival (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.72–1.76; p=0.60). Competing risk analysis revealed no significant differences in the risks of mitral reoperation (HR, 1.07; 95% CI, 0.50–2.27; p=0.86) and development of SVD (HR, 1.57; 95% CI, 0.56–4.36; p=0.39) between the groups. Matched population analysis confirmed similar results regarding reoperation (HR, 0.99; 95% CI, 0.40–3.22; p=0.98) and SVD (HR, 1.39; 95% CI, 0.41– 4.73; p=0.60). Conclusion: No significant differences in survival or valve durability were observed between bovine pericardial and porcine bioprosthetic MVR. These findings require further validation through studies with larger sample sizes.

The 2020 American College of Cardiology focused update on the mitral regurgitation (MR) pathway provides an excellent summary of the decision-making trees in the treatment of severe MR, in which 2 main branches of the flowchart are suggested depending on whether MR is primary or secondary. Surgery is suggested as preferable over transcatheter edge-to-edge repair (TEER) in primary MR that needs intervention. The decision-making for secondary MR generally prioritizes TEER over surgery according to the guidelines, but further stratification is necessary based on the pathophysiologic mechanisms of MR. TEER is probably the more suitable option in secondary MR caused by left ventricular dysfunction or dilatation, given the high perceived surgical risks, despite the lack of sufficient evidence in support of overt clinical benefits from surgical therapy in these patients. In atrial functional MR associated with atrial fibrillation (AF), however, concomitant ablation of AF seems to be a desirable option, as it has been demonstrated to be a key factor leading to improved survival, reduced stroke risk, and more durable mitral and tricuspid function in patients undergoing mitral surgery. Therefore, atrial functional MR requiring intervention may be best treated by surgical therapy that combines mitral repair and AF ablation in the majority of patients. This particular issue, however, needs further research to obtain scientific evidence to guide optimal management strategies.

Extensive thoracic aortic disease involving the ascending aorta, the aortic arch, and the descending thoracic aorta may require multiple surgical and interventional managements, which impose a burden in terms of cumulative surgical trauma and the risk of interval mortality. Herein, we describe a single-stage arch and descending thoracic aorta replacement via sternotomy in a patient with multiple comorbidities presenting with an extensive thoracic aortic aneurysm.

Background: Sutureless and rapid deployment valves for aortic valve replacement (AVR) were introduced in Korea in December 2016. This study evaluated changing trends in the prosthetic valves used for AVR in Korea after the introduction of sutureless and rapid deployment valves. Methods: From December 2016 to December 2018, 4,899 patients underwent AVR in Korea. After applying the exclusion criteria, 4,872 patients were analyzed to determine changes in the type of prosthetic valve used for AVR. The study period was divided into 5 groups corresponding to 5-month intervals. Results: The total number of AVR cases was 194.88±28.78 per month during the study period. Mechanical valves were used in approximately 27% to 33% of cases, and the proportion of mechanical valve use showed a tendency to decrease, with marginal significance overall (p=0.078) and significant decreases in patients less than 60 years of age and in men (p=0.013 and p=0.023, respectively). The use of sutureless valves increased from 13.4% to 25.8% of cases (p70 years) and those requiring concomitant surgery. In a comparison between sutureless and rapid deployment valves, the use of Perceval S valves (a type of sutureless valve), gradually increased (p

Abstract The purpose of this study was to evaluate whether bicuspid anatomy affects the discrepancy between CT-derived annular size and intraoperative size. We retrospectively analyzed annular measurements in 667 patients who underwent surgical aortic valve replacement (AVR). Preoperative CT measurements of the aortic annulus were compared to surgically implanted valve sizes. To evaluate whether the bicuspid valve affects the differences between CT annulus diameter and surgical AVR size, patients with diameter larger by > 10% (CT-Lg group) on CT, compared to surgical AVR size, were compared with those having size difference

Background: The lesion sets for surgical ablation of atrial fibrillation (AF) that provide optimal outcomes have remained controversial. Objectives: We evaluated the effects of left-atrial (LA) ablation of AF compared with bi-atrial (BA) ablation on the clinical and rhythm outcomes, and examined the predictors for AF recurrence and permanent pacing in consideration of ablation lesion sets. Methods: Between 2001 and 2018, 1,965 patients underwent surgical ablation during cardiac surgery at our institution. Among these, 796 and 1,169 patients underwent LA and BA ablation, respectively. The clinical outcomes were evaluated after propensity score adjustment, with death accounting for a competing event. The probability of AF recurrence was estimated with the generalized estimating equations model. Results: The patients with BA ablation had morbidities greater than those with LA ablation. The probability of AF recurrence at 1 and 5 years was 13.9% and 37.1% in patients with LA ablation, and 11.2% and 30.1% in those with BA ablation (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 0.96-1.61; P = 0.100). After adjustment, LA ablation was associated with a decreased risk of early death (

Abstract In thoracoabdominal aortic aneurysm repair, repairing the visceral and segmental arteries is challenging. Although there is a pre-hand-sewn and multi-branched graft based on the conventional image-based technique, it has shortcomings in precisely positioning and directing the visceral and segmental arteries. Here, we introduce two new reconstruction techniques using patient-specific 3D-printed graft reconstruction guides: (1) model-based technique that presents the projected aortic graft, visualizing the main aortic body and its major branches and (2) guide-based technique in which the branching vessels in the visualization model are replaced by marking points identifiable by tactile sense. We demonstrate the effectiveness by evaluating conventional and new techniques based on accuracy, marking time requirement, reproducibility, and results of survey to surgeons on the perceived efficiency and efficacy. The graft reconstruction guides cover the segmentation, design, fabrication, post-processing, and clinical application of open surgical repair of thoracoabdominal aneurysm, and proved to be efficient for accurately reconstructing customized grafts.

BackgroundThere is a paucity of direct data on the incidence and predictors of intracranial bleeding (ICB) after coronary artery bypass graft surgery (CABG).MethodsThe Korean National Health Insurance database was used to identify patients without prior ICB who underwent CABG. The outcomes of interest were the time-dependent incidence rates of ICB and the associated mortality.ResultsAmong 35,021 patients who underwent CABG between 2007 and 2018, 895 (2.6%) experienced an ICB during a median follow-up of 6.0 years. The 1-year cumulative incidence of ICB was 0.76%, with a relatively high incidence rate (9.93 cases per 1,000 person-years) within the first 1–30 days. Subsequent incidence rates showed a sharp decline until 3 years, followed by a steady decrease up to 10 years. The 1-year mortality rate after ICB was 38.1%, with most deaths occurring within 30 days (23.6%). The predictors of ICB after CABG were age ≥ 75 years, hypertension, pre-existing dementia, history of ischemic stroke or transient ischemic attack, and end-stage renal disease.ConclusionsIn an unselected nationwide population undergoing CABG, the incidence of ICB was non-negligible and showed a relatively high incidence rate during the early postoperative period. Post-CABG ICB was associated with a high risk of premature death. Further research is needed to stratify high-risk patients and personalize therapeutic decisions for preventing ICB after CABG.

Although it is attractive, a limitation of aortic valve (AV) replacement (AVR) through a mini-thoracotomy approach (mini-AVR) is the limited exposure of the AV. Here, we present a simple exposure technique named “suspending commissural sutures” for a more efficient mini-AVR. The technique involves making 3 half-depth stitches with 1-0 silk at each of the commissures, which are anchored to each corresponding pericardial surface. These stitches are tightened up so that the aortic root is axially expanded and is pulled upward. The technique of suspending commissural stitches seems to offer reasonable exposure of the AV in mini-AVR, and shows excellent early surgical outcomes.

Background: This study aimed to develop a new risk prediction model for operative mortality in a Korean cohort undergoing heart valve surgery using the Korea Heart Valve Surgery Registry (KHVSR) database. Methods: We analyzed data from 4,742 patients registered in the KHVSR who underwent heart valve surgery at 9 institutions between 2017 and 2018. A risk prediction model was developed for operative mortality, defined as death within 30 days after surgery or during the same hospitalization. A statistical model was generated with a scoring system by multiple logistic regression analyses. The performance of the model was evaluated by its discrimination and calibration abilities. Results: Operative mortality occurred in 142 patients. The final regression models identified 13 risk variables. The risk prediction model showed good discrimination, with a c-statistic of 0.805 and calibration with Hosmer-Lemeshow goodness-of-fit p-value of 0.630. The risk scores ranged from -1 to 15, and were associated with an increase in predicted mortality. The predicted mortality across the risk scores ranged from 0.3% to 80.6%. Conclusion: This risk prediction model using a scoring system specific to heart valve surgery was developed from the KHVSR database. The risk prediction model showed that operative mortality could be predicted well in a Korean cohort.

Background: We aimed to assess the clinical outcomes of patients who underwent surgical repair of Kommerell diverticulum (KD) with individualized surgical methods. Methods: A retrospective analysis was performed of adult patients (aged ≥17 years) who underwent surgery to treat KD between June 2008 and October 2019. Results: Nine patients (median age, 45 years; range, 19–67 years; 7 men) underwent surgical repair. The indications for surgical therapy were acute aortic dissection in 2 patients, the presence of compressive symptoms due to dilated KD in 4 patients, and aneurysm growth in 3 patients. Various surgical techniques were used: (1) resection of the diverticulum stump and revascularization of the aberrant subclavian artery (n=3), (2) one-stage total-arch replacement including the diverticulum segment (n=3), and (3) hybrid repair (n=3). Early mortality occurred in 1 case of hybrid repair. Transient paraparesis occurred in a patient who underwent total arch repair as part of complicated acute aortic dissection. During follow-up (median duration, 30 months; range, 7–130 months), no late death or associated aortic complications were documented. All survivors were free from symptoms and had no abnormal findings on follow-up computed tomography. Conclusion: With a customized surgical approach and appropriate consideration of patient- specific anatomy and associated comorbidities, KD can be repaired with favorable outcomes.

Background: Attaining an adequate effective orifice area (EOA) is definitive goal in aortic valve replacement (AVR). The simple interrupted suture (SIS) technique could be a solution to achieve this goal, but limited data are available in the literature. This study aimed to compare hemodynamic differences between the SIS and non-everting mattress suture (NMS) techniques. Methods: From our database, 215 patients who underwent AVR for severe aortic stenosis were extracted to form the overall cohort. From March 2015 to November 2016, the SIS technique was used in 79 patients, while the NMS technique was used in 136 patients. Hemodynamic outcomes were evaluated, as detected by transthoracic echocardiography and computed tomography. Results: There were no significant differences in baseline characteristics between the 2 groups. On immediate postoperative echocardiography, the SIS group showed a significantly wider EOA (1.6±0.4 vs. 1.4±0.5 cm2, p=0.007) and a lower mean pressure gradient (PG) (13.3±5.4 vs. 17.0±6.0 mm Hg, p

Background: Malignant primary cardiac tumors are extremely rare, but have a poor prognosis. This study evaluated the surgical outcomes of patients with this disease. Methods: Forty patients who underwent surgery for malignant primary cardiac tumors between January 1998 and December 2018 were enrolled. Participants were divided into 3 groups based on resection margins (R0, 14 patients; R1, 11 patients; and R2, 11 patients) and their surgical outcomes were compared. Heart transplantation was performed in 4 patients with unresectable tumors. Results: Early mortality was reported in 2 cases (5%) due to postoperative bleeding and cerebral hemorrhage secondary to brain metastasis. The 1- and 2-year survival rates were 67.5% and 42.5%, respectively. The median survival time of the patients was 20.3 months (range, 9.2–37.6 months). The median survival time was 48.7, 20.3, and 4.8 months in patients with R0, R1, and R2 resections, respectively (p=0.023). Tumor recurrence occurred in 21 patients (61.7%), including 4 cases of local recurrence and 17 cases of distant metastasis. In patients who underwent heart transplantation, the median survival time was 29.5 months, with 3 cases of distant metastasis. Conclusion: Although surgery for malignant primary cardiac tumors has a poor prognosis, complete resection of the tumor may improve surgical outcomes.

Background Various ECG criteria for left ventricular hypertrophy (LVH) have been proposed, but their association with clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement is unknown. We investigated the prevalence of ECG LVH according to different criteria and its prognostic impact on clinical outcomes after transcatheter aortic valve replacement. Methods and Results In this prospective observational cohort, we evaluated 700 patients who underwent transcatheter aortic valve replacement between March 2010 and December 2019. Baseline preprocedural LVH was defined by 3 ECG criteria—Sokolow‐Lyon, Romhilt‐Estes, and Cornell voltage criteria. The primary outcome was major adverse cardiac or cerebrovascular event (MACCE; composite of death, myocardial infarction, stroke, or rehospitalization from cardiovascular cause); the key secondary outcome was all‐cause and cardiovascular mortality. Among 596 eligible patients, the prevalence of LVH was determined as 56.3% by Sokolow‐Lyon, 31.1% by Romhilt‐Estes, and 48.1% by Cornell criteria. Regardless of the criteria, patients with ECG LVH had more severe aortic stenosis hemodynamics and higher left ventricular mass index. After multivariate adjustment, the presence of LVH by the Cornell criteria was significantly associated with lower risks of MACCE (adjusted hazard ratio [HR], 0.68; 95% CI, 0.51–0.91; P=0.009), all‐cause mortality (adjusted HR, 0.55; 95% CI, 0.34–0.90 [P=0.017]), and cardiovascular mortality (adjusted HR, 0.40; 95% CI, 0.20–0.79 [P=0.008]). However, this association was absent with the Sokolow‐Lyon and Romhilt‐Estes criteria. Conclusions ECG LVH by Cornell criteria only was significantly associated with lower risks of MACCE and all‐cause or cardiovascular mortality. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03298178.

Abstract Background We aimed to evaluate the effect of limited volume of hydroxyethyl starch (HES) administration on postoperative renal function in patients undergoing cardiac surgery under cardiopulmonary bypass (CPB). Methods One thousand six hundred fifty-seven patients undergoing cardiac surgery under CPB over two years were included. The patients were divided according to the amount of HES administrated during the first 2 days post-surgery; moderate dose HES (≥20 ml/kg) versus low dose HES (

Selective autophagy controls cellular homeostasis by degrading unnecessary or damaged cellular components. Melanosomes are specialized organelles that regulate the biogenesis, storage, and transport of melanin in melanocytes. However, the mechanisms underlying melanosomal autophagy, known as the melanophagy pathway, are poorly understood. To better understand the mechanism of melanophagy, we screened an endocrine-hormone chemical library and identified nalfurafine hydrochlorides, a κ-opioid receptor agonist, as a potent inducer of melanophagy. Treatment with nalfurafine hydrochloride increased autophagy and reduced melanin content in alpha-melanocyte-stimulating hormone (α-MSH)-treated cells. Furthermore, inhibition of autophagy blocked melanosomal degradation and reversed the nalfurafine hydrochloride-induced decrease in melanin content in α-MSH-treated cells. Consistently, treatment with other κ-opioid receptor agonists, such as MCOPPB or mianserin, inhibited excessive melanin production but induced autophagy in B16F1 cells. Furthermore, nalfurafine hydrochloride inhibited protein kinase A (PKA) activation, which was notably restored by forskolin, a PKA activator. Additionally, forskolin treatment further suppressed melanosomal degradation as well as the anti-pigmentation activity of nalfurafine hydrochloride in α-MSH-treated cells. Collectively, our data suggest that stimulation of κ-opioid receptors induces melanophagy by inhibiting PKA activation in α-MSH-treated B16F1 cells.

Abstract As a dynamic organelle, mitochondria continuously fuse and divide with adjacent mitochondria. Imbalance in mitochondria dynamics leads to their dysfunction, which implicated in neurodegenerative diseases. However, how mitochondria alteration and glucose defect contribute to pathogenesis of Alzheimer’s disease (AD) is still largely unknown. Dynamin‐related protein 1 (Drp1) is an essential regulator for mitochondria fission. Among various posttranslational modifications, O-GlcNAcylation plays a role as a sensor for nutrient and oxidative stress. In this study, we identified that Drp1 is regulated by O-GlcNAcylation in AD models. Treatment of Aβ as well as PugNAc resulted in mitochondrial fragmentation in neuronal cells. Moreover, we found that AD mice brain exhibits an upregulated Drp1 O-GlcNAcylation. However, depletion of OGT inhibited Drp1 O-GlcNAcylation in Aβ-treated cells. In addition, overexpression of O-GlcNAc defective Drp1 mutant (T585A and T586A) decreased Drp1 O-GlcNAcylation and Aβ-induced mitochondria fragmentation. Taken together, these finding suggest that Aβ regulates mitochondrial fission by increasing O-GlcNAcylation of Drp1.

Although autophagy regulates the quality and quantity of cellular compartments, the regulatory mechanisms underlying peroxisomal autophagy (pexophagy) remain largely unknown. In this study, we identified several BRD4 inhibitors, including molibresib, a novel pexophagy inducer, via chemical library screening. Treatment with molibresib promotes loss of peroxisomes selectively, but not mitochondria, ER, or Golgi apparatus in HeLa cells. Consistently, depletion of BRD4 expression also induced pexophagy in RPE cells. In addition, the inhibition of BRD4 by molibresib increased autophagic degradation of peroxisome ATG7-dependency. We further found that molibresib produced reactive oxygen species (ROS), which potentiates ATM activation. Inhibition of ROS or ATM suppressed the loss of peroxisomes in molibresib-treated cells. Taken together, our data suggest that inhibition of BRD4 promotes pexophagy by increasing ROS and ATM activation.

Primary cilia help to maintain cellular homeostasis by sensing conditions in the extracellular environment, including growth factors, nutrients, and hormones that are involved in various signaling pathways. Recently, we have shown that enhanced primary ciliogenesis in dopamine neurons promotes neuronal survival in a Parkinson’s disease model. Moreover, we performed fecal metabolite screening in order to identify several candidates for improving primary ciliogenesis, including L-carnitine and acetyl-L-carnitine. However, the role of carnitine in primary ciliogenesis has remained unclear. In addition, the relationship between primary cilia and neurodegenerative diseases has remained unclear. In this study, we have evaluated the effects of carnitine on primary ciliogenesis in 1-methyl-4-phenylpyridinium ion (MPP+)-treated cells. We found that both L-carnitine and acetyl-L-carnitine promoted primary ciliogenesis in SH-SY5Y cells. In addition, the enhancement of ciliogenesis by carnitine suppressed MPP+-induced mitochondrial reactive oxygen species overproduction and mitochondrial fragmentation in SH-SY5Y cells. Moreover, carnitine inhibited the production of pro-inflammatory cytokines in MPP+-treated SH-SY5Y cells. Taken together, our findings suggest that enhanced ciliogenesis regulates MPP+-induced neurotoxicity and inflammation.

Abstract Background Surgical management of the mitral valve (MV) in patients with mild-to-moderate mitral dysfunction undergoing aortic valve replacement is still controversial. We investigated the echocardiographic data from patients with mild-to-moderate mitral dysfunction who did not undergo MV surgery. Materials and methods From January 1989 to June 2012, a total of 2731 patients underwent aortic valve replacement. Among these, 560 patients with mild-to-moderate mitral dysfunction were screened. Of these, 292 patients (61.9 ± 13.0 years; 113 females) who had not undergone MV surgery formed our study cohort. Survival, valve-related complication, and echocardiographic data were evaluated. Results There were three early deaths. During the mean follow-up period of 56.9 ± 46.5 months, there were 23 late deaths and 28 valve-related complications. Valve-related event-free survival at 5 years was 85.9% ± 2.4%. In serial postoperative echocardiographic evaluations (mean follow-up duration: 40.8 ± 44.5 months), 21 patients experienced a progression in late mitral dysfunction. At 5 years, 88.8% ± 2.7% of patients did not suffer from late mitral dysfunction. Based on multivariate analysis, rheumatic pathology of MV (Hazard Ratio: 3.88, 95% confidence intervals 1.60–9.39, p = 0.003) was an independent predictor of late mitral dysfunction. Conclusions Conservatively treated patients with mild-to-moderate mitral dysfunction exhibited acceptable clinical outcomes. Rheumatic pathology of MV is associated with a higher risk of progressive native MV dysfunction.

A 61-year-old woman who presented with claudication and dyspnea on exertion was found to have severe calcified narrowing of the descending aorta and severe insufficiency of the aortic valve. These findings were compatible with Takayasu arteritis. To treat these hemodynamic abnormalities, extra-aortic bypass surgery combined with replacement of the aortic valve and ascending aorta-to-hemiarch replacement was performed through a separated upper hemi-sternotomy and limited median laparotomy. We present our successful surgical experience with this case.

Neo-aortic insufficiency associated with root enlargement following an arterial switch operation is a serious late complication. To achieve successful surgical correction of this condition, multiple factors should be considered, including the individual patient’s anatomy, the challenging nature of the redo procedure, and the patient’s young age. However, limited publications have described the use of valve-sparing techniques for the treatment of neo-aortic insufficiency associated with root enlargement following an arterial switch operation. Herein, we report our recent experience of a valve-sparing aortic root procedure with ascending aorta and hemiarch replacement despite the presence of a discrepancy in leaflet size and nearby severe adhesions.

The melanosome is a specialized membrane-bound organelle that is involved in melanin synthesis, storage, and transportation. In contrast to melanosome biogenesis, the processes underlying melanosome degradation remain largely unknown. Autophagy is a process that promotes degradation of intracellular components' cooperative process between autophagosomes and lysosomes, and its role for process of melanosome degradation remains unclear. Here, we assessed the regulation of autophagy and its contributions to depigmentation associated with Melasolv (3,4,5-trimethoxycinnamate thymol ester). B16F1 cells-treated with Melasolv suppressed the α-MSH-stimulated increase of melanin content and resulted in the activation of autophagy. However, introduction of bafilomycin A1 strongly suppressed melanosome degradation in Melasolv-treated cells. Furthermore, inhibition of autophagy by ATG5 resulted in significant suppression of Melasolv-mediated depigmentation in α-MSH-treated cells. Taken together, our results suggest that treatment with Melasolv inhibits skin pigmentation by promoting melanosome degradation via autophagy activation.

Background: Prosthetic valve endocarditis (PVE) is a serious complication of cardiac valve replacement, and many p atients with P VE r equire r eoperation. The aim of t his study was to r eview our institutional 2 0 -year experience of surgical reoperative valve replacement in patients with PVE. Methods: A retrospective study was performed on 84 patients (mean age, 54.8±12.7 years; 51 males) who were diagnosed with PVE and underwent reoperative valve replacement from January 1995 to December 2016. Results: PVE was found in 1 valve in 61 cases (72.6%), and in 2 or more valves in 23 cases (27.4%). The median follow-up duration was 47.3 months (range, 0 to 250 months). Postoperative complications occurred in 39 patients (46.4%). Reinfection occurred in 6 cases, all within 1 year. The freedom from reinfection rate at 5 years was 91.0%±3.5%. The overall survival rates at 5 and 10 years were 64.4%±5.8% and 54.3%±7.3%, respectively. In stepwise multivariable Cox proportional hazard models, older age (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.05 to 2.10; p=0.027) and cardiopulmonary bypass (CPB) time (HR, 1.03; 95% CI, 1.00 to 1.0 1; p =0 . 0 33) e merged a s independent risk f actors f or d eath. Conclusion: Older age and a longer CPB time were associated with an increased risk of overall mortality in PVE patients.

As mediastinal sarcomas commonly present as large tumors invading adjacent vital structures, complete re-section is frequently challenging. For such tumors, aggressive surgical strategies, such as the resection and reconstruction of the invaded vital structures under cardiopulmonary bypass, may be required to achieve complete resection and to improve survival. Herein, we report a case of recurrent mediastinal sarcoma in-vading the aortic arch and arch vessels that was successfully removed by total arch replacement.

Particulate matters (PMs) increase oxidative stress and inflammatory response in different tissues. PMs disrupt the formation of primary cilia in various skin cells, including keratinocytes and melanocytes. In this study, we found that 2-isopropylmalic acid (2-IPMA) promoted primary ciliogenesis and restored the PM2.5-induced dysgenesis of primary cilia in dermal fibroblasts. Moreover, 2-IPMA inhibited the generation of excessive reactive oxygen species and the activation of stress kinase in PM2.5-treated dermal fibroblasts. Further, 2-IPMA inhibited the production of pro-inflammatory cytokines, including IL-6 and TNF-α, which were upregulated by PM2.5. However, the inhibition of primary ciliogenesis by IFT88 depletion reversed the downregulated cytokines by 2-IPMA. Moreover, we found that PM2.5 treatment increased the MMP-1 expression in dermal fibroblasts and a human 3-D-skin model. The reduced MMP-1 expression by 2-IPMA was further reversed by IFT88 depletion in PM2.5-treated dermal fibroblasts. These findings suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in dermal fibroblasts.

Primary cilia mediate the interactions between cells and external stresses. Thus, dysregulation of primary cilia is implicated in various ciliopathies, e.g., degeneration of the retina caused by dysregulation of the photoreceptor primary cilium. Particulate matter (PM) can cause epithelium injury and endothelial dysfunction by increasing oxidative stress and inflammatory responses. Previously, we showed that PM disrupts the formation of primary cilia in retinal pigment epithelium (RPE) cells. In the present study, we identified 2-isopropylmalic acid (2-IPMA) as a novel inducer of primary ciliogenesis from a metabolite library screening. Both ciliated cells and primary cilium length were increased in 2-IPMA-treated RPE cells. Notably, 2-IPMA strongly promoted primary ciliogenesis and restored PM2.5-induced dysgenesis of primary cilia in RPE cells. Both excessive reactive oxygen species (ROS) generation and activation of a stress kinase, JNK, by PM2.5 were reduced by 2-IPMA. Moreover, 2-IPMA inhibited proinflammatory cytokine production, i.e., IL-6 and TNF-α, induced by PM2.5 in RPE cells. Taken together, our data suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in RPE cells.

The formation of aortic thrombi is an extremely rare complication of acute pancreatitis. Here we report a case of acute pancreatitis complicated by a paraesophageal pseudocyst, necrotizing mediastinitis, and the formation of multiple thrombi in the ascending aorta. The patient was successfully treated by surgical therapy, which included extensive debridement of the mediastinum and removal of the aortic thrombi under cardiopulmonary bypass. Although esophageal resection was not carried out concomitantly, the lesions were resolved and the patient remained free of complications over 2 years of follow-up care.

Background: The standard approach in treating cardiac myxoma is the median full sternotomy. With the evolution of surgical techniques, the right minithoracotomy approach has emerged as an alternative method. Since few studies have been published assessing the right minithoracotomy approach, we performed a retrospective study to compare the clinical outcomes of the right minithoracotomy approach with those of the sternotomy approach. Methods: From January 2005 to December 2014, 203 patients underwent resection of a cardiac myxoma. Patients with preexisting cardiac problems were excluded from this study. 146 patients were enrolled in this study; 83 patients were treated using a median sternotomy and 63 patients were treated using a right minithoracotomy. Results: No early mortalities were recorded in either group. Although the cardiopulmonary bypass time and aorta cross-clamp time were significantly shorter in the sternotomy group (p＜0.001 and p=0.005), postoperative blood transfusions and arrhythmia events were significantly less common in the thoracotomy group (p=0.004 and p=0.025, respectively). No significant differences were found in the duration of the hospital stay, postoperative intubation time, the duration of the intensive care unit stay, and recurrence. Conclusion: The minimally invasive right minithoracotomy approach is a good alternative method for treating cardiac myxoma because it was found to be associated with a lower incidence of postoperative complications and a shorter postoperative recovery period.

Background: The advantages of using a homograft in valve replacement surgery are the excellent hemodynamic profile, low risk of thromboembolism, and low risk of prosthetic valve infection. The aim of this study was to evaluate the long-term outcomes of homograft implantation in the aortic valve position. Methods: This is a retrospective study of 33 patients (＞20 years old) who underwent aortic valve replacement or root replacement with homografts between April 1995 and May 2015. Valves were collected within 24 hours from explanted hearts of heart transplant recipients (＜60 years) and organ donors who were not suitable for heart transplantation. The median follow-up duration was 35.6 months (range, 0 to 168 months). Results: Aortic homografts were used in all patients. The 30-day mortality rate was 9.1%. The 1- and 5-year survival rates were 80.0%±7.3% and 60.8%±10.1%, respectively. The 1-, 5-, and 10-year freedom from reoperation rates were 92.3%±5.2%, 68.9%±10.2%, and 50.3%±13.6%, respectively. The 1-, 5-, and 10-year freedom from significant aortic dysfunction rates were 91.7%±8.0%, 41.7%±14.2%, and 25.0%±12.5%, respectively. Conclusion: Homografts had the advantages of a good hemodynamic profile and low risk of thromboembolic events, and with good outcomes in cases of aortitis.

Background: Generalization of standardized surgical techniques to treat aortic valve (AV) and aortic root diseases has benefited large numbers of patients. As a consequence of the proliferation of patients receiving aortic root surgeries, surgeons are more frequently challenged by reoperative aortic root procedures. The aim of this study was to evaluate the outcomes of redo-aortic root replacement (ARR). Methods: We retrospectively reviewed 66 patients (36 male; mean age, 44.5±9.5 years) who underwent redo-ARR following AV or aortic root procedures between April 1995 and June 2015. Results: Emergency surgeries comprised 43.9% (n=29). Indications for the redo-ARR were aneurysm (n=12), pseudoaneurysm (n=1), or dissection (n=6) of the residual native aortic sinus in 19 patients (28.8%), native AV dysfunction in 8 patients (12.1%), structural dysfunction of an implanted bioprosthetic AV in 19 patients (28.8%), and infection of previously replaced AV or proximal aortic grafts in 30 patients (45.5%). There were 3 early deaths (4.5%). During follow- up (median, 54.65 months; quartile 1–3, 17.93 to 95.71 months), there were 14 late deaths (21.2%), and 9 valve-related complications including reoperation of the aortic root in 1 patient, infective endocarditis in 3 patients, and hemorrhagic events in 5 patients. Overall survival and event-free survival rates at 5 years were 81.5%±5.1% and 76.4%±5.4%, respectively. Conclusion: Despite technical challenges and a high rate of emergency conditions in patients requiring redo-ARR, early and late outcomes were acceptable in these patients.

Background: The use of extracorporeal life support (ECLS) in the setting of cardiopulmonary resuscitation (CPR) has shown improved outcomes compared with conventional CPR. The aim of this study was to determine factors predictive of survival in extracorporeal CPR (E-CPR). Methods: Consecutive 85 adult patients (median age, 59 years; range, 18 to 85 years; 56 males) who underwent E-CPR from May 2005 to December 2012 were evaluated. Results: Causes of arrest were cardiogenic in 62 patients (72.9%), septic in 18 patients (21.2%), and hypovolemic in 3 patients (3.5%), while the etiology was not specified in 2 patients (2.4%). The survival rate in patients with septic etiology was significantly poorer compared with those with another etiology (0% vs. 24.6%, p=0.008). Septic etiology (hazard ratio [HR], 2.84; 95% confidence interval [CI], 1.49 to 5.44; p=0.002) and the interval between arrest and ECLS initiation (HR, 1.05 by 10 minutes increment; 95% CI, 1.02 to 1.09; p=0.005) were independent risk factors for mortality. When the predictive value of the E-CPR timing for in-hospital mortality was assessed using the receiver operating characteristic curve method, the greatest accuracy was obtained at a cutoff of 60.5 minutes (area under the curve, 0.67; 95% CI, 0.54 to 0.80; p=0.032) with 47.8% sensitivity and 88.9% specificity. The survival rate was significantly different according to the cutoff of 60.5 minutes (p=0.001). Conclusion: These results indicate that efforts should be made to minimize the time between arrest and ECLS application, optimally within 60 minutes. In addition, E-CPR in patients with septic etiology showed grave outcomes, suggesting it to be of questionable benefit in these patients.