Current management of tricuspid regurgitation: a focus on the spiral suspension approach.

The indication for surgery for tricuspid regurgitation (TR) has reached a major turning point. It has become clear that the presence of moderate or severe TR alone worsens the prognosis of life, and the previous guidelines of Japanese Circulation Society, in which the indication for surgery was recommended at the timing of "right heart failure difficult to treat medically," now recommends surgery with a trigger of "repeated right heart failure" in the 2020 edition. In addition, a new repair technique targeting at subvalvular structure has been developed for end-stage TR to overcome a high TR recurrence rate that is associated with severe right ventricular enlargement and leaflet tethering. This review focuses on the spiral suspension technique, in which the papillary muscles are spirally suspended towards the septal leaflet annulus to correct tethering and enhances the understanding of its application in the context of TR management.

Fractality of Cranial Sutures.

It has long been known that skull suture has a typical fractal structure. Although the fractal dimension has been utilized to assess morphology, the mechanism of the fractal structure formation remains to be elucidated. Recent advances in the mathematical modeling of biological pattern formation provided useful frameworks for understanding this mechanism. This chapter describes how various proposed mechanisms tried to explain the formation of fractal structures in cranial sutures.

Impact of Low Bone Mineral Content Index on Cardiovascular Outcomes in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

The prognostic value of bone mineral content (BMC) for the clinical outcomes of patients with coronary artery disease (CAD) remains unknown. The present study evaluated the association between BMC index (BMCI) and cardiovascular events between January 2020 to June 2021, in consecutive patients (n = 257) with CAD undergoing percutaneous coronary intervention (PCI) at the Nagano Municipal Hospital. BMCI was measured using bioelectrical impedance analysis and calculated as the BMC divided by height squared. Patients were classified as low (<0.918) or high BMCI (≥0.918) groups according to the receiver operating characteristics curve analysis for the primary endpoint, major adverse cardiovascular events (MACE), including cardiovascular death, spontaneous myocardial infarction, stroke, and any revascularization. During a median follow-up of 744 days, the low BMCI group (n = 152) had an increased risk of MACE compared with the high group (n = 105) (19.7 vs 6.7%, P = .004). A low BMCI was significantly associated with MACE in the multivariable Cox and the Inverse Probability of Treatment Weighting analyses (hazard ratio: 3.16, 95% confidence interval: 1.15-8.67, P = .025). In conclusion, among patients with CAD undergoing PCI, BMCI was a predictor for cardiovascular events. Further research is required to determine whether medical interventions for BMC can improve patient prognosis.

Angioplasty of the inferior vena cava with a bovine pericardial patch by the modified open-chest dorsal approach for Budd-Chiari syndrome: A case report.

INTRODUCTION AND IMPORTANCE: Surgical treatment of Budd-Chiari syndrome (BCS) includes endovenectomy followed by angioplasty of the inferior vena cava (IVC). Herein, we report a case of surgery using an open-chest approach in a patient with BCS. We modified the technique reported by Kuniyoshi et al. CASE PRESENTATION: A 45-year-old male, was diagnosed with BCS and referred to our hospital. We used an open-chest approach to remove stenosis in the IVC and angioplasty with a bovine pericardial patch. Endovenectomy and angioplasty were performed by clamping the stenosis above and below it with Pringle's clamping under extracorporeal circulation. The patient is currently undergoing outpatient follow-up 14 months after the surgery, and his liver function and blood test results were normal, with no symptoms. CLINICAL DISCUSSION: The main advantage of this technique is that the liver is not mobilized from the diaphragm, which allows for the preservation of collateral blood flow between the diaphragm and liver, reducing the amount of intraoperative blood loss and damage to the liver parenchyma due to intraoperative congestion. In addition, no mobilization of the liver from the diaphragm will prevent future surgical difficulties due to adhesions during total hepatectomy when liver transplantation becomes necessary. CONCLUSION: The techniques described in this article include procedures that cardiovascular surgeons usually perform such as thoracotomy, pericardiotomy, and extracorporeal circulation. Collaborative work by hepatobiliary surgeons and cardiovascular surgeons can achieve successful outcomes with this procedure in patients with BCS.

Effectiveness of endovascular therapy using stents in a patient with celiac artery compression syndrome due to the median arcuate ligament: A case report.

Celiac artery compression syndrome (CACS) is a disease caused by celiac artery compression by the median arcuate ligament (MAL), resulting in intestinal ischemic symptoms. However, a clear method for the invasive treatment of CACS has not yet been established because of limited treatment indications. In particular, only a few reports of endovascular therapy (EVT) using stents as the initial invasive treatment are available. Here, we report a case where EVT was performed using a stent in the celiac artery, resulting in good outcomes. A 59-year-old male patient presented to our hospital with postprandial abdominal pain and was diagnosed with MAL-induced CACS since the abdominal contrast computed tomography examination showed stenosis of a celiac artery origin. He was aware of the abdominal pain symptoms; therefore, we decided to treat CACS with EVT as an invasive treatment. A bare metal stent was placed in the celiac artery, whose lumen was well dilated using intravascular ultrasound. Consequently, he no longer felt abdominal pain and had good stent patency after 15 months. Minimally invasive EVT may be considered the first-line treatment for CACS. Learning objective: The efficacy of endovascular therapy (EVT) using stents for the invasive treatment of celiac artery compression syndrome (CACS) resulting from the compression of the median arcuate ligament has not yet been established. Specifically, the efficacy of EVT using stents for CACS is unknown. We can safely perform EVT with stent placement using intravascular ultrasound for maintaining long-term patency. Therefore, minimally invasive EVT may be considered the first-line treatment for CACS.

Analyzing the effect of cell rearrangement on Delta-Notch pattern formation.

The Delta-Notch system plays a vital role in many areas of biology and typically forms a salt and pepper pattern in which cells strongly expressing Delta and cells strongly expressing Notch are alternately aligned via lateral inhibition. In this study, we consider cell rearrangement events, such as cell mixing and proliferation, that alter the spatial structure itself and affect the pattern dynamics. We model cell rearrangement events by a Poisson process and analyze the model while preserving the discrete properties of the spatial structure. We investigate the effects of the intermittent perturbations arising from these cell rearrangement events on the discrete spatial structure itself in the context of pattern formation and by using an analytical approach, coupled with numerical simulation. We find that the homogeneous expression pattern is stabilized if the frequency of cell rearrangement events is sufficiently large. We analytically obtain the balanced frequencies of the cell rearrangement events where the decrease of the pattern amplitude, as a result of cell rearrangement, is balanced by the increase in amplitude due to the Delta-Notch interaction dynamics. Our framework, while applied here to the specific case of the Delta-Notch system, is applicable more widely to other pattern formation mechanisms.

Mechanism of interdigitation formation at apical boundary of MDCK cell.

It has been reported that the MDCK cell tight junction shows stochastic fluctuation and forms the interdigitation structure, but the mechanism of the pattern formation remains to be elucidated. In the present study, we first quantified the shape of the cell-cell boundary at the initial phase of pattern formation. We found that the Fourier transform of the boundary shape shows linearity in the log-log plot, indicating the existence of scaling. Next, we tested several working hypotheses and found that the Edwards-Wilkinson equation, which consists of stochastic movement and boundary shortening, can reproduce the scaling property. Next, we examined the molecular nature of stochastic movement and found that myosin light chain puncta may be responsible. Quantification of boundary shortening indicates that mechanical property change may also play some role. Physiological meaning and scaling properties of the cell-cell boundary are discussed.

In vitro selection of macrocyclic peptide inhibitors containing cyclic γ2,4-amino acids targeting the SARS-CoV-2 main protease.

γ-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of γ-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic γ2,4-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (Mpro). Two kinds of cyclic γ2,4-amino acids, cis-3-aminocyclobutane carboxylic acid (γ1) and (1R,3S)-3-aminocyclopentane carboxylic acid (γ2), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent Mpro inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ1 at the fourth position, manifests a 5.2 nM dissociation constant. An Mpro:GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The γ1 interacts with the S1' catalytic subsite and contributes to a 12-fold increase in proteolytic stability compared to its alanine-substituted variant. Knowledge of interactions between GM4 and Mpro enabled production of a variant with a 5-fold increase in potency.

Association between complete revascularization of the coronary artery and clinical outcomes in peripheral artery disease: a sub-analysis of the I-PAD Nagano registry.

Peripheral artery disease (PAD) is commonly caused by atherosclerosis and has an unfavorable prognosis. Complete revascularization (CR) of the coronary artery reduces the risk of major adverse cardiovascular event (MACE) in patients with coronary artery disease (CAD). However, the impact of CR in patients with PAD has not been established to date. Therefore, we evaluated the impact of CR of CAD on the five-year clinical outcomes in patients with PAD. This study was based on a prospective, multicenter, observational registry in Japan. We enrolled 366 patients with PAD undergoing endovascular treatment. The primary endpoint was MACE, defined as a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke. After excluding ineligible patients, 96 and 68 patients received complete revascularization of the coronary artery (CR group) and incomplete revascularization of the coronary artery (ICR group), respectively. Freedom from MACE in the CR group was significantly higher than in the ICR group at 5 years (66.7% vs 46.0%, p < 0.01). Multivariate analysis revealed that CR emerged as an independent predictor of MACE (Hazard ratio: 0.56, 95% confidential interval: 0.34-0.94, p = 0.03). CR of CAD was significantly associated with improved clinical outcomes in patients with PAD undergoing endovascular treatment.

Eosinophilic granulomatosis with polyangiitis presenting with eosinophilic myocarditis as the only organ involvement.

A 45-year-old man with a history of bronchial asthma had fever and elevated eosinophils on the day of surgery for sinusitis, resulting in cancellation of the surgery. Two days later, he was referred to our department for electrocardiographic abnormalities. We suspected eosinophilic myocarditis (EM) since he presented with fever, left ventricular hypokinesis, and hypertrophy on echocardiography, and eosinophilia with elevated cardiac enzymes. We immediately performed an endomyocardial biopsy that showed eosinophilic infiltration of the myocardium. He was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) since he suffered from asthma, eosinophilia, sinusitis, and EM. Methylprednisolone pulse therapy followed by oral prednisolone and intravenous cyclophosphamide pulse therapy decreased his eosinophils to within the normal range, and his symptoms subsequently improved. In EGPA, cardiac involvement is less commonly seen compared to other organ involvement. Moreover, patients with EGPA who have cardiac involvement generally have other organ involvement as well. In this report, the patient had only cardiac involvement as organ damage associated with EGPA, except for asthma and sinusitis in the prodromal phase, making it clear that patients with EGPA could present with cardiac involvement alone. Therefore, it is recommended to thoroughly examine for cardiac involvement in patients with suspected EGPA. Learning objective: We report a case of eosinophilic granulomatosis with polyangiitis (EGPA) presenting with cardiac involvement alone as organ damage, subsequently diagnosed with eosinophilic myocarditis as confirmed by an endomyocardial biopsy. EGPA usually involves other organs in addition to the cardiovascular system; however, patients with EGPA could present with cardiac involvement alone, as in this case. Thus, we should thoroughly investigate for cardiac involvement in patients with suspected EGPA.

Effects of changing the timing of warfarin administration in combination with fluconazole on prolongation of the PT-INR: a case report.

BACKGROUND: Fluconazole (FLCZ) inhibits cytochrome P450 (CYP) 2C9, 2C19, and 3A4 and has a drug-drug interaction that potentiates the effects of warfarin and prolong the prothrombin time-international normalized ratio (PT-INR). Although a drug-drug interaction have been reported between FLCZ and warfarin, the effects of the timing of their administration on this interaction have not yet been investigated. CASE PRESENTATION: A female patient in her 30s with Marfan syndrome had undergone the Bentall procedure with a mechanical valve and total arch replacement for acute aortic dissection Stanford A type and rupture of the ascending aorta. Warfarin was administered to prevent thromboembolism. She was hospitalized 1 year ago for graft infection caused by Candida albicans, and treatment with FLCZ was initiated. She received FLCZ 200 mg once a day in the morning and warfarin 1.75 mg once a day in the evening, and the PT-INR remained stable at approximately 2.0 and within the therapeutic range. However, 42 days after changing the timing of administration of warfarin from evening to morning, the PT-INR was prolonged by approximately 3-fold to 6.25. The PT-INR then decreased to the previous level by changing the timing of administration of warfarin from morning to evening. CONCLUSIONS: The timing of administration of FLCZ and warfarin may affect the magnitude of drug-drug interaction.

Validation and Comparison of the Prognosis Predicting Ability of Inflammation-Based Scores Following Endovascular Treatment for Peripheral Artery Disease.

We assessed the prognostic ability of several inflammation-based scores and compared their long-term outcomes in patients with peripheral artery disease (PAD) following endovascular treatment (EVT). We included 278 patients with PAD who underwent EVT and classified them according to their inflammation-based scores (Glasgow prognostic score [GPS], modified GPS [mGPS], platelet to lymphocyte ratio [PLR], prognostic index [PI], and prognostic nutritional index [PNI]). Major adverse cardiovascular events (MACE) at 5 years were examined, and C-statistics in each measure were calculated to compare their MACE predictive ability. During the follow-up period, 96 patients experienced MACE. Kaplan-Meier analysis showed that higher scores of all measures were associated with a higher MACE incidence. Multivariate Cox proportional hazard analysis showed that GPS 2, mGPS 2, PLR 1, and PNI 1, compared with GPS 0, mGPS 0, PLR 0, and PNI 0, were associated with an increased risk of MACE. C-statistics for MACE for PNI (.683) were greater than those for GPS (.635, P = .021), mGPS (.580, P = .019), PLR (.604, P = .024), and PI (.553, P < .001). PNI is associated with MACE risk and has a better prognosis-predicting ability than other inflammation-scoring models for patients with PAD following EVT.

Successful treatment of recurrent superior vena cava syndrome due to pulmonary adenocarcinoma using intravascular ultrasound.

Patients with malignant diseases may develop symptoms of superior vena cava syndrome (SVCS) quickly because rapid tumor growth does not allow adequate time to develop collateral blood flow. Therefore, malignant SVCS is a medical emergency associated with neurological or pharyngeal-laryngeal signs. Recently, interventional endovascular treatment (EVT) has achieved acceptable results. We describe the case of a 55-year-old woman with pulmonary adenocarcinoma and laryngeal edema. In the first EVT, bare-metal-stent was implanted into the SVCS with intravascular ultrasound (IVUS) guidance. The IVUS showed insufficient stent-mid expansion. We did not use additional ballooning because of the risk of superior vena cava (SVC) rupture. Three months later, the SVCS recurred. A second EVT was performed, and IVUS imaging suggested tumor ingrowth into the SVC through the stent struts. We considered that the tumor ingrowth could be covered in the SVC using stent-graft. The patient showed no recurrence of SVCS for about 12 months. IVUS-guided implantation of stent for the treatment of malignant SVCS has not been reported. This case report revealed that stent therapy using IVUS for SVCS is useful. Learning objective: Superior vena cava syndrome (SVCS) due to malignancy is not rare. Recently, endovascular treatment for SVCS has achieved acceptable results. However, SVC stenting in SVCS as having primary patency rate varies for each report. Intravascular ultrasound (IVUS) guided implantation of stent for malignant SVCS treatment has not been reported. In this case, we suspected insufficient stent expansion and tumor ingrowth as the possible cause of in-stent restenosis. Therefore, stent therapy using IVUS for malignant SVCS can be helpful.

Pericytes and shear stress each alter the shape of a self-assembled vascular network.

Blood vessel morphology is dictated by mechanical and biochemical cues. Flow-induced shear stress and pericytes both play important roles, and they have previously been studied using on-chip vascular networks to uncover their connection to angiogenic sprouting and network stabilization. However, it is unknown which shear stress values promote angiogenesis, how pericytes are directed to sprouts, and how shear stress and pericytes affect the overall vessel morphology. Here, we employed a microfluidic device to study these phenomena in three-dimensional (3D) self-assembled vasculature. Computational fluid dynamics solver (COMSOL) simulations indicated that sprouts form most frequently at locations of relatively low shear stresses (0.5-1.5 dyn cm-2). Experimental results show that pericytes limit vascular diameter. Interestingly, when treated with imatinib or crenolanib, which are chemotherapeutic drugs and inhibitors of platelet-derived growth factor receptor ß (PDGFRß), the pericyte coverage of vessels decreased significantly but vessel diameter remained unchanged. This furthers our understanding of the mechanisms underlying vascular development and demonstrates the value of this microfluidic device in future studies on drug development and vascular biology.

Electrochemical sensing of oxygen metabolism for a three-dimensional cultured model with biomimetic vascular flow.

Microphysiological systems (MPSs) with three-dimensional (3D) cultured models have attracted considerable interest because of their potential to mimic human health and disease conditions. Recent MPSs have shown significant advancements in engineering perfusable vascular networks integrated with 3D culture models, realizing a more physiological environment in vitro; however, a sensing system that can monitor their activity under biomimetic vascular flow is lacking. We designed an open-top microfluidic device with sensor capabilities and demonstrated its application in analyzing oxygen metabolism in vascularized 3D tissue models. We first validated the platform by using human lung fibroblast (hLF) spheroids. Then, we applied the platform to a patient-derived cancer organoid and evaluated the changes in oxygen metabolism during drug administration through the vascular network. We found that the platform could integrate a perfusable vascular network with 3D cultured cells, and the electrochemical sensor could detect the change in oxygen metabolism in a quantitative, non-invasive, and real-time manner. This platform would become a monitoring system for 3D cultured cells integrated with a perfusable vascular network.

Effects of forest bathing (shinrin-yoku) on serotonin in serum, depressive symptoms and subjective sleep quality in middle-aged males.

BACKGROUND: We previously found that a forest bathing (shinrin-yoku) program significantly reduced the scores for depression, anxiety, anger, fatigue, and confusion and increased the score for vigor in the profile of mood states (POMS) test and showed a potential preventive effect on the depressive status in both males and females. In the present study, we investigated the effects of a forest bathing program on the level of serotonin in serum, depressive symptoms and subjective sleep quality in middle-aged males. METHODS: Twenty healthy male subjects aged 57.3 ± 8.4 years were selected after obtaining informed consent. These subjects took day trips to a forest park, the birthplace of forest bathing in Japan named Akasawa Shizen Kyuyourin, Agematsu, Nagano Prefecture (situated in central Japan), and to an urban area of Nagano Prefecture as a control in June 2019. On both trips, they walked 2.5 km for 2 hours each in the morning and afternoon on Saturday and Sunday, respectively. Blood was sampled in the afternoon before and after each trip. Concentrations of serotonin and lactic acid in serum were measured. The POMS test and a questionnaire for subjective sleep quality were conducted before and after the trips. Ambient temperature and humidity were monitoring during the trips. The Ethics Committees of the Nippon Medical School and Nagano Prefectural Kiso Hospital approved this study. RESULTS: The forest bathing program significantly increased level of serotonin in serum, and significantly increased the score for vigor and decreased the score for fatigue in the POMS test. The forest bathing program also improved the sleepiness on rising and feeling refreshed (recovery from fatigue) in the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA). CONCLUSIONS: Taken together, the present study suggests that forest bathing may have potential preventive effects on depression (depressive status).

Minimally Invasive Valvular Surgery in the Elderly　- Safety, Early Recovery, and Long-Term Outcomes.

BACKGROUND: For elderly people, the benefit of minimally invasive cardiac surgery (MICS) is unclear, so we evaluated the safety, recovery, and long-term survival in elderly MICS patients.Methods and Results: 63 propensity score-matched pairs of 213 consecutive patients (≥70 years old) who underwent mitral and/or tricuspid valve surgery between 2010 and 2020 (121 right mini-thoracotomies vs. 92 full sternotomies) were compared. The primary outcome was safety (composite endpoint of in-hospital death or major complication). Secondary outcomes were early ambulation and discharge to home. There were no differences between the groups for in-hospital death (3.2% vs. 0.0%, P=0.157) and primary outcome (14.3% vs. 17.5%, P=0.617). The rate of early ambulation (73.0% vs. 55.6%, P=0.048) and discharge to home (66.7% vs. 49.2%, P=0.034) were significantly higher in the mini-thoracotomy group. Major complication was an independent negative predictor of early ambulation for mini-thoracotomy but not for a conservative approach. Survival was 87.8±4.4% vs. 86.8±4.7% at 5 years, which was not significantly different. CONCLUSIONS: Similar safety but better recovery were observed for mini-thoracotomy, and long-term survival was comparable between groups. Major complication was a negative predictor of early ambulation after mini-thoracotomy. Careful preoperative risk stratification would enhance the benefits of MICS in elderly patients.

Tmsb10 triggers fetal Leydig differentiation by suppressing the RAS/ERK pathway.

Leydig cells in fetal testes play crucial roles in masculinizing fetuses through androgen production. Gene knockout studies have revealed that growth factors are implicated in fetal Leydig cell (FLC) differentiation, but little is known about the mechanisms regulating this process. We investigate this issue by characterizing FLC progenitor cells using single-cell RNA sequencing. The sequence datasets suggest that thymosin ß10 (Tmsb10) is transiently upregulated in the progenitors. While studying the function of Tmsb10, we reveal that platelet-derived growth factor (PDGF) regulates ciliogenesis through the RAS/ERK and PI3K/AKT pathways, and thereby promotes desert hedgehog (DHH)-dependent FLC differentiation. Tmsb10 expressed in the progenitor cells induces their differentiation into FLCs by suppressing the RAS/ERK pathway. Through characterizing the transiently expressed Tmsb10 in the FLC progenitors, this study unveils the molecular process of FLC differentiation and shows that it is cooperatively induced by DHH and PDGF.

Symptomatic and severe pulmonary hypertension due to hyperthyroidism.

Hyperthyroidism has been recognised as the cause of secondary pulmonary hypertension (PH). However, several studies have reported that most PH cases due to hyperthyroidism are asymptomatic and not severe. Here, we report the case of a woman in her 30s with symptomatic and severe PH due to hyperthyroidism. She presented with a 2-month history of dyspnoea on exertion, palpitation and lower-extremity oedema. Echocardiography showed severe PH with estimated pulmonary arterial systolic pressure (ePASP) of 62 mm Hg. The diagnostic work-up showed severe PH due to hyperthyroidism. After treatment for hyperthyroidism, improvement of thyroid function contributed to a decrease in ePASP to 30 mm Hg. Similar to the present case, PH due to hyperthyroidism generally improves with the treatment of hyperthyroidism. Therefore, we must not overlook hyperthyroidism as a cause of PH and diagnose and start treatment for PH-causing hyperthyroidism at an early stage.