Impact of hyper-polypharmacy due to non-cardiovascular medications on long-term clinical outcomes following endovascular treatment for lower limb artery disease: A sub-analysis of the I-PAD Nagano registry.

BACKGROUND: Lower limb artery disease (LEAD) is accompanied by multiple comorbidities; however, the effect of hyperpolypharmacy on patients with LEAD has not been established. This study investigated the associations between hyperpolypharmacy, medication class, and adverse clinical outcomes in patients with LEAD. METHODS: This study used data from a prospective multicenter observational Japanese registry. A total of 366 patients who underwent endovascular treatment (EVT) for LEAD were enrolled in this study. The primary endpoints were major adverse cardiac events (MACE), including myocardial infarction, stroke, and all-cause death. RESULTS: Of 366 patients with LEAD, 12 with missing medication information were excluded. Of the 354 remaining patients, 166 had hyperpolypharmacy (≥10 medications, 46.9 %), 162 had polypharmacy (5-9 medications, 45.8 %), and 26 had nonpolypharmacy (<5 medications, 7.3 %). Over a 4.7-year median follow-up period, patients in the hyperpolypharmacy group showed worse outcomes than those in the other two groups (log-rank test, p < 0.001). Multivariate analysis revealed that the total number of medications was significantly associated with an increased risk of MACE (hazard ratio per medication increase 1.07, 95 % confidence interval 1.02-1.13 p = 0.012). Although an increased number of non-cardiovascular medications was associated with an elevated risk of MACE, the increase in cardiovascular medications was not statistically significant (log-rank test, p = 0.002 and 0.35, respectively). CONCLUSIONS: Hyperpolypharmacy due to non-cardiovascular medications was significantly associated with adverse outcomes in patients with LEAD who underwent EVT, suggesting the importance of medication reviews, including non-cardiovascular medications.

In Vitro Selection of Macrocyclic l-α/d-α/ß/γ-Hybrid Peptides Targeting IFN-γ/IFNGR1 Protein-Protein Interaction.

Nonproteinogenic amino acids, including d-α-, ß-, and γ-amino acids, present in bioactive peptides play pivotal roles in their biochemical activities and proteolytic stabilities. d-α-Amino acids (dαAA) are widely used building blocks that can enhance the proteolytic stability. Cyclic ß2,3-amino acids (cßAA), for instance, can fold peptides into rigid secondary structures, improving the binding affinity and proteolytic stability. Cyclic γ2,4-amino acids (cγAA) are recently highlighted as rigid residues capable of preventing the proteolysis of flanking residues. Simultaneous incorporation of all dαAA, cßAA, and cγAA into a peptide is expected to yield l-α/d-α/ß/γ-hybrid peptides with improved stability and potency. Despite challenges in the ribosomal incorporation of multiple nonproteinogenic amino acids, our engineered tRNAPro1E2 successfully reaches such a difficulty. Here, we report the ribosomal synthesis of macrocyclic l-α/d-α/ß/γ-hybrid peptide libraries and their application to in vitro selection against interferon gamma receptor 1 (IFNGR1). One of the resulting l-α/d-α/ß/γ-hybrid peptides, IB1, exhibited remarkable inhibitory activity against the IFN-γ/IFNGR1 protein-protein interaction (PPI) (IC50 = 12 nM), primarily attributed to the presence of a cßAA in the sequence. Additionally, cγAAs and dαAAs in the resulting peptides contributed to their serum stability. Furthermore, our peptides effectively inhibit IFN-γ/IFNGR1 PPI at the cellular level (best IC50 = 0.75 µM). Altogether, our platform expands the chemical space available for exploring peptides with high activity and stability, thereby enhancing their potential for drug discovery.

Gerbode defect resulting from Group B Streptococcus infective endocarditis: a case report.

BACKGROUND: Gerbode defect is an unusual abnormal communication between the left ventricle and the right atrium and is a serious complication of aortic infective endocarditis. Group B Streptococcus is an uncommon cause of infective endocarditis and has a markedly destructive effect on valvular tissue. Acute fistulation between the left ventricle and the right atrium associated with this form of infective endocarditis is a life-threatening, aggressive complication that often requires urgent surgical intervention. However, the identification of actual communication is often extremely difficult. Herein, we describe an unusual case of Gerbode defect resulting from Group B Streptococcus infective endocarditis and discuss the issues surrounding such a rare cardiac defect and such an infection. CASE PRESENTATION: A 60-year-old man with underlying uncontrolled diabetes mellitus underwent endoscopic retrograde biliary drainage for acute cholangitis. On the 10th postoperative day, the patient developed multiple acute cerebral embolisms. Transthoracic echocardiography demonstrated severe aortic regurgitation and a large mobile vegetation near the tricuspid annulus. No obvious fistula between the left ventricle and the right atrium could be demonstrated. The blood culture examination was positive for Group B Streptococcus. The patient was diagnosed with Group B Streptococcus infective endocarditis, and antibiotic therapy was initiated. Transesophageal echocardiogram performed after referral to our hospital confirmed detachment of the right coronary cusp of the aortic valve from the annulus and an abnormal cavity immediately below the right coronary cusp. Color Doppler imaging finally revealed systolic blood flows from the left ventricle into the right atrium through the cavity. Therefore, we diagnosed the patient with Gerbode defect resulting from Group B Streptococcus infective endocarditis. In addition to aortic valve replacement, defect closure and left ventricular outflow tract repair were successfully performed urgently for severely complicated and uncommon infective endocarditis. The patient was uneventfully discharged without any complications. CONCLUSIONS: We reported successful surgical treatment of unusual active IE and Gerbode defect caused by GBS. Careful preoperative echocardiographic work-up is imperative for accurate early diagnosis and successful repair.

Recurrent cardiac tamponade following coronavirus disease 2019 mRNA vaccination: a case report.

A 64-year-old woman with a history of subarachnoid hemorrhage, breast cancer, cervical spine tumor, and syringomyelia developed recurrent pericardial effusion and cardiac tamponade after receiving the third dose of coronavirus disease 2019 mRNA vaccine, mRNA-1273 (Spikevax, Moderna). The cardiac tamponade of unknown etiology was intractable with nonsteroidal anti-inflammatory drugs, colchicine, and prednisolone. She underwent thoracoscopic pericardiectomy, and microthrombi were detected in the pericardial tissue. Although the exact causal relationship between vaccination and recurrent cardiac tamponade was unclear, the vaccine possibly caused or triggered the microthrombi formation, resulting in recurrent cardiac tamponade. Because of the potential for cardiovascular side effects such as thrombosis and myocarditis following vaccination, it was deemed necessary to accumulate and analyze such cases.

Cyclic ß2,3-amino acids improve the serum stability of macrocyclic peptide inhibitors targeting the SARS-CoV-2 main protease.

Due to their constrained conformations, cyclic ß2,3-amino acids (cßAA) are key building blocks that can fold peptides into compact and rigid structures, improving peptidase resistance and binding affinity to target proteins, due to their constrained conformations. Although the translation efficiency of cßAAs is generally low, our engineered tRNA, referred to as tRNAPro1E2, enabled efficient incorporation of cßAAs into peptide libraries using the flexible in vitro translation (FIT) system. Here we report on the design and application of a macrocyclic peptide library incorporating 3 kinds of cßAAs: (1R,2S)-2-aminocyclopentane carboxylic acid (ß1), (1S,2S)-2-aminocyclohexane carboxylic acid (ß2), and (1R,2R)-2-aminocyclopentane carboxylic acid. This library was applied to an in vitro selection against the SARS-CoV-2 main protease (Mpro). The resultant peptides, BM3 and BM7, bearing one ß2 and two ß1, exhibited potent inhibitory activities with IC50 values of 40 and 20 nM, respectively. BM3 and BM7 also showed remarkable serum stability with half-lives of 48 and >168 h, respectively. Notably, BM3A and BM7A, wherein the cßAAs were substituted with alanine, lost their inhibitory activities against Mpro and displayed substantially shorter serum half-lives. This observation underscores the significant contribution of cßAA to the activity and stability of peptides. Overall, our results highlight the potential of cßAA in generating potent and highly stable macrocyclic peptides with drug-like properties.

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.

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.

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.

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.