Transcatheter edge-to-edge mitral valve repair for mitral regurgitation in patients with cardiogenic shock: A systematic review and meta-analysis.

BACKGROUND: There is currently little evidence for transcatheter edge-to-edge mitral valve repair (TEER) for mitral regurgitation (MR) in patients with cardiogenic shock (CS). Therefore, this study investigated the characteristics and outcomes of CS patients who underwent TEER for MR. METHODS: PubMed, EMBASE were searched in July 2023. Case series and observational studies reporting clinical characteristics and outcomes in CS patients with MR who underwent TEER were included. We performed a one-group meta-analysis using a random effects model. RESULTS: A total of 4060 patients from 7 case series and 5 observational studies were included. The mean age was 68.2 (95% confidence interval [CI]: 64.1-72.2) years, and 41.4% of patients (95% CI: 39.1%-43.7%) were female. Pre-TEER, severe MR was present in 85.3% (95% CI: 76.1%-91.3%) of patients. Mean left ventricular ejection fraction was 36.7% (95% CI: 29.2%-44.2%), and 54.6% (95% CI: 36.9%-71.2%) of patients received mechanical circulatory support. The severity of MR post-TEER was less than 2+ in 88% (95% CI: 87%-89%) of patients. In-hospital mortality was 11% (95% CI: 10%-13%), whereas 30-day and 1-year mortality rates were 15% (95% CI: 13%-16%), and 36% (95% CI: 21%-54%), respectively. CONCLUSIONS: This systematic review and meta-analysis assessed the clinical characteristics and outcomes of TEER in CS patients with MR. TEER for MR in patients with CS has been successful in reducing MR in most of the patients, but with a high mortality rate. Randomized controlled trials of TEER for MR and CS are needed.

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

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

Mitochondria-dependent synthetic small-molecule vaccine adjuvants for influenza virus infection.

Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.

Chondroprotective effects of CDK4/6 inhibition via enhanced ubiquitin-dependent degradation of JUN in synovial fibroblasts.

OBJECTIVE: Targeting synovial fibroblasts (SF) using a cyclin-dependent kinase (CDK) 4/6 inhibitor (CDKI) could be a potent therapy for RA via inhibition of proliferation and MMP-3 production. This study was designed to elucidate the mechanism of chondroprotective effects on SFs by CDK 4/6 inhibition. METHODS: CDK4/6 activity was inhibited using CDKI treatment or enhanced by adenoviral gene transduction. Chondroprotective effects were evaluated using a collagen-induced arthritis model (CIA). Gene and protein expression were evaluated with quantitative PCR, ELISA and Western blotting. The binding of nuclear extracts to DNA was assessed with an electrophoresis mobility shift assay. RNA-Seq was performed to identify gene sets affected by CDKI treatment. RESULTS: CDKI attenuated cartilage destruction and MMP-3 production in CIA. In RASFs, CDKI impaired the binding of AP-1 components to DNA and inhibited the production of MMP-1 and MMP-3, which contain the AP-1 binding sequence in their promoter. CDK4/6 protected JUN from proteasome-dependent degradation by inhibiting ubiquitination. The RNA-Seq analysis identified CDKI-sensitive inflammatory genes, which were associated with the pathway of RA-associated genes, cytokine-cytokine receptor interaction and IL-17 signalling. Notably, the AP-1 motif was enriched in these genes. CONCLUSION: The mechanism of chondroprotective effects by CDK4/6 inhibition was achieved by the attenuation of AP-1 transcriptional activity via the impaired stability of JUN. Because the pharmacologic inhibition of CDK4/6 has been established as tolerable in cancer treatment, it could also be beneficial in patients with RA due to its chondroprotective and anti-inflammatory effects.

Short-Term Outcomes of Magnetically Levitated Left Ventricular Assist Device in Advanced Heart Failure　- The Japanese Cohort.

BACKGROUND: The superiority of a fully magnetically levitated centrifugal-flow left ventricular assist device (LVAD) in terms of overall survival, stroke events and pump thrombosis has been demonstrated in previous international analyses, so we evaluated a Japanese cohort for the same.Methods and Results: This retrospective observational study was conducted at Osaka University Medical Hospital and the National Cerebral and Cardiovascular Center in Japan. A total of 75 consecutive patients who underwent HeartMate3 (HM3) implantation were included. The primary endpoint was on-device survival, and the secondary endpoint was the incidence of LVAD-related complications at 2 years. All parameters were compared with those of the previously performed HeartMate II (HMII) implantation in 197 cases. The on-device survival rates were 94.7% and 92.3% in the HM3 and HMII groups, respectively, at the 2-year follow-up (P=0.62). The rehospitalization-free rate after implantation was 61.8% in the HM3 group, which was significantly higher than that in the HMII group (relative risk, 0.35; 95% confidence interval [CI], 0.23-0.55; P<0.0001). Event-free survival rates from cerebral cerebrovascular events and pump thrombosis in the HM3 group were significantly higher than those in the HMII group, at 97.2% and 100%, respectively (relative risk, 0.14; 95% CI 0.03-0.58); P=0.0015 and relative risk, not calculated; P=0.049, respectively). CONCLUSIONS: Satisfactory short-term outcomes were observed after HM3 implantation in a Japanese cohort.

Risk factors of gynecological bleeding in female patients with left-ventricular assist device.

Women with implantable left-ventricular assist devices (LVADs) experience gynecological bleeding (GYN-bleeding). However, a few studies have investigated female-specific problems. Therefore, this study aimed to identify the risk factors for adverse GYN-bleeding after LVAD implantation. We retrospectively analyzed 59 women (mean age: 41 ± 15 years) with long-term implantable LVAD support (≥ 6 months) at our institution between 2005 and 2018. The history of GYN-bleeding before implantation was defined as abnormal utero-ovarian bleeding, excessive menstruation, uterine fibroids, and endometrial lesions. GYN-bleeding after implantation was defined as a requirement of emergency outpatient visits and/or hospitalization, blood transfusions, hormonal therapy, and/or surgery. Additionally, risk factors for GYN-bleeding were identified using the Cox regression model. Twenty-four GYN-bleeding cases were seen in 15 patients (two times: five patients, three times: two patients, 0.18 events per patient-year). The 1- and 2-year GYN-bleeding-free rates were 84% and 73%, respectively. Twelve patients (17 events) required RBC ≥ 4 units, and five patients (7 events) required FFP ≥ 4 units. Seven patients required pseudomenopausal treatment after blood transfusion, and four patients required surgical treatment. Fifteen patients with GYN-bleeding after implantation were significantly younger than the remaining 44 patients without GYN-bleeding (34 ± 12 years vs. 43 ± 16 years, P = 0.02). Multivariable risk analysis showed a history of GYN-bleeding before implantation was a significant risk factor (hazard ratio 3.7 [1.2-10.6], P = 0.004). Patients with a history of GYN-bleeding before LVAD implantation have a high risk of developing GYN-bleeding after implantation. We should identify the high-risk population and prepare for the management of GYN-bleeding.

Sudden severe left ventricular assist device inflow cannula obstruction caused by huge thrombus after closure of mechanical aortic valve: case report.

Thrombus formation is a troublesome and sometimes lethal complication occurring in patients with severe heart failure and supported by a left ventricular assist device (LVAD). Appropriate treatment for pump thrombosis especially in emergency cases with severe pump failure is difficult to choose. Herein, we present important findings of a case of unexpected LVAD pump thrombosis that rapidly developed into serious pump failure and circulatory arrest due to total obstruction of the LVAD inflow tract by a huge thrombus.

Multijurisdictional Outbreak of Enterohemorrhagic Escherichia coli O157 Caused by Consumption of Ready-to-Eat Grilled Skewered Meat in Niigata, Japan.

Enterohemorrhagic Escherichia coli O157 (EHEC) causes severe complications such as hemolytic uremic syndrome. Contaminated ready-to-eat (RTE) food is one of the vehicles of multijurisdictional outbreaks of foodborne disease worldwide. Multijurisdictional (covering cities, towns, and villages) outbreaks of EHEC are usually linked to an increase in cases, and here we describe such an outbreak involving 29 cases in October 2017 in the Niigata Prefecture. After prefecture-wide active case finding, we conducted a case-control study of 29 cases with eligible data who tested positive for EHEC. To determine the association of the outbreak with risk factors, we compared these cases with 38 controls selected from family and acquaintances who were both symptom free and tested negative for EHEC. The largest number of cases was in the 20-29-year age group (7/29; 24%) and most were women (20/29; 69%). All 29 cases had an identical or similar multilocus variable number tandem-repeat analysis (MLVA) profile. Of these, 76% (22/29) had consumed some type of grilled skewered meat. Also, 69% (20/29) had consumed grilled skewered meat produced by company X. EHEC infection was strongly associated with the consumption of grilled skewered meat produced by any food processing company (odds ratio [OR] = 11.8, confidence interval [95% CI]: 3.7-37.4) and by company X (OR = 9.8, 95% CI: 3.2-30.7). At company X, the skewered meat was grilled to 95°C and then removed from the grilling area to meat trays. The meat trays were not sufficiently washed and disinfected. Testing indicated that the facility was negative for EHEC but four asymptomatic employees tested positive for EHEC. Company X was temporarily closed and voluntarily recalled the foods. We recommend that all employees sufficiently wash and disinfect meat trays to prevent contamination of RTE food, avoid cross-contamination of grilled skewered meat through the environment by regularly cleaning the facility, and appropriately practice self-health care.

[Clinical Outcome of Heart Transplantation in Osaka University].

In this article, we analyzed 114 adult heart transplantation( HTx) cases from 1999 to 2021. Of these cases, 94% of patients underwent left ventricular assist device ( LVAD) implantation before HTx. The mean period of LVAD support was 3.0 ±1.2 years. Thirty-day mortality was 0.8% and the 10-year survival rate was 89% after HTx. Preoperative and postoperative renal function was the prognostic factors. Long LVAD support was not associated with the long-term survival after HTx.

Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation.

In the face of emerging infectious diseases, there remains an unmet need for vaccine development where adjuvants that enhance immune responses to pathogenic antigens are highly desired. Using high-throughput screens with a cell-based nuclear factor κB (NF-κB) reporter assay, we identified a sulfamoyl benzamidothiazole bearing compound 1 that demonstrated a sustained activation of NF-κB after a primary stimulus with a Toll-like receptor (TLR)-4 agonist, lipopolysaccharide (LPS). Here, we explore systematic structure-activity relationship (SAR) studies on compound 1 that indicated the sites on the scaffold that tolerated modification and yielded more potent compounds compared to 1. The selected analogs enhanced release of immunostimulatory cytokines in the human monocytic cell line THP-1 cells and murine primary dendritic cells. In murine vaccination studies, select compounds were used as co-adjuvants in combination with the Food and Drug Administration approved TLR-4 agonistic adjuvant, monophosphoryl lipid A (MPLA) that showed significant enhancement in antigen-specific antibody titers compared to MPLA alone. Additionally, our SAR studies led to identification of a photoaffinity probe which will aid the target identification and mechanism of action studies in the future.

Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy.

The Keap1-Nrf2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes. However, the interplay between these two pathways remains largely unknown. Here, we show that phosphorylation of the autophagy-adaptor protein p62 markedly increases p62's binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2. Thus, p62 phosphorylation induces expression of cytoprotective Nrf2 targets. p62 is assembled on selective autophagic cargos such as ubiquitinated organelles and subsequently phosphorylated in an mTORC1-dependent manner, implying coupling of the Keap1-Nrf2 system to autophagy. Furthermore, persistent activation of Nrf2 through accumulation of phosphorylated p62 contributes to the growth of human hepatocellular carcinomas (HCCs). These results demonstrate that selective autophagy and the Keap1-Nrf2 pathway are interdependent, and that inhibitors of the interaction between phosphorylated p62 and Keap1 have potential as therapeutic agents against human HCC.

Successful surgical resection and reconstruction for a huge primary cardiac lymphoma filling the right heart.

Primary cardiac lymphoma (PCL) is rare, with a frequency of 1.0%-1.6% among cardiac malignant tumors. Chemotherapy is often selected as a first-line treatment for PCL. However, when the tumor causes heart failure or life-threatening hemodynamic collapse, antecedent urgent surgery is required. We herein report a successful case of complete tumor resection and reconstruction of the right atrium and right ventricle using a bovine pericardial patch combined with tricuspid valve replacement in a patient with a huge PCL filling the right heart that manifested as tricuspid valve stenosis and subsequent heart failure.

Surgical exclusion of an idiopathic saccular aneurysm in the left main trunk of the coronary artery.

PURPOSE: A coronary artery aneurysm (CAA) can result in critical cardiac events such as thromboembolic complications or rupture. A saccular CAA located in the left main trunk (LMT) is the most critical form of this pathology and its surgical repair is challenging. We conducted this single-center study to review the surgical outcomes of patients with a saccular CAA in the LMT. METHODS: Between May, 2012 and June, 2020, five patients with a saccular CAA in the LMT underwent surgery at our center. The median age at operation was 66.5 (59.7-69) years and the median diameter of the CAA was 13.0 mm (IQR 11-14 mm). RESULTS: The CAA was fully excluded by patch closure of the LMT orifice and direct closure of the distal LMT, supplemented by coronary artery bypass grafting with the exclusive use of arterial conduits. There was no in-hospital mortality, although one patient suffered graft spasm-related myocardial infarction with complete recovery. Post-operative angiography showed a fully excluded LMT in all patients. There was no mortality or adverse cardiac events during follow-up. CONCLUSIONS: Our surgical policy for CAA in the LMT is feasible and safe; however, coronary blood flow is dependent on reliable bypasses.

Trans-radial percutaneous coronary intervention for patients with severe chronic renal insufficiency and/or on dialysis.

Periprocedural bleeding is associated with an increased risk of mortality during percutaneous coronary intervention (PCI), especially in patients with severe chronic renal insufficiency. Therefore, trans-radial intervention (TRI) should be considered in these patients; however, PCI operators usually avoid this approach because of the risk of radial artery occlusion. We aimed to investigate the associations of TRI and in-hospital complications in these patients. This study included 306 consecutive patients with severe chronic renal insufficiency and/or on dialysis who underwent PCI. Patients were prospectively enrolled and divided according to the access site into TRI group and trans-femoral intervention group. Severe renal insufficiency was defined as estimated glomerular filtration rate < 30 mL/min/1.73 m2. Radial access was limited to the opposite side of the arteriovenous fistula in patients on hemodialysis. The primary study endpoint was the composite of in-hospital bleeding complications and death. TRI benefit was evaluated by inverse probability treatment weighted analysis. TRI was performed in 112 (37.3%) patients. TRI group included older patients with significantly lower rates of diabetes mellitus, dialysis, and three-vessel disease. Crossover to the other approach occurred only in TRI group (2.6%). The primary endpoint was significantly lower in TRI group (11.5% vs. 2.6%, P = 0.006). After an inverse probability treatment weighted analysis, TRI was an independent prognostic factor for a decrease in the primary endpoint (OR 0.19; 95% CI 0.051-0.73; P = 0.015). Radial artery occlusion occurred in three patients on dialysis (9.1%). TRI may determine better in-hospital outcomes in patients with severe chronic renal insufficiency and/or on dialysis.

Effect of Continuous-Flow Mechanical Circulatory Support on Microvasculature Remodeling in the Failing Heart.

Left ventricle (LV) unloading caused by a left ventricular assist device (LVAD) has been shown to enhance reverse LV remodeling in end-stage cardiomyopathy. Several reports consistently suggest that a pulsatile-flow LVAD has more profound effects compared to continuous-flow LVAD, though the responsible mechanisms are not fully understood. We hypothesized that arterial pulsatility, being affected by the type of LVAD, may affect microvasculature and functional/pathological LV remodeling in end-stage cardiomyopathy. The study included 18 patients with chronic heart failure who underwent LVAD implantation. Eight patients were implanted with pulsatile-flow LVAD, and 10 patients were implanted with continuous-flow LVAD. The results of serial echocardiograms and histopathological assessment of transmural LV tissues, which were collected during the implantation and removal of LVADs, were compared between the groups. The results of echocardiography showed that LV systolic dimension and LV ejection fraction improved greatly in the pulsatile-flow LVAD group compared to the continuous-flow LVAD group. Histological analysis showed that in both groups, increased microvasculature density and decreased cardiomyocyte size during LVAD support had no significant difference. In contrast, only the patients with continuous-flow LVADs had presented with significant increase in α-smooth muscle actin (α-SMA)-positive layer thickness and the number of proliferating cell nuclear antigen (PCNA)-positive cells of myocardial arterioles. We concluded that the use of long-term continuous-flow LVAD support, having less pulsatility, had induced more thickening to the medial layer of myocardial arterioles compared to the use of pulsatile-flow LVADs. Our findings suggest that the pathological impairment of myocardial microvascular structure during continuous-flow LVAD support may be a novel mechanism which accounts for the difference in LV remodeling depending on the type of LVAD.

Physical Meanings of Fractal Behaviors of Water in Aqueous and Biological Systems with Open-Ended Coaxial Electrodes.

The dynamics of a hydrogen bonding network (HBN) relating to macroscopic properties of hydrogen bonding liquids were observed as a significant relaxation process by dielectric spectroscopy measurements. In the cases of water and water rich mixtures including biological systems, a GHz frequency relaxation process appearing at around 20 GHz with the relaxation time of 8.2 ps is generally observed at 25 °C. The GHz frequency process can be explained as a rate process of exchanges in hydrogen bond (HB) and the rate becomes higher with increasing HB density. In the present work, this study analyzed the GHz frequency process observed by suitable open-ended coaxial electrodes, and physical meanings of the fractal nature of water structures were clarified in various aqueous systems. Dynamic behaviors of HBN were characterized by a combination of the average relaxation time and the distribution of the relaxation time. This fractal analysis offered an available approach to both solution and dispersion systems with characterization of the aggregation or dispersion state of water molecules. In the case of polymer-water mixtures, the HBN and polymer networks penetrate each other, however, the HBN were segmented and isolated more by dispersed and aggregated particles in the case of dispersion systems. These HBN fragments were characterized by smaller values of the fractal dimension obtained from the fractal analysis. Some examples of actual usages suggest that the fractal analysis is now one of the most effective tools to understand the molecular mechanism of HBN in aqueous complex materials including biological systems.

The Adaptive Remodeling of the Anterior Mitral Leaflet and Chordae Tendineae Is Associated with Mitral Valve Function in Advanced Ischemic and Nonischemic Dilated Cardiomyopathy.

The degree or nature of functional mitral regurgitation (MR) is not necessarily correlated with the size or function of the left ventricle (LV). We hypothesized that the anatomical structure of the mitral valve (MV) complex might play a role in functional MR in ischemic or nonischemic dilated cardiomyopathy (DCM).The structure of the LV and MV complex in DCM patients (n = 29) was assessed using electrocardiogram-gated 320-slice computed tomography and was compared with that in healthy patients (n = 12). Twenty-five DCM patients with mild or low MR (DCM-lowMR) had markedly greater length, diameter, and sphericity index of the LV and a larger tenting area than the controls. The distance between the papillary muscle (PM) tip and the mitral annular plane was not different between DCM-lowMR and normal hearts despite the greater LV length observed in DCM-lowMR. Furthermore, DCM-lowMR had markedly longer chordae tendineae (DCM-lowMR: 24 [20-26] mm; controls: 14 [13-16] mm; P < 0.01) and larger anterior leaflets (DCM-lowMR: 30 [27-31] mm; controls: 22 [20-24] mm; P < 0.01), thus suggesting the adaptive remodeling of the MV complex. Four DCM patients with moderate-severe MR had unbalanced remodeling, such as excessive LV dilatation, short anterior mitral leaflets, and short chordae tendineae.The development of functional MR might be associated with the remodeling of LV and MV components, such as the PMs, chordae tendineae, or anterior MV leaflets. Detailed anatomical assessments of the LV and MV complex would contribute to the adequate staging of ischemic or nonischemic DCM.

A case of chronic myelomonocytic leukemia complicated with spondyloarthritis.

Chronic myelomonocytic leukemia (CMML), a clonal hematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap feature, is frequently associated with autoimmune diseases, such as vasculitis, polyarthritis, and neutrophilic dermatosis. We herein report the first case of CMML complicated with spondyloarthritis (SpA). A 64-year-old female patient, admitted to our hospital with buttock pain alternating left and right, was found to have sacroiliitis and spondylitis by contrast magnetic resonance imaging. Peripheral blood test and bone marrow biopsy revealed an increase of monocytes with trilineage dysplasia. We made a diagnosis of CMML. Although arthritic symptoms and imaging findings initially improved by azacitidine, CMML was thereafter transformed into acute myeloid leukemia. She is scheduled to hematopoietic stem cell transplantation. The concomitant onset of sacroiliitis with CMML suggested that her SpA feature was a paraneoplastic phenomenon of CMML. Thus, we must be aware that myelodysplastic syndrome including CMML can manifest as SpA.