An AsCas12f-based compact genome-editing tool derived by deep mutational scanning and structural analysis.

SpCas9 and AsCas12a are widely utilized as genome-editing tools in human cells. However, their relatively large size poses a limitation for delivery by cargo-size-limited adeno-associated virus (AAV) vectors. The type V-F Cas12f from Acidibacillus sulfuroxidans is exceptionally compact (422 amino acids) and has been harnessed as a compact genome-editing tool. Here, we developed an approach, combining deep mutational scanning and structure-informed design, to successfully generate two AsCas12f activity-enhanced (enAsCas12f) variants. Remarkably, the enAsCas12f variants exhibited genome-editing activities in human cells comparable with those of SpCas9 and AsCas12a. The cryoelectron microscopy (cryo-EM) structures revealed that the mutations stabilize the dimer formation and reinforce interactions with nucleic acids to enhance their DNA cleavage activities. Moreover, enAsCas12f packaged with partner genes in an all-in-one AAV vector exhibited efficient knock-in/knock-out activities and transcriptional activation in mice. Taken together, enAsCas12f variants could offer a minimal genome-editing platform for in vivo gene therapy.

Generation of inducible mitophagy mice.

Mitophagy is programmed selective autophagy of mitochondria and is important for mitochondrial quality control and cellular homeostasis. Mitochondrial dysfunction and impaired mitophagy are closely associated with various diseases, including heart failure and diabetes. To better understand the pathophysiological role of mitophagy, we generated doxycycline-inducible mitophagy mice using a synthetic mitophagy adaptor protein consisting of an outer mitochondrial membrane targeting sequence and an engineered LIR. To evaluate the activation of mitophagy upon doxycycline treatment, we also generated mitophagy reporter mito-QC mice in which mitochondria tandemly express mCherry and GFP, and only GFP signals are lost in acidic lysosomes subjected to mitophagy. With the ROSA26 promoter-driven rtTA, mitophagy was observed at least in heart, liver, and skeletal muscle. We investigated the relationship between mitophagy activation and pressure overload heart failure or high fat diet-induced obesity. Unexpectedly, we were unable to confirm the protective effect of mitophagy in these two pathological models. Further titration of the level of mitophagy induction is required to demonstrate the potency of the protective effects of mitophagy in disease models.

Cathepsin L prevents the accumulation of alpha-synuclein fibrils in the cell.

The deposition of α-synuclein (α-Syn) fibrils in neuronal cells has been implicated as a causative factor in Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). α-Syn can be degraded by autophagy, proteasome, and chaperone-mediated autophagy, and previous studies have suggested the potency of certain cathepsins, lysosomal proteases, for α-Syn degradation. However, no studies have comprehensively evaluated all cathepsins. Here, we evaluated the efficacy of all 15 cathepsins using a cell model of α-Syn fibril propagation and found that overexpression of cathepsin L (CTSL) was the most effective in preventing the accumulation of α-Syn aggregates. CTSL-mediated degradation of α-Syn aggregates was dependent on the autophagy machinery, and CTSL itself promoted autophagy flux. Interestingly, CTSL was effective in autophagic degradation of wild-type (WT) α-Syn, but not in the case of A53T and E46K missense mutations, which are causative for familial PD. These results suggest that CTSL is a potential therapeutic strategy for sporadic PD pathology in WT α-Syn.

Endothelial CLEC-1b plays a protective role against cancer hematogenous metastasis.

Metastasis, which is the spread of cancer cells into distant organs, is a critical determinant of prognosis in patients with cancer, and blood vessels are the major route for cancer cells to spread systemically. Extravasation is a critical process for the hematogenous metastasis; however, its underlying molecular mechanisms remain poorly understood. Here, we identified that senescent ECs highly express C-type lectin domain family 1 member B (CLEC-1b), and that endothelial CLEC-1b inhibits the hematogenous metastasis of a certain type of cancer. CLEC-1b expression was enhanced in ECs isolated from aged mice, senescent cultured human ECs, and ECs of aged human. CLEC-1b overexpression in ECs prevented the disruption of endothelial integrity, and inhibited the transendothelial migration of cancer cells expressing podoplanin (PDPN), a ligand for CLEC-1b. Notably, target activation of CLEC-1b in ECs decreased the hematogenous metastasis in the lungs by cancer cells expressing PDPN in mice. Our data reveal the protective role of endothelial CLEC-1b against cancer hematogenous metastasis. Considering the high CLEC-1b expression in senescent ECs, EC senescence may play a beneficial role with respect to the cancer hematogenous metastasis.

Impact of Sleep Apnea on Nocturnal Parasympathetic Activity in Atrial Fibrillation Patients After Catheter Ablation　- Implications for Heart Rate Variability Analysis.

BACKGROUND: The impact of sleep apnea (SA) on heart rate variability (HRV) in atrial fibrillation (AF) patients has not been investigated.Methods and Results: Of 94 patients who underwent AF ablation between January 2021 and September 2022, 76 patients who had a nocturnal Holter electrocardiography and polysomnography conducted simultaneously were included in the analysis. A 15-min duration of HRV, as determined by an electrocardiogram during apnea and non-apnea time, were compared between patients with and without AF recurrence at 12 months' postoperatively. Patients had a mean age of 63.4±11.6 years, 14 were female, and 20 had AF recurrence at 12 months' follow-up. The root mean square of the difference between consecutive normal-to-normal intervals (RMSSD, ms) an indicator of a parasympathetic nervous system, was more highly increased in patients with AF recurrence than those without, during both apnea and non-apnea time (apnea time: 16.7±4.5 vs. 13.5±3.3, P=0.03; non-apnea time: 20.9±9.5 vs. 15.5±5.9, P<0.01). However, RMSSD during an apneic state was decreased more than that in a non-apneic state in both groups of patients with and without AF recurrence (AF recurrence group: 16.7±4.5 vs. 20.9±9.5, P<0.01; non-AF recurrence group; 13.5±3.3 vs. 15.5±5.9, P=0.03). Consequently, the effect of AF recurrence on parasympathetic activity was offset by SA. Similar trends were observed for other parasympathetic activity indices; high frequency (HF), logarithm of HF (lnHF) and the percentage of normal-to-normal intervals >50 ms (pNN50). CONCLUSIONS: Without considering the influence of SA, the results of nocturnal HRV analysis might be misinterpreted. Caution should be taken when using nocturnal HRV as a predictor of AF recurrence.

Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

Infrapopliteal 3-Vessel Occlusive Disease Is the Only Predictor of Wound Recurrence After Complete Wound Healing via Endovascular Therapy in Patients With Chronic Limb-threatening Ischemia.

PURPOSE: To determine the predictors of wound recurrence after complete wound healing in patients with chronic limb-threatening ischemia (CLTI) who underwent endovascular therapy (EVT) for infrapopliteal (IP) lesions with consideration of IP arterial anatomic severity, including classification by the Global Limb Anatomic Staging System (GLASS). MATERIALS AND METHODS: This retrospective single-center study assessed patients with de novo CLTI limbs with tissue loss treated via EVT for IP lesions from September 2016 to May 2021. Among these patients, 149 consecutive limbs from 133 patients who achieved complete wound healing were enrolled. The Kaplan-Meier method was used to estimate the wound recurrence rate after complete wound healing. The Cox proportional hazard model was used to assess the association between baseline characteristics and wound recurrence. RESULTS: The cumulative wound recurrence rate 1 year after complete wound healing was 30%. The mean time for wound recurrence was 7±5 months. Only IP arterial anatomic characteristics remained as a predictor of wound recurrence, whereas wound status and management, including the Wound, Ischemia, and foot Infection (WIfI) clinical stage and minor amputation, were not associated with wound recurrence. Multivariate analysis revealed independent associations between wound recurrence and IP 3-vessel occlusive disease (hazard ratio, 2.97; 95% confidence interval, 1.39-6.35), but not poor below-the-ankle runoff, IP Peripheral Arterial Calcium Scoring System (PACSS) grade, and the GLASS IP grade. CONCLUSION: The only independent predictor of wound recurrence after complete wound healing via EVT in patients with CLTI was IP 3-vessel occlusive disease. CLINICAL IMPACT: In patients with chronic limb-threatening ischemia (CLTI), wound recurrence after complete wound healing remains a challenge, and studies focused exclusively on wound recurrence are still limited. The present study aimed to determine the risk factors for wound recurrence after complete wound healing in patients with CLTI who underwent endovascular therapy (EVT) for infrapopliteal (IP) lesions, with consideration of IP arterial anatomic severity for the first time. The results showed that IP 3-vessel occlusive disease was the only predictor of wound recurrence, whereas wound status/management and other arterial anatomic characteristics including WIfI clinical stages and GLASS grades were not predictors.

Clinical Significance of Physical Examination for Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) show various physical findings, but their clinical significance has not been systematically evaluated.Methods and Results: This study evaluated 105 consecutive patients with HCM who had undergone phonocardiography and external pulse recording. Physical examinations included a visible jugular a-wave (Jug-a), audible 4th sound (S4), and double or sustained apex beat. The primary outcome was a composite of all-cause death and hospitalization for cardiovascular disease. A total of 104 non-HCM subjects served as controls. The prevalence of visible Jug-a in the seated or supine position, audible S4, and a sustained or double apex beat in patients with HCM were 10%, 71%, 70%, 42%, and 27%, respectively, all of which were significantly higher than in the controls (0%, 20%, 11%, 17%, and 2%; P<0.001 for all comparisons). The combination of visible Jug-a in the supine position and audible S4 yielded a specificity of 94% and sensitivity of 57%. During a follow-up period of 6.6 years, 6 patients died and 10 were hospitalized. The absence of audible S4 was a predictor of cardiovascular events (hazard ratio, 3.91; 95% confidence interval, 1.41 to 10.8; P=0.005). CONCLUSIONS: Detection of these findings has clinical importance in the diagnosis and risk stratification of HCM prior to the use of advanced imaging techniques.

Sex Differences in Process-of-Care and In-Hospital Prognosis Among Elderly Patients Hospitalized With Acute Myocardial Infarction.

BACKGROUND: Limited studies have demonstrated sex differences in the clinical outcomes and quality of care among elderly patients hospitalized with acute myocardial infarction (AMI).Methods and Results: Using nationwide cardiovascular registry data collected in Japan between 2012 and 2019, we enrolled patients aged ≥45 years. The 30-day and all in-hospital mortality rates, as well as process-of-care measures, were assessed, and mixed-effects logistic regression analysis was performed. A total 254,608 patients were included and stratified into 3 age groups: middle-aged, old and oldest old. The 30-day mortality rates for females and males were as follows: 3.0% vs. 2.7%, with an adjusted odds ratio (OR) of 1.17 (95% confidence interval (CI): 1.01-1.36, P=0.030) in middle-aged patients; 7.2% vs. 5.8%, with an OR of 1.14 (95% CI: 1.09-1.21, P<0.001) in old patients; and 19.6% vs. 15.5% with an OR of 1.17 (95% CI: 1.09-1.26, P<0.001) in the oldest old patients. Moreover, significantly higher numbers of female AMI patients across all age groups died in hospital, as well as having fewer invasive procedures and cardiovascular prescriptions, compared with their male counterparts. CONCLUSIONS: This nationwide cohort study revealed that female middle-aged and elderly patients experienced suboptimal quality of care and poorer in-hospital outcomes following AMI, compared with their male counterparts, highlighting the need for more effective management in consideration of sex-specific factors.

A Multicenter Prospective Interventional Trial of Therapeutic Angiogenesis Using Bone Marrow-Derived Mononuclear Cell Implantation for Patients With Critical Limb-Threatening Ischemia Caused by Thromboangiitis Obliterans.

BACKGROUND: Thromboangiitis obliterans (TAO) can lead to the development of critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients (<50 years) still require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has been tested and shown to have reasonable efficacy in CLTI. In this multicenter prospective clinical trial, we evaluated the safety and efficacy of BM-MNC implantation in CLTI patients with TAO.Methods and Results: We enrolled 22 CLTI patients with skin perfusion pressure (SPP) <30 mmHg. The primary endpoint of this trial is the recovery of SPP in the treated limb after a 180-day follow-up period. Secondary endpoints include the pain scale score and transcutaneous oxygen pressure (TcPO2). One patient dropped out during follow-up, leaving 21 patients (mean age 48 years, 90.5% male, Fontaine Class IV) for analysis. BM-MNC implantation caused no serious adverse events and increased SPP by 1.5-fold compared with baseline. Surprisingly, this effect was sustained over the longer term at 180 days. Secondary endpoints also supported the efficacy of this novel therapy in relieving pain and increasing TcPO2. Major amputation-free and overall survival probabilities at 3 years among all enrolled patients were high (95.5% and 89.5%, respectively). CONCLUSIONS: BM-MNC implantation showed safety and significant efficacy in CLTI patients with TAO.

Gastrointestinal Angiodysplasia in Patients with Severe Aortic Stenosis: The Endoscopic Features of Heyde's Syndrome.

INTRODUCTION: Aortic stenosis (AS) is sometimes associated with gastrointestinal bleeding, and this phenomenon is known as Heyde's syndrome. Such bleeding is most often considered to originate from gastrointestinal angiodysplasias, but the frequency and endoscopic features of such bleeding remain unclear. This study aimed to determine the frequency and endoscopic features of gastrointestinal angiodysplasia in patients with severe AS. PATIENTS AND METHODS: In this multicenter, retrospective study, we evaluated consecutive patients who underwent transcatheter aortic valve implantation (TAVI) with severe AS from May 2016 to December 2019. We extracted the data on the clinicopathological features according to the status of anemia, the proportion of patients who underwent gastrointestinal endoscopic examinations and demonstrated gastrointestinal angiodysplasia, and identified the endoscopic features associated with such patients. RESULTS: In 325 patients, the rates of moderate/severe anemia (hemoglobin < 11 g/dL) were 52%. Regarding medicine, there were no significant differences between the patients with and without moderate/severe anemia. Patients were examined by esophagogastroduodenoscopy (21%), colonoscopy (12%), and balloon-assisted enteroscopy or small bowel capsule endoscopy (1.5%). Patients with moderate/severe anemia had significantly more angiodysplasia (38.3% vs. 7.7%; p < 0.0001) and active bleeding (23.4% vs. 0%; p < 0.01). Angiodysplasia was detected in 21 patients (stomach, n = 9; small intestine, n = 5, and colon, n = 10). CONCLUSIONS: The results suggest, for the first time, that patients with severe AS who underwent TAVI and moderate/severe anemia frequently had gastrointestinal angiodysplasia and active bleeding throughout the entire gastrointestinal tract.

Comparison of maximum-sized visually guided laser balloon and cryoballoon ablation.

Balloon ablation therapy has recently been used for atrial fibrillation (AF) ablation. Laser balloons possess the property in which the balloon size can be changed. Standard laser balloon ablation (Standard LBA) was followed by additional ablation using a maximally extended balloon (Extended LBA) and its lesion characteristics were compared to cryoballoon ablation (CBA), another balloon technology. From June 2020 to July 2021, patients with paroxysmal AF who underwent an initial pulmonary vein (PV) isolation were enrolled. Sixty-five patients with paroxysmal AF were included, 32 in the LBA and 33 in the CBA group. To measure the isolated surface area after the ablation procedures, left atrial voltage mapping was performed after Standard LBA, Extended LBA, and CBA. The baseline patient characteristics did not differ between LBA and CBA. Extended LBA could successfully increase the isolated area more than Standard LBA for all four PVs. Compared to CBA, the isolated area of both superior PVs was significantly greater with Extended LBA (left superior PV: 8.5 ± 2.1 vs 7.3 ± 2.4, p = 0.04, right superior PV: 11.4 ± 3.7 vs 8.7 ± 2.7, p < 0.01), and thus the non-isolated posterior wall (PW) was smaller (8.5 ± 3.4 vs 12.4 ± 3.3, p < 0.01). Nevertheless, changes in the cardiac injury markers were significantly lower with LBA than CBA. There was no significant correlation between the cardiac injury level and isolated area in both groups. In conclusion, Extended LBA exhibited a significantly greater isolation of both superior PVs and resulted in a smaller non-isolated PW, but the cardiac injury markers were significantly suppressed as compared to CBA.

High Global Limb Anatomic Staging System Femoropopliteal Grade is Positively Associated with Wound Healing in Patients with Chronic Limb-Threatening Ischemia Undergoing Endovascular Therapy Only for Femoropopliteal Disease.

BACKGROUND: To investigate the prognostic impact of femoropopliteal (FP) arterial anatomic severity including classification by the global limb anatomic staging system (GLASS) on wound healing in patients with chronic limb-threatening ischemia (CLTI) who had undergone endovascular therapy (EVT) only for FP lesions. METHODS: This was a retrospective single-center study. We treated 349 consecutive de novo CLTI limbs with tissue loss from January 2017 to May 2021. Among these, 91 limbs treated via EVT only for FP lesions were enrolled. We compared the clinical background, infrapopliteal (IP)/FP arterial anatomical characteristics, and EVT results between the limbs with GLASS FP grade 1 or 2 (low GLASS FP, n = 20) and those with GLASS FP grade 3 or 4 (high GLASS FP, n = 71). The Kaplan-Meier method was used to estimate the wound healing rate. The Cox proportional hazard model was used to assess the association between baseline characteristics and wound healing. RESULTS: No patient underwent EVT for IP lesions. IP arterial anatomical characteristics did not show any significant difference between the low and high GLASS FP groups. The cumulative wound healing rate after EVT was significantly higher in the high GLASS FP group than in the low GLASS FP group (88% vs. 39% at 6 months; P < 0.001). Multivariate analysis revealed that low wound, ischemia, and foot infection (WIfI) clinical stage (stage 1 or 2) (hazard ratio [HR] 2.33; 95% confidence interval [CI] 1.32-4.17) and high GLASS FP (grade 3 or 4) (HR 5.18; 95% CI 1.99-13.51) were independent factors for wound healing. CONCLUSIONS: High GLASS FP grade was positively associated with wound healing after EVT only for FP lesions.

Mitral valve leaflet stiffness predicts residual mitral regurgitation after transcatheter edge-to-edge mitral valve repair.

BACKGROUND: Residual regurgitation after transcatheter edge-to-edge mitral valve repair (TMVR) is a predictor of poor prognosis in patients with functional mitral regurgitation (FMR). This study sought to identify the mitral valve (MV) parameters measured by three-dimensional transesophageal echocardiography (3D-TEE) and MV leaflet features that predict residual mitral regurgitation (MR) after TMVR in patients with FMR. METHODS: Consecutive patients with FMR who underwent TMVR were classified into two groups based on the degree of residual MR just after TMVR: < 2+ in the optimal MR reduction group and ≥ 2+ in the suboptimal MR reduction group. The two groups were compared with respect to 3D-TEE parameters and the MV leaflet features, including the following parameters: stiffness, defined as a leaflet that remains at a fixed angle even during diastole, and thickness, measured in both clear and rough zones. RESULTS: Thirty-four of 46 patients (74%) were classified as the optimal MR reduction group. Multivariable analysis showed that anterior mitral leaflet + posterior mitral leaflet length/anteroposterior annulus diameter (p = .044) and MV leaflet stiffness (p = .007) were independent predictors of residual MR. CONCLUSION: MV leaflet stiffness and the ratio of MV leaflet lengths to the annulus diameter may be good predictors of residual MR after TMVR in patients with FMR.

Predictors of delayed wound healing after simultaneous endovascular treatment and minor forefoot amputation for chronic limb-threatening ischemia with wound infection.

OBJECTIVES: To assess wound healing after simultaneous endovascular treatment (EVT) and minor forefoot amputation and identify the predictors of delayed wound healing in patients with chronic limb-threatening ischemia (CLTI) and bacterial infections of the wounds. METHODS: In this single-center retrospective cohort study, we evaluated 79 consecutive limbs with tissue loss from 73 CLTI patients who underwent simultaneous EVT and minor forefoot amputation between November 2017 and May 2020. To estimate the rate of wound healing after the simultaneous procedure, we used the Kaplan-Meier method. To assess the association between baseline characteristics and delayed wound healing, we used the Cox proportional hazard model. RESULTS: All patients who underwent the simultaneous procedure had ischemic wounds with bacterial infection. The rate of wound healing at 6 months reached 82%. The median time for wound healing was 76 days. According to multivariable analysis, Lisfranc/Chopart amputation (hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.09-6.60), absence of above-the-knee (ATK) occlusive lesions (HR 1.89, 95% CI 1.04-3.45), and poor below-the-ankle (BTA) runoff (HR 1.77, 95% CI 1.01-3.11) were independent predictors of delayed wound healing. CONCLUSION: Lisfranc/Chopart amputation, absence of ATK occlusive lesions, and poor BTA runoff were independent predictors of delayed wound healing after simultaneous EVT and minor forefoot amputation in patients with CLTI and bacterial infections of the wound.

Jugular Venous Pressure and Kussmaul's Sign as Predictors of Outcome in Heart Failure.

Simplifying the estimation of internal jugular venous pressure (JVP) as visible or not visible above the right clavicle in the sitting position has attracted attention for risk assessment in patients with heart failure (HF). It remains unclear whether this simple assessment, combined with its inspiration response known as Kussmaul's sign, is useful in patients with HF who vary in features such as HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).This study consisted of 246 patients who were admitted for the management of HF. JVP was assessed before discharge and considered high if visible at rest. The inspiration response was also examined. The primary outcome was a composite of all-cause death and hospitalization for worsening HF.One year after discharge, primary outcome events occurred in 91 patients (37%). The incidence of primary outcome was higher in patients with a high JVP at rest (odds ratio, 5.06; 95% confidence interval, 2.31-11.1; P = 0.0001) or with inspiration (odds ratio, 5.93; 95% confidence interval, 2.14-16.4; P < 0.01) than in patients without high JVP conditions. These findings were similarly observed among patients with HFrEF and HFpEF (odds ratios, 3.53 and 6.76; 95% confidence intervals, 1.68-8.68 and 2.19-15.5; P = 0.01 and < 0.01, respectively) and in subgroup analysis stratified by baseline characteristics of the patients.A high JVP at rest and with inspiration as assessed by this simple, practical method may be useful for risk assessment in patients with HF, independent of baseline characteristics.

Kidney vascular congestion exacerbates acute kidney injury in mice.

Heart failure is frequently accompanied by kidney failure and co-incidence of these organ failures worsens the mortality in patients with heart failure. Recent clinical observations revealed that increased kidney venous pressure, rather than decreased cardiac output, causes the deterioration of kidney function in patients with heart failure. However, the underlying pathophysiology is unknown. Here, we found that decreased blood flow velocity in peritubular capillaries by kidney congestion and upregulation of endothelial nuclear factor-κB (NF-κB) signaling synergistically exacerbate kidney injury. We generated a novel mouse model with unilateral kidney congestion by constriction of the inferior vena cava between kidney veins. Intravital imaging highlighted the notable dilatation of peritubular capillaries and decreased kidney blood flow velocity in the congestive kidney. Damage after ischemia reperfusion injury was exacerbated in the congestive kidney and accumulation of polymorphonuclear leukocytes within peritubular capillaries was noted at the acute phase after injury. Similar results were obtained in vitro, in which polymorphonuclear leukocytes adhesion on activated endothelial cells was decreased in flow velocity-dependent manner but cancelled by inhibition of NF-κB signaling. Pharmacological inhibition of NF-κB for the mice subjected by both kidney congestion and ischemia reperfusion injury ameliorated the accumulation of polymorphonuclear leukocytes and subsequent exacerbation of kidney injury. Thus, our study demonstrates the importance of decreased blood flow velocity accompanying activated NF-κB signaling in aggravation of kidney injury. Hence, inhibition of NF-κB signaling may be a therapeutic candidate for the vicious cycle between heart and kidney failure with increased kidney venous pressure.

Selexipag for the treatment of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remain limited. Selexipag, an oral selective IP prostacyclin receptor agonist approved for pulmonary arterial hypertension, is a potential treatment option for CTEPH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, 78 Japanese patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and/or balloon pulmonary angioplasty were randomly assigned to receive placebo or selexipag. The primary end-point was the change in pulmonary vascular resistance (PVR) from baseline to week 20. Secondary end-points were changes in other haemodynamic parameters: 6-min walk distance (6MWD), Borg dyspnoea scale score, World Health Organization (WHO) functional class, EuroQol five-dimension five-level tool and N-terminal pro-brain natriuretic peptide. RESULTS: The change in PVR was -98.2±111.3 dyn·s·cm-5 and -4.6±163.6 dyn·s·cm-5 in the selexipag and placebo groups, respectively (mean difference -93.5 dyn·s·cm-5; 95% CI -156.8 to -30.3; p=0.006). The changes in cardiac index (p<0.001) and Borg dyspnoea scale score (p=0.036) were also significantly improved over placebo. 6MWD and WHO functional class were not significantly improved. The common adverse events in the selexipag group corresponded to those generally observed following administration of a prostacyclin analogue. CONCLUSION: Selexipag significantly improved PVR and other haemodynamic variables in patients with CTEPH, although exercise capacity remained unchanged. Further large-scale investigation is necessary to prove the role of selexipag in CTEPH.

Additional balloon aortic valvuloplasty to overcome the difficult removal of a self-expandable transcatheter aortic valve system due to valve infolding.

Transcatheter aortic valve replacement (TAVR) is a well-established treatment for severe aortic stenosis. Advances in the devices used and operators' technique have reduced the frequency of complications. However, valve infolding is a rare but serious outcome after the implantation of self-expanding prostheses. We report a case of a successful bailout of a device that was difficult to remove because of valve infolding. TAVR using a 26 mm Evolut PRO+ system (Medtronic) was planned for a 91-year-old woman with severe aortic stenosis. After the valve was deployed in a satisfactory position on the second release, the system could not be removed because the nose cone was hooked to the basal frame of the deployed valve. To overcome this situation, an additional balloon was inserted from the contralateral femoral side and inflated, and we extracted the system successfully by pulling out the device while simultaneously deflating the balloon. Postoperative computed tomography revealed valve infolding, which was considered to cause the difficulty in system removal. Infoldings of self-expandable prostheses should be considered when faced with difficulty in removing the catheter system, and the method elucidated in this case report can be effective to manage it.

Serial changes in cardiac sympathetic nervous function after transcatheter aortic valve replacement: A prospective observational study using 123I-meta-iodobenzylguanidine imaging.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) can rapidly improve cardiac sympathetic nervous function (CSNF) within 2 weeks in patients with aortic stenosis (AS). However, whether such short-term improvements will be sustained thereafter remains unclear. METHODS: Patients with severe AS who underwent TAVR between October 2017 and June 2019 were enrolled in this single-center, prospective, observational study. 123I-meta-iodobenzylguanidine imaging was performed at baseline, within 2 weeks after TAVR, and at 6 to 12 months post-TAVR to evaluate the heart-mediastinum ratio (H/M) and washout rate. RESULTS: Of 183 consecutive patients, 75 (19 men; median age: 86 years) were evaluated. The late H/M significantly improved within 2 weeks after TAVR (P = .041) and further improved over 6 to 12 months after TAVR (P = .041). Multivariate analysis revealed that the baseline mean aortic valve pressure gradient (mPG) was an independent predictor of mid-term improvement in the late H/M (> 0.1) (P = .037). Patients with a high baseline mPG (≥ 58 mmHg) exhibited a significantly greater increase in the late H/M than those with a low baseline mPG (< 42 mmHg) (0.24 vs 0.01; P = .029). CONCLUSION: CSNF demonstrated sustained improvement from within 2 weeks after TAVR until 6 to 12 months later. Such improvement was related to baseline hemodynamic AS severity.