Edoxaban for 12 Versus 3 Months in Cancer-associated Isolated Distal Deep Vein Thrombosis According to Different Doses: Insights from the ONCO DVT study.

BACKGROUND: The ONCO DVT study revealed the superiority of 12-month relative to 3-month edoxaban treatment for cancer-associated isolated distal deep vein thrombosis (DVT) regarding the thrombotic risk. METHODS: In this pre-specified subgroup analysis of the ONCO DVT study, we stratified the patients into those with a standard edoxaban dose (60 mg/day; N=151) and those with a reduced edoxaban dose (30 mg/day; N=450) and evaluated the clinical outcomes for the 12-month and 3-month treatments. RESULTS: The cumulative 12-month incidence of symptomatic recurrent venous thromboembolism was lower in the 12-month than 3-month group for both the 60 mg (1.3% vs. 11.6%, P=0.02; odds ratio [OR], 0.12; 95% CI, 0.01-0.97) and 30 mg (1.1% vs. 7.6%, P=0.002; OR, 0.14; 95% CI, 0.03-0.60) edoxaban subgroups, which was consistent across the edoxaban doses without a significant interaction (P =0.90). The 12-month cumulative incidence of major bleeding was higher in the 12-month group than 3-month group for the 60 mg edoxaban subgroup (14.3% vs. 4.4%, P=0.046; OR, 3.61; 95% CI, 0.97-13.52), whereas it did not significantly differ between the two groups for the 30 mg edoxaban subgroup (8.7% vs. 8.6%, P=0.89; OR, 0.97; 95% CI, 0.49-1.91), signaling there was a potential interaction (P=0.07). CONCLUSIONS: A 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However, caution was suggested for the standard dose of edoxaban due to the potential for an increased risk of bleeding with prolonged anticoagulation therapy.

Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

The impact of renal function on clinical outcomes of patients with cancer-associated isolated distal deep vein thrombosis: Insights from the ONCO DVT study.

BACKGROUND: The multicenter, open-label, randomized clinical trial ONCO DVT compared 3-month and 12-month edoxaban treatment regimens for isolated distal deep vein thrombosis (DVT) and suggested potential benefits of prolonged edoxaban treatment in terms of thrombotic risk. However, the risk-benefit balance of prolonged edoxaban treatment in patients with renal function remains unclear. OBJECTIVES: To compare the safety and efficacy of 3-month and 12-month edoxaban treatment regimens in patients with cancer-associated isolated distal DVT and different renal functions. METHODS: This pre-specified subgroup analysis of the ONCO DVT study included 601 patients divided into subgroups according to renal function using a 50 mL/min creatinine clearance (Ccr) cutoff. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) and VTE-related death at 12 months and the major secondary endpoint was major bleeding at 12 months. RESULTS: Among the 601 patients, 131 (21.8 %) comprised the renal dysfunction subgroup. The primary endpoint occurred in 6 (9.7 %) and 1 (1.4 %) patients in the 3-month and 12-month edoxaban groups in the renal dysfunction subgroup, respectively, and in 16 (6.6 %) and 2 (0.9 %) patients in the no renal dysfunction subgroup, respectively. The major secondary endpoint occurred in 9 (14.5 %) and 7 (10.1 %) patients in the 12-month and 3-month edoxaban groups in the renal dysfunction subgroup, and in 13 (5.3 %) and 21 (9.3 %) patients in the no renal dysfunction subgroup, respectively. CONCLUSIONS: A 12-month edoxaban regiment was superior to a 3-month treatment in terms of thrombotic risk irrespective of renal function. A higher bleeding risk was not identified in patients with renal dysfunction who received prolonged edoxaban treatment.

The Cavin-1/Caveolin-1 interaction attenuates BMP/Smad signaling in pulmonary hypertension by interfering with BMPR2/Caveolin-1 binding.

Caveolin-1 (CAV1) and Cavin-1 are components of caveolae, both of which interact with and influence the composition and stabilization of caveolae. CAV1 is associated with pulmonary arterial hypertension (PAH). Bone morphogenetic protein (BMP) type 2 receptor (BMPR2) is localized in caveolae associated with CAV1 and is commonly mutated in PAH. Here, we show that BMP/Smad signaling is suppressed in pulmonary microvascular endothelial cells of CAV1 knockout mice. Moreover, hypoxia enhances the CAV1/Cavin-1 interaction but attenuates the CAV1/BMPR2 interaction and BMPR2 membrane localization in pulmonary artery endothelial cells (PAECs). Both Cavin-1 and BMPR2 are associated with the CAV1 scaffolding domain. Cavin-1 decreases BMPR2 membrane localization by inhibiting the interaction of BMPR2 with CAV1 and reduces Smad signal transduction in PAECs. Furthermore, Cavin-1 knockdown is resistant to CAV1-induced pulmonary hypertension in vivo. We demonstrate that the Cavin-1/Caveolin-1 interaction attenuates BMP/Smad signaling and is a promising target for the treatment of PAH.

Cavin-2 promotes fibroblast-to-myofibroblast trans-differentiation and aggravates cardiac fibrosis.

AIMS: Transforming growth factor ß (TGF-ß) signalling is one of the critical pathways in fibroblast activation, and several drugs targeting the TGF-ß/Smad signalling pathway in heart failure with cardiac fibrosis are being tested in clinical trials. Some caveolins and cavins, which are components of caveolae on the plasma membrane, are known for their association with the regulation of TGF-ß signalling. Cavin-2 is particularly abundant in fibroblasts; however, the detailed association between Cavin-2 and cardiac fibrosis is still unclear. We tried to clarify the involvement and role of Cavin-2 in fibroblasts and cardiac fibrosis. METHODS AND RESULTS: To clarify the role of Cavin-2 in cardiac fibrosis, we performed transverse aortic constriction (TAC) operations on four types of mice: wild-type (WT), Cavin-2 null (Cavin-2 KO), Cavin-2flox/flox , and activated fibroblast-specific Cavin-2 conditional knockout (Postn-Cre/Cavin-2flox/flox , Cavin-2 cKO) mice. We collected mouse embryonic fibroblasts (MEFs) from WT and Cavin-2 KO mice and investigated the effect of Cavin-2 in fibroblast trans-differentiation into myofibroblasts and associated TGF-ß signalling. Four weeks after TAC, cardiac fibrotic areas in both the Cavin-2 KO and the Cavin-2 cKO mice were significantly decreased compared with each control group (WT 8.04 ± 1.58% vs. Cavin-2 KO 0.40 ± 0.03%, P < 0.01; Cavin-2flox/flox , 7.19 ± 0.50% vs. Cavin-2 cKO 0.88 ± 0.44%, P < 0.01). Fibrosis-associated mRNA expression (Col1a1, Ctgf, and Col3) was significantly attenuated in the Cavin-2 KO mice after TAC. α1 type I collagen deposition and non-vascular αSMA-positive cells (WT 43.5 ± 2.4% vs. Cavin-2 KO 25.4 ± 3.2%, P < 0.01) were reduced in the heart of the Cavin-2 cKO mice after TAC operation. The levels of αSMA protein (0.36-fold, P < 0.05) and fibrosis-associated mRNA expression (Col1a1, 0.69-fold, P < 0.01; Ctgf, 0.27-fold, P < 0.01; Col3, 0.60-fold, P < 0.01) were decreased in the Cavin-2 KO MEFs compared with the WT MEFs. On the other hand, αSMA protein levels were higher in the Cavin-2 overexpressed MEFs compared with the control MEFs (2.40-fold, P < 0.01). TGF-ß1-induced Smad2 phosphorylation was attenuated in the Cavin-2 KO MEFs compared with WT MEFs (0.60-fold, P < 0.01). Heat shock protein 90 protein levels were significantly reduced in the Cavin-2 KO MEFs compared with the WT MEFs (0.69-fold, P < 0.01). CONCLUSIONS: Cavin-2 loss suppressed fibroblast trans-differentiation into myofibroblasts through the TGF-ß/Smad signalling. The loss of Cavin-2 in cardiac fibroblasts suppresses cardiac fibrosis and may maintain cardiac function.

Mitral regurgitation outcomes after transcatheter atrial septal defect closure.

BACKGROUND: Worsening mitral regurgitation (MR) is a complication of intervention for atrial septal defect (ASD). Little is known about mitral valve (MV) characteristics associated with worsening MR. We aimed to elucidate MR outcomes and predictors of worsening MR after transcatheter ASD closure. METHODS: We analyzed changes in MR from prior to transcatheter ASD closure to 6 months after the procedure and predictors of worsening MR via baseline transthoracic echocardiography in 238 patients (64.7% females; mean age, 53 ± 22 years). RESULTS: Worsening MR was defined as worsening to moderate in patients with less than or equal to mild MR at baseline or vena contracta width increasing of ≥2 mm by 6-month follow-up in patients with moderate MR. Worsening MR was observed in 29 patients (12.2%). The associated echocardiographic findings were pseudoprolapse, hamstringing, stiffness, and anteroposterior and intercommissural mitral annulus diameter in the univariable logistic regression analysis (all P < 0.05). Multivariable analysis after adjusting for age; long-standing persistent atrial fibrillation; and ASD size showed that models combining MV leaflet findings such as pseudoprolapse or hamstringing, or anterior leaflet stiffness with the ratio of the sum of anterior and posterior leaflet lengths to intercommissural mitral annulus diameter were statistically significant for predicting worsening MR (R2 = 0.393, P < 0.001 and R2 = 0.385, P < 0.001, respectively). CONCLUSIONS: Worsening MR after transcatheter ASD closure might depend on MV leaflet findings and annulus size in patients with long-standing persistent atrial fibrillation.

Adult-onset idiopathic peripheral pulmonary artery stenosis.

BACKGROUND: Peripheral pulmonary artery stenosis (PPS) refers to stenosis of the pulmonary artery from the trunk to the peripheral arteries. Although paediatric PPS is well described, the clinical characteristics of adult-onset idiopathic PPS have not been established. Our objectives in this study were to characterise the disease profile of adult-onset PPS. METHODS: We collected data in Japanese centres. This cohort included patients who underwent pulmonary angiography (PAG) and excluded patients with chronic thromboembolic pulmonary hypertension or Takayasu arteritis. Patient backgrounds, right heart catheterisation (RHC) findings, imaging findings and treatment profiles were collected. RESULTS: 44 patients (median (interquartile range) age 39 (29-57) years; 29 females (65.9%)) with PPS were enrolled from 20 centres. In PAG, stenosis of segmental and peripheral pulmonary arteries was observed in 41 (93.2%) and 36 patients (81.8%), respectively. 35 patients (79.5%) received medications approved for pulmonary arterial hypertension (PAH) and 22 patients (50.0%) received combination therapy. 25 patients (56.8%) underwent transcatheter pulmonary angioplasty. RHC data showed improvements in both mean pulmonary arterial pressure (44 versus 40 mmHg; p<0.001) and pulmonary vascular resistance (760 versus 514 dyn·s·cm-5; p<0.001) from baseline to final follow-up. The 3-, 5- and 10-year survival rates of patients with PPS were 97.5% (95% CI 83.5-99.6%), 89.0% (95% CI 68.9-96.4%) and 67.0% (95% CI 41.4-83.3%), respectively. CONCLUSIONS: In this study, patients with adult-onset idiopathic PPS presented with segmental and peripheral pulmonary artery stenosis. Although patients had severe pulmonary hypertension at baseline, they showed a favourable treatment response to PAH drugs combined with transcatheter pulmonary angioplasty.

Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis (ONCO DVT Study): An Open-Label, Multicenter, Randomized Clinical Trial.

BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Cavin-2 loss exacerbates hypoxia-induced pulmonary hypertension with excessive eNOS phosphorylation and protein nitration.

Pulmonary hypertension (PH) is associated with a poor prognosis even in recent years. Caveolin-1 (CAV1), a caveolae-associated protein, is a causal gene in PH. Cavin-2, one of the other caveolae-associated proteins, forms protein complexes with CAV1 and influences each other's functions. However, the role of Cavin-2 in PH has not been thoroughly investigated. To clarify the role of Cavin-2 in PH, we exposed Cavin-2-deficient (Cavin-2 KO) mice to hypoxia. A part of the analyses was confirmed in human pulmonary endothelial cells (HPAECs). After 4-week 10% O2 hypoxic exposure, we performed physiological, histological, and immunoblotting analyses. Right ventricular (RV) systolic pressure elevation and RV hypertrophy were exacerbated in Cavin-2 KO mice with hypoxia-induced PH (Cavin-2 KO PH mice). The vascular wall thickness of pulmonary arterioles was aggravated in Cavin-2 KO PH mice. Cavin-2 loss reduced CAV1 and induced sustained endothelial nitric oxide synthase (eNOS) hyperphosphorylation in the Cavin-2 KO PH lungs and HPAECs. NOx production associated with eNOS phosphorylation was also increased in the Cavin-2 KO PH lung and HPAECs. Furthermore, the nitration of proteins, including protein kinase G (PKG), was raised in the Cavin-2 KO PH lungs. In conclusion, we revealed that Cavin-2 loss exacerbated hypoxia-induced PH. Our results suggest that Cavin-2 loss leads to sustained eNOS hyperphosphorylation in pulmonary artery endothelial cells via CAV1 reduction, resulting in Nox overproduction-mediated nitration of proteins, including PKG, in smooth muscle cells.

Pulmonary artery blood flow dynamics in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension is caused by incomplete resolution and organization of thrombi. Blood flow dynamics are involved in thrombus formation; however, only a few studies have reported on pulmonary artery blood flow dynamics in patients with chronic thromboembolic pulmonary hypertension. Furthermore, the effects of treatment interventions on pulmonary artery blood flow dynamics are not fully understood. The aim of the study was to evaluate pulmonary artery blood flow dynamics in patients with chronic thromboembolic pulmonary hypertension before and after pulmonary endarterectomy and balloon pulmonary angioplasty, using computational fluid dynamics. We analyzed patient-specific pulmonary artery models of 10 patients with chronic thromboembolic pulmonary hypertension and three controls using computational fluid dynamics. In patients with chronic thromboembolic pulmonary hypertension, flow velocity and wall shear stress in the pulmonary arteries were significantly decreased, and the oscillatory shear index and blood stagnation volume were significantly increased than in controls. Pulmonary endarterectomy induced redistribution of pulmonary blood flow and improved blood flow dynamics in the pulmonary artery. Balloon pulmonary angioplasty improved pulmonary blood flow disturbance, decreased blood flow stagnation, and increased wall shear stress, leading to vasodilatation of the distal portion of the pulmonary artery following balloon pulmonary angioplasty treatment.

Efficacy and safety of guide extension catheter in balloon pulmonary angioplasty for treatment of complex lesions in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is used for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and residual pulmonary hypertension after pulmonary endarterectomy (PEA) to improve hemodynamics, right ventricular function, and exercise capacity. However, the effectiveness and safety of guide extension catheters for BPA treatment in patients with CTEPH have not been demonstrated. METHODS: We retrospectively analyzed 91 lesions in 55 sessions of 28 patients with CTEPH who underwent BPA using a guide extension catheter. The purpose (backup, coaxial, and extension), efficacy, and safety of the guide extension catheters were explored. The efficacy of the guide extension catheter was assessed based on the success of the procedures and safety was evaluated based on procedure-related complications. RESULTS: Regarding the intended use, a guide extension catheter was used to strengthen the backup force of the guiding catheter in 52% of cases, extend the tip of the catheter in 38% of cases, and maintain the coaxiality of the guiding catheter in 10% of cases. Procedural success was achieved in 92.7% of 55 sessions and in 95.6% of 91 lesions. Complex lesions had a lower success rate than simple lesions (p = 0.04). Regarding safety concerns, complications were observed in 5 of 55 sessions (9.1%) and 6 of 91 lesions (6.6%). Only one case of pulmonary artery dissection using a guide extension catheter was reported. Except for this one case, extension catheter-related complications were not observed. CONCLUSIONS: A guide extension catheter can be used safely in BPA procedures with anatomically complex pulmonary artery branches and complex lesions by increasing backup support.

Clot-regression effects of rivaroxaban in venous thromboembolism treatment in cancer patients-a prospective interventional study.

Rivaroxaban, a direct oral anticoagulant, is effective against venous thromboembolism (VTE) recurrence without increasing the risk of major bleeding in patients with cancer-associated venous thromboembolism (CAT). However, its clot regression effects are poorly understood. This single-arm, prospective interventional study aimed to investigate the clot regression effects of rivaroxaban in 40 CAT patients, through a contrast-enhanced computed tomography at baseline, 3 weeks, and 3 months of rivaroxaban treatment. The primary endpoint was the clot-regression ratio calculated from the thrombus volumes at 3 weeks and 3 months. Compared with baseline, the total clot volume was significantly reduced at both 3 weeks and 3 months after initiation (p < 0.01). The clot-regression rates were statistically significant with 83.1% (95% confidence interval [CI], 73.8-92.3%) at 3 weeks and 98.7% (95% CI, 97.1-100.2%) at 3 months, with complete resolution in 36.1% and 80.8% of patients at 3 weeks and 3 months, respectively. One patient had recurrent VTE after dose reduction, and seven had non-fatal major bleeding. Therefore, rivaroxaban had a sufficient clot-regression effect against CAT with caution of bleeding complication.

The effectiveness of scoring balloon angioplasty in the treatment of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is an effective treatment for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The purpose of this study is to evaluate the therapeutic effect and safety of the non-slip element percutaneous transluminal angioplasty (NSE PTA) scoring balloons in BPA. METHODS: 108 pulmonary artery branches in 14 CTEPH patients who underwent BPA using NSE PTA scoring balloon (the NSE PTA group) or plain balloon (the POBA group) and pressure gradient evaluation were analyzed. We compared the improvement of the pressure ratios after BPA (Δ Pressure ratio) of both groups. RESULTS: There was no significant difference in the Δ Pressure ratios of the two groups (0.241 ± 0.196 POBA, 0.259 ± 0.177 NSE PTA, p = 0.63). No complications occurred in the NSE PTA group, while 3 episodes of hemoptysis were seen in the POBA group. This, however, was not found to be significant (p = 0.27). In the cases where balloon-to-vessel ratio exceeded 1.0 (n = 35), multivariate analysis showed that the use of NSE PTA scoring balloon and pressure ratio before BPA were significantly correlated with Δ Pressure ratio (ß coefficient: 0.047, 95% CI: 0.0016 to 0.093, p = 0.043 and ß coefficient: -0.60, 95% CI: -0.78 to -0.42, p < 0.01, respectively). CONCLUSIONS: Although NSE PTA scoring balloon was safe, there was no significant pressure gradient improvement with NSE PTA scoring balloon compared to conventional BPA. Nevertheless, the NSE PTA scoring balloon showed effective blood-flow improvement in the case of large balloon-to-vessel ratio.

Requirement of Cavin-2 for the expression and stability of IRß in adequate adipocyte differentiation.

OBJECTIVE: Adipogenesis plays an essential role in maintaining energy and hormonal balance. Cavin-2, one of the caveolae-related proteins, is abundant in adipocytes, the leading site of adipogenesis. However, the details of the roles of Cavin-2 in adipogenesis remain unknown. Here, we demonstrate the requirement of Cavin-2 for the expression and stability of IRß in adequate adipocyte differentiation. METHODS: Cavin-2 knockout (Cavin-2 KO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 8 weeks. We evaluated body weight, food intake, and several tissues. Glucose homeostasis was assessed by glucose and insulin tolerance tests. Insulin signaling in epididymal white adipose tissue (eWAT) was determined by Akt phosphorylation. In vitro study, we evaluated adipocyte differentiation, adipogenesis-related genes, and insulin signaling to clarify the relationship between Cavin-2 and adipogenesis under the manipulation of Cavin-2 expression. RESULTS: Caveolae structure decreased in eWAT of Cavin-2 KO mice and Cavin-2 knockdown 3T3-L1 cells. Cavin-2 enhanced the stability of insulin receptor (IR) through direct association at the plasma membrane in adipocytes, resulting in accelerated insulin/IR/Akt signaling-induced adipogenic gene expression in insulin-containing solution-stimulated 3T3-L1 adipocytes. IR-mediated Akt activation also enhanced Cavin-2 and IR expression. Cavin-2 knockout mice showed insulin resistance with dyslipidemia and pathological hypertrophic adipocytes after a HFD. CONCLUSIONS: Cavin-2 enhances IR stability through binding IR and regulates insulin signaling, promoting adequate adipocyte differentiation. Our findings highlight the pivotal role of Cavin-2 in adipogenesis and lipid metabolism, which may help to develop novel therapies for pathological obesity and adipogenic disorders.

Assessment of biventricular hemodynamics and energy dynamics using lumen-tracking 4D flow MRI without contrast medium.

BACKGROUND: Biventricular physiological interaction remains a challenging problem in cardiology. We developed a four-dimensional (4D) flow magnetic resonance imaging (MRI) scan and clinically available analysis protocol based on beat tracking of the cardiovascular lumen without contrast medium, which enabled measurement of the biventricular hemodynamics and energetic performance by calculating flow energy loss (EL) and kinetic energy (KE). The aim of this study was to observe the flow patterns and energy dynamics to reveal the physiology of the right and left ventricular systems. METHODS: 4D flow MRI studies were performed in 19 healthy volunteers including 11 male and 8 female. The right and left ventricular systems were segmented to visualize the flow patterns and to quantify the hemodynamics and energy dynamics. RESULTS: A large vortex was observed in the left ventricle (LV), along the longitudinal axis, during end diastole and early systole. At early systole, the vortex appeared to facilitate smooth ejection with little EL. In contrast, in the right ventricle (RV), there were vortices near the free wall in both the short and long axes during the diastolic filling phase. Mean EL index during a single cardiac cycle in the right and left heart systems was 0.63 ± 0.16 (0.42-0.99) mW/m2, and 1.02 ± 0.26 (0.58-1.58) mW/m2, respectively. EL is inevitable loss caused by the vortex flow to facilitate smooth right and left ventricular function and left-sided EL tended to correlate positively with heart rate and right ventricular stroke volume. Kinetic energy at the aortic valve was influenced by LV end-diastolic volume/stroke volume. No gender difference was observed. CONCLUSIONS: The RV appears to function as a regulator of the energy dynamics of the LV system.

Favorable changes of left ventricular function in the circumferential direction following transcatheter atrial septal defect closure: a strain imaging study.

To clarify the impact on left ventricular (LV) function of percutaneous atrial septal defect (ASD) closure in adult patients. Echocardiograms of 46 patients (52 ± 18 years) who underwent ASD closure with a significant left-to-right shunt obtained before and 1 month after the procedure were retrospectively analyzed. Functional parameters were obtained by 2-dimensional speckle-tracking imaging. Global longitudinal strain and strain rate at early diastole (SRe) was calculated from the three standard apical views, while circumferential and radial parameters were calculated from basal, middle, and apical LV short-axis views. Along with a diminished right ventricular (RV) volume, the LV volume and ejection fraction increased (end-diastolic volume: 61 ± 12 to 76 ± 15 mL, p < 0.001; and 63% ± 4 to 64% ± 4% p = 0.03; respectively). Both global strain and SRe was augmented only in the circumferential direction (- 16.2% ± 2.9% to - 19.8% ± 2.8%; and 1.07 ± 0.29 to 1.34 ± 0.28 s-1, both p < 0.001). Augmentation of circumferential SRe correlated with both the changes in and the pre-procedural value of diastolic LV eccentricity index (r = - 0.57, p < 0.001; and r = 0.37, p = 0.01; respectively), a morphological parameter of RV volume overload. Following ASD closure in adults, both LV systolic and diastolic function could favorably change in the circumferential direction, and the degree of diastolic functional change is associated with RV volume overload, i.e., severity of ventricular interdependence.

Knowledge, perception, and level of confidence regarding COVID-19 care among healthcare workers involved in cardiovascular medicine: a web-based cross-sectional survey in Japan.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) has a significant impact on daily practice in cardiovascular medicine. The preparedness of healthcare workers (HCWs) can affect the spread of infection and the maintenance of the healthcare system. This study aimed to investigate the knowledge, perception, and level of confidence regarding COVID-19 care among HCWs involved in cardiovascular medicine. METHODS: A cross-sectional, web-based study about COVID-19 was performed between April 22 and May 7, 2020, among 311 HCWs in cardiovascular departments. The demographic information, COVID-19-related knowledge, and perception and level of confidence toward COVID-19 care were assessed. RESULTS: The median age of the participants was 38 years, and 215 (69.8%) were male. There were 134 (43.1%) physicians and 177 (56.9%) non-physician HCWs. The HCWs, especially non-physician HCWs, had insufficient knowledge about infection-prevention measures for COVID-19, such as how to isolate patients with COVID-19, how to use personal protective equipment, and how to prevent infection during aerosol-generating procedures. Most HCWs showed a low level of confidence toward COVID-19 care, and such poor confidence was associated with the lack of knowledge on optimal infection-prevention measures. CONCLUSIONS: This survey revealed the lack of knowledge about adequate infection-prevention measures for COVID-19. More attention should be paid to the preparedness of HCWs, and educating and supporting HCWs involved in cardiovascular medicine is an urgent need.

Prolonged Elevation of Tricuspid Regurgitation Pressure Gradient After Exercise in Patients With Exercise-induced Pulmonary Hypertension.

It is necessary to measure the peak tricuspid regurgitation pressure gradient (TRPG) that is recorded at maximum exercise intensity when diagnosing exercise-induced pulmonary hypertension (ePH) on exercise stress echocardiography (ESE). However, it is difficult to measure maximum TRPG during the treadmill exercise. If ePH induced TRPG elevation continues during recovery period after exercise termination, this elevation will serve as a practical diagnostic standard. We aimed to assess whether the elevation of postexercise peak TRPG prolong soon after finishing exercise in patients with ePH. Seventy-four patients underwent symptom-limited ESE by using a semirecumbent bicycle ergometer. ePH was defined as peak TRPG > 50 mm Hg at maximum exercise. We measured peak TRPG during exercise and until 5 minutes afterward. Thirty-five patients were diagnosed with ePH; their median TRPG was 57 mm Hg [interquartile range: 52-62 mm Hg] at maximum exercise. Peak TRPG in patients with ePH was > 40 mm Hg until 2 minutes after exercise. The cut-off values of peak TRPG to detect ePH were 43 mm Hg just after exercise and 41 mm Hg at 1 minute afterward (areas under the curve: 0.98, 0.92, respectively; both p < 0.001). In conclusion, elevated peak TRPG persisted for at least 2 minutes after finishing exercise, and this time frame will therefore provide a new window for diagnosing ePH by ESE.

Acute coronary syndrome with large thrombus successfully managed with no-stenting revascularization based on intravascular imaging in a patient with hyperhomocysteinemia: a case report.

BACKGROUND: Hyperhomocysteinemia is caused by genetic and environmental factors, which can result in systemic arteriosclerosis and arteriovenous thrombosis including acute coronary syndrome. Thrombus burden in patients with acute coronary syndrome and hyperhomocysteinemia might involve the culprit lesion as compared with those without any coagulopathy. The primary percutaneous coronary intervention with stent implantation had been established as the treatment strategy for patients with acute coronary syndrome. However, in patients with acute coronary syndrome with high thrombus burden or uncontrolled coagulopathy, stent implantation might lead to slow-flow phenomenon or stent thrombosis. Therefore, the treatment strategy in these patients was not established. CASE PRESENTATION: A 49-year-old Japanese man with history of splenic infarction of unknown cause had continued anticoagulant therapy since its diagnosis, but stopped taking the medication several months ago. He presented with sudden-onset chest dorsalgia. Contrast computed tomography showed a small pulmonary embolism and his troponin I level was elevated on initial laboratory test. Coronary angiography revealed a contrast defect caused by a large thrombus from the proximal to mid portion of the left anterior descending artery. Near-infrared spectroscopy-intravascular ultrasonography showed a large amount of thrombus without lipid plaque. Therefore, revascularization was performed using a thrombus-aspiration catheter and intracoronary thrombolysis. In addition, , hyperhomocysteinemia and a deep vein thrombosis occurred. He was diagnosed with acute coronary syndrome complicated with pulmonary embolism and deep vein thrombosis simultaneously induced by hyperhomocysteinemia. After 1 week of antithrombotic therapy, near-infrared spectroscopy-intravascular ultrasonography and optical coherence tomography revealed a decreased thrombus and no significant residual organic stenosis in the left anterior descending artery. He continued conservative therapy with antithrombotic medications including aspirin and warfarin and had no cardiovascular events after discharge. Follow-up coronary angiography and optical coherence tomography at 9 months revealed complete disappearance of the thrombus and no severe stenosis. CONCLUSIONS: Hyperhomocysteinemia should be considered as a cause of arterial vein thrombosis of unknown cause. The antithrombotic therapy and percutaneous revascularization without stenting based on intravascular imaging might be a safe and effective treatment option in patients with acute coronary syndrome complicated with hyperhomocysteinemia.

Two effective cases of additional pedal artery angioplasty for severe lower limb ischemia following acute thrombotic artery occlusion with hypercoagulable state diseases.

BACKGROUND: Acute limb ischemia (ALI) and critical limb ischemia (CLI) following ALI are life-threatening diseases. The rare potential causes of ALI include hypercoagulable state diseases, such as antiphospholipid syndrome (APS) and essential thrombocythemia (ET). Hypercoagulability often make revascularization for arterial occlusion, especially associated with infrapopliteal lesions, difficult. This is because the vessels have poor run-off, and elevated peripheral vascular resistance associated with microcirculation failure, due to a high thrombus burden. There is no established treatment for this issue. CASE PRESENTATION: A 45 years-old and a 56 years-old male suffered from thrombotic arterial occlusion as a first manifestation of APS and ET, respectively. Combination therapy with aggressive anti-thrombotic therapy and revascularization, such as endovascular therapy and surgical thrombectomy based on the angiosome concept, was performed. However, the high thrombus burden caused a poor pedal outflow, and significant limb ischemia remained. Additional pedal artery angioplasty was performed to improve residual limb ischemia in each case and provided sufficient blood flow to the foot. CONCLUSION: The pedal artery angioplasty for thrombotic pedal artery occlusion cases, associated with hypercoagulable state diseases, seems to be a treatment option for relieving residual limb ischemia.