Serum mature and furin-cleaved proprotein convertase subtilisin/kexin type 9 levels and their association with cardiovascular events in statin-treated patients with cardiovascular disease.

BACKGROUND AND AIMS: Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events partly due to measurement methods that cannot distinguish between uncleaved and furin-cleaved forms of PCSK9. METHODS: This is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The primary endpoint was major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In this case-cohort study, serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among 426 participants who developed MACCE (cases) and 1,478 randomly selected participants (sub-cohort). RESULTS: From 1,478 patients in sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of the primary endpoint in patients with the highest quartile of mature PCSK9 levels was similar to that in the lowest quartile (hazard ration [HR] 0.809; 95% confidence intervals [CI], 0.541-1.209). Similarly, the HR for the highest to lowest quartiles of furin-cleaved PCSK9 was 0.948 [95% CI, 0.645-1.392] (P = 0.784). Compared to the lowest quartile, neither serum mature nor furin-cleaved PCSK9 levels predicted MACCE. CONCLUSIONS: In a large-scale secondary prevention cohort, serum mature and furin-cleaved PCSK9 levels did not provide useful information for predicting future cardiovascular events in statin-treated patients with stable CAD.

Clinical advantages of reduced expiratory positive airway pressure setting in adaptive servo-ventilation therapy.

The clinical ramifications of adaptive servo-ventilation (ASV) therapy have stirred debate within the medical community. Given the potential detrimental effect of elevated expiratory positive airway pressure (EPAP) on cardiac output, we hypothesized that relatively lower EPAP may be recommended for successful ASV therapy. In-hospital patients with congestive heart failure refractory to medical therapy were included in the prospective cohort study of ASV therapy on prognosis in repeatedly hospitalized patients with chronic heart failure: longitudinal observational study of effects on readmission and mortality (SAVIOR-L) study. Assignment to either the ASV treatment group or the medical management group was at the discretion of the attending physicians. For the purposes of this retrospective study, our focus remained solely on the ASV cohort. We conducted an extensive analysis to elucidate the influence of lower EPAP settings on midterm mortality. A total of 108 patients were included. The median age was 74 years, and 83 (77%) patients were male. The median EPAP setting employed was 4 cmH2O, with 60 patients subjected to EPAP levels below 5 cmH2O. There were no significant differences in the baseline characteristics between the lower and higher EPAP groups, which were divided at the EPAP cutoff of 4.5 cmH2O (p > 0.05 for all). A trend toward reduced mortality emerged among patients with EPAP settings below 5 cmH2O, exhibiting a hazard ratio of 0.48 (95% confidence interval 0.22-1.07, p = 0.072) after adjusting for potential confounding factors: 2-year mortality 26% vs. 38%; p = 0.095. Heart failure readmission rates were not significantly different between the two groups (p = 0.61). The adoption of relatively lower EPAP settings during ASV therapy may be advisable. Such an approach has the potential to ameliorate mortality rates while concurrently maintaining heart failure recurrence rates at levels commensurate with those with default EPAP settings.

Significance of Persistent Inflammation in Patients With Chronic Coronary Syndrome: Insights From the REAL-CAD Study.

Background: The prognostic implications of persistent low-grade inflammation in patients with chronic coronary syndrome (CCS) are underexplored. The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) study demonstrated the benefit of higher intensity pitavastatin in Japanese patients with CCS. Objectives: This prespecified subanalysis of the REAL-CAD study aimed to assess the prognostic effect of the persistent low-grade inflammation represented by high-sensitivity C-reactive protein (hs-CRP) in CCS patients. Methods: The present analysis involved patients without events until 6 months after randomization and whose hs-CRP levels were available at baseline and 6 months (n = 10,460). The primary endpoint was the composite of cardiovascular mortality, myocardial infarction, stroke, and unstable angina hospitalization. Landmark analyses evaluated the prognostic impact of continuous inflammation in 4 groups based on the median levels of hs-CRP (0.5 mg/L for both) at baseline and 6 months. The 4 groups included patient with persistently low, elevated (increased), reduced, and persistently high hs-CRP. Results: Adjusted Cox proportional hazard analyses demonstrated an increased risk of the primary endpoint in the group with persistently high hs-CRP when compared to the group with persistently low hs-CRP as a reference (adjusted HR: 1.48, 95% CI: 1.18-1.89; P = 0.001), but with a similar risk in the group with elevated (HR: 1.07, 95% CI: 0.77-1.49, P = 0.68) and reduced (HR: 0.92; 95% CI: 0.66-1.27; P = 0.60) hs-CRP. Conclusions: The study shows that persistent low-grade inflammation is associated with poor outcomes and underscores the need to address residual inflammatory risk in CCS patients. (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease [REAL-CAD]; NCT01042730).

Delayed migration of a Sapien 3 Ultra Resilia following transcatheter aortic valve implantation after selection of a smaller-sized valve.

This report discusses a rare case of delayed migration of a Sapien 3 Ultra Resilia (S3UR) valve following transcatheter aortic valve implantation. An 81-year-old Japanese woman had a borderline aortic annular size of 20-23 mm according to the manufacturer's size chart. We chose to implant a smaller S3UR of 20 mm with an 80/20 depth ratio to allow for a second intervention, ensuring good hemodynamics and minimizing paravalvular leak. The patient initially had a favorable outcome despite an accidental 50/50 depth ratio during implantation. On postoperative day 3, the S3UR migrated into the left ventricular outflow tract. Emergency surgical aortic valve replacement was performed to retrieve the migrated valve. Use of the S3UR has led to a growing preference for smaller valve sizes. However, the risk of migration should be recognized. When an accidental 50/50 depth ratio implantation is encountered, post-dilation or second valve implantation should be performed immediately.

[Successful induction therapy for acute myeloid leukemia under management with extracorporeal membrane oxygenation].

A 53-year-old woman presented with shortness of breath and hyperleukocytosis and was admitted to our hospital. Shortly after, she went into cardiopulmonary arrest and was resuscitated. Her white blood cell count was 566,000/µl, with 94.5% cup-like blasts positive for MPO staining and FLT3-ITD positive, so she was diagnosed with acute myeloid leukemia (AML) M1. She also had disseminated intravascular coagulation and tumor lysis syndrome. Extracorporeal membrane oxygenation (ECMO) was started to manage bilateral pulmonary thromboembolism that had developed due to deep vein thrombosis, and induction therapy was performed under ECMO. On the third day of illness, the patient developed cerebral hemorrhage. Hematological remission was confirmed on the 39th day of illness. After consolidation therapy with chemotherapy and an FLT3 inhibitor, she underwent allogeneic hematopoietic stem cell transplantation, and remains alive. Case reports suggest strong evidence of mortality benefit from ECMO in patients with hematologic malignancies, particularly when ECMO served as a bridge through chemotherapy. Our patient suffered from cardiopulmonary arrest due to hyperleukocytosis and pulmonary thromboembolism, but was saved by induction of remission under ECMO. Improvements in supportive care should lead to reduction in early deaths during induction therapy.

Mitral regurgitation is associated with similar loss of von Willebrand factor large multimers but lower frequency of anemia compared with aortic stenosis.

Background: Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR. Objectives: To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics. Methods: Moderate or severe MR patients (n = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed. Results: At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%). Conclusion: Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients.

Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.

BACKGROUND: In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. METHODS: We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. RESULTS: Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. CONCLUSIONS: This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.

Manual compression hemostasis using a hemostatic pad for the distal radial artery approach.

BACKGROUND: The method of hemostasis for the distal radial approach has not been standardized, although this approach has become increasingly popular due to its advantages. In this study, we investigated the feasibility of manual compression hemostasis using a calcium alginate pad after coronary angiography via the distal radial approach. METHODS: We retrospectively collected 150 consecutive patients (mean age, 74.9 ± 8.0 years; male, 75 %) who underwent coronary angiography via the distal radial artery with a predominantly 4 Fr sheath from April 2021 to December 2022 and were hemostatic according to the following methods. After sheath removal, hemostasis was achieved by manual compression for 10 min using a hemostatic pad containing calcium alginate. When hemostasis was confirmed, a small log-shaped gauze was placed over the pad and fixed using a self-adhesive elastic bandage for 2 h. All procedures were performed by four fellows just beginning the distal radial approach. RESULTS: The mean compression time was 12.4 ± 4.8 min, and hemostasis was successfully achieved in all patients, allowing the release of the elastic bandage after 2 h, with only one patient oozing the next morning. There were no major complications, while one patient had a >10 cm hematoma. Compared to that of the first 15 patients, for each fellow, the compression time of the subsequent patients was significantly shorter (14.5 ± 6.7 vs 11.1 ± 2.1 min, p < 0.01). CONCLUSIONS: Manual compression hemostasis using calcium alginate pads for the distal radial artery approach appears feasible with a simple learning.

Differential Hypoxia Risk in Cardiopulmonary Arrest Patients Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation and IMPELLA Support.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a therapeutic strategy for managing cardiogenic shock. However, it carries the risk of cardiogenic pulmonary edema, potentially leading to differential hypoxia. Although IMPELLA can mitigate pulmonary congestion, the combination of VA-ECMO and IMPELLA has frequently resulted in differential hypoxia, requiring a transition from VA-ECMO to veno-arteriovenous extracorporeal membrane oxygenation (VAV-ECMO). Therefore, this study aimed to examine the influence of IMPELLA on the incidence of differential hypoxia, necessitating a shift to VAV-ECMO. This single-center, retrospective, observational study included patients who experienced cardiopulmonary arrest and received treatment with VA-ECMO combined with an intra-aortic balloon pump (IABP) or IMPELLA between 2017 and 2022. The primary endpoint assessed the incidence of differential hypoxia, necessitating a switch to VAV-ECMO. Patients with cardiopulmonary arrest received treatment with VA-ECMO in combination with IABP (N = 28) or IMPELLA (N = 29). There was a significant increase in differential hypoxia 96 hours post-VA-ECMO initiation in the IMPELLA group, necessitating a transition to VAV-ECMO. The combination of VA-ECMO and IMPELLA in patients experiencing cardiopulmonary arrest may significantly increase the risk of differential hypoxia. A multidisciplinary approach employing mechanical circulatory support is crucial, with ongoing consideration of the potential risks associated with differential hypoxia.

Chronic Effects of Adaptive Servo-Ventilation Therapy on Mortality and the Urgent Rehospitalization Rate in Patients Experiencing Recurrent Admissions for Heart Failure　- A Multicenter Prospective Observational Study (SAVIOR-L).

BACKGROUND: This study investigated whether the chronic use of adaptive servo-ventilation (ASV) reduces all-cause mortality and the rate of urgent rehospitalization in patients with heart failure (HF). METHODS AND RESULTS: This multicenter prospective observational study enrolled patients hospitalized for HF in Japan between 2019 and 2020 who were treated either with or without ASV therapy. Of 845 patients, 110 (13%) received chronic ASV at hospital discharge. The primary outcome was a composite of all-cause death and urgent rehospitalization for HF, and was observed in 272 patients over a 1-year follow-up. Following 1:3 sequential propensity score matching, 384 patients were included in the subsequent analysis. The median time to the primary outcome was significantly shorter in the ASV than in non-ASV group (19.7 vs. 34.4 weeks; P=0.013). In contrast, there was no significant difference in the all-cause mortality event-free rate between the 2 groups. CONCLUSIONS: Chronic use of ASV did not impact all-cause mortality in patients experiencing recurrent admissions for HF.

Postoperative anticoagulation management using subcutaneous unfractionated heparin for a patient with nonbacterial thrombotic endocarditis: a case report.

Nonbacterial thrombotic endocarditis (NBTE) presents nonbacterial vegetation on cardiac valves. NBTE requires appropriate anticoagulant therapy to prevent recurrence after surgery. However, there has not yet been established evidence for anticoagulant therapy in NBTE, and low molecular weight heparin is not approved in Japan. We present a case of NBTE that was successfully managed with anticoagulant therapy using subcutaneous unfractionated heparin. A 59-year-old woman was diagnosed with NBTE on the mitral and tricuspid valve associated with breast cancer, underwent valve replacement. Warfarin and continuous intravenous unfractionated heparin were started. However, disseminated intravascular coagulation occurred after heparin was discontinued. Continuous intravenous unfractionated heparin injection was resumed immediately, and subcutaneous unfractionated heparin was administered before discharge. Postoperative echocardiography revealed no vegetation on the prosthetic valves thereafter. Subcutaneous unfractionated heparin therapy is useful to prevent the recurrence of NBTE as the anticoagulation in outpatients.

Examination of knee extensor and valgus moment arms of the patellar tendon in older individuals with and without knee osteoarthritis.

BACKGROUND: Joint moment arm is a major element that determines joint torque. This study aimed to investigate factors associated with knee extensor and valgus moment arms of the patellar tendon in older individuals with and without knee osteoarthritis. METHODS: Thirty-six participants with knee osteoarthritis (mean age, 78.1 ± 6.0 years) and 43 healthy controls (mean age, 73.0 ± 6.3 years) were analyzed. Magnetic resonance images (MRI) from the knee joint and thigh were acquired using a 3.0 T MRI scanner. The three-dimensional moment arm was defined as the distance between the contact point of the tibiofemoral joint and the patellar tendon line. The three-dimensional moment arm was decomposed into sagittal and coronal components, which were calculated as knee extensor and valgus moment arms, respectively. Quadriceps muscle volume, epicondylar width, bisect offset, Insall-Salvati ratio, and Kellgren-Lawrence grade were assessed. Multiple regression analyses were performed in the healthy control and knee osteoarthritis groups, with knee extensor and valgus moment arms as dependent variables. FINDINGS: Knee extensor moment arm was significantly associated with epicondylar width and the Insall-Salvati ratio in the healthy control group and with Kellgren-Lawrence grade, epicondylar width, and quadriceps muscle volume in the knee osteoarthritis group. Valgus knee moment arm was significantly associated with bisect offset in both the groups. INTERPRETATION: Knee size, osteoarthritis severity, and quadriceps muscle volume affect the knee extensor moment arm in knee osteoarthritis, whereas lateral patellar displacement affects the valgus knee moment arms in older individuals with and without knee osteoarthritis.

Characteristics of Acute Cartilage Response After Mechanical Loading in Patients with Early-Mild Knee Osteoarthritis.

This study determined whether the acute cartilage response, assessed by cartilage thickness and echo intensity, differs between patients with early-mild knee osteoarthritis (OA) and healthy controls. We recruited 56 women aged ≥ 50 years with Kellgren-Lawrence (KL) grade ≤ 2 (age, 70.6 ± 7.4 years; height, 153.7 ± 5.2 cm; weight, 51.9 ± 8.2 kg). Based on KL grades and knee symptoms, the participants were classified into control (KL ≤ 1, asymptomatic, n = 27) and early-mild knee OA groups (KL 1 and symptomatic, KL 2, n = 29). Medial femoral cartilage thickness and echo intensity were assessed using ultrasonographic B-mode images before and after treadmill walking (15 min, 3.3 km/h). To investigate the acute cartilage response, repeated-measures analysis of covariance (groups × time) with adjusted age, external knee moment impulse, steps during treadmill walking, and cartilage thickness at pre-walking was performed. A significant interaction was found at the tibiofemoral joint; after walking, the cartilage thickness was significantly decreased in the early-mild knee OA group compared to the control group (p = 0.002). At the patellofemoral joint, a significant main effect of time was observed, but no interaction was detected (p = 0.802). No changes in cartilage echo intensity at either the tibiofemoral or patellofemoral joints, and no interactions were noted (p = 0.295 and p = 0.063). As acute cartilage response after walking, the thickness of the medial tibiofemoral joint in the early-mild knee OA was significantly reduced than that in the control group. Thus, greater acute deformation after walking might be a feature found in patients with early-mild knee OA.