Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial

Background

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial.

Methods

The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e’) assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study.

Conclusions

The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

     

Efficacy and safety of benralizumab in Japanese patients with severe,uncontrolled eosinophilic asthma

Background

In the Phase III CALIMA trial, benralizumab significantly reduced asthma exacerbations, increased lung function, and alleviated symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate the efficacy and safety of benralizumab for Japanese patients in the CALIMA trial.

A prospective multicenter phase II study of intrabone marrow transplantation of unwashed cord blood using reduced‐intensity conditioning

Cord blood transplantation (CBT) is associated with delayed hematopoietic recovery and graft failure. To overcome these problems, we conducted a prospective, multicenter phase II study of intrabone marrow transplantation in which patients received reduced‐intensity conditioning without anti‐thymocyte globulin (ATG). The primary endpoint was the probability of full donor engraftment. Forty patients with hematologic malignancies were enrolled. Cord blood (CB) cells were injected without washing into 4 iliac bone sites (2 at each hemipelvis), at which approximately 6 mL of CB was administered at one site with local anesthesia. Full donor engraftment rate was 86.8%. The cumulative incidence of neutrophil and platelet engraftment was 86.4% and 85.5%, respectively. The median time to neutrophil (>0.5 × 10⁹/L) and platelet (2.0 × 10⁹/L) recovery was 17.5 and 44 days, respectively. The probability of severe acute graft‐vs‐host disease (GVHD) was 47.5%. The cumulative incidence of extensive chronic GVHD was 3.0%. The probability of relapse and non‐relapse mortality was 30.4% and 28.0%, respectively. The survival rate at 3 years was 45.6%, although most patients were at an advanced stage. These results suggest that our intrabone marrow‐CBT procedure without using ATG improves hematopoietic recovery and decreases the incidence of chronic GVHD, but does not decrease the incidence of acute GVHD.     

Contrast‐enhanced harmonic endoscopic ultrasonography for differential diagnosis of localized gallbladder lesions

Background and Aim

Differential diagnosis of localized gallbladder lesions is challenging. The aim of the present study was to evaluate the utility of contrast‐enhanced harmonic endoscopic ultrasonography (CH‐EUS) for diagnosis of localized gallbladder lesions.

Methods

One hundred and twenty‐five patients with localized gallbladder lesions were evaluated by CH‐EUS between March 2007 and February 2014. This was a single‐center retrospective study. Utilities of fundamental B‐mode EUS (FB‐EUS) and CH‐EUS in the differentiation of gallbladder lesions and sludge plug were initially compared. Thereafter, these two examinations were compared with respect to their accuracy in the diagnosis of malignant lesions. Five reviewers blinded to the clinicopathological results evaluated microcirculation patterns in the vascular and perfusion images.

Results

In the differentiation between gallbladder lesions and sludge plug, FB‐EUS had a sensitivity, specificity, and accuracy of 82%, 100%, and 95%, respectively, whereas CH‐EUS had a sensitivity, specificity, and accuracy of 100%, 99%, and 99%, respectively. FB‐EUS‐based diagnosis of carcinomas based on tumor size and/or shape had a sensitivity, specificity, and accuracy of 61–87%, 71–88%, and 74–86%, respectively. Additional information regarding irregular vessel patterns in the vascular image and/or heterogeneous enhancement in the perfusion image on CH‐EUS increased the sensitivity, specificity, and accuracy for the diagnosis of carcinomas to 90%, 98%, and 96%, respectively. There was a significant difference between FB‐EUS and CH‐EUS in terms of carcinoma diagnosis.

Conclusion

CH‐EUS was useful for the evaluation of localized gallbladder lesions.     

Assessment of autonomic nervous system modulation after novel catheter ablation techniques for atrial fibrillation using multiple short-term electrocardiogram recordings

Purpose

The effect of novel catheter ablation techniques for atrial fibrillation (AF) on the autonomic nervous system (ANS) is unclear. This study aimed to assess the ANS after three novel catheter ablation techniques for paroxysmal AF by evaluating heart rate variability (HRV) parameters using a 3-min electrocardiogram recording.

Methods

Two hundred and thirty-five patients who underwent catheter ablation for paroxysmal AF (119 in irrigated-tip, 51 in contact-force sensing-guided, and 65 patients in second-generation cryoballoon ablation) were included. HRV analysis was performed at baseline and 1, 3, 6, and 12 months after the ablation.

Results

The three ablation groups had similarly decreased HRV parameters after the ablation, and this change was maintained > 1 year. A reduction in parasympathetic nervous function was more apparent after the ablation, compared to changes in the sympathetic nervous function. Of the total population, 45 patients had recurrence. Ln high frequency (HF) 12 months after the ablation was significantly higher in the recurrence group than in the non-recurrence group (1.52 ± 0.47 vs. 1.26 ± 0.57 ms², p = 0.007). Multivariate analysis demonstrated that AF duration (hazards ratio 1.09, 95% confidence interval 1.04–1.15, p = 0.001) and ln HF 12 months after ablation (hazards ratio 1.91, 95% confidence interval 1.12–3.25, p = 0.017) were independent predictors of AF recurrence after the ablation.

Conclusions

ANS modulation after the three catheter ablation methods was similar and maintained > 1 year after the procedure. Higher parasympathetic nervous function at 1 year after ablation was associated with AF recurrence after the ablation.

     

Defective T cell function for inhibition of growth of Mycobacterium avium-intracellulare complex (MAC) in patients with MAC disease: restoration by cytokines

To define the immunopathologic mechanism underlying pulmonary Mycobacterium avium-intracellulare complex (MAC) disease in patients without AIDS, the ability of CD4(+) and gammadelta T cells to induce growth inhibition of MAC in monocytes was compared between patients and healthy control subjects. T cell-dependent growth inhibition and production of interferon-gamma and macrophage colony-stimulating factor decreased in patients. CD4(+) T and gammadelta T cells from patients were equally defective in inducing anti-MAC activity. The combination of these cytokines restored the ability of patients' T cells to control MAC growth. In experiments with allogeneic cocultures of gammadelta T cells and infected monocytes from patients and control subjects, healthy control T cells could augment growth inhibition of MAC in monocytes from patients, whereas patients' T cells could not, even in the presence of healthy control monocytes. These results indicate that the defect in T cells may be associated with impaired protective immunity against MAC in these patients.     

Neurological Manifestations and Long-term Sequelae in Hospitalized Patients with COVID-19

Objective Various neurological manifestations have been increasingly reported in coronavirus disease 2019 (COVID-19). We determined the neurological features and long-term sequelae in hospitalized COVID-19 patients. Methods We retrospectively studied 95 consecutive hospitalized patients with COVID-19 between March 1 and May 13, 2020. Acute neurological presentations (within two weeks of the symptom onset of COVID-19) were compared between 60 non-severe and 35 severely infected patients who required high-flow oxygen. In the 12 ventilated patients (the most severe group), we evaluated neurological complications during admission, subacute neurological presentations, and neurological sequelae (51 and 137 days from the onset [median], respectively). Results Of the 95 patients (mean age 53 years old; 40% women), 63% had acute neurological presentations, with an increased prevalence in cases of severe infections (83% vs. 52%, p＜0.001). Impaired consciousness and limb weakness were more frequent in severe patients than in non-severe ones (0% vs. 49%; p＜0.001, and 0% vs. 54%; p＜0.001, respectively). In the most severe group (mean age 72 years old; 42% women), 83% of patients had neurological complications [cerebrovascular disease (17%), encephalopathy (82%), and neuropathy (55%)], and 92% had subacute neurological presentations [impaired consciousness (17%), higher brain dysfunction (82%), limb weakness (75%), and tremor (58%)]. Neurological sequelae were found in 83% of cases, including higher brain dysfunction (73%), limb weakness (50%), and tremor (58%). Conclusions Neurological manifestations are common in COVID-19, with the possibility of long-lasting sequelae.     

The effect of synthetic retinoid, Am80, on T helper cell development and antibody production in murine collagen-induced arthritis

Retinoids are known to promote T helper (Th)2 and regulatory T cell (Treg) differentiation, and suppress Th1 and Th17 in vitro. Am80, a synthetic retinoid, is reported to ameliorate collagen-induced arthritis (CIA). The aims of this study are to determine the effects of Am80 on CIA in detail, and on Th development and antibody (Ab) production in vivo. Murine CIA was induced by immunization with bovine type II collagen (CII) at days 1 and 22. Treatment with Am80 from day 1 to 35 significantly lowered clinical arthritis score, suppressed cellular infiltration and bone destruction in the joint, decreased interleukin (IL)-17 and increased interferon (IFN)-γ production by CII-stimulated splenocytes, and decreased proportion of Foxp3⁺ splenic CD4 T cells and serum anti-CII Ab levels. Thus, Am80 inhibited Th17 and Treg and enhanced Th1 differentiation in vivo. In contrast, Am80 applied from day 15 to 35 did not alter arthritis score, IL-17 or IFN-γ production by CII-stimulated splenocytes, but decreased the proportion of Foxp3⁺ splenic CD4 T cells and serum anti-CII Ab levels. Am80 exhibits inhibitory effects on CIA and might regulate both Th development and Ab production in vivo. Decreased Th17 by treatment with Am80 might be responsible for the attenuation of arthritis.     

Clinical and procedural characteristics of acute hemodynamic responders undergoing triple-site ventricular pacing for advanced heart failure

The advantages of triple-site ventricular pacing (Tri-V) compared to conventional biventricular site pacing (Bi-V) have been reported. We sought to identify the predictors of acute hemodynamic Tri-V responders. Acute hemodynamic studies were performed in 32 patients with advanced heart failure during Tri-V implantation. After the right ventricular (RV) and left ventricular (LV) leads were implanted for a conventional Bi-V system, an additional pacing lead was implanted in the RV outflow tract for Tri-V. The LV peak +dP/dt and tau were measured during AAI, Bi-V, and Tri-V pacing. A Tri-V responder was defined as a patient whose percentage of increase in the peak +dP/dt during Tri-V was >10% compared to of that during Bi-V. The baseline clinical variables and RV outflow tract lead location were analyzed to identify the characteristics of the Tri-V responders. Of the 32 patients, 10 (31%) were classified as Tri-V responders. The LV end-diastolic volume was greater (246 ± 48 vs 173 ± 53 ml, p <0.01), and the RV outflow tract lead was implanted at a greater outflow tract portion (p <0.05) in the Tri-V responders. Multivariate analysis revealed that only the baseline LV end-diastolic volume (per 50-ml greater) predicted the Tri-V response (odds ratio 2.87, 95% confidence interval 1.03 to 8.00, p <0.05). The area under the receiver operating characteristic curve for the LV end-diastolic volume was 0.84 (p <0.01) and an LV end-diastolic volume of >212 ml had a sensitivity of 80% and specificity of 77% to distinguish Tri-V responders. In conclusion, Tri-V provides greater hemodynamic effect for patients with a larger LV end-diastolic volume owing to its resynchronization effects on the LV anterior wall.