Effects of tafamidis on the left ventricular and left atrial strain in patients with wild-type transthyretin cardiac amyloidosis.

AIMS: Although tafamidis is used in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), its specific effect on cardiac function is unclear. Thus, this study aimed to investigate the effect of tafamidis on left atrial (LA) and left ventricular function using speckle-tracking echocardiography for 1 year of treatment in patients with ATTRwt-CA. METHODS AND RESULTS: We included 23 patients (mean age, 76 years) with ATTRwt-CA confirmed via biopsy. We analysed the left ventricular and LA strain using 2D speckle-tracking echocardiography and compared these parameters before and 1 year after starting treatment with tafamidis between 16 patients with sinus rhythm (SR) and 7 patients with atrial fibrillation (AF). In ATTRwt-CA patients with SR, LA reservoir strain significantly improved by 1-year tafamidis treatment (10.5 ± 5.0% to 11.9 ± 5.3%, P = 0.0307) although global longitudinal strain (GLS) did not (-10.6 ± 3.1% to -11.3 ± 3.0%, P = 0.0608). In contrast, LA reservoir strain was not significantly changed (5.4 ± 2.9% to 4.9 ± 1.7%, P = 0.4571), and GLS deteriorated (-8.4 ± 2.3% to -6.8 ± 1.4%, P = 0.0267) in ATTRwt-CA patients with AF. CONCLUSION: LA function improved with tafamidis treatment in ATTRwt-CA patients with SR but not left ventricular function. However, these cardiac functions did not improve with tafamidis treatment in ATTRwt-CA patients with AF.

Analysis of absorption-enhancing mechanisms for combinatorial use of spermine with sodium taurocholate in Caco-2 cells.

Previously, we reported that the combined use of spermine (SPM) and sodium taurocholate (STC) (SPM-STC) significantly improves the oral absorption of rebamipide (BCS class IV) and pulmonary absorption of interferon-α without any harmful histopathological changes in the gastrointestinal tract and lungs, respectively. In the present study, we examined the effect of SPM-STC on the transport of fluorescein isothiocyanate-labeled dextrans (FDs) across Caco-2 cell monolayers and attempted to clarify the mechanisms underlying the transport enhancement caused by SPM-STC. SPM-STC were found to significantly enhance the transport of FDs, while the treatment with SPM-STC was not harmful, and the decrease in transepithelial electrical resistance was transient and reversible. The voltage-clamp study clearly indicated that the opening of the paracellular route could be mainly responsible for the enhanced transport of FD-4. As for the mechanisms, it was found that SPM-STC caused a significant increase in membrane fluidity, which would lead to the enhanced transport of small-molecule drugs such as rebamipide. Since SPM-STC increased intracellular Ca2+ via Ca2+ uptake through Ca2+ channels and Ca2+ release from the endoplasmic reticulum stimulated by the IP3 pathway, the subsequent possible activation of the MLCK signaling pathway would have led to the contraction of the actin-myosin ring. The rearrangement of tight junction-constituting proteins induced through the MAPK pathway has also been suggested as a possible mechanism for opening tight junctions. Claudin-4, a key protein constituting the tight junction, merged with F-actin along with the plasma membrane, was significantly decreased, which would be at least partial structural evidence for the tight-junction opening.

Right Ventricular Dyssynchrony in Patients With Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are characterized by elevated pulmonary arterial pressure resulting in right heart failure. Right ventricular (RV) dyssynchrony may be associated with early-stage RV dysfunction; however, the differences in RV dyssynchrony between CTEPH and PAH and the factors contributing to RV dyssynchrony remain unclear.Methods and Results: Forty-four patients (CTEPH, 26; PAH, 18) were enrolled in this study. RV dyssynchrony was assessed by determining the standard deviation of the intervals from the peak QRS to peak systolic strain for 6 segments of the RV free and septal wall by using 2-dimensional speckle-tracking echocardiography (RV-6SD). The RV-6SD, pulmonary hemodynamics, echocardiographic findings, and patient demographics in CTEPH and PAH patients were compared and their correlations with RV-6SD were investigated. CTEPH patients were older and had significantly higher pulse pressure of the pulmonary artery (PP), tricuspid valve regurgitation pressure gradient, and RV-6SD, and lower pulmonary arterial compliance (PAC), despite showing comparable pulmonary arterial pressures. Age-adjusted multiple logistic analysis showed that RV-6SD and PAC were predictors of CTEPH rather than PAH. RV-SD6 was positively correlated with PP and RV dimension and negatively correlated with PAC. CONCLUSIONS: CTEPH patients showed more evident RV dyssynchrony than PAH patients. Low PAC and a widened PP may delay RV free wall motion and cause RV dyssynchrony.

Comparison of Dasatinib- and Imatinib-Related Cardiotoxic Adverse Events in Japanese Patients With Chronic Myeloid Leukemia and Gastrointestinal Stromal Tumor.

Background: Despite the beneficial effects of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), they may also cause adverse events (AEs), especially cardiovascular toxicity. The incidence of TKI-induced AEs may vary among ethnic groups, and there is little specific information for Japanese patients. Methods and Results: Sixty-nine consecutive patients who were started on treatment with dasatinib (n=25) or imatinib (n=44) for CML or gastrointestinal stromal tumor (GIST) between December 2008 and December 2019 were retrospectively recruited to the study. We determined the prevalence of AEs through October 2020 and compared the incidence of AEs between the 2 drugs. Baseline characteristics were comparable between the 2 groups. However, compared with the imatinib-treated group, the dasatinib-treated group had a higher incidence of congestive heart failure (CHF; 20.0% vs. 2.3%; P=0.04), pleural effusion (48% vs. 20.5%; P=0.03), pericardial effusion (24% vs. 4.6%; P=0.02), QT prolongation (4 vs. 0 patients; P=0.02), and pulmonary hypertension (3 vs. 0 patients; P=0.04). In the dasatinib-treated group, CHF tended to be associated with tricuspid valve regurgitation pressure gradient, and pleural effusion was observed in all patients. All-cause mortality and other cardiovascular events did not differ significantly between the 2 groups. Conclusions: Cardiotoxic AEs occurred more frequently in Japanese patients with CML and GIST treated with dasatinib than imatinib.

Randomized, Open-Label, Cross-Over Comparison of the Effects of Benzbromarone and Febuxostat on Endothelial Function in Patients with Hyperuricemia.

Uric acid is generated with reactive oxygen species via xanthine oxidase (XO), and hyperuricemia, which is identified as the excess of uric acid in the blood, has been associated with vascular endothelial dysfunction. However, the effects of urate-lowering medicines on endothelial function have not been fully elucidated. Thus this study determined and compared the effects of benzbromarone (urate transporter 1 inhibitor) and febuxostat (XO inhibitor) on endothelial function.This randomized, cross-over, open-label study initially recruited 30 patients with hyperuricemia. They were divided into two groups, treated initially with benzbromarone or febuxostat for three months and then were switched for the next three months. Endothelial function was defined as reactive hyperemia indexes (RHI) determined using Endo-PAT 2000 before and at three and six months after medication using the two agents. Blood levels of asymmetric dimethylarginine (ADMA) and high-molecular-weight (HMW) adiponectin were also compared. We finally analyzed data from 24 patients whose endothelial function was assessed as described above.Our findings show that levels of uric acid significantly decreased, whereas those of HMW adiponectin and the RHI have significantly increased after treatment with benzbromarone. Meanwhile, in patients administered with febuxostat, uric acid levels tended to decrease and RHI significantly decreased. Neither of the two agents altered ADMA levels. The changes in RHI (P = 0.026) and HMW adiponectin levels (P = 0.001) were found to be significantly greater in patients treated with benzbromarone than febuxostat. Changes in the levels of HMW adiponectin and of uric acid were significantly correlated (r = -0.424, P = 0.039).Benzbromarone has increased adiponectin besides reducing uric acid levels, and thus, this might confer more benefits on endothelial function than febuxostat.

Evaluation of echocardiographic parameters in Japanese patients aged over 90 years at a single institution.

PURPOSE: The number of patients aged over 90 years undergoing transthoracic echocardiography (TTE) has increased. Normal echocardiographic measurement values in healthy Japanese aged 20-79 years have been reported by Daimon et al., and in those aged 10-89 years by Okura et al. To date, no researchers have published normal values in healthy Japanese aged over 90 years. To understand the echocardiographic characteristics and establish the normal range, we evaluated patients aged over 90 years who had preserved left ventricular (LV) ejection fraction without cardiovascular disease. METHOD: Enrolled in the study were consecutive patients aged over 90 years who were examined by TTE at the Ultrasound Imaging Center at Nagasaki University Hospital, Japan, between September 2009 and May 2016. We selected patients with LV ejection fraction > 55%, and without cardiac, renal, or aortic disease. RESULTS: Among a total of 956 patients, 73 patients (19 males, 54 females) were admitted. Compared with females, males had significantly higher values of aortic diameter at the sinus of Valsalva and LV diastolic diameter and systolic diameter (P < 0.01), significantly lower E wave velocities (P < 0.01) and left ventricle mass (P < 0.01), and lower values of relative wall thickness (P < 0.01). Compared with subjects in their 70s and 80s in the studies by Daimon and Okura, the E and A wave velocities were higher. CONCLUSION: We established the normal range of TTE parameters in elderly patients who had LV ejection fraction > 55% without cardiac, renal, or aortic disease. Sex differences were present as well as a tendency towards age-related changes in LV geometry and diastolic function. Most of the patients aged over 90 years had LV hypertrophy and potential diastolic dysfunction.

Doppler ultrasound diagnosis of transient leg malperfusion caused by dynamic obstruction in a patient with chronic aortic dissection.

Leg malperfusion caused by dynamic obstruction is a serious complication of aortic dissection. A diagnosis of the malperfusion is difficult because it is made mainly on the basis of nonspecific symptoms such as intermittent claudication and numbness on walking. In the present study, we reported on a case of a 51-year-old man with leg malperfusion in chronic aortic dissection diagnosed by Doppler ultrasound. The combination of bisferious and dampened velocity waveform changes after walking may lead us to suspect a leg malperfusion caused by dynamic obstruction.

Cardiac Calcified Amorphous Tumors in a Patient with Hemodialysis for Diabetic Nephropathy.

Calcified amorphous tumor (CAT) is a rare, non-neoplastic tumor involving calcium deposition in amorphous materials. Although its etiology is unknown, cases have frequently been reported in patients with hemodialysis for chronic kidney disease. We herein describe a case of cardiac CAT in a 64-year-old woman who had been on hemodialysis for diabetic nephropathy for 20 years, and the findings of the present patient, in association with the findings of previous case reports, suggest that end-stage renal disease seems to play an important role in the onset of CAT, especially in CAT formation at the mitral annulus, which appears to differ from CAT occurring at other sites.

Comparison of saddle-shape flexibility and elliptical-shape stability between Cosgrove-Edwards and Memo-3D annuloplasty rings using three-dimensional analysis software.

OBJECTIVE: To compare three-dimensional dynamics between implanted Cosgrove-Edwards and Sorin Memo-3D annuloplasty rings during the cardiac cycle. METHODS: We examined 11 Cosgrove-Edwards rings and 20 Sorin Memo-3D rings after mitral plasty using real-time three-dimensional transesophageal echocardiography. We evaluated ring height, ellipticity, and geometry during one cardiac cycle. Four evenly spaced phases each selected during systole and diastole were assessed using REAL VIEW software. RESULTS: The height of the Cosgrove-Edwards and Sorin Memo-3D rings was similar (2.3 ± 0.8 vs. 1.9 ± 0.9 mm, p = 0.44). The maximum difference in ring height during one cardiac cycle (change in height) was larger for the Cosgrove-Edwards than the Sorin Memo-3D rings (2.3 ± 0.8 vs. 1.5 ± 0.6 mm, p = 0.014). Ellipticity and the maximum difference in ellipticity during one cardiac cycle (change in ellipticity) were larger for Cosgrove-Edwards than Sorin Memo-3D rings (80.0 ± 9.1 vs. 72.0 ± 4.8 %, p = 0.014, respectively, and 12.0 ± 3.1 vs. 6.0 ± 1.8 %, p < 0.001). CONCLUSIONS: Cosgrove-Edwards rings were more flexible, whereas Sorin Memo-3D rings maintained the elliptical shape more effectively.

Longitudinal strain of right ventricular free wall by 2-dimensional speckle-tracking echocardiography is useful for detecting pulmonary hypertension.

AIMS: Echocardiography is widely used for screening pulmonary hypertension (PH). More recently developed two-dimensional speckle-tracking echocardiography (2D-STE) can assess regional deformation of the myocardium and is useful for detecting left ventricular dysfunction. However, its usefulness to assess right ventricular (RV) dysfunction is not clear. Therefore, the aim of this study was to investigate the ability of peak systolic strain (PSS) and post-systolic strain index (PSI) at the RV free wall determined by 2D-STE to detect PH. MAIN METHODS: Thirty-six images (27 images from PH patients, nine from patients with connective tissue disease without PH) obtained by 2D-STE were analysed. We investigated the relationship between RV hemodynamics measured by right heart catheterization and PSS, PSI and other echocardiographic parameters reflecting RV overload including RV end-diastolic diameter (RVDd) and tricuspid valve regurgitant pressure gradient (TRPG). KEY FINDINGS: PSS, PSI, RVDd and TRPG were all correlated with mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR). Furthermore, when PSS and MPAP were measured twice, the change in PSS was correlated with the change in MPAP (r=0.633, p=0.037). Multivariate logistic regression analysis identified PSS as the only independent factor associated with MPAP ≥ 35mmHg [odds ratio (OR), 1.616; 95% confidence interval (CI) 1.017-2.567; p=0.042] and PVR ≥ 400dyn·s·cm(-5) (OR, 1.804; 95% CI 1.131-2.877; p=0.013). Furthermore, the optimal PSS cut-off value to detect an elevated MPAP and PVR was -20.75%, based on receiver operating characteristic curve analysis. SIGNIFICANCE: PSS of the RV free wall might serve as a useful non-invasive indicator of PH.

Cleft-like formation of the aortic valve in an adult patient with a single coronary artery.

A 51-year-old woman was admitted to our hospital with heart failure due to aortic regurgitation. Examination showed severe aortic regurgitation mainly due to cleft-like deformity of the right coronary cusp and single coronary artery. Aortic valve replacement was performed, and the deformity was seen in all aortic cusps. Histological study showed elongation of the leaflets by myofibrotic and fibrotic hyperplasia without calcification and inflammation in the aortic valve. This deformity likely arose from an acquired modification of a congenitally malformed aortic valve.

Comparison of the diagnostic power of transthoracic and transesophageal echocardiography to detect ruptured chordae tendineae.

Preoperative information concerning the severity and etiology of MR is very important for selecting the most appropriate surgical strategy. Ruptured chordae tendineae (RCT) are one of the most important preoperative findings. We compared the diagnostic power of transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE) to detect RCT in patients with MR. We studied 61 patients with MR (30 men, 31 women; mean age, 61 ± 12 years) who underwent mitral valve repair or replacement. Both TTE and TEE were performed before the operations, and the sensitivity and specificity of TTE and TEE to detect RCT were determined. In addition, other factors that influenced the detection of RCT by these two methods were investigated. At the time of an operation, RCT was confirmed in 39 of 61 cases. Transesophageal echocardiography had a higher sensitivity than TTE (74% versus 44%; P = 0.006) to detect RCT, although the specificity was not significantly different. In patients with a body mass index (BMI) > 22 (P = 0.023) or MR grade 4 (P = 0.026), TEE had a significantly higher diagnostic sensitivity than TTE, although there was no significant difference in patients with BMI < 22 or MR grade ≤ 3. In the lateral and medial segments of the mitral valve, TEE had a significantly higher diagnostic sensitivity to detect RCT than TTE (P = 0.0012), although there was no significant difference in the middle segments. There was no significant difference between TTE and TEE with respect to the sensitivity to detect RCT in myxomatous mitral valves. Although the sensitivity of TEE was higher than that of TTE to detect RCT, it was affected by BMI, MR grade, the RCT-presenting segments, and the etiology of MR.

Effects of dopamine antagonists on methamphetamine-induced dopamine release in high and low alcohol preference rats.

The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1 mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10 min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD-HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre-treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference.

Identification of antisense RNA stem-loops that inhibit RNA-protein interactions using a bacterial reporter system.

Many well-characterized examples of antisense RNAs from prokaryotic systems involve hybridization of the looped regions of stem-loop RNAs, presumably due to the high thermodynamic stability of the resulting loop-loop and loop-linear interactions. In this study, the identification of RNA stem-loops that inhibit U1A protein binding to the hpII RNA through RNA-RNA interactions was attempted using a bacterial reporter system based on phage lambda N-mediated antitermination. As a result, loop sequences possessing 7-8 base complementarity to the 5' region of the boxA element important for functional antitermination complex formation, but not the U1 hpII loop, were identified. In vitro and in vivo mutational analysis strongly suggested that the selected loop sequences were binding to the boxA region, and that the structure of the antisense stem-loop was important for optimal inhibitory activity. Next, in an attempt to demonstrate the ability to inhibit the interaction between the U1A protein and the hpII RNA, the rational design of an RNA stem-loop that inhibits U1A-binding to a modified hpII was carried out. Moderate inhibitory activity was observed, showing that it is possible to design and select antisense RNA stem-loops that disrupt various types of RNA-protein interactions.

Positive identification facilitated by implanted metallic plate and screws.

Personal identification is an essential subject in forensic practice. With skeletonized remains, an anthropological examination is performed for personal identification. Here we describe the positive identification of skeletonized human remains from the serial numbers of implanted metallic plate and screws.