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Background: We previously demonstrated the clinical events in patients who underwent catheter ablation (CA) for atrial fibrillation (AF). Data on the association between the period of atrial tachyarrhythmia (ATA) recurrence after CA and long-term major adverse clinical events (MACE) remain unclear. In this study, we evaluated this issue in patients with systolic impairment (left ventricular ejection fraction

Left ventricular (LV) diastolic dysfunction is increasingly common in heart failure with preserved ejection fraction (HFpEF), and new drug therapy is desired. We recently reported that dantrolene (DAN) attenuates pressure-overload induced hypertrophic signaling through stabilization of tetrameric structure of cardiac ryanodine receptor (RyR2). Because cardiac hypertrophy substantially affects LV diastolic properties, we investigated the effect of DAN on LV diastolic properties in mineralocorticoid-salt–induced hypertensive rat model exhibiting the HFpEF phenotype.Male Sprague-Dawley (SD) rats (8 weeks old) received an uninephrectomy (UNX), subcutaneous implantation of a 200 mg pellet of deoxycorticosterone acetate (DOCA), and 0.9% NaCl water (UNX + DOCA-salt). UNX, a control pellet, and water without NaCl served as controls (UNX control). The effect of oral administration of 100 mg/kg/d DAN was examined in UNX control and UNX + DOCA-salt groups (UNX + DAN and UNX + DOCA-salt + DAN).UNX + DOCA-salt treatment resulted in mild hypertension. Chronic administration of DAN to UNX + DOCA-salt rats (UNX + DOCA-salt + DAN) did not affect blood pressure. DAN treatment increased the mitral annular early relaxation velocity in the UNX + DOCA-salt group. The size of cardiomyocytes increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. LV fibrotic area was significantly smaller in the UNX + DOCA-salt + DAN group than in the UNX + DOCA-salt group (2.0 ± 0.2% vs 4.0 ± 0.4%). The LV chamber stiffness significantly increased in the UNX + DOCA-salt group, whereas the increase was suppressed by DAN treatment. DAN treatment normalized the CaM-RyR2 interaction and inhibited aberrant Ca2+ release.DAN improved left ventricular diastolic properties with respect to both myocardial relaxation and chamber stiffness. DAN may be a new treatment option for HFpEF.

Abstract Aims Data regarding prognostic events following catheter ablation (CA) for atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) are scarce. We conducted this study to compare the incidence of major adverse clinical events (MACE) following CA for AF between patients with HFpEF and those with systolic heart failure (HF). Methods and results This single‐centre observational study included 142 patients with HF who underwent CA for AF (median follow‐up: 4.0 [2.6, 6.3] years). The patients were grouped based on the presence of HFpEF (n = 84) and systolic HF (left ventricular ejection fraction

Abstract Although the 6 min walk test (6MWT) is well-established for assessing desaturation in patients with interstitial lung disease (ILD), it cannot be easily performed in primary healthcare settings. This retrospective observational study aimed to evaluate the usefulness of the 1 min sit-to-stand test (1STST) for assessing desaturation during 6MWT in ILD patients with normal resting blood oxygen levels. We included 116 patients, and the pulse oxygen saturation (SpO2) for both methods was analyzed. The SpO2 nadir during the 1STST and 6MWT correlated strongly (ρ = 0.82). The frequency of patients with nadir SpO2

Abstract Background This study aimed to investigate the correlation between left atrial low‐voltage areas (LVAs) and an arrhythmogenic superior vena cava (SVC) and the impact on the efficacy of an empiric SVC isolation (SVCI) along with a pulmonary vein isolation (PVI) of non‐paroxysmal atrial fibrillation (non‐PAF) with or without LVAs. Methods We retrospectively enrolled 153 consecutive patients with non‐PAF who underwent a PVI alone (n = 51) or empiric PVI plus an SVCI (n = 102). Left atrial voltage maps were constructed during sinus rhythm to identify the LVAs (

Purpose: The purpose of this study was to analyze the role of homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (Herpud1) gene in the development of cardiomyocyte hypertrophy. Method: In order to examine the effect of suppressing Herpud1 expression, Herpud1 small interfering RNA (siRNA) was introduced into H9C2 cells, which are cell lines derived from rat myocardium, and the degree of Herpud1 protein expression and cell hypertrophy in the Herpud1 siRNA-transfected group and the control group was compared by immunostaining 48 h after Herrpud1 siRNA introduction. To examine whether hypertrophy induced by angiotensin II (Ang II) can be suppressed by the overexpression of Herpud1, the green fluorescent protein (GFP)-Herpud1 plasmid was introduced into H9C2 cells, and the degree of cell hypertrophy was examined in the GFP-Herpud1-and control groups for 48 h. Nuclear translocation of nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4), a transcription factor for hypertrophic genes, was also examined. Results: [1] Herpud1 siRNA-transfected cells showed decreased Herpud1 protein expression and hypertrophy formation compared to control cells [2]; Overexpression of Herpud1 suppresses Ang II-induced cell hypertrophy; and [3] Overexpression of Herpud1 inhibits nuclear translocation of NFATc4. Discussion: It was suggested that Herpud1 might be an anti-hypertrophic gene in Ang II induced cardiomyocytes hypertrophy.

Physical inactivity correlates with poor prognosis in chronic obstructive pulmonary disease (COPD) and is suggested to be related to lung hyperinflation. We examined the association between physical activity and the expiratory to inspiratory (E/I) ratio of mean lung density (MLD), the imaging biomarker of resting lung hyperinflation. COPD patients (n = 41) and healthy controls (n = 12) underwent assessment of pulmonary function and physical activity with an accelerometer, as well as computed tomography at full inspiration and expiration. E/IMLD was calculated by measuring inspiratory and expiratory MLD. Exercise (EX) was defined as metabolic equivalents × duration (hours). COPD patients had higher E/IMLD (0.975 vs. 0.964) than healthy subjects. When dividing COPD patients into sedentary (EX < 1.5) and non-sedentary (EX ≥ 1.5) groups, E/IMLD in the sedentary group was statistically higher than that in the non-sedentary group (0.983 vs. 0.972). E/IMLD > 0.980 was a good predictor of sedentary behavior in COPD (sensitivity, 0.815; specificity, 0.714). Multivariate analysis showed that E/IMLD was associated with sedentary behavior (odds ratio, 0.39; p = 0.04), independent of age, symptomology, airflow obstruction, and pulmonary diffusion. In conclusion, higher E/IMLD scores are associated with sedentary behavior and can be a useful imaging biomarker for the early detection of physical inactivity in COPD.

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in App NL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from App NL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.

In the title molecule, C48H33N, the central N atom shows no pyramidalization, so that the N atom and the three C atoms bound to the N atom lie almost in the same plane. The three para-phenylene rings bonded to the N atom are in a propeller form. All of the naphthalene ring systems are slightly bent. In the crystal, molecules form an inversion dimer, through two pairs of C—H...π interactions, which further interacts with the adjacent dimer via another two pairs of C—H...π interactions, forming a column structure along the a axis. There are no significant interactions between these column structures.

Background Catheter ablation can improve long‐term prognosis of patients with atrial fibrillation with systolic impairment. However, atrial tachyarrhythmia (ATA) recurrence increases during long‐term follow‐up. We aimed to investigate the impact of ATA recurrence on the development of long‐term adverse clinical events following catheter ablation for atrial fibrillation and to identify predictors for the development of adverse clinical events. Methods and Results This single‐center observational study included 75 patients with systolic impairment (left ventricular ejection fraction

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of antineutrophil cytoplasmic antibody-associated vasculitis. Patients often present with peripheral neuropathy and purpura, suggesting impairment of small vessels, especially capillaries. However, medium-sized vessels and small vessels with a vascular diameter larger than that of capillaries may also be impaired, causing atypical findings. We report a case of EGPA treated with corticosteroids, cyclophosphamide, and mepolizumab. Renal biopsy revealed vasculitis of the interlobular arteries as the cause of glomerulonephritis and interstitial nephritis. This case suggests the importance of considering vessels upstream of capillaries dominant EGPA as a differential diagnosis in patients with eosinophilia.

Aim To investigate the characteristics of coronary artery bifurcation type (parallel or perpendicular type) using three-dimensional (3D) optical coherence tomography (OCT), and determine the feasibility, reproducibility, assessment time and correlation with bifurcation angles measured by 3D quantitative coronary angiography (QCA). Methods and results We evaluated 60 lesions at the coronary bifurcation that were treated by main vessel (MV) stenting with kissing balloon inflation (KBI) under OCT/optical frequency domain imaging (OFDI) guidance. Inter- and intra-observer agreement regarding the assessment of 3D bifurcation types were 0.88 and 0.94, respectively. The assessment times of 3D-OCT bifurcation type with OCT and OFDI were within about 30 seconds. 3D-OCT bifurcation types showed the greatest correlation with the distal bifurcation angle assessed by 3D-QCA among the three bifurcation angles (distal bifurcation angle, proximal bifurcation angle and main vessel angle), and the optimal cut-off distal bifurcation angle to predict a perpendicular type bifurcation, as determined by ROC analysis, was 51.0° (AUC 0.773, sensitivity 0.80, specificity 0.67). Based on this cut-off value for the distal bifurcation angle (51°), the diagnostic accuracy for perpendicular type bifurcation in cases with a BA ≥ 51° (n = 34) was 70.6% (24/34) and that of the parallel type bifurcation in cases of BA < 51° (n = 26) was 76.9% (20/26). Conclusion Performing 3D-OCT for assessment of coronary artery bifurcation type is feasible and simple, and can be done in a short time with high reproducibility.

Diffuse alveolar haemorrhage and central nervous system vasculitis are life-threatening complications of anti-neutrophil cytoplasmic antibody-associated vasculitis. The simultaneous occurrence of diffuse alveolar haemorrhage and central nervous system vasculitis is a rare presentation of antibody-associated vasculitis. Its diagnosis by histopathology is difficult because biopsy is difficult to perform, and urgent treatment is needed. We report a case of a Japanese man with diffuse alveolar haemorrhage and central nervous system vasculitis associated with antibody-associated vasculitis. New classification criteria may be needed for diffuse alveolar haemorrhage and central nervous system vasculitis associated with systemic vasculitis. When antibiotic-resistant atypical bilateral pneumonia is noted in the acute phase of a cerebral stroke, with elements suggestive of vasculitis, clinicians should be aware that diffuse alveolar haemorrhage and central nervous system vasculitis may occur simultaneously.

The contour of an arbitrary figure can be represented as a group of circles of curvature in contact with it, with each curvature circle represented by its center OC and radius r. We propose a series of cell models for detecting this circle, which is composed of a lateral geniculate nucleus (LGN) cell, nondirectionally selective (NDS) simple cell, and curvature-circle detection cell (CDC). The LGN and NDS simple cells were previously modeled. The CDC has been modeled as follows. Each tangent in contact with this circle is detected by an NDS simple cell that performs the Hough transformation of LGN cell responses, and then this tangent is transformed to a three-dimensional (3D) normal line in a CDC column. This transformation has been named a 3D normal-line transform. Performing this transformation for all tangents causes a CDC at the intersection of these normal lines to fire most intensively, and thus the OC and r of the circle is detected as the coordinates of this intersection. Therefore, the CDC has been modeled as this 3D normal-line transform. Based on this CDC, we model two types of constancy CDC: a position-invariant CDC and a curvature-invariant CDC. These three types of CDC reflect the response to various stimuli in actual area V4 cells. In order to validate these CDC types neurophysiologically, we propose an experimental method using microelectrodes. Cell models previously reported correspond to this hierarchy: the S1, S2, and C2 cells correspond to the NDS simple cell, CDC, and position-invariant CDC, respectively.

Long-duration atrial high-rate episodes (AHREs) monitored using cardiac implantable electronic devices (CIEDs) can predict long-term major adverse cardiovascular events (MACEs). This study aimed to compare the impact of long-duration AHRE on MACE development between patients with and without a history of atrial fibrillation (AF). This single-center observational study included 132 CIED-implanted patients with AHREs detected via remote monitoring. The population was dichotomized into groups: with (n = 69) and without (n = 63) AF. In each group, cumulative incidences of MACEs comprising all-cause deaths, heart failure hospitalizations, strokes, and acute coronary syndromes were compared between patients with AHRE durations of ≥24 h and p = 0.005). MACE incidence did not significantly differ between AHRE ≥24 h and p = 0.44). After a multivariate adjustment, AHRE duration of ≥24 h emerged as the only independent predictor of MACEs among patients without AF (p = 0.03). In conclusion, a long-duration AHRE was prognostic in patients without a history of AF but not in patients with a history of AHREs.

Introduction: Our previous studies demonstrated that dantrolene, a ryanodine receptor stabilizer, prevents endoplasmic reticulum (ER) stress in the heart. ER stress is a strong mediator of impaired lipid metabolism in the liver, thereby contributing to fatty liver disease. In this study, we investigated the effects of dantrolene on fatty liver disease in mice and ER stress in hepatocytes. Methods and results: Eight weeks old C57BL/6 mice were fed high-fat diet (HFD) for 8 weeks with or without the oral administration of dantrolene (100 mg/kg/day). The livers of mice without dantrolene (HFD group) showed severe fatty liver, whereas the livers of the mice treated with dantrolene (HFD + DAN group) only showed slightly fatty liver. To address the preventive effects of dantrolene, primary hepatocytes were cultured with palmitate in the presence or absence of dantrolene. Dantrolene reduced lipid load and prevents palmitate-induced increase in cytoplasmic Ca2+ and ER stress. Based on these findings, we propose that dantrolene is a potential new therapeutic agent against fatty liver disease.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease that causes heart failure and/or sudden cardiac death. Several desmosomal genes (DSC2, PKG, PKP2, DSP, and RyR2) are thought to be the causative gene involved in ARVC. Out of them, DSC2 mutations account for 2% of ARVC genetic abnormalities. This study aimed to clarify the effect of G790del mutation in DSC2 on the arrhythmogenic mechanism and cardiac function in a mouse model. Result: Neither the heterozygous +/G790del nor homozygous G790del/G790del mice showed structural and functional defects in the right ventricle (RV) or lethal arrhythmia. The homozygous G790del/G790del 6-month-old mice slightly showed left ventricular (LV) dysfunction. Cell shortening decreased with prolongation of intracellular Ca2+ transient in cardiomyocytes isolated from the homozygous G790del/G790del mice, and spontaneous Ca2+ transients were frequently observed in response to isoproterenol. Conclusions: G790del mutation in DSC2 was not relevant to the pathogenesis of ARVC, but showed a slight contractile dysfunction and Ca2+ dysregulation in the LV. Keywords: Desmocollin-2 (DSC2), Arrhythmogenic right ventricular cardiomyopathy (ARVC)

Background: Recently, we showed an age-related increase in augmentation pressure (AP) measured using Mobil-O-Graph (MOG) in normotensive Japanese individuals. However, AP might be a poor index of wave reflection due to the overlap between the forward wave and reflected wave. Methods: We enrolled untreated hypertensive patients and patients currently on antihypertensive treatment. For 70 patients (median age, 70.5 years; 34 men), M-mode echocardiography was performed for determination of left ventricular hypertrophy (LVH), while hemodynamic measurements were taken using MOG. We investigated the influence of central hemodynamic parameters on LVH. Results: Spearman correlation coefficients between various parameters [age, height, systolic blood pressure (SBP), mean BP, diastolic BP, central systolic BP (cSBP), and AP] were calculated for LV mass indexed to body surface area (LVMI; g/m2). In men, age (r = 0.600, p = 0.0002), height (r = −0.495, p = 0.003), SBP (r = 0.423, p = 0.013), cSBP (r = 0.454, p = 0.007), and AP (r = 0.661, p < 0.0001) were correlated to LVMI. In women, cSBP (r = 0.334, p = 0.044) and AP (r = 0.480, p = 0.003) were correlated to LVMI. In men, LVMI (R2 = 0.578, p = 0.0001) was significantly associated with AP (β = 1.32 ± 0.56, p = 0.027) in multivariate regression analysis. In women, no significant independent parameter for LVMI was observed. ROC curve analysis was performed to estimate the utility of AP for the detection of LVH (LVMI >115 g/m2) in men. Area under the ROC curve was 0.83 (95% CI: 0.68–0.99). The optimal cut-off point of 12.5 mmHg produced 79.0% sensitivity and 86.7% specificity. Conclusion: Higher AP showing >12.5 mmHg calculated by MOG was a significant independent predictor of LVH in male hypertensive patients.

Abstract Background Steroid therapy, a key therapy for inflammatory, allergic, and immunological disorders, is often associated with steroid myopathy as one of the side effects. Steroid therapy is considered the first-line therapy for myositis; however, there have been no reports strictly comparing the muscle mass in patients with myositis before and after steroid therapy. Thus, it is currently unclear whether steroid therapy for such patients affects muscle volume in addition to muscle strength. We aimed to determine the change in muscle mass after steroid therapy via cross-sectional computed tomography (CT) in patients with myositis. Methods Data from seven patients with myositis and eight controls, who were all treated with high doses of steroids, were assessed before and after steroid therapy. Clinical factors in patients with myositis included serum muscle enzyme levels and muscular strength. The cross-sectional area of skeletal muscle and the low muscle attenuation rate at the level of the caudal end of the third lumbar vertebra were obtained using CT and measured using an image analysis program for all patients. Data were subjected to statistical analysis using several well-established statistical tests. The Wilcoxon signed-rank test was used for comparing paired data for each patient. The Mann-Whitney U test was used to compare sets of data sampled from two groups. The Spearman’s rank correlation coefficient was used for determining the correlations between two variables. Statistical significance was set at p

Background: In patients with idiopathic pulmonary fibrosis (IPF), continuing treatment with antifibrotic agents is crucial to decrease the reduction of forced vital capacity and mortality rate. However, predictive factors for the discontinuation of antifibrotic agents are unknown. This study aims to investigate the clinical characteristics and predictive factors for the discontinuation of antifibrotic agents in patients with IPF. Methods: This was a double-center retrospective study that enrolled patients with IPF treated with pirfenidone or nintedanib between 2009 and 2017. We compared clinical parameters between the medication-continuing group and the discontinued group. The predictive factors were determined using Cox proportional hazards analyses. Results: A total of 66 subjects were included: 43 received pirfenidone and 23 received nintedanib. At 1 year, 23 of 66 patients had discontinued due to adverse events ( n = 12), disease progression ( n = 9), or death ( n = 2). The characteristics of the discontinuation group were poor performance status (PS) and delay from diagnosis to treatment. In the receiver operating characteristic (ROC) analysis associated with the discontinuation of antifibrotic agents, PS was the highest area under the ROC curve (AUC) value (cut-off value, 2; AUC, 0.83; specificity, 63%; sensitivity, 87%). This finding was consistent even when analyzing, except for examples of death and adjusting for the type of antifibrotic agent. The treatment persistence rate by PS was PS 0–1 = 90%, PS 2 = 65%, and PS 3 = 19%. Analysis of the relationship between PS and administration period of antifibrotic agents revealed that delays from diagnosis to treatment led to worsening of dyspnea, a decline in lung function, and deterioration of PS. Conclusions: PS may be informative for predicting discontinuation of medication. Our data reinforced the importance of early initiation of antifibrotic treatment, and we suggest PS should be used as a guide for starting antifibrotic agents in everyday practice. The reviews of this paper are available via the supplementary material section.

A 79-year-old man with situs inversus and dextrocardia underwent catheter ablation of symptomatic paroxysmal atrial fibrillation. Pulmonary vein isolation (PVI), using second-generation cryoballoon under Ensite NavX system guidance, was performed successfully in a reverse manner, which required short procedure and fluoroscopy times, as required in a PVI performed on a normal heart without any complications. Cryoballoon-based PVI under Ensite NavX guidance was feasible and safe to achieve a favorable outcome in this patient with abnormal anatomy.

Background: HEM-9000AI (HEM) is an established device for measurement of radial augmentation index (rAIx) used by applanation tonometry in Japan. Mobil-O-Graph (MOG) is a cuff-based oscillometric device for assessment of central aortic AIx (cAIx) and the usefulness to Europeans has been reported. We compared the AIx between HEM and MOG in Japanese normotensive subjects. Methods: We enrolled 106 normotensive volunteers (47 male, 21 to 79 years). The left radial arterial waveform was recorded with the HEM. MOG were taken on the left arms, which arm circumferences (ACs) were measured to allow the correct choice of cuff (two sizes available; 20–24 and 24–32 cm). We performed multiple regressions for AIx and key variables in HEM and MOG. Results: The ACs in M and F were 25.7±1.9 (mean±SD) cm and 23.5±2.1cm, respectively. Both rAIx (70.5±15.3% vs 83.6±11.9%, p < 0.001) and cAIx (17.2±7.3% vs 29.7±9.8%, p < 0.001) in M were smaller than those in F. Multiple regression analysis revealed that cAIx in M (R2 = 0.5176) was significantly associated with age (β = 0.17, p = 0.004) and cuff size (p = 0.001). cAIx obtained using the smaller cuff was significantly increased compared to the larger cuff (25.1±5.9% vs 14.8±5.9%). In F, cAIx (R2 = 0.2245) tended to be associated with age (β = 0.16, p = 0.072) and was significantly associated with height (β = −0.62, p = 0.007) and heart rate (β = −0.26, p = 0.0029). Conclusions: The brachial cuff-based waveform recordings are useful for Japanese normotensive individuals. However, the mean AC is close to the bound of two cuff sizes and the measurement of lower cAx using the larger cuff is less sensitive.

This paper proposes a new computational method for retrieving shapes under unpredictable conditions such as when occlusion, geometric distortion, and differences in image resolution occur simultaneously. The human visual system retrieves shapes from incomplete information in the real world, and it has inspired a lot of computational methods of retrieving shapes. In order to retrieve shapes, the observed shapes are decided to be alike or unlike remembered shapes in memory after the comparison of these shapes. To compare the observed and remembered shapes, they must first be appropriately represented so that the points on each shape can be mapped and compared. For this reason, the shape retrieval process needs an appropriate shape representation and shape mapping methods. Moreover, the shape representations should be normalized before the mapping process. However, a normalization process for representations under unpredictable conditions has not yet been established. In this paper, we describe a shape retrieval method that enables us to retrieve shapes under unpredictable conditions with a suitable normalization process. Using curvature partition and angle-length profile, our shape retrieval method normalizes the shape representation before it does the mapping. As a result, unlike the previously proposed methods, it can be used under unpredictable conditions such as when occlusion, geometric distortion, and differences in image resolution occur simultaneously.

An estimated 0.9% to 2.4% of patients with systemic lupus erythematosus (SLE) also have hemophagocytic lymphohistiocytosis (HLH). HLH associated with autoimmune diseases is often refractory to corticosteroid treatment; thus, additional immunosuppressive drugs, such as cyclosporine, cyclophosphamide, or tacrolimus, are required. Here, we describe the case of a 44-year-old Japanese woman who developed HLH associated with lupus nephritis. Initially, her HLH was refractory to treatment with a corticosteroid, tacrolimus, and mizoribine. However, alternative treatment with a corticosteroid, mycophenolate mofetil, and tacrolimus improved both her HLH and lupus nephritis. This case suggests the possibility of mycophenolate mofetil as a key drug for treating HLH associated with SLE.

Catecholamines induce intracellular reactive oxygen species (ROS), thus enhancing diastolic Ca2+ leakage through the ryanodine receptor during heart failure (HF). However, little is known regarding the effect of atrial natriuretic peptide (ANP) on ROS generation and Ca2+ handling in failing cardiomyocytes. The aim of the present study was to clarify the mechanism by which an exogenous ANP exerts cardioprotective effects during HF. Cardiomyocytes were isolated from the left ventricles of a canine tachycardia-induced HF model and sham-operated vehicle controls. The degree of mitochondrial oxidized DNA was evaluated by double immunohistochemical (IHC) staining using an anti-VDAC antibody for the mitochondria and an anti-8-hydroxy-2'-deoxyguanosine antibody for oxidized DNA. The effect of ANP on ROS was investigated using 2,7-dichlorofluorescin diacetate, diastolic Ca2+ sparks assessed by confocal microscopy using Fluo 4-AM, and the survival rate of myocytes after 48 h. The double IHC study revealed that isoproterenol (ISO) markedly increased oxidized DNA in the mitochondria in HF and that the ISO-induced DNA damage was markedly inhibited by the co-presence of ANP. ROS production and Ca2+ spark frequency (CaSF) were increased in HF compared to normal controls, and were further increased in the presence of ISO. Notably, ANP significantly suppressed both ISO-induced ROS and CaSF without changing sarcoplasmic reticulum Ca2+ content in HF (p

OBJECTIVES:The purpose of this study was to investigate whether adding a low-dose β1-blocker to milrinone improves cardiac function in failing cardiomyocytes and the underlying cardioprotective mechanism. BACKGROUND:The molecular mechanism underlying how the combination of low-dose β1-blocker and milrinone affects intracellular Ca(2+) handling in heart failure remains unclear. METHODS:We investigated the effect of milrinone plus landiolol on intracellular Ca(2+) transient (CaT), cell shortening (CS), the frequency of diastolic Ca(2+) sparks (CaSF), and sarcoplasmic reticulum Ca(2+) concentration ({Ca(2+)}SR) in normal and failing canine cardiomyocytes and used immunoblotting to determine the phosphorylation level of ryanodine receptor (RyR2) and phospholamban (PLB). RESULTS:In failing cardiomyocytes, CaSF significantly increased, and peak CaT and CS markedly decreased compared with normal myocytes. Administration of milrinone alone slightly increased peak CaT and CS, while CaSF greatly increased with a slight increase in {Ca(2+)}SR. Co-administration of β1-blocker landiolol to failing cardiomyocytes at a dose that does not inhibit cardiomyocyte function significantly decreased CaSF with a further increase in {Ca(2+)}SR, and peak CaT and CS improved compared with milrinone alone. Landiolol suppressed the hyperphosphorylation of RyR2 (Ser2808) in failing cardiomyocytes but had no effect on levels of phosphorylated PLB (Ser16 and Thr17). Low-dose landiolol significantly inhibited the alternans of CaT and CS under a fixed pacing rate (0.5 Hz) in failing cardiomyocytes. CONCLUSION:A low-dose β1-blocker in combination with milrinone improved cardiac function in failing cardiomyocytes, apparently by inhibiting the phosphorylation of RyR2, not PLB, and subsequent diastolic Ca(2+) leak.