Published papers

© 2019, Japanese Society of Echocardiography. Takotsubo cardiomyopathy (TC) is characterized by transient wall motion abnormalities most commonly involving the left ventricle (LV). Although biventricular TC had been considered uncommon condition, recently biventricular TC has been reported as a new variant observed in 19–42% of all TC presentations. Since biventricular TC has a poor prognosis as compared with isolated TC, it is important to distinguish between isolated LV TC and biventricular TC. We present a case of 70-year-old female with dyspnea persisting for 2 days. Electrocardiogram showed symmetrical T-wave inversion in leads V2–V4. Transthoracic echocardiography (TTE) revealed diffuse hypo-kinesis except for the apical inferior LV and LV ejection fraction of 32%. Hyper-kinesis of the right ventricular (RV) basal segment and dys-kinesis of the RV apical segment. 2 weeks after admission, coronary angiography showed no evidence of significant stenosis. LV ejection fraction improved to 51% and wall motion abnormalities of the RV basal and apical segments were ameliorated to normo-kinesis. Electrocardiogram revealed symmetrical and deepened T-wave inversion in leads V2–V3. The presence of a transient abnormality in biventricular wall motion beyond a single coronary artery perfusion territory with new electrocardiographic change met the diagnostic criteria of definite TC defined by Mayo Clinic criteria. 4 weeks after admission, no recurrence of wall motion abnormalities in both ventricles were found and T-wave inversion ameliorated. To our knowledge, this is the first report of biventricular TC with asymmetrical abnormities of wall motion between LV and RV.

© 2018, The Japan Society of Ultrasonics in Medicine. Abiraterone is an agent effective for castration-resistant prostate cancer, but there have been no reports of cardiotoxic effects inducing cardiomyopathy, to our knowledge. We present a case of an 86-year-old man with castration-resistant prostate cancer treated with abiraterone. He had received an androgen receptor antagonist (bicalutamide) and a gonadotropin-releasing hormone antagonist (degarelix) for 3 years. These agents were changed to enzalutamide due to elevation of plasma prostate-specific antigen level of 129 ng/mL. One year later, the oral androgen receptor inhibitor (enzalutamide) caused drug-induced lung injury and was changed to abiraterone. Transthoracic echocardiography (TTE) revealed normal left ventricular systolic function, and left ventricular ejection fraction (LVEF) was 67%. Four weeks after administration of abiraterone, he complained of dyspnea on effort and bilateral leg edema, and he was diagnosed with heart failure. TTE showed hypokinesis of the diffuse LV, and LVEF decreased to 45%. The various causes of heart failure were excluded. Since a cardiotoxic effect of abiraterone was suspected, administration of abiraterone was discontinued. Two weeks after cessation of abiraterone, LVEF ameliorated to 57%, and then 5 months after cessation of abiraterone, LVEF further improved to 65%. To our knowledge, this is the first report of definite cancer therapeutics-related cardiac dysfunction due to a hormonal agent such as abiraterone diagnosed according to the American Society of Echocardiography and European Association of Cardiovascular Imaging criteria.

© 2018 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Increase in saturated fatty acid (SFA) content in membrane phospholipids dramatically affects membrane properties and cellular functioning. We sought to determine whether exogenous SFA from the diet directly affects the degree of membrane phospholipid unsaturation in adult hearts and if these changes correlate with contractile dysfunction. Although both SFA-rich high fat diets (HFDs) and monounsaturated FA (MUFA)-rich HFDs cause the same degree of activation of myocardial FA uptake, triglyceride turnover, and mitochondrial FA oxidation and accumulation of toxic lipid intermediates, the former induced more severe diastolic dysfunction than the latter, which was accompanied with a decrease in membrane phospholipid unsaturation, induction of unfolded protein response (UPR), and a decrease in the expression of Sirt1 and stearoyl-CoA desaturase-1 (SCD1), catalyzing the conversion of SFA to MUFA. When the SFA supply in the heart overwhelms the cellular capacity to use it for energy, excess exogenous SFA channels to membrane phospholipids, leading to UPR induction, and development of diastolic dysfunction.

© 2018, The Japan Society of Ultrasonics in Medicine. To our knowledge, only 15 cases of delayed traumatic hemopericardium resulting from non-penetrating chest trauma have been reported. We present the case of a 63-year-old man with delayed hemopericardium, 2 months after striking the anterior chest on a mailbox when he fell down three steps during a postal delivery. Our case and review of the previously reported cases suggest that some cases might show quite slow progression of blood accumulation. Therefore, careful observation of patients who have experienced blunt trauma of the anterior chest is necessary.

© 2018, The Author(s). Acute cardiac rupture and adverse left ventricular (LV) remodeling causing heart failure are serious complications of acute myocardial infarction (MI). While cardio-hepatic interactions have been recognized, their role in MI remains unknown. We treated cultured cardiomyocytes with conditioned media from various cell types and analyzed the media by mass spectrometry to identify α1-microglobulin (AM) as an Akt-activating hepatokine. In mouse MI model, AM protein transiently distributed in the infarct and border zones during the acute phase, reflecting infiltration of AM-bound macrophages. AM stimulation activated Akt, NFκB, and ERK signaling and enhanced inflammation as well as macrophage migration and polarization, while inhibited fibrogenesis-related mRNA expression in cultured macrophages and cardiac fibroblasts. Intramyocardial AM administration exacerbated macrophage infiltration, inflammation, and matrix metalloproteinase 9 mRNA expression in the infarct and border zones, whereas disturbed fibrotic repair, then provoked acute cardiac rupture in MI. Shotgun proteomics and lipid pull-down analysis found that AM partly binds to phosphatidic acid (PA) for its signaling and function. Furthermore, systemic delivery of a selective inhibitor of diacylglycerol kinase α-mediated PA synthesis notably reduced macrophage infiltration, inflammation, matrix metalloproteinase activity, and adverse LV remodeling in MI. Therefore, targeting AM signaling could be a novel pharmacological option to mitigate adverse LV remodeling in MI.

© 2018 American Heart Association, Inc. BACKGROUND: Both osteopontin (OPN) and galectin-3 have been implicated in phagocytic clearance of dead cells and reparative fibrosis during wound healing. CD206+ macrophages are involved in tissue repair through phagocytosis and fibrosis after myocardial infarction (MI). However, the relationship among OPN, galectin-3, and macrophage polarization in the context of MI remains unclear. METHODS: The time course of Spp1 (encoding OPN) expression in the heart after MI showed a strong activation of Spp1 on day 3 after MI. To identify where in the body and in which cells the transcriptional activity of Spp1 increased after MI, we analyzed EGFP (enhanced green fluorescent protein)-Spp1 knockin reporter mice on day 3 after MI. RESULTS: The transcriptional activity of Spp1 increased only in CD206+ macrophages in the infarct myocardium, and most of CD206+ macrophages have strong transcriptional activation of Spp1 after MI. The temporal expression pattern of Lgal3 (encoding galectin-3) in cardiac macrophages after MI was similar to that of Spp1, and OPN is almost exclusively produced by galectin-3hiCD206+ macrophages. Although both interleukin (IL)-4 and IL-10 were reported to promote CD206+ macrophage-mediated cardiac repair after MI, IL-10- but not IL-4-stimulated CD11b+Ly6G− cells could differentiate into OPN-producing galectin-3hiCD206+ macrophages and showed enhanced phagocytic ability. Inhibition of STAT3 tyrosine phosphorylation suppressed IL-10-induced expression of intracellular galectin-3 and transcriptional activation of Spp1. Knockdown of galectin-3 suppressed their ability to differentiate into OPN-producing cells, but not STAT3 activation. The tyrosine phosphorylation of STAT3 and the appearance rate of galectin-3hiCD206+ cells on cardiac CD11b+Ly6G− cells in Spp1 knockout mice were the same as those in wild-type mice. Spp1 knockout mice showed vulnerability to developing post-MI left ventricular chamber dilatation and the terminal deoxynucleo-tidyltransferase 2'-Deoxyuridine-5'-triphosphate nick-end labeling (TUNEL)-positive cells in the infarcted myocardium after MI remained higher in number in Spp1 knockout mice than in wild-type mice. CONCLUSIONS: OPN is almost exclusively produced by galectin-3hiCD206+ macrophages, which specifically appear in the infarct myocardium after MI. The IL-10-STAT3-galectin-3 axis is essential for OPN-producing reparative macrophage polarization after myocardial infarction, and these macrophages contribute to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results suggest that galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling OPN levels.

© 2018, Springer Japan KK, part of Springer Nature. Balloon pulmonary angioplasty (BPA) has emerged as an effective treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Renal function has been identified as a prognostic marker in patients with pulmonary hypertension in previous studies. We, therefore, aimed to investigate the clinical parameters associated with improvements in renal function in patients with CTEPH. A total of 45 consecutive patients with inoperable CTEPH undergoing BPA (mean age 62.2 ± 15.1 years) were included in the study. We evaluated the patients’ clinical characteristics at baseline and at 1-year post-BPA, and investigated the association between renal function and hemodynamic parameters, including right heart function. Hemodynamics and renal function showed sustained improvements at 1 year after BPA in 64.4% of patients. Improved estimated glomerular filtration rate (eGFR) was significantly correlated with increased cardiac index (r = 0.433, p = 0.003) and mixed venous oxygen saturation (SvO 2 ; r = 0.459, p = 0.002), and with decreased mean pulmonary arterial pressure (r = − 0.420, p = 0.004) and pulmonary vascular resistance (r = -− 0.465, p = 0.001). Multivariate analysis revealed that an increase in SvO 2 immediately after the final BPA was associated with improved eGFR after the 1st year (odds ratio 1.041; 95% confidence interval 1.004–1.078; P = 0.027). The cut-off value for predicting improved eGFR was an increase in SvO 2 after the final BPA of >125.4% over the baseline value (specificity 100%, sensitivity 24.1%). In conclusion, BPA improved symptoms, right heart function, hemodynamics, and renal function up to the chronic phase. Increasing SvO 2 by >125.4% above baseline in the acute phase is important for improving renal function at 1 year after BPA in CTEPH patients.

© 2019 Shirakawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. We previously found that senescence of cluster of differentiation 4 (CD4) T cells is accelerated in the visceral adipose tissue (VAT) of mice with diet-induced obesity (DIO) due to a high-fat diet (HFD), and that these senescent-Associated T cells cause chronic inflammation of visceral adipose tissue through secretion of osteopontin, provoking systemic insulin resistance. In this study, we examined whether the development of chronic inflammation and senescence-Associated T cells in VAT of DIO mice was improved by long-Term weight loss after switching to normal chow (NC) or by administration of a sodium glucose cotransporter 2 inhibitor (tofogliflozin). Wild-Type mice were fed an HFD for 26 weeks from 4 weeks old. At 30 weeks of age, half of these DIO mice were switched to NC with or without 0.005% tofogliflozin for 38 weeks. The other mice remained on the HFD with or without 0.005% tofogliflozin for 38 weeks. When DIO mice were switched to NC, their weight decreased to that of mice kept on NC since weaning. After 38 weeks (68 weeks of age), chronic inflammation of the VAT subsided with disappearance of senescence-Associated T cells. In the HFD groups, the carbohydrate intake per mouse was half or less of that in the NC group, and urinary glucose excretion by the effect of tofogliflozin was lower in the HFD mice than in the NC mice. Mice that remained on the HFD showed no improvement in chronic inflammation in VAT, possibly because urinary glucose excretion was not sufficiently promoted by tofogliflozin due to the low carbohydrate intake. Thus, no improvement in glucose metabolism or weight loss was observed in these mice.

© 2019 Wiley Periodicals, Inc. Quadricuspid aortic valve has been classified based on leaflet size. However, no association is seen between classification and severity of aortic regurgitation (AR). Bicuspid aortic valve is classified according to the number of cusps, with significantly higher prevalence of AR in cases with a raphe. We classified cases according to raphe number. In 1 patient with no raphe, AR severity did not change into the eighth decade. However, AR severity worsened in patients with a raphe, in 1 case requiring aortic valve replacement in the fifth decade. Unequal shear stress may lead to leaflet fibrosis and progressive AR.

© 2019 Wiley Periodicals, Inc. The aortic valve (AV) is the most commonly affected site in multiple papillary fibroelastomas, but the frequency of embolism caused by the attachment side of the AV has not been elucidated. According to the review of the previous literature, 16 cases have been found attached to the AV. Of these, 6 of these have been found to be attached on the aortic side and 4 on the left ventricular side, 1 was bilateral, and 5 cases were unknown. Of the cases found on the aortic side, embolism occurred in 3 of them, and of the left ventricular side cases, embolism occurred in 2 of them. The frequency of embolism is equivalent even if papillary fibroelastoma attached to either side of the AV.

© 2019 Glucocorticoid receptor (GR) is abundantly expressed in cardiomyocytes. However, the role of GR in regulating cardiac hypertrophy and heart failure in response to pressure overload remains unclear. Cardiomyocyte-specific GR knockout (GRcKO) mice, mineralocorticoid receptor (MR) knockout (MRcKO), and GR and MR double KO (GRMRdcKO) mice were generated using the Cre-lox system. In response to pressure overload, GRcKO mice displayed worse cardiac remodeling compared to control (GR f/f ) mice, including a greater increase in heart weight to body weight ratio with a greater increase in cardiomyocytes size, a greater decline in left ventricular contractility, and higher reactivation of fetal genes. MRcKO mice showed a comparable degree of cardiac remodeling compared to control (MR f/f ) mice. The worse cardiac remodeling in pressure overloaded GRcKO mice is not due to compensatory activation of cardiomyocyte MR, since pressure overloaded GRMRdcKO mice displayed cardiac remodeling to the same extent as GRcKO mice. Pressure overload suppressed GR-target gene expression in the heart. Although plasma corticosterone levels and subcellular localization of GR (nuclear/cytoplasmic GR) were not changed, a chromatin immunoprecipitation assay revealed that GR recruitment onto the promoter of GR-target genes was significantly suppressed in response to pressure overload. Rescue of the expression of GR-target genes to the same extent as sham-operated hearts attenuated adverse cardiac remodeling in pressure-overloaded hearts. Thus, GR works as a repressor of adverse cardiac remodeling in response to pressure overload, but GR-mediated transcription is suppressed under pressure overload. Therapies that maintain GR-mediated transcription in cardiomyocytes under pressure overload can be a promising therapeutic strategy for heart failure.

© 2018 Suzuki-Eguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Transcatheter aortic valve implantation (TAVI) is an alternative therapy for surgically highrisk patients with severe aortic stenosis (AS). Although TAVI improves survival of patients with severe AS, the mechanism of this effect remains to be clarified. We investigated the effects of TAVI on left ventricular (LV) function and identified the predictive parameters for cardiac events after TAVI. Methods and results We studied 128 patients with severe symptomatic AS who underwent TAVI. Echocardiographic assessments were performed before and after TAVI. In addition to the conventional echocardiographic parameters such as LV ejection fraction (LVEF) and LV mass index (LVMI), the LV global longitudinal strain (GLS) and early diastolic peak strain rate (SR-E) using two-dimensional speckle tracking echocardiography were also evaluated. All patients were assessed for clinical events including major adverse cardiac events and stroke according to Valve Academic Research Consortium-2 criteria. GLS, early diastolic peak velocity (e'), aortic regurgitation (AR) severity, and SR-E were significantly improved after TAVI. Thirteen patients had an event during the observational period of 591 days (median). Patients with events had higher LVMI, more severe AR, and worse GLS compared to those without events. Furthermore, receiver-operating curve analysis revealed that GLS was the strongest predictor for clinical events (p = 0.009; area under the curve, 0.73). Conclusion Preoperative LV geometric deformation and dysfunction, as a consequence of the cumulative burden of pressure overload, improved after TAVI and could predict cardiac events after TAVI.

© 2019 Elsevier Ltd Background: The fatty acid (FA)composition of membrane phospholipid reflects at least in part dietary fat composition. Saturated FA (SFA)suppress Sirt1 activity, while monounsaturated FA (MUFA)counteract this effect. Objective: We explored a role of Sirt1 in homeostatic control of the fatty acid composition of membrane phospholipid in the presence of SFA overload. Methods and results: Sirt1 deficiency in cardiomyocytes decreased the expression levels of liver X receptor (LXR)-target genes, particularly stearoyl-CoA desaturase-1 (Scd1), a rate-limiting enzyme in the cellular synthesis of MUFA from SFA, increased membrane SFA/MUFA ratio, and worsened left ventricular (LV)diastolic function in mice fed an SFA-rich high fat diet. In cultured cardiomyocytes, Sirt1 knockdown (KD)exacerbated the palmitate overload-induced increase in membrane SFA/MUFA ratio, which was associated with decrease in the expression of LXR-target genes, including Scd1. Forced overexpression of Scd1 in palmitate-overloaded Sirt1KD cardiomyocytes lowered the SFA/MUFA ratio. Nicotinamide mononucleotide (NMN)increased Sirt1 activity and Scd1 expression, thereby lowering membrane SFA/MUFA ratio in palmitate-overloaded cardiomyocytes. These effects of NMN were not observed for Scd1KD cardiomyocytes. LXRα/βKD exacerbated palmitate overload-induced increase in membrane SFA/MUFA ratio, while LXR agonist T0901317 alleviated it. NMN failed to rescue Scd1 protein expression and membrane SFA/MUFA ratio in palmitate-overloaded LXRα/βKD cardiomyocytes. The administration of NMN or T0901317 showed a dramatic reversal in membrane SFA/MUFA ratio and LV diastolic function in SFA-rich HFD-fed mice. Conclusion: Cardiac Sirt1 counteracted SFA overload-induced decrease in membrane phospholipid unsaturation and diastolic dysfunction via regulating LXR-mediated transcription of the Scd1 gene.

© 2017, Springer Science+Business Media B.V., part of Springer Nature. Chronic thromboembolic pulmonary hypertension (CTEPH) has a poor prognosis because of the associated progressive right heart failure. Accurate evaluation of right ventricular (RV) function would thus be useful to predict prognosis. However, the significance of RV diastolic function remains unclear. We aimed to identify which echocardiographic measures are most accurate, and potentially useful, in assessing RV diastolic function in patients with CTEPH, and to study the effects of balloon pulmonary angioplasty (BPA) on them. We enrolled 53 CTEPH patients who underwent BPA. Echocardiographic parameters, including two-dimensional speckle-tracking echocardiography, were compared to the hemodynamic parameters measured by right heart catheterization before and after BPA. RV strain rate during early diastole (SR_E), tricuspid e′ and right atrial area (RAA) were ameliorated after BPA, concomitant with a decrease in the time constant of the RV pressure curve during diastole (tau), indicating the improvement of RV diastolic function. Among them, SR_E had the strongest correlation with tau (r = − 0.39, p < 0.001). Furthermore, the receiver operating characteristic analyses revealed that E/SR_E (AUC 0.704) and inferior vena cava diameter (AUC 0.726) had a stronger association with higher mean right atrial pressure than RAA (AUC 0.632). In contrast, RAA had a stronger correlation with 6 min-walk distances than SR_E (r = − 0.39, p < 0.001 vs. r = 0.30, p = 0.005). Taken together, echocardiographic assessment of RV diastolic function might be associated with hemodynamics as well as exercise tolerance in patients with CTEPH, indicating its benefits in evaluating the therapeutic effects of BPA.