Accumulating evidence indicates alteration of the β-adrenoceptor (AR), such as desensitization and subtype switching of its coupling G protein, plays a role in the protection against catecholamine toxicity in heart failure. However, in human takotsubo syndrome (TTS), which is associated with a surge of circulating catecholamine in the acute phase, there is no histologic evidence of β-AR alteration. The purpose of this study was to investigate the involvement of alteration of β-AR signaling in the mechanism of TTS development. Left ventricular (LV) biopsied samples from 26 patients with TTS, 19 with normal LV function, and 26 with dilated cardiomyopathy (DCM) were studied. G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, which initiate the alteration of β-AR signaling, were more abundantly expressed in the myocardium in acute-phase TTS than in those of DCM and normal control as indicated by immunohistochemistry. The percentage of cardiomyocytes that showed positive membrane staining for GRK2 and β-arrestin2 was also significantly higher in acute-phase TTS. Sequential biopsies in the recovery-phase for two patients with TTS revealed that membrane expression of GRK2 and β-arrestin2 faded over time. This study provided the first histologic evidence of the involvement of alteration of β-ARs in the development of TTS.

The energy spacing between the ground-state spin doublet of 4 Λ He(1 + ,0 + ) was determined to be 1406 ± 2 ± 2 keV, by measuring γ rays for the 1 + → 0 + transition with a high efficiency germanium detector array in coincidence with the 4 He(K − , π − ) 4Λ He reaction at J-PARC. In comparison to the corresponding energy spacing in the mirror hypernucleus 4 Λ H, the present result clearly indicates the existence of charge symmetry breaking (CSB) in ΛN interaction. It is also found that the CSB effect is large in the 0 + ground state but is by one order of magnitude smaller in the 1 + excited state, demonstrating that the ΛN CSB interaction has spin dependence.

Abstract-Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti-placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart. Correspondence to Yoshihiko Saito, First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan. E-mail saitonaramed@gmail.com Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to MyocardialRemodeling and Heart Failure Ayako Seno, Yukiji Takeda, Masaru Matsui, Aya Okuda, Tomoya Nakano, Yasuki Nakada, Takuya Kumazawa, Hitoshi Nakagawa, Taku Nishida, Kenji Onoue, Satoshi Somekawa, Makoto Watanabe, Hiroyuki Kawata, Rika Kawakami, Hiroyuki Okura, Shiro Uemura, Yoshihiko Saito © 2016 American Heart Association, Inc. function in patients with acute coronary syndrome. 6 Therefore, it seems that insufficient sFlt-1 production is associated with adverse cardiovascular outcomes.On the contrary, several previous reports have shown that upregulation of sFlt-1 contributes to the development of heart failure, with antiangiogenesis activity by binding to VEGF. 7,8 In clinical settings, plasma levels of sFlt-1 are not only directly correlated with the severity of heart failure but also strongly associated with poor outcomes in patients with heart failure.9,10 These observations provide a plausible interpretation that increased sFlt-1 production aggravates heart failure with adverse car...

The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced accumulation of glycolytic metabolites, including L-serine, L-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEAD1 and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.

Y. Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction. Am J Physiol Heart Circ Physiol 310: H813-H820, 2016. First published January 8, 2016 doi:10.1152/ajpheart.00602.2015.-In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, Ͻ50%, heart failure with reduced EF, or HFrEF) or preserved (EF Ն50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients (P ϭ 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981-1.399; P ϭ 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120 -1.481; P ϭ 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes. acute decompensated heart failure; B-type natriuretic peptide; sex differences; preserved ejection fraction