Gender Differences in Patients with Takotsubo Cardiomyopathy: Multi-Center Registry from Tokyo CCU Network

Background

The clinical features of gender differences in takotsubo cardiomyopathy (TC) remain to be determined. The aim of this study was to evaluate the differences in clinical characteristics of male and female patients with TC.

Methods

We obtained the clinical information of 368 patients diagnosed with TC (84 male, 284 female) from the Tokyo CCU Network database collected from 1 January 2010 to 31 December 2012; the Network is comprised of 71 cardiovascular centers in the Tokyo (Japan) metropolitan area. We attempted to characterize clinical differences during hospitalization, comparing male and female patients with TC.

Results

There were no significant differences in apical ballooning type, median echocardiography ejection fraction, serious ventricular arrhythmias (such as ventricular tachycardia or fibrillation), or cardiovascular death between male and female patients. Male patients were younger than female patients (median age at hospitalization for male patients was 72 years vs. 76 years for female patients; p = 0.040). Prior physical stress was more common in male than female patients (50.0% vs.31.3%; p = 0.002), while emotional stress was more common in female patients (19.0% vs. 31.0%; p = 0.039). Severe pump failure (defined as Killip Class > III) (20.2% vs. 10.6%; p = 0.020) and cardiopulmonary supportive therapies (28.6% vs. 12.7%, p < 0.001) were more common in male than female patients. Multivariate analysis revealed that male gender (odds ratio = 4.32, 95% CI = 1.41–13.6, p = 0.011) was an independent predictor of adverse composite cardiac events, including cardiovascular death, severe pump failure, and serious ventricular arrhythmia.

Conclusions

Cardiac complications in our dataset appeared to be more common in male than female patients with TC during their hospitalization. Further investigation is required to clarify the underlying mechanisms responsible for the observed gender differences.     

Relevance of anti-reactive oxygen species activity to anti-inflammatory activity of components of Eviprostat, a phytotherapeutic agent for benign prostatic hyperplasia

Inflammation is a common finding in benign prostatic hyperplasia (BPH). The phytotherapeutic agent eviprostat is a popular treatment for BPH in Japan and Germany. This agent consists of five components; four are extracted from Chimaphila umbellata, Populus tremula, Pulsatilla pratensis and Equisetum arvense (coded as EVI-1, EVI-2, EVI-3 and EVI-4, respectively) and the fifth is germ oil from Triticum aestivum (coded as EVI-5). In this study, the effects of each component on the reactive oxygen species (ROS), superoxide anion (O2-) and hydroxyl radical (OH*) generated in cell-free systems and human neutrophils, and on carrageenin-induced paw edema in rats were investigated. EVI-1, EVI-2 and EVI-4 suppressed the O2- levels in the xanthine/xanthine oxidase system, and EVI-1, EVI-2, EVI-3 and EVI-4 abolished the OH* produced in a Fenton-type reaction system, so that EVI-1, EVI-2 and EVI-4 possessed inhibitory action with respect to both O2- and OH*. EVI-1, EVI-2 and EVI-4 also reduced ROS levels in phorbol myristate acetate-stimulated neutrophils. The paw swelling was inhibited by a mixture of EVI-1, EVI-2, EVI-3, EVI-4 and EVI-5 (a mixture which is equivalent to eviprostat) or by a mixture of EVI-1, EVI-2 and EVI-4, even though each component alone did not significantly inhibit the swelling. These findings suggest that the suppression of ROS by EVI-1, EVI-2 and EVI-4 may partly contribute to the anti-inflammatory action of eviprostat, and this action may be implicated in its therapeutic effect on BPH.     

Zinc deficiency decreases plasma erythropoietin concentration in rats

In 1985, Paterson and Bettger found hypoplastic hematopoiesis in severely zinc-deficient rats. Therefore, we investigated plasma erythropoietin concentration in zinc-deficient rats. Forty 4-wk-old male Sprague-Dawley rats were assigned into 4 dietary treatment groups of 10 for the 4-wk study: zinc-deficient group (4.5 mg zinc and 35 mg iron/kg; −Zn), iron-deficient group (30 mg zinc/kg, no supplemental iron; −Fe), zinc/iron-deficient group (4.5 mg zinc/kg, no supplemental iron; −Zn−Fe), and control group (AIN-93G; Cont). Water intake determined at d 19 was similar among all treatment groups. At d 27–28, bioimpedance was measured. The intracellular water/extracellular water ratio was significantly increased in the −Zn group (p<0.05). Compared to the Cont, group, the plasma erythropoietin concentration was increased by iron deficiency and decreased by zinc deficiency (p<0.01). Hematocrit was significantly decreased in both the −Fe and −Zn−Fe groups and was significantly increased in the −Zn group (p<0.01). Transferrin saturation in the −Fe and −Zn−Fe groups was significantly lower than the Cont group (p<0.01), and that of the −Zn group was highest among all groups. The low plasma erythropoietin concentration might account for depressed hematopoiesis associated with zinc deficiency.     

Inactivation of tensin3 in mice results in growth retardation and postnatal lethality

Tensin family is a group of focal adhesion proteins that interact with integrins, actin, and phosphotyrosine-containing proteins. To explore the in vivo functions of a new member of the family, tensin3, we have generated mutant mice with a disrupted tensin3 gene. Inactivation of tensin3 resulted in growth retardation and postnatal lethality in one third of the homozygous mutants. Histological analysis of those mutants showed incomplete development of the small intestine, lung, and bone. Villus formation in the small intestine was affected and cells migrated slower in the runt mutants. Their lungs also displayed enlarged air space suggesting defects in alveogenesis. In addition, the resting zone was thicker and fewer proliferating cells were present in the growth plates of tensin3(-/-) tibiae. These observations indicate that tensin3 is essential for normal development and functions of the small intestine, lung, and bone. These phenotypes of the runt tensin3(-/-) mice are similar to some clinical features of Silver-Russell syndrome (SRS) which is a genetically inherited defect. About 10% of SRS cases have been linked to abnormality in chromosome 7p11.2-13, where human tensin3 gene is located, suggesting a potential link between tensin3 and SRS.     

TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor

T cell death-associated gene 8 (TDAG8) has been reported to be a receptor for psychosine. Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4, G-protein-coupled receptors (GPCRs) closely related to TDAG8, however, have recently been identified as proton-sensing or extracellular pH-responsive GPCRs that stimulate inositol phosphate and cAMP production, respectively. In the present study, we examined whether TDAG8 senses extracellular pH change. In the several cell types that were transfected with TDAG8 cDNA, cAMP was markedly accumulated in response to neutral to acidic extracellular pH, with a peak response at approximately pH 7.0-6.5. The pH effect was inhibited by copper ions and was reduced or lost in cells expressing mutated TDAG8 in which histidine residues were changed to phenylalanine. In the membrane fractions prepared from TDAG8-transfected cells, guanosine 5'-O-(3-thiotriphosphate) binding activity and adenylyl cyclase activity were remarkably stimulated in response to neutral and acidic pH. The concentration-dependent effect of extracellular protons on cAMP accumulation was shifted to the right in the presence of psychosine. The inhibitory psychosine effect was also observed for pH-dependent actions in OGR1- and GPR4-expressing cells but not for prostaglandin E(2)- and sphingosine 1-phosphate-induced actions in any pH in native and sphingosine 1-phosphate receptor-expressing cells. Glucosylsphingosine and sphingosylphosphorylcholine similarly inhibited the pH-dependent action, although to a lesser extent. Psychosine-sensitive and pH-dependent cAMP accumulation was also observed in mouse thymocytes. We concluded that TDAG8 is one of the proton-sensing GPCRs coupling to adenylyl cyclase and psychosine, and its related lysosphingolipids behave as if they were antagonists against protein-sensing receptors, including TDAG8, GPR4, and OGR1.