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Background: Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart. Methods: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2′(3′)- O -(4-benzoylbenzoyl)-ATP, MCC950, anti–IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1β and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. Results: Genetic disruption of NLRP3 resulted in significant loss of IL-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1β production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1β–dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy during pressure overload. Conclusions: Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.

Dopamine D1 receptor (D1R), coded by the Drd1 gene, is induced in cardiomyocytes of failing hearts, triggering heart failure-associated ventricular arrhythmia, and therefore could be a potential therapeutic target for chronic heart failure. The regulation of D1R expression, however, is not fully understood. Here, we explored the molecular mechanism by which cardiomyocyte D1R is induced in failing hearts. We performed motif analysis for the promoter region of the Drd1 gene using the transcription factor affinity prediction (TRAP) method and identified nuclear factor-kappa B (NF-κB) as a candidate transcriptional factor regulating the expression of the Drd1 gene. We next employed murine models of heart failure from chronic pressure overload by transverse aortic constriction (TAC), and assessed myocardial Drd1 expression levels and NF-κB activity, as well as endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of heart failure. Drd1 induction in TAC hearts was dependent on the severity of heart failure, and was associated with NF-κB activation and ER stress, as assessed by p65 phosphorylation and the expression of ER stress-related genes, respectively. We further tested if Drd1 was induced by ER stress via NF-κB activation in cultured neonatal rat ventricular myocytes. Tunicamycin activated NF-κB pathway in an ER stress-dependent manner and increased Drd1 expression. Importantly, inhibition of NF-κB pathway by pretreatment with Bay11-7082 completely suppressed the tunicamycin-induced upregulation of Drd1, suggesting that NF-κB activation is essential to this regulation. Our study demonstrates the pivotal role for the ER stress-induced NF-κB activation in the induction of D1R in cardiomyocytes. Intervention of this pathway might be a potential new therapeutic strategy for heart failure-associated ventricular arrhythmia.

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor γ co-activator-1α (PGC1α) in the PDE5i-conferred cardioprotection, utilizing PGC1α null mice. In PGC1α(+/+) hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1α(−/−) hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG–PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant

Although chronic heart failure is clinically associated with acute kidney injury (AKI), the precise mechanism that connects kidney and heart remains unknown. Here, we elucidate the effect of pre-existing heart failure with reduced ejection fraction (HFrEF) on kidney via sympathetic activity, using the combining models of transverse aortic constriction (TAC) and unilateral renal ischemia reperfusion (IR). The evaluation of acute (24 h) and chronic (2 weeks) phases of renal injury following IR 8 weeks after TAC in C57BL/6 mice revealed that the development of renal fibrosis in chronic phase was significantly attenuated in TAC mice, but not in non-TAC mice, whereas no impact of pre-existing heart failure was observed in acute phase of renal IR. Expression of transforming growth factor-β, monocyte chemoattractant protein-1, and macrophage infiltration were significantly reduced in TAC mice. Lastly, to investigate the effect of sympathetic nerve activity, we performed renal sympathetic denervation two days prior to renal IR, which abrogated attenuation of renal fibrosis in TAC mice. Collectively, we demonstrate the protective effect of pre-existing HFrEF on long-term renal ischemic injury. Renal sympathetic nerve may contribute to this protection; however, further studies are needed to fully clarify the comprehensive mechanisms associated with attenuated renal fibrosis and pre-existing HFrEF.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. Furthermore, hyperactivation of the prelimbic layer 5 excitatory neurons, which are known to be a neuronal substrate of cognitive inflexibility, was also normalized by the pharmacological and microglia-specific genetic interventions. The RR compound may offer a mechanism-driven, translational opportunity against stress-induced cognitive inflexibility. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Background: Inflammation plays a primordial role in atherosclerosis. Perivascular adipose tissue (PVAT) that surrounds the vasculature has been reported to undergo phenotypic changes in response to vascular inflammation. However, regulatory roles of PVAT in vascular inflammation and subsequent pathological remodeling remain unclear. Methods and Results: Endovascular injury was generated by wire insertion into the mice femoral artery. Here, we showed that vascular injury induced the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulated in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by adipose tissue-specific genetic ablation of PRDM16, a key regulator to beiging, exacerbated inflammation and vascular remodeling following injury. Local knockdown of Prdm16 in perivascular tissues of wild-type mice using small interfering RNA similarly exacerbated inflammation and vascular remodeling. Conversely, activation of PVAT beiging attenuated inflammation and pathological vascular remodeling. Single-cell RNA sequencing revealed that beige adipocytes abundantly expressed neuregulin 4 ( Nrg4 ) which critically regulated alternative macrophage activation. Furthermore, Nrg4 knockdown abolished the PVAT-mediated anti-inflammatory effects on macrophages. Importantly, significant beiging was observed in the diseased aortic PVAT in patients with acute aortic dissection. Conclusions: Endovascular injury induced the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitated alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrated the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.

This study aimed to clarify the usefulness of the Ikari-curve left (IL) guiding catheter for balloon pulmonary angioplasty (BPA).The current BPA strategy for chronic thromboembolic pulmonary hypertension is dilation of as many branches as possible to normalize hemodynamics and oxygenation. The shape of the guiding catheter is a major factor in achieving this. However, conventional guiding catheters are difficult to introduce into particular branches. The IL guiding catheter may be suitable; however, its utility remains unclear.We retrospectively analyzed 202 consecutive BPA sessions of 40 patients from November 2016 to October 2019 and divided these sessions into two groups: the IL group where the IL guiding catheter was used and the non-IL group where other catheters were utilized. The occurrence of lung injury was determined by the presence of bloody sputum. We compared the rates of successful introduction into target vessels and assessed for the occurrence of lung injury.The average age of enrolled patients was 60.3 ± 14.4 years, with females comprising 65%. There were 99 sessions in the IL group. The median treated branches per session differed between the 2 groups (IL group: 15 versus non-IL group: 10, P < 0.05). The occurrence of lung injury was lower in the IL group (4.0% versus 11.7%, P = 0.07). The IL group had more successful vessel insertions than the non-IL group (78.8% versus 42.7%, P < 0.01).The IL guiding catheter may be introduced into branches that cannot be accessed by conventional guiding catheters.

The conventional treatment goal for chronic thromboembolic pulmonary hypertension (CTEPH) is improving hemodynamic status, particularly mean pulmonary artery pressure (mPAP); however, some patients complain of impaired quality of life (QOL) caused by dyspnea on effort, even after hemodynamic status has fully improved. It remains unclear whether treatment for CTEPH can improve patients' QOL or whether quantitative measures of QOL correlate with hemodynamic status. This study quantified QOL among Japanese CTEPH patients and investigated whether balloon pulmonary angioplasty (BPA) improved QOL.We calculated the QOL scores of 45 CTEPH patients using the European Quality of Life Five Dimension scale (EQ-5D). The mean QOL score among 12 of those 45 not involved in any therapy except supplemental oxygen at the time of initial measurement was 0.673 ± 0.251. QOL was measured before and after BPA for 17 patients, and the mean significantly improved (QOL from 0.741 ± 0.195 to 0.802 ± 0.160, p 0.05; mPAP from 33.0 ± 8.4 to 23.4 ± 4.2 mmHg, p 0.05; pulmonary vascular resistance from 441.4 ± 214.2 to 268.4 ± 85.6 dyne/s/cmBPA improved QOL in patients with CTEPH mainly by improving "usual activities," besides the improvement in mPAP.

Pathophysiological roles of cardiac dopamine system remain unknown. Here, we show the role of dopamine D1 receptor (D1R)-expressing cardiomyocytes (CMs) in triggering heart failure-associated ventricular arrhythmia. Comprehensive single-cell resolution analysis identifies the presence of D1R-expressing CMs in both heart failure model mice and in heart failure patients with sustained ventricular tachycardia. Overexpression of D1R in CMs disturbs normal calcium handling while CM-specific deletion of D1R ameliorates heart failure-associated ventricular arrhythmia. Thus, cardiac D1R has the potential to become a therapeutic target for preventing heart failure-associated ventricular arrhythmia., The pathophysiological role of dopamine D1 receptor (D1R) in chronic heart failure remains elusive. Here the authors show that D1R-expressing cardiomyocytes appear in chronic heart failure and play a pivotal role in triggering lethal ventricular arrhythmias.

Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor-α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate-phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.

Background Balloon pulmonary angioplasty (BPA) has been performed in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, some patients have inoperable CTEPH despite having lesions suitable for surgical treatment. The effectiveness of BPA in such cases is unclear. The aim of this study was to clarify the effectiveness of BPA in these cases. Methods We retrospectively investigated patients with inoperable CTEPH and divided them into two groups: BPA-suitable and BPA-unsuitable groups based on the findings of pulmonary angiography, computed tomography, and perfusion scintigraphy. The BPA-unsuitable group included patients whose lesions are suitable for surgical treatment but who did not undergo the procedure for any specified reason. We analyzed the hemodynamic, respiratory, and functional status of the patients before and after BPA. Results Forty-three consecutive patients with inoperable CTEPH (age, 62.6 ± 13.5 years; 31 women) were included; all of them underwent BPA. There were 10 patients in the BPA-unsuitable group. In all patients, the mean pulmonary artery pressure, pulmonary vascular resistance, arterial oxygen saturation level, and 6-min walking distance significantly improved after BPA (mean pulmonary artery pressure, from 43.3 ± 7.8 mmHg to 23.9 ± 4.7 mmHg; pulmonary vascular resistance, from 924.1 ± 462.2 dynes/s/cm−5 to 319.7 ± 163.8 dynes/s/cm−5; arterial oxygen saturation level, from 89.3 ± 4.3% to 93.4 ± 3.3%; 6-min walking distance, from 370.0 ± 107.4 m to 443.8 ± 101.4 m). Notably, none of the parameters significantly differed between the groups after BPA. Importantly, the amount of lung bleeding did not differ between them. However, several sessions were required in the BPA-unsuitable group (BPA-unsuitable group: six sessions vs. BPA-suitable group: four sessions). Conclusions BPA safely improved the hemodynamic and functional statuses of the patients with CTEPH who are judged as inoperable for any reason despite lesion being suitable for surgical treatment. However, numerous BPA sessions were required in these patients.

Great progress has been made in the understanding of the pathophysiology of cardiovascular diseases (CVDs), and this has improved the prevention and prognosis of CVDs. However, while sex differences in CVDs have been well documented and studied for decades, their full extent remains unclear. Results of the latest clinical studies provide strong evidence of sex differences in the efficacy of drug treatment for heart failure, thereby possibly providing new mechanistic insights into sex differences in CVDs. In this review, we discuss the significance of sex differences, as rediscovered by recent studies, in the pathogenesis of CVDs. First, we provide an overview of the results of clinical trials to date regarding sex differences and hormone replacement therapy. Then, we discuss the role of sex differences in the maintenance and disruption of cardiovascular tissue homeostasis.

The 83rdAnnual Scientific Meeting of the Japanese Circulation Society was held in Yokohama, Japan, on March 29-31, 2019, just as the cherry blossoms came into full bloom. Because the environment around cardiovascular healthcare is rapidly changing, it becomes highly important to make a breakthrough at the dawn of a new era. The main theme of this meeting was "Renaissance of Cardiology for the Creation of Future Medicine". The meeting benefited from the participation of 18,825 people, and there were in-depth and extensive discussions at every session, focusing on topics covering clinical and basic research, medical care provision system, human resource development, and public awareness in cardiovascular medicine. The meeting was completed with great success, and we greatly appreciate the tremendous cooperation and support from all affiliates.

Heart transplantation (HTx) is the gold standard therapy to improve quality and quantity of life in end‐stage heart failure patients. However, recipients are at risk of experiencing allograft rejection and post‐transplant complications, in the acute as well as chronic phase. A 43‐year‐old man with a history of left ventricular non‐compaction underwent orthotopic HTx. On Day 7, transthoracic echocardiography showed a sudden decrease in cardiac function with hypokinesis in a left ventricular anterior wall distribution. Coronary angiography revealed a large thrombus in the left main trunk. With intra‐aortic balloon pump support, emergency percutaneous coronary intervention was performed. Endomyocardial biopsy showed no rejection. A left main trunk thrombus is rare in the early phase after HTx, but it can be a life‐threatening complication. Transthoracic echocardiography is well known to be important in the management of heart transplant recipients, and coronary angiography as well as myocardial biopsy should be considered when left ventricular wall motion is impaired.

Visual Abstract, Highlights • New CMs in adult mammalians are generated at a low rate, and Hippo–YAP signaling plays crucial roles in the postnatal cardiac regeneration. • After chemical screenings to identify compounds that activate YAP–TEADs activities and CM proliferation in vitro, the authors synthesized a novel multifaceted fluorinated compound TT-10 (C11H10FN3OS2) from a biologically hit compound. • TT-10 induces proliferation of cultured CMs via nuclear translocation of YAP and activation of Wnt/β-catenin signaling, and also activates NRF2-mediated antioxidant and antiapoptotic effects. • The intraperitoneal injection of TT-10 ameliorates cardiac remodeling after MI in mice, which is partially mediated by CM proliferation and by direct antioxidant and antiapoptotic effects in vivo. • Stimulating CM proliferation and/or protection with TT-10 might complement current therapies for MI., Summary Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (C11H10FN3OS2) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction–induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.

The prevalence of mitral valve prolapse (MVP) among middle- and older-aged individuals is estimated to be 2–4% in Western countries. However, few studies have been conducted among Asian individuals and young adults. This study included a sample of 2442 consecutive military adults aged 18–39 years in Hualien, Taiwan. MVP was defined as displacement of the anterior or posterior leaflet of the mitral valve to the mid portion of the annular hinge point > 2 mm in the parasternal long-axis view of echocardiography. Cardiac chamber size and wall thickness were measured based on the latest criteria of the American Society of Echocardiography. The clinical features of participants with MVP and those without MVP were compared using a two-sample t test, and the cardiac structures were compared using analysis of covariance with adjustment for body surface area (BSA). Eighty-two participants were diagnosed with MVP, and the prevalence was 3.36% in the overall population. Compared with those without MVP, participants with MVP had a lower body mass index (kg/m2) (24.89 ± 3.70 vs. 23.91 ± 3.45, p = 0.02) and higher prevalence of somatic symptoms related to exercise (11.0% vs. 4.9%, p = 0.02) and systolic click in auscultation (18.3% vs. 0.6%, p

Percutaneous coronary intervention (PCI) is sometimes considered as an alternative therapeutic strategy to surgical revascularization in patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). However, the types or conditions of patients that receive the clinical benefit of left ventricular reverse remodelling (LVRR) remain unknown. The purpose of this study was to investigate the determinants of LVRR following PCI in CAD patients with reduced LVEF. From 4394 consecutive patients who underwent PCI, a total of 286 patients with reduced LV systolic function (LVEF

BACKGROUND: Sex differences in heart failure mortality might be affected by age, race, and treatment response. Many large studies in Western countries have shown conflicting results, however few studies have been conducted in Asian patients. OBJECTIVES: We prospectively investigated the mortality risk in a multicenter cohort of 1,093 male and 416 female heart failure patients with reduced ejection fraction (HFrEF) hospitalized for worsening symptoms in Taiwan between 2013 and 2015. METHODS: Kaplan-Meier curve and Cox proportional regression analyses were used to determine the one-year mortality risk by sex. RESULTS: There were no significant differences in major adverse cardiovascular events, re-admission rate, and mortality between sexes in the overall cohort and the young subgroup during one-year of follow-up. In the elderly subgroup, the overall and cardiac mortality rate of the male patients were higher than those of the female patients (p = 0.035, p = 0.049, respectively). We found that the prognostic effect of old age on overall mortality rate appeared to be stronger in the male patients (p < 0.0001) than in the female patients (p = 0.69) in Cox regression analysis and Kaplan-Meier survival curves. Male sex was a risk factor for all-cause mortality in the elderly (hazard ratio: 1.50, 95% confidence interval 1.02-2.25) independently of systolic blood pressure, diabetes mellitus, hemoglobin concentration, kidney function, and medications. CONCLUSIONS: In the Taiwan HFrEF registry, the highest mortality risk was observed in male patients aged 65 years or more. Clinicians need to pay more attention to these patients.

Background The current strategy of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH) is to dilate branches as many as possible without lung injury to normalize mean pulmonary artery pressure and oxygenation. The shape of guiding catheter is one of the important factors to achieve this strategy. However, conventional guiding catheters which are typically used for BPA are difficult to introduce into particular branches. The Ikari-curve left (IL) guiding catheter may be suitable for this purpose by adjusting its curves (Figure 1); however, its utility and effectiveness for lung injury are unclear. Purpose The aim of this study is to clarify utility and safety of IL guiding catheter for BPA. Methods We retrospectively analyzed 202 consecutive BPA sessions of 40 patients with CTEPH from November 2016 to October 2019 and divided them into two groups; IL group, in which we used IL guiding catheter; and non-IL group in which we used others. IL guiding catheter was used for branches of left lung which are difficult to introduce by conventional catheter prior Nov. 2018. After Nov.2018, we also used it for the same type branches of right lung. The occurrence of lung injury was determined by the presence of bloody sputum during the perioperative period. We compared success rate of introduction into target vessels and of occurrence of lung injury. Results The average age of enrolled patients was 60.3±14.4 year-old and female was 65%. There were 99 sessions in IL group. The median treated branches significantly differed between groups (IL group: 15 vs. non-IL group: 10, p Conclusion IL guiding catheter can be introduced into branches that cannot be accessed via conventional guiding catheters and has potential to reduce the occurrence of lung injury. 2228 characters including space Figure1 Funding Acknowledgement Type of funding source: None

Background and introduction The difference in cardiovascular disease risk between age-matched women and men narrows as transition through menopause in observational studies. Estrogen exerts complex physiological effects via its non-nuclear and nuclear actions. Experimental studies have shown that endothelial estrogen receptors mediate vasoprotection via endothelial nitric oxide production, reendothelialization, and atherosclerosis. Prior studies in vitro addressed estrogen's effects on endothelial cells and vascular smooth muscle cells, leading to vasoprotection. However, the in vivo evidences are lacking for beneficial effects of endothelium non-nuclear ERα signaling on vascular remodelling in response to injury. Purpose This study aims to clarify the impact of endothelial ERα non-nuclear signaling in the vasoprotection, using a novel mouse model lacking tissue-specific ERα non-nuclear signaling. Methods We identified the amino acids of ERα which were responsible for its binding to p85α subunit of phosphatidylinositol 3-kinase in vitro. We generated a novel mouse model in which non-nuclear signaling of ERα was ablated in endothelial cells by crossing Tie2-Cre transgenic mice with floxed ERα mutants (RR259/260AA) in which p85α and ERα interaction was disrupted. Results In endothelial cells isolated from ERαKI/KITie2 cre/+ animals, E2 failed to induce phosphorylation of Akt, confirming the absence of ERα non-nuclear signaling. Baseline characteristics at 8 to 12 weeks of age were undistinguishable between the genotypes, including body weight, systolic blood pressure, uterine weight and echocardiographic fractional shortening. We then assessed how vascular remodelling process was impacted in a carotid artery wire injury model. Histological analyses with Elastica van Gieson staining two weeks after injury revealed that estrogen dependent suppression of remodelling response (intima to medial ratio) was abolished in ERαki/kiTie2cre/+mice (P=0.0004). Masson's Trichrome staining showed that in the presence of E2 fibrosis was significantly higher in ERαki/kiTie2cre/+ mice than ERαki/kiTie2cre/− mice (P=0.0015). Conclusions We generated a novel mouse model for tissue-specific ablation of ERα non-nuclear signaling by interfering ERα-PI3K interaction. Our results demonstrate that the pivotal role for ERα non-nuclear signaling of endothelial cells in carotid arterial protection following injury with its minimal impact on baseline cardiovascular phenotype. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Japan Heart Foundation Research Grant, SENSHIN Medical Research Foundation

An error appeared in the article entitled "Diagnosing Heart Failure from Chest X-Ray Images Using Deep Learning" by Takuya Matsumoto, Satoshi Kodera, Hiroki Shinohara, Hirotaka Ieki, Toshihiro Yamaguchi, Yasutomi Higashikuni, Arihiro Kiyosue, Kaoru Ito, Jiro Ando, Eiki Takimoto, Hiroshi Akazawa, Hiroyuki Morita, Issei Komuro (Vol. 61, No. 4, 781-786, 2020). The Figure 5on page 784 should be replaced by the following figure.

Background: An inverse relationship of serum liver transaminases and mortality might be due to better blood pressure control in hypertensive patients. Whether it holds true regarding such an association for long-term blood pressure variability (BPV) in those without antihypertensive therapy is unclear. Methods: A population of 1112 military males without antihypertensive medications, aged 32 years, was collected from a retrospective longitudinal study in Taiwan. Serum liver aspartate and alanine transaminase (AST and ALT) levels were obtained from a 12 h-fast blood sample of each participant. BPV was assessed by standard deviation (SD) and average real variability (ARV) of systolic and diastolic blood pressure (SBP and DBP), respectively across 4 visits during the study period (2012&ndash, 2014, 2014&ndash, 2015, 2015&ndash, 2016, and 2016&ndash, 2018). Multivariable linear regression analysis was utilized to determine the association adjusting for demographics, anthropometric indexes, SBP, DBP, and lipid profiles. Results: In the unadjusted model, ALT was significantly and positively correlated with SDDBP and ARVDBP (&beta, (standard errors) = 0.36 (0.16) and 0.24 (0.12), respectively), and so was AST (&beta, = 0.19 (0.08) and 0.14 (0.06), respectively). All the associations were insignificant with adjustments. However, ALT was significantly and negatively correlated with SDSBP and ARVSBP (&beta, = &minus, 0.35 (0.14) and &minus, 0.25 (0.11), respectively) and so was AST (&beta, 0.14 (0.07) and &minus, 0.12 (0.06), respectively) with adjustments. Conclusion: Our findings suggested that serum liver transaminases were negatively correlated with long-term systolic BPV in young male adults without antihypertensive therapy, and the clinical relevance needs further investigations.

The development of deep learning technology has enabled machines to achieve high-level accuracy in interpreting medical images. While many previous studies have examined the detection of pulmonary nodules in chest X-rays using deep learning, the application of this technology to heart failure remains rare. In this paper, we investigated the performance of a deep learning algorithm in terms of diagnosing heart failure using images obtained from chest X-rays. We used 952 chest X-ray images from a labeled database published by the National Institutes of Health. Two cardiologists verified and relabeled a total of 260 "normal" and 378 "heart failure" images, with the remainder being discarded because they had been incorrectly labeled. Data augmentation and transfer learning were used to obtain an accuracy of 82% in diagnosing heart failure using the chest X-ray images. Furthermore, heatmap imaging allowed us to visualize decisions made by the machine. Deep learning can thus help support the diagnosis of heart failure using chest X-ray images.

Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes., The mechanisms underlying the transition from cardiac hypertrophy to heart failure following pressure overload are incompletely understood. Here the authors identify the gene programs encoding the morphological and functional characteristics of cardiomyocytes during the transition from early hypertrophy to heart failure via single-cell transcriptomics, establishing a key role for p53 signalling.

Pathological stressors disrupt cellular homeostasis, causing various diseases. We report a non-glycolytic role for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathological growth response of the heart. In cellular and animal models for cardiac hypertrophy, nuclear translocation of GAPDH was elicited in cardiac myocytes, followed by activation of p300 histone acetyl-transferase (HAT), an inducer of heart hypertrophy gene programs. The hypertrophy was inhibited by a compound antagonizing the nuclear GAPDH cascade. In mice with selective deletion of GAPDH’s nuclear function in cardiac myocytes, the stress-induced cardiac hypertrophy and functional deficits were normalized. Nuclear GAPDH cascade plays a pivotal role in stress response/homeostatic control in the heart. GAPDH may act as a key homeostatic mediator in living organisms through its stress-responsive nuclear translation.One-sentence summaryNon-glycolytic function of GAPDH critically regulates heart homeostasis and mediates cardiac pathological hypertrophy