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The relationship between in-hospital coronary revascularization rate (CRR) and post-discharge mortality rates in survivors of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) at a system level is unclear. The purpose of this study was to evaluate CRR and 2-year post-discharge mortality rate (2YMR) in NSTE-ACS. CRR and 2YMR were analyzed by hospital rate of CRR (in deciles), by country, and by world region in 11,931 patients with NSTE-ACS who survived to discharge and were enrolled in the EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients) and EPICOR Asia: twin multinational, observational, prospective cohort studies. Significant differences in patient baseline characteristics, medical therapies, CRR, and 2YMR were found. Mean CRR ranged from 0.0% to 96.8% in the first and tenth decile, respectively (p

Objective Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2). Results The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. Conclusion These data provide new evidence for targeting p53 as a strategy to treat liver disease., Highlights • Intraperitoneal and oral low-dose doxorubicin ameliorates NAFLD and NASH in animal models. • Doxorubicin requires p53 for its hepatic actions. • Doxorubin decreases lipid content in human hepatocytes without affecting cell viability and apoptosis.

Atherosclerosis progression predicts cardiovascular events; however, progression of multiterritorial subclinical atherosclerosis is incompletely understood. This study sought to study short-term progression of atherosclerosis using different noninvasive imaging techniques and their relationship with cardiovascular risk. The study included 3,514 PESA (Progression of Early Subclinical Atherosclerosis) study participants (45.7 ± 4.2 years of age; 63% men). Participants underwent 2-dimensional vascular ultrasound (2DVUS) of abdominal aorta, carotid, iliac, and femoral territories to determine a plaque number score; 3DVUS to quantify carotid and femoral plaque volume; and coronary artery calcium score (CACS) at baseline and 2.8 years later. The authors calculated the rate of new disease incidence and changes in disease extent. Logistic regression models were used to evaluate associations of progression rates with baseline cardiovascular risk factors and estimated 10-year risk. Imaging detected short-term (3-year) atherosclerosis progression in 41.5% of participants (26.4% by 2DVUS, 21.3% by 3DVUS, and 11.5% by CACS), particularly in peripheral territories examined by vascular ultrasound. New atherosclerosis onset accounted for approximately one-third of total progression, also more frequently by 2DVUS and 3DVUS (29.1% and 16.6%, respectively), than by CACS (2.9%). Participants with baseline disease by all 3 modalities (n = 432) also showed significant atherosclerosis progression (median: 1 plaque [interquartile range (IQR): -1 to 3 plaques] by 2DVUS; 7.6 mm3 [IQR: -32.2 to 57.6 mm3] by 3DVUS; and 21.6 Agatston units [IQR: 4.8 to 62.6 Agatston units] by CACS). Age, sex, dyslipidemia, hypertension, smoking, and family history of premature cardiovascular disease contributed to progression, with dyslipidemia the strongest modifiable risk factor. Although disease progression correlated with cardiovascular risk, progression was detected in 36.5% of participants categorized as low risk. With this multimodal and multiterritorial approach, the authors detected short-term progression of early subclinical atherosclerosis in a substantial proportion (41.5%) of apparently healthy middle-aged men and women, more frequently by peripheral 2D/3DVUS than by CACS. Disease progression, as defined in this study, correlated with almost all cardiovascular risk factors and estimated risk. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318). The PESA-CNIC-Santander study is funded by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The study also receives funding from the Instituto de Salud Carlos III (ISC III) (PI15/02019) and the European Regional Development Fund (ERDF) “Una manera de hacer Europa.” The CNIC is supported by the Ministerio de Ciencia e Innovación, the ISC III and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Dr. Bueno has received research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 & PI17/01799); has received research funding from AstraZeneca, Bristol-Myers Squibb, and Novartis; has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb–Pfizer, and Novartis; and has received speaker fees or support for attending scientific meetings from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb–Pfizer, Novartis, and MEDSCAPE–the heart.org. Sí

BACKGROUND Clinical practice guidelines recommend assessment of subclinical atherosclerosis using imaging techniques in individuals with intermediate atherosclerotic cardiovascular risk according to standard risk prediction tools. OBJECTIVES The purpose of this study was to develop a machine-learning model based on routine, quantitative, and easily measured variables to predict the presence and extent of subclinical atherosclerosis (SA) in young, asymptomatic individuals. The risk of having SA estimated by this model could be used to refine risk estimation and optimize the use of imaging for risk assessment. METHODS The Elastic Net (EN) model was built to predict SA extent, defined by a combined metric of the coronary artery calcification score and 2-dimensional vascular ultrasound. The performance of the model for the prediction of SA extension and progression was compared with traditional risk scores of cardiovascular disease (CVD). An external independent cohort was used for validation. RESULTS EN-PESA (Progression of Early Subclinical Atherosclerosis) yielded a c-statistic of 0.88 for the prediction of generalized subclinical atherosclerosis. Moreover, EN-PESA was found to be a predictor of 3-year progression independent of the baseline extension of SA. EN-PESA assigned an intermediate to high cardiovascular risk to 40.1% (n = 1,411) of the PESA individuals, a significantly larger number than atherosclerotic CVD (n = 267) and SCORE (Systematic Coronary Risk Evaluation) (n = 507) risk scores. In total, 86.8% of the individuals with an increased risk based on EN-PESA presented signs of SA at baseline or a significant progression of SA over 3 years. CONCLUSIONS The EN-PESA model uses age, systolic blood pressure, and 10 commonly used blood/urine tests and dietary intake values to identify young, asymptomatic individuals with an increased risk of CVD based on their extension and progression of SA. These individuals are likely to benefit from imaging tests or pharmacological treatment., The PESA study is cofunded equally by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019) and the European Regional Development Fund Una manera de hacer Europa. The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Dr. Bueno has received research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 and PI17/01799), AstraZeneca, Bristol-Myers Squibb and Novartis; has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, and Novartis; and has received speaker fees or support for attending scientific meetings from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, Novartis, and MEDSCAPE-the heart.org. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Matthew Budoff, MD, served as Guest Associate Editor for this paper. P.K. Shah, MD, served as Guest Editor-in-Chief for this paper. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.

Therapeutic strategies - such as duration of dual antiplatelet therapy after coronary artery stenting - usually generate a large quantity of meta-analyses. The meta-analyses that include the same randomized clinical trials should produce similar results. Our aim in the study is to analyze the quality and to compare the results of meta-analyses focused on a controversial topic such as dual antiplatelet therapy after percutaneous coronary intervention. We searched all published meta-analyses published up to November 2015 (near DAPT trial publication) selecting those that included the same randomized clinical trials comparing patterns of briefer versus longer-term double antiplatelet therapy. Seventeen meta-analyses achieved our selection criteria. Of the seventeen analyzed, we identified seven (41.1%) based on the same ten randomized clinical trials (RCTs), yet their results varied widely. Many of the meta-analyses differed in only some minor aspect of the design (i.e. eligible studies, length of comparators and statistical methods used). Some authors differed in the number of patients participating in RCTs and even, despite reviewing the same underlying trials, only 2 of the 7 meta-analyses included the same number of patients. Meta-analyses around cardiovascular, all-cause or non-cardiovascular death differ frequently. In the DAPT duration setting, several meta-analyses have been recently published based on the same data, presenting several issues making it difficult to determine clear recommendations on certain points. IN receives research funding from Astrazeneca; has received minor consulting fees from Boston, Medtronic, Astrazeneca; and speaking fees or support for attending scientificmeetings fromBoehringer, Daiichi-Sankyo, Lilly, AstraZeneca and Pfizer. AE is Astrazeneca employee. HB receives research funding from the Instituto de Salud Carlos III (PIE16/00021), AstraZeneca, BMS, Janssen and Novartis; has received consulting fees from Abbott, AstraZeneca, Bayer, BMS-Pfizer, Novartis; and speaking fees or support for attending scientificmeetings from AstraZeneca, Bayer, BMS-Pfizer, Ferrer, Novartis, Servier and MEDSCAPE-the heart.og. The other authors pose no relevant disclosures regarding this manuscript. Sí

p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity., Emerging studies suggest that p53 is an important regulator of energy metabolism, yet there is little known about the metabolic function of this tumor suppressor in the hypothalamus. Here, authors illustrate that p53, specifically in AgRP neurons, is required for adaptation to diet-induced obesity.

Therapeutic variability not explained by patient clinical characteristics is a potential source of avoidable morbidity and mortality. We aimed to explore regional variability in the management and mortality of patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). 11,931 NSTE-ACS hospital survivors enrolled in two prospective registries: EPICOR [5625 patients, 555 hospitals, 20 countries in Europe (E) and Latin America (LA), September 2010-March 2011] and EPICOR Asia (6306 patients, 218 hospitals, 8 countries, June 2011-May 2012) were compared among eight pre-defined regions: Northern E (NE), Southern E (SE), Eastern E (EE); Latin America (LA); China (CN), India (IN), South-East Asia (SA), and South Korea, Hong Kong and Singapore (KS). Patient characteristics differed between regions: mean age (lowest 59 years, IN; highest 65.9 years, SE), diabetes (21.4% NE; 35.5% IN) and smoking (32% NE; 62% IN). Variations in dual antiplatelet therapy at discharge (lowest 83.1%, IN; highest 97.5%, SA), coronary angiography (53.9% SA; 90.6% KS), percutaneous coronary intervention (35.8% SA; 78.6% KS) and coronary artery bypass graft (0.7% KS; 5.7% NE) were observed. Unadjusted 2-year mortality ranged between 3.8% in KS and 11.7% in SE. Two-year, risk-adjusted mortality rates ranged between 5.1% (95% confidence interval 2.9-7.3%) in KS to 10.5% (8.3-12.7%) in LA. Wide regional variations in patient features, hospital care, coronary revascularization and post-discharge mortality are present among patients hospitalized for NSTE-ACS. Focused regional interventions to improve the quality of care for NSTE-ACS patients are still needed. Sí

Summary Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism., Graphical Abstract, Highlights • Central T3 regulates lipogenesis in liver via the parasympathetic nervous system • Central T3 regulates lipid oxidation in BAT via the sympathetic nervous system • Ablation of AMPK in SF1 neurons of the VMH recapitulates the effects of T3 • Hypothalamic JNK1 and ceramides/ER stress mediate T3 actions on liver and BAT, Martínez-Sánchez et al. show that thyroid hormones act in the hypothalamus to regulate hepatic lipogenesis and brown fat lipid oxidation via the parasympathetic and sympathetic nervous systems. These peripheral effects are orchestrated by two distinct signaling pathways in the VMH, JNK1 and ceramides/ER stress, which are under AMPK control.

p53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation. Here we show that p63 regulates hepatic lipid metabolism. Mice with liver-specific p53 deletion develop steatosis and show increased levels of p63. Down-regulation of p63 attenuates liver steatosis in p53 knockout mice and in diet-induced obese mice, whereas the activation of p63 induces lipid accumulation. Hepatic overexpression of N-terminal transactivation domain TAp63 induces liver steatosis through IKK beta activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKK beta and XBP1s is also increased in livers of obese patients with NAFLD. In cultured human hepatocytes, TAp63 inhibition protects against oleic acid-induced lipid accumulation, whereas TAp63 overexpression promotes lipid storage, an effect reversible by IKK beta silencing. Our findings indicate an unexpected role of the p63/IKK beta/ER stress pathway in lipid metabolism and liver disease. We deeply thank Dr Manuel Serrano (Spanish National Cancer Research Center, CNIO, Spain) for kindly providing p53 null mice and critically reading the article. This work has been supported by grants from Ministerio de Economia y Competitividad (C.D.: BFU2014-55,871; R.N.: BFU2015-70,664-R; M.M.M.: BFU2013-44229-R; A.C.: SAF2016-79381-R, FEDER/UE; GS: SAF2013-43506-R; M.L.M.-C.: SAF2014-54658-R; M.L.: SAF2015-71026-R; P.A.: SAF2015-64352-R; B.G.-T.: FPI Severo Ochoa CNIC program SVP-2013-067639), Xunta de Galicia (M.L.: 2015-CP079; R.N.: 2015-CP080 and PIE13/00024), Comunidad de Madrid (G.S.: S2010/BMD-2326); Fondo de Investigaciones Sanitarias (M.M.: PI10/01692), Fundacion SEEN (R.N.), GV-Departamento de Salud-2013111114 (to M.L.M.-C.), ISCIII: PIE14/00031 (to M.L.M.-C.), Junta Provincial de Bizkaia-AECC (to M.L.M.-C.), AECC (T.C.D.); Basque Department of Industry, Tourism and Trade (Etortek) (A.C.), the BBVA foundation (A.C.), Fundacion AstraZeneca (R.N.) Centro de Investigacion Biomedica en Red (CIBER) de Fisiopatologia de la Obesidad y Nutricion (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. The participation of A.C. and A.Z.-L. as part of CIBERONC was co-funded with FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: A.C.: ERC StG-336343; R.N.: ERC StG-281408 and G.S.: ERC StG-260464. Sí

INTRODUCTION: Real-world, country-specific studies of dual antiplatelet therapy (DAPT) duration among survivors of acute coronary syndrome (ACS) are important for improving long-term prognosis. AIMS: To investigate DAPT duration after hospital discharge for ACS in Spain. RESULTS: Data from patients enrolled in the Spanish cohort of the EPICOR (long-tErm follow-up of antithrombotic management Patterns In acute CORonary syndrome patients) study (NCT01171404) were analyzed for changes to antithrombotic medication up to 2 years postdischarge according to index event diagnosis and patient characteristics. Deaths, coronary events, and bleeding events were analyzed over the same period. Overall, a high proportion of patients remained on DAPT at 2 years (53.1%). Among patients who experienced any on-treatment bleeding event, almost two-thirds remained on DAPT at the end of follow-up. Patients >65 years, diabetic, or those that were medically managed were more likely to continue with DAPT until 2 years following discharge. At 2 years, the incidence of bleeding events requiring hospitalization was low compared with the incidence of coronary events (1.4% vs 6.6%). There was a numerical reduction in coronary events, but no increase in bleeding events, with DAPT continuation compared with single antiplatelet therapy. CONCLUSIONS: More than half of patients in this unselected cohort study remained on DAPT at 2 years following discharge for ACS. Continuation with DAPT was greater among patients with additional cardiovascular risk factors, which suggests that treating physicians in Spain prioritizes ischemic risk reduction over bleeding risk in patients with ACS, according to patient's risk profile.

Many patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are medically managed without coronary revascularization. The reasons vary and may impact prognosis. EPICOR Asia (NCT01361386) is a prospective study of hospital survivors post-ACS enrolled in 218 hospitals from 8 countries/regions in Asia (06/2011-05/2012). All medically managed NSTE-ACS patients were classified into 3 groups: 1) no coronary angiography (CAG-); 2) non-significant coronary artery disease (CAD) on angiogram (CAG+ CAD-); and 3) significant CAD (CAG+ CAD+). We compared baseline differences between patients medically managed and patients undergoing revascularization, and also between the medically managed groups. Adverse events were reported and compared up to 2years. Of 6163 NSTE-ACS patients, 2272 (37%) were medically managed, with 1339 (59%), 254 (11%), and 679 (30%) in the CAG-, CAG+ CAD-, and CAG+ CAD+ groups, respectively. There were marked differences in the proportion of medically managed patients among the 8 countries/regions (13-81%). Medically managed patients had higher mortality at 2years compared with revascularization (8.7% vs. 3.0%, p

BACKGROUND: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. METHODS: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. RESULTS: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). CONCLUSION: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. IMPACT: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. This study was supported by Research Grant FIS PI060386 from Spain’s Health Research Fund (Fondo de Investigación Sanitaria); the EPY 1306/06 Collaboration Agreement between Astra-Zeneca and the Instituto de Salud Carlos III; and a grant from the Spanish Federation of Breast Cancer (FECMA). Sí