Centro Cardiologico Monzino

Publicado também em: https://repositorio.unifesp.br/handle/11600/53933

A study in vitro of specimens of human aortic and common carotid arteries was carried out to determine the feasibility of direct measurement (i.e., not from residual lumen) of arterial wall thickness with B mode real-time imaging. Measurements in vivo by the same technique were also obtained from common carotid arteries of 10 young normal male subjects. Aortic samples were classified as class A (relatively normal) or class B (with one or more atherosclerotic plaques). In all class A and 85% of class B arterial samples a characteristic B mode image composed of two parallel echogenic lines separated by a hypoechoic space was found. The distance between the two lines (B mode image of intimal + medial thickness) was measured and correlated with the thickness of different combinations of tunicae evaluated by gross and microscopic examination. On the basis of these findings and the results of dissection experiments on the intima and adventitia we concluded that results of B mode imaging of intimal + medial thickness did not differ significantly from the intimal + medial thickness measured on pathologic examination. With respect to the accuracy of measurements obtained by B mode imaging as compared with pathologic findings, we found an error of less than 20% for measurements in 77% of normal and pathologic aortic walls. In addition, no significant difference was found between B mode-determined intimal + medial thickness in the common carotid arteries evaluated in vitro and that determined by this method in vivo in young subjects, indicating that B mode imaging represents a useful approach for the measurement of intimal + medial thickness of human arteries in vivo.

BACKGROUND: Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation. Radiofrequency ablation is the most common method, and cryoballoon ablation is the second most frequently used technology. METHODS: We conducted a multicenter, randomized trial to determine whether cryoballoon ablation was noninferior to radiofrequency ablation in symptomatic patients with drug-refractory paroxysmal atrial fibrillation. The primary efficacy end point in a time-to-event analysis was the first documented clinical failure (recurrence of atrial fibrillation, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day period after the index ablation. The noninferiority margin was prespecified as a hazard ratio of 1.43. The primary safety end point was a composite of death, cerebrovascular events, or serious treatment-related adverse events. RESULTS: A total of 762 patients underwent randomization (378 assigned to cryoballoon ablation and 384 assigned to radiofrequency ablation). The mean duration of follow-up was 1.5 years. The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 34.6% and 35.9%, respectively; hazard ratio, 0.96; 95% confidence interval [CI], 0.76 to 1.22; P<0.001 for noninferiority). The primary safety end point occurred in 40 patients in the cryoballoon group and in 51 patients in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 10.2% and 12.8%, respectively; hazard ratio, 0.78; 95% CI, 0.52 to 1.18; P=0.24). CONCLUSIONS: In this randomized trial, cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation, and there was no significant difference between the two methods with regard to overall safety. (Funded by Medtronic; FIRE AND ICE ClinicalTrials.gov number, NCT01490814.).

BACKGROUND: Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking. We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. METHODS AND RESULTS: We assessed left ventricular ejection fraction (LVEF), at baseline, every 3 months during chemotherapy and for the following year, every 6 months over the following 4 years, and yearly afterward in a heterogeneous cohort of 2625 patients receiving anthracycline-containing therapy. In case of cardiotoxicity (LVEF decrease >10 absolute points, and <50%), heart failure therapy was initiated. Recovery from cardiotoxicity was defined as partial (LVEF increase >5 absolute points and >50%) or full (LVEF increase to the baseline value). The median follow-up was 5.2 (quartile 1 to quartile 3, 2.6-8.0) years. The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3-6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year. Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery. At multivariable analysis, end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33-1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04-1.15 for each 50 mg/m(2) increment) were independent correlates of cardiotoxicity. CONCLUSIONS: Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.

Catheter ablation of AF is a very commonly performed procedure in hospitals throughout the world. Surgical ablation of AF, although less widely available than catheter-based AF ablation, is also an important therapeutic option for patients with AF at many major medical centers. This document provides an up-to-date review of the indications, techniques, and outcomes of catheter and surgical ablation of AF. Areas for which a consensus can be reached concerning AF ablation are identified, and a series of consensus definitions have been developed for use in future clinical trials of AF ablation. Also included within this document are recommendations concerning indications for AF ablation, technical performance of this procedure, and training. It is our hope to improve patient care by providing a foundation for those involved with care of patients with AF as well as those who perform AF ablation. It is recognized that this field continues to evolve rapidly and that this document will need to be updated. Successful AF ablation programs optimally should consist of a cooperative team of cardiologists, electrophysiologists, and surgeons to ensure appropriate indications, procedure selection, and follow-up.

Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. Insulin is an important anabolic hormone, and its deficiency leads to various metabolic abnormalities in proteins, lipids, and carbohydrates. Atherosclerosis develops as a result of a multistep process ultimately leading to cardiovascular disease associated with high morbidity and mortality. Alteration of lipid metabolism is a risk factor and characteristic feature of atherosclerosis. Possible links between the two chronic disorders depending on altered metabolic pathways have been investigated in numerous studies. It was shown that both types of diabetes mellitus can actually induce atherosclerosis development or further accelerate its progression. Elevated glucose level, dyslipidemia, and other metabolic alterations that accompany the disease development are tightly involved in the pathogenesis of atherosclerosis at almost every step of the atherogenic process. Chronic inflammation is currently considered as one of the key factors in atherosclerosis development and is present starting from the earliest stages of the pathology initiation. It may also be regarded as one of the possible links between atherosclerosis and diabetes mellitus. However, the data available so far do not allow for developing effective anti-inflammatory therapeutic strategies that would stop atherosclerotic lesion progression or induce lesion reduction. In this review, we summarize the main aspects of diabetes mellitus that possibly affect the atherogenic process and its relationship with chronic inflammation. We also discuss the established pathophysiological features that link atherosclerosis and diabetes mellitus, such as oxidative stress, altered protein kinase signaling, and the role of certain miRNA and epigenetic modifications.

Italian experience about the reduction in MI hospital admission during the first wave of COVID-19 pandemic

BACKGROUND: Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death. METHODS AND RESULTS: Clinical data were collected for 200 patients (152 men, 48 women; age, 41+/-18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the SCN5A gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and SCN5A mutations, the combined presence of a spontaneous ST-segment elevation in leads V1 through V3 and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21; P<0.002). CONCLUSIONS: The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator.

INTRODUCTION: Sexual health is an integral part of overall health. Sexual dysfunction can have a major impact on quality of life and psychosocial and emotional well-being. AIM: To provide evidence-based, expert-opinion consensus guidelines for clinical management of sexual dysfunction in men. METHODS: An international consultation collaborating with major urologic and sexual medicine societies convened in Paris, July 2009. More than 190 multidisciplinary experts from 33 countries were assembled into 25 consultation committees. Committee members established scope and objectives for each chapter. Following an exhaustive review of available data and publications, committees developed evidence-based guidelines in each area. Main Outcome Measures. New algorithms and guidelines for assessment and treatment of sexual dysfunctions were developed based on work of previous consultations and evidence from scientific literature published from 2003 to 2009. The Oxford system of evidence-based review was systematically applied. Expert opinion was based on systematic grading of medical literature, and cultural and ethical considerations. RESULTS: Algorithms, recommendations, and guidelines for sexual dysfunction in men are presented. These guidelines were developed in an evidence-based, patient-centered, multidisciplinary manner. It was felt that all sexual dysfunctions should be evaluated and managed following a uniform strategy, thus the International Consultation of Sexual Medicine (ICSM-5) developed a stepwise diagnostic and treatment algorithm for sexual dysfunction. The main goal of ICSM-5 is to unmask the underlying etiology and/or indicate appropriate treatment options according to men's and women's individual needs (patient-centered medicine) using the best available data from population-based research (evidence-based medicine). Specific evaluation, treatment guidelines, and algorithms were developed for every sexual dysfunction in men, including erectile dysfunction; disorders of libido, orgasm, and ejaculation; Peyronie's disease; and priapism. CONCLUSIONS: Sexual dysfunction in men represents a group of common medical conditions that need to be managed from a multidisciplinary perspective.

MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative gene expression regulators. In the present study, we investigated miRNAs role in endothelial cell response to hypoxia. We found that the expression of miR-210 progressively increased upon exposure to hypoxia. miR-210 overexpression in normoxic endothelial cells stimulated the formation of capillary-like structures on Matrigel and vascular endothelial growth factor-driven cell migration. Conversely, miR-210 blockade via anti-miRNA transfection inhibited the formation of capillary-like structures stimulated by hypoxia and decreased cell migration in response to vascular endothelial growth factor. miR-210 overexpression did not affect endothelial cell growth in both normoxia and hypoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, in both normoxia and hypoxia. We determined that one relevant target of miR-210 in hypoxia was Ephrin-A3 since miR-210 was necessary and sufficient to down-modulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences; indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210 prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. We conclude that miR-210 up-regulation is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration, and differentiation. MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative gene expression regulators. In the present study, we investigated miRNAs role in endothelial cell response to hypoxia. We found that the expression of miR-210 progressively increased upon exposure to hypoxia. miR-210 overexpression in normoxic endothelial cells stimulated the formation of capillary-like structures on Matrigel and vascular endothelial growth factor-driven cell migration. Conversely, miR-210 blockade via anti-miRNA transfection inhibited the formation of capillary-like structures stimulated by hypoxia and decreased cell migration in response to vascular endothelial growth factor. miR-210 overexpression did not affect endothelial cell growth in both normoxia and hypoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, in both normoxia and hypoxia. We determined that one relevant target of miR-210 in hypoxia was Ephrin-A3 since miR-210 was necessary and sufficient to down-modulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences; indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210 prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. We conclude that miR-210 up-regulation is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration, and differentiation. Hypoxia occurs during several physio-pathological circumstances such as rapid tissue growth, acute and chronic ischemia, organ and tumor development, and high altitude (1Giaccia A.J. Simon M.C. Johnson R. Genes Dev. 2004; 18: 2183-2194Crossref PubMed Scopus (297) Google Scholar). Diminished oxygen concentration induces an articulate program of responses aimed at relieving tissue hypoxia and removing irreversibly damaged cells (2Pouyssegur J. Dayan F. Mazure N.M. Nature. 2006; 441: 437-443Crossref PubMed Scopus (1384) Google Scholar, 3Pugh C.W. Ratcliffe P.J. Nat. Med. 2003; 9: 677-684Crossref PubMed Scopus (1999) Google Scholar). These responses include endothelial cell (EC) 2The abbreviations used are: EC, endothelial cell; HUVEC, human umbilical vein endothelial cells; miRNA, microRNA; qPCR, real-time PCR; pSUPER, p-SUPER.retro.puro vector; EFNA3, ephrin-A3; anti-miR-210, miR-210 complementary locked nucleic acid; VEGF, vascular endothelial growth factor; UTR, untranslated region. proliferation, migration, and angiogenesis, but also growth arrest and apoptotic cell death; the nature of the outcome depends on numerous parameters, including cell histological origin and genotype, as well as the severity and the duration of the hypoxic stress. Thus, it is of pivotal importance in understanding the molecular mechanisms triggered by cell exposure to low oxygen tension. Little is known about the role played by microRNAs (miRNAs) in EC response to hypoxia (4Kulshreshtha R. Davuluri R.V. Calin G.A. Ivan M. Cell Death Differ. 2008; 15: 667-671Crossref PubMed Scopus (223) Google Scholar). miRNAs are 21–23-nucleotide RNA molecules that regulate the stability or the translational efficiency of target messenger RNAs (5Bartel D.P. Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (29625) Google Scholar, 6Zamore P.D. Haley B. Science. 2005; 309: 1519-1524Crossref PubMed Scopus (1130) Google Scholar). The biogenesis of miRNAs begins with a primary transcript, termed the pri-miRNA, and the combined action of Drosha and Dicer ribonucleases generates the mature miRNA species. This product is loaded into the RNA-induced silencing complex, where it mediates the translational inhibition of target mRNA, albeit the opposite effect has been described as well (7Vasudevan S. Tong Y. Steitz J.A. Science. 2007; 318: 1931-1934Crossref PubMed Scopus (2198) Google Scholar). miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation, and apoptosis (5Bartel D.P. Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (29625) Google Scholar). Although it is clear that miRNAs have essential functions in mammalian biology, few miRNA genes have been functionally linked to specific cellular pathways. In this study, we show that miR-210 is a key player of EC response to low oxygen tension and identify Ephrin-A3 as a relevant target of miR-210 in hypoxic conditions. Cell Cultures—Human umbilical vein EC (HUVEC; Clonetics) were grown in EGM-2 (BioWhittaker) containing 2% fetal bovine serum. U2OS osteosarcoma cell line and Phoenix-ampho cells (American Type Culture Collection) were grown in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum. The induction of acidosis and hypoxia is described in supplemental materials. miRNA and mRNA Quantification—Total RNA was extracted using TRIzol (Invitrogen). Small RNA and mRNA fractions were enriched using the PureLink miRNA isolation kit and Micro-to-Midi isolation kit (Invitrogen), respectively, according to the manufacturer's instructions. miRNA levels were analyzed using the TaqMan real-time PCR (qPCR) method (1 ng/assay) and quantified with the ABI Prism 7000 SDS (Applied Biosystems). Primers for 157 miRNA, 28 positive and negative controls, and the reagents for reverse transcriptase and qPCR reactions were all obtained from Applied Biosystems. Relative expression was calculated using the comparative Ct method (2-[Δ][Δ]Ct) (8Livak K.J. Schmittgen T.D. Methods (Amst.). 2001; 25: 402-408Google Scholar). Different samples were normalized to miR-16 expression. For miRNA profiling, miRNAs were assayed in a 96-well format, and samples were also normalized to the median Ct value, obtaining almost identical results. mRNAs levels were analyzed using the SYBR-GREEN qPCR method (1–3 μg/assay, Ambion, see supplemental materials for details). Northern blottings are described in the supplemental materials. Small Interfering RNA-mediated Gene Silencing—Small interfering RNAs targeting HIF1α, HIF2α, or a scramble sequence (Santa Cruz Biotechnology) were transfected into HUVEC, according to the manufacturer's instruction (see the supplemental materials for details). miRNA Down-modulation and Overexpression—Locked Nucleic Acid oligonucleotides against miR-210 or a control scramble sequence (Exiqon) were transfected by small interfering RNA transfection reagent (Santa Cruz Biotechnology) in 40% confluent HUVEC (4 × 103/cm2) at the final concentration of 40 nm. After 16 h, cells were re-fed with fresh medium, and experiments were performed 24 h later. Alternatively, cells were incubated with fresh medium for 2 h and then shifted to hypoxic conditions. miRIDIAN miR-210 Mimic or a control scramble sequence (Dharmacon) were transfected using the same protocol. To obtain stable miR-210-overexpressing cells, HUVEC were infected by retroviral vectors bearing pre-miR210 sequence (see the supplemental materials). miRNAs Target Prediction—Bioinformatic prediction of target genes and miRNA binding sites was performed using four different programs: MiRanda (version 2005), TargetScan (version 3.1), Sanger MirBase (version 4), and PicTar (version 2006) (9Krek A. Grun D. Poy M.N. Wolf R. Rosenberg L. Epstein E.J. MacMenamin P. da Piedade I. Gunsalus K.C. Stoffel M. Rajewsky N. Nat. Genet. 2005; 37: 495-500Crossref PubMed Scopus (3903) Google Scholar, 10Sethupathy P. Megraw M. Hatzigeorgiou A.G. Nat. Methods. 2006; 3: 881-886Crossref PubMed Scopus (479) Google Scholar, 11Rajewsky N. Nat. Genet. 2006; 38: S8-S13Crossref PubMed Scopus (939) Google Scholar). Only common targets were considered for experimental analysis. Additional Information—See the supplemental materials for information on apoptosis, cell cycle analysis, adenoviral infection, capillary-like formation assay, chemotaxis, immunofluorescence, reporter construct generation and luciferase assay. Statistical Analysis—Variables were analyzed by both Student's t test and one-way analysis of variance and a of p ≤ 0.05 was deemed statistically significant. Values are expressed as ±standard error (S.E.). miR-210 Induction by Hypoxia—To assess whether hypoxia regulates miRNA expression in EC, HUVEC were exposed to 1% oxygen for different time periods. To control that cells responded to low oxygen tension, cell proliferation was measured. As expected, hypoxia induced cell death and growth arrest, as assessed by growth curves (Fig. S1A) and by the rate of DNA synthesis with bromodeoxyuridine incorporation (Fig. S1, B and C) (1Giaccia A.J. Simon M.C. Johnson R. Genes Dev. 2004; 18: 2183-2194Crossref PubMed Scopus (297) Google Scholar, 2Pouyssegur J. Dayan F. Mazure N.M. Nature. 2006; 441: 437-443Crossref PubMed Scopus (1384) Google Scholar, 3Pugh C.W. Ratcliffe P.J. Nat. Med. 2003; 9: 677-684Crossref PubMed Scopus (1999) Google Scholar). Low molecular weight RNA was extracted, and miRNA expression profile at each time point was determined (Tables S1 and S2). To normalize different samples, we used miR-16 expression, which previous experiments showed was not regulated by hypoxia (Fig. S2A). As found in different experimental systems (4Kulshreshtha R. Davuluri R.V. Calin G.A. Ivan M. Cell Death Differ. 2008; 15: 667-671Crossref PubMed Scopus (223) Google Scholar), miR-210 levels were strongly induced by hypoxia. miR-210 increased as early as 4 h after hypoxia induction, it was more than 35-fold higher than normoxic control at 48 h, and miRNA up-regulation was maintained for the next 72 h (Fig. 1A). miR-150 and 328 were up-regulated as well, albeit to a lower extent and with slower kinetics (Fig. S2, B and C). When miR-210 regulation by hypoxia was further investigated, it was found that its activation was inversely proportional to O2 tension (Fig. S3A). Moreover, upon HUVEC reoxygenation after 24 h of hypoxia, miR-210 levels remained high for the next 8 h and slowly declined thereafter, indicating the maintenance of this adaptive response (Fig. 1A). Finally, miR-210 induction by hypoxia was confirmed by northern blotting (Fig. 1B). Hypoxia is associated to increased oxidative stress and acidosis (12Zaccagnini G. Martelli F. Fasanaro P. Magenta A. Gaetano C. Di Carlo A. Biglioli P. Giorgio M. Martin-Padura I. Pelicci P.G. Capogrossi M.C. Circulation. 2004; 109: 2917-2923Crossref PubMed Scopus (103) Google Scholar, 13Mekhail K. Khacho M. Gunaratnam L. Lee S. Cell Cycle. 2004; 3: 1027-1029Crossref PubMed Scopus (25) Google Scholar, 14Guzy R.D. Schumacker P.T. Exp. Physiol. 2006; 91: 807-819Crossref PubMed Scopus (681) Google Scholar). Thus, it was assessed whether either oxidative stress or acidification in the absence of hypoxia were sufficient to induce miR-210 positive modulation (Fig. S3B). We found that HUVEC exposure to 400 μm H2O2 for 8 and 24 h did not induce miR-210 modulation; similarly, cell culture at both pH 6.6 and pH 7.0 for 24 and 48 h did not increase miR-210. In keeping with these data, a buffered medium that prevented hypoxia-induced acidosis (15Luo F. Liu X. Yan N. Li S. Cao G. Cheng Q. Xia Q. Wang H. BMC Cancer. 2006; 6: 26Crossref PubMed Scopus (60) Google Scholar) did not inhibit miR-210 activation by hypoxia. Finally, we found that glucose supplementation did not prevent miR-210 induction by hypoxia (Fig. S3C) and that this event was not endothelium-specific (Fig. S4). Many hypoxia effects are mediated by HIF transcription factor (1Giaccia A.J. Simon M.C. Johnson R. Genes Dev. 2004; 18: 2183-2194Crossref PubMed Scopus (297) Google Scholar, 2Pouyssegur J. Dayan F. Mazure N.M. Nature. 2006; 441: 437-443Crossref PubMed Scopus (1384) Google Scholar, 3Pugh C.W. Ratcliffe P.J. Nat. Med. 2003; 9: 677-684Crossref PubMed Scopus (1999) Google Scholar). To analyze the role of HIF in the induction of miR-210 by hypoxia in EC, the expression of HIF1α and HIF2α was knocked down by the transfection of specific small interfering RNAs. Although the knock down of both HIF isoforms was highly effective (Fig. S5, A and B), only HIF1α RNA interference decreased the induction of miR-210 by hypoxia significantly (Fig. S5C). In keeping with this observation, HIF1α overexpression was sufficient to induce miR-210 expression in the absence of hypoxia (Fig. S5, D and E). We conclude that miR-210 displays a rapid and dose-dependent induction in response to hypoxia and that its up-regulation is maintained over time. Neither oxidative stress nor acidosis appears to play a role in this event and, in keeping with previous observations (4Kulshreshtha R. Davuluri R.V. Calin G.A. Ivan M. Cell Death Differ. 2008; 15: 667-671Crossref PubMed Scopus (223) Google Scholar), HIF1α is necessary and sufficient for miR-210 activation. miR-210 Expression Stimulates Capillary-like Formation and Cell Migration—One main feature of hypoxia is the stimulation of angiogenesis (3Pugh C.W. Ratcliffe P.J. Nat. Med. 2003; 9: 677-684Crossref PubMed Scopus (1999) Google Scholar). Several aspects of angiogenesis can be studied in vitro, taking advantage of the ability of EC to form capillary-like structures once plated on Matrigel or other extracellular components (16Kubota Y. Kleinman H.K. Martin G.R. Lawley T.J. J. Cell Biol. 1988; 107: 1589-1598Crossref PubMed Scopus (984) Google Scholar). To this aim, HUVEC were first exposed to 24 h of hypoxia and, afterward, their ability to form capillary-like structures in low growth factor-containing medium was assessed. In keeping with previous reports (17Yamakawa M. Liu L.X. Date T. Belanger A.J. Vincent K.A. Akita G.Y. Kuriyama T. Cheng S.H. Gregory R.J. Jiang C. Circ. Res. 2003; 93: PubMed Scopus Google Scholar), hypoxia significantly increased tubulogenesis (Fig. A and To whether this event at in on miR-210 HUVEC were transfected with a miR-210 complementary Nucleic Acid that with high and to the complementary miRNA, its A and show that 24 h of miR-210 decreased the ability of HUVEC to form capillary-like both in cells exposed to hypoxia and in control To assess whether miR-210 induction capillary-like formation in the absence of hypoxia, HUVEC were a that expressed mature miR-210 levels with these in hypoxic cells (Fig. We found that miR-210 overexpression significantly increased capillary-like formation HUVEC were plated in low growth factor medium (Fig. D and E). EC migration is a crucial event in the (3Pugh C.W. Ratcliffe P.J. Nat. Med. 2003; 9: 677-684Crossref PubMed Scopus (1999) Google Scholar). Thus, we assessed whether the modulation of miR-210 expression chemotaxis. To this aim, HUVEC were transfected with anti-miR-210, and then their ability to in response to was A and show that miR-210 blockade significantly decreased chemotaxis. Conversely, miR-210 up-regulation to levels to these induced by hypoxia significantly increased HUVEC ability to in response to (Fig. and Finally, to the of miR-210 action in the gene expression the mRNA levels of hypoxia target genes were both in HUVEC exposed to hypoxia and in cells miR-210 in normoxic (Fig. Although hypoxia up-regulated the expression of all miR-210 did not affect their We that miR-210 expression not to affect the gene expression response to hypoxia by miR-210 EC was whether miR-210 induction EC To this we growth curves of HUVEC with retroviral vectors miR-210 or with in the or absence of hypoxia. was found that miR-210 expression did not affect cell significantly both in normoxic and in hypoxic (Fig. a HUVEC were transfected with anti-miR-210, and cells were We found that 24 h of miR-210 decreased HUVEC proliferation in normoxic cells and that exposure to hypoxia further decreased EC (Fig. This at in to apoptotic cell death since apoptotic DNA was increased by anti-miR-210 transfection (Fig. were obtained by a not Conversely, DNA synthesis was we found that anti-miR-210 only bromodeoxyuridine incorporation rate (Fig. Hypoxia Ephrin-A3 via further the of miR-210 regulation in cell response to hypoxia, an in of targets was performed using Sanger and (9Krek A. Grun D. Poy M.N. Wolf R. Rosenberg L. Epstein E.J. MacMenamin P. da Piedade I. Gunsalus K.C. Stoffel M. Rajewsky N. Nat. Genet. 2005; 37: 495-500Crossref PubMed Scopus (3903) Google Scholar, 10Sethupathy P. Megraw M. Hatzigeorgiou A.G. Nat. Methods. 2006; 3: 881-886Crossref PubMed Scopus (479) Google Scholar, 11Rajewsky N. Nat. Genet. 2006; 38: S8-S13Crossref PubMed Scopus (939) Google Scholar). of the common targets of these was Ephrin-A3 the crucial role of in the of the and in vascular S. Med. 2007; PubMed Scopus Google Scholar), we to this target To this aim, HUVEC were exposed to hypoxia for 24 and 48 h, and was by and show that was in normoxic cells, its expression decreased to almost levels hypoxia This was not to decreased mRNA levels since by qPCR an increase of mRNA (Fig. Although regulation further we can conclude that is by hypoxia. it was assessed whether was to increased miR-210 To this HUVEC were transfected with anti-miR-210 and exposed to hypoxia. that miR-210 prevented it was investigated whether miR-210 up-regulation in the absence of hypoxia regulated We found that was strongly in miR-210-overexpressing cells (Fig. in the absence of mRNA regulation (Fig. these a up-regulation and by hypoxia. To whether miR-210 regulated expression, an was in which the of the gene was of a luciferase Alternatively, to the interference of other miRNA binding only the miR-210 target and the were As we the sequence complementary to miR-210 sequence in this construct The different luciferase were transfected into U2OS cells with a a expression for miR-210 or for a control U2OS were for their high efficiency of A significant negative effect on luciferase was in both bearing an miR-210 binding with the control (Fig. levels of miR-210 induced by hypoxia were sufficient to and reporter was (Fig. We that is a direct target of miR-210. Down-modulation for miR-210-mediated of and investigated whether is an of increase of EC migration and To this aim, miR-210 was in the of an allele that is of sequence and be targeted by miR-210. was expressed using a retroviral miR-210 was transfected as mature that expression prevented increase of capillary-like the expression of miR-210 and decreased tubulogenesis control expression had effect We found that the same was also in cells, in the absence of miR-210 that the expression of prevented hypoxia-induced increase of EC tubulogenesis and that the of capillary-like structures was we assayed whether inhibition played a role in miR-210 stimulation of EC as that expression did not affect EC in response to VEGF, miR-210 and inhibited it the expression of prevented the increase in induced by hypoxia (Fig. In this study, we miR-210 regulation and its functional in EC response to hypoxia. was found that miR-210 up-regulation was rapid and and it did not a response to stress since was found that either pH or increased oxygen played a role in miR-210 activation. We also found that growth factor nor stress miR-210 Y. M. C. and F. the high of the hypoxic in miR-210 Moreover, miR-210 modulation by hypoxia is not to Thus, it is to a role of miR-210 induction in the hypoxic In keeping with this found that the of the miRNAs by hypoxia according to the cell used as as the and the time of hypoxia R. M. R. H. Davuluri R. Liu M. Calin G.A. Ivan M. Cell. Biol. 2006; Scholar, C. K. N. Cancer. 2007; 6: PubMed Scopus Google Scholar, Q. G. D. Y. C. Wang J. Y. 2006; PubMed Scopus Google Scholar, Y. 2007; PubMed Scopus Google Scholar, C. S. J. C. H. J. Res. 2008; PubMed Scopus Google Scholar). However, the activation of miR-210 not linked to experimental or to a specific cell R. M. R. H. Davuluri R. Liu M. Calin G.A. Ivan M. Cell. Biol. 2006; Scholar, C. K. N. Cancer. 2007; 6: PubMed Scopus Google Scholar, Q. G. D. Y. C. Wang J. Y. 2006; PubMed Scopus Google Scholar, C. S. J. C. H. J. Res. 2008; PubMed Scopus Google Scholar, A. R. J. S. J. K. Li C. A. D. Simon C. G. L. Biol. 2007; PubMed Scopus Google Scholar). other miR-210 information is almost to expression analysis. Thus, we on the of the functional of miR-210 regulation in EC response to hypoxia. was that miR-210 up-regulation in normoxic EC tubulogenesis and migration, miR-210 blockade in the of hypoxia capillary-like EC migration, and EC and induces In keeping with this it has been that miR-210 inhibition R. M. R. H. Davuluri R. Liu M. Calin G.A. Ivan M. Cell. Biol. 2006; Scholar, J. Nucleic Res. 2005; PubMed Scopus Google Scholar). that the effects on migration and tubulogenesis are mediated by Although this is a mechanisms play a role as both cell and apoptosis induced by anti-miR-210 transfection were only the inhibition of tubulogenesis was almost Moreover, anti-miR-210 transfected cells a of The specific effect of miR-210 blockade was to their ability to their migration in response to main that has the of miRNA is the of miRNA targets P. Megraw M. Hatzigeorgiou A.G. Nat. Methods. 2006; 3: 881-886Crossref PubMed Scopus (479) Google Scholar, 11Rajewsky N. Nat. Genet. 2006; 38: S8-S13Crossref PubMed Scopus (939) Google Scholar). the of only targets has been in to by the To genes regulated by a was using four target prediction and targets that were not by at of that is a miR-210 miR-210 overexpression induced the of but not of Hypoxia induced mRNA was miR-210 by complementary Nucleic Acid prevented induced by hypoxia. containing a miR-210 binding sequence decreased the expression of a reporter luciferase gene upon hypoxia or miR-210 expression. Although all these that miR-210 regulates expression it is that mechanisms increase the of miR-210 and their have been to play a crucial role in the of the and in vascular S. Med. 2007; PubMed Scopus Google Scholar). numerous have the importance of in the regulation of angiogenesis and S. Med. 2007; PubMed Scopus Google Scholar, A. H. P.J. Science. PubMed Scopus Google Scholar). Although the specific role of in the regulation of angiogenesis is has been to as well as S. T. M. Science. PubMed Scopus Google Scholar). We that is a necessary event of miR-210-mediated stimulation of capillary-like formation and EC in response to Thus, it is to that of expression to the response to We can conclude that further are the modulation of miR-210 expression be a to control angiogenesis, either or The of in experiments using the hypoxic and of of in O2 concentration is with

AIMS: Circulating microRNAs (miRNAs) may represent a novel class of biomarkers; therefore, we examined whether acute myocardial infarction (MI) modulates miRNAs plasma levels in humans and mice. METHODS AND RESULTS: Healthy donors (n = 17) and patients (n = 33) with acute ST-segment elevation MI (STEMI) were evaluated. In one cohort (n = 25), the first plasma sample was obtained 517 ± 309 min after the onset of MI symptoms and after coronary reperfusion with percutaneous coronary intervention (PCI); miR-1, -133a, -133b, and -499-5p were ~15- to 140-fold control, whereas miR-122 and -375 were ~87-90% lower than control; 5 days later, miR-1, -133a, -133b, -499-5p, and -375 were back to baseline, whereas miR-122 remained lower than control through Day 30. In additional patients (n = 8; four treated with thrombolysis and four with PCI), miRNAs and troponin I (TnI) were quantified simultaneously starting 156 ± 72 min after the onset of symptoms and at different times thereafter. Peak miR-1, -133a, and -133b expression and TnI level occurred at a similar time, whereas miR-499-5p exhibited a slower time course. In mice, miRNAs plasma levels and TnI were measured 15 min after coronary ligation and at different times thereafter. The behaviour of miR-1, -133a, -133b, and -499-5p was similar to STEMI patients; further, reciprocal changes in the expression levels of these miRNAs were found in cardiac tissue 3-6 h after coronary ligation. In contrast, miR-122 and -375 exhibited minor changes and no significant modulation. In mice with acute hind-limb ischaemia, there was no increase in the plasma level of the above miRNAs. CONCLUSION: Acute MI up-regulated miR-1, -133a, -133b, and -499-5p plasma levels, both in humans and mice, whereas miR-122 and -375 were lower than control only in STEMI patients. These miRNAs represent novel biomarkers of cardiac damage.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P &amp;lt; 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

BACKGROUND AND PURPOSE: Current guidelines on cerebral venous thrombosis (CVT) diagnosis and management were issued by the European Federation of Neurological Societies in 2010. We aimed to update the previous European Federation of Neurological Societies guidelines using a clearer and evidence-based methodology. METHOD: We followed the Grading of Recommendations, Assessment, Development and Evaluation system, formulating relevant diagnostic and treatment questions, performing systematic reviews and writing recommendations based on the quality of available scientific evidence. RESULTS: We suggest using magnetic resonance or computed tomographic angiography for confirming the diagnosis of CVT and not routinely screening patients with CVT for thrombophilia or cancer. We recommend parenteral anticoagulation in acute CVT and decompressive surgery to prevent death due to brain herniation. We suggest preferentially using low-molecular-weight heparin in the acute phase and not direct oral anticoagulants. We suggest not using steroids and acetazolamide to reduce death or dependency. We suggest using antiepileptics in patients with an early seizure and supratentorial lesions to prevent further early seizures. We could not make recommendations concerning duration of anticoagulation after the acute phase, thrombolysis and/or thrombectomy, therapeutic lumbar puncture, and prevention of remote seizures with antiepileptic drugs. We suggest that, in women who have suffered a previous CVT, contraceptives containing oestrogens should be avoided. We suggest that subsequent pregnancies are safe, but use of prophylactic low-molecular-weight heparin should be considered throughout pregnancy and puerperium. CONCLUSIONS: Multicentre observational and experimental studies are needed to increase the level of evidence supporting recommendations on the diagnosis and management of CVT.

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING: The funding sources are cited at the end of the paper.

AIMS: Traditional prognostic risk assessment in patients undergoing non-invasive imaging is based upon a limited selection of clinical and imaging findings. Machine learning (ML) can consider a greater number and complexity of variables. Therefore, we investigated the feasibility and accuracy of ML to predict 5-year all-cause mortality (ACM) in patients undergoing coronary computed tomographic angiography (CCTA), and compared the performance to existing clinical or CCTA metrics. METHODS AND RESULTS: The analysis included 10 030 patients with suspected coronary artery disease and 5-year follow-up from the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry. All patients underwent CCTA as their standard of care. Twenty-five clinical and 44 CCTA parameters were evaluated, including segment stenosis score (SSS), segment involvement score (SIS), modified Duke index (DI), number of segments with non-calcified, mixed or calcified plaques, age, sex, gender, standard cardiovascular risk factors, and Framingham risk score (FRS). Machine learning involved automated feature selection by information gain ranking, model building with a boosted ensemble algorithm, and 10-fold stratified cross-validation. Seven hundred and forty-five patients died during 5-year follow-up. Machine learning exhibited a higher area-under-curve compared with the FRS or CCTA severity scores alone (SSS, SIS, DI) for predicting all-cause mortality (ML: 0.79 vs. FRS: 0.61, SSS: 0.64, SIS: 0.64, DI: 0.62; P< 0.001). CONCLUSIONS: Machine learning combining clinical and CCTA data was found to predict 5-year ACM significantly better than existing clinical or CCTA metrics alone.

During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure. In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.2 The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic. The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardiacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B. In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations. The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.3,4 It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended. The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group. Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.5,6 This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient. The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

In December 2019, the world started to face a new pandemic situation, the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Although coronavirus disease (COVID-19) clinical manifestations are mainly respiratory, major cardiac complications are being reported. Cardiac manifestations etiology seems to be multifactorial, comprising direct viral myocardial damage, hypoxia, hypotension, enhanced inflammatory status, ACE2-receptors downregulation, drug toxicity, endogenous catecholamine adrenergic status, among others. Studies evaluating patients with COVID-19 presenting cardiac injury markers show that it is associated with poorer outcomes, and arrhythmic events are not uncommon. Besides, drugs currently used to treat the COVID-19 are known to prolong the QT interval and can have a proarrhythmic propensity. This review focus on COVID-19 cardiac and arrhythmic manifestations and, in parallel, makes an appraisal of other virus epidemics as SARS-CoV, Middle East respiratory syndrome coronavirus, and H1N1 influenza.

BACKGROUND: New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed by the Food and Drug Administration. METHODS: In this multicenter, noninferiority trial with minimal exclusion criteria, we randomly assigned 2292 patients to undergo treatment with coronary stents releasing either zotarolimus or everolimus. Twenty percent of patients were randomly selected for repeat angiography at 13 months. The primary end point was target-lesion failure, defined as a composite of death from cardiac causes, any myocardial infarction (not clearly attributable to a nontarget vessel), or clinically indicated target-lesion revascularization within 12 months. The secondary angiographic end point was the extent of in-stent stenosis at 13 months. RESULTS: At least one off-label criterion for stent placement was present in 66% of patients. The zotarolimus-eluting stent was noninferior to the everolimus-eluting stent with respect to the primary end point, which occurred in 8.2% and 8.3% of patients, respectively (P<0.001 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, any myocardial infarction, or revascularization. The rate of stent thrombosis was 2.3% in the zotarolimus-stent group and 1.5% in the everolimus-stent group (P=0.17). The zotarolimus-eluting stent was also noninferior regarding the degree (+/-SD) of in-stent stenosis (21.65+/-14.42% for zotarolimus vs. 19.76+/-14.64% for everolimus, P=0.04 for noninferiority). In-stent late lumen loss was 0.27+/-0.43 mm in the zotarolimus-stent group versus 0.19+/-0.40 mm in the everolimus-stent group (P=0.08). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS: At 13 months, the new-generation zotarolimus-eluting stent was found to be noninferior to the everolimus-eluting stent in a population of patients who had minimal exclusion criteria. (ClinicalTrials.gov number, NCT00617084.)

Villa et al. find significant differences in the transcriptomes of microglia isolated from the brains of healthy adult male and female mice. They find that microglia from female mice are neuroprotective and that they retain this functional ability when transferred into the brains of male mice.