Artigos e Materiais de Revistas Científicas - LIM/13

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A coleção de Artigos e Materiais de Revistas Científicas engloba artigos originais, artigos de revisão, artigos de atualização, artigos técnicos, relatos de experiências, resenhas, ensaios, editoriais, cartas ao editor, debates, notas científicas e técnicas, depoimentos, entrevistas e pontos de vista. Consideram-se como artigos científicos originais os trabalhos redigidos para divulgação de informações e resultados sobre determinada pesquisa científica, publicados em periódico científico após avaliação por outros pesquisadores.

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Rivaroxaban versus warfarin in postoperative atrial fibrillation: Cost-effectiveness analysis in a single-center, randomized, and prospective trial
(2023) PEREIRA, M. D. P.; LIMA, E. G.; PITTA, F. G.; GOWDAK, L. H. W.; MIOTO, B. M.; CARVALHO, L. N. S.; DARRIEUX, F. C. D. C.; MEJIA, O. A. V.; JATENE, F. B.; SERRANO JR., C. V
Objectives: Postoperative atrial fibrillation is the most common clinical complication after coronary artery bypass graft surgery. It is associated with a high risk of both stroke and death and increases the length of hospital stay and costs. This study aimed to evaluate anticoagulants in postoperative atrial fibrillation. Methods: A single-center, randomized, prospective, and open-label study. The trial was conducted in Heart Institute at University of São Paulo, Brazil. Patients who developed postoperative atrial fibrillation were randomized to anticoagulation with rivaroxaban or warfarin plus enoxaparin bridging. The primary objective was the cost-effectiveness evaluated by quality-adjusted life years, using the SF-6D questionnaire. The secondary end point was the combination of death, stroke, myocardial infarction, thromboembolic events, infections, bleeding, readmissions, and surgical reinterventions. The safety end point was any bleeding using the International Society on Thrombosis and Haemostasis score. Follow-up period was 30 days after hospital discharge. Results: We analyzed 324 patients and 53 patients were randomized. The median cost-effectiveness was $1423.20 in the warfarin group versus $586.80 in the rivaroxaban group (P = .002). The median cost was lower in the rivaroxaban group, $450.20 versus $947.30 (P < .001). The secondary outcome was similar in both groups, 44.4% in warfarin group versus 38.5% in the rivaroxaban group (P = .65). Bleeding occured in 25.9% in the warfarin group versus 11.5% in the rivaroxaban group (P = .18). Conclusions: Rivaroxaban was more cost-effective when compared with warfarin associated with enoxaparin bridging in postoperative atrial fibrillation after isolated coronary artery bypass grafting.
Paradoxical Findings in Homozygous Familial Hypercholesterolemia in Japan: Longer Life But Still Not Totally Better!
(2023) SANTOS, R. D.; MIZUTA, M. H.
Update on Sitosterolemia and Atherosclerosis
(2023) ROCHA, Viviane Zorzanelli; TADA, Mauricio Teruo; CHACRA, Ana Paula Marte; MINAME, Marcio Hiroshi; MIZUTA, Marjorie H. H.
Purpose of ReviewThe purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease.Recent FindingsSince hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia.Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.
Effect of Low-Dose Progesterone on Glycemic Metabolism, Morphology and Function of Adipose Tissue and Pancreatic Islets in Diet-Induced Obese Female Mice
(2023) SANTOS, Matheus P.; CAUDURO, Leonardo F. R.; FERREIRA, Marilia Marcondes; MARTUCCI, Luiz Felipe; VECCHIATTO, Bruno; VILAS-BOAS, Eloisa Aparecida; AMERICO, Anna Laura V.; PEREIRA, Renata O.; ROGERO, Marcelo Macedo; FIORINO, Patricia; EVANGELISTA, Fabiana S.; AZEVEDO-MARTINS, Anna Karenina
Background: Obesity is a worldwide concern due to its global rapid expansion and remarkable impact on individual's health by predisposing to several other diseases. About twice as many women as men suffer from severe obesity and, in fact, there are stages in a woman's life when weight gain and adiposity can result in greater damage to health. For example, obesity triples the chance of a woman developing gestational diabetes. Many hormones promote the metabolic adaptations of pregnancy, including progesterone, whose role in female obesity is still not well known despite being involved in many physiological and pathological processes. Methods: Here we investigated whether progesterone treatment at low dose can worsen the glucose metabolism and the morpho functional aspects of adipose tissue and pancreas in obese females. Mice were assigned into four groups: normocaloric diet control (NO-CO), high-fat and -fructose diet control (HFF-CO), normocaloric diet plus progesterone (NO-PG) and high-fat and -fructose diet plus progesterone (HFF-PG) for 10 weeks. Infusion of progesterone (0.25 mg/kg/day) was done by osmotic minipump in the last 21 days of protocol. Results: Animals fed a hypercaloric diet exhibited obesity with increased body weight (p < 0.0001), adipocyte hypertrophy (p < 0.0001), hyperglycemia (p = 0.03), and glucose intolerance (p = 0.001). HFF-CO and HFF-PG groups showed lower adiponectin concentration (p < 0.0001) and glucose-stimulated insulin secretion (p = 0.03), without differences in islet size. Progesterone attenuated glucose intolerance in the HFFPG group (p = 0.03), however, did not change morphology or endocrine function of adipose tissue and pancreatic islets. Conclusions: Taken together, our results showed that low dose of progesterone does not worsen the effects of hypercaloric diet in glycemic metabolism, morphology and function of adipose tissue and pancreatic islets in female animals. These results may improve the understanding of the mechanisms underlying the pathogenesis of obesity in women and eventually open new avenues for therapeutic strategies and better comprehension of the interactions between progesterone effects and obesity.
Integrated systems biology approach identifies gene targets for endothelial dysfunction
(2023) PINHEIRO-DE-SOUSA, Iguaracy; FONSECA-ALANIZ, Miriam Helena; GIUDICE, Girolamo; VALADAO, Iuri Cordeiro; MODESTIA, Silvestre Massimo; MATTIOLI, Sarah Viana; ROSA JUNIOR, Ricardo; ZALMAS, Lykourgos-Panagiotis; FANG, Yun; PETSALAKI, Evangelia; KRIEGER, Jose Eduardo
Endothelial dysfunction (ED) is critical in the development and progression of cardiovascular (CV) disorders, yet effective therapeutic targets for ED remain elusive due to limited understanding of its underlying molecular mechanisms. To address this gap, we employed a systems biology approach to identify potential targets for ED. Our study combined multi omics data integration, with siRNA screening, high content imaging and network analysis to prioritise key ED genes and identify a pro- and anti-ED network. We found 26 genes that, upon silencing, exacerbated the ED phenotypes tested, and network propagation identified a pro-ED network enriched in functions associated with inflammatory responses. Conversely, 31 genes ameliorated ED phenotypes, pointing to potential ED targets, and the respective anti-ED network was enriched in hypoxia, angiogenesis and cancer-related processes. An independent screen with 17 drugs found general agreement with the trends from our siRNA screen and further highlighted DUSP1, IL6 and CCL2 as potential candidates for targeting ED. Overall, our results demonstrate the potential of integrated system biology approaches in discovering disease-specific candidate drug targets for endothelial dysfunction. imageMulti-omics data integration, genetic and pharmacological perturbations, and network analysis on endothelial cells are combined to identify endothelial dysfunction network signatures and prioritise candidate therapeutic targets.Multi-omics data integration of endothelial cells treated with mimics of major cardiovascular disease factors identified 81 putative endothelial dysfunction (ED) genes.Upon siRNA-mediated gene knockdown, 83% of ED gene candidates affected at least one ED phenotype (26 exacerbating and 31 ameliorating the ED phenotypes).The analyses reveal emergent properties of disease networks, distinguishing between adaptation and rewiring for survival and those associated with deregulation that can be targeted for ED treatment.An orthogonal drug screen on treated endothelial cells provided additional support for DUSP1, IL6 and CCL2 as putative targets for ED. Multi-omics data integration, genetic and pharmacological perturbations, and network analysis on endothelial cells are combined to identify endothelial dysfunction network signatures and prioritise candidate therapeutic targets.image
Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci
(2023) FUENTES, Lisa de las; SCHWANDER, Karen L. M.; BROWN, Michael R.; BENTLEY, Amy R.; WINKLER, Thomas W.; SUNG, Yun Ju; MUNROE, Patricia B.; MILLER, Clint L.; ASCHARD, Hugo; ASLIBEKYAN, Stella; BARTZ, Traci M.; BIELAK, Lawrence F.; CHAI, Jin Fang; CHENG, Ching-Yu; DORAJOO, Rajkumar; FEITOSA, Mary F.; GUO, Xiuqing; HARTWIG, Fernando P.; HORIMOTO, Andrea; KOLCIC, Ivana; LIM, Elise; LIU, Yongmei; MANNING, Alisa K.; MARTEN, Jonathan; MUSANI, Solomon K.; NOORDAM, Raymond; PADMANABHAN, Sandosh; RANKINEN, Tuomo; RICHARD, Melissa A.; RIDKER, Paul M.; SMITH, Albert V.; VOJINOVIC, Dina; ZONDERMAN, Alan B.; ALVER, Maris; BOISSEL, Mathilde; CHRISTENSEN, Kaare; FREEDMAN, Barry I.; GAO, Chuan; GIULIANINI, Franco; HARRIS, Sarah E.; HE, Meian; HSU, Fang-Chi; KUEHNEL, Brigitte; LAGUZZI, Federica; LI, Xiaoyin; LYYTIKAINEN, Leo-Pekka; NOLTE, Ilja M.; POVEDA, Alaitz; RAURAMAA, Rainer; RIAZ, Muhammad; ROBINO, Antonietta; SOFER, Tamar; TAKEUCHI, Fumihiko; TAYO, Bamidele O.; MOST, Peter J. van der; VERWEIJ, Niek; WARE, Erin B.; WEISS, Stefan; WEN, Wanqing; YANEK, Lisa R.; ZHAN, Yiqiang; AMIN, Najaf; ARKING, Dan E.; BALLANTYNE, Christie; BOERWINKLE, Eric; BRODY, Jennifer A.; BROECKEL, Ulrich; CAMPBELL, Archie; CANOUIL, Mickael; CHAI, Xiaoran; CHEN, Yii-Der Ida; CHEN, Xu; CHITRALA, Kumaraswamy Naidu; CONCAS, Maria Pina; FAIRE, Ulf de; MUTSERT, Renee de; SILVA, H. Janaka de; VRIES, Paul S. de; DO, Ahn; FAUL, Jessica D.; FISHER, Virginia; FLOYD, James S.; FORRESTER, Terrence; FRIEDLANDER, Yechiel; GIROTTO, Giorgia; GU, C. Charles; HALLMANS, Goeran; HEIKKINEN, Sami; HENG, Chew-Kiat; HOMUTH, Georg; HUNT, Steven; IKRAM, M. Arfan; JACOBS JR., David R.; KAVOUSI, Maryam; KHOR, Chiea Chuen; KILPELAINEN, Tuomas O.; KOH, Woon-Puay; KOMULAINEN, Pirjo; LANGEFELD, Carl D.; LIANG, Jingjing; LIU, Kiang; LIU, Jianjun; LOHMAN, Kurt; MAGI, Reedik; MANICHAIKUL, Ani W.; MCKENZIE, Colin A.; MEITINGER, Thomas; MILANESCHI, Yuri; NAUCK, Matthias; NELSON, Christopher P.; O'CONNELL, Jeffrey R.; PALMER, Nicholette D.; PEREIRA, Alexandre C.; PERLS, Thomas; PETERS, Annette; POLASEK, Ozren; RAITAKARI, Olli T.; RICE, Kenneth; RICE, Treva K.; RICH, Stephen S.; SABANAYAGAM, Charumathi; SCHREINER, Pamela J.; SHU, Xiao-Ou; SIDNEY, Stephen; SIMS, Mario; SMITH, Jennifer A.; STARR, John M.; STRAUCH, Konstantin; TAI, E. Shyong; TAYLOR, Kent D.; TSAI, Michael Y.; UITTERLINDEN, Andre G.; HEEMST, Diana van; WALDENBERGER, Melanie; WANG, Ya-Xing; WEI, Wen-Bin; WILSON, Gregory; XUAN, Deng; YAO, Jie; YU, Caizheng; YUAN, Jian-Min; ZHAO, Wei; BECKER, Diane M.; BONNEFOND, Amelie; BOWDEN, Donald W.; COOPER, Richard S.; DEARY, Ian J.; DIVERS, Jasmin; ESKO, Tonu; FRANKS, Paul W.; FROGUEL, Philippe; GIEGER, Christian; JONAS, Jost B.; KATO, Norihiro; LAKKA, Timo A.; LEANDER, Karin; LEHTIMAKI, Terho; MAGNUSSON, Patrik K. E.; NORTH, Kari E.; NTALLA, Ioanna; PENNINX, Brenda; SAMANI, Nilesh J.; SNIEDER, Harold; SPEDICATI, Beatrice; HARST, Pim van der; VOELZKE, Henry; WAGENKNECHT, Lynne E.; WEIR, David R.; WOJCZYNSKI, Mary K.; WU, Tangchun; ZHENG, Wei; ZHU, Xiaofeng; BOUCHARD, Claude; CHASMAN, Daniel; EVANS, Michele; FOX, Ervin R.; GUDNASON, Vilmundur; HAYWARD, Caroline; HORTA, Bernardo L.; KARDIA, Sharon L. R.; KRIEGER, Jose Eduardo; MOOK-KANAMORI, Dennis O.; PEYSER, Patricia A.; PROVINCE, Michael M.; PSATY, Bruce M.; RUDAN, Igor; SIM, Xueling; SMITH, Blair H.; DAM, Rob M. van; DUIJN, Cornelia M. van; WONG, Tien Yin; ARNETT, Donna K.; RAO, Dabeeru C.; GAUDERMAN, James; LIU, Ching-Ti; MORRISON, Alanna C.; ROTTER, Jerome I.; FORNAGE, Myriam
Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: ""Some College"" (yes/no, for any education beyond high school) and ""Graduated College"" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 x 10(-8)) and suggestive (p < 1 x 10(-6)) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.
Challenges and Applications of Genetic Testing in Dilated Cardiomyopathy: Genotype, Phenotype and Clinical Implications
(2023) FURQUIM, Silas Ramos; LINNENKAMP, Bianca; SANGIORGI, Natalia Quintella; GIUGNI, Fernando Rabioglio; LIPARI, Layara Fernanda Vicente Pereira; ANDRADE, Fernanda Almeida; KRIEGER, Jose Eduardo
Genetic tests for dilated cardiomyopathy (DCM) have a diagnostic yield of up to 40%, but there is significant genetic heterogeneity and other challenges, such as variable expressivity and incomplete penetrance. Pedigree analysis is essential for distinguishing between sporadic and familial DCM cases by assessing family history. Familial DCM yields higher results in genetic testing, but sporadic DCM does not rule out the possibility of a genetic cause. Some genes have specific phenotypes, with the Lamin gene (LMNA) being associated with a phenotype of malignant arrhythmias and advanced heart failure (HF). The presence of a causal genetic variant can also aid in prognostic evaluation, identifying more severe cases with lower rates of reverse remodeling (RR) compared to individuals with a negative genotype. Current guidelines recommend genetic evaluation and counseling for individuals with DCM, along with cascade screening in first-degree relatives in cases where one or more variants are identified, offering an opportunity for early diagnosis and treatment. Relatives with a positive genotype and negative phenotype are candidates for serial evaluation, with frequency varying by age. Genotype also assists in individualized recommendations for implantable cardioverter-defibrillator (ICD) placement and advice regarding physical activity and family planning. Ongoing studies are progressively elucidating the details of genotype/ phenotype relationships for a large number of variants, making molecular genetics increasingly integrated into clinical practice.
Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification
(2023) VRIES, Paul S. de; CONOMOS, Matthew P.; SINGH, Kuldeep; NICHOLSON, Christopher J.; JAIN, Deepti; HASBANI, Natalie R.; JIANG, Wanlin; LEE, Sujin; CARDENAS, Christian L. Lino; LUTZ, Sharon M.; WONG, Doris; GUO, Xiuqing; YAO, Jie; YOUNG, Erica P.; TCHEANDJIEU, Catherine; HILLIARD, Austin T.; BIS, Joshua C.; BIELAK, Lawrence F.; BROWN, Michael R.; MUSHAROFF, Shaila; CLARKE, Shoa L.; TERRY, James G.; PALMER, Nicholette D.; YANEK, Lisa R.; XU, Huichun; HEARD-COSTA, Nancy; WESSEL, Jennifer; SELVARAJ, Margaret Sunitha; LI, Rebecca H.; SUN, Xiao; TURNER, Adam W.; STILP, Adrienne M.; KHAN, Alyna; NEWMAN, Anne B.; RASHEED, Asif; FREEDMAN, Barry I.; KRAL, Brian G.; MCHUGH, Caitlin P.; HODONSKY, Chani; SALEHEEN, Danish; HERRINGTON, David M.; JACOBS JR., David R.; NICKERSON, Deborah A.; BOERWINKLE, Eric; WANG, Fei Fei; HEISS, Gerardo; JUN, Goo; KINNEY, Greg L.; SIGURSLID, Haakon H.; DODDAPANENI, Harshavardhan; HALL, Ira M.; BENSENOR, Isabela M.; BROOME, Jai; CRAPO, James D.; WILSON, James G.; SMITH, Jennifer A.; BLANGERO, John; VARGAS, Jose D.; MOSQUERA, Jose Verdezoto; SMITH, Joshua D.; VIAUD-MARTINEZ, Karine A.; RYAN, Kathleen A.; YOUNG, Kendra A.; TAYLOR, Kent D.; LANGE, Leslie A.; EMERY, Leslie S.; BITTENCOURT, Marcio S.; BUDOFF, Matthew J.; MONTASSER, May E.; YU, Miao; MAHANEY, Michael C.; MAHAMDEH, Mohammed S.; FORNAGE, Myriam; FRANCESCHINI, Nora; LOTUFO, Paulo A.; NATARAJAN, Pradeep; WONG, Quenna; MATHIAS, Rasika A.; GIBBS, Richard A.; DO, Ron; MEHRAN, Roxana; TRACY, Russell P.; KIM, Ryan W.; NELSON, Sarah C.; DAMRAUER, Scott M.; KARDIA, Sharon L. R.; RICH, Stephen S.; FUSTER, Valentin; NAPOLIONI, Valerio; ZHAO, Wei; TIAN, Wenjie; YIN, Xianyong; I, Yuan- Min; MANNING, Alisa K.; PELOSO, Gina; KELLY, Tanika N.; O'DONNELL, Christopher J.; MORRISON, Alanna C.; CURRAN, Joanne E.; ZAPOL, Warren M.; BOWDEN, Donald W.; BECKER, Lewis C.; CORREA, Adolfo; MITCHELL, Braxton D.; PSATY, Bruce M.; CARR, John Jeffrey; PEREIRA, Alexandre C.; ASSIMES, Themistocles L.; STITZIEL, Nathan O.; HOKANSON, John E.; LAURIE, Cecelia A.; ROTTER, Jerome I.; VASAN, Ramachandran S.; POST, Wendy S.; PEYSER, Patricia A.; MILLER, Clint L.; MALHOTRA, Rajeev
Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification and a potential drug target for vascular calcific disease. de Vries, Conomos, Singh and Nicholson et al. identify two additional loci associated with coronary artery calcification (ARSE and MMP16) via a genome-wide association study in 22,400 participants from multiple ancestral groups and prove that ARSE is a mediator of vascular smooth muscle cell calcification and phenotype switching.
Percentiles of predicted 10-year cardiovascular disease risk by sex and age in Brazil and their association with estimated risk of long-term atherosclerotic events
(2023) CESENA, Fernando Yue; GENEROSO, Giuliano; SANTOS, Itamar de S.; DUNCAN, Bruce B.; RIBEIRO, Antonio Luiz P.; BRANT, Luisa Caldeira; MILL, Jose Geraldo; PEREIRA, Alexandre C.; BITTENCOURT, Marcio Sommer; SANTOS, Raul D.; LOTUFO, Paulo A.; BENSENOR, Isabela M.
Objective: Expressing the cardiovascular disease (CVD) risk in relation to peers may complement the estimation of absolute CVD risk. We aimed to determine 10-year CVD risk percentiles by sex and age in the Brazilian population and evaluate their association with estimated long-term atherosclerotic CVD (ASCVD) risk.Methods: A cross-sectional analysis of baseline data from the ELSA-Brasil study was conducted in individuals aged 40-74 years without prior ASCVD. Ten-year CVD risk and long-term ASCVD risk were estimated by the WHO risk score and the Multinational Cardiovascular Risk Consortium tool, respectively. Ten-year risk percentiles were determined by ranking the calculated risks within each sex and age group.Results: Ten-year CVD risk versus percentile plots were constructed for each sex and age group using data from 13,364 participants (55% females; median age, 52 [IQR, 46-59] years). Long-term ASCVD risk was calculated in 12,973 (97.1%) participants. Compared to individuals at the <25th risk percentile, those at the >= 75th percentile had a greater risk of being in the highest quartile of long-term risk (ORs [95% CIs] 6.57 [5.18-8.30] in females and 11.59 [8.42-15.96] in males) in regression models adjusted for age, race, education, and 10-year CVD risk. In both sexes, the association between risk percentile and long-term risk weakened after age 50. A tool for calculating 10-year CVD risk and the corresponding percentile is available at https://bit.ly/3CzPUi6.Conclusions: We established percentiles of predicted 10-year CVD risk by sex and age in the Brazilian population, which independently reflect the estimated long-term ASCVD risk in younger individuals.
Cysteine and glycine-rich protein 3 (Crp3) as a critical regulator of elastolysis, inflammation, and smooth muscle cell apoptosis in abdominal aortic aneurysm development
(2023) MATTOS, Ana Barbosa Marcondes de; RIBEIRO-SILVA, Joao Carlos; FONSECA-ALANIZ, Miriam Helena; VALADAO, Iuri Cordeiro; SILVA, Erasmo Simao da; KRIEGER, Jose Eduardo; MIYAKAWA, Ayumi Aurea
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease for which surgical or endovascular repair are the only currently available therapeutic strategies. The development of AAA involves the breakdown of elastic fibers (elastolysis), infiltration of inflammatory cells, and apoptosis of smooth muscle cells (SMCs). However, the specific regulators governing these responses remain unknown. We previously demonstrated that Cysteine and glycine-rich protein 3 (Crp3) sensitizes SMCs to apoptosis induced by stretching. Building upon this finding, we aimed to investigate the influence of Crp3 on elastolysis and apoptosis during AAA development. Using the elastase-CaCl2 rat model, we observed an increase in Crp3 expression, aortic diameter, and a reduction in wall thickness in wild type rats. In contrast, Crp3-/- rats exhibited a decreased incidence of AAA, with minimal or no changes in aortic diameter and thickness. Histopathological analysis revealed the absence of SMC apoptosis and degradation of elastic fibers in Crp3-/- rats, accompanied by reduced inflammation and diminished proteolytic capacity in Crp3-/- SMCs and bone marrow-derived macrophages. Collectively, our findings provide evidence that Crp3 plays a crucial role in AAA development by modulating elastolysis, inflammation, and SMC apoptosis. These results underscore the potential significance of Crp3 in the context of AAA progression and offer new insights into therapeutic targets for this disease.
Understanding yellow fever-associated myocardial injury: an autopsy study
(2023) GIUGNI, Fernando Rabioglio; DEMARCHIAIELLO, Vera; FARIA, Caroline Silverio; POUR, Shahab Zaki; CUNHA, Marielton dos Passos; GIUGNI, Melina Valdo; PINESI, Henrique Trombini; LEDESMA, Felipe Lourenco; MORAIS, Carolina Esteves; HO, Yeh-Li; SZTAJNBOK, Jaques; FERNEZLIAN, Sandra de Morais; SILVA, Luiz Fernando Ferraz da; MAUAD, Thais; ALVES, Venancio Avancini Ferreira; SALDIVA, Paulo Hilario do Nascimento; ANTONANGELO, Leila; DOLHNIKOFF, Marisa; DUARTE-NETO, Amaro Nunes
Background Yellow fever (YF) is a viral hemorrhagic fever, endemic in parts of South America and Africa. There is scarce evidence about the pathogenesis of the myocardial injury. The objective of this study is to evaluate the cardiac pathology in fatal cases of YF.Methods This retrospective autopsy study included cases from the Sao Paulo (Brazil) epidemic of 2017-2019. We reviewed medical records and performed cardiac tissue histopathological evaluation, electron microscopy, immunohistochemical assays, RT-qPCR for YF virus (YFV)-RNA, and proteomics analysis on inflammatory and endothelial biomarkers.Findings Seventy-three confirmed YF cases with a median age of 48 (34-60) years were included. We observed myocardial fibrosis in 68 (93.2%) patients; cardiomyocyte hypertrophy in 68 (93.2%); endothelial alterations in 67 (91.8%); fiber necrosis in 50 (68.5%); viral myocarditis in 9 (12.3%); and secondary myocarditis in 5 (6.8%). Four out of five patients with 17DD vaccine-associated viscerotropic disease presented with myocarditis. The cardiac conduction system showed edema, hemorrhages and endothelial fibrinoid necrosis. Immunohistochemistry detected CD68-positive inflammatory interstitial cells and YFV antigens in endothelial and inflammatory cells. YFV-RNA was detected positive in 95.7% of the cardiac samples. The proteomics analysis demonstrated that YF patients had higher levels of multiple inflammatory and endothelial biomarkers in comparison to cardiovascular controls, and higher levels of interferon gamma-induced protein 10 (IP-10) in comparison to sepsis (p = 0.01) and cardiovascular controls (p < 0.001) in Dunn test.Interpretation Myocardial injury is frequent in severe YF, due to multifactorial mechanisms, including direct YFV-mediated damage, endothelial cell injury, and inflammatory response, with a possible prominent role for IP-10.
Survival of Heart Transplant Patients with Chagas' Disease Under Different Antiproliferative Immunosuppressive Regimens
(2023) FURQUIM, Silas Ramos; GALBIATI, Luana Campoli; AVILA, Monica S.; MARCONDES-BRAGA, Fabiana G.; FUKUSHIMA, Julia; MANGINI, Sandrigo; SEGURO, Luis Fernando Bernal da Costa; CAMPOS, Iascara Wozniak de; STRABELLI, Tania Mara Varejao; BARONE, Fernanda; PAULO, Audrey Rose da Silveira Amancio de; OHE, Luciana Akutsu; GALANTE, Mariana Cappelletti; GAIOTTO, Fabio Antonio; BACAL, Fernando
Background: Chagas' disease (CD) is an important cause of heart transplantation (HT). The main obstacle is Chagas' disease reactivation (CDR), usually associated to high doses of immunosuppressants. Previous studies have suggested an association of mycophenolate mofetil with increased CDR. However, mortality predictors are unknown.Objectives: To identify mortality risk factors in heart transplant patients with CD and the impact of antiproliferative regimen on survival.Methods: Retrospective study with CD patients who underwent HT between January 2004 and September 2020, under immunosuppression protocol that prioritized azathioprine and change to mycophenolate mofetil in case of rejection. We performed univariate regression to identify mortality predictors; and compared survival, rejection and evidence of CDR between who received azathioprine, mycophenolate mofetil and those who changed from azathioprine to mycophenolate mofetil after discharge (""Change"" group). A p-value < 0.05 was considered statistically significant. Results: Eighty-five patients were included, 54.1% men, median age 49 (39-57) years, and 91.8% were given priority in waiting list. Nineteen (22.4%) used azathioprine, 37 (43.5%) mycophenolate mofetil and 29 (34.1%) switched therapy; survival was not different between groups, 2.9 (1.6-5.0) x 2.9 (1.8-4.8) x 4.2 (2.0-5.0) years, respectively; p=0.4. There was no difference in rejection (42%, 73% and 59% respectively; p=0.08) or in CDR (T. cruzi positive by endomyocardial biopsy 5% x 11% x 7%; p=0.7; benznidazole use 58% x 65% x 69%; p=0.8; positive PCR for T. cruzi 20% x 68% x 42% respectively; p=0.1) rates.Conclusions: This retrospective study did not show difference in survival in heart transplant patients with CD receiving different antiproliferative regimens. Mycophenolate mofetil was not associated with statistically higher rates of CDR or graft rejection in this cohort. New randomized clinical trials are necessary to address this issue.
Peripheral Artery Disease Diagnosed by Pulse Palpation as a Predictor of Coronary Artery Disease in Patients with Chronic Kidney Disease
(2023) SANTOS, Daniel B. C. Dos; GOWDAK, Luis Henrique W.; DAVID-NETO, Elias; NATANIEL, Felizardo A.; LIMA, Jose J. G. De; BORTOLOTTO, Luiz A.
There is a need of simple, inexpensive, and reliable noninvasive testing to predict coronary artery disease (CAD) in patients with chronic kidney disease (CKD), where the prevalence of cardiovascular (CV) events and death is elevated. We analyzed the association between peripheral artery disease (PAD) and CAD in 201 patients with stage 5 CKD on dialysis using a prospective observational cohort. Diagnosis of PAD by both palpation and USD were significantly correlated. In patients with PAD diagnosed by palpation, CAD was observed in 80%, while in those diagnosed by USD, CAD was present in 79.1%. The absence of a pulse by palpation predicted CAD with a sensitivity of 55% and a specificity of 76%; USD showed a sensitivity of 62% and specificity of 60% to predict CAD. The risk of combined serious CV events and death was significantly higher in subjects with PAD diagnosed by palpation, but not by USD. PAD assessed by palpation also correlated with the occurrence of multivessel CAD and with the probability of coronary intervention. Both methods are moderately useful for predicting CAD, but PAD diagnosis by palpation was a better predictor of combined CV events and death and was also associated with CAD severity and likelihood of intervention.
Before and after AlphaFold2: An overview of protein structure prediction
(2023) BERTOLINE, Leticia M. F.; LIMA, Angelica N.; KRIEGER, Jose E.; TEIXEIRA, Samantha K.
Three-dimensional protein structure is directly correlated with its function and its determination is critical to understanding biological processes and addressing human health and life science problems in general. Although new protein structures are experimentally obtained over time, there is still a large difference between the number of protein sequences placed in Uniprot and those with resolved tertiary structure. In this context, studies have emerged to predict protein structures by methods based on a template or free modeling. In the last years, different methods have been combined to overcome their individual limitations, until the emergence of AlphaFold2, which demonstrated that predicting protein structure with high accuracy at unprecedented scale is possible. Despite its current impact in the field, AlphaFold2 has limitations. Recently, new methods based on protein language models have promised to revolutionize the protein structural biology allowing the discovery of protein structure and function only from evolutionary patterns present on protein sequence. Even though these methods do not reach AlphaFold2 accuracy, they already covered some of its limitations, being able to predict with high accuracy more than 200 million proteins from metagenomic databases. In this mini-review, we provide an overview of the breakthroughs in protein structure prediction before and after AlphaFold2 emergence.
Artificial Intelligence-Driven Screening System for Rapid Image-Based Classification of 12-Lead ECG Exams: A Promising Solution for Emergency Room Prioritization
(2023) DIAS, Felipe Meneguitti; RIBEIRO, Estela; MORENO, Ramon Alfredo; RIBEIRO, Adele Helena; SAMESIMA, Nelson; PASTORE, Carlos Alberto; KRIEGER, Jose Eduardo; GUTIERREZ, Marco Antonio
The electrocardiogram (ECG) serves as a valuable diagnostic tool, providing crucial information about life-threatening cardiac conditions such as atrial fibrillation and myocardial infarction. A prompt and efficient assessment of ECG exams in environments such as Emergency Rooms (ERs) can significantly enhance the chances of survival for high-risk patients. Despite the presence of numerous works on ECG classification, most of these studies have concentrated on one-dimensional ECG signals, which are commonly found in publicly available ECG datasets. Nevertheless, the practical relevance of such methods is limited in hospital settings, where ECG exams are usually stored as images. In this study, we have developed an artificial intelligence-driven screening system specifically designed to analyze 12-lead ECG images. Our proposed method has been trained on an extensive dataset comprising 99,746 12-lead ECG exams collected from the ambulatory section of a tertiary hospital. The primary goal was to precisely classify the exams into three classes: Normal (N), Atrial Fibrillation (AFib), and Other (O). The evaluation of our approach yielded AUROC scores of 93.2%, 99.2%, and 93.1% for N, AFib, and O, respectively. To further validate our approach, we conducted evaluations using the 2018 China Physiological Signal Challenge (CPSC) database. In this evaluation, we achieved AUROC scores of 91.8%, 97.5%, and 70.4% for the classes N, AFib, and O, respectively. Additionally, we assessed our method using 1,074 exams acquired in the ER and obtained AUROC values of 98.3%, 98.0%, and 97.7% for the classes N, AFib, and O, respectively. Furthermore, we developed and deployed a system with a trained model within the ER of a tertiary hospital for research purposes. This system automatically retrieves newly captured ECG chart images from the Picture Archiving and Communication System (PACS) within the ER. These images undergo necessary preprocessing steps and serve as input for our proposed classification method. This comprehensive approach established an efficient and versatile end-to-end framework for ECG classification. The results of our study highlight the potential of leveraging artificial intelligence in the screening of ECG exams, offering a promising solution for the rapid assessment and prioritization of patients in the ER.
Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults
(2023) ALBUQUERQUE, Joao; MEDEIROS, Ana Margarida; ALVES, Ana Catarina; JANNES, Cinthia Elim; MANCINA, Rosellina M.; PAVANELLO, Chiara; CHORA, Joana Rita; MOMBELLI, Giuliana; CALABRESI, Laura; PEREIRA, Alexandre da Costa; KRIEGER, Jose Eduardo; ROMEO, Stefano; BOURBON, Mafalda; ANTUNES, Marilia
Background and aims: The early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy.Methods: The area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics.Results: AUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p < 0.01), Swedish (p < 0.01), and Italian testing sets (p < 0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets.Conclusions: Compared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.
Association between carotid intima-media thickness and cognitive decline differs by race
(2023) FERREIRA, Naomi Vidal; BERTOLA, Laiss; SANTOS, Itamar S.; GOULART, Alessandra C.; BITTENCOURT, Marcio S.; BARRETO, Sandhi Maria; GIATTI, Luana; CARAMELLI, Paulo; PEREIRA, Alexandre; LOTUFO, Paulo Andrade; BENSENOR, Isabela M.; SUEMOTO, Claudia Kimie
IntroductionCommon carotid intima-media thickness (cIMT) is a marker of subclinical atherosclerosis and is associated with cognitive decline. Although carotid atherosclerosis is more frequent in White than in Black participants, little is known whether race modifies the association between cIMT and cognitive decline. MethodsIn this longitudinal analysis of the ELSA-Brasil, we assessed cIMT using ultrasound and cognitive performance using different domain tests. We used linear mixed models, interaction analysis, and race stratified analyses. ResultsBaseline high IMT values were associated with memory (p < 0.001), verbal fluency (p < 0.001), TMT-B (p < 0.001)), and global cognitive decline (p < 0.001). Race was an effect modifier in the association between IMT and global cognitive decline (0.043), with stronger association in White (p < 0.001) than in Black (p = 0.009) participants. DiscussionBaseline IMT was associated with global and domain-specific cognitive decline and race modified this relationship, with stronger associations in White participants. HighlightsCarotid intima-media thickness (cIMT) was associated with cognitive decline.cIMT and cognitive decline association was stronger in White than in Black participants.We used inverse probability weighting to address attrition bias.
The Effect of Gene Editing by CRISPR-Cas9 of miR-21 and the Indirect Target MMP9 in Metastatic Prostate Cancer
(2023) CAMARGO, Juliana A.; VIANA, Nayara I.; PIMENTA, Ruan; GUIMARAES, Vanessa R.; SANTOS, Gabriel A. dos; CANDIDO, Patricia; GHAZARIAN, Vitoria; ROMAO, Poliana; SILVA, Iran A.; BIRBRAIR, Alexander; SROUGI, Miguel; NAHAS, William C.; LEITE, Katia R.; TRARBACH, Ericka B.; REIS, Sabrina T.
Prostate cancer (PCa) has a high prevalence and represents an important health problem, with an increased risk of metastasis. With the advance of CRISPR-Cas9 genome editing, new possibilities have been created for investigating PCa. The technique is effective in knockout oncogenes, reducing tumor resistance. MMP9 and miR-21 target genes are associated with PCa progression; therefore, we evaluated the MMP-9 and miR-21 targets in PCa using the CRISPR-Cas9 system. Single guide RNAs (sgRNAs) of MMP9 and miR-21 sequences were inserted into a PX-330 plasmid, and transfected in DU145 and PC-3 PCa cell lines. MMP9 and RECK expression was assessed by qPCR, WB, and IF. The miR-21 targets, integrins, BAX and mTOR, were evaluated by qPCR. Flow cytometry was performed with Annexin5, 7-AAD and Ki67 markers. Invasion assays were performed with Matrigel. The miR-21 CRISPR-Cas9-edited cells upregulated RECK, MARCKS, BTG2, and PDCD4. CDH1, ITGB3 and ITGB1 were increased in MMP9 and miR-21 CRISPR-Cas9-edited cells. Increased BAX and decreased mTOR were observed in MMP9 and miR-21 CRISPR-Cas9-edited cells. Reduced cell proliferation, increased apoptosis and low invasion in MMP9 and miR-21 edited cells was observed, compared to Scramble. CRISPR-Cas9-edited cells of miR-21 and MMP9 attenuate cell proliferation, invasion and stimulate apoptosis, impeding PCa evolution.
Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
(2023) RASOOLY, Danielle; PELOSO, Gina M.; PEREIRA, Alexandre C.; DASHTI, Hesam; GIAMBARTOLOMEI, Claudia; WHEELER, Eleanor; AUNG, Nay; FEROLITO, Brian R.; PIETZNER, Maik; FARBER-EGER, Eric H.; WELLS, Quinn Stanton; KOSIK, Nicole M.; GAZIANO, Liam; POSNER, Daniel C.; BENTO, A. Patricia; HUI, Qin; LIU, Chang; ARAGAM, Krishna; WANG, Zeyuan; CHAREST, Brian; HUFFMAN, Jennifer E.; WILSON, Peter W. F.; PHILLIPS, Lawrence S.; WHITTAKER, John; MUNROE, Patricia B.; PETERSEN, Steffen E.; CHO, Kelly; LEACH, Andrew R.; MAGARINOS, Maria Paula; GAZIANO, John Michael; LANGENBERG, Claudia; SUN, Yan V.; JOSEPH, Jacob; CASAS, Juan P.
We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure. Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.
Coronavirus disease-2019 and heart: assessment of troponin and cardiovascular comorbidities as prognostic markers in patients hospitalized with coronavirus disease-2019 in a tertiary center in Brazil
(2023) PINESI, Henrique Trombini; GIUGNI, Fernando Rabioglio; MATUCK, Bruna Romanelli Scarpa; PITTA, Fabio Grusnpun; GARZILLO, Cibele Larrosa; LIMA, Eduardo Gomes; KALIL FILHO, Roberto; SERRANO JUNIOR, Carlos Vicente
OBJECTIVE: Our study aimed to evaluate the correlation of cardiac troponin T levels with comorbidities and in-hospital outcomes in patients with coronavirus disease-2019 in Brazil.METHODS: Data from a cohort of 3,596 patients who were admitted with suspected coronavirus disease-2019 in a Brazilian tertiary center, between March and August 2020, were reviewed. A total of 2,441 (68%) patients had cardiac troponin T determined in the first 72 h of admission and were stratified into two groups: elevated cardiac troponin T (cardiac troponin T >0.014 ng/mL) and normal cardiac troponin T. Associations between troponin, comorbidities, biomarkers, and outcomes were assessed. Regression models were built to assess the association of several variables with in-hospital mortality.RESULTS: A total of 2,441 patients were embraced, of which 924 (38%) had normal cardiac troponin T and 1,517 (62%) had elevated cardiac troponin T. Patients with elevated cardiac troponin T were older and had more comorbidities, such as cardiovascular disease, hypertension, diabetes, arrhythmia, renal dysfunction, liver disease, stroke, cancer, and dementia. Patients with abnormal cardiac troponin T also had more altered laboratory parameters on admission (i.e., leukocytes, C-reactive protein, D-dimer, and B-type natriuretic peptide), as well as more need for intensive care unit, vasoactive drugs, mechanical ventilation, dialysis, and blood transfusion. All-cause mortality was markedly higher among patients with increased cardiac troponin T (42 vs. 16%, P<0.001). Multiple regression analysis demonstrated that in-hospital mortality was not independently associated with troponin elevation.CONCLUSION: This study showed that cardiac troponin T elevation at admission was common and associated with several comorbidities, biomarkers, and clinical outcomes in patients hospitalized with coronavirus disease-2019, but it was not an independent marker of in-hospital mortality.

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