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1.
Eur Heart J ; 43(19): 1829-1831, 2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35567561
2.
Immunity ; 55(5): 862-878.e8, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35508166

RESUMO

Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1op/op) causes severe musculoskeletal defects that may indirectly affect hematopoiesis. Indeed, we show here that osteolineage-derived Csf1 prevented developmental abnormalities but had no effect on monopoiesis in adulthood. However, ubiquitous deletion of Csf1 conditionally in adulthood decreased monocyte survival, differentiation, and migration, independent of its effects on bone development. Bone histology revealed that monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular mesenchymal stromal cells (MSCs). Targeted deletion of Csf1 from sinusoidal ECs selectively reduced Ly6C- monocytes, whereas combined depletion of Csf1 from ECs and MSCs further decreased Ly6Chi cells. Moreover, EC-derived CSF-1 facilitated recovery of Ly6C- monocytes and protected mice from weight loss following induction of polymicrobial sepsis. Thus, monocytes are supported by distinct cellular sources of CSF-1 within a perivascular BM niche.

3.
Curr Atheroscler Rep ; 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35524914

RESUMO

PURPOSE OF REVIEW: The elevated adverse cardiovascular event rate among patients with low high-density lipoprotein cholesterol (HDL-C) formed the basis for the hypothesis that elevating HDL-C would reduce those events. Attempts to raise endogenous HDL-C levels, however, have consistently failed to show improvements in cardiovascular outcomes. However, steady-state HDL-C concentration does not reflect the function of this complex family of particles. Indeed, HDL functions correlate only weakly with serum HDL-C concentration. Thus, the field has pivoted from simply raising the quantity of HDL-C to a focus on improving the putative anti-atherosclerotic functions of HDL particles. Such functions include the ability of HDL to promote the efflux of cholesterol from cholesterol-laden macrophages. Apolipoprotein A-I (apoA-I), the signature apoprotein of HDL, may facilitate the removal of cholesterol from atherosclerotic plaque, reduce the lesional lipid content and might thus stabilize vulnerable plaques, thereby reducing the risk of cardiac events. Infusion of preparations of apoA-I may improve cholesterol efflux capacity (CEC). This review summarizes the development of apoA-I therapies, compares their structural and functional properties and discusses the findings of previous studies including their limitations, and how CSL112, currently being tested in a phase III trial, may overcome these challenges. RECENT FINDINGS: Three major ApoA-I-based approaches (MDCO-216, CER-001, and CSL111/CSL112) have aimed to enhance reverse cholesterol transport. These three therapies differ considerably in both lipid and protein composition. MDCO-216 contains recombinant ApoA-I Milano, CER-001 contains recombinant wild-type human ApoA-I, and CSL111/CSL112 contains native ApoA-I isolated from human plasma. Two of the three agents studied to date (apoA-1 Milano and CER-001) have undergone evaluation by intravascular ultrasound imaging, a technique that gauges lesion volume well but does not assess other important variables that may relate to clinical outcomes. ApoA-1 Milano and CER-001 reduce lecithin-cholesterol acyltransferase (LCAT) activity, potentially impairing the function of HDL in reverse cholesterol transport. Furthermore, apoA-I Milano can compete with and alter the function of the recipient's endogenous apoA-I. In contrast to these agents, CSL112, a particle formulated using human plasma apoA-I and phosphatidylcholine, increases LCAT activity and does not lead to the malfunction of endogenous apoA-I. CSL112 robustly increases cholesterol efflux, promotes reverse cholesterol transport, and now is being tested in a phase III clinical trial. Phase II-b studies of MDCO-216 and CER-001 failed to produce a significant reduction in coronary plaque volume as assessed by IVUS. However, the investigation to determine whether the direct infusion of a reconstituted apoA-I reduces post-myocardial infarction coronary events is being tested using CSL112, which is dosed at a higher level than MDCO-216 and CER-001 and has more favorable pharmacodynamics.

4.
Eur Heart J ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35512309

RESUMO

In September 2020, the new Editors of the European Heart Journal (EHJ) wrote the following in their inaugural editorial: "The fundamental mission of the Journal remains the reduction of the global burden of cardiovascular disease. We aspire to advance this aim by worldwide teamwork to communicate practice-changing research, inspire clinical cardiologists, and pursue rigour and transparency in the application of science at the service of human health. The Journal will strive to lead the field in its impact, influence, and reach". After more than one year of experience the Editors hope the cardiological community will agree that they are fulfilling this mission. As stewards of the EHJ, the Editor's primary goal is not solely to achieve a high Impact Factor (which attests to the scientific quality and influence of our publications) but also to elevate the practice of cardiovascular medicine worldwide. Accordingly, various initiatives of the EHJ strive to strengthen further links among Editors, Authors, Reviewers and Readers through a series of coordinated and diverse activities, including webinars, active social media presence, and active participation at congresses worldwide. The Editors are proud to serve one of the most important scientific journals in cardiovascular medicine.

5.
Cardiovasc Res ; 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35394031

RESUMO

AIMS: Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy. METHODS AND RESULTS: A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and ß-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient ΔdblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. ΔdblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In ΔdblGATA and wild-type mice, administration of EOS cationic protein mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-ß signaling and fibrotic protein synthesis. Use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-ß signaling. CONCLUSION: Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of EOS cationic proteins in this human CVD.

6.
Sci Adv ; 8(16): eabl4602, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35452290

RESUMO

Coronary artery disease (CAD) remains the leading cause of death despite scientific advances. Elucidating shared CAD/pneumonia pathways may reveal novel insights regarding CAD pathways. We performed genome-wide pleiotropy analyses of CAD and pneumonia, examined the causal effects of the expression of genes near independently replicated SNPs and interacting genes with CAD and pneumonia, and tested interactions between disruptive coding mutations of each pleiotropic gene and smoking status on CAD and pneumonia risks. Identified pleiotropic SNPs were annotated to ADAMTS7 and IL6R. Increased ADAMTS7 expression across tissues consistently showed decreased risk for CAD and increased risk for pneumonia; increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. We similarly observed opposing CAD/pneumonia effects for NLRP3. Reduced ADAMTS7 expression conferred a reduced CAD risk without increased pneumonia risk only among never-smokers. Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R, and related genes.


Assuntos
Doença da Artéria Coronariana , Pleiotropia Genética , Pneumonia , Proteína ADAMTS7/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pneumonia/genética , Pneumonia/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética
7.
JAMA Cardiol ; 7(5): 521-528, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35385050

RESUMO

Importance: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1ß signaling. Objective: To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1ß neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS). Design, Setting, and Participants: This randomized clinical trial took place from April 2011 to June 2017 at more than 1000 clinical sites in 39 countries. Targeted deep sequencing of genes previously associated with CHIP in a subset of trial participants using genomic DNA prepared from baseline peripheral blood samples were analyzed. All participants had prior myocardial infarction and elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis took place between June 2017 and December 2021. Interventions: Canakinumab, an anti-IL-1ß antibody, given at doses of 50, 150, and 300 mg once every 3 months. Main Outcomes and Measures: Major adverse cardiovascular events (MACE). Results: A total of 338 patients (8.6%) were identified in this subset with evidence for clonal hematopoiesis. As expected, the incidence of CHIP increased with age; the mean (SD) age of patients with CHIP was 66.3 (9.2) years and 61.5 (9.6) years in patients without CHIP. Unlike other populations that were not preselected for elevated C-reactive protein, in the CANTOS population variants in TET2 were more common than DNMT3A (119 variants in 103 patients vs 86 variants in 85 patients). Placebo-treated patients with CHIP showed a nonsignificant increase in the rate of MACE compared with patients without CHIP using a Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04]; P = .21). Exploratory analyses of placebo-treated patients with a somatic variant in either TET2 or DNMT3A (n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI, 0.97-2.80]; P = .06). Patients with CHIP due to somatic variants in TET2 also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (P for interaction = .14). Conclusions and Relevance: These results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those with TET2 variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis. Trial Registration: ClinicalTrials.gov Identifier: NCT01327846.

8.
Nat Rev Cardiol ; 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449407

RESUMO

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application.

10.
Artigo em Inglês | MEDLINE | ID: mdl-35234840

RESUMO

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs both prescribed and over the counter. The long-term cardiovascular safety of NSAIDs in patients with arthritis has engendered controversy. Concerns remain regarding the relative incidence and severity of adverse cardiorenal effects, particularly in arthritis patients with established CV disease, or risk factors for disease as illustrated by the PRECISION trial participants (NCT00346216). HYPOTHESIS: The selective COX-2 Inhibitor celecoxib has a superior cardiorenal safety profile when compared to ibuprofen or naproxen in the PRECISION population. METHODS: 24,081 patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and had increased CV risk randomly received celecoxib, ibuprofen or naproxen. The current prespecified secondary analysis assessed the incidence, severity and NSAID-related risk of the pre-specified composite cardiorenal outcome [adjudicated renal event, hospitalization for congestive heart failure (CHF), or hospitalization for hypertension (HTN)] in the intention-to-treat (ITT) population. An on-treatment analysis assessed safety in those taking the study medication. RESULTS: Following a mean treatment duration of 20.3±16.0 months and a mean follow-up of 34.1±13.4 months, the primary cardiorenal composite outcome occurred in 423 patients (1.76%) in the ITT population. Of these 423 patients, 118 (28%) were in the celecoxib, 166 (39%) in the ibuprofen and 139 (33%) in the naproxen group. In a multivariable Cox regression model adjusted for independent clinical variables, celecoxib showed a significantly lower risk compared with ibuprofen (hazard ratio [HR] 0.67, confidence interval [CI] 0.53 - 0.85, p = 0.001) and a trend to lower risk compared to naproxen (HR 0.79, CI 0.61 - 1.00, p = 0.058).In the intention-to-treat analysis, clinically significant renal events occurred in 220 patients with events rates of 0.71%, 1.14% and 0.89% for celecoxib, ibuprofen and naproxen respectively (p = 0.052), while in the on -treatment analysis the rates were 0.52%, 0.91% and 0.78% (p<0.001). CONCLUSION: In the current era, long-term NSAID use was associated with few cardiorenal events in arthritis patients. At the doses studied, celecoxib displayed fewer renal events and hence more favorable cardiovascular safety compared to ibuprofen or naproxen. These results have considerable clinical implications for practitioners managing individuals with chronic arthritis pain and high risk of impaired renal function and/or heart failure. (Funded by Pfizer) Clinical Trial Registration: NCT00346216.

12.
Nat Immunol ; 23(4): 605-618, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35352063

RESUMO

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.


Assuntos
Acetilcolina , Hematopoese , Animais , Linfócitos B , Colinérgicos , Hematopoese/genética , Camundongos , Nicho de Células-Tronco
13.
J Am Coll Cardiol ; 79(8): 837-847, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35210039

RESUMO

Aging and inflammation both contribute pivotally to cardiovascular (CV) and cerebrovascular disease, the leading causes of death and disability worldwide. The concept of inflamm-aging recognizes that low-grade inflammatory pathways observed in the elderly contribute to CV risk. Understanding the mechanisms that link inflammation and aging could reveal new therapeutic targets and offer options to cope with the growing aging population worldwide. This review reports recent scientific advances in the pathways through which inflamm-aging mediates age-dependent decline in CV function and disease onset and considers critically the translational potential of such concepts into everyday clinical practice.


Assuntos
Envelhecimento , Doenças Cardiovasculares/etiologia , Inflamação/complicações , Humanos
14.
Circulation ; 145(7): 531-548, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35157519

RESUMO

BACKGROUND: Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The underlying mechanisms of chronic valvular damage remain unexplored and regulators of sex predisposition are unknown. METHODS: Proteomics analysis of human heart valves (nondiseased aortic valves, nondiseased mitral valves [NDMVs], valves from patients with rheumatic aortic valve disease, and valves from patients with rheumatic mitral valve disease; n=30) followed by system biology analysis identified ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells were performed using multiparameter flow cytometry and quantitative polymerase chain reaction. In silico analysis of the RHVD and Streptococcus pyogenes proteomes were used to identify mimic epitopes. RESULTS: A comparison of NDMV and nondiseased aortic valve proteomes established the baseline differences between nondiseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMVs. Comparison of NDMVs versus valves from patients with rheumatic mitral valve disease and nondiseased aortic valves versus valves from patients with rheumatic aortic valve disease identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8+ T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8+ T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8+ T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8+ T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and S pyogenes proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8+ T-cell activation in vitro. CONCLUSIONS: ProTα-dependent CD8+ T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8+ T cells, suggesting mechanisms provoking autoimmunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Colágeno Tipo I/metabolismo , Receptor alfa de Estrogênio/metabolismo , Doenças das Valvas Cardíacas/etiologia , Doenças das Valvas Cardíacas/metabolismo , Precursores de Proteínas/metabolismo , Timosina/análogos & derivados , Sequência de Aminoácidos , Colágeno Tipo I/química , Biologia Computacional/métodos , Suscetibilidade a Doenças , Epitopos de Linfócito T/imunologia , Doenças das Valvas Cardíacas/diagnóstico , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Modelos Biológicos , Modelos Moleculares , Ligação Proteica , Precursores de Proteínas/química , Precursores de Proteínas/genética , Proteoma , Proteômica/métodos , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/etiologia , Cardiopatia Reumática/metabolismo , Relação Estrutura-Atividade , Timosina/química , Timosina/genética , Timosina/metabolismo
15.
Eur Heart J ; 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35051271

RESUMO

Lipid risk factors for cardiovascular disease depend in part on lifestyle, but optimum control of lipids often demands additional measures. Low-density lipoprotein (LDL) doubtless contributes causally to atherosclerosis. Recent human genetic findings have substantiated a number of novel targets for lipid-lowering therapy including apolipoprotein C-III, angiopoietin-like protein 3 and 4, apolipoprotein V, and ATP citrate lyase. These discoveries coupled with advances in biotechnology development afford new avenues for management of LDL and other aspects of lipid risk. Beyond LDL, new treatments targeting triglyceride-rich lipoproteins and lipoprotein(a) have become available and have entered clinical development. Biological and RNA-directed agents have joined traditional small-molecule approaches, which themselves have undergone considerable refinement. Innovative targeting strategies have increased efficacy of some of these novel interventions and markedly improved their tolerability. Gene-editing approaches have appeared on the horizon of lipid management. This article reviews this progress offering insight into novel biological and therapeutic discoveries, and places them into a practical patient care perspective.

16.
Sci Rep ; 12(1): 577, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022435

RESUMO

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.


Assuntos
Hematopoiese Clonal , Infecções por HIV/complicações , Adulto , Estudos de Casos e Controles , Feminino , Infecções por HIV/genética , Infecções por HIV/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
17.
Clin Cardiol ; 45(3): 299-307, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35019162

RESUMO

BACKGROUND: Despite low-density lipoprotein cholesterol-lowering therapies and other standard-of-care therapy, there remains a substantial residual atherosclerotic risk among patients with an acute coronary syndrome (ACS). This study aims to estimate the risk of early and late recurrent major adverse cardiovascular events (MACE) and address its implications on trial design. METHODS: A literature search was performed to collect phase III interventional trials on high-risk ACS patients. Pooled event rates at 90 and 360 days were estimated by fitting random-effects models using the DerSimonian-Laird method. Under the assumption of a total sample size of 10,000 and 1:1 allocation at a one-sided alpha of 0.025 using the log-rank test, the relationship between power and relative risk reduction (RRR) or absolute risk reduction (ARR) was explored for early versus late MACE endpoint. RESULTS: Seven trials representing 82,727 recent ACS patients were analyzed. The pooled rates of recurrent MACE were 4.1% and 8.3% at 90 and 360 days. Approximately 49% of events occurred within the first 90 days. Based on the estimated risks at 90 and 360 days, to attain 90% statistical power, a lower magnitude of RRR is required for late MACE than early MACE (22% vs. 30%), whereas a lower magnitude of ARR is required for early MACE than late MACE (1.2% vs. 1.8%). CONCLUSION: The initial 90-day window after ACS represents a vulnerable period for recurrent events. From a trial design perspective, determining a clinically important benefit by RRR versus ARR may influence the decision between early and late MACE as the study endpoint.


Assuntos
Síndrome Coronariana Aguda , Aterosclerose , Síndrome Coronariana Aguda/terapia , LDL-Colesterol , Ensaios Clínicos Fase III como Assunto , Humanos , Projetos de Pesquisa , Fatores de Risco
18.
Am J Pathol ; 192(1): 112-120, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599881

RESUMO

Severe coronavirus disease 2019 (COVID-19) increases the risk of myocardial injury that contributes to mortality. This study used multiparameter immunofluorescence to extensively examine heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, with or without cardiovascular disease. Consistent with prior reports, no evidence of viral infection or lymphocytic infiltration indicative of myocarditis was found. However, frequent and extensive thrombosis was observed in large and small vessels in the hearts of the COVID-19 cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3, or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi in patients with COVID-19, including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than in the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.


Assuntos
COVID-19 , Vasos Coronários , Miocardite , Miocárdio , SARS-CoV-2/metabolismo , Trombose , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Plaquetas/patologia , COVID-19/metabolismo , COVID-19/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Ativação de Neutrófilo , Neutrófilos/metabolismo , Neutrófilos/patologia , Agregação Plaquetária , Trombose/metabolismo , Trombose/patologia
19.
Arch Cardiol Mex ; 92(1): 99-112, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34187049

RESUMO

BACKGROUND: Hypertension, hyperglycemia, dyslipidemia, overweight, obesity, and tobacco (smoking, chewing, and vaping), together with a pro-inflammatory and procoagulant state, are the main risk factors related to atherosclerotic cardiovascular disease. OBJECTIVE AND METHODS: A group of experts from the Americas, based on their clinical expertise in cardiology, cardiovascular prevention, and cardiometabolic (CM) diseases, joined together to develop these practical recommendations for the optimal evaluation and treatment of residual CM risk factors in Latin America, using a modified Delphi methodology (details in electronic TSI) to generate a comprehensive CM risk reduction guideline, and through personalized medicine and patient-centered decision, considering the cost-benefit ratio The process was well defined to avoid conflicts of interest that could bias the discussion and recommendations. RESULTS: Residual risk reduction should consider therapeutic options adapted to specific patient needs, based on five treatment objectives: triglyceride-rich lipoproteins, inflammation, impaired glucose metabolism, high blood pressure, and prothrombotic status. Comprehensive control of all CM risk factors should be a priority to deal with this important public health problem and prevent premature deaths. The recommendations in this paper address the evidence-based treatment of CM risk and are intended for clinical application in Latin American countries.


Antecedentes: Un grupo de factores de riesgo cardiometabólicos (hipertensión, hiperglucemia, dislipidemia, sobrepeso, obesidad y tabaco (fumado, masticado, vaporizado), junto con un estado proinflamatorio y procoagulante, son los principales factores de riesgo relacionados con la enfermedad cardiovascular aterosclerótica. Objetivo y métodos: Basándose en su experiencia en cardiología, prevención cardiovascular y enfermedades cardiometabólicas, un grupo de expertos de las Américas se unió para desarrollar estas recomendaciones prácticas para la evaluación y tratamiento óptimos de los factores de riesgo cardiometabólicos residuales en América Latina, utilizando una metodología Delphi modificada con el objetivo de generar una guía integral de pautas para la reducción del riesgo cardiometabólico, mediante la medicina personalizada y la decisión centrada en el paciente teniendo en cuenta la relación costo-beneficio. El proceso fue bien definido para evitar conflictos de intereses que podrían sesgar la discusión y las recomendaciones. Resultados: La reducción del riesgo residual debe considerar opciones terapéuticas adaptadas a las necesidades específicas del paciente, basadas en 5 objetivos de tratamiento: lipoproteínas ricas en triglicéridos inflamación, metabolismo de la glucosa, presión arterial alta y estado protrombótico. El Control integral de todos los factores de riesgo cardiometabólicos debe ser una prioridad para hacer frente a este importante problema de salud pública y prevenir las muertes prematuras. Las recomendaciones de este documento abordan el tratamiento basado en evidencia del riesgo cardiometabólico y están destinadas a la aplicación clínica en los países de América Latina.


Assuntos
Aterosclerose , Cardiologia , Consenso , Endotélio , Humanos , América Latina , Lipídeos , Estados Unidos
20.
Cardiol Discov ; 1(4): 233-258, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34888547

RESUMO

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely ranks among the deadliest diseases in human history. As with other coronaviruses, SARS-CoV-2 infection damages not only the lungs but also the heart and many other organs that express angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2. COVID-19 has upended lives worldwide. Dietary behaviors have been altered such that they favor metabolic and cardiovascular complications, while patients have avoided hospital visits because of limited resources and the fear of infection, thereby increasing out-hospital mortality due to delayed diagnosis and treatment. Clinical observations show that sex, age, and race all influence the risk for SARS-CoV-2 infection, as do hypertension, obesity, and pre-existing cardiovascular conditions. Many hospitalized COVID-19 patients suffer cardiac injury, acute coronary syndromes, or cardiac arrhythmia. SARS-CoV-2 infection may lead to cardiomyocyte apoptosis and necrosis, endothelial cell damage and dysfunction, oxidative stress and reactive oxygen species production, vasoconstriction, fibrotic and thrombotic protein expression, vascular permeability and microvascular dysfunction, heart inflammatory cell accumulation and activation, and a cytokine storm. Current data indicate that COVID-19 patients with cardiovascular diseases should not discontinue many existing cardiovascular therapies such as ACE inhibitors, angiotensin receptor blockers, steroids, aspirin, statins, and PCSK9 inhibitors. This review aims to furnish a framework relating to COVID-19 and cardiovascular pathophysiology.

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