RESUMO
BACKGROUND: Elevated plasma ceramides and microvascular dysfunction both independently predict adverse cardiac events. Despite the known detrimental effects of ceramide on the microvasculature, evidence suggests that activation of the shear-sensitive, ceramide-forming enzyme NSmase (neutral sphingomyelinase) elicits formation of vasoprotective nitric oxide (NO). Here, we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults (non-coronary artery disease [CAD]) and patients diagnosed with CAD. METHODS: Human arterioles were dissected from discarded surgical adipose tissue (n=166), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO and mitochondrial hydrogen peroxide (H2O2) production were measured in arterioles using fluorescence microscopy. H2O2 fluorescence was assessed in isolated human umbilical vein endothelial cells. RESULTS: Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to NOX-2 (NADPH-oxidase 2)-dependent H2O2-mediated flow-induced dilation. Endothelial dysfunction was prevented by treatment with sphingosine-1-phosphate (S1P) and partially prevented by C2-ceramide and an agonist of S1P-receptor 1 (S1PR1); the inhibition of the S1P/S1PR1 signaling axis induced endothelial dysfunction via NOX-2. Ceramide increased NO production in arterioles from non-CAD adults, an effect that was diminished with inhibition of S1P/S1PR1/S1P-receptor 3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired the overall ability to induce mitochondrial H2O2 production and subsequently dilate to flow, an effect not restored with exogenous S1P. Acute ceramide administration to arterioles from patients with CAD promoted H2O2 as opposed to NO production, an effect dependent on S1P-receptor 3 signaling. CONCLUSION: These data suggest that despite differential downstream signaling between health and disease, NSmase-mediated ceramide formation is necessary for proper functioning of the human microvascular endothelium. Therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.
Assuntos
Doença da Artéria Coronariana , Doenças Vasculares , Adulto , Humanos , Ceramidas , Peróxido de Hidrogênio , Células Endoteliais da Veia Umbilical Humana , EndotélioRESUMO
BACKGROUND: Growing evidence correlated changes in bioactive sphingolipids, particularly S1P (sphingosine-1-phosphate) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood. METHODS: We used an established model of coronary atherosclerosis in mice, combined with sphingolipidomics, RNA-sequencing, flow cytometry, and immunostaining to investigate the contribution of sphingolipid metabolism and signaling to endothelial cell (EC) activation and dysfunction. RESULTS: We demonstrated that hemodynamic stress induced an early metabolic rewiring towards endothelial sphingolipid de novo biosynthesis, favoring S1P signaling over ceramides as a protective response. This finding is a paradigm shift from the current belief that ceramide accrual contributes to endothelial dysfunction. The enzyme SPT (serine palmitoyltransferase) commences de novo biosynthesis of sphingolipids and is inhibited by NOGO-B (reticulon-4B), an ER membrane protein. Here, we showed that NOGO-B is upregulated by hemodynamic stress in myocardial EC of ApoE-/- mice and is expressed in the endothelium lining coronary lesions in mice and humans. We demonstrated that mice lacking NOGO-B specifically in EC (Nogo-A/BECKOApoE-/-) were resistant to coronary atherosclerosis development and progression, and mortality. Fibrous cap thickness was significantly increased in Nogo-A/BECKOApoE-/- mice and correlated with reduced necrotic core and macrophage infiltration. Mechanistically, the deletion of NOGO-B in EC sustained the rewiring of sphingolipid metabolism towards S1P, imparting an atheroprotective endothelial transcriptional signature. CONCLUSIONS: These data demonstrated that hemodynamic stress induced a protective rewiring of sphingolipid metabolism, favoring S1P over ceramide. NOGO-B deletion sustained the rewiring of sphingolipid metabolism toward S1P protecting EC from activation under hemodynamic stress and refraining coronary atherosclerosis. These findings also set forth the foundation for sphingolipid-based therapeutics to limit atheroprogression.
Assuntos
Aterosclerose , Doença da Artéria Coronariana , Humanos , Animais , Camundongos , Ceramidas/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/prevenção & controle , Proteínas Nogo , Esfingolipídeos/metabolismo , Esfingosina/metabolismo , Lisofosfolipídeos/metabolismo , Endotélio/metabolismo , Aterosclerose/genética , Aterosclerose/prevenção & controle , Apolipoproteínas ERESUMO
Ceramides, a group of biologically active sphingolipids, have been described as the new cholesterol given strong evidence linking high plasma ceramide with endothelial damage, risk for early adverse cardiovascular events, and development of cardiometabolic disease. This relationship has sparked great interest in investigating therapeutic targets with the goal of suppressing ceramide formation. However, the growing data challenge this paradigm of ceramide as solely eliciting detrimental effects to the cardiovascular system. Studies show that ceramides are necessary for maintaining proper endothelial redox states, mechanosensation, and membrane integrity. Recent work in preclinical models and isolated human microvessels highlights that the loss of ceramide formation can in fact propagate vascular endothelial dysfunction. Here, we delve into these conflicting findings to evaluate how ceramide may be capable of exerting both beneficial and damaging effects within the vascular endothelium. We propose a unifying theory that while basal levels of ceramide in response to physiological stimuli are required for the production of vasoprotective metabolites such as S1P (sphingosine-1-phosphate), the chronic accumulation of ceramide can promote activation of pro-oxidative stress pathways in endothelial cells. Clinically, the evidence discussed here highlights the potential challenges associated with therapeutic suppression of ceramide formation as a means of reducing cardiovascular disease risk.
Assuntos
Doenças Cardiovasculares , Ceramidas , Endotélio Vascular , Estresse Oxidativo , Esfingosina , Ceramidas/metabolismo , Humanos , Endotélio Vascular/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Lisofosfolipídeos/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Transdução de SinaisRESUMO
An increasing body of evidence suggests a pivotal role for the microvasculature in the development of cardiovascular disease. A dysfunctional coronary microvascular network, specifically within endothelial cells-the inner most cell layer of vessels-is considered a strong, independent risk factor for future major adverse cardiac events. However, challenges exist with evaluating this critical vascular bed, as many of the currently available techniques are highly invasive and cost prohibitive. The more easily accessible peripheral microcirculation has surfaced as a potential surrogate in which to study mechanisms of coronary microvascular dysfunction and likewise may be used to predict poor cardiovascular outcomes. In this review, we critically evaluate a variety of prognostic, physiological, and mechanistic studies in humans to answer whether the peripheral microcirculation can add insight into coronary microvascular health. A conceptual framework is proposed that the health of the endothelium specifically may link the coronary and peripheral microvascular beds. This is supported by evidence showing a correlation between human coronary and peripheral endothelial function in vivo. Although not a replacement for investigating and understanding coronary microvascular function, the microvascular endothelium from the periphery responds similarly to (patho)physiological stress and may be leveraged to explore potential therapeutic pathways to mitigate stress-induced damage.
Assuntos
Vasos Coronários , Microcirculação , Microvasos , Humanos , Vasos Coronários/fisiopatologia , Endotélio Vascular/metabolismo , Circulação Coronária , Animais , Doenças Cardiovasculares/fisiopatologiaRESUMO
Reduced peripheral microvascular reactivity is associated with an increased risk for major adverse cardiac events (MACEs). Tools for noninvasive assessment of peripheral microvascular function are limited, and existing technology is poorly validated in both healthy populations and patients with cardiovascular disease (CVD). Here, we used a handheld incident dark-field imaging tool (CytoCam) to test the hypothesis that, compared with healthy individuals (no risk factors for CVD), subjects formally diagnosed with coronary artery disease (CAD) or those with ≥2 risk factors for CAD (at risk) would exhibit impaired peripheral microvascular reactivity. A total of 17 participants (11 healthy, 6 at risk) were included in this pilot study. CytoCam was used to measure sublingual microvascular total vessel density (TVD), perfused vessel density (PVD), and microvascular flow index (MFI) in response to the topical application of acetylcholine (ACh) and sublingual administration of nitroglycerin (NTG). Baseline MFI and PVD were significantly reduced in the at-risk cohort compared with healthy individuals. Surprisingly, following the application of acetylcholine and nitroglycerin, both groups showed a significant improvement in all three microvascular perfusion parameters. These results suggest that, despite baseline reductions in both microvascular density and perfusion, human in vivo peripheral microvascular reactivity to both endothelial-dependent and -independent vasoactive agents remains intact in individuals with CAD or multiple risk factors for disease.NEW & NOTEWORTHY To our knowledge, this is the first study to comprehensively characterize in vivo sublingual microvascular structure and function (endothelium-dependent and -independent) in healthy patients and those with CVD. Importantly, we used an easy-to-use handheld device that can be easily translated to clinical settings. Our results indicate that baseline microvascular impairments in structure and function can be detected using the CytoCam technology, although reactivity to acetylcholine may be maintained even during disease in the peripheral microcirculation.
Assuntos
Doença da Artéria Coronariana , Microcirculação , Microvasos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/diagnóstico por imagem , Idoso , Projetos Piloto , Microvasos/diagnóstico por imagem , Microvasos/fisiopatologia , Acetilcolina/farmacologia , Adulto , Vasodilatadores/farmacologia , Nitroglicerina/administração & dosagem , Nitroglicerina/farmacologia , Estudos de Casos e Controles , Soalho Bucal/irrigação sanguínea , Densidade Microvascular , Vasodilatação/efeitos dos fármacosRESUMO
At the American Physiology Summit 2023 session entitled, "Mental Health for Graduate Students," numerous students expressed struggling with poor mental well-being primarily because of negative experiences during their graduate training. In fact, studies show that up to 50% of graduate students report symptoms of depression, anxiety, or burnout during their training, and poor mental well-being is a major contributor to students' decision to leave academia. Most of the current solutions focus on treatment or wellness strategies; while these are important and necessary, the training environment or culture that often contributes to worsening well-being continues to persist. In this collaborative article between trainees and mentors across various career stages, we discuss how the pace of scientific advancements and the associated competition, lack of sufficient support for students from diverse backgrounds, and mentor-mentee relationships crucially influence graduate students' mental well-being. We then offer specific solutions at the individual, institutional, and national levels that can serve as a starting point for improving graduate students' mental health and overall training experience.
Assuntos
Saúde Mental , Bem-Estar Psicológico , Humanos , EstudantesRESUMO
Despite data showing that estrogen is vasculoprotective in large conduit arteries, hormone therapy (HT) during menopause has not proven to mitigate cardiovascular disease (CVD) risk. Estrogen exposure through prolonged oral contraceptive use and gender-affirming therapy can also increase cis- and trans-females' risk for future CVD, respectively. The microvasculature is a unique vascular bed that when dysfunctional can independently predict future adverse cardiac events; however, studies on the influence of estrogen on human microvessels are limited. Here, we show that isolated human arterioles from females across the life span maintain nitric oxide (NO)-mediated dilation to flow, whereas chronic (16-20 h) exposure to exogenous (100 nM) 17ß-estradiol promotes microvascular endothelial dysfunction in vessels from adult females of <40 and ≥40 yr of age. The damaging effect of estrogen was more dramatic in arterioles from biological males, as they exhibited both endothelial and smooth muscle dysfunction. Furthermore, females of <40 yr have greater endothelial expression of estrogen receptor-ß (ER-ß) and G protein-coupled estrogen receptor (GPER) compared with females of ≥40 yr and males. Estrogen receptor-α (ER-α), the prominent receptor associated with protective effects of estrogen, was identified within the adventitia as opposed to the endothelium across all groups. To our knowledge, this is the first study to report the detrimental effects of estrogen on the human microvasculature and highlights differences in estrogen receptor expression.NEW & NOTEWORTHY Microvascular dysfunction is an independent predictor of adverse cardiac events; however, the effect of estrogen on the human microcirculation represents a critical knowledge gap. To our knowledge, this is the first study to report sex-specific detrimental effects of chronic estrogen on human microvascular reactivity. These findings may offer insight into the increased CVD risk associated with estrogen use in both cis- and trans-females.
Assuntos
Receptores de Estrogênio , Doenças Vasculares , Masculino , Adulto , Feminino , Humanos , Arteríolas/metabolismo , Receptores de Estrogênio/metabolismo , Vasodilatação , Estradiol/farmacologia , Estradiol/metabolismo , Estrogênios/farmacologia , Estrogênios/metabolismo , Doenças Vasculares/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Endotélio Vascular/metabolismoRESUMO
Cardiovascular disease risk increases with age regardless of sex. Some of this risk is attributable to alterations in natural hormones throughout the life span. The quintessential example of this being the dramatic increase in cardiovascular disease following the transition to menopause. Plasma levels of adiponectin, a "cardioprotective" adipokine released primarily by adipose tissue and regulated by hormones, also fluctuate throughout one's life. Plasma adiponectin levels increase with age in both men and women, with higher levels in both pre- and postmenopausal women compared with men. Younger cohorts seem to confer cardioprotective benefits from increased adiponectin levels yet elevated levels in the elderly and those with existing heart disease are associated with poor cardiovascular outcomes. Here, we review the most recent data regarding adiponectin signaling in the vasculature, highlight the differences observed between the sexes, and shed light on the apparent paradox regarding increased cardiovascular disease risk despite rising plasma adiponectin levels over time.
Assuntos
Adiponectina/metabolismo , Envelhecimento/metabolismo , Endotélio Vascular/metabolismo , Animais , Endotélio Vascular/crescimento & desenvolvimento , Humanos , Transdução de SinaisRESUMO
Microvascular disease plays a critical role in systemic end-organ dysfunction, and treatment of microvascular pathologies may greatly reduce cardiovascular morbidity and mortality. The Call for Papers collection: New Developments in Translational Microcirculatory Research highlights key advances in our understanding of the role of microvessels in the development of chronic diseases as well as therapeutic strategies to enhance microvascular function. This Mini Review provides a concise summary of these advances and draws from other relevant research to provide the most up-to-date information on the influence of cutaneous, cerebrovascular, coronary, and peripheral microcirculation on the pathophysiology of obesity, hypertension, cardiovascular aging, peripheral artery disease, and cognitive impairment. In addition to these disease- and location-dependent research articles, this Call for Papers includes state-of-the-art reviews on coronary endothelial function and assessment of microvascular health in different organ systems, with an additional focus on establishing rigor and new advances in clinical trial design. These articles, combined with original research evaluating cellular, exosomal, pharmaceutical, exercise, heat, and dietary interventional therapies, establish the groundwork for translating microcirculatory research from bench to bedside. Although numerous studies in this collection are focused on human microcirculation, most used robust preclinical models to probe mechanisms of pathophysiology and interventional benefits. Future work focused on translating these findings to humans are necessary for finding clinical strategies to prevent and treat microvascular dysfunction.
Assuntos
Hipertensão , Doenças Vasculares Periféricas , Humanos , Microcirculação/fisiologia , Microvasos , EndotélioRESUMO
BACKGROUND: Hypotension that is resistant to phenylephrine is a complication that occurs in anesthetized patients treated with angiotensin converting enzyme (ACE) inhibitors. We tested the hypothesis that Ang 1-7 and the endothelial Mas receptor contribute to vasodilation produced by propofol in the presence of captopril. METHODS: The internal diameters of human adipose resistance arterioles were measured before and after administration of phenylephrine (10-9 to 10-5 M) in the presence and absence of propofol (10-6 M; added 10 min before the phenylephrine) or the Mas receptor antagonist A779 (10-5 M; added 30 min before phenylephrine) in separate experimental groups. Additional groups of arterioles were incubated for 16 to 20 h with captopril (10-2 M) or Ang 1-7 (10-9 M) before experimentation with phenylephrine, propofol, and A779. RESULTS: Propofol blunted phenylephrine-induced vasoconstriction in normal vessels. Captopril pretreatment alone did not affect vasoconstriction, but the addition of propofol markedly attenuated the vasomotor response to phenylephrine. A779 alone did not affect vasoconstriction in normal vessels, but it restored vasoreactivity in arterioles pretreated with captopril and exposed to propofol. Ang 1-7 reduced the vasoconstriction in response to phenylephrine. Addition of propofol to Ang 1-7-pretreated vessels further depressed phenylephrine-induced vasoconstriction to an equivalent degree as the combination of captopril and propofol, but A779 partially reversed this effect. CONCLUSIONS: Mas receptor activation by Ang 1-7 contributes to phenylephrine-resistant vasodilation in resistance arterioles pretreated with captopril and exposed to propofol. These data suggest an alternative mechanism by which refractory hypotension may occur in anesthetized patients treated with ACE inhibitors.
Assuntos
Hipotensão , Propofol , Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Arteríolas/fisiologia , Captopril/farmacologia , Humanos , Fenilefrina/farmacologia , Propofol/farmacologiaRESUMO
Traditionally thought of primarily as the predominant regulator of myocardial perfusion, it is becoming more accepted that the human coronary microvasculature also exerts a more direct influence on the surrounding myocardium. Coronary microvascular dysfunction (CMD) not only precedes large artery atherosclerosis, but is associated with other cardiovascular diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy. It is also highly predictive of cardiovascular events in patients with or without atherosclerotic cardiovascular disease. This review focuses on this recent paradigm shift and delves into the clinical consequences of CMD. Concepts of how resistance arterioles contribute to disease will be discussed, highlighting how the microvasculature may serve as a potential target for novel therapies and interventions. Finally, both invasive and non-invasive methods with which to assess the coronary microvasculature both for diagnostic and risk stratification purposes will be reviewed.
Assuntos
Insuficiência Cardíaca , Microvasos , Circulação Coronária , Humanos , Volume SistólicoRESUMO
Almost three-quarters of all heart failure patients who are older than 65 have heart failure with preserved ejection fraction (HFpEF). The proportion and hospitalization rate of patients with HFpEF are increasing steadily relative to patients in whom heart failure occurs as result of reduced ejection fraction. The predominance of the HFpEF phenotype most likely is explained by the prevalence of medical conditions associated with an aging population. A multitude of age-related, medical, and lifestyle risk factors for HFpEF have been identified as potential causes for the sustained low-grade proinflammatory state that accelerates disease progression. Profound left ventricular (LV) systolic and diastolic stiffening, elevated LV filling pressures, reduced arterial compliance, left atrial hypertension, pulmonary venous congestion, and microvascular dysfunction characterize HFpEF, but pulmonary arterial hypertension, right ventricular dilation and dysfunction, and atrial fibrillation also frequently occur. These cardiovascular features make patients with HFpEF exquisitely sensitive to the development of hypotension in response to acute declines in LV preload or afterload that may occur during or after surgery. With the exception of symptom mitigation, lifestyle modifications, and rigorous control of comorbid conditions, few long-term treatment options exist for these unfortunate individuals. Patients with HFpEF present for surgery on a regular basis, and anesthesiologists need to be familiar with this heterogeneous and complex clinical syndrome to provide successful care. In this article, the authors review the diagnosis, pathophysiology, and treatment of HFpEF and also discuss its perioperative implications.
Assuntos
Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Idoso , Diástole , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Ventrículos do Coração , Humanos , Volume Sistólico , Função Ventricular EsquerdaRESUMO
The primary function of the arterial microvasculature is to ensure that regional perfusion of blood flow is matched to the needs of the tissue bed. This critical physiological mechanism is tightly controlled and regulated by a variety of vasoactive compounds that are generated and released from the vascular endothelium. Although these substances are required for modulating vascular tone, they also influence the surrounding tissue and have an overall effect on vascular, as well as parenchymal, homeostasis. Bioactive lipids, fatty acid derivatives that exert their effects through signaling pathways, are included in the list of vasoactive compounds that modulate the microvasculature. Although lipids were identified as important vascular messengers over three decades ago, their specific role within the microvascular system is not well defined. Thorough understanding of these pathways and their regulation is not only essential to gain insight into their role in cardiovascular disease but is also important for preventing vascular dysfunction following cancer treatment, a rapidly growing problem in medical oncology. The purpose of this review is to discuss how biologically active lipids, specifically prostanoids, epoxyeicosatrienoic acids, sphingolipids, and lysophospholipids, contribute to vascular function and signaling within the endothelium. Methods for quantifying lipids will be briefly discussed, followed by an overview of the various lipid families. The cross talk in signaling between classes of lipids will be discussed in the context of vascular disease. Finally, the potential clinical implications of these lipid families will be highlighted.
Assuntos
Ácidos Graxos/metabolismo , Microvasos/metabolismo , Fosfolipídeos/metabolismo , Esfingolipídeos/metabolismo , Animais , Ensaios Enzimáticos/métodos , Fluorometria/métodos , Humanos , Espectrometria de Massas/métodos , Transdução de SinaisRESUMO
Randomized controlled trials (RCTs) provide important data to guide clinical decisions. Publication bias may limit the applicability of RCTs because many clinical investigators prefer to submit and journals more selectively accept studies with positive results. The authors tested the hypothesis that positive RCTs published in the Journal of Cardiothoracic and Vascular Anesthesia were more likely to be associated with factors known to predict publication of positive versus negative RCTs in other journals. This observational study was an internet analysis of all issues of Journal of Cardiothoracic and Vascular Anesthesia from 2004-2018. Each issue was searched to identify human RCTs. The numbers of centers and enrolled patients in each RCT were tabulated. The corresponding author determined the country of origin (United States v international). A trial was "positive" or "negative" based on rejection or confirmation of the null hypothesis, respectively, for the primary outcome variable or the majority of measured outcomes if a primary outcome was not identified. The presence or absence of a hypothesis, randomization methodology, sample size calculation, and blinded research design was recorded. Registration in a public database, Consolidated Statements of Reporting Trials (CONSORT) guideline compliance, and the source of funding also were determined. The number of citations for each RCT was determined by using Google Scholar; the citation rate was calculated as the ratio of the number of total citations and the duration in years since the trial's original publication. A total of 296 RCTs were identified, of which 58.8% reported positive results. Most RCTs were single center, relatively small, and international in origin. Total citations/RCT decreased over time, but citations/year did not. The percentage of RCTs that identified a randomization method, were registered, or followed CONSORT guidelines increased in a time-dependent manner. No differences in any factors associated with publication of RCTs were observed when positive and negative trials were compared. The Journal of Cardiothoracic and Vascular Anesthesia publishes more positive than negative RCTs, but factors that have been previously associated with RCT publication in other journals were similar between groups.
Assuntos
Anestesia , Anestesiologia , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Chemotherapy (CT) is a necessary treatment to prevent the growth and survival of cancer cells. However, CT has a well-established adverse impact on the cardiovascular (CV) system, even years after cessation of treatment. The effects of CT drugs on tumor vasculature have been the focus of much research, but little evidence exists showing the effects on the host microcirculation. Microvascular (MV) dysfunction is an early indicator of numerous CV disease phenotypes, including heart failure. The goal of this study was to evaluate the direct effect of doxorubicin (Dox) on human coronary MV function. To study the effect of CT on the cardiac MV function, flow-mediated dilation (FMD), pharmacologically-induced endothelial dependent dilation to acetylcholine (ACh), and smooth muscle-dependent dilation to papaverine were investigated. Vessels were freshly isolated from atrial appendages of adult patients undergoing cardiopulmonary bypass surgery or from cardiac tissue of pediatric patients, collected at the time of surgery to repair congenital heart defects. Isolated vessels were incubated in endothelial culture medium containing vehicle or Dox (100 nm, 15-20 h) and used to measure dilator function by video microscopy. Ex vivo treatment of adult human coronary microvessels with Dox significantly impaired flow-mediated dilation (FMD). Conversely, in pediatric coronary microvessels, Dox-induced impairment of FMD was significantly reduced in comparison with adult subjects. In both adult and pediatric coronary microvessels, ACh-induced constriction was reversed into dilation in the presence of Dox. Smooth muscle-dependent dilation remained unchanged in all groups tested. In vessels from adult subjects, acute treatment with Dox in clinically relevant doses caused significant impairment of coronary arteriolar function, whereas vessels from pediatric subjects showed only marginal impairment to the same stressor. This interesting finding might explain the delayed onset of future adverse CV events in children compared with adults after anthracycline therapy.NEW & NOTEWORTHY We have characterized, for the first time, human microvascular responses to acute ex vivo exposure to doxorubicin in coronary vessels from patients without cancer. Our data show an augmented impairment of endothelial function in vessels from adult subjects compared with pediatric samples.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Arteríolas/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Doxorrubicina/toxicidade , Vasodilatação/efeitos dos fármacos , Adolescente , Fatores Etários , Idoso , Arteríolas/fisiopatologia , Cardiotoxicidade , Estudos de Casos e Controles , Criança , Pré-Escolar , Vasos Coronários/fisiopatologia , Feminino , Humanos , Técnicas In Vitro , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Vasodilatadores/farmacologiaRESUMO
OBJECTIVE: Gender-based differences in scholarship among cardiothoracic anesthesiologists have not been studied. The authors examined the gender distribution of authorship of original research articles, case reports, review articles, and editorials in the Journal of Cardiothoracic and Vascular Anesthesia (JCVA) originating from the United States during four 3-year intervals to determine temporal changes in productivity of women in cardiothoracic anesthesiology. The authors tested the hypothesis that scholarly output of women has increased progressively in JCVA over time concomitant with greater participation in first, last, and corresponding author roles. DESIGN: Observational study. SETTING: Internet analysis. PARTICIPANTS: Authors of research articles, case reports, review articles, and editorials published in JCVA in 1990-92, 1999-2001, 2008-10, and 2015-17. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The gender of each author was determined by inspection of the first name. If gender could not be established easily, the author's institutional website was examined or an internet search using the Google search engine was conducted. First, last, and corresponding authors as well as coauthors were noted for each article. A total of 1,195 publications with 4,982 authors (1,032 women; 20.7%) were examined. Gender was identified positively in 98.5% of authors. Women were first, last, and corresponding authors on 22.4%, 10.3%, and 14.6% of publications, respectively. The percentage of women who were authors increased from 12.1% in 1990-92 to 20.9% in 1999-2001 (p < 0.05), but plateaued in 2008 to 2010 (22.3%) and 2015 to 2017 (22.9%). Greater percentages of women were first authors (26.2%), senior authors (11.8%), and corresponding authors (16.6%) in 2015 to 2017 compared with 1990 to 1992 (9.6%, 7.0%, and 8.7%, respectively; p < 0.05 for each). The contributions of women to research articles and case reports were primarily responsible for these observed increases, although women also made a substantial impact with review articles in 2015 to 2017. The percentage of publications that included at least 1 female author in any capacity increased in a time-dependent manner (p < 0.05) from 31.0% (1990-1992) to 74.4% (2015-2017). The proportion of female first or last authors (35.0%) appearing in JCVA during 2015 to 2017 was modestly higher than the current percentage of female cardiothoracic anesthesiologists practicing in departments with accredited fellowship programs (29.1%). CONCLUSION: The results indicate that scholarly output of women rose in JCVA over time, but gains in productivity have plateaued more recently. These findings are encouraging, but women continue to be underrepresented in corresponding and last author roles.
Assuntos
Anestesia em Procedimentos Cardíacos/tendências , Autoria , Publicações Periódicas como Assunto/tendências , Fatores Sexuais , Credenciamento/tendências , Feminino , Humanos , Masculino , Fatores de Tempo , Estados UnidosRESUMO
OBJECTIVE: Gender disparities in editorial board composition exist in the vast majority of specialties including anesthesiology. If a similar lack of gender parity exists in cardiothoracic anesthesiology is unknown. The authors examined the gender composition and trends of the Journal of Cardiothoracic and Vascular Anesthesia (JCVA) editorial board from the initial year of its publication (1987) to 2019. The authors tested the hypothesis that the proportion of women serving on the JCVA editorial board has steadily increased over the journal's history, but women are underrepresented compared with the percentage of those currently practicing academic cardiothoracic anesthesia in the United States (US). DESIGN: Observational study. SETTING: Internet analysis. PARTICIPANTS: All members of the JCVA editorial board, 1987-2019. INTERVENTIONS: The JCVA editor-in-chief, the associate editor-in-chief, associate editors, section editors, and general editors on the board were extracted from the masthead of a single issue from each calendar year. The years were divided into quartiles (1987-1995, 1996-2003, 2004-2011, and 2012-2019) to collect representative samples of editorial board composition for analysis. MEASUREMENTS AND MAIN RESULTS: A total of 2,797 members of the JCVA editorial board were positively identified (2,477 [88.6%] men; 310 [11.1%] women); 10 (0.3%) editors could not be identified. Four hundred and fourteen associate and section editors were recorded (men 360 [87.0%], women 54 [13.0%]). There were also 2,353 general editors (2,087 [88.7%] men; 256 [10.9%] women). The total number of JCVA board members, associate and section editors, and general editors progressively increased from 1987 to 1995 to 2012 to 2019. The percentage of women serving on the editorial board increased from 2.5% to 15.8%. Increases in the proportion of female general editors from 2.9% to 16.2% were responsible for this overall increase. A gender gap between the percentage of female first authors (data obtained from a previous publication) and editorial board members was observed in each quartile. Editorial board composition was also different than last author distribution in 1987 to 1995 and 2012 to 2019, but not the other 2 time periods. CONCLUSIONS: The results demonstrate that the proportion of women serving on the JCVA editorial board has steadily increased over the journal's history. Nevertheless, women continue to be underrepresented on the JCVA board compared with the percentage of US female academic cardiothoracic anesthesiologists, and gender gaps between first and last authorship and board composition also persist.
Assuntos
Desempenho Acadêmico , Anestesia em Procedimentos Cardíacos , Anestesiologia , Autoria , Docentes de Medicina/organização & administração , Publicações Periódicas como Assunto , Feminino , Humanos , Masculino , Distribuição por Sexo , Estados UnidosRESUMO
The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However, there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculoparenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of reactive oxygen species mediates both dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events and help identify new approaches to treatment and prevention.
Assuntos
Endotélio Vascular/fisiologia , Microcirculação/fisiologia , Vasodilatação/fisiologia , Animais , Circulação Sanguínea/fisiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , HumanosRESUMO
RATIONALE: Telomerase is a nuclear regulator of telomere elongation with recent reports suggesting a role in regulation of mitochondrial reactive oxygen species. Flow-mediated dilation in patients with cardiovascular disease is dependent on the formation of reactive oxygen species. OBJECTIVE: We examined the hypothesis that telomerase activity modulates microvascular flow-mediated dilation, and loss of telomerase activity contributes to the change of mediator from nitric oxide to mitochondrial hydrogen peroxide in patients with coronary artery disease (CAD). METHODS AND RESULTS: Human coronary and adipose arterioles were isolated for videomicroscopy. Flow-mediated dilation was measured in vessels pretreated with the telomerase inhibitor BIBR-1532 or vehicle. Statistical differences between groups were determined using a 2-way analysis of variance repeated measure (n≥4; P<0.05). L-NAME (N(ω)-nitro-L-arginine methyl ester; nitric oxide synthase inhibitor) abolished flow-mediated dilation in arterioles from subjects without CAD, whereas polyethylene glycol-catalase (PEG-catalase; hydrogen peroxide scavenger) had no effect. After exposure to BIBR-1532, arterioles from non-CAD subjects maintained the magnitude of dilation but changed the mediator from nitric oxide to mitochondrial hydrogen peroxide (% max diameter at 100 cm H2O: vehicle 74.6±4.1, L-NAME 37.0±2.0*, PEG-catalase 82.1±2.8; BIBR-1532 69.9±4.0, L-NAME 84.7±2.2, PEG-catalase 36.5±6.9*). Conversely, treatment of microvessels from CAD patients with the telomerase activator AGS 499 converted the PEG-catalase-inhibitable dilation to one mediated by nitric oxide (% max diameter at 100 cm H2O: adipose, AGS 499 78.5±3.9; L-NAME 10.9±17.5*; PEG-catalase 79.2±4.9). Endothelial-independent dilation was not altered with either treatment. CONCLUSIONS: We have identified a novel role for telomerase in re-establishing a physiological mechanism of vasodilation in arterioles from subjects with CAD. These findings suggest a new target for reducing the oxidative milieu in the microvasculature of patients with CAD.