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Brief Secondhand Smoke Exposure Depresses Endothelial Progenitor Cells Activity and Endothelial Function. Sustained Vascular Injury and Blunted Nitric Oxide Production
Abstract
This study sought to analyze the effects of acute secondhand smoke (SHS) exposure on the number and function of endothelial progenitor cells (EPCs) over 24 h.
Secondhand smoke increases the risk of vascular disease and is a major public health concern, but the mechanism(s) of action are not fully understood.
Healthy nonsmokers (age SEM 30.3 +/- 1.3 years, n = 10) were exposed to 30 min of SHS yielding cotinine levels commonly observed in passive smokers and to smokefree air on 2 separate days. Measurements were taken before exposure (baseline), immediately after (0 h), and at 1 h, 2.5 h, and 24 h after. The EPCs (CD133(+)/KDR(+), CD34(+)/KDR(+)) and endothelial microparticles (EMPs: CD31(+)/CD41(-), CD144(+), CD62e(+)) were determined in blood using flow cytometry. The EPC chemotaxis toward vascular endothelial growth factor was measured. Endothelial function was assessed as flow-mediated dilation (FMD) using ultrasound.
Secondhand smoke exposure increased EPCs and plasma vascular endothelial growth factor and completely abolished EPC chemotaxis during 24 h after exposure. Secondhand smoke increased EMPs and decreased FMD. Although FMD returned to baseline at 2.5 h, EMPs and vascular endothelial growth factor levels remained elevated at 24 h, suggesting endothelial activation and injury with functional impairment of the vascular endothelium. Exposure to smokefree air had no effect. Incubation of EPCs from nonexposed subjects with plasma isolated from SHS-exposed subjects in vitro decreased chemotaxis by blockade of vascular endothelial growth factor-stimulated nitric oxide production.
Brief exposure to real-world levels of SHS leads to sustained vascular injury characterized by mobilization of dysfunctional EPCs with blocked nitric oxide production. Our results suggest that SHS not only affects the vascular endothelium, but also the function of EPCs.
... Cigarette smoke also interferes with endothelial regeneration and maintenance processes carried out by endothelial progenitor cells (EPCs) either through the paracrine system (including Vascular Endothelial Growth Factor, Fibroblast Growth Factor, IL-6, IL-8, IL-11) or differentiate into endothelium to replace the damaged endothelium (10,11) . EPC markers that are often used are Cluster of differentiation 133+ (CD133+), CD34+ and Vascular Endothelial Growth Factor Receptor 2+ (VEGFR2+) atau Fetal Liver Kinase-1 (Flk-1). ...
... EPC markers that are often used are Cluster of differentiation 133+ (CD133+), CD34+ and Vascular Endothelial Growth Factor Receptor 2+ (VEGFR2+) atau Fetal Liver Kinase-1 (Flk-1). Research showed that cigarette smoke decreased the amount and functional activity of EPC in blood circulation with CD34+ and VEGFR2 markers (11) . In this research, CD34+ was used to detect progenitor cell in tunica intima coronary artery. ...
This research aimed to evaluate cardioprotective effects of cacao in smoking exposure condition that the effects were mediated through the anti-oxidant pathway by measure plasma F2-isoprostane level, Endothelial Progenitor Cell (EPC) enhancement by expression of CD34, while dysfunction endothelial condition was measured by expression of ICAM-1 in coronary arteries. This study subjected rats, divided into four groups: the normal control group (2 ml of aqua bidest, air exposure); the cigarette control group (2 ml of aqua bidest, cigarette smoke); cacao group 1 (1205 mg/kg BW/day, cigarette smoke); cocoa group 2 (2410 mg/kg BW/day, cigarette smoke). The oxidant biomarker, F2-isoprostane level was assessed using ELISA; CD34, and ICAM-1 expression in coronary arteries by immunohistochemistry. Cacao 1205 mg/kg BW/day significantly decreases plasma F2-isoprostane level, and ICAM-1 expression of coronary arteries in cigarette smoking exposed rat (p < 0.05) but there was not a significant increases CD34 (p < 0.05). Cocoa in cigarette smoke-exposed rats can prevent endothelial dysfunction through decrease F2-isoprostane but not increase CD34. The results of this study can be used as a basis for preventing endothelial dysfunction due to cigarette smoke by using cacao.
... Urine cotinine concentration was used only as confirmation of cigarette smoke inhalation. While the average of basal cotinine levels (T0) was 0.66 ± 0.64 ng/g, in agreement with the literature for non-smokers [31], after SS exposure, urine cotinine levels were significantly increased. Compared to T0, urine cotinine was significantly increased at 1 h (2.58 ± 0.5 vs. 0.66 ± 0.64 ng/g, p < 0.00001), and it remained significantly stable after 2 h and 24 h (2.71 ± 0.85 and 2.5 ± 1.01 vs. 0.66 ± 0.64 p < 0.00001 and p < 0.001 respectively). ...
... Starting from this evidence, in the present study, we analysed NGF and its receptors in a group of non-smokers, adult volunteers exposed to short-term SS in a controlled homelike environment [27,44]. Determination of cotinine levels in urine samples was used as the classical, standard biomarker of SS exposure, as described in the literature [31,45]. Although cotinine is commonly used as a biomarker to validate self-reported smoking status, the selection of optimal cotinine cut-off values to distinguish smokers and non-smokers and the fluctuation of this analyte reveals a lack of standardization among studies [46]. ...
Environmental tobacco smoke remains a major risk factor, for both smokers and non-smokers, able to trigger the initiation and/or the progression of several human diseases. Although in recent times governments have acted with the aim of banning or strongly reducing its impact within public places and common spaces, environmental tobacco smoke remains a major pollutant in private places, such as the home environment or cars. Several inflammatory and long-term biomarkers have been analysed and well-described, but the list of mediators modulated during the early phases of inhalation of environmental tobacco smoke needs to be expanded. The aim of this study was to measure the short-term effects after exposure to side-stream smoke on Nerve Growth Factor and its receptors Tropomyosin-related kinase A and neurotrophin p75, molecules already described in health conditions and respiratory diseases. Twenty-one non-smokers were exposed to a home-standardized level of SS as well as to control smoke-free air. Nerve Growth Factor and inflammatory cytokines levels, as well the expression of Tropomyosin-related kinase A and neurotrophin receptor p75, were analysed in white blood cells. The present study demonstrates that during early phases, side-stream smoke exposure induced increases in the percentage of neurotrophin receptor p75-positive white blood cells, in their mean fluorescent intensity, and in gene expression. In addition, we found a positive correlation between the urine cotinine level and the percentage of neurotrophin receptor-positive white blood cells. For the first time, the evidence that short-term exposure to side-stream smoke is able to increase neurotrophin receptor p75 expression confirms the very early involvement of this receptor, not only among active smokers but also among non-smokers exposed to SS. Furthermore, the correlation between cotinine levels in urine and the increase in neurotrophin receptor p75-positive white blood cells could represent a potential novel molecule to be investigated for the detection of SS exposure at early time points.
... 12,14,16,17 Chronic active smoking and both chronic and acute exposure to secondhand tobacco smoke impair FMD in humans. [18][19][20][21] Acute and chronic use of e-cigarettes and heated tobacco products have also been reported to impair FMD in humans, [22][23][24][25] although not all studies have detected this effect (eg, Haptonstall et al 26 ). Although a single impairment of FMD by smoke is transient and has not been demonstrated to lead to adverse health outcomes per se, Celermajer et al's work 19 indicated that repeated exposures to secondhand smoke ultimately led to chronic endothelial dysfunction. ...
Background
Marijuana leaf vaporizers, which heat plant material and sublimate Δ‐9‐tetrahydrocannabinol without combustion, are popular alternatives to smoking cannabis that are generally perceived to be less harmful. We have shown that smoke from tobacco and marijuana, as well as aerosol from e‐cigarettes and heated tobacco products, impair vascular endothelial function in rats measured as arterial flow‐mediated dilation (FMD).
Methods and Results
We exposed 8 rats per group to aerosol generated by 2 vaporizer systems (Volcano and handheld Yocan) using marijuana with varying Δ‐9‐tetrahydrocannabinol levels, in a single pulsatile exposure session of 2 s/min over 5 minutes, and measured changes in FMD. To model secondhand exposure, we exposed rats for 1 minute to diluted aerosol approximating release of uninhaled Volcano aerosol into typical residential rooms. Exposure to aerosol from marijuana with and without cannabinoids impaired FMD by ≈50%. FMD was similarly impaired by aerosols from Yocan (237 °C), and from Volcano at both its standard temperature (185 °C) and the minimum sublimation temperature of Δ‐9‐tetrahydrocannabinol (157 °C), although the low‐temperature aerosol condition did not effectively deliver Δ‐9‐tetrahydrocannabinol to the circulation. Modeled secondhand exposure based on diluted Volcano aerosol also impaired FMD. FMD was not affected in rats exposed to clean air or water vapor passed through the Volcano system.
Conclusions
Acute direct exposure and modeled secondhand exposure to marijuana leaf vaporizer aerosol, regardless of cannabinoid concentration or aerosol generation temperature, impair endothelial function in rats comparably to marijuana smoke. Our findings indicate that use of leaf vaporizers is unlikely to reduce the vascular risk burden of smoking marijuana.
... 14 In the context of chronic nicotine exposure, previous work indicates that nAChR-mediated nitric oxide (NO) signaling pathways play an important role in pathophysiology. 14 Studies involving second-hand smoke also showed endothelial dysfunction and decreased NO production, 40 although these effects have not been linked to nicotine specifically. This result was observed in umbilical vein ECs, where the decrease in angiogenic function was postulated to be related to NO production. ...
Objective:
Lifestyle choices such as tobacco and e-cigarette use are a risk factor for peripheral arterial disease (PAD) and may influence therapeutic outcomes. The effect of chronic nicotine exposure on the angiogenic capacity of human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) was assessed in a murine model of PAD.
Methods:
Mice were exposed to nicotine or phosphate-buffered saline (PBS) for 28 days, followed by induction of limb ischemia and iPSC-EC transplantation. Cells were injected into the ischemic limb immediately after induction of hindlimb ischemia and again 7 days later. Limb perfusion was assessed by laser Doppler spectroscopy, and transplant cell survival was monitored for 14 days afterward using bioluminescence imaging, followed by histological analysis of angiogenesis.
Results:
Transplant cell retention progressively decreased over time after implantation based on bioluminescence imaging, and there were no significant differences in cell survival between mice with chronic exposure to nicotine or PBS. However, compared with mice without nicotine exposure, mice with prior nicotine exposure had had an impaired therapeutic response to iPSC-EC therapy based on decreased vascular perfusion recovery. Mice with nicotine exposure, followed by cell transplantation, had significantly lower mean perfusion ratio after 14 days (0.47 ± 0.07) compared with mice undergoing cell transplantation without prior nicotine exposure (0.79 ± 0.11). This finding was further supported by histological analysis of capillary density, in which animals with prior nicotine exposure had a lower capillary density (45.9 ± 4.7 per mm2) compared with mice without nicotine exposure (66.5 ± 8.1 per mm2). Importantly, the ischemic limbs mice exposed to nicotine without cell therapy also showed significant impairment in perfusion recovery after 14 days, compared with mice that received PBS + iPSC-EC treatment. This result suggested that mice without chronic nicotine exposure could respond to iPSC-EC implantation into the ischemic limb by inducing perfusion recovery, whereas mice with chronic nicotine exposure did not respond to iPSC-EC therapy.
Conclusions:
Together, these findings show that chronic nicotine exposure adversely affects the ability of iPSC-EC therapy to promote vascular perfusion recovery and angiogenesis in a murine PAD model.
... EMPs are crucial for angiogenesis, endothelial function, coagulation, and inflammation. Additionally, they rise in response to numerous stimuli including endotoxins and CS [48]. ...
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease characterized by progressive airflow limitation. The complex biological processes of COPD include protein hydrolysis tissue remodeling, innate immune inflammation, disturbed host-pathogen response, abnormal cellular phenotype conversion, and cellular senescence. Extracellular vesicles (EVs) (including apoptotic vesicles, microvesicles and exosomes), are released by almost all cell types and can be found in a variety of body fluids including blood, sputum and urine. EVs are key mediators in cell-cell communication and can be used by using their bioactive substances (DNA, RNA, miRNA, proteins and other metabolites) to enable cells in adjacent and distant tissues to perform a wide variety of functions, which in turn affect the physiological and pathological functions of the body. Thus, EVs is expected to play an important role in the pathogenesis of COPD, which in turn affects its acute exacerbations and may serve as a diagnostic marker for it. Furthermore, recent therapeutic approaches and advances have introduced EVs into the treatment of COPD, such as the modification of EVs into novel drug delivery vehicles. Here, we discuss the role of EVs from cells of different origins in the pathogenesis of COPD and explore their possible use as biomarkers in diagnosis, and finally describe their role in therapy and future prospects for their application.
Graphical Abstract
... Smoking is an established risk factor for hypertension and other CVDs [32][33][34][35][36]. A possible explanation of how smoking increases blood pressure is that smoking causes acute vascular injury that leads to impairment of epithelial function [37] and stimulates atherosclerosis [38]. ...
Hypertension is the leading risk factor for cardiovascular diseases and represents a major public health challenge worldwide. There is a paucity of information regarding the hypertension status of adults in Somaliland. We aimed to assess the magnitude of, and factors associated with, hypertension among adult patients seeking care at Hargeisa group hospital in Hargeisa city, Somaliland. We conducted a health facility-based cross-sectional study enrolling adult outpatients. We used the World Health Organization (WHO) STEPwise surveillance approach to obtain patient information. A total of 319 participants (54.2% males; mean age 40.4 ± 14.0 years) had complete data records. The prevalence of hypertension was 22.6% (95% confidence interval; 18.2–27.6%). The prevalence of hypertension increased with age and was higher in males (24.9%) than in females (19.9%). Age, cholesterolaemia and obesity were significantly associated with hypertension. Separate analyses for females and males revealed that obesity was significantly associated with hypertension in females but not in males. On the contrary, cholesterolaemia was significantly associated with hypertension in males but not in females. We found a high prevalence of hypertension and multiple risk factors for non-communicable diseases (NCDs) in outpatients seeking care in Hargeisa. Our findings emphasise the need for enhanced focus on the prevention and management of NCDs in Somaliland.
... Further, EC-EV levels were able to indicate severe shunting in HPS. Vascular endothelial cells have multiple critical roles in maintaining vascular homeostasis, especially in cellular communication, through the delivery of metabolites and even oxygen to tissues [21]. One major function of endothelial cells includes optimizing gas exchange, reducing vascular tone or aiding in the modulation of vasoconstriction. ...
Background:
Hepatopulmonary syndrome (HPS) is a pulmonary vasculature complication in the setting of liver disease that is characterized by pathological vasodilation resulting in arterial oxygenation defects. We investigated the role of extracellular vesicles (EV) in cirrhosis patients with HPS, as well as the functional effect of EV administration in a common bile duct ligation (CBDL) HPS mouse model.
Methods:
A total of 113 cirrhosis patients were studied: 42 (Gr. A) with HPS and 71 (Gr. B) without HPS, as well as 22 healthy controls. Plasma levels of EV associated with endothelial cells, epithelial cells, and hepatocytes were measured. The cytokine cargoes were estimated using ELISA. The effect of EV administered intranasally in the CBDL mouse model was investigated for its functional effect in vascular remodeling and inflammation.
Results:
We found endothelial cells (EC) associated EV (EC-EV) were elevated in cirrhosis patients with and without HPS (p < 0.001) than controls. EC-EV levels were higher in HPS patients (p = 0.004) than in those without HPS. The epithelial cell EVs were significantly high in cirrhosis patients than controls (p < 0.001) but no changes found in patients with HPS than without. There was a progressive increase in EC-EV levels from mild to severe intrapulmonary shunting in HPS patients (p = 0.02 mild vs. severe), and we were able to predict severe HPS with an AUROC of 0.85; p < 0.001. An inverse correlation of EC-EVs was found with hemoglobin (r = -0.24; p = 0.031) and PaO2 (r = 0.690; p = 0.01) and a direct correlation with MELD (r = 0.32; p = 0.014). Further, both TNF-α (p = 0.001) and IL-1β (p = 0.021) as cargo levels were significantly elevated inside the EVs of HPS patients than without HPS. Interestingly, upon administration of intranasal EVs, there was a significant decrease in Evans blue accumulation and lung wet-dry ratio (p = 0.042; 0.038). A significant reduction was also noticed in inflammation and cholestasis.
Conclusion:
High levels of plasma EC-EV levels were found in patients with HPS with elevated pro-inflammatory cytokine cargoes. EC-EVs were indicative of severe HPS condition. In the CBDL HPS model, we were able to prove the beneficial effects of improving vascular tone, inflammation, and liver pathogenesis.
... In our experiment, immune and non-immune cells did release an increased amount of EVs, after the acute tobacco smoking intervention. These data are in line with previous literature in which the amount of EVs (microparticles, an old designation for mEVs) was increased after cigarette smoking (Mobarrez et al., 2014;Heiss et al., 2008). ...
Tobacco smoking is strongly linked to vascular damage contributing to the development of hypertension, atherosclerosis, as well as increasing the risk for neurodegeneration. Still, the involvement of the innate immune system in the development of vascular damage upon chronic tobacco use before the onset of clinical symptoms is not fully characterized. Our data provide evidence that a single acute exposure to tobacco elicits the secretion of extracellular vesicles expressing CD105 and CD49e from endothelial cells, granting further recognition of early preclinical biomarkers of vascular damage. Furthermore, we investigated the effects of smoking on the immune system of healthy asymptomatic chronic smokers compared to never-smokers, focusing on the innate immune system. Our data reveal a distinct immune landscape representative for early stages of vascular damage in clinically asymptomatic chronic smokers, before tobacco smoking related diseases develop. These results indicate a dysregulated immuno-vascular axis in chronic tobacco smokers that are otherwise considered as healthy individuals. The distinct alterations are characterized by increased CD36 expression by the blood monocyte subsets, neutrophilia and increased plasma IL-18 and reduced levels of IL-33, IL-10 and IL-8. Additionally, reduced levels of circulating BDNF and elevated sTREM2, which are associated with neurodegeneration, suggest a considerable impact of tobacco smoking on CNS function in clinically healthy individuals. These findings provide profound insight into the initial and ongoing effects of tobacco smoking and the potential vascular damage contributing to neurodegenerative disorders, specifically cerebrovascular dysfunction and dementia.
... EVs released by endothelial cells, particularly circulating microparticles (EMPs), are increased in patients with several diseases such as COPD [237] or in response to various stresses such as cigarette smoke extract [238]. CSE reduced the trafficking of α1AT mediated by endothelial-cell-derived EVs to lung epithelial cells [239]. ...
In keeping with the extraordinary interest and advancement of extracellular vesicles (EVs) in pathogenesis and diagnosis fields, we herein present an update to the knowledge about their role in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Although CF and COPD stem from a different origin, one genetic and the other acquired, they share a similar pathophysiology, being the CF transmembrane conductance regulator (CFTR) protein implied in both disorders. Various subsets of EVs, comprised mainly of microvesicles (MVs) and exosomes (EXOs), are secreted by various cell types that are either resident or attracted in the airways during the onset and progression of CF and COPD lung disease, representing a vehicle for metabolites, proteins and RNAs (especially microRNAs), that in turn lead to events as such neutrophil influx, the overwhelming of proteases (elastase, metalloproteases), oxidative stress, myofibroblast activation and collagen deposition. Eventually, all of these pathomechanisms lead to chronic inflammation, mucus overproduction, remodeling of the airways, and fibrosis, thus operating a complex interplay among cells and tissues. The detection of MVs and EXOs in blood and biological fluids coming from the airways (bronchoalveolar lavage fluid and sputum) allows the consideration of EVs and their cargoes as promising biomarkers for CF and COPD, although clinical expectations have yet to be fulfilled.
... [39][40][41] Notably, FMD is impaired in humans by active and passive tobacco smoking as well as e-cigarette use. [1][2][3][4][5][6] Here, we used a wellestablished method to measure FMD in rats that we previously developed 42 and used to demonstrate impairment of FMD by smoke and e-cigarette aerosol, [8][9][10][11][12][13] to assess the role of individual smoke constituents in causing endothelial dysfunction and identify which are primarily responsible for this effect. ...
Background:
Exposure to tobacco or marijuana smoke, or e-cigarette aerosols, causes vascular endothelial dysfunction in humans and rats. We aimed to determine what constituent, or class of constituents, of smoke is responsible for endothelial functional impairment.
Methods:
We investigated several smoke constituents that we hypothesized to mediate this effect by exposing rats and measuring arterial flow-mediated dilation (FMD) pre- and post-exposure. We measured FMD before and after inhalation of sidestream smoke from research cigarettes containing normal and reduced nicotine level with and without menthol, as well as 2 of the main aldehyde gases found in both smoke and e-cigarette aerosol (acrolein and acetaldehyde), and inert carbon nanoparticles.
Results:
FMD was reduced by all 4 kinds of research cigarettes, with extent of reduction ranging from 20% to 46% depending on the cigarette type. While nicotine was not required for the impairment, higher nicotine levels in smoke were associated with a greater percent reduction of FMD (41.1±4.5% reduction versus 19.2±9.5%; P=0.047). Lower menthol levels were also associated with a greater percent reduction of FMD (18.5±9.8% versus 40.5±4.8%; P=0.048). Inhalation of acrolein or acetaldehyde gases at smoke-relevant concentrations impaired FMD by roughly 50% (P=0.001). However, inhalation of inert carbon nanoparticles at smoke-relevant concentrations with no gas phase also impaired FMD by a comparable amount (P<0.001). Bilateral cervical vagotomy blocked the impairment of FMD by tobacco smoke.
Conclusions:
There is no single constituent or class of constituents responsible for acute impairment of endothelial function by smoke; rather, we propose that acute endothelial dysfunction by disparate inhaled products is caused by vagus nerve signaling initiated by airway irritation.
... Of these, approximately 158 have toxic properties and may cause environmental pollution when released into the atmosphere. (5) According to Heiss et al. (6) passive smokers inhale 10 to 100 times less smoke compared to active smokers. Still, severe cardiovascular damage may result in both cases. ...
Objective:
To determine whether passive smoking causes morphological and structural changes in the arcuate arteries of rats exposed for 7 to 28 days.
Methods:
Wistar rats aged eight weeks and weighing 260g on average were allocated to a Control or a Smoker Group. Groups were further divided into 4 groups containing 5 animals each. Morphological-functional analysis of the right kidneys was carried out after 7 and 28 days of exposure to the smoke of 40 cigarettes per day. Cigarettes were burned at set times using automated cigarette-burning equipment ("Smoking Machine" - SM-MC-01). At the end of each exposure period, the kidneys were dissected and submitted to histological processing for morphological and quantitative analysis.
Results:
Exposure to cigarette smoke for 7 days led to a decrease in inner vascular diameter. Decreased thickness of the vascular tunica media was observed after exposure for 28 days. Increased thickness of the tunica adventitia, increased total vascular wall thickness, increased total vascular diameter and qualitative increase in collagen deposition were observed. Vascular volume increased after 28 days of exposure.
Conclusion:
Passive smoking has a negative impact on renal vasculature.
... This raises the question as to which factors explain the remaining 81% of the variability. Both exogenous factors (environmental factors collectively termed 'exposome') including exposure to air pollution, 55 second-hand smoke, 24 noise, 55 diet, 56 psychosocial stress, [57][58][59] and endogenous factors such as genetic predisposition, 60 positive family history, 61 or depression 62 are known to affect endothelial function and CVD risk. Our data indicate that FMD and SCORE provide different information. ...
Aims
Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper is to assess FMD values in apparently healthy individuals and provide reference values to facilitate wider clinical use.
Methods and Results
In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body-mass-index, glucose, cholesterol, blood pressure, and brachial artery diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m2), smoking (-0.7%), and brachial artery diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller brachial artery diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (<5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c = 0.841, p < 0.001) showed that FMD of >6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD <3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n = 3,509) using similar FMD methodology showed that despite considerable heterogeneity (I2 = 0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R2 = 0.13).
Conclusions
We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of CV health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.
... Participants discussed four themes: (1) their perceptions and experiences with residential SHS; (2) strategies used to minimise SHS exposure from neighbours; (3) strategies used to minimise SHS exposure from smokers in the household; and (4) views on what it means to smoke in a socially responsible manner. In what follows, we discuss findings from key informants, smokers and non-smoking residents, with quotes to illustrate our points where relevant. ...
Background
People remain exposed to secondhand smoke, a serious health hazard, inside their home as households face challenges in setting no-smoking rules or are exposed to secondhand smoke drifting in from neighbouring homes. This study explores the psychosocial impacts, views, and experiences with residential secondhand smoke in a densely populated urban setting.
Methods
In-depth online or face to face interviews with 18 key informants who had been involved in public discourse, policy, advocacy or handling complaints related to residential secondhand smoke, 14 smokers, and 16 non-smokers exposed to secondhand smoke inside their home. All participants were residents of Singapore, a densely populated, multi-ethnic city-state. Interview transcripts were coded in NVivo using a deductive and inductive coding process.
Findings
Secondhand smoke has wide-reaching impacts on physical and psychosocial wellbeing, even if smokers tried to minimise secondhand smoke. Feelings of anxiety and stress are generally tied to feeling discomfort in one’s personal space, a perceived lack of control over the situation, resentment towards smokers, and concerns over the health effects. Family, community, and cultural dynamics add complexities to tackling the issue, especially in patriarchal households. Secondhand smoke exposure from neighbours is considered a widespread issue, exacerbated by structural factors such as building layout and the COVID-19 pandemic. Resolving the issue amicably is considered challenging due to the absence of regulations and a reluctance to stir up conflict with neighbours. While smokers took measures to reduce secondhand smoke, these were described as ineffective by other participants. Smokers appeared to have contrasting views from other participants on what it means to smoke in a socially responsible manner.
Conclusion
Given the wide-reaching psychosocial impacts of residential secondhand smoke, there is a case for stronger interventions, especially in densely populated urban settings where it is more difficult to avoid.
... We have previously shown that when FMD is impaired by tobacco or marijuana sidestream smoke, endothelium-independent vasodilation induced by nitroglycerin remains intact, indicating that impaired FMD reflects an impaired endothelial function. 28,30 Our results in the rodent FMD model indicate that the known consequences of cigarette smoke on vascular function 21,22,43 are not avoided by using these products even at the low exposure level of a single session of 10 cycles of pulsatile 5-second exposure over 5 minutes. Furthermore, Caporale et al. 4 showed that vaping nicotine-free e-cigarettes transiently impacts vascular function, consistent with our results that the e-cigarette aerosol with or without nicotine or flavors impaired endothelial function comparably to cigarettes. ...
Introduction
Electronic nicotine delivery systems (ENDS; i.e., vaping devices) such as e-cigarettes, heated tobacco products, and newer coil-less ultrasonic vaping devices are promoted as less harmful alternatives to combustible cigarettes. However, their cardiovascular effects are understudied. We investigated whether exposure to aerosol from a wide range of ENDS devices, including a new ultrasonic vaping device, impairs endothelial function.
Methods
We measured arterial flow-mediated dilation (FMD) in rats (n=8/group) exposed to single session of 10 cycles of pulsatile 5s exposure over 5 minutes to aerosol from e-liquids with and without nicotine generated from a USONICIG ultrasonic vaping device, previous generation e-cigarettes, 5% nicotine JUUL pods (Virginia Tobacco, Mango, Menthol), and an IQOS heated tobacco product; with Marlboro Red cigarette smoke and clean air as controls. We evaluated nicotine absorption and serum nitric oxide levels after exposure, and effects of different nicotine acidifiers on platelet aggregation.
Results
Aerosol/smoke from all conditions except air significantly impaired FMD. Serum nicotine varied widely from highest in the IQOS group to lowest in USONICIG and previous generation e-cig groups. NO levels were not affected by exposure. Exposure to JUUL and similarly acidified nicotine salt e-liquids did not affect platelet aggregation rate. Despite lack of heating coil, the USONICIG under airflow conditions heated e-liquid to ~77˚C.
Conclusions
A wide range of ENDS, including multiple types of e-cigarettes with and without nicotine, a heated tobacco product, and an ultrasonic vaping device devoid of heating coil, all impair FMD after a single vaping session comparably to combusted cigarettes.
Implications
The need to understand the cardiovascular effects of various ENDS is of timely importance, as we have seen a dramatic increase in the use of these products in recent years, along with the growing assumption among its users that these devices are relatively benign. Our conclusion that a single exposure to aerosol from a wide range of ENDS impairs endothelial function comparably to cigarettes indicates that vaping can cause similar acute vascular functional impairment to smoking and is not a harmless activity.
... The risk of measurement of exposure in Lu's study (Lu et al. 2013b) was low risk, while others were high risk. 2013a), six of the articles included in the study showed that SHS exposure was associated with features of vascular injury (Argacha et al. 2008;Celermajer et al. 1996;Heiss et al. 2008;Lu et al. 2013b;Panagiotakos et al. 2004;Woo et al. 2000) and three articles revealed no positive or negative association (Agarwal 2009;Agarwal and Naderi 2014;Jensen et al. 2005). Result from Ngu et al. showed moderate evidence supporting the higher risk of PAD in SHS exposure. ...
Purpose
The association between secondhand smoke (SHS) and peripheral arterial disease (PAD) was inconsistent and the studies were relatively scarce, hence, we conducted a meta-analysis of the association between SHS and PAD.
Materials and methods
We systematically searched three electronic databases (PubMed, EMBASE, and Web of Science), and calculated the pooled prevalence risk ratio (RR) and estimated standard error by random effect model from the meta-analysis. Furthermore, we performed a subgroup meta-analysis according to the location of SHS exposure.
Results
We initially identified 502 articles from the electronic database, and 6 articles, cross-sectional data from 4 cross-sectional studies and 2 prospective cohort studies, were included in the meta-analysis. Among these six articles, two studies showed a significant correlation between SHS exposure and PAD, whereas no study showed a negative correlation between SHS exposure and PAD. In the meta-analysis, pooled prevalence showed a significant association between SHS exposure and PAD (RR = 1.23; 95% confidence interval [CI] 1.08–1.41; z = 3.02, p = 0.003). In the subgroup analysis based on location of SHS exposure, the prevalence RR of PAD at home was 1.30 (95% CI 1.14–1.49, Z-3.99, p < 0.0001). The prevalence RR in the subgroup of SHS exposure at work was not significant (RR = 0.89; 95% CI 0.55–1.44; z = 0.48, p = 0.63).
Conclusion
Exposure to SHS was significantly and positively associated with PAD. Moreover, we found a significant association between exposure to SHS and PAD at home, but the association was not significant at work.
... Passive smoking may have adverse effects on vasoconstriction and/or vasodilation, due to nicotine causes vasoconstriction, which results in transient increases in BP. Further, Passive smoking may also lead to vascular endothelial dysfunction by affecting vascular endothelial cells [47,48]. Zhang J et al. [49] posited the endothelial dysfunction was mediated as a result of systemic inflammation. ...
Background
Vitamin D deficiency (VDD) may increase the risk of hypertension in women of childbearing age, who may be exposed to secondhand smoke (SHS) simultaneously. Till now, few studies have investigated the joint effects of VDD and SHS on hypertension in this population. We evaluated whether exposure to SHS modified the association between VDD and hypertension.
Methods
Data from National Health and Nutrition Examination Surveys (NHANES) 2007-2014 were analyzed. Our research subjects were 2826 nonsmoking and nonpregnant women of childbearing age (20-44 years old). Hypertension was defined based either on systolic blood pressure (SBP) ≥ 130 mmHg and/or diastolic blood pressure (DBP) ≥ 80 mmHg or on now taking prescribed medicine for hypertension. The directed acyclic graphs (DAG) and the back-door criterion were used to select a minimal sufficient adjustment set of variables (MSAs) that would identify the unconfounded effect of 25(OH)D and hypertension. The interactive effect of VDD and SHS on hypertension was evaluated by using logistic regression models, followed by strata-specific analyses.
Results
The prevalence of VDD in the hypertension group was significantly higher than that in the non-hypertension group (48.2% vs 41.0%, P = 0.008), as well as the exposure rate of SHS (39.1% vs 33.8%, P = 0.017). VDD was independently associated with nearly 50% increased risk of hypertension [adjusted odds ratio (aOR) = 1.43, 95% confidence interval (CI): 1.01, 2.04], while no significant association was observed between SHS and hypertension. However, SHS showed a significant synergistic effect on VDD with a higher aOR of 1.79 (95% CI: 1.14, 2.80) ( P interaction = 0.011). This synergistic effect was more obvious when stratified by BMI (in overweight women, aOR, 95% CI =4.74, 1.65-13.60 for interaction vs 2.33, 1.01-5.38 for VDD only) and race (in Non-Hispanic Black women, aOR, 95% CI =5.11, 1.58-16.54 for interaction vs 2.69, 1.10-6.62 for VDD only).
Conclusion
There exist synergistic effects of SHS and VDD on the prevalence of hypertension in American women of childbearing age, with more significant effects in women who were overweight or Non-Hispanic Black. Further studies are warranted to verify this finding in other populations, and the molecular mechanisms underlying the joint effect of SHS and VDD need to be elucidated.
... 142 Moreover, microvesicles can influence the breakdown of underlying structural proteins through matrix metalloproteinases (MMP), which microvesicles can carry at their surface. In vitro generated macrophage microvesicles display MMP-14 after smoke exposure, 18 ...
Extracellular vesicles (EVs) are membrane particles released by most cell types in response to different stimuli. They are composed of a lipid bilayer that encloses a wide range of bioactive material, including proteins and nucleic acids. EVs have garnered increasing attention over recent years, as their role in intercellular communication has been brought to light. As such, they have been found to regulate pathophysiologic pathways like inflammation, angiogenesis, or senescence, and are therefore implicated in key aspects atherosclerosis initiation and progression. Interestingly, EVs appear to have a multifaceted role; depending on their cargo, they can either facilitate or hamper the development of atherosclerotic lesions. In this review, we examine how EVs of varying origins may be implicated in the different phases of atherosclerotic lesion development. We also discuss the need to standardize isolation and analysis procedures to fully fulfil their potential as biomarkers and therapeutics for cardiovascular diseases. Review of the role of extracellular vesicles during the different phases of atherosclerotic lesion development that describes the need to standardize isolation and analysis procedures to fully realize their potential as biomarkers and therapeutics for cardiovascular diseases.
... EMPs, a submicron vesicle-like substance, are markers of endothelial dysfunction and released via cell activation and apoptosis [26]. Previous literature proposed many methods to measure these vesicles, since the accumulation could lead to atherosclerotic plaque formation, and found an association with atherosclerosis [27]. ...
(1) Background: In previous research, higher levels of urine heavy metals, especially lead and cadmium, have been associated with increased cardiovascular risk. However, there is no information linking exposure to heavy metal to endothelial and platelet microparticles (EMPs and PMPs), particularly in the younger population, which are novel biomarkers of endothelial dysfunction. (2) Methods: From a nationwide database, which was incepted in 1992–2000, screening for renal health among Taiwanese school children, a total of 789 subjects were recruited. Cross-sectional analysis was performed to evaluate the association between serum EMPs/PMPs and urine iron, nickel, copper, cadmium, lead, chromium, manganese, and zinc levels in the adolescent and young adult population. (3) Results: After we adjusted the conventional cardiovascular risk factors, CD31+/CD42a− and CD31+/CD42a+ counts, in subjects’ serum, respective markers of EMP and PMP displayed a significant positive dose-response relationship with urinary lead and cadmium levels. Higher quartiles of urine lead and cadmium levels were associated with an increased risk of higher EMPs/PMPs (≥75th percentile) in a multivariate logistic regression model. (4) Conclusion: Higher urinary lead and cadmium concentrations are strongly associated with endothelium–platelet microparticles in this adolescent and young adult population, which could help explain, in part, the mechanism through which heavy metal exposure results in cardiotoxicity.
... After adjusting for vascular risk factors, only CD62E + EPCs counts remained significantly lower in the control group, suggesting that migraine (independent of their subtype) itself is a vascular risk factor. These findings indicate that chronic migraine patients have higher endothelial turnover rates than controls and persistent endothelial activation [13,16]. ...
Migraine still causes a high rate of disability and is reported to increase the risk of cardiovascular and cerebrovascular diseases. Endothelial dysfunction is considered to be one of the underlying mechanisms linking migraine and vascular disorders. Investigation of endothelial function in migraine includes a variety of examinations including biomarkers and ultrasonography-based studies. Several proposed biomarkers for endothelial dysfunction are endothelial progenitor cells (EPCs), von Willebrand factor (vWF), nitric oxide (NO), tissue-type plasminogen activator antigen (tPA antigen), C-reactive protein (CRP), endothelin-1 (ET-1), and vascular endothelial growth factor (VEGF).
Brachial flow-mediated dilatation (FMD) is quite commonly used to reflect systemic endothelial dysfunction, while cerebral endothelial function can be assessed using breath holding index (BHI) on transcranial Doppler (TCD). The results of most studies in migraine sufferers indicate that endothelial dysfunction is found locally in the cerebral circulation, especially at the posterior circulation, while evidence for endothelial dysfunction in the systemic circulation remains controversial.
... Passive smoking may have adverse effects on vasoconstriction and/or vasodilation, due to nicotine causes vasoconstriction, which results in transient increases in BP. Further, Passive smoking may also lead to vascular endothelial dysfunction by affecting vascular endothelial cells43,44 . Zhang J et. al45 posited the endothelial dysfunction was mediated as a result of systemic in ammation. ...
Background
Vitamin D deficiency (VDD) may increase the risk for hypertension in women of childbearing age, and they may expose to secondhand smoke exposure (SHS) simultaneously. Till now, few studies have investigated the joint effects of VDD and SHS. We evaluated whether exposure to SHS modified the association between VDD and hypertension.Methods
Data from 2007-2014 National Health and Nutrition Examination Surveys (NHANES) were analyzed. Our research subjects were 2802 nonsmoking and nonpregnant women of childbearing age (20-44 years old). Hypertension was defined based either on systolic blood pressure (SBP) ≥ 130 mmHg and/or diastolic blood pressure (DBP) ≥ 80 mmHg or on now taking prescribed medicine for hypertension. The interactive effect of VDD and SHS on hypertension was evaluated by using logistic regression models, followed by strata-specific analyses.ResultsThe prevalence of VDD in the hypertension group was significantly higher than that in the non-hypertension group (48.2% vs 40.7%, P = 0.005), as well as the exposure rate of SHS (35.7% vs 30.5%, P = 0.017). VDD was positively associated with hypertension [adjusted odds ratio (aOR): 1.47, 95% confidence interval (CI): 1.03-2.08]. There was no association between secondhand smoke exposure and hypertension (aOR: 1.10, 95%CI: 0.85-1.43). However, when exposed to SHS and VDD simultaneously, the aOR estimation of the risk of hypertension increased to 1.83 (1.17, 2.87) with a significant interactive effect between SHS and VDD ( P adjusted = 0.009). When stratified according to BMI and race, the interactive effect was about twice the effect of VDD on hypertension alone in women who were overweight (for VDD: aOR = 2.37, 95%CI: 1.05-5.47; for interaction: aOR = 4.14, 95%CI: 1.48-11.58), and a similar pattern could also be observed in Non-Hispanic Black (for VDD: aOR = 2.74, 95%CI: 1.11-6.73; for interaction: aOR = 4.60, 95%CI: 1.53-13.80).ConclusionThere exist synergistic effects of SHS and VDD on the prevalence of hypertension in American women of childbearing age, with more significant effects in overweight women and Non-Hispanic Black women. Further studies are warranted to verify in other populations, and the molecular mechanisms underlying the joint effect of SHS and VDD need to be elucidated.
... These recent advancements can improve our understanding and accuracy in pinpointing the sites of endothelial dysfunction. EVs have also been shown to be upregulated in patients with endothelial dysfunction [162], and steep increases in EV numbers are associated with pathological conditions of endothelial dysfunction such as arterial and venous thrombosis [157]. Currently, a few clinical trials are measuring EVs as biomarkers or direct effectors of thrombosis, tumor spread, endothelial dysfunction and inflammation [163]. ...
Endothelium has a rich vesicular network that allows the exchange of macromolecules between blood and parenchymal cells. This feature of endothelial cells, along with their polarized secretory machinery, makes them the second major contributor, after platelets, to the particulate secretome in circulation. Extracellular vesicles (EVs) produced by the endothelial cells mirror the remarkable molecular heterogeneity of their parent cells. Cargo molecules carried by EVs were shown to contribute to the physiological functions of endothelium and may support the plasticity and adaptation of endothelial cells in a paracrine manner. Endothelium-derived vesicles can also contribute to the pathogenesis of cardiovascular disease or can serve as prognostic or diagnostic biomarkers. Finally, endothelium-derived EVs can be used as therapeutic tools to target endothelium for drug delivery or target stromal cells via the endothelial cells. In this review we revisit the recent evidence on the heterogeneity and plasticity of endothelial cells and their EVs. We discuss the role of endothelial EVs in the maintenance of vascular homeostasis along with their contributions to endothelial adaptation and dysfunction. Finally, we evaluate the potential of endothelial EVs as disease biomarkers and their leverage as therapeutic tools.
Transdermal nicotine patches (TNPs), administering nicotine into the bloodstream through skin, have been widely used as nicotine replacement therapy, and exposure to nicotine can be detected by measurement of plasma cotinine concentration. In animal studies, nicotine treatment could increase the number of endothelial progenitor cells (EPCs), but the effect of TNPs on circulating EPCs and their activity in humans remained unclear. This study aimed to explore the influence of TNPs on circulating EPCs with surface markers of CD34, CD133, and/or KDR, and colony‐forming function plus migration activity of early EPCs derived from cultured peripheral blood mononuclear cells before and after TNP treatments in young healthy nonsmokers. In parallel, pulse wave analysis (PWA) was applied to evaluate the vascular effect of TNP treatments. Twenty‐one participants (25.8 ± 3.6 years old, 10 males) used TNP (nicotine: 4.2 mg/day) for 7 consecutive days. During the treatment, the CD34 ⁺ EPCs progressively increased in number. In addition, the number of EPCs positive for CD34/KDR, CD133, and CD34/CD133 were also increased on day 7 of the treatment. Furthermore, the early EPC colony‐forming function and migration activity were increased with the plasma cotinine level positively correlating with change in colony‐forming unit number. PWA analyses on day 7, compared with pretreatment, did not show significant change except diastolic pressure time index, which was prolonged and implied potential vascular benefit. In conclusion, 7‐day TNP treatments could be a practical strategy to enhance angiogenesis of circulating EPCs to alleviate tissue ischemia without any hemodynamic concern.
Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation in the arteries, leading to narrowing and thrombosis that causes mortality. Emerging evidence has confirmed that atherosclerosis affects younger people and is involved in the majority of deaths worldwide. EVs are associated with critical steps in atherosclerosis, cholesterol metabolism, immune response, endothelial dysfunction, vascular inflammation, and remodeling. Endothelial cell-derived EVs can interact with platelets and monocytes, thereby influencing endothelial dysfunction, atherosclerotic plaque destabilization, and the formation of thrombus. EVs are potential diagnostic and prognostic biomarkers in atherosclerosis (AS) and cardiovascular disease (CVD). Importantly, EVs derived from stem/progenitor cells are essential mediators of cardiogenesis and cardioprotection and may be used in regenerative medicine and tissue engineering.
Objective
We investigated the relationship between using a rotary compression device (RCD) with or without sterile gauze and adverse events in transradial access (TRA) for coronary intervention.
Methods
In this study involving 933 patients at Yueyang Hospital, we recorded TRA-related adverse events, such as bleeding, forearm hematoma, swollen palms, radial artery occlusion (RAO) and others. Logistic regression was applied to assess the association.
Results
Of the 933 patients (66.7% males, average age 67.8 years), 511 used RCD with sterile gauze, whereas 422 used RCD without sterile gauze. The most common adverse events were radial artery hemorrhage (7.4%), hand swelling (4.8%) and RAO (4.6%). Logistic regression analysis revealed that the use of RCD with sterile gauze was associated with a higher prevalence of adverse events [odds ratio (OR), 1.74; 95% confidence interval (CI), 1.22–2.49), even with the adjustment of potential confounders (OR, 1.71; 95% CI, 1.19–2.45). Moreover, patients who used RCD with sterile gauze exhibited an increased risk of radial artery hemorrhage (OR, 1.83; 95% CI, 1.07–3.12), swelling of the hand (OR, 1.96; 95% CI, 1.02–3.75) and RAO (OR, 3.17; 95% CI, 1.49–6.72).
Conclusions
The use of RCD with sterile gauze in TRA is associated with a higher incidence of adverse events.
Nurses play a key role in advising patients to quit smoking, especially those with long-term conditions including cardiovascular disease. Peripheral artery disease (PAD) is an increasingly prevalent condition, and is the third most common presentation of atherosclerotic disease after coronary heart disease and stroke. Smoking cessation is crucial for patients with PAD but can be very challenging. Stopping smoking reduces cardiovascular morbidity and mortality, and improves claudication symptoms in patients with PAD. Those who continue to smoke are at higher risk of disease progression, amputation, myocardial infarction and death, and have poorer therapeutic outcomes. Quitting smoking is difficult, and patients should be offered a combination of behavioural and drug therapy. Nurses can provide several interventions to help patients quit and prevent relapse. A pilot study in a large London hospital found that no smokers had been referred to smoking cessation services by their vascular clinician (although some had been referred by their GP), given brief cessation advice or told how smoking cessation was essential for vascular preservation. Many thought smoking cessation programmes would not work.
Secondhand smoke (SHS) is a well-established cause of lung cancer, respiratory disease, heart disease and developmental issues in children, with an overwhelming evidence base spanning over four decades. In this narrative review, we describe studies which have also linked self-reported or cotinine-assessed SHS exposure in the home, workplace and other settings to mental health disorders including depression, suicide, anxiety, and psychological distress in children and adults, sleeping disorders, Attention Deficit Hyperactivity Disorder and behavioural issues in children, and dementia in older adults. In general, evidence indicates that SHS exposure is associated with these disorders in a dose-response manner, with higher odds reported in people who are exposed to SHS at high levels, frequently, and in the home environment. Most studies so far are cross-sectional albeit in large, nationally representative samples from various countries with a smaller number of longitudinal studies. More research is needed in this area to determine whether SHS is a direct cause of adverse mental health outcomes, and whether creating smokefree environments leads to improved mental wellbeing. In particular, more research is needed on the impact of smokefree home environments, an area which has received relatively little focus in smokefree interventions which generally target public places.
Aim: To elucidate the mechanism by which cigarette smoking causes vascular damage, we examined the relationship between cumulative cigarette consumption and abdominal obesity, and the possible mediating effect of smoking on arterial stiffness.
Methods: Cross-sectional data from 19499 never smokers and 5406 current smokers receiving health screening was analyzed. Abdominal obesity was assessed by ABSI, and arterial stiffness by CAVI. High CAVI was defined as CAVI ≥ 9.0.
Results: Current smoker showed higher ABSI than never smokers after propensity score matching. Cumulative cigarette consumption expressed in pack-years correlated with ABSI (Rs: 0.312 in men, 0.252 in women), and was also extracted as an independent factor associated with ABSI by multiple regression analysis. A linear relationship between pack-year and CAVI was observed (Rs: 0.544 in men, 0.423 in women). Pack-year had almost equal discriminatory power in predicting high CAVI in both sexes (C-statistic: 0.774 in men, 0.747 in women), and the best cut-offs of pack-year for high CAVI were 24.5 in men and 14.7 in women. Bivariate logistic regression models revealed that the association between pack-year higher than cut-off and high CAVI was independent of traditional risks. A mediating effect of ABSI (mediation rate: 9.9% in men and 11.2% in women), but not waist circumference (WC), on the association of pack-year with CAVI was observed, after adjusting for traditional risks.
Conclusion: Cumulative cigarette smoking in pack-years was independently associated with ABSI. ABSI partially mediates the association between pack-year and CAVI, suggesting that abdominal obesity partially mediates smoking-related vascular dysfunction.
Peripheral artery disease (PAD) is associated with increased risk of cardiovascular morbidity and mortality, poor functional status, and lower quality of life. Cigarette smoking is a major preventable risk factor for PAD and is strongly associated with a higher risk of disease progression, worse post-procedural outcomes, and increased healthcare utilization. The arterial narrowing due to atherosclerotic lesions in PAD leads to decreased perfusion to the limbs and can ultimately cause arterial obstruction and limb ischemia. Endothelial cell dysfunction, oxidative stress, inflammation, and arterial stiffness are among the key events during the development of atherogenesis. In this review, we discuss the benefits of smoking cessation among patients with PAD and the use of smoking cessation methods including pharmacological treatment. Given that smoking cessation interventions remain underutilized, we highlight the importance of incorporating smoking cessation treatments as part of the medical management of patients with PAD. Regulatory approaches to reduce the uptake of tobacco product use and support smoking cessation have the potential to reduce the burden of PAD.
Chronic liver diseases are a source of morbidity and mortality worldwide with huge
implications on public health. Nonalcoholic fatty liver disease (NAFLD) is the most
common cause of chronic liver disease, mirroring the rising rates of metabolic syndrome worldwide. NAFLD results from the accumulation of fat in the liver, in the
absence of alcohol consumption or other secondary etiologies of fat accumulation.
The disease spectrum ranges from nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), typically differentiated by evidence of hepatic necroinflammation and hepatocyte injury found in NASH. With disease progression, advanced fibrosis can develop, eventually leading to cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD has been described as the hepatic manifestation of metabolic syndrome. The prevalence rates of NAFLD have been reported to be 30% 36% in the United States and 20%-30% in Europe. Given the growing prevalence
of NAFLD, it is likely to be the leading cause of liver transplantation by
2030. There is emerging evidence on the extra-hepatic complications of NAFLD,
with its increasing recognition as a multisystem disease. Cardiovascular diseases
(CVDs) are the leading cause of mortality among NAFLD patients, followed by extra-hepatic cancers and then liver-related complications. The presence of NAFLD is not only associated with several cardiovascular manifestations, but studies have also demonstrated a positive correlation between the severity of NAFLD and CVD. In comparison to the general population, NAFLD patients have an increased all-cause mortality by 57%, mainly comprising liver-related and cardiovascular-related causes. Although adverse liver-related outcomes tend to develop only after the development of fibrosis, the CVD risk can occur earlier in the disease spectrum. This CVD risk is increased by approximately twofold with the presence of type 2 diabetes mellitus.
The pathogenic factors associated with NAFLD are multifactorial. This chapter summarizes the underlying putative mechanisms of NAFLD, NASH, and CVD. The cardiovascular manifestations of NAFLD and NASH, as well as possible management strategies, are also discussed.
Introduction
The aims of this study were to characterize particle size in a thirdhand smoke aerosol and measure the effects of controlled inhalational exposure to thirdhand smoke on biomarkers of tobacco smoke exposure, inflammation and oxidative stress in human subjects Secondhand cigarette smoke changes physically and chemically after release into the environment. Some of the resulting chemicals persist indoors as thirdhand cigarette smoke. Thirdhand smoke that is sorbed to surfaces can emit particles back into the air.
Methods
Smoke particle size was measured with a scanning mobility particle sizer/condensation particle counter. Using a crossover study design, 18 healthy nonsmokers received a three-hour inhalational exposure to thirdhand smoke and to filtered, conditioned air. Thirdhand smoke was generated with a smoking machine and aged overnight in a chamber. The chamber was flushed with clean air to create the THS aerosol. The tobacco smoke metabolites cotinine, 3-hydroxycotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) were measured in urine. Vascular endothelial growth factor and interleukin-6 in plasma, and 8-isoprostane in urine, were measured using enzyme-linked immunosorbent assay kits.
Results
Mean smoke particle size increased with aging (171 nm to 265 nm). We found significant increases in urinary cotinine and 3-hydroxycotinine after three hours of exposure to thirdhand smoke and no significant increases in NNAL, interleukin-6, vascular endothelial growth factor or 8-isoprostane.
Conclusions
Acute inhalational exposure to 22-hour old tobacco smoke aerosol caused increases in the metabolites of nicotine but not the metabolites of the tobacco-specific nitrosamine NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone). This corroborates the utility of cotinine and NNAL for secondhand and thirdhand smoke exposure screening.
Implications
This study shows that a three-hour inhalational exposure to the tobacco smoke aerosol that forms in a room that has been smoked in and left unventilated overnight causes increases in urinary metabolites of nicotine, but not of the tobacco-specific nitrosamine NNK. This suggests that cleaning personnel and others who live and work in rooms polluted with aged or thirdhand cigarette smoke regularly may have inhalational exposures and potential health effects related to their exposure to nicotine and other smoke toxicants.
Background
Circulating angiogenic cells (CACs) are indicative of vascular health and repair capacity; however, their relationship with chronic e-cigarette use is unclear. This study aims to assess the association between e-cigarette use and CAC levels.
Methods
We analyzed CAC levels in 324 healthy participants aged 21–45 years from the cross-sectional Cardiovascular Injury due to Tobacco Use study in four groups: never tobacco users ( n = 65), sole e-cigarette users ( n = 19), sole combustible cigarette users ( n = 212), and dual users ( n = 28). A total of 15 CAC subpopulations with four cell surface markers were measured using flow cytometry: CD146 (endothelial), CD34 (stem), CD45 (leukocyte), and AC133 (early progenitor/stem). Generalized linear models with gamma distribution and log-link were generated to assess association between CACs and smoking status. Benjamini-Hochberg were used to adjust p-values for multiple comparisons.
Results
The cohort was 47% female, 51% Black/African American, with a mean (± SD) age of 31 ± 7 years. Sole cigarette use was significantly associated with higher levels of two endothelial marker CACs (Q ⩽ 0.05). Dual users had higher levels of four endothelial marker CACs and one early progenitor/stem marker CAC (Q ⩽ 0.05). Sole e-cigarette users had higher levels of one endothelial and one leukocyte marker CAC (Q ⩽ 0.05).
Conclusion
Dual use of e-cigarettes and combustible cigarettes was associated with higher levels of endothelial origin CACs, indicative of vascular injury. Sole use of e-cigarettes was associated with higher endothelial and inflammatory CACs, suggesting ongoing systemic injury. Distinct patterns of changes in CAC subpopulations suggest that CACs may be informative biomarkers of changes in vascular health due to tobacco product use.
La revascularisation des îlots greffés est déterminante pour le succès de la greffe. Le contact des îlots avec le sang de la veine porte induit une réaction inflammatoire précoce appelée IBMIR caractérisée par la production de cytokines pro-inflammatoires dans l'environnement des îlots. Une des réponses endothéliales au stress de l'ischémie et de l'IBMIR est la transition endothélio-mésenchymateuse (EndTM). Notre étude réside dans la caractérisation de l'EndTM et dans l’étude de l’effet protecteur du Dulaglutide sur l'endothélium intra-insulaire contre l'EndMT induite par les cytokines de l'IBMIR. Nos données indiquent une diminution progressive des marqueurs endothéliaux et l'acquisition de marqueurs mésenchymateux des cellules endothéliales accompagnée de la libération de microvésicules pro-inflammatoires. Le Dulaglutide exerce une cytoprotection contre les réponses induites par les cytokines de manière GLP-1R dépendante, ainsi que diminue l'effet proinflammatoire cytotoxique des MVs. Le Dulaglutide représente une potentielle thérapie adjuvante pour améliorer l’efficacité de la greffe d’îlots.
Tobacco smoking is strongly linked to vascular damage contributing to the development of hypertension, atherosclerosis, as well as an increased risk for neurodegeneration. Still, the contribution of the innate immune system to the development of vascular damage upon chronic tobacco use before the onset of clinical symptoms is not fully elucidated. Notably, our data provide evidence that a single acute exposure to tobacco in never smokers elicits a secretion of extracellular vesicles by endothelial cells expressing CD105 and CD49e, granting further recognition of early preclinical biomarker of vascular damage. Further, we investigated the effects of smoking on the immune system of healthy asymptomatic chronic smokers compared to never-smokers and focused on the innate immune system. Our data reveal a distinct immune landscape representative for early stages of vascular damage before tobacco smoking related disease develop in clinically asymptomatic chronic smokers. These results indicate a dysregulated immuno-vascular axis in chronic tobacco smokers that are considered healthy individuals. The distinct alterations are characterized by increased CD36 expression by blood monocyte subsets, neutrophilia, increased plasma IL-18 and reduced levels of IL-33, IL-10 and IL-8. Further, the detection of lower circulating BDNF and elevated sTREM2, specific markers for neurodegeneration, suggests a considerable pre-clinical impact of tobacco smoking on CNS function in clinically healthy individuals. These findings provide further insight into the initial and ongoing effects of tobacco smoking and the potential vascular damage contributing to the progression of neurodegenerative disorders, specifically cerebrovascular dysfunction and dementia.
Background
Thirdhand smoke (THS) exposure correlated with significant metabolism of carcinogenic chemicals and the potential to cause detrimental health effects. Human harm research of THS exposure is limited to one other study and overall, there is a general lack of knowledge of the human health responses to THS exposure.
Methods
This was a clinical investigation to evaluate the health effects of 3-h dermal THS exposure from urine and plasma. 10 healthy, non-smoking subjects were recruited for dermal exposure for 3 h exposed to clothing impregnated with filtered clean air or THS. Exposures to clean air or THS occurred 20-30 days apart.
Findings
In THS-exposed group, there was a significant elevation of urinary 8-OHdG, 8-isoprostane, protein carbonyls. The THS 3-h exposure identified proteomics pathways of inflammatory response (p=2.18 × 10⁻⁸), adhesion of blood cells (p=2.23 × 10⁻⁸), atherosclerosis (p=2.78 × 10⁻⁹), and lichen planus (p=1.77 × 10⁻⁸). Nine canonical pathways were significantly activated including leukocyte extravasation signaling (z-score=3.0), and production of nitric oxide and reactive oxygen in macrophages (z-score=2.1). The THS 22-h proteomics pathways revealed inflammation of organ (p=3.09 × 10⁻⁸), keratinization of the epidermis (p=4.0 × 10⁻⁷), plaque psoriasis (p=5.31 × 10⁻⁷), and dermatitis (p=6.0 × 10⁻⁷). Two activated canonical pathways were production of nitric oxide and reactive oxygen in macrophages (z-score=2.646), and IL-8 signaling (z-score=2.0).
Interpretation
This is a clinical study demonstrating that acute dermal exposure to THS mimics the harmful effects of cigarette smoking, alters the human plasma proteome, initiates mechanisms of skin inflammatory disease, and elevates urinary biomarkers of oxidative harm.
Funding
Funding was provided by the Tobacco Related Disease Research Program (TRDRP) 24RT-0037 TRDRP, 24RT-0039 TRDRP, and 28PT-0081 TRDRP.
Extracellular vehicles (EVs) are nanoscale lipid bilayer vesicles that carry biologically active biomolecule cargos like proteins, lipids, and nucleic acids (DNA, RNA) outside of the cell. Blood (serum/plasma), urine, and bronchoalveolar lavage fluid are all examples of biofluids from which they may be collected. EVs play a vital role in intracellular communication. The molecular signature of EVs largely depends on the parental cell's status. EVs are classified into two groups, (1) exosomes (originated by endogenous route) and (2) microvesicles (originated from the plasma membrane, also known as ectosomes). The quantity and types of EV cargo vary during normal conditions compared to pathological conditions (chronic inflammatory lung diseases or lung cancer). Consequently, EVs contain novel biomarkers that differ based on the cell type of origin and during lung diseases. Small RNAs (e.g., microRNAs) are transported by EVs, which is one of the most rapidly evolving research areas in the field of EVs biology. EV‐mediated cargos transport small RNAs that can result in reprograming the target/recipient cells. Multiple chronic inflammatory lung illnesses, such as chronic obstructive pulmonary disease, asthma, pulmonary hypertension, pulmonary fibrosis, cystic fibrosis, acute lung injury, and lung cancer, have been demonstrated to be regulated by EV. In this review, we will consolidate the current knowledge and literature on the novel role of EVs and their small RNAs concerning chronic lung diseases (CLDs). Additionally, we will also provide better insight into the clinical and translational impact of mesenchymal stem cells‐derived EVs as novel therapeutic agents in treating CLDs.
The widespread legalization of recreational marijuana raises growing concerns about exposure to secondhand marijuana smoke. An important location for marijuana smoking is the home, but few measurements of air pollutant concentrations in the home are available for a marijuana joint fully smoked in one of its rooms. We used research grade calibrated real-time continuous PM2.5 air monitors in controlled 5-hour experiments to measure fine particle concentrations in the 9 rooms of a detached, two-story, 4-bedroom home with either a tobacco cigarette or a marijuana joint fully smoked in the home's living room. The master bedroom's door was closed, and the other bedroom doors were open, as was the custom of occupants of this residence. In two experiments with a Marlboro tobacco cigarette smoked by a machine in the living room, the 5-hour mean PM2.5 concentration in 9 rooms of the home were 15.2 μg/m³ (SD 5.6 μg/m³) and 15.0 μg/m³ (SD 3.7 μg/m³). In contrast, three experiments with pre-rolled marijuana joints smoked in the same manner in the living room produced 5-hour mean PM2.5 concentrations of 38.3 μg/m³ (SD 10.0 μg/m³), 79.8 μg/m³ (SD 25.7 μg/m³) and 80.7 μg/m³ (SD 28.8 μg/m³). In summary, the average secondhand PM2.5 concentrations from smoking a marijuana joint in the home were found to be 4.4 times as great as the secondhand PM2.5 concentrations from smoking a tobacco cigarette. Opening 3 windows by 12.7 cm reduced the high PM2.5 concentrations from marijuana smoking by 67 %, but the PM2.5 levels still exceeded those produced by tobacco smoking with the windows closed.
Secondhand smoke (SHS) remains a common health threat in densely populated, urban settings. We estimated the prevalence of exposure and associated respiratory symptoms, knowledge, attitudes, and behaviors in a multi‐ethnic, weighted sample of Singapore residents using a cross‐sectional survey of 1806 adults. We weighted data to match the national population in terms of gender, ethnicity, and education level and analyzed data using descriptive statistics, bivariate analyses, multiple linear and logistic regressions, and a multinomial logistic regression model. About 88% of respondents reported regular SHS exposure. Nearly 57% reported exposure to neighbors' SHS at home. Respiratory symptoms were reported by 32.5% and significantly associated with exposure to daily (AOR = 2.63, 95% CI = 1.62–4.36), non‐daily (AOR = 1.75, 95% CI = 1.14–2.77), and neighbors' (AOR = 1.37, 95% CI = 1.07–1.76) SHS. More knowledge of SHS was associated with male gender (β = 0.28, p = 0.0009) and higher household income (linear trend; p = 0.0400). More negative attitudes to SHS were associated with older age (linear trend; p < 0.0001). Engaging in behaviors to avoid SHS was associated with a more negative attitude to SHS (AOR = 1.09–1.23). SHS exposure is common in Singapore's densely populated setting and associated with respiratory symptoms, even if exposure is non‐daily or from neighboring homes.
Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality all over the world. Extracellular vesicles (EVs), small lipid-bilayer membrane vesicles released by most cellular types, exert pivotal and multifaceted roles in physiology and disease. Emerging evidence emphasizes the importance of EVs in intercellular communication processes with key effects on cell survival, endothelial homeostasis, inflammation, neoangiogenesis, and thrombosis. This review focuses on EVs as effective signaling molecules able to both derail vascular homeostasis and induce vascular dysfunction, inflammation, plaque progression, and thrombus formation as well as drive anti-inflammation, vascular repair, and atheroprotection. We provide a comprehensive and updated summary of the role of EVs in the development or regression of atherosclerotic lesions, highlighting the link between thrombosis and inflammation. Importantly, we also critically describe their potential clinical use as disease biomarkers or therapeutic agents in atherothrombosis.
Background
The prevalence of hypertension may be affected by environmental pollution and personal behavior.
Objectives
We aimed to evaluate the interaction effects of secondhand smoke exposure and overweight on hypertension.
Methods
In this cross-sectional study, a total of 627 workers from a coking plant in China and 1011 individuals from the NHANES database in the United States from 2013 to 2016 were selected as the research participants. The concentrations of 11 urinary polycyclic aromatic hydrocarbons (PAHs) metabolites and 3 tobacco metabolites were measured. An interaction effect was tested in the modified Poisson regression models.
Results
For smokers among Chinese coke oven workers, the only statistically significant positive association was with hypertension in the highest tertile of nicotine metabolized ratio (NMR) (PR: 1.539, 95% CI: 1.013–2.337). Nonsmoking Chinese workers with 3rd tertile urinary nicotine levels were associated with a 114.8% significantly increased prevalence of hypertension (PR: 2.148, 95% CI: 1.025–4.500) compared to nonsmokers 1st tertile with nicotine levels. Association between tobacco exposure and hypertension is possibly modified by PAHs exposure (PR: 2.335, 95% CI: 0.933–5.841). Nonsmokers in the NHANES database with high urinary nicotine levels were associated with a 17.3% significantly increased prevalence of hypertension (PR: 1.173, 95% CI: 1.028–1.338) compared to those with low nicotine levels. We observed that overweight people with high nicotine levels had a significantly higher likelihood of hypertension than no overweight people with low nicotine levels among nonsmoking Chinese coke oven workers and NHANES participants (PR = 4.686, 95% CI: 1.488–14.754; PR = 1.251, 95% CI: 1.039–1.506).
Conclusions
Tobacco exposure and overweight are important risk factors for hypertension, and secondhand smoke exposure and overweight have an interactive effect on the incidence of hypertension in nonsmoking Chinese coke oven workers and NHANES participants.
Cardiovascular disease remains the main cause of human morbidity and mortality in the developed countries. Microparticles (MPs) are small vesicles originating from the cell membrane as a result of various stimuli and particularly of biological processes that constitute the pathophysiology of atherosclerosis, such as endothelial damage. They form vesicles that can transfer various molecules and signals to remote target cells without direct cell to cell interaction. Circulating microparticles have been associated with cardiovascular diseases. Therefore, many studies have been designed to further investigate the role of microparticles as biomarkers for diagnosis, prognosis, and disease monitoring. To this concept the pro-thrombotic and atherogenic potential of platelets and endothelial derived MPs has gain research interest especially concerning accelerate atherosclerosis and acute coronary syndrome triggering and prognosis. MPs especially of endothelial origin have been investigated in different clinical scenarios of heart failure and in association of left ventricular loading conditions. Finally, most cardiovascular risk factors present unique patterns of circulating MPs population, highlighting their pathophysiologic link to cardiovascular disease progression. In this review article we present a synopsis of the biogenesis and characteristics of microparticles, as well as the most recent data concerning their implication in the cardiovascular settings.
Bu kitapta sağlık kavramı açıklanarak, fiziksel aktivitenin birey ve toplum
sağlığın korunması ve iyileştirilmesi üzerindeki etkileri kapsamlı olarak ele alınmaktadır.
Bireyin günlük yaşamını sürdürmesi için gerekli olan enerji harcaması
olarak tanımlanan fiziksel aktivite ile sağlıkla ilgili fiziksel uygunluğun bir
veya birkaç bileşenini iyileştirmeyi amaçlayan egzersiz eğitimiyle ilgili konular
farklı yönleriyle ve zengin bir içerikte fizyoterapist bakış açısıyla yer bulmaktadır.
Beslenme ile ilgili temel prensipler, yaşamın farklı dönemlerinde, kronik
hastalıklarda, engelli bireylerde, çalışan kişilerde ve sporcularda sağlığın korunmasında
beslenmenin önemi diyetisyen bakış açısıyla kapsamlı olarak irdelenmektedir.
Omurga, diş, işitme sağlığı, bilişsel sağlık, üreme sistemi ve cinsel
sağlık, uyku ve tütün kontrolü gibi sağlığın korunması açısından özel konular
hakkındaki bilgiler alanlarında değerli deneyime sahip akademisyenler tarafından
kitapta yer bulmaktadır.
Exposure to fine particulate matter (PM2.5) air pollution is associated with quantitative deficits of circulating endothelial progenitor cells (EPCs) in humans. Related exposures of mice to concentrated ambient PM2.5 (CAP) likewise reduces levels of circulating EPCs and induces defects in their proliferation and angiogenic potential as well. These changes in EPC number or function are predictive of larger cardiovascular dysfunction. To identify global, PM2.5-dependent mRNA and miRNA expression changes that may contribute to these defects, we performed a transcriptomic analysis of cells isolated from exposed mice. Compared with control samples, we identified 122 upregulated genes and 44 downregulated genes in EPCs derived from CAP-exposed animals. Functions most impacted by these gene expression changes included regulation of cell movement, cell and tissue development, and cellular assembly and organization. With respect to miRNA changes, we found that 55 were upregulated while 53 were downregulated in EPCs from CAP-exposed mice. The top functions impacted by these miRNA changes included cell movement, cell death and survival, cellular development, and cell growth and proliferation. A subset of these mRNA and miRNA changes were confirmed by qRT-PCR, including some reciprocal relationships. These results suggest that PM2.5-induced changes in gene expression may contribute to EPC dysfunction and that such changes may contribute to the adverse cardiovascular outcomes of air pollution exposure.
Environmental air pollution exposure is a leading cause of death worldwide, and with increasing industrialization and urbanization, its disease burden is expected to rise even further. The majority of air pollution exposure-associated deaths are linked to cardiovascular disease (CVD). Although ample research demonstrates a strong correlation between air pollution exposure and CVD risk, the mechanisms by which inhalation of polluted air affects cardiovascular health are not completely understood. Inhalation of environmental air pollution has been associated with endothelial dysfunction, which suggests that air pollution exposure impacts CVD health by inducing endothelial injury. Interestingly, recent studies demonstrate that air pollution exposure affects the number and function of endothelial progenitor cells (EPCs) - subpopulations of bone marrow-derived pro-angiogenic cells that have been shown to play an essential role in maintaining cardiovascular health. In line with their beneficial function, chronically low levels of circulating EPCs and EPC dysfunction (e.g., in diabetic patients) have been associated with vascular dysfunction, poor cardiovascular health, and increases in the severity of cardiovascular outcomes. In contrast, treatments that improve EPC number and function (e.g., exercise) have been found to attenuate cardiovascular dysfunction. Considering the critical, non-redundant role of EPCs in maintaining vascular health, air pollution exposure-induced impairments in EPC number and function could lead to endothelial dysfunction, consequently increasing the risk for CVD. This review article covers novel aspects and new mechanistic insights of the adverse effects of air pollution exposure on cardiovascular health associated with changes in EPC number and function.
After more than a decade of electronic cigarette (E-cig) use in the U.S., uncertainty persists regarding E-cig use and long-term cardiopulmonary disease risk. As all E-cigs use propylene glycol and vegetable glycerin (PG:VG) and generate abundant saturated aldehydes, mice were exposed by inhalation to either PG:VG-derived aerosol, formaldehyde (FA), acetaldehyde (AA), or filtered air. Biomarkers of exposure and cardiopulmonary injury were monitored by mass spectrometry (urine metabolites); radiotelemetry (respiratory reflexes); isometric myography (aorta); and, flow cytometry (blood markers). Acute PG:VG exposure significantly affected multiple biomarkers including pulmonary reflex (decreased respiratory rate, -50%); endothelium-dependent relaxation (-61.8±4.2%); decreased WBC (-47±7%); and, increased RBC (+6±1%) and hemoglobin (+4±1%) vs air control group. Notably, FA exposure recapitulated the prominent effects of PG:VG aerosol on pulmonary irritant reflex and endothelial dysfunction, whereas AA exposure did not. To attempt to link PG:VG exposure with FA or AA exposure, urinary formate and acetate levels were measured by GC-MS. Although neither FA nor AA exposure altered excretion of their primary metabolite, formate or acetate, respectively, compared with air-exposed controls, PG:VG aerosol exposure significantly increased post-exposure urinary acetate but not formate. These data suggest that E-cig use may increase cardiopulmonary disease risk independent of the presence of nicotine and/or flavorings. This study indicates that FA levels in tobacco product-derived aerosols should be regulated to levels that do not induce biomarkers of cardiopulmonary harm. There remains a need for reliable biomarkers of exposure to inhaled FA and AA.
Respiratory diseases and their comorbidities, such as cardiovascular disease and muscle atrophy, have been increasing in the world. Extracellular vesicles (EVs), which include exosomes and microvesicles, are released from almost all cell types and play crucial roles in intercellular communication, both in the regulation of homeostasis and the pathogenesis of various diseases. Exosomes are of endosomal origin and range in size from 50-150 nm in diameter, while microvesicles are generated by the direct outward budding of the plasma membrane in size ranges of 100-2000 nm in diameter. EVs can contain various proteins, metabolites, and nucleic acids, such as mRNA, non-coding RNA species, and DNA fragments. In addition, these nucleic acids in EVs can be functional in recipient cells through EV cargo. The endothelium is a distributed organ of considerable biological importance, and disrupted endothelial function is involved in the pathogenesis of respiratory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), and acute respiratory distress syndrome (ARDS). Endothelial cell-derived EVs (EC-EVs) play crucial roles in both physiological and pathological conditions by traveling to distant sites through systemic circulation. This review summarizes the pathological roles of vascular microRNAs contained in EC-EVs in respiratory diseases, mainly focusing on COPD, PH, and ARDS. Furthermore, this review discusses the potential clinical usefulness of EC-EVs as therapeutic agents in respiratory diseases.
Aims
Endothelial microparticles (EMPs) are extracellular vesicles secreted by endothelial cells. The purpose of this research is to explore that the clinical significance and roles in angiogenesis and endothelial dysfunction of circulating microparticles in Perthes disease.
Main methods
We collected platelet-poor plasma (PPP) from patients and controls, then microparticles (MPs) were extracted. Flow cytometry was performed to calculate the concentrations of CD31+/CD42b-, CD62E+ and CD31+/CD42b+ MPs. ELISA was performed to detect the expression level of biomarkers of endothelial dysfunction and inflammatory factors in plasma. In vitro experiments to evaluate the effect of circulating MPs and EMPs derived from IL-6-stimulated human umbilical vein endothelial cells (HUVECs) on angiogenesis and endothelial dysfunction.
Key findings
Our results revealed that the CD31+/CD42b- EMPs were significantly higher in Perthes disease group than in the control group. The Perthes-MPs being taken up by HUVECs promoted endothelial cell apoptosis, endothelial dysfunction and inhibited angiogenesis in vitro. Moreover, the level of IL-6 in plasma significantly increased in patients with Perthes, which was tightly correlated with the elevated level of circulating CD31+/CD42b- EMPs. IL-6 promoted HUVECs to secrete CD31+/CD42b- MPs, and EMPs derived from high concentration IL-6-stimulated (100 and 1000 pg/mL) HUVECs promoted endothelial cell apoptosis, endothelial dysfunction and inhibited angiogenesis.
Significance
In summary, our study suggests that circulating EMPs in the phenotypic spectrum revealed unique phenotypes of endothelial dysfunction, showing close correlation with the secretion of IL-6. These circulating EMPs may give rise to endothelial cell apoptosis, endothelial dysfunction and angiogenesis in Perthes disease.
Electronic nicotine delivery systems (often known as e-cigarettes) are a novel tobacco product with growing popularity, particularly among younger demographics. The implications for public health are twofold, as these products may represent a novel source of tobacco-associated disease but may also provide a harm reduction strategy for current tobacco users. There is increasing recognition that e-cigarettes impact vascular function across multiple organ systems. Herein, we provide a comparison of evidence regarding the role of e-cigarettes versus combustible tobacco in vascular disease and implications for blood-brain barrier dysfunction and cognitive decline. Multiple non-nicotinic components of tobacco smoke have been identified in e-cigarette aerosol, and their involvement in vascular disease is discussed. In addition, nicotine and nicotinic signaling may modulate peripheral immune and endothelial cell populations in a highly context-dependent manner. Direct preclinical evidence for electronic nicotine delivery system–associated neurovascular impairment is provided, and a model is proposed in which non-nicotinic elements exert a proinflammatory effect that is functionally antagonized by the presence of nicotine.
Passive smoking has been linked to an increased risk of dying from atherosclerotic heart disease. Since endothelial dysfunction is an early feature of atherogenesis and occurs in young adults who actively smoke cigarettes, we hypothesized that passive smoking might also be associated with endothelial damage in healthy young-adult nonsmokers.
We studied 78 healthy subjects (39 men and 39 women) 15 to 30 years of age (mean +/- SD, 22 +/- 4): 26 control subjects who had never smoked or had regular exposure to environmental tobacco smoke, 26 who had never smoked but had been exposed to environmental tobacco smoke for at least one hour daily for three or more years, and 26 active smokers. Using ultrasonography, we measured the brachial-artery diameter under base-line conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent dilator).
Flow-mediated dilatation was observed in all control subjects (8.2 +/- 3.1 percent; range, 2.1 to 16.7) but was significantly impaired in the passive smokers (3.1 +/- 2.7 percent; range, 0 to 9; P < 0.001 for the comparison with the controls) and in the active smokers (4.4 +/- 3.1 percent; range, 0 to 10; P < 0.001 for the comparison with the controls; P = 0.48 for the comparison with the passive smokers). In the passive smokers, there was an inverse relation between the intensity of exposure to tobacco smoke and flow-mediated dilatation (r = -0.67, P < 0.001). In contrast, dilatation induced by nitroglycerin was similar in all groups.
Passive smoking is associated with dose-related impairment of endothelium-dependent dilatation in healthy young adults, suggesting early arterial damage.
The concentrations of environmental tobacco smoke (ETS) to which workers are exposed have been measured, using nicotine or other tracers, in diverse workplaces. Policies restricting workplace smoking to a few designated areas have been shown to reduce concentrations of ETS, although the effectiveness of such policies varies among work sites. Policies that ban smoking in the workplace are the most effective and generally lower all nicotine concentrations to less than 1 microg/m3; by contrast, mean concentrations measured in workplaces that allow smoking generally range from 2 to 6 microg/m3 in offices, from 3 to 8 microg/m3 in restaurants, and from 1 to 6 microg/m3 in the workplaces of blue-collar workers. Mean nicotine concentrations from 1 to 3 microg/m3 have been measured in the homes of smokers. Furthermore, workplace concentrations are highly variable, and some concentrations are more than 10 times higher than the average home levels, which have been established to cause lung cancer, heart disease, and other adverse health effects. For the approximately 30% of workers exposed to ETS in the workplace but not in the home, workplace exposure is the principal source of ETS. Among those with home exposures, exposures at work may exceed those resulting from home. We conclude that a significant number of U.S. workers are exposed to hazardous levels of ETS.
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Figure 4
Vascular endothelial growth factor (VEGF) has been shown to promote neovascularization in animal models and, more recently, in human subjects. This feature has been assumed to result exclusively from its direct effects on fully differentiated endothelial cells, i.e. angiogenesis. Given its regulatory role in both angiogenesis and vasculogenesis during fetal development, we investigated the hypothesis that VEGF may modulate endothelial progenitor cell (EPC) kinetics for postnatal neovascularization. Indeed, we observed an increase in circulating EPCs following VEGF administration in vivo. VEGF-induced mobilization of bone marrow-derived EPCs resulted in increased differentiated EPCs in vitro and augmented corneal neovascularization in vivo. These findings thus establish a novel role for VEGF in postnatal neovascularization which complements its known impact on angiogenesis.
Background:
The mechanisms involved in the dysfunction of both endothelium-dependent vasodilatation (EDV) and NO biosynthesis related to smoking are unclear. In this study, EDV was assessed in healthy smokers and nonsmokers in vivo and, using serum from the same individuals, was related to the NO biosynthetic pathway in vitro.
Methods and results:
Flow-mediated EDV of the brachial artery was measured in 23 male patients (8 nonsmokers and 15 smokers). Serum was collected, added to confluent ( approximately 85%) monolayers of human umbilical vein endothelial cells (HUVECs), and incubated for 12 hours. Basal and substance P-stimulated NO production was measured. The HUVECs used for measuring basal NO production were lysed, and both endothelial NO synthase (eNOS) protein expression and eNOS activity were determined. EDV was lower in smokers compared with nonsmokers (P<0.001). HUVECs treated with serum from smokers compared with nonsmokers showed significantly lower basal (P<0.0001) and stimulated (P<0.02) NO production, higher eNOS expression (P<0.0001), but lower eNOS activity (P<0.004). There was a significant positive correlation between in vivo EDV and in vitro substance P-stimulated NO production (rho=0.57, P<0.01) and between basal NO production and eNOS activity (r=0.54, P<0.008) and a negative correlation between basal NO production and eNOS protein expression (r=-0.60, P<0.003). CONCLUIONS: This is the first study to combine an in vivo model with a near-physiological in vitro model to demonstrate an association between decreased NO production and reduced EDV. Cigarette smoking was associated with reduced EDV, NO generation, and eNOS activity in the presence of increased eNOS protein expression.
This study was performed to establish whether microparticles from plasma of women with preeclampsia cause endothelial dysfunction, as described for isolated myometrial arteries in preeclampsia.
Myometrial arteries were isolated from biopsy specimens obtained at cesarean delivery from healthy pregnant women (n = 22) and mounted in a wire myograph. Bradykinin concentration-response curves were obtained before and after 1-hour incubation or after overnight incubation with one of the following preparations of plasma from individual women with preeclampsia (n = 16): Whole plasma, microparticle-free plasma, isolated microparticles resuspended in physiologic saline solution or physiologic saline solution. Overnight incubation was also performed with microparticles isolated from healthy pregnant women (n = 6). One-hour incubation was performed with 2% or 10% solution and overnight incubation with 5% solution.
No effect of preeclamptic plasma, with or without microparticles, on bradykinin-mediated relaxation was observed. Overnight, but not 1-hour, incubation with preeclamptic microparticles caused abolishment of bradykinin-mediated relaxation in contrast to healthy pregnant microparticles (P <.005).
Preeclamptic microparticles, but not healthy pregnant microparticles cause endothelial dysfunction in isolated myometrial arteries from healthy pregnant women after overnight incubation, whereas other preeclamptic plasma constituents protect the endothelium from this effect.
Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression.
We measured the number of colony-forming units of endothelial progenitor cells in peripheral-blood samples from 45 men (mean [+/-SE] age, 50+/-2 years). The subjects had various degrees of cardiovascular risk but no history of cardiovascular disease. Endothelium-dependent and endothelium-independent function was assessed by high-resolution ultrasonography of the brachial artery.
We observed a strong correlation between the number of circulating endothelial progenitor cells and the subjects' combined Framingham risk factor score (r=-0.47, P=0.001). Measurement of flow-mediated brachial-artery reactivity also revealed a significant relation between endothelial function and the number of progenitor cells (r=0.59, P<0.001). Indeed, the levels of circulating endothelial progenitor cells were a better predictor of vascular reactivity than was the presence or absence of conventional risk factors. In addition, endothelial progenitor cells from subjects at high risk for cardiovascular events had higher rates of in vitro senescence than cells from subjects at low risk.
In healthy men, levels of endothelial progenitor cells may be a surrogate biologic marker for vascular function and cumulative cardiovascular risk. These findings suggest that endothelial injury in the absence of sufficient circulating progenitor cells may affect the progression of cardiovascular disease.
Passive smoking impairs the elasticity of the aorta in patients with coronary heart disease. We therefore studied the effect of passive smoking on wave reflection in the aorta, a marker of arterial stiffness, in healthy subjects.
We examined the effects of acute exposure to passive smoking on blood pressure and the aortic pressure waveform in healthy young men (n = 10) and women (n = 11), aged 26 +/- 5 years (mean +/- SEM) compared with 12 healthy controls, aged 24 +/- 2 years (six female) who were exposed to room air. The aortic pressure waveform was derived with radial applanation tonometry (SphygmoCor, AtCor Medical, version 6.2) and the augmentation index, a measure of arterial wave reflection in the aorta, calculated. Blood pressure (Omron Model HEM-705 CP, Omron Corporation, Tokyo, Japan) and augmentation index were measured at baseline, 15, 30 and 60 min after exposure to environmental tobacco smoke (carbon monoxide 25-30 p.p.m. for 60 min) or room air.
Passive smoking was associated with an increase in brachial (124 +/- 4-137 +/- 3 mmHg, P < 0.01) and aortic systolic blood pressure (110 +/- 3-123 +/- 4 mmHg, P < 0.01) at 60 min in the male subjects only. The augmentation index increased from -1.7 +/- 5 to 14 +/- 5 at 60 min (P < 0.001) only in the male subjects. The transit time of the pulse did not change significantly. The change in augmentation index was independent of the increase in blood pressure. Brachial and aortic diastolic blood pressure and heart rate did not change significantly in either male or female subjects. No haemodynamic changes were observed in the control group.
Acute exposure to passive smoking has a deleterious effect on the arterial pressure waveform in healthy young males but not in females, suggesting a possible protection of female gender from functional changes in arteries.
Long-term smoking is believed to cause endothelial dysfunction via increased oxidative stress, whereas short-term smoking impairs vasodilatation through an as yet undefined mechanism. However, red wine and its constituents have a powerful antioxidant effect both in long-term and acute consumption. The aim of the current study was to investigate whether red wine, with or without alcohol, influences endothelial dysfunction induced by acute cigarette smoking.
Sixteen healthy volunteers (8 males and 8 females) were recruited for a double-blind, crossover study, comprising 3 study days. Each subject smoked 1 cigarette, or smoked and drank 250 mL of red wine, or smoked and drank 250 mL of dealcoholized red wine. Flow-mediated dilatation (FMD) was measured after fasting and 15, 30, 60, and 90 minutes after each trial (smoke or smoke and drink either beverage).
Acute smoking of 1 cigarette caused a reduction in FMD (P <.001), which was statistically significant 15, 30, and 60 minutes after the inhalation of smoke compared to baseline levels (P <.001, P <.001, P =.043, respectively). However, simultaneous ingestion of either red wine or dealcoholized red wine with smoking did not lead to a change in FMD.
Acute smoking caused a significant impairment in endothelial function. Simultaneous consumption of red wine or dealcoholized red wine with smoking decreased smoke's harmful effect on endothelium.
To determine whether there was a change in hospital admissions for acute myocardial infarction while a local law banning smoking in public and in workplaces was in effect.
Analysis of admissions from December 1997 through November 2003 using Poisson analysis.
Helena, Montana, a geographically isolated community with one hospital serving a population of 68 140.
All patients admitted for acute myocardial infarction.
Number of monthly admissions for acute myocardial infarction for people living in and outside Helena.
During the six months the law was enforced the number of admissions fell significantly (- 16 admissions, 95% confidence interval - 31.7 to - 0.3), from an average of 40 admissions during the same months in the years before and after the law to a total of 24 admissions during the six months the law was effect. There was a non-significant increase of 5.6 (- 5.2 to 16.4) in the number of admissions from outside Helena during the same period, from 12.4 in the years before and after the law to 18 while the law was in effect.
Laws to enforce smoke-free workplaces and public places may be associated with an effect on morbidity from heart disease.
Inflammation has a pivotal role in the development of atherosclerosis and acute activation of the vascular wall with consecutive local thrombosis and altered vasomotion. This process is orchestrated by the interactions between inflammatory cells, such as platelets and T and B lymphocytes, and vascular cells, endothelial cells, and smooth muscle cells. When they are activated by an agonist, shear stress, or apoptosis, these cells release vesicles shed from the blebbing plasma membrane called microparticles. Microparticles harbor cell surface proteins and contain cytoplasmic components of the original cell. They exhibit negatively charged phospholipids, chiefly phosphatidylserine, at their surface, which accounts for their procoagulant character and proinflammatory properties, including alteration of vascular function. Elevated levels of circulating microparticles have been detected in pathological states associated with vascular dysfunction, including attenuation of endothelium-dependent vasodilatation and/or alteration of responsiveness of vascular smooth muscle to vasoconstrictor stimuli in conductance and resistance arteries. This review points out the characteristics of microparticles as well as the biological messages they can mediate. In particular, it summarizes the signaling cascades involved in microparticle-induced vascular dysfunction with special attention to the cellular origin of these vesicles (platelet, endothelial, and leukocytic), which may explain their differential consequences on vascular remodeling. The available information provides a rationale for the paracrine role of microparticles as vectors of transcellular exchange of message between circulating cells and cells from the vascular wall.
In humans, the biological limitations to cardiac regenerative growth create both a clinical imperative--to offset cell death in acute ischemic injury and chronic heart failure--and a clinical opportunity; that is, for using cells, genes, and proteins to rescue cardiac muscle cell number or in other ways promote more efficacious cardiac repair. Recent experimental studies and early-phase clinical trials lend credence to the visionary goal of enhancing cardiac repair as an achievable therapeutic target.
We investigated whether human age-related endothelial dysfunction is accompanied by quantitative and qualitative alterations of the endothelial progenitor cell (EPC) pool.
Circulating progenitor cells with an endothelial phenotype contribute to the regeneration and repair of the vessel wall. An association between the loss of endothelial integrity and EPC modification may provide a background to study the mechanistic nature of such age-related vascular changes.
In 20 old and young healthy individuals (61 +/- 2 years and 25 +/- 1 year, respectively) without major cardiovascular risk factors, endothelial function, defined by flow-mediated dilation of the brachial artery via ultrasound, as well as the number and function of EPCs isolated from peripheral blood, were determined.
Older subjects had significantly impaired endothelium-dependent dilation of brachial artery (flow-mediated dilation [FMD] 5.2 +/- 0.5% vs. 7.1 +/- 0.6%; p < 0.05). Endothelium-independent dilation after glycerol trinitrate (GTN) was not different, but the FMD/GTN ratio was significantly lower in old subjects (49 +/- 4% vs. 37 +/- 3%; p < 0.05), suggesting endothelial dysfunction. There were no differences in the numbers of circulating EPCs, defined as CD34/KDR or CD133/KDR double-positive cells in peripheral blood. In contrast, lower survival (39 +/- 6 cells/mm(2) vs. 65 +/- 11 cells/mm(2); p < 0.05), migration (80 +/- 12 vs. 157 +/- 16 cells/mm(2); p < 0.01), and proliferation (0.20 +/- 0.04 cpm vs. 0.44 +/- 0.07 cpm; p < 0.05) implicate functional impairment of EPCs from old subjects. The FMD correlated univariately with EPC migration (r = 0.52, p < 0.05) and EPC proliferation (r = 0.49, p < 0.05). Multivariate analysis showed that both functional features represent independent predictors of endothelial function.
Maintenance of vascular homeostasis by EPCs may be attenuated with age based on functional deficits rather than depletion of CD34/KDR or CD133/KDR cells.
Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk in patients with end-stage renal failure (ESRF). Microparticles are membrane fragments shed from damaged or activated cells. Because microparticles can affect endothelial cells, this study investigated the relationship between circulating microparticles and arterial dysfunction in patients with ESRF and identified the cellular origin of microparticles associated with these alterations. Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that circulating levels of Annexin V+ microparticles were increased compared with 32 healthy subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets (16.5-fold), and erythrocytes (1.6-fold). However, when arterial function was evaluated noninvasively in patients with ESRF, only endothelial microparticle levels correlated highly with loss of flow-mediated dilation (r = -0.543; P = 0.004), increased aortic pulse wave velocity (r = 0.642, P < 0.0001), and increased common carotid artery augmentation index (r = 0.463, P = 0.0017), whereas platelet-derived, erythrocyte-derived, and Annexin V+ microparticle levels did not. In vitro, microparticles from patients with ESRF impaired endothelium-dependent relaxations and cyclic guanosine monophosphate generation, whereas microparticles from healthy subjects did not. Moreover, in vitro endothelial dysfunction correlated with endothelial-derived (r = 0.891; P = 0.003) but not platelet-derived microparticle concentrations. In fact, endothelial microparticles alone decreased endothelial nitric oxide release by 59 +/- 7% (P = 0.025). This study suggests that circulating microparticles of endothelial origin are tightly associated with endothelial dysfunction and arterial dysfunction in ESRF.
RESPIRE, a randomized trial of an improved cookstove, was conducted in Guatemala to assess health effects of long-term reductions in wood smoke exposure. Given the evidence that ambient particles increase blood pressure, we hypothesized that the intervention would lower blood pressure.
TWO STUDY DESIGNS WERE USED: a) between-group comparisons based on randomized stove assignment, and b) before-and-after comparisons within subjects before and after they received improved stoves. From 2003 to 2005, we measured personal fine particle (particulate matter with aerodynamic diameter < 2.5 microm; PM(2.5)) exposures and systolic (SBP) and diastolic blood pressure (DBP) among women > 38 years of age from the chimney woodstove intervention group (49 subjects) and traditional open wood fire control group (71 subjects). Measures were repeated up to three occasions.
Daily average PM(2.5) exposures were 264 and 102 microg/m(3) in the control and intervention groups, respectively. After adjusting for age, body mass index, an asset index, smoking, secondhand tobacco smoke, apparent temperature, season, day of week, time of day, and a random subject intercept, the improved stove intervention was associated with 3.7 mm Hg lower SBP [95% confidence interval (CI), -8.1 to 0.6] and 3.0 mm Hg lower DBP (95% CI, -5.7 to -0.4) compared with controls. In the second study design, among 55 control subjects measured both before and after receiving chimney stoves, similar associations were observed.
The between-group comparisons provide evidence, particularly for DBP, that the chimney stove reduces blood pressure, and the before-and-after comparisons are consistent with this evidence.
Improved methods have been developed for the determination of nicotine and its major metabolite, cotinine, in blood, plasma, and urine samples. These methods utilize gas chromatography with alkali flame ionization (nitrogen--phosphorus) detection and structural analogs of nicotine and cotinine as internal standards.
Nitric acid (HNO3) is the most prevalent acid air pollutant in the western United States and has the potential to cause adverse respiratory effects through both acidification and oxidation reactions. To study this potential, we measured physiologic (specific airway resistance, SRaw, FEV1, and FVC) and bronchoalveolar lavage (total and differential cell counts, LDH, fibronectin, and total protein) end points in a group of 10 healthy, athletic subjects who were exposed to 500 micrograms/m3 of HNO3 gas or filtered air for 4 h during moderate exercise (ventilatory rate, 40 L/min) and underwent bronchoscopy 18 h later. Under an identical protocol, 10 healthy subjects were exposed to 500 micrograms/m3 of HNO3 gas plus 0.20 ppm ozone (O3) or 0.20 ppm O3 alone to determine if HNO3 might enhance the toxicity of O3. In addition to bronchoalveolar lavage (BAL), we employed the techniques of isolated left mainstem bronchial lavage and bronchial biopsy to determine if proximal airway injury was caused by pollutant exposure and whether there was any correlation with the degree of distal lung injury as assessed by BAL. We found no significant differences in pulmonary function tests or in the cellular or biochemical constituents in either the BAL or the left mainstem lavage fluids between the HNO3 and the air exposures. Similarly, there were no differences in these end points between the HNO3/O3 and the O3 exposures. Furthermore, there were no significant differences in the bronchial biopsy specimens between the HNO3 and air exposures or between the HNO3/O3 and O3 exposures.(ABSTRACT TRUNCATED AT 250 WORDS)
To estimate the risk of ischaemic heart disease caused by exposure to environmental tobacco smoke and to explain why the associated excess risk is almost half that of smoking 20 cigarettes per day when the exposure is only about 1% that of smoking.
Meta-analysis of all 19 acceptable published studies of risk of ischaemic heart disease in lifelong non-smokers who live with a smoker and in those who live with a non-smoker, five large prospective studies of smoking and ischaemic heart disease, and studies of platelet aggregation and studies of diet according to exposure to tobacco smoke.
The relative risk of ischaemic heart disease associated with exposure to environmental tobacco smoke was 1.30 (95% confidence interval 1.22 to 1.38) at age 65. At the same age the estimated relative risk associated with smoking one cigarette per day was similar (1.39 (1.18 to 1.64)), while for 20 per day it was 1.78 (1.31 to 2.44). Two separate analyses indicated that non-smokers who live with smokers eat a diet that places them at a 6% higher risk of ischaemic heart disease, so the direct effect of environmental tobacco smoke is to increase risk by 23% (14% to 33%), since 1.30/1.06 = 1.23. Platelet aggregation provides a plausible and quantitatively consistent mechanism for the low dose effect. The increase in platelet aggregation produced experimentally by exposure to environmental tobacco smoke would be expected to have acute effects increasing the risk of ischaemic heart disease by 34%.
Breathing other people's smoke is an important and avoidable cause of ischaemic heart disease, increasing a person's risk by a quarter.
Nitric oxide is a gaseous, free radical which plays a role as an intracellular second messenger and a diffusable intercellular messenger. To obtain direct evidence for NO functions in vivo, we have designed and synthesized diaminofluoresceins (DAFs) as novel fluorescent indicators for NO. The fluorescent chemical transformation of DAFs is based on the reactivity of the aromatic vicinal diamines with NO in the presence of dioxygen. The N-nitrosation of DAFs, yielding the highly green-fluorescent triazole form, offers the advantages of specificity, sensitivity, and a simple protocol for the direct detection of NO (detection limit 5 nM). The fluorescence quantum efficiencies are increased more than 100 times after the transformation of DAFs by NO. Fluorescence detection with visible light excitation and high sensitivity enabled the practical assay of NO production in living cells. Membrane-permeable DAF-2 diacetate (DAF-2 DA) can be used for real-time bioimaging of NO with fine temporal and spatial resolution. The dye was loaded into activated rat aortic smooth muscle cells, where the ester bonds are hydrolyzed by intracellular esterase, generating DAF-2. The fluorescence in the cells increased in a NO concentration-dependent manner.
Secondhand smoke (SHS) and hypercholesterolemia increase cardiovascular risk. We hypothesized that L-arginine, the precursor of nitric oxide (NO), might protect against atherogenesis and endothelial dysfunction caused by SHS. The effects of L-arginine supplementation (2.25% solution ad libitum) and SHS (smoking chambers for 10 weeks) were examined in 32 hypercholesterolemic rabbits. Eight normal rabbits served as controls. Acetylcholine- and nitroglycerin-induced vasorelaxation was assessed in aortic rings precontracted with norepinephrine. Hypercholesterolemia increased intimal lesion area (P=0.012), reduced endothelium-dependent relaxation (P=0.009), and reduced basal (P=0.005) and stimulated (P<0.0005) production of NOs. SHS increased intimal lesion area (P=0. 01) norepinephrine-induced contraction (P=0.001) and reduced endothelium-dependent relaxation (P=0.02). SHS-induced increase in norepinephrine contraction was abolished by the inhibition of NO synthase and removal of endothelium. L-Arginine improved endothelium-dependent relaxation (P=0.001) and attenuated SHS-induced endothelial dysfunction (P=0.007) and atherogenesis (P=0. 001). Basal production of nitrogen oxides correlated inversely with intimal lesion area (r=-0.66; P<0.0005) and stimulated production of NOs correlated with endothelium-dependent relaxation (r=-0.66; P<0. 001). SHS causes endothelial dysfunction and increased adrenergic responsiveness and atherogenesis in hypercholesterolemic rabbits. Chronic dietary supplementation with the NO precursor L-arginine mitigates these effects. The adverse vascular consequences of SHS appear to be mediated via deleterious effects on endothelial function.
Recent studies provide increasing evidence that postnatal neovascularization involves bone marrow-derived circulating endothelial progenitor cells (EPCs). The regulation of EPCs in patients with coronary artery disease (CAD) is unclear at present. Therefore, we determined the number and functional activity of EPCs in 45 patients with CAD and 15 healthy volunteers. The numbers of isolated EPCs and circulating CD34/kinase insert domain receptor (KDR)-positive precursor cells were significantly reduced in patients with CAD by approximately 40% and 48%, respectively. To determine the influence of atherosclerotic risk factors, a risk factor score including age, sex, hypertension, diabetes, smoking, positive family history of CAD, and LDL cholesterol levels was used. The number of risk factors was significantly correlated with a reduction of EPC levels (R=-0.394, P=0.002) and CD34-/KDR-positive cells (R=-0.537, P<0.001). Analysis of the individual risk factors demonstrated that smokers had significantly reduced levels of EPCs (P<0.001) and CD34-/KDR-positive cells (P=0.003). Moreover, a positive family history of CAD was associated with reduced CD34-/KDR-positive cells (P=0.011). Most importantly, EPCs isolated from patients with CAD also revealed an impaired migratory response, which was inversely correlated with the number of risk factors (R=-0.484, P=0.002). By multivariate analysis, hypertension was identified as a major independent predictor for impaired EPC migration (P=0.043). The present study demonstrates that patients with CAD revealed reduced levels and functional impairment of EPCs, which correlated with risk factors for CAD. Given the important role of EPCs for neovascularization of ischemic tissue, the decrease of EPC numbers and activity may contribute to impaired vascularization in patients with CAD. The full text of this article is available at http://www.circresaha.org.
Cigarette smoking is an important risk factor for both vascular disease and various forms of cancer. Vascular endothelial growth factor (VEGF) is an endothelial-specific mitogen that is normally expressed only in low levels in normal arteries but may be involved in the progression of both vascular disease and cancer. Some clinical evidence suggests that cigarette smoking may increase plasma VEGF levels, but there is a lack of basic science studies investigating this possibility. We show here, using an intact porcine common carotid artery perfusion culture model, that nicotine and cotinine, the major product of nicotine metabolism, cause a significant increase in endothelial cell VEGF expression. VEGF mRNA levels were compared between groups using reverse transcriptase-polymerase chain reaction, whereas protein level changes were demonstrated with Western blotting and immunohistochemistry. Our results showed significant increases in endothelial cell VEGF mRNA and protein levels because of nicotine and cotinine at concentrations representative of plasma concentrations seen in habitual smokers. VEGF immunostaining also paralleled these results. These findings may give a clue as to the mechanisms by which nicotine and cotinine from cigarette smoking increase vascular disease progression and tumor growth and metastasis.
Our group has previously shown that human umbilical vein endothelial cells exposed to smokers' serum decreased nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in the presence of increased eNOS expression. In the present study, we examined whether these observations extended to human coronary artery endothelial cells (HCAECs). In addition, the role of reactive oxygen species in the observed alterations was examined.
HCAECs were incubated with serum from 10 nonsmokers and 15 smokers for 12 hours with or without the addition of either polyethylene glycol-superoxide dismutase (PEG-SOD, 300 U/mL), PEG-SOD+PEG-catalase (1000 U/mL), chelerythrine (3 micromol/L), or tetrahydrobiopterin (20 micromol/L). At the end of incubation, NO, eNOS protein, and eNOS activity were measured from the same culture. HCAECs incubated with smokers' serum alone showed significantly lower NO production (P<0.05) and eNOS activity (P<0.005) but higher eNOS expression (P<0.005) compared with nonsmokers. In smokers, addition of PEG-SOD, PEG-SOD+PEG-catalase, or tetrahydrobiopterin significantly (P<0.05) improved NO levels and eNOS activity. Interestingly, in the same smokers, a significant decrease in eNOS expression was only seen with the addition of PEG-SOD+PEG-catalase (P<0.05) and treatment with PEG-SOD alone insignificantly increased eNOS expression.
The present study indicates that in vitro, HCAECs show similar changes in NO biosynthesis as human umbilical vein endothelial cells when exposed to smokers' serum and also confirms that oxidative stress plays a central role in smoking-mediated dysfunction of NO biosynthesis in endothelial cells. Furthermore, these data support other studies suggesting a role for hydrogen peroxide in the upregulation of eNOS.
Endothelial cells (EC) shed endothelial microparticles (EMP) in activation and apoptosis.
We compared the antigenic expression of EMP species released during activation as compared to apoptosis, in three cell lines.
EC from renal and brain microvascular (MiVEC) and coronary macrovascular (MaVEC) origin were incubated with TNF-alpha to induce activation, or deprived of growth factors to induce apoptosis. Antigens expressed on EMP and EC were assayed flow cytometrically and included constitutive markers (CD31, CD51/61, CD105), inducible markers (CD54, CD62E and CD106), and annexin V binding.
It was found that in apoptosis, constitutive markers in EMP were markedly increased (CD31>CD105), with a concomitant decrease in expression in EC. Annexin V EC surface binding and annexin V+ EMP were more sharply increased in apoptosis than in activation. In contrast, in activation, inducible markers in EMP were markedly increased in both EMP and EC (CD62E>CD54>CD106). Coronary MaVEC released significantly less EMP than MiVEC.
EC release qualitatively and quantitatively distinct EMP during activation compared to apoptosis. Analysis of EMP phenotypic signatures may provide clinically useful information on the status of the endothelium.
Exposure to second hand smoke (SHS) is believed to cause lung cancer. Pathological angiogenesis is a requisite for tumor growth. Lewis lung cancer cells were injected subcutaneously into mice, which were then exposed to sidestream smoke (SHS) or clean room air and administered vehicle, cerivastatin, or mecamylamine. SHS significantly increased tumor size, weight, capillary density, VEGF and MCP-1 levels, and circulating endothelial progenitor cells (EPC). Cerivastatin (an inhibitor of HMG-coA reductase) or mecamylamine (an inhibitor of nicotinic acetylcholine receptors) suppressed the effect of SHS to increase tumor size and capillary density. Cerivastatin reduced MCP-1 levels, whereas mecamylamine reduced VEGF levels and EPC. These studies reveal that SHS promotes tumor angiogenesis and growth. These effects of SHS are associated with increases in plasma VEGF and MCP-1 levels, and EPC, mediated in part by isoprenylation and nicotinic acetylcholine receptors.
Experimental and initial clinical studies suggest that transplantation of circulating blood- (CPC) or bone marrow-derived (BMC) progenitor cells may beneficially affect postinfarction remodeling processes after acute myocardial infarction (AMI). To relate functional characteristics of the infused cells to quantitative measures of outcome at 4-month follow-up, we performed serial contrast-enhanced MRI and assessed the migratory capacity of the transplanted progenitor cells immediately before intracoronary infusion.
In 28 patients with reperfused AMI receiving either BMCs or CPCs into the infarct artery 4.7+/-1.7 days after AMI, serial contrast-enhanced MRI performed initially and after 4 months revealed a significant increase in global ejection fraction (from 44+/-10% to 49+/-10%; P=0.003), a decrease in end-systolic volume (from 69+/-26 to 60+/-28 mL; P=0.003), and unchanged end-diastolic volumes (122+/-34 versus 117+/-37 mL; P=NS). Infarct size, measured as late enhancement (LE) volume, decreased significantly, from 46+/-32 to 37+/-28 mL (P<0.05). There was a significant correlation between the reduction in LE volume and global ejection fraction improvement. The migratory capacity of transplanted cells as assessed ex vivo toward a gradient of vascular endothelial growth factor for CPCs and stromal cell derived factor-1 for BMCs was closely correlated with the reduction of LE volume. By multivariate analysis, migratory capacity remained the most important independent predictor of infarct remodeling.
Analysis of serial contrast-enhanced MRI suggests that intracoronary infusion of adult progenitor cells in patients with AMI beneficially affects postinfarction remodeling processes. The migratory capacity of the infused cells is a major determinant of infarct remodeling, disclosing a causal effect of progenitor cell therapy on regeneration enhancement.
Cigarette smoking (CS) continues to be a major health hazard, and it contributes significantly to cardiovascular morbidity and mortality. Cigarette smoking impacts all phases of atherosclerosis from endothelial dysfunction to acute clinical events, the latter being largely thrombotic. Both active and passive (environmental) cigarette smoke exposure predispose to cardiovascular events. Whether there is a distinct direct dose-dependent correlation between cigarette smoke exposure and risk is debatable, as some recent experimental clinical studies have shown a non-linear relation to cigarette smoke exposure. The exact toxic components of cigarette smoke and the mechanisms involved in CS-related cardiovascular dysfunction are largely unknown, but CS increases inflammation, thrombosis, and oxidation of low-density lipoprotein cholesterol. Recent experimental and clinical data support the hypothesis that cigarette smoke exposure increases oxidative stress as a potential mechanism for initiating cardiovascular dysfunction.
Circulating endothelial progenitor cells (EPCs) contribute to postnatal angiogenesis. The number of circulating EPCs has an inverse correlation with coronary risk scores. However, the effect of smoking on the number of circulating EPCs is not well-known.
We examined the effects of chronic smoking and of smoking cessation on EPC levels. Circulating EPCs were quantified by flow cytometry as CD45lowCD34+CD133+ (progenitor cells [PCs]) or CD45lowCD34+CD133+VEGFR2+ (EPCs) in 14 nonsmokers and in 15 smokers. All smokers quit smoking. Eight quit smoking with nicotine patch and 7 without nicotine patch. PC/EPC levels were inversely correlated with the number of cigarettes smoked. Circulating PCs/EPCs increased rapidly after cessation (P<0.0001) and decreased again after resumption of smoking to the level similar to that before cessation (P=0.0031). The magnitude of increase in EPCs was greater in light smokers than in heavy smokers.
The number of circulating PCs/EPCs was reduced in chronic smokers. Smoking cessation led to a rapid restoration of PC/EPC levels. The recovery of EPC levels was greater in light smokers than in heavy smokers. The decreased number of circulating EPCs would make smokers susceptible to cardiovascular disease, and even short-time cessation of smoking may be an effective means to reduce cardiovascular risk.
Cigarette-induced endothelial dysfunction could be an early mediator of atherosclerosis. In this study, we explored the mechanisms of cigarette smoke extract (CSE)-induced human aortic endothelial cells (HAEC) apoptosis. We found that 10-65% of HAECs underwent apoptotic changes when HAECs were exposed to 0.001-0.02 cigarette equivalent unit of CSE for 4 h. CSE activated the caspases-3 and 8, the p38 MAP kinase and stress activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK). Specific inhibitors of p38 MAP or SAPK/JNK reduced CSE-induced caspase activation. We further showed that eNOS pre-activation by L-arginine reduced endothelial apoptosis from 65% to 5%; and eNOS inhibition by N-omega-nitro-L-arginine methyl ester accentuated CSE-induced endothelial apoptosis. We suggest that appropriate endogenous NO production may be an important protective mechanism against smoking-induced endothelial damage.
To relate levels of vascular endothelial growth factor (VEGF) and its soluble receptor, sFlt-1, with endothelial function in healthy smokers.
Plasma levels of VEGF and sFlt-1 were measured by ELISA in 22 healthy smokers and 22 matched healthy non-smoking controls, and compared to flow- (FMD) and acetylcholine-mediated (AMD) vasodilatation (endothelial-dependent) (EDV) and nitroglycerine-mediated (NMD) vasodilatation (endothelial-independent) of lower extremities were measured with plethysmography.
Smokers and controls had similar plasma VEGF levels, but sFlt-1 levels were lower in smokers than in controls (p<0.01). AMD was lower in smokers compared to controls (p<0.05), but FMD and NMD levels were similar. Smokers and controls with high AMD (>12 ml/100 ml tissue/min) had significantly lower plasma VEGF levels (p<0.001). An inverse correlation was found in both groups, between VEGF and AMD (smokers: r=-0.6, p<0.01; controls: r=-0.71, p<0.005) and with FMD (smokers: r=-0.56, p<0.05; controls: r=-0.58, p<0.005). There were no significant correlations between sFlt-1 with VEGF levels or endothelial-dependent dilatation.
In conclusion, healthy smokers demonstrate abnormal AMD, and an inverse correlation between plasma VEGF levels (but not sFlt-1) with indices of endothelial dysfunction (FMD and AMD) exists. VEGF, and not sFlt-1, may be related to the pathogenesis of endothelial dysfunction in healthy smoking individuals.
Objectives:
The purpose of this study was to examine whether CD144-EMP (endothelium-derived microparticles) is useful as a specific marker of endothelial cell (EC) dysfunction and to determine whether plasma levels of circulating CD144-EMP predicted coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM).
Background:
Endothelial cell dysfunction is involved in atherogenesis; however, the quantitative assessment of EC dysfunction has yet to be established clinically. Endothelium-derived microparticles are small, membrane-shed vesicles that are generated from the EC surface in response to cellular dysfunction and/or injury. Diabetes mellitus is known to be associated with EC dysfunction and accelerated atherosclerosis.
Methods:
We characterized EMP using anti-CD144 (VE-Cadherin) antibody in various atherosclerosis-related cells and investigated the association between the levels of CD144-positive microparticles and hydrogen-peroxide-induced EC injury and acetylcholine-induced coronary vasomotion. Furthermore, we evaluated plasma CD144-EMP levels in patients with and without DM.
Results:
We demonstrated that CD144-positive microparticles were derived selectively from human EC. The levels of CD144-EMP reflected the degree of in vitro hydrogen-peroxide-induced EC injury and impairment of in vivo endothelium-dependent coronary vasodilation (p < 0.01). Plasma CD144-EMP levels were increased significantly in DM patients compared with patients without DM (p < 0.001). In DM patients, the elevated levels of CD144-EMP were the most significant risk factor for CAD relative to all other traditional risk factors (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.8 to 6.9, p < 0.001). Notably, plasma CD144-EMP identified a subpopulation of established CAD patients in DM subjects without typical anginal symptoms (OR 10.6, 95% CI 3.9 to 29.5, p < 0.001).
Conclusions:
The CD144-positive EMP exist in human plasma, and plasma CD144-EMP levels can be a clinically specific and quantitative marker of EC dysfunction and/or injury. Measurement of CD144-EMP, by providing a quantitative assessment of EC dysfunction, may be useful for identifying DM patients with increased risk of CAD.
Secondhand smoke increases the risk of coronary heart disease by approximately 30%. This effect is larger than one would expect on the basis of the risks associated with active smoking and the relative doses of tobacco smoke delivered to smokers and nonsmokers.
We conducted a literature review of the research describing the mechanistic effects of secondhand smoke on the cardiovascular system, emphasizing research published since 1995, and compared the effects of secondhand smoke with the effects of active smoking. Evidence is rapidly accumulating that the cardiovascular system--platelet and endothelial function, arterial stiffness, atherosclerosis, oxidative stress, inflammation, heart rate variability, energy metabolism, and increased infarct size--is exquisitely sensitive to the toxins in secondhand smoke. The effects of even brief (minutes to hours) passive smoking are often nearly as large (averaging 80% to 90%) as chronic active smoking.
The effects of secondhand smoke are substantial and rapid, explaining the relatively large risks that have been reported in epidemiological studies.
This study was designed to assess the effect of flavanol-rich food on the circulating pool of bioactive nitric oxide (NO) and endothelial dysfunction in smokers.
Studies suggest that smoking-related vascular disease is caused by impaired NO synthesis and that diets rich in flavanols can increase bioactive NO in plasma.
In smokers (n = 11), the effects of flavanol-rich cocoa on circulating NO species in plasma (RXNO) measured by reductive gas-phase chemiluminescence and endothelial function as assessed by flow-mediated dilation (FMD) were characterized in a dose-finding study orally administering cocoa containing 88 to 370 mg flavanols and in a randomized double-blind crossover study using 100 ml cocoa drink with high (176 to 185 mg) or low (<11 mg) flavanol content on two separate days. In addition to cocoa drink, ascorbic acid and NO-synthase inhibitor L-NMMA (n = 4) were applied.
There were significant increases in RXNO (21 +/- 3 nmol/l to 29 +/- 5 nmol/l) and FMD (4.5 +/- 0.8% to 6.9 +/- 0.9%, each p < 0.05) at 2 h after ingestion of 176 to 185 mg flavanols, a dose potentially exerting maximal effects. These changes correlated with increases in flavanol metabolites. Cocoa-associated increases in RXNO and FMD were reversed by L-NMMA. Ascorbic acid had no effect.
The circulating pool of bioactive NO and endothelium-dependent vasodilation is acutely increased in smokers following the oral ingestion of a flavanol-rich cocoa drink. The increase in circulating NO pool may contribute to beneficial vascular health effects of flavanol-rich food.
Endothelial dysfunction is one of the earliest pathological effects of cigarette smoking. It has recently been suggested that endothelial progenitor cells (EPCs) could contribute to ongoing endothelial maintenance and repair. Accordingly, we tested the hypothesis that cigarette smoking is associated with EPC dysfunction.
EPCs were isolated from the peripheral venous blood of 15 healthy smokers and 11 age-matched nonsmokers. The number of EPCs was significantly reduced in smokers versus control subjects (51.6+/-1.9 versus 120.3+/-10.0 per power field, p<0.001). Moreover, the functional activities of EPCs isolated from smokers were severely compromised. First, the proliferative and migratory response of EPCs isolated from smokers were reduced by 75% and 19%, respectively (p<0.05). Second, EPCs from smokers showed an important decreased adherence to HUVECs that had been previously activated with tumor necrosis factor-alpha (TNF-alpha) (p<0.01). Finally, the participation of EPCs to tube formation in a matrigel assay was reduced by 38% in smokers versus control subjects (p<0.001). We found that EPCs from smokers had a significant reduction in the expression of the endothelial cell-specific markers (VE-cadherin, KDR, and vWF). Moreover, ROS formation was significantly increased in EPCs from smokers, whereas the serum antioxidant and nitrite levels of smokers were reduced and correlated with impaired EPC number and functional activity.
Cigarette smoking is associated with a reduced number of EPCs together with an important impairment of EPC differentiation and functional activities. Our results suggest that EPC dysfunction could contribute to impair blood vessel healing and growth in smokers.
The aim of this study was to compare cotinine determinations in three biological fluids for assessing environmental tobacco smoke (ETS) exposure in female non-smokers (n=1605) in Italy.
Information about ETS exposure at home, in the workplace, and in other places within the previous week was collected via questionnaire. Plasma, salivary and urinary cotinine levels were measured. Cotinine levels of > or =0.1 ng/mL for plasma, > or =0.2 ng/mL for saliva, and > or =0.5 ng/mL for urine were used to determine biochemical exposure.
Median cotinine levels were significantly higher in exposed than in unexposed women (0.21 vs. 0.05 ng/mL in plasma, 0.80 vs. 0.41 ng/mL in saliva, and 9.74 vs. 5.30 ng/mL in urine). Self-reported ETS exposure was significantly related to biochemical exposure [odds ratio 2.99, (95% CI 2.40-3.72) for plasma; 1.90 (1.51-2.39) for saliva; and 2.67 (2.14-3.34) for urine]. Cotinine significantly increased with increasing exposure level, regardless of the exposure source. Among self-reported exposed subjects, higher percentages of cotinine level above the cut-off, i.e., indicating exposure, were found in saliva (76%) and urine (75%) than in plasma (52%).
In general, women correctly reported their ETS exposure status. Both non-invasive salivary and urinary cotinine determinations seem preferable in epidemiological studies, in view of their higher sensitivity, when compared to plasma cotinine.
Endothelial dysfunction is one of the earliest pathological effects of cigarette smoking. Vascular endothelial growth factor (VEGF) has been shown to be an important regulator of endothelial healing and growth. Accordingly, we tested the hypothesis that cigarette smoke exposure impairs VEGF actions in endothelial cells. In human umbilical vein endothelial cells (HUVECs), cigarette smoke extracts (CSE) inhibited VEGF-induced tube formation in the matrigel assay. CSE did not affect HUVECs proliferation, but significantly reduced cellular migration in response to VEGF. This impaired migratory activity was associated with a reduced expression of alpha(v)beta(3), alpha(v)beta(5), alpha(5)beta(1) and alpha(2)beta(1) integrins. The Akt/eNOS/NO pathway has been shown to be important for VEGF-induced endothelial cell migration. We found that CSE inhibited Akt/eNOS phosphorylation and NO release in VEGF-stimulated HUVECs. This was associated with an increased generation of reactive oxygen species (ROS). Importantly, in HUVECs exposed to CSE, treatment with antioxidants (NAC, vitamin C) reduced ROS formation and rescued VEGF-induced NO release, cellular migration and tube formation. Moreover, treatment with NO donors (SNAP, SNP) or a cGMP analog (8-Br-cGMP) rescued integrin expression, cellular migration and tube formation in endothelial cells exposed to CSE. (1) Cigarette smoke exposure impairs VEGF-induced endothelial cell migration and tube formation. (2) The mechanism involves increased generation of ROS, decreased expression of surface integrins together with a blockade of the Akt/eNOS/NO pathway. (3) These findings could contribute to explain the negative effect of cigarette smoking on endothelial function and vessel growth.
The disruption of endothelial integrity is at the crossroads of the initiation and progression of multiple cardiovascular diseases pathophysiology. During these last years, it has been evidenced that endothelium is a highly dynamic tissue in equilibrium with a circulating compartment composed of various sub-populations offering important opportunities for a non-invasive exploration. Among these, circulating endothelial cells (CEC) are mature cells detached from injured vessels. Rarely found in blood in the health, CEC number is raised in a wide variety of pathological conditions associated with profound vascular insult. An additional population are the endothelial progenitor cells derived from bone marrow and characterised by their ability to participate in endothelial repair. Reduced number and impaired function of EPC have been related to situations with increased cardiovascular risk or to clinical atherosclerotic diseases. This review will focus on present data concerning CEC and endothelial cells and progenitors (PEC) in the setting of cardiovascular diseases. Particular emphasis will be given on the clinical value of these endothelial biomarkers to monitor endothelial homeostasis depending on the balance between endothelial injury and repair.
Recent studies have shown that passive smoking impairs vascular endothelial function and induces oxidative stress in humans. However, in most of the previous human data regarding tobacco-induced pathophysiology, vascular endothelial dysfunction and oxidative stress have been separately assessed. This study was designed to determine the association between the acute effect of passive smoking on vascular endothelial function and in-vivo oxidative stress status. We studied 30 healthy male Japanese volunteers (32 +/- 7 years) including 15 habitual smokers and 15 nonsmokers. After baseline echocardiographic, hemodynamic recording, and blood sampling, subjects were exposed to passive smoking for 30 min. Endothelium-dependent vasodilation was measured by using % flow-mediated vasodilation (%FMD) of the brachial artery and plasma levels of 8-isoprostane was measured by enzyme immunoassay before and after the passive smoking exposure. Baseline %FMD was lower (4.3% +/- 1.2% vs. 10.9% +/- 3.1%, p < 0.001) and baseline plasma 8-isoprostane level was higher (41.5 +/- 5.8 pg/mL vs. 26.9 +/- 5.4 pg/mL, p < 0.001) in smokers than those in nonsmokers. The %FMD and 8-isoprostane level did not change after passive smoking in smokers. In nonsmokers, however, the %FMD decreased (to 5.0% +/- 1.9%, p < 0.001) and the 8-isoprostane level increased (to 37.8 +/- 9.6 pg/mL, p < 0.001) significantly after 30 min passive smoking exposure, equivalently to the levels of smokers. Sixty corrected samples before and after passive smoking exposure in all patients showed a significant negative correlation between the % FMD and the plasma 8-isoprostane levels (n = 60, r = -0.69, p < 0.001). Even 30 min of passive smoking rapidly impairs vascular endothelial function, which is associated with oxidative stress. Our data provide the pathophysiological insight for the recent epidemiological evidence about the increased risk of coronary heart disease among nonsmokers exposed to passive smoking.
We used the hospital discharge records of Piedmont region (northern Italy) to evaluate whether a national law banning smoking in public resulted in a short-term reduction in hospital admissions for acute myocardial infarction (AMI).
Rates of admission for AMI before the ban (October-December 2004) and during the ban (February-June 2005) were analysed. Each period was compared with the corresponding period 12 months before. Among persons aged under 60, the number of admissions for AMI decreased significantly after the introduction of the ban: from 922 cases in February-June 2004 to 832 cases in February-June 2005 (sex- and age-adjusted rate ratio, 0.89; 95% confidence interval, 0.81-0.98). No decrease was seen before the ban. No effect was found among persons aged at least 60. We estimated that the observed reduction in active smoking after the introduction of the ban could account for a 0.7% decrease in admissions for AMI during the study period, suggesting that most of the observed effect (11%) might be due to the reduction of passive smoking.
Our study, based on a population of about 4 million inhabitants, suggests that smoke-free policies may result in a short-term reduction in admissions for AMI.
Apoptosis and vascular cell activation are main contributors to the release of procoagulant microparticles (MPs), deleterious partners in atherothrombosis. Elevated levels of circulating platelet, monocyte, or endothelial-derived MPs are associated with most of the cardiovascular risk factors and appear indicative of poor clinical outcome. In addition to being a valuable hallmark of vascular cell damage, MPs are at the crossroad of atherothrombosis processes by exerting direct effects on vascular or blood cells. Under pathological circumstances, circulating MPs would support cellular cross-talk leading to vascular inflammation and tissue remodeling, endothelial dysfunction, leukocyte adhesion, and stimulation. Exposed membrane phosphatidylserine and functional tissue factor (TF) are 2 procoagulant entities conveyed by circulating MPs. At sites of vascular injury, P-selectin exposure by activated endothelial cells or platelets leads to the rapid recruitment of MPs bearing the P-selectin glycoprotein ligand-1 and blood-borne TF, thereby triggering coagulation. Within the atherosclerotic plaque, sequestered MPs constitute the main reservoir of TF activity, promoting coagulation after plaque erosion or rupture. Lesion-bound MPs, eventually harboring proteolytic and angiogenic effectors are additional actors in plaque vulnerability. Pharmacological strategies aimed at modulating the release of procoagulant MPs appear a promising therapeutic approach of both thrombotic processes and bleeding disorders.
Secondhand smoke exposure increases the risk of acute myocardial infarction (AMI). One study (Helena, Mont) examined the issue and found a decrease in AMI associated with a smoke-free ordinance. We sought to determine the impact of a smoke-free ordinance on AMI admission rates in another geographically isolated community (Pueblo, Colo).
We assessed AMI hospitalizations in Pueblo during a 3-year period, 1.5 years before and 1.5 years after implementation of a smoke-free ordinance. We compared the AMI hospitalization rates among individuals residing within city limits, the area where the ordinance applied, versus those outside city limits. We also compared AMI rates during this time period with another geographically isolated but proximal community, El Paso County, Colo, that did not have an ordinance. A total of 855 patients were hospitalized with a diagnosis of primary AMI in Pueblo between January 1, 2002, and December 31, 2004. A reduction in AMI hospitalizations was observed in the period after the ordinance among Pueblo city limit residents (relative risk [RR]=0.73, 95% confidence interval [CI] 0.63 to 0.85). No significant changes in AMI rates were observed among residents outside city limits (RR=0.85, 95% CI 0.63 to 1.16) or in El Paso County during the same period (RR=0.97, 95% CI 0.89 to 1.06). The reduction in AMI rate within Pueblo differed significantly from changes in the external control group (El Paso County) even after adjustment for seasonal trends (P<0.001).
A public ordinance reducing exposure to secondhand smoke was associated with a decrease in AMI hospitalizations in Pueblo, Colo, which supports previous data from a smaller study.
The aim of the study was to compare acute endothelial dysfunction caused by smoking one cigarette between smokers and non-smokers.
Thirty volunteers, 15 smokers and 15 non-smokers, were asked to smoke the same type of cigarette and endothelial function was assessed by FMD (flow mediated dilatation) at fast, 30, 60 and 90 min post-smoking.
Overall response of FMD after smoking was significantly different between smokers and non-smokers (p=0.011). Endothelial dysfunction after smoking remained significant for 1-h in smokers (p=0.002), but only for 30 min in non-smokers (p=<0.001). FMD 1-h after smoking was significantly higher in non-smokers than in smokers (p=0.002).
Smokers seem to have sustained and more intensive unfavourable effects in endothelial function than non-smokers after smoking one cigarette. It is possible that long-term smoking diminishes the capacity of endothelium to counterbalance external factors that cause endothelial dysfunction.
We aimed to determine the role of endothelial progenitor cells (EPCs) in cholinergic angiogenesis.
Recently, we provided evidence for a new angiogenic pathway mediated by endothelial nicotinic acetylcholine receptors (nAChR). Increasing evidence suggests that circulating EPCs also contribute to postnatal neovascularization by homing to sites of neovascularization, a process termed postnatal vasculogenesis. Therefore, we investigated whether nAChR activation increases mobilization and/or recruitment of EPCs to a site of angiogenesis.
To identify EPCs from reservoirs both inside and outside of the bone marrow and to avoid the adverse effects of total body irradiation, we employed a murine parabiosis model with tie-2-LacZ FvB/N mice connected to wild-type FvB/N mice and induced unilateral hind limb ischemia in the wild-type animal.
Administration of nicotine increased capillary density in the ischemic hind limb, and increased soluble Kit ligand plasma levels. The effect of systemic administration was greater than that of local delivery of nicotine (45% vs. 76% increase in capillary density by comparison to vehicle control, intramuscular vs. oral administration of nicotine; p < 0.05). Ischemia-induced incorporation of EPC in the control group was rare, but was increased 5-fold by systemic administration of nicotine. Exposure to nicotine in vitro increased EPC count and EPC transmigration. Finally, systemic administration of nicotine increased EPC number in the bone marrow and spleen during hind limb ischemia.
Nicotine treatment increased the number of EPCs in the bone marrow and spleen, and increased their incorporation into the vasculature of ischemic tissue. Administration of nicotine increased markers of EPC mobilization. This study indicates that the known angiogenic effect of nicotine may be mediated in part by mobilization of precursor cells.
Members of the vascular endothelial growth factor (VEGF) family are among the most powerful modulators of vascular biology. They regulate vasculogenesis, angiogenesis, and vascular maintenance during embryogenesis and in adults. Because of their profound effects on blood vessels, VEGFs have received much attention regarding their potential therapeutic use in cardiovascular medicine, especially for therapeutic vascular growth in myocardial and peripheral ischemia. However, completed randomized controlled VEGF trials have not provided convincing evidence of clinical efficacy. On the other hand, recent preclinical proangiogenic VEGF studies have given insight, and anti-VEGF studies have shown that the disturbance of vascular homeostasis by blocking VEGF-A may lead to endothelial dysfunction and adverse vascular effects. Excess VEGF-A may contribute to neovascularization of atherosclerotic lesions but, currently, there is no evidence that transient overexpression by gene transfer could lead to plaque destabilization. Here, we review the biology and effects of VEGFs as well as the current status of clinical applications and future perspectives of the therapeutic use of VEGFs in cardiovascular medicine.
Acute smoking causes endothelial dysfunction through impairment of nitric oxide (NO) production, or increased oxidative stress, but the exact mechanism still needs to be elucidated. In healthy non-smokers acute endothelial dysfunction caused by smoking one cigarette was counterbalanced by red wine's antioxidants. The aim of the present study is to investigate whether red wine's antioxidant substances could counteract the acute endothelial dysfunction induced by acute cigarette smoking in healthy smokers as well.
Twenty healthy volunteers (12 males) participated in a double-blind, cross-over study, comprised of three study days. All subjects either smoked one cigarette, or smoked and drank 250 ml of red wine, or smoked and drank 250 ml of dealcoholized red wine in each one of the study days. Flow mediated dilatation (FMD) was measured at fast and 30, 60 and 90 minutes after each trial.
Smoking one cigarette induced a significant decrease in FMD (p < 0.001), which remained significant 30 (p < 0.001), and 60 (p = 0.003) minutes after the end of smoking. FMD remained statistically unchanged after consumption of either regular red wine, or dealcoholized red wine together with smoking.
The observed endothelial dysfunction following smoking of one cigarette was counterbalanced by consumption of either red wine or dealcoholized red wine in healthy smokers. It is possible that acute endothelial dysfunction caused by smoking could be attributed to increased oxidative stress and red wine's antioxidants counteract these acute effects of smoke on endothelium.