John C. Rutledge

Depressive Symptoms and Risks of Coronary Heart Disease and Mortality in Elderly Americans

BackgroundSeveral epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. Methods and ResultsIn a prospective cohort of 5888 elderly Americans (≥65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P =0.006); the ratio for all-cause mortality was 1.29 (P <0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P =0.006) and that for all-cause mortality was 1.16 (P =0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. ConclusionsAmong elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

Induction of Inflammation in Vascular Endothelial Cells by Metal Oxide Nanoparticles: Effect of Particle Composition

Background The mechanisms governing the correlation between exposure to ultrafine particles and the increased incidence of cardiovascular disease remain unknown. Ultrafine particles appear to cross the pulmonary epithelial barrier into the bloodstream, raising the possibility of direct contact with the vascular endothelium. Objectives Because endothelial inflammation is critical for the development of cardiovascular pathology, we hypothesized that direct exposure of human aortic endothelial cells (HAECs) to ultrafine particles induces an inflammatory response and that this response depends on particle composition. Methods To test the hypothesis, we incubated HAECs for 1–8 hr with different concentrations (0.001–50 μg/mL) of iron oxide (Fe2O3), yttrium oxide (Y2O3), and zinc oxide (ZnO) nanoparticles and subsequently measured mRNA and protein levels of the three inflammatory markers intra-cellular cell adhesion molecule-1, interleukin-8, and monocyte chemotactic protein-1. We also determined nanoparticle interactions with HAECs using inductively coupled plasma mass spectrometry and transmission electron microscopy. Results Our data indicate that nanoparticle delivery to the HAEC surface and uptake within the cells correlate directly with particle concentration in the cell culture medium. All three types of nanoparticles are internalized into HAECs and are often found within intracellular vesicles. Fe2O3 nanoparticles fail to provoke an inflammatory response in HAECs at any of the concentrations tested; however, Y2O3 and ZnO nanoparticles elicit a pronounced inflammatory response above a threshold concentration of 10 μg/mL. At the highest concentration, ZnO nanoparticles are cytotoxic and lead to considerable cell death. Conclusions These results demonstrate that inflammation in HAECs following acute exposure to metal oxide nanoparticles depends on particle composition.

Triglyceride-Rich Lipoproteins Prime Aortic Endothelium for an Enhanced Inflammatory Response to Tumor Necrosis Factor-α

High levels of triglyceride-rich lipoproteins (TGRLs) in blood are linked to development of atherosclerosis, yet the mechanisms by which these particles initiate inflammation of endothelium are unknown. TGRL isolated from human plasma during the postprandial state was examined for its capacity to bind to cultured human aortic endothelial cells (HAECs) and alter the acute inflammatory response to tumor necrosis factor-α. HAECs were repetitively incubated with dietary levels of freshly isolated TGRL for 2 hours per day for 1 to 3 days to mimic postprandial lipidemia. TGRL induced membrane upregulation of the low-density lipoprotein family receptors LRP and LR11, which was inhibited by the low-density lipoprotein receptor–associated protein-1. TGRLs alone did not elicit inflammation in HAECs but enhanced the inflammatory response via a 10-fold increase in sensitivity to cytokine stimulation. This was reflected by increased mitogen-activated protein kinase activation, nuclear translocation of NF-&kgr;B, amplified expression of endothelial selectin and VCAM-1, and a subsequent increase in monocyte-specific recruitment under shear flow as quantified in a microfabricated vascular mimetic device.

Angiogenesis and oxidative stress: Common mechanisms linking psoriasis with atherosclerosis

Shared angiogenic and oxidative mechanisms underlie the pathophysiology of psoriasis and atherosclerosis. During the pathogenesis of both diseases, stimuli such as injury or local hypoxia trigger the release of pro-angiogenic factors including IL-8, HIF-1α, ETS-1, and VEGF. These factors stimulate increased permeability and encourage leukocyte transmigration into areas of inflammation by enhanced expression of cell adhesion molecules. Psoriasis and atherosclerosis also share common enzymatic sources of reactive oxygen species (ROS), and these ROS influence several cellular signaling pathways implicated in the pathogenesis of both diseases. Pharmacologic and genetic therapies that target key factors in these pathways could provide innovative approaches to the management of psoriasis and potentially mitigate the cardiovascular complications suffered by psoriasis patients.

Lipoprotein Lipase Increases Lipoprotein Binding to the Artery Wall and Increases Endothelial Layer Permeability by Formation of Lipolysis Products

Mechanisms responsible for the accumulation of low-density lipoprotein (LDL) were investigated in a new model, the perfused hamster aorta. To do this, we developed a method to study LDL flux in real time in individually perfused arteries; each artery served as its own control. Using quantitative fluorescence microscopy, the rates of LDL accumulation and efflux were separately determined. Perfusion of arteries with buffer plus lipoprotein lipase (LpL) increased LDL accumulation 5-fold (0.1 +/- 0.03 mV/min [control] versus 0.5 +/- 0.05 mV/min [LpL]) by increasing LDL retention in the artery wall. This effect was blocked by heparin and monoclonal antibodies directed against the amino-terminal region of apolipoprotein B (apo B). This suggests that specific regions of apo B are involved in LDL accumulation within arteries. Also, the effect of hydrolysis of triglyceride-rich lipoproteins on endothelial barrier function was studied. We compared endothelial layer permeability using a water-soluble reference molecule, fluorescently labeled dextran. When LpL was added to hypertriglyceridemic plasma, dextran accumulation within the artery wall increased > 4-fold (0.024 +/- 0.01 mV/min [control] versus 0.098 +/- 0.05 mV/min [LpL]). Under the same conditions, LpL increased LDL accumulation approximately 3-fold (0.016 +/- 0.003 mV/min [control] versus 0.047 +/- 0.013 mV/min [LpL]). Rapid efflux of LDL from the artery wall indicated that increased endothelial layer permeability was the primary mechanism during periods of increased lipolysis. Our data demonstrate two LpL-mediated effects that may increase the amount of LDL in the artery wall. These findings may pertain to the observed relationship between increased postprandial lipemia and atherosclerosis.

The vascular contribution to Alzheimer's disease.

AD (Alzheimers disease) is a progressive neurodegenerative disease of unknown origin. Despite questions as to the underlying cause(s) of this disease, shared risk factors for both AD and atherosclerotic cardiovascular disease indicate that vascular mechanisms may critically contribute to the development and progression of both AD and atherosclerosis. An increased risk of developing AD is linked to the presence of the apoE4 (apolipoprotein E4) allele, which is also strongly associated with increased risk of developing atherosclerotic cardiovascular disease. Recent studies also indicate that cardiovascular risk factors, including elevated blood cholesterol and triacylglycerol (triglyceride), increase the likelihood of AD and vascular dementia. Lipids and lipoproteins in the circulation interact intimately with the cerebrovasculature, and may have important effects on its constituent brain microvascular endothelial cells and the adjoining astrocytes, which are components of the neurovascular unit. The present review will examine the potential mechanisms for understanding the contributions of vascular factors, including lipids, lipoproteins and cerebrovascular Abeta (amyloid beta), to AD, and suggest therapeutic strategies for the attenuation of this devastating disease process. Specifically, we will focus on the actions of apoE, TGRLs (triacylglycerol-rich lipoproteins) and TGRL lipolysis products on injury of the neurovascular unit and increases in blood-brain barrier permeability.

Inflammasome-Mediated Secretion of IL-1β in Human Monocytes through TLR2 Activation; Modulation by Dietary Fatty Acids

Many studies have shown that TLR4- and TLR2-deficient mice are protected from high-fat diet–induced inflammation and insulin resistance, suggesting that saturated fatty acids derived from the high-fat diet activate TLR-mediated proinflammatory signaling pathways and induce insulin resistance. However, evidence that palmitic acid, the major dietary saturated fatty acid, can directly activate TLR has not been demonstrated. In this article, we present multiple lines of evidence showing that palmitic acid directly activates TLR2, a major TLR expressed on human monocytes, by inducing heterodimerization with TLR1 in an NADPH oxidase–dependent manner. Dimerization of TLR2 with TLR1 was inhibited by the n-3 fatty acid docosahexaenoic acid. Activation of TLR2 by palmitic acid leads to expression of pro–IL-1β that is cleaved by caspase-1, which is constitutively present in monocytes, to release mature IL-1β. Our results reveal mechanistic insight about how palmitic acid activates TLR2, upregulates NALP3 expression, and induces inflammasome-mediated IL-1β production in human monocytes, which can trigger enhanced inflammation in peripheral tissues, and suggest that these processes are dynamically modulated by the types of dietary fat we consume.

Molecular characterization of stool microbiota in HIV-infected subjects by panbacterial and order-level 16S ribosomal DNA (rDNA) quantification and correlations with immune activation.

Background:The relationship between gut microbial community composition at the higher-taxonomic order level and local and systemic immunologic abnormalities in HIV disease may provide insight into how bacterial translocation impacts HIV disease. Methods:Antiretroviral-naive patients with HIV underwent upper endoscopy before and 9 months after starting antiretroviral treatment. Duodenal tissue was paraffin-embedded for immunohistochemical analysis and digested for fluorescence activated cell sorting for T-cell subsets and immune activation (CD38+/HLA-DR+) enumeration. Stool samples were provided from patients and control subjects for comparison. Metagenomic microbial DNA was extracted from feces for optimized 16S ribosomal RNA gene (rDNA) real-time quantitative polymerase chain reaction assays designed to quantify panbacterial loads and the relative abundances of proinflammatory Enterobacteriales order and the dominant Bacteroidales and Clostridiales orders. Results:Samples from 10 HIV subjects before initiating and from six subjects receiving antiretroviral treatment were available for analysis. There was a trend for a greater proportion of Enterobacteriales in HIV-positive subjects compared with control subjects (P = 0.099). There were significant negative correlations between total bacterial load and duodenal CD4+ and CD8+ T-cell activation levels (r = −0.74, P = 0.004 and r = −0.67, P = 0.013, respectively). The proportions of Enterobacteriales and Bacteroidales were significantly correlated with duodenal CD4+ T-cell depletion and peripheral CD8+ T-cell activation, respectively. Conclusions:These data represent the first report of quantitative molecular and cellular correlations between total/universal and order-level gut bacterial populations and gastrointestinal-associated lymphoid tissue levels of immune activation in HIV-infected subjects. The correlations between lower overall 16S rDNA levels and tissue immune activation suggest that the gut microbiome may contribute to immune activation and influence HIV progression.

SMOKING AND CARDIOVASCULAR DISEASE

Mainstream and ETS exposure are strong risk factors for cardiovascular disease in men and women. The relationships between smoking and cardiovascular disease result from multiple mechanisms that interact to contribute to atherosclerosis, vascular injury, thrombosis, and vascular dysfunction. We are only now beginning to understand how smoking contributes to the genesis and progression of cardiovascular disease. Because of the complexity of the interactions between nicotine and the components of MSS, ETS, and sidestream smoke with the vasculature, it will take a great deal of time and effort to fully unravel the mechanisms by which smoking contributes to cardiovascular disease. In addition, cardiovascular risk in female smokers is complicated by hormonal variables that may contribute to greater relative risk. It is important that health care providers, educators, and policy makers recognize the changing patterns of smoking and the impact of smoking on cardiovascular disease, and continue campaigns aimed at enhancing smoking cessation in the general population and in teens. Rigorous research is needed on the changing cultural, psychosocial, and environmental factors that influence tobacco use to improve our understanding of racial/ethnic smoking patterns, and identify strategic tobacco control opportunities. The capacity of tobacco control efforts to keep pace with patterns of tobacco use and cessation depends on timely recognition of emerging prevalence and cessation patterns and the resulting development of appropriate community-based programs to address the factors involved. Smoking trends today will determine how heavy the health burden of cardiovascular disease and others will be among communities tomorrow. Programs that aim at early intervention and reflect cultural diversity will be the cornerstone in the battle against tobacco use. Continued interest in research, educational, and prevention efforts are needed to help curb the risk of cardiovascular disease from smoking in men and women.

Hyperhomocysteinemia Evoked by Folate Depletion: Effects on Coronary and Carotid Arterial Function

High circulating concentrations of homocysteine (ie, hyperhomocysteinemia [Hhcy]) impair the vascular function of peripheral conduit arteries and arterioles perfusing splanchnic and skeletal muscle regions. The effects of HHcy on coronary resistance vessel function and other indexes of vascular function, ie, arterial permeability and stiffening, are unclear. We tested the hypotheses that HHcy impairs coronary resistance vessel reactivity; increases carotid arterial permeability; and initiates arterial stiffening. Male rats that consumed folate-replete (CON, n=44) or folate-deplete (HHcy, n=48) chow for 4 to 5 weeks had total plasma homocysteine concentrations of 7±2 or 58±4 &mgr;mol/L, respectively. Maximal acetylcholine-evoked relaxation (≈40% vs ≈60%) and tension development from baseline in response to nitric oxide synthase inhibition (≈20% vs ≈40%) were lower (both P <0.05) in coronary resistance vessels (≈120 &mgr;m, internal diameter) isolated from HHcy versus CON animals, respectively, whereas sodium nitroprusside-evoked relaxation and contractile responses to serotonin and potassium chloride were similar between groups. Permeability to 4400 MW and 65 000 MW fluorescently labeled (TRITC) dextran reference macromolecules (quantitative fluorescence microscopy) was ≈44% and ≈24% greater (P <0.05), respectively, in carotid arteries from HHcy versus CON rats. Maximal strain, evaluated by using a vessel elastigraph, was less (≈32% vs 42%, P <0.05) in carotid arterial segments from HHcy versus CON animals, respectively. Finally, estimates of oxidative (copper-zinc+manganese superoxide dismutase activity) and glycoxidative (pentosidine) stress were elevated (P <0.05) in arterial tissue from HHcy versus CON rats. These findings suggest that moderately severe HHcy evoked by folate-depletion impairs endothelium-dependent relaxation of coronary resistance vessels, increases carotid arterial permeability, and initiates arterial stiffening. HHcy may produce these effects by a mechanism associated with increased oxidative and glycoxidative stress.