Search

Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed., Competing Interests: Funding Support and Author Disclosures The Centre for Research Excellence is supported by National Health & Medical Research Council of Australia (grant number GNT1196629). Dr Figtree is funded by a National Health & Medical Research Council Practitioner Fellowship (GNT1135920). Dr Ellinor is supported by grants from the National Institutes of Health (1RO1HL092577, 1R01HL157635, 1R01HL157635), by a grant from the American Heart Association Strategically Focused Research Networks (18SFRN34110082), and by a grant from the European Union (MAESTRIA 965286). Dr Psaltis is funded by a National Heart Foundation Level 3 Future Leader Fellowship (106656). Dr Redfern is supported by grants from the National Health & Medical Research Council of Australia (GNT2007946 and GNT1182301). Dr Wilson is supported by grants from the National Health & Medical Research Council of Australia (GNT119600, GNT9100001, GNT1153479). Dr Guzik is funded by the British Heart Foundation and European Research Council (ERC-InflammaTENSION 726318). Dr Arnott has received honoraria from Amgen and AstraZeneca. Dr Brown has received consulting fees from Novartis. Dr Bhatt has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, Cincor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Pharmaceuticals, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89bio; has received royalties from Elsevier; has received consulting fees from Broadview Ventures, Hims, and McKinsey; has received payment or honoraria from the American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Slack Publications, WebMD, Wiley, and Society of Cardiovascular Patient Care; has received payment for expert testimony from Arnold and Porter law firm; has received travel or meeting support from the American College of Cardiology, Society of Cardiovascular Patient Care, and American Heart Association; has been named (no income) on a patent application for sotagliflozin, assigned to Brigham and Women’s Hospital, who assigned to Lexicon; serves on a Data Safety Monitoring Board for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, and Population Health Research Institute; has served on an Advisory Board for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for the American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft; has stock or stock options with AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; has financial or other nonfinancial interests in Clinical Cardiology, NCDR-ACTION Registry Steering Committee, Contego Medical, American Heart Association Quality Oversight Committee, VA CART Research and Publications Committee; and is a coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical, Phillips SpectraWAVE, Svelte, and Vascular Solutions. Dr Brieger has received research grant support from Novartis and has received honoraria from BMS/Pfizer. Dr Chong has received consulting fees from Implicit Bioscience Pty; and has a provisional patent for a cell surface marker signature for arrhythmogenic pluripotent stem cell-derived cardiomyocyte. Dr Cistulli has received research grant support from ResMed and SomnoMed; has received consulting fees from RedMed, SomnoMed, and Signifier Medical Technologies; and has received honoraria from ResMed and SomnoMed. Dr Ellinor has received sponsored research support from Bayer AG and IBM Research; and has served on Advisory Boards or consulted for Bayer AG, MyoKardia, and Novartis. Dr Figtree has received personal fees from Amgen, AstraZeneca, Bayer, CSL, and Janssen; has received grants from Abbott Diagnostic and Sanofi; is a founding director and chief medical officer of Prokardia; has a patent, “Biomarkers and Oxidative Stress,” awarded in the United States in May 2017 (US9638699B2) licensed to Northern Sydney Local Health District; has a patent, “Use of P2X7R Antagonists in Cardiovascular Disease” (PCT/AU2018/050905), licensed to Prokardia; has a patent, “Methods for Treatment and Prevention of Vascular Disease” (PCT/AU2015/000548) licensed to the University of Sydney/Northern Sydney Local Health District; and has a filed provisional patent application, “Methods for Predicting Coronary Artery Disease” (USYD Ref: 2022-009-PRO-0; 2022902660) to the University of Sydney/Northern Sydney Local Health District. Dr Hagström has received research grant support to his institution from Amgen and Pfizer; and has received honoraria from Amgen, AstraZeneca, Bayer, Novo Nordisk, Amarin, and Sanofi. Dr Jenkins has received research grant support from Abbott, Medtronic, and Mylan; and has served on Advisory Boards for Abbott Diabetes Care, Amgen, Insulet, and Medtronic. Dr Keech has received grant support from Abbott, Amgen, and Mylan; has received consulting fees from AstraZeneca, Pfizer, and Sanofi; and has participated as a Data Safety Monitoring Board member for the PROMINENT trial (Kowa Research Institute). Dr Kritharides has received research grant support from Amgen; and has received consulting fees from Seqiris. Dr Meikle has a license agreement with Juvenescence Ltd; and has received consultancy payments (made to Baker Institute) from BCAL Scientific and Juvenescence Ltd. Dr Mehran has received research grant support to her institution from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Applied Therapeutics, Arena, AstraZeneca, AtriCure, BAIM, Bayer, Beth Israel Deaconess Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi-Sankyo, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe AG, Magenta, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, RenalPro, RM Global, Shockwave, and Vivasure Zoll; has received consulting fees from Cine-Med Research; has served on an Advisory Board with all payments made to institution for Abbott, Janssen, Medtronic, and Novartis; and she and/or her spouse has stock or stock options in Applied Therapeutics, ControlRad, Elixir Medical, and Stel. Dr Natarajan has received research grant support from Apple, Amgen, AstraZeneca, Boston Scientific, and Novartis; has received consulting fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genetech/Roche, Invitae, Novartis, and TenSixteen Bio; has served on Advisory Boards for Esperion Therapeutics, geneXwell, and TenSixteen Bio; and holds stock or stock options in TenSixteen Bio and geneXwell. Dr Nicholls has received research grant support from AstraZeneca, Amgen, Anthera, Cerenis, Eli Lilly, Esperion, InfraReDx, LipoScience, The Medicines Company, New Amsterdam Pharma, Novartis, Resverlogix, Roche, and Sanofi-Regeneron; and has received consulting fees from Akcea, Amarin, Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Omthera, Merck, Resverlogix, Sanofi-Regeneron, Takeda, and Vaxxinity. Dr Psaltis has received consulting fees from Amgen, Esperion Therapeutics, and Novartis; has received speaker honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Sanofi; has received meeting travel support from Amgen and AstraZeneca; and has submitted a provisional patent for a method and composition for promoting neovascularization. Dr Sundström has stock or stock options with Anagram Kommunikation AB and Symptoms Europe AB. Dr Steg has received research grant support from Amarin, Bayer, Sanofi, and Servier Laboratories; has received consulting fees from Amgen, AstraZeneca, BMS/Myokardia, Merck, Novo Nordisk, and Regeneron; has served on Steering Committees or Critical Event Committees for Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Novartis, PhaseBio, Pfizer, Sanofi, and Servier; has received honoraria from AstraZeneca, Novartis, and Novo Nordisk; and has served on Data Safety Monitoring Boards for Servier, Sanofi, and PHRI. Dr Guzik has received research funding from the European Commission (ImmuneHyperCog and BrainGutCVD studies); has served as Editor-in-Chief for Cardiovascular Research; and has served as Board Committee member for the European Society of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the β 3 -adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating β 3 -Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication., Methods and Analysis: The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care., Ethics and Dissemination: The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes., Trial Registration Number: ACTRN12619000423112; Results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This case study is a rare example of cardiac hydatidosis in a high-income country, where a middle-aged man presented with a ruptured right ventricular cyst causing anaphylaxis, pulmonary emboli and dissemination of Echinococcus throughout the lung. He survived the cyst rupture and underwent cardiac surgery but had incomplete resection and experienced progressive cardiopulmonary hydatidosis despite antihelminthic therapy. As a result, he experienced an array of cardiopulmonary sequelae over his lifespan. This case report highlights rare clinical manifestations of hydatid disease and potential complications of its treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The authors performed a systematic review and meta-analysis to determine the efficacy of renal denervation (RDN) in patients with refractory ventricular arrhythmias (VA) or electrical storm (ES)., Background: Although catheter ablation is efficacious for the treatment of structural heart disease ventricular tachycardia (VT), there are proportion of patients who have refractory VT despite multiple procedures. In this setting, novel adjunctive therapies such as renal denervation have been performed., Methods: A systematic review of published data was performed. Studies that evaluated patients undergoing RDN for VA or ES were included. Outcome measures of VA, sudden cardiac death, ES, or device therapy were required. Case reports, editorials, and conference presentations were excluded. Random effects meta-analysis was conducted to explore change or final mean values in the study outcomes., Results: A total of 328 articles were identified by the literature search. Seven studies met the eligibility criteria and were included in the systematic review, with a total of 121 pooled patients. The weighted mean age was 63.8 ± 13.1 years, ejection fraction 30.5 ± 10.3%, 76% were men, 99% were on a beta blocker, 79% were on amiodarone, 46% had previously undergone catheter ablation, and 8.3% had previously undergone cardiac sympathetic denervation. Meta-analysis demonstrated a significant effect of RDN in reducing implantable cardiac defibrillator therapies, with a standardized mean difference (SMD) of -3.11 (p < 0.001). RDN also reduced the number of VA episodes (SMD -2.13; p < 0.001), antitachycardia pacing episodes (SMD -2.82; p = 0.002), and shocks (SMD -2.82; p = 0.002)., Conclusions: RDN is an effective treatment for refractory VAs and ES, although randomized data are lacking., Competing Interests: Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: Dyslipidemia in type 2 diabetes contributes to an increased risk of cardiovascular disease. Fenofibrate, a lipid-regulating peroxisome proliferator-activated receptor-α (PPARα) agonist, has been shown to reduce vascular complications in adults with type 2 diabetes. The mechanisms for such benefit, however, are not yet well understood. We examined the effects of fenofibrate on carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, in adults with type 2 diabetes., Methods: In a prospectively designed substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, we assessed carotid IMT in a subset of 422 representative adults. Traditional risk factors and IMT were assessed at 2 and 4 years after randomisation to fenofibrate (200 mg daily) or placebo. The prespecified primary study endpoint was the difference in IMT between treatment groups at 4 years. Post-hoc analyses were performed according to dyslipidemia and metabolic syndrome status., Results: There was no difference in carotid IMT comparing those assigned to fenofibrate or placebo at 2 or 4 years, despite statistically significant improvement in lipid and lipoprotein parameters at 2 and 4 years, including TC, LDL-C and TG, and HDL-C at 4 months and 2 years. Similarly, there was no difference in carotid IMT on fenofibrate compared with placebo in those with dyslipidemia or metabolic syndrome., Conclusions: Fenofibrate was not associated with improved carotid IMT in adults with type 2 diabetes when compared with placebo, despite a statistically significant improvement in TC, LDL-C and TG at 2 and 4 years, and HDL-C at 4 months and 2 years., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Reduced telomere length is a measure of biological aging that is predictive of cardiac events in adults, and has been mechanistically implicated in the onset and progression of atherosclerosis. We sought to describe the early life factors associated with leukocyte telomere length in early childhood, and to determine whether telomere length measured during early childhood is associated with arterial wall thickening later in childhood., Design: A longitudinal birth cohort recruited antenatally in Sydney from 1997 to 1999., Methods: Leukocyte telomere length was measured in 331 children at age 3.6 years (SD 1.0); of whom 268 children without diabetes had carotid intima-media thickness assessed by ultrasound at age 8 years., Results: Male sex, younger paternal age and higher maternal body mass index were associated with shorter telomere length in early childhood, which in turn was associated with greater carotid intima-media thickness at age 8 years (standardised β = -0.159, P = 0.01). There was a graded association across quartiles of telomere length (Ptrend = 0.001) with the highest odds of elevated intima-media thickness (>75th percentile) being in children with the shortest telomeres (odds ratio 4.00 (95% confidence interval 1.58 to 10.14) relative to those with the longest telomeres, P = 0.003). This association remained after adjustment for early life risk factors (Ptrend = 0.001)., Conclusions: Reduced telomere length in early childhood is independently associated with arterial wall thickness in later childhood, suggesting that reduced telomere length during early childhood may be a marker of vascular disease risk., (© The European Society of Cardiology 2015.)

Objectives: Experimental evidence suggests that structural changes to the arterial adventitia may be a key vascular determinant of early arterial stiffening, although this has not been directly studied. Accordingly, we hypothesized that in young children, in whom this relationship would not be altered by atheroma, carotid extramedial thickness (EMT), a measure that incorporates the thickness of the arterial adventitia, perivascular tissues and the internal jugular venous wall, would be associated with localized arterial stiffness of the same arterial region., Methods: We studied 248 healthy prepubescent children (aged 8 years). Carotid diameter and carotid EMT were measured by high-resolution ultrasound. Carotid blood pressure was derived from brachial blood pressure and carotid tonometry. Three measures of localized arterial stiffness (β stiffness index, distensibility coefficient and incremental modulus of elasticity) were calculated for the common carotid artery. Results were adjusted for heart rate and DBP, two important hemodynamic determinants of arterial stiffness., Results: Carotid EMT was associated with all three measures of arterial stiffness (β stiffness index: standardized β = 0.121, P = 0.03; distensibility coefficient: standardized β = -0.121, P = 0.05; incremental modulus of elasticity: standardized β = 0.140, P = 0.02). These associations remained significant after adjustment for potential confounders such as sex, height, waist circumference, BMI and body surface area., Conclusion: Carotid EMT is associated with the stiffness of the same arterial segment in children, suggesting that the arterial adventitia may be involved in early changes in arterial stiffness during childhood.

Objective: Dislipidaemia in type 2 diabetes mellitus contributes to arterial endothelial dysfunction and an increased risk of cardiovascular disease. Fenofibrate, a lipid-regulating peroxisome proliferator-activated receptor-α (PPARα) agonist, has been shown to reduce vascular complications in adults with type 2 diabetes. However, the mechanisms for such benefit are not well understood. We examined the effects of fenofibrate on brachial artery endothelial function in adults with type 2 diabetes., Methods: In a prospectively designed substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, we assessed arterial flow-mediated dilatation (FMD; endothelium-dependent dilatation) and dilator responses to glyceryl trinitrate (GTN, an endothelium-independent dilator) in a subset of 193 representative adults. Traditional risk factors were assessed at baseline, 4 months and 2 years after randomised treatment allocation to fenofibrate (200 mg daily) or placebo. The prespecified primary study endpoint was the difference in FMD between treatment groups at 4 months., Results: Fenofibrate was associated with a significant improvement at 4 months compared with placebo (+1.05% (absolute); P=0.03); GTN-dilator responses were unchanged (P=0.77). After 2 years, FMD was similar in both groups (P=0.46). In multivariable models, none of the fenofibrate-related changes in lipoproteins and lipids were significantly associated with improved FMD on fenofibrate at 4 months., Conclusion: Treatment with fenofibrate significantly improved arterial endothelial function after 4 months. However, the effect was no longer apparent after 2 years. The long-term beneficial vascular effects of fenofibrate in type 2 diabetes are likely to be mediated via mechanisms other than improvement in endothelium-dependent dilatation of conduit arteries, and may differ for the microcirculation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aim: Impaired arterial function has been implicated in diabetes-related atherosclerosis, but its determinants in high-risk adults have not been well characterised. We investigated factors associated with impaired arterial function in adults with type 2 diabetes., Methods: Flow-mediated dilatation (a marker of endothelial function) and dilator response to glyceryl trinitrate (to assess smooth muscle function) of the brachial artery were assessed at baseline in 193 patients with type 2 diabetes from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Traditional risk factors were assessed and a multivariable model was constructed to identify factors independently associated with impaired arterial function., Results: Median age was 64 years (interquartile range, 58-69; 61% male) and duration of diabetes was 4 years (interquartile range, 2-9). Flow-mediated dilatation (3.06 ± 0.25%, mean ± SEM) was severely impaired but not significantly associated with other risk factors. Dilator responses to glyceryl trinitrate (10.56 ± 0.52%) were significantly and independently impaired in past and present cigarette smokers (P = 0.005) and in subjects with increased urinary albumin/creatinine ratio (P = 0.01)., Conclusions: In adults with type 2 diabetes and known or suspected atherosclerosis, arterial smooth muscle-dependent dilatation was shown to be significantly impaired in cigarette smokers and those with elevated urinary albumin levels., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Early life is an important period for determining future risk of cardiovascular disease. Carotid extra-medial thickness is a novel noninvasive measure that estimates arterial adventitial thickness, information concerning vascular health not captured by assessment of arterial intima-media thickness alone. We sought to determine whether fetal growth and early postnatal growth are associated with carotid extra-medial thickness in 8 year old children., Methods: Carotid extra-medial thickness was assessed by high-resolution ultrasound in 379 non-diabetic children aged 8-years, with complete data for birth weight, gestational age, early postnatal weight gain and carotid extra-medial thickness., Results: Weight gain during infancy, from birth to 18 months of age, was significantly and positively associated with carotid EMT (11 μm per kg length-adjusted weight gain [95% CI 3, 18], P=0.007). This association was significantly stronger in boys than girls (Pheterogeneity=0.005). By contrast, there was no significant association between birth weight and carotid EMT (6 μm/kg birth weight [95% CI -12, 24], P=0.51)., Conclusion: Excessive weight gain during infancy is associated with increased carotid extra-medial thickness, indicating that the alterations to the vasculature associated with excessive early postnatal growth likely include arterial adventitial thickening., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: We hypothesized that early weight gain would be associated with incident obesity, higher blood pressure, systemic inflammation, and arterial wall thickening in later childhood., Methods: A longitudinal birth cohort was recruited antenatally from 2 maternity hospitals in Sydney, Australia, between September 1997 and December 1999. Three hundred ninety-five nondiabetic children who were followed to age 8 years had complete data for early weight gain and arterial wall thickness., Results: Independent predictors of excess early weight gain (age 0-18 months; adjusted for height gain) included male gender (0.411 kg [SE: 0.103], P < .001), fewer weeks' gestation (-0.121 kg [SE: 0.044] per week, P = .006), birth length (0.156 kg [SE: 0.024] per cm, P < .001), and failure to breastfeed to 6 months of age (0.498 kg [SE: 0.108], P < .001). Early height-adjusted weight gain was significantly associated with later childhood overweight (odds ratio [OR]: 1.67 [95% confidence interval (CI): 1.26 to 2.20] per kg) and obesity (OR: 2.07 [95% CI: 1.53 to 2.79] per kg), excess central adiposity (OR: 1.54 [95% CI: 1.20 to 1.98] per kg), higher systolic blood pressure (1.24 mm Hg [SE: 0.33] per kg, P < .001), higher C-reactive protein (0.17 mg/dL [SE: 0.06] per 100% increase in weight gain, P = .006), and greater carotid intima-media thickness (0.012 mm [SE: 0.004] per kg, P = .002)., Conclusions: Early postnatal weight gain from birth to age 18 months is significantly associated with later childhood overweight and obesity, excess central adiposity, and greater arterial wall thickness.

Smokers have an elevated risk of atherosclerosis but the origin of this elevated risk is incompletely defined, though increasing evidence supports a role for the oxidant-generating enzyme myeloperoxidase (MPO). In previous studies we have demonstrated that smokers have elevated levels of thiocyanate ions (SCN(-)), relative to nonsmokers, and increased thiol oxidation, as SCN(-) is a favored substrate for MPO, and the resulting hypothiocyanous acid (HOSCN) targets thiol groups rapidly and selectively. In this study we show that increased HOSCN formation by MPO diminishes damage to nonthiol targets on both model proteins and human plasma proteins. Thus high SCN(-) levels protect against HOCl- and MPO-mediated damage to methionine, tryptophan, lysine, histidine, and tyrosine residues on proteins. Furthermore, levels of the HOCl-mediated marker compound 3-chlorotyrosine and the cross-linked product dityrosine are decreased. Plasma protein 3-chlorotyrosine levels induced by HOCl exposure in nonsmokers are elevated over the levels detected in smokers when exposed to identical oxidative insult (P<0.05), and a strong inverse correlation exists between plasma SCN(-) levels and 3-chlorotyrosine concentrations (r=0.6182; P<0.0001). These correlations were also significant for smokers (r=0.2724; P<0.05) and nonsmokers (r=0.4141; P<0.01) when analyzed as individual groups. These data indicate that plasma SCN(-) levels are a key determinant of the extent and type of protein oxidation induced by MPO on isolated and plasma proteins and that smoking status and resulting high SCN(-) levels can markedly modulate the levels of the widely used biomarker compound 3-chlorotyrosine., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Structural modification of the arterial adventitia may be an early event in atherosclerosis. Carotid extra-medial thickness is a new measure of arterial adventitial thickness. We examined the association of cardiovascular risk factors with extra-medial thickness, in childhood., Methods: Carotid extra-medial thickness was assessed by high-resolution ultrasound in 389 non-diabetic children aged 8-years. A non-fasting blood sample was collected from 314 participants. Associations of gender, age, lipoproteins, blood pressure, BMI z-score, waist:height ratio and parental history of early vascular disease, with extra-medial thickness were examined., Results: Carotid extra-medial thickness was lower in girls (r=-.163, P=.001) and directly associated with systolic (r=.128, P=.009), diastolic blood pressure (r=.130, P=.009), and height (r=.170, P=.0006). These associations remained after adjustment for carotid intima-media thickness. In multivariable analysis including carotid intima-media thickness, only gender and height were significantly associated with carotid extra-medial thickness. In gender-stratified analysis, the strongest associations with extra-medial thickness were BMI z-score (r=.181, P=.01), height (r=.210, P=.003) and diastolic blood pressure (r=.167, P=.02) for boys; and systolic blood pressure (r=.153, P=.03) and parental history of premature cardiovascular disease (r=.139, P=.05) for girls. The association of BMI z-score with extra-medial thickness differed by gender (P-interaction=.04)., Conclusions: Carotid extra-medial thickness is independently associated with gender and height in childhood. Extra-medial thickness may provide important information concerning early arterial health, particularly related to the arterial adventitia., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Impaired fetal growth is an independent cardiovascular risk factor and is associated with arterial wall thickening in children. No preventive strategy has been identified. We sought to determine whether dietary ω-3 fatty acid supplementation during early childhood prevents the association between impaired fetal growth and carotid arterial wall thickening., Methods: The Childhood Asthma Prevention Study was a randomized, controlled single-blind trial in 616 children born at term, recruited antenatally from maternity hospitals in Sydney. Participants were randomized to either a 500-mg-daily fish oil supplement and canola-based margarines and cooking oil (ω-3 group), or a 500-mg-daily sunflower oil supplement and ω-6 fatty acid-rich margarines and cooking oil (control group), from the start of bottle-feeding or 6 months of age until 5 years of age. Carotid intima-media thickness (IMT), a noninvasive measure of subclinical atherosclerosis, was the primary endpoint of a cardiovascular substudy (CardioCAPS) at age 8 years. We examined the association of fetal growth with carotid IMT in children with birth weight <90th percentile (ω-3 group [n = 187], control group [n = 176])., Results: In the control group, fetal growth was inversely associated with carotid IMT, but this was prevented in the ω-3 group (difference between groups of 0.041 mm [95% confidence interval 0.006, 0.075] per kg birth weight, adjusted for gestational age and gender, P(heterogeneity) = .02)., Conclusions: The inverse association of fetal growth with arterial wall thickness in childhood can be prevented by dietary ω-3 fatty acid supplementation over the first 5 years of life.

Smokers have an elevated risk of atherosclerosis but the origins of this elevated risk are incompletely defined, though evidence supports an accumulation of the oxidant-generating enzyme myeloperoxidase (MPO) in the inflamed artery wall. We hypothesized that smokers would have a high level of thiocyanate (SCN(-)), a preferred substrate for MPO, which in turn would predispose to thiol oxidation, an established independent risk factor for atherosclerosis. In this study it is shown that on exposure to MPO/H(2)O(2), thiols on plasma proteins from nonsmokers were increasingly oxidized with increasing added SCN(-) concentrations. Plasma from smokers contained significantly higher endogenous levels of SCN(-) than that from nonsmokers (131±31 vs 40±24 μM, P<0.0001). When plasma from smokers and nonsmokers was exposed to MPO/H(2)O(2)-stimulated oxidation, a strong positive correlation (r=0.8139, P<0.0001) between the extent of thiol oxidation and the plasma SCN(-) concentrations was observed. Computational calculations indicate a changeover from HOCl to HOSCN as the major MPO-generated oxidant in plasma, with increasing SCN(-) levels. These data indicate that plasma SCN(-) levels are a key determinant of the extent of thiol oxidation on plasma proteins induced by MPO, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage to proteins in smokers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: Smoking in pregnancy is common. Its effects on lipoprotein levels and arterial structure in childhood are not well characterized. We aimed to determine the effects of maternal smoking in pregnancy on lipoprotein levels and arterial wall thickness in healthy pre-pubertal children., Methods and Results: A community-based longitudinal study with prospective ascertainment of exposure to smoking in pregnancy and environmental tobacco smoke (ETS) since birth and then lipoprotein and arterial measurements at age 8 years. In 616 newborn infants (gestation >36 weeks and birth weight >2.5 kg) data were collected prospectively by questionnaire on smoking in pregnancy and ETS exposure in childhood. At age 8-years, 405 of the children had measurements of lipoproteins, blood pressure (BP) and carotid intima-media thickness. Children born to mothers who smoked in pregnancy had lower HDL cholesterol [1.32 vs. 1.50 mmol/L, 95% confidence interval (CI) for difference -0.28 to -0.08, P = 0.0005], higher triglycerides (1.36 vs. 1.20 mmol/L, 95% CI for ratio 1.01-1.30, P = 0.04) and higher systolic BP (102.1 vs. 99.9 mmHg, 95% CI for difference 0.6-3.8, P = 0.006). After adjustment for maternal passive smoking, post-natal ETS exposure, gender, breast feeding duration, physical inactivity, and adiposity, smoking in pregnancy remained significantly associated with lower HDL cholesterol (difference = -0.22 mmol/L, 95% CI -0.36 to -0.08, P = 0.003) but not with higher systolic BP. Neither smoking in pregnancy nor post-natal ETS exposure was associated with alterations of carotid artery wall thickness., Conclusion: Smoking in pregnancy is independently associated with significantly lower HDL cholesterol in healthy 8-year-old children.

Aims: To study the association between childhood snoring and cardiovascular risk factors., Methods: Cross-sectional analyses of a population-based birth cohort, who had been participants in a randomised controlled trial of interventions to prevent asthma and who were assessed at age 8 years. The presence and frequency of snoring were assessed by parent-completed questionnaire. We measured a wide range of cardiovascular function markers including non-fasting serum lipoproteins, blood pressure, high-sensitivity C-reactive protein, carotid artery intima media thickness (by ultrasound), brachial pulse wave velocity and augmentation index (by applanation tonometry)., Results: Of 409 children whose snoring status was assessed at age 8 years, 321 had lipid and 386 had arterial structure and function measurements. Snoring was not independently associated with blood pressure, carotid artery intima media thickness or measures of arterial stiffness (all P > 0.05). Increasing snoring frequency was independently associated with lower high-density lipoprotein cholesterol (-0.032 g/dL per step, 95% confidence interval -0.060 to -0.003), although the difference in high-density lipoprotein between snorers and non-snorers was not significant (P = 0.052). An association of snoring frequency with brachial pulse wave velocity differed according to body mass index (P = 0.03) and was the reverse of that expected., Conclusions: Parentally reported snoring was not independently associated with adverse measurements of metabolic markers, vascular structure or function in 8-year-old children. Parental reports of snoring may be below the treatment threshold without additional diagnosis via sleep studies., (© 2011 The Authors. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Background: In older adults, an independent association exists between impaired lung function and cardiovascular disease. This interaction might be related to the effects of aging and/or smoking. In order to explore possible childhood antecedents to this association, we hypothesized that decreased lung function and vascular stiffness might be related, in early life., Objective: To determine the relationship between lung function and carotid augmentation index (AIx), a measure of vascular stiffness, in 8-year old children., Methods: Data on brachial blood pressure, lung function (FEV(1), FVC, FEV(1)/FVC, obtained by spirometry) and carotid AIx75 (AIx standardised to an arbitrary heart rate of 75 beats per minute, obtained by applanation tonometry) was available in 249 community-based 8-year old children. These healthy children had been subjects in a randomised controlled trial of two interventions (omega-3 fatty acid supplementation and house-dust mite avoidance) to prevent asthma. Smoking in pregnancy and childhood environmental tobacco smoke (ETS) exposure was prospectively collected by questionnaire. The association between lung function and carotid AIx75 was assessed in multivariate models that included sex, height, smoking status during pregnancy, ETS exposure and randomisation groups (house dust mite avoidance and dietary intervention) as covariates., Results: In the fully adjusted models, Carotid AIx75 was independently associated with FEV1 (standardised β = -0.17,b = -6.72, partial R(2) = .02, p = 0.03), FVC (standardised β = -0.29, b = -9.31, partial R(2) = 0.04, p<0.001) and FEV1/FVC (standardised β = .13, b = 18.4, partial R(2) = 0.02, p = 0.04)., Conclusion: Lower lung volumes are associated with increased vascular stiffness at an early age. The interaction between lung function and vascular stiffness may thus represent more than just age-related alterations in both the pulmonary and vascular systems.

The degree of arterial dilatation induced by exogenous nitrates (nitrate-mediated dilatation, NMD) has been similar in obese and normal-weight adults after single high-dose glyceryl trinitrate (GTN). We examined whether NMD is impaired in obesity by performing a GTN dose-response study, as this is a potentially more sensitive measure of arterial smooth muscle function. In this cross-sectional study, subjects were 19 obese (age 31.0 ± 1.2 years, 10 male, BMI 44.1 ± 2.1) and 19 age- and sex-matched normal-weight (BMI 22.4 ± 0.4) young adults. Blood pressure (BP), triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)-cholesterol, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), carotid intima-media thickness (CIMT), and flow-mediated dilatation (FMD) were measured. After incremental doses of GTN, brachial artery maximal percent dilatation (maximal NMD) and the area under the dose-response curve (NMD AUC) were calculated. Maximal NMD (13.4 ± 0.9% vs. 18.3 ± 1.1%, P = 0.002) and NMD AUC (54,316 ± 362 vs. 55,613 ± 375, P = 0.018) were lower in obese subjects. The obese had significantly higher hs-CRP, insulin, and CIMT and lower HDL-cholesterol. Significant bivariate associations existed between maximal NMD or NMD AUC and BMI-group (r = -0.492, P = 0.001 or r = -0.383, P = 0.009), hs-CRP (r = -0.419, P = 0.004 or r = -0.351, P = 0.015), and HDL-cholesterol (r = 0.374, P = 0.01 or r = 0.270, P = 0.05). On multivariate analysis, higher BMI-group remained as the only significant determinant of maximal NMD (r² = 0.242, β = -0.492, P = 0.002) and NMD AUC (r² = 0.147, β = -0.383, P = 0.023). In conclusion, arterial smooth muscle function is significantly impaired in the obese. This may be important in their increased cardiovascular risk.

As humans spend a significant amount of time in the postprandial state, we examined whether vascular reactivity (a key indicator of cardiovascular health) was different after a high-fat meal in 11 obese (median BMI 46.4, age 32.1 +/- 6.3 years, 7 men) and 11 normal weight (median BMI 22.6) age- and sex-matched controls. At baseline and 1 and 3 h postmeal, blood pressure (BP), heart rate (HR), reactive hyperemia peripheral artery tonometry (RH-PAT) index, radial augmentation index adjusted for HR (AIx75), brachial pulse wave velocity (PWV(b)), glucose, insulin, total and high-density lipoprotein (HDL) cholesterol, and triglycerides were measured. Brachial flow-mediated dilatation (FMD) and, by venous plethysmography, resting and hyperemic forearm blood flows (FBFs) were measured at baseline and 3 h. At baseline, obese subjects had higher systolic BP, HR, resting FBF, insulin and equivalent FMD, RH-PAT, hyperemic FBF, AIx75, PWV(b), glucose, total cholesterol, triglycerides, and lower HDL cholesterol. In obese and lean subjects, FMD at baseline and 3 h was not significantly different (6.2 +/- 1.7 to 5.8 +/- 4.3% for obese and 4.7 +/- 4.1 to 4.3 +/- 3.9% for normal weight, P = 0.975 for group x time). The meal did not produce significant changes in RH-PAT, hyperemic FBF, and PWV(b) in either group (P > 0.1 for the effect of time and for group x time interactions). In conclusion, the vascular responses to a high-fat meal are similar in obese and normal weight young adults. An exaggerated alteration in postprandial vascular reactivity is thus unlikely to contribute importantly to the increased cardiovascular risk of obesity.

Objectives: Central arterial pulse wave augmentation, quantified by the augmentation index (AIx), is a key marker of arterial health, an important contributor to cardiac afterload and is significantly greater in older women than men. We measured carotid AIx in 8-year-old children to examine the influences of sex, height and arterial stiffness on central arterial pulse wave augmentation, Methods: Four hundred and five children (age 8.0 +/- 0.1 years, 49% girls) had anthropometry, brachial systolic and diastolic blood pressure, heart rate and carotid artery pressure waveforms (by applanation tonometry), diastolic diameter and distensibility assessed., Results: Carotid AIx was significantly higher in girls than boys (-11.7 +/- 8.1 versus -16.5 +/- 9.3%, respectively, P < 0.001). Boys and girls had similar height (129 +/- 6 versus 128 +/- 6 cm), systolic blood pressure (100 +/- 7 versus 101 +/- 7 mmHg), diastolic blood pressure (59 +/- 6 versus 60 +/- 5 mmHg) and heart rate (80 +/- 10 versus 82 +/- 10 bpm). Carotid diastolic diameter was smaller in girls than boys (0.45 +/- 0.03 versus 0.47 +/- 0.04 cm, P < 0.001). The sex difference in AIx remained significant after adjustment for height, heart rate, blood pressure, diastolic diameter and birth weight. The time to the onset of the reflected wave was shorter in girls (155 +/- 19 versus 163 +/- 18 ms, P < 0.001). Girls had greater carotid artery distensibility (6.2 +/- 1.8 versus 5.8 +/- 1.5% per 10 mmHg, P = 0.016), suggesting lower regional carotid artery stiffness., Conclusion: Greater pulse wave augmentation in prepubertal girls results from earlier wave reflection and is independent of height, carotid artery diameter and stiffness. When combined with age-related changes in arterial compliance, this may contribute to adverse cardiovascular outcomes in older women.

Background: n-3 Fatty acid supplementation in adults results in cardiovascular benefits. However, the cardiovascular effects of n-3 supplementation in early childhood are unknown., Objective: The objective was to evaluate blood pressure (BP) and arterial structure and function in 8-y-old children who had participated in a randomized controlled trial of dietary n-3 and n-6 modification over the first 5 y of life., Design: The children (n = 616; 49% girls) were randomly assigned antenatally to active (n = 312; increase in n-3 intake and decrease in n-6 intake) or control (n = 304) diet interventions implemented from the time of weaning or introduction of solids until 5 y of age. At age 8.0 +/- 0.1 y, BP, carotid intima-media thickness, carotid artery distensibility, augmentation index, and brachial pulse wave velocity were measured in 405 of these children. Venous blood was collected for measurement of plasma fatty acids, lipoproteins, high-sensitivity C-reactive protein, and asymmetric dimethylarginine. Plasma fatty acid concentrations were also assessed during the intervention., Results: Plasma concentrations of n-3 fatty acids were higher and of n-6 were lower in the active than in the control diet group at 18 mo and 3 and 5 y (P < 0.0001). Concentrations of n-3 and n-6 fatty acids were similar at 8 y. At 8 y of age, no significant differences were found in BP, carotid intima-media thickness, carotid artery distensibility, augmentation index, asymmetric dimethylarginine, high-sensitivity C-reactive protein, or lipoproteins between diet groups., Conclusion: A dietary supplement intervention to increase n-3 and decrease n-6 intakes from infancy until 5 y does not result in significant improvements in arterial structure and function at age 8 y. This trial was registered at the Australian Clinical Trials Registry as ACTRN012605000042640.

Objective: Atherosclerosis is found at autopsy in the arteries of adolescents and young adults. Arterial wall thickening may be assessed in vivo by ultrasound measurement of the carotid intima media thickness (CIMT), a marker of subclinical atherosclerosis. As the determinants of arterial wall thickness in childhood are unknown, we assessed the influence of cardiovascular risk factors on CIMT in 8-year-old children., Methods and Results: A community-based sample of 405 children (age 8.0+/-0.1 years, 49% girls) had anthropometry, family history, blood pressure (BP), and CIMT measured. A blood sample was collected for HDL and non-HDL cholesterol, apolipoproteins A1 and B, high-sensitivity C-reactive protein, bilirubin, and asymmetric dimethylarginine (ADMA, an endogenous nitric oxide inhibitor). CIMT was significantly associated with systolic BP (r=0.17, P<0.001), diastolic BP (r=0.10, P=0.04), HDL (r=-0.13, P=0.02), and ADMA (r=0.18, P=0.001). CIMT was significantly higher in children with premature parental CHD (0.63+/-0.07 versus 0.59+/-0.06 mm, P=0.03). On multivariate analysis, HDL (beta coefficient=-0.02, P=0.04), ADMA (beta coefficient=0.05, P<0.001), and systolic BP (beta coefficient=0.001, P=0.003) were significantly and independently associated with CIMT., Conclusions: Lower HDL-cholesterol, higher levels of ADMA, and systolic BP are significantly associated with greater arterial wall thickness in early childhood.

Aims: The mechanisms by which obesity confers increased cardiovascular risk and the effects of moderate weight loss on cardiovascular health are incompletely understood. We sought to characterize the preclinical changes in cardiac and vascular health that accompany obesity and the influence of lifestyle modification on these parameters., Methods: Preclinical markers of vasculopathy in resistance vessels and conduit arteries and left ventricular structure and function were assessed in 39 obese subjects (BMI > 30 kg/m(2)) and 11 healthy weight controls. The influence of serum on cellular adhesion molecule (CAM) expression on human endothelial cells was studied ex vivo in a subgroup of 13 obese and nine healthy weight subjects. These analyses were repeated in all 17 of the obese subjects who complied with 4-9 months of lifestyle modification treatment (six with weight loss >5% and 11 with weight loss <5%)., Results: Compared with healthy weight controls, obese subjects had decreased peak hyperaemic forearm blood flow (p = 0.015), increased carotid intima-media thickness (p = 0.009), increased left ventricular wall thickness and volume and evidence of systolic and diastolic dysfunction as assessed using tissue Doppler imaging (S', p = 0.09; E'/A', p = 0.02), and serum from obese subjects increased the intercellular CAM-1 expression on human endothelial cells (p = 0.009). However, arterial endothelial function assessed by flow-mediated dilatation was not altered (p = 0.99). Lifestyle modification treatment resulted in potentially beneficial changes in fibrinogen (p = 0.003), HDL cholesterol (p = 0.05) and soluble vascular CAM-1 (p = 0.06). In subjects with weight loss greater than 5% of body weight, there was also a decrease in low-level inflammation (high-sensitivity C-reactive protein, p = 0.05), lipid peroxidation (thiobarbituric acid-reactive substances, p = 0.05) and triglycerides (p = 0.07)., Conclusions: Obesity is associated with widespread alterations in cardiac and vascular structure and function. Moderate short-term weight loss by lifestyle modification results in some beneficial changes in serum profile; however, these are not accompanied by significant alterations to either cardiac or vascular structure and function.

Asian Indians appear particularly susceptible to coronary heart disease compared with other ethnic groups. We compared the effects of vascular risk factors on carotid intima-media thickness (IMT) in a population of South Asians from Andhra Pradesh, India with a population of Caucasians from Perth, Australia. Cardiovascular risk factors and ultrasound-assessed carotid IMT were measured in randomly selected adults from two villages in rural India (n=303) and compared to those for randomly sampled adults from Australia (n=1111). Regression models with interaction terms were used to compare the strengths of associations between risk factors and carotid IMT, in these two populations. There were stronger associations of cholesterol (p for interaction=0.009) and diabetes (p=0.04) with carotid IMT in the Indian compared to the Australian population. Also, while increasing HDL-cholesterol was associated with decreasing carotid IMT in the Australian population the reverse was true for the Indian population (p<0.001). The associations with IMT of blood pressure, triglycerides, age, HDL to total cholesterol ratio, glucose, BMI, waist, waist to hip ratio and smoking were not different between the populations. Greater adverse effects of total cholesterol and diabetes on atherosclerosis and no protective effect of HDL-cholesterol amongst Asian Indians provide a novel possible explanation for observed excess rates of cardiovascular disease amongst these populations.

Objective: Prader-Willi syndrome (PWS) is a genetic obesity syndrome characterized by hyperphagia, behavioural disturbance and intellectual disability. PWS appears to be associated with a high incidence of sudden death, suspected to be cardiopulmonary in origin. We therefore sought to provide an assessment of cardiac and vascular structure and function in patients with PWS., Patients: Nine patients with genetically confirmed PWS, mean age 28 years, body mass index (BMI) 42 kg/m2, were compared with nine age- and gender-matched lean controls., Measurements: Lipid parameters, high-sensitivity C-reactive protein (hs-CRP) and fasting glucose and insulin were measured. To assess cardiac structure and function, a resting electrocardiogram (ECG), exercise stress test, 24-h continuous ECG monitoring, and echocardiogram were obtained. Patients and control subjects also underwent comprehensive noninvasive vascular assessment, including venous-occlusion forearm plethysmography, brachial artery flow-mediated dilatation (FMD), radial artery tonometry and carotid intima-media thickness (IMT) measurements., Results: All patients with PWS had significantly elevated hs-CRP (> 3.0 mg/l) (mean 11.5 mg/l, median 11.47, interquartile range: 4.48-15.8 mg/l), compared with controls (P < 0.001). Five of nine patients with PWS had subnormal exercise capacity (< 4 mets on exercise stress testing). Twenty-four-hour ECG monitoring revealed prolonged sinus pauses in one patient, up to 4.8 s, requiring pacemaker insertion. Microvascular function as assessed by peak hyperaemic flow response was decreased in PWS (6.1 +/- 1.0 times baseline flow vs. controls 13.5 +/- 1.6 times baseline flow, P = 0.01). Other measures were similar between PWS and controls., Conclusions: This group of PWS patients had significantly raised levels of the inflammatory marker hs-CRP and evidence of microcirculatory dysfunction, both of which are associated with coronary artery disease and early sudden death. The sinus node dysfunction may in itself be a risk factor for sudden cardiac death.

Objectives: The purpose of this study was to investigate the influence of dietary fatty acids on the anti-inflammatory properties of high-density lipoproteins (HDL) and vascular function., Background: The effect of dietary fatty acids on atherogenesis remains uncertain., Methods: Fourteen adults consumed an isocaloric meal containing either a polyunsaturated or a saturated fat on 2 occasions. The effects of post-prandial HDL on endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined. Flow-mediated dilation (FMD) and microvascular reactivity were assessed before and 3 and 6 h after the meal., Results: Plasma triglycerides, insulin, and nonesterified fatty acids rose after the meals. The HDL collected 6 h after the saturated meal were less effective than HDL isolated from fasting plasma in terms of their ability to inhibit expression of ICAM-1 and VCAM-1, whereas HDL collected 6 h after the polyunsaturated meal had an inhibitory activity that was greater than that of HDL collected from fasting plasma (p < 0.004 and p = 0.01 for comparison of effect of meals on ICAM-1 and VCAM-1, respectively). Post-hyperemic microvascular flow significantly increased at 3 h after the polyunsaturated meal by 45 +/- 14% and by 21 +/- 11% after the saturated meal. The FMD decreased 3 h after the saturated meal by 2.2 +/- 0.9% (p< 0.05 compared with baseline) and by 0.9 +/- 1% after the polyunsaturated meal., Conclusions: Consumption of a saturated fat reduces the anti-inflammatory potential of HDL and impairs arterial endothelial function. In contrast, the anti-inflammatory activity of HDL improves after consumption of polyunsaturated fat. These findings highlight novel mechanisms by which different dietary fatty acids may influence key atherogenic processes.

Objectives: We sought to assess the effects of raloxifene, a selective estrogen receptor modulator, on arterial physiology and biology in postmenopausal women with coronary artery disease (CAD)., Background: Raloxifene improves endothelial function and markers of vascular health in vitro in experimental animals and in healthy postmenopausal women. In women whose arteries are affected by advanced atherosclerosis, however, the vascular effects of estrogen receptor modulation are unknown., Methods: We conducted a prospective, randomized, double-blinded, placebo-controlled, crossover trial of raloxifene, 60 mg/day for 8 weeks, in 33 consecutively eligible and consenting postmenopausal women age 50 to 75 years with known CAD. Parameters measured at the beginning and end of each treatment period included brachial artery flow-mediated dilation (FMD), the primary end point, as well as nitroglycerin-induced dilation, peripheral artery tonometry, serum lipoprotein levels, and markers of vascular function, including urinary prostaglandin, serum endothelin-1, and fibrinogen levels., Results: Baseline FMD was impaired in these women, as expected (2.84 +/- 0.60%), but there was no significant difference between the effect of raloxifene (0.26 +/- 0.66% increase) and placebo (0.01 +/- 0.63% decrease) on this marker of endothelial function (p = 0.82). No significant raloxifene-related effects were observed on derived aortic pressure, pulse pressure, augmentation index, total cholesterol or low- and high-density lipoprotein subfractions, markers of thrombosis, or vasoconstrictor or vasodilator substances., Conclusions: In postmenopausal women with treated CAD, selective estrogen receptor modulation with raloxifene does not improve a comprehensive set of parameters examining vascular function and serum lipoprotein levels.

Antiphospholipid (aPL) syndrome (APS) is characterized by thromboembolic events, thrombocytopenia, or recurrent miscarriage associated with aPL Abs with specificity for beta2-glycoprotein-I (beta2GPI). We recently reported that at least 44% of patients with the APS possess circulating type 1 (Th1) CD4+ T cells that proliferate and secrete IFN-gamma when stimulated with beta2GPI in vitro. In this study, we show that stimulation of PBMCs from 20 APS patients with beta2GPI induced substantial monocyte tissue factor (TF) (80 +/- 11 TF stimulation index (TF-SI)), whereas no induction was observed using PBMCs from 13 patients with aPL Abs without APS (6 +/- 1 TF-SI) or 7 normal and 7 autoimmune controls (5 +/- 1 and 3 +/- 1 TF-SI, respectively) (p < 0.0001). TF induction on monocytes by beta2GPI was dose dependent and required CD4+ T lymphocytes and class II MHC molecules. Because monocyte TF induction by beta2GPI was observed in all patients with APS, but not in any patient with aPL Abs without APS, this response is a potentially useful predictor for APS in patients with aPL Abs, as well as providing mechanistic insight into thrombosis and fetal loss in these patients.