ORCID Profile
0000-0002-6983-5423
Current Organisation
University of Oxford
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Publisher: Japan Atherosclerosis Society
Date: 2011
DOI: 10.5551/JAT.11700
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.NANO.2012.05.006
Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed countries, with an increasing prevalence due to an aging population. The pathology underpinning CVD is atherosclerosis, a chronic inflammatory state involving the arterial wall. Accumulation of low density lipoprotein (LDL) laden macrophages in the arterial wall and their subsequent transformation into foam cells lead to atherosclerotic plaque formation. Progression of atherosclerotic lesions may gradually lead to plaque related complications and clinically manifest as acute vascular syndromes including acute myocardial or cerebral ischemia. Nanotechnology offers emerging therapeutic strategies, which may have advantage overclassical treatments for atherosclerosis. In this review, we present the potential applications of nanotechnology toward prevention, identification and treatment of atherosclerosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-05-2023
DOI: 10.1161/CIRCULATIONAHA.122.062021
Abstract: Sodium–glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF n=36 left ventricular ejection fraction ≤40% New York Heart Association class ≥II NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF n=36 left ventricular ejection fraction ≥50% New York Heart Association class ≥II NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin – placebo], –0.25 [95% CI, –0.58 to 0.09] P =0.14) or HFpEF (adjusted mean treatment difference, –0.16 [95% CI, –0.60 to 0.29] P =0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, –0.13 [95% CI, –0.35 to 0.09] P =0.23) or HFpEF (adjusted mean treatment difference, –0.22 [95% CI, –0.66 to 0.23] P =0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. URL: www.clinicaltrials.gov Unique identifier: NCT03332212.
Publisher: European Respiratory Society (ERS)
Date: 28-05-2015
DOI: 10.1183/09031936.00023215
Abstract: There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress. 59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) events·h −1 ) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using s les from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. “Treatment” effects (sham CPAP versus CPAP) were calculated via linear regression. Sham CPAP provoked moderate-to-severe OSA (mean ODI 46 events·h −1 ), but blood markers of oxidative stress did not change significantly (MDA “treatment” effect (95% CI) −0.02 (−0.23 to +0.19) μmol·L −1 ). Urinary F2-isoprostane fell significantly by ∼30% (−0.26 (−0.42 to −0.10) ng·mL −1 ) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng·mL −1 ). We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress.
Publisher: Elsevier BV
Date: 04-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-03-2012
DOI: 10.1161/CIRCULATIONAHA.111.038919
Abstract: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states. URL: www.clinicaltrials.gov . Unique identifier: NCT00423280.
Publisher: Elsevier BV
Date: 02-2013
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.MATURITAS.2011.12.014
Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed countries, with an increasing prevalence due to an aging population. The pathology underpinning CVD is atherosclerosis, a chronic inflammatory state involving the arterial wall. Accumulation of low density lipoprotein (LDL) laden macrophages in the arterial wall and their subsequent transformation into foam cells lead to atherosclerotic plaque formation. Progression of atherosclerotic lesions may gradually lead to plaque related complications and clinically manifest as acute vascular syndromes including acute myocardial or cerebral ischemia. Nanotechnology offers emerging therapeutic strategies, which may have advantage overclassical treatments for atherosclerosis. In this review, we present the potential applications of nanotechnology toward prevention, identification and treatment of atherosclerosis.
Publisher: Elsevier BV
Date: 07-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
DOI: 10.1161/ATVBAHA.114.303828
Abstract: To explore the role of systemic inflammation in the regulation of adiponectin levels in patients with ischemic heart disease. In a cross-sectional study of 575 subjects, serum adiponectin was compared between healthy subjects, patients with coronary artery disease with no/mild/severe heart failure (HF), and patients with nonischemic HF. Adiponectin expression and release from femoral, subcutaneous and thoracic adipose tissue was determined in 258 additional patients with coronary artery bypass grafting. Responsiveness of the various human adipose tissue depots to interleukin-6, tumor necrosis factor-α, and brain natriuretic peptide (BNP) was examined by using ex vivo models of human fat. The effects of inducible low-grade inflammation were tested by using the model of Salmonella typhi vaccine-induced inflammation in healthy in iduals. In the cross-sectional study, HF strikingly increased adiponectin levels. Plasma BNP was the strongest predictor of circulating adiponectin and its release from all adipose tissue depots in patients with coronary artery bypass grafting, even in the absence of HF. Femoral AT was the depot with the least macrophages infiltration and the largest adipocyte cell size and the only responsive to systemic and ex vivo proinflammatory stimulation (effect reversible by BNP). Low-grade inflammation reduced circulating adiponectin levels, while circulating BNP remained unchanged. This study demonstrates the regional variability in the responsiveness of human adipose tissue to systemic inflammation and suggests that BNP (not systemic inflammation) is the main driver of circulating adiponectin in patients with advanced atherosclerosis even in the absence of HF. Any interpretation of circulating adiponectin as a biomarker should take into account the underlying disease state, background inflammation, and BNP levels.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-06-2013
DOI: 10.1161/CIRCULATIONAHA.112.001133
Abstract: Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis. The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O 2 − ) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O 2 − production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O 2 − and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ–dependent mechanism. We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2011
DOI: 10.2174/157489011795933837
Abstract: Recently, adipose tissue has been implicated in the regulation of vascular function in humans. This regulatory function is mediated via the release of vasoactive cytokines called adipokines. Adiponectin is an adipokine with powerful anti-inflammatory and antioxidant properties being dysregulated in obesity and in insulin resistance states. In both in vitro and in vivo models adiponectin has been shown to increase nitric oxide bioavailability, improve endothelial function, and exert beneficial effects on vascular smooth muscle cell function. Strategies to upregulate adiponectin expression or to potentiate adiponectin signalling may favourably modulate vascular redox state and therefore reduce cardiovascular risk. Various drug classes such as glitazones, newer sulfonylureas, angiotensin receptor blockers, ACE inhibitors and nicotinic acid exert beneficial effects on insulin resistance partly by increasing plasma adiponectin levels. Others such as tetrahydrobiopterin or certain antioxidants are also promising in normalizing plasma adiponectin levels. Given the central role of adiponectin in vascular disease states and obesity-related metabolic disorders, improving adiponectin vascular or systemic bioavailability via existing drugs or novel therapeutic strategies may be valuable in the prevention of cardiovascular disease in humans. The discussion of recent patents for the adiponectin as a regulator of vascular redox state also included in this review article.
Publisher: Elsevier BV
Date: 2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-11-2022
DOI: 10.1161/CIRCULATIONAHA.122.060308
Abstract: Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for s le size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.
Publisher: Elsevier BV
Date: 09-2013
Publisher: Elsevier BV
Date: 06-2017
Publisher: Bentham Science Publishers Ltd.
Date: 2012
DOI: 10.2174/157016112798829751
Abstract: Persistent oxidative stress in the vascular wall may lead to endothelial dysfunction, a pathological process widely implicated in the morbidities observed in a spectrum of cardiovascular disease. The production of reactive oxygen species (ROS) is regulated by various oxidase enzymes and mitochondrial electron transport mechanisms. Nitric oxide (NO) is a key mediator of endothelial function via its effect on endothelium dependent vascular relaxation. Therapeutic interventions aimed to increase NO bioavailability in the vasculature may improve the long term cardiovascular outcome for healthy in iduals, high-risk subjects, and patients with advanced atherosclerosis. Current therapeutic strategies focus on enhancing synthesis or lowering oxidative inactivation of NO in human vasculature. Of the available therapeutic agents, angiotensin converting enzyme inhibitors and statins have shown most promise at improving endothelial function and cardiovascular outcome after long term administration. Other therapeutic approaches may also be useful towards improving endothelial dysfunction. These strategies include targeting NO synthesis by modulation of endothelial nitric oxide synthase (eNOS) coupling, such as folates and tetrahydrobiopterin. Evidence for the benefits of gene therapy to improve endothelial function is also emerging. However, the long term direct clinical benefit of these strategies aimed to improve endothelial function still remains unclear.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Charalambos Antoniades.