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Evaluation of a novel clinical platform for cardiovascular drug development

ABSTRACT: Objectives –To determine whether inflammation biomarkers can be used as indicators of therapeutic response, an exploratory study was performed to ascertain whether short term improvements in risk parameters will have measureable effects on a pre-defined panel of plaque inflammation biomarkers. Methods and Results – Patients (n=121) with peripheral arterial disease were enrolled into one of three sub-studies based upon the presence of hypercholesterolemia, hypertension, or diabetes. Patients were randomized to 6 weeks of drug treatment vs. placebo and underwent catheter excision of atherosclerotic tissue from one extremity at baseline and the contralateral extremity after treatment. Simvastatin 40mg once daily reduced LDL-C by 43% (p<0.01), losartan 50mg once daily reduced diastolic blood pressure by 4 mm Hg (p=0.099), and pioglitazone 30mg once daily reduced serum glucose by 66mg/dL (p=0.008). Despite these effects, there were no consistent treatment effects on a large panel of plaque protein, RNA and lipid biomarkers. Conclusions – Short term treatment with drugs that improve cardiovascular risk parameters did not result in a measureable reduction in the levels of peripheral arterial plaque inflammation biomarkers. Further studies are required to identify biomarkers that are sufficiently predictive to be used to identify drug candidates for testing in large cardiovascular outcome studies. (ClinicalTrials.gov: NCT00720577)

ORGANISM(S): Homo sapiens

PROVIDER: GSE37824 | GEO | 2012/05/16

SECONDARY ACCESSION(S): PRJNA167021

REPOSITORIES: GEO

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Evaluation of a novel clinical platform for cardiovascular drug development

Project description:Objectives M-bM-^@M-^STo determine whether inflammation biomarkers can be used as indicators of therapeutic response, an exploratory study was performed to ascertain whether short term improvements in risk parameters will have measureable effects on a pre-defined panel of plaque inflammation biomarkers. Methods and Results M-bM-^@M-^S Patients (n=121) with peripheral arterial disease were enrolled into one of three sub-studies based upon the presence of hypercholesterolemia, hypertension, or diabetes. Patients were randomized to 6 weeks of drug treatment vs. placebo and underwent catheter excision of atherosclerotic tissue from one extremity at baseline and the contralateral extremity after treatment. Simvastatin 40mg once daily reduced LDL-C by 43% (p<0.01), losartan 50mg once daily reduced diastolic blood pressure by 4 mm Hg (p=0.099), and pioglitazone 30mg once daily reduced serum glucose by 66mg/dL (p=0.008). Despite these effects, there were no consistent treatment effects on a large panel of plaque protein, RNA and lipid biomarkers. Conclusions M-bM-^@M-^S Short term treatment with drugs that improve cardiovascular risk parameters did not result in a measureable reduction in the levels of peripheral arterial plaque inflammation biomarkers. Further studies are required to identify biomarkers that are sufficiently predictive to be used to identify drug candidates for testing in large cardiovascular outcome studies. (ClinicalTrials.gov: NCT00720577) Human peripheral atherosclerosis plaque was extracted from lower extremities, and RNA, lipids and proteins extracted. RNA was analyzed in an Agilent two-color platform.

2012-05-15 | E-GEOD-37824 | biostudies-arrayexpress

Proteomic analysis of the extracellular matrix of human atherosclerotic plaques shows marked changes between plaque types

Project description:Cardiovascular disease (CVD) is the leading cause of death, with atherosclerosis a major underlying cause. While often asymptomatic for decades, plaque destabilisation and rupture can arise suddenly and cause acute arterial occlusion or peripheral embolisation resulting in acute myocardial infarction, stroke and lower limb ischaemia. Hard plaques are typically considered as stable, and soft plaques as unstable. Extracellular matrix (ECM) remodelling can result in plaque destabilisation, but the mechanisms that drive the development of unstable lipid-rich plaques with a thin fibrous cap, versus stable fibrotic plaques with a thick cap, are not fully understood. We hypothesised that there would be significant differences in ECM composition between hard (stable) and soft (unstable and rupture-prone) plaques. We identified and quantified >46700 proteins, including 367 ECM proteins, with unprecedented coverage and high reproducibility. We identified 575 proteins with differential abundances between hard (stable) and soft (unstable) plaques. Proteins involved in inflammation and ECM remodeling, including multiple proteases were enriched, and ECM proteins decreased, in soft plaques. These data provide a unique insight into inflammatory mechanisms and ECM remodelling as an explanation for plaque destabilization. Furthermore they provide a first step towards identifying circulating biomarkers for individualised risk profiling of arteriosclerosis.

2024-01-15 | PXD039077 | Pride

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Serum proteomics of Premature Carotid atherosclerosis: The Cardiovascular Risk in Young Finns Study

Project description:Cardiovascular diseases represent a leading cause of deaths globally; of which atherosclerosis is a major contributor. Selective retention of circulating apolipoprotein B particles in the sub endothelial space by arterial wall proteoglycans and their subsequent modification is currently thought to be a hallmark of the disease. The exact mechanism responsible for lesion development is not fully understood. Currently, ultrasonic assessment of carotid artery intima media thickness (IMT) is commonly used as a pre-clinical marker of atherosclerosis. However, as the onset of atherosclerotic process and the appearance of carotid artery plaque can vary, the identification of additional biomarkers showing potential etiological aspects of disease is an important goal. This study describes the use of a label free mass spectrometry approach in the proteomics analysis of serum samples from control and atherosclerotic subjects. The samples were from a study cohort recruited in The Cardiovascular Risk in Young Finns Study, with a goal of identifying biomarkers for atherosclerosis. Samples from 43 individuals with a early non-obstructive plaques and 43 controls were used (Matched by age, sex, body size and systolic blood pressure).

2018-07-30 | PXD008278 | Pride

Cyclodextrin treatment leads to atherosclerosis regression by dissolution of cholesterol crystals and LXR activation

Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Since cholesterol retention and cholesterol crystals in arterial walls are key pathogenetic factors for atherogenesis, we assessed the therapeutic potential of increasing cholesterol solubility in vivo. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal (CC) load and promoted plaque regression even under continuing Western diet. CD solubilized CC and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor-mediated transcriptional reprogramming with increased cholesterol efflux and decreased inflammation. CD treatment may thus be used to increase cholesterol solubility and clearance to prevent or treat atherosclerosis.

2017-07-01 | GSE47696 | GEO

Bone marrow adipocytes fuel emergency hematopoiesis

Project description:Hematopoiesis advances cardiovascular disease by generating inflammatory leukocytes that attack the arteries, heart and brain. While it is well documented that the bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, it is less clear how cardiovascular disease affects the vasculature forming this niche. Here we show that arterial hypertension, atherosclerosis and myocardial infarction alter the anatomy and function of bone marrow vasculature. Hypertension and atherosclerosis instigated vascular fibrosis, leakage and endothelial dysfunction in the bone marrow. Myocardial infarction induced vascular leakage and bone marrow angiogenesis via Vegf signaling. Endothelial cell-specific deletion of the Vegf receptor 2 limited emergency hematopoiesis after myocardial infarction, indicating that new vasculature supports higher blood cell production. RNA-sequencing of bone marrow endothelial cells revealed inflammatory gene expression in mice with cardiovascular disease. Endothelial cell-specific deletion of interleukin 6 or versican, which were highly expressed in mice with atherosclerosis or myocardial infarction, respectively, reduced hematopoiesis and systemic myeloid cells. Taken together, cardiovascular disease affects the vascular bone marrow niche, thus influencing hematopoietic stem cell behavior and expanding innate immune cell supply to atherosclerotic plaque and ischemic myocardium. Interrupting this feed back loop may constrain cardiovascular inflammation.

2023-11-04 | GSE169267 | GEO

Cardiovascular disease perturbs the vascular hematopoietic stem cell niche

2021-09-27 | GSE144498 | GEO

Low density granulocytes and their gene signature associate with vascular inflammation and coronary atheroclerosis in systemic lupus erythematosus patients

Project description:Patients with systemic lupus erythematosus (SLE) display an increased risk of cardiovascular disease that is not fully explained by traditional risk factors. This study correlated RNA sequencing data from whole blood of patients with SLE and healthy controls with markers of cardiovascular risk including coronary plaque measured by CT angiogram and vascular inflammation by FDG-PET CT.

2018-05-09 | GSE110685 | GEO

Muscle H3K27ac landscape remodeling with glucocorticoid steroid regimens

Project description:Duchenne muscular dystrophy is caused by genetic defects in the gene encoding dystrophin and leads to progressive muscle degeneration. Glucocorticoid steroids are current mainstay pharmacological regimen to decrease muscle inflammation and prolong the ambulatory period in these patients, but daily intake of glucocorticoids like prednisone and deflazacort causes adverse side effects like osteoporosis, adrenal suppression, insulin resistance and obesity. Intermittent steroid dosing has been proposed as alternative to maintain benefits and limit side effects, but a detailed understanding of the mechanisms underpinning the regimen-specific effects in muscle is still missing. Here we explore how once-daily versus once-weekly prednisone (4 week-long treatment) affect the epigenomic landscape in mdx mouse muscle (genetic model of Duchenne muscular dystrophy; DBA/2J background) through H3K27 acetylation profiles.

2019-11-30 | GSE137992 | GEO

A 6-month systems toxicology inhalation study in ApoE−/− mice demonstrates reduced cardiovascular effects of E-vapor aerosols compared to cigarette smoke.

Project description:Smoking cigarettes is harmful to the cardiovascular system. Considerable attention has been paid to the reduced harm potential of alternative nicotine-containing inhalable products such as e-cigarettes. We investigated the effects of E-vapor aerosols or cigarette smoke (CS) on atherosclerosis progression, cardiovascular function, and molecular changes in the heart and aorta of female ApoE−/− mice. The mice were exposed to aerosols from three different E-vapor formulations: (1) carrier (propylene glycol and vegetable glycerol), (2) base (carrier and nicotine) or (3) test (base and flavor) or to CS from 3R4F reference cigarettes for up to 6 months. Concentrations of CS and base or test aerosols were matched at 35 µg nicotine/L. Exposure to CS, compared with sham-exposed fresh air controls, accelerated atherosclerotic plaque formation, while no such effect was seen for any of the three E-vapor aerosols. Molecular changes indicated disease mechanisms related to oxidative stress and inflammation in general, plus changes in calcium regulation, and altered cytoskeletal organization and microtubule dynamics in the left ventricle. While ejection fraction, fractional shortening, cardiac output, and isovolumic contraction time remained unchanged following E-vapor aerosols exposure, the nicotine-containing base and test aerosols caused an increase in isovolumic relaxation time similar to CS. A nicotine-related increase in pulse wave velocity and arterial stiffness was also observed, but it was significantly lower for base and test aerosols than for CS. These results demonstrate that in comparison with CS, E-vapor aerosols induce substantially lower biological responses associated with smoking-related cardiovascular diseases.

2020-05-12 | E-MTAB-8578 | biostudies-arrayexpress

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