Dataset Information

A transcriptomic model to predict increase in fibrous cap thickness in response to high-dose statin treatment: Validation by serial intracoronary OCT imaging.

ABSTRACT: BACKGROUND:Fibrous cap thickness (FCT), best measured by intravascular optical coherence tomography (OCT), is the most important determinant of plaque rupture in the coronary arteries. Statin treatment increases FCT and thus reduces the likelihood of acute coronary events. However, substantial statin-related FCT increase occurs in only a subset of patients. Currently, there are no methods to predict which patients will benefit. We use transcriptomic data from a clinical trial of rosuvastatin to predict if a patient's FCT will increase in response to statin therapy. METHODS:FCT was measured using OCT in 69 patients at (1) baseline and (2) after 8-10?weeks of 40? mg rosuvastatin. Peripheral blood mononuclear cells were assayed via microarray. We constructed machine learning models with baseline gene expression data to predict change in FCT. Finally, we ascertained the biological functions of the most predictive transcriptomic markers. FINDINGS:Machine learning models were able to predict FCT responders using baseline gene expression with high fidelity (Classification AUC?=?0.969 and 0.972). The first model (elastic net) using 73 genes had an accuracy of 92.8%, sensitivity of 94.1%, and specificity of 91.4%. The second model (KTSP) using 18 genes has an accuracy of 95.7%, sensitivity of 94.3%, and specificity of 97.1%. We found 58 enriched gene ontology terms, including many involved with immune cell function and cholesterol biometabolism. INTERPRETATION:In this pilot study, transcriptomic models could predict if FCT increased following 8-10 weeks of rosuvastatin. These findings may have significance for therapy selection and could supplement invasive imaging modalities.

SUBMITTER: Johnson KW

PROVIDER: S-EPMC6607084 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A transcriptomic model to predict increase in fibrous cap thickness in response to high-dose statin treatment: Validation by serial intracoronary OCT imaging.

Johnson Kipp W KW Glicksberg Benjamin S BS Shameer Khader K Vengrenyuk Yuliya Y Krittanawong Chayakrit C Russak Adam J AJ Sharma Samin K SK Narula Jagat N JN Dudley Joel T JT Kini Annapoorna S AS

EBioMedicine 20190522

<h4>Background</h4>Fibrous cap thickness (FCT), best measured by intravascular optical coherence tomography (OCT), is the most important determinant of plaque rupture in the coronary arteries. Statin treatment increases FCT and thus reduces the likelihood of acute coronary events. However, substantial statin-related FCT increase occurs in only a subset of patients. Currently, there are no methods to predict which patients will benefit. We use transcriptomic data from a clinical trial of rosuvast ...[more]

PMID: 31126891

Similar Datasets

Project description:ObjectiveVulnerable plaques with fibrous cap thickness (FCT) of ≤65 μm are prone to rupture and/or thrombosis. However, plaques with FCT > 65 μm cause acute myocardial infarction and even sudden death. We aimed to investigate the relationship between 65 < FCT ≤ 80 μm and plaque rupture and/or thrombosis using optical coherence tomography (OCT).MethodsOCT was performed on culprit lesions in 502 consecutively enrolled patients to identify FCT. Patients were classified into three groups according to FCT: Group A (FCT ≤ 65 μm, n = 147), Group B (65 < FCT ≤ 80 μm, n = 84) and Group C (FCT > 80 μm, n = 271). Clinical and laboratory data was collected from the inpatient medical record system.ResultsPlaques with thinner FCT, especially < 65 μm, were more susceptible to rupture and/or thrombosis (P < 0.001). Plaques with FCT between 65 and 80 μm had a higher probability of rupture and/or thrombosis than those with FCT > 80 μm (P < 0.001). In multivariable analysis, FCT ≤ 65 μm and 65 < FCT ≤ 80 μm were independent predictors for plaque rupture ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 8.082, 95% CI = 4.861 to 13.435, P < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 2.463, 95% CI = 1.370 to 4.430, P = 0.003), thrombosis ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 25.224, 95% CI = 13.768 to 46.212, P < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 3.675, 95% CI = 2.065 to 6.542, P < 0.001) and plaque rupture with thrombosis ([FCT ≤ 65 μm vs. FCT > 80 μm]: OR = 22.593, 95% CI = 11.426 to 44.674, P < 0.001; [65 < FCT ≤ 80 μm vs. FCT > 80 μm]: OR = 4.143, 95% CI = 1.869 to 9.184, P < 0.001).ConclusionsOCT-assessed 65 < FCT ≤ 80 μm was independently associated with increased risk of plaque rupture and/or thrombosis compared with FCT > 80 μm.

Project description:OBJECTIVE:Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis. APPROACH AND RESULTS:Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis. CONCLUSIONS:Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.

Project description:ObjectivesThe aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease.BackgroundAdvancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden.MethodsAs part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models.ResultsOf the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment.ConclusionsAmong patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk.

Dataset Information

A transcriptomic model to predict increase in fibrous cap thickness in response to high-dose statin treatment: Validation by serial intracoronary OCT imaging.

Publications

A transcriptomic model to predict increase in fibrous cap thickness in response to high-dose statin treatment: Validation by serial intracoronary OCT imaging.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets