Dataset Information

Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.

ABSTRACT: 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.

SUBMITTER: Yu EPK

PROVIDER: S-EPMC5701734 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.

Yu Emma P K EPK Reinhold Johannes J Yu Haixiang H Starks Lakshi L Uryga Anna K AK Foote Kirsty K Finigan Alison A Figg Nichola N Pung Yuh-Fen YF Logan Angela A Murphy Michael P MP Bennett Martin M

Arteriosclerosis, thrombosis, and vascular biology 20170928 12

<h4>Objective</h4>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.<h4>Approach and results ...[more]

PMID: 28970293

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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:Thin-cap fibroatheroma (TCFA) is a prominent risk factor for plaque rupture. Intravascular optical coherence tomography (IVOCT) enables identification of fibrous cap (FC), measurement of FC thicknesses, and assessment of plaque vulnerability. We developed a fully-automated deep learning method for FC segmentation. This study included 32,531 images across 227 pullbacks from two registries (TRANSFORM-OCT and UHCMC). Images were semi-automatically labeled using our OCTOPUS with expert editing using established guidelines. We employed preprocessing including guidewire shadow detection, lumen segmentation, pixel-shifting, and Gaussian filtering on raw IVOCT (r,θ) images. Data were augmented in a natural way by changing θ in spiral acquisitions and by changing intensity and noise values. We used a modified SegResNet and comparison networks to segment FCs. We employed transfer learning from our existing much larger, fully-labeled calcification IVOCT dataset to reduce deep-learning training. Postprocessing with a morphological operation enhanced segmentation performance. Overall, our method consistently delivered better FC segmentation results (Dice: 0.837 ± 0.012) than other deep-learning methods. Transfer learning reduced training time by 84% and reduced the need for more training samples. Our method showed a high level of generalizability, evidenced by highly-consistent segmentations across five-fold cross-validation (sensitivity: 85.0 ± 0.3%, Dice: 0.846 ± 0.011) and the held-out test (sensitivity: 84.9%, Dice: 0.816) sets. In addition, we found excellent agreement of FC thickness with ground truth (2.95 ± 20.73 µm), giving clinically insignificant bias. There was excellent reproducibility in pre- and post-stenting pullbacks (average FC angle: 200.9 ± 128.0°/202.0 ± 121.1°). Our fully automated, deep-learning FC segmentation method demonstrated excellent performance, generalizability, and reproducibility on multi-center datasets. It will be useful for multiple research purposes and potentially for planning stent deployments that avoid placing a stent edge over an FC.

Dataset Information

Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.

Publications

Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.

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