Arteriosclerosis, Thrombosis, and Vascular Biology

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ISSN / EISSN : 1079-5642 / 1524-4636
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Paola León-Mimila, Hugo Villamil-Ramírez, , Leonor Jacobo-Albavera, Blanca E. López-Contreras, , Carlos Posadas-Romero, Sandra Romero-Hidalgo, Sofía Morán-Ramos, Mayra Domínguez-Pérez, et al.
Arteriosclerosis, Thrombosis, and Vascular Biology; doi:10.1161/atvbaha.120.315391

Abstract:
Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP , ABCA1 , LIPC , and SIDT2 . The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts ( P =5.9×10 −18 in the conjoint analysis). The SIDT2 /Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.
Mengmeng Guo, Sisi Ma, Yitong Xu, , Mingming Gao, Xiaobing Wu, Xiaoyan Dong, Yuhui Wang, George Liu,
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2141-2148; doi:10.1161/atvbaha.120.315719

Abstract:
Objective: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare human disease characterized by very low HDL (high-density lipoprotein) and elevated free cholesterol, in which renal injury has been confirmed in, but whether familial LCAT deficiency patients were at higher risk of atherosclerosis-related cardiovascular disease was highly controversial. Using CRISPR/Cas9 gene-editing technology, we established LCAT knockout (LCAT −/− ) hamster model showing both diet-induced and spontaneous atherosclerosis, indicating that this animal model provides a platform for the therapeutic study of renal disease and atherosclerosis caused by LCAT deficiency. Approach and Results: To explore an efficient therapy for familial LCAT deficiency and then investigate whether correction of LCAT deficiency will exert a beneficial role in atherosclerosis-related cardiovascular disease, herein we established a liver-specific adeno-associated virus 8 expressing human LCAT (AAV-hLCAT) to determine the efficacy of gene therapy for dyslipidemia, renal injury, and atherosclerosis-related cardiovascular disease in LCAT −/− hamsters. Single administration of AAV-hLCAT via intrajugular vein could completely restore LCAT expression in LCAT −/− animals in a dose-dependent manner and rapidly normalize plasma HDL levels within 2 weeks. In addition, upon high-fat diet intervention for 4 weeks, AAV-hLCAT administered LCAT −/− hamsters exhibited improved atherogenic lipoprotein profiles, lower urine protein/creatinine ratio, a significant increase in red blood cells and hemoglobin, thus eventually protecting against atherosclerotic development. Conclusions: Single administration of AAV-hLCAT effectively corrects LCAT deficiency for a long-term in LCAT −/− hamsters and completely rescue multiple abnormalities, including renal injury, anemia, and atherosclerosis, suggesting that AAV8-mediated hLCAT expression in liver will be a promising therapeutic approach for familial LCAT deficiency.
Pierre R. Moreau, Vanesa Tomas Bosch, Maria Bouvy-Liivrand, Kadri Õunap, Tiit Örd, Heidi H. Pulkkinen, Petri Pölönen, Merja Heinäniemi, , , et al.
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2149-2167; doi:10.1161/atvbaha.121.315579

Abstract:
Objective: Atherosclerosis is the underlying cause of most cardiovascular diseases. The main cell types associated with disease progression in the vascular wall are endothelial cells, smooth muscle cells, and macrophages. Although their role in atherogenesis has been extensively described, molecular mechanisms underlying gene expression changes remain unknown. The objective of this study was to characterize microRNA (miRNA)-related regulatory mechanisms taking place in the aorta during atherosclerosis. Approach and Results: We analyzed the miRNA expression changes in primary human aortic endothelial cells and human umbilical vein endothelial cells, human aortic smooth muscle cells, and macrophages (CD14+) under various proatherogenic stimuli by integrating GRO-seq, miRNA-seq, and RNA-seq data. Despite the highly cell-type-specific expression of multi-variant primary miRNAs, the majority of mature miRNAs were found to be common to all cell types and dominated by 2 to 5 abundant miRNA species. We demonstrate that transcription contributes significantly to the mature miRNA levels although this is dependent on miRNA stability. An analysis of miRNA effects in relation to target mRNA pools highlighted pathways and targets through which miRNAs could affect atherogenesis in a cell-type-dependent manner. Finally, we validate miR-100-5p as a cell-type specific regulator of inflammatory and HIPPO-YAP/TAZ-pathways. Conclusions: This integrative approach allowed us to characterize miRNA dynamics in response to a proatherogenic stimulus and identify potential mechanisms by which miRNAs affect atherogenesis in a cell-type-specific manner.
, Ryutaro Ikegami, Mohamad B. Kassab, Joseph A. Gardecki, Mie Kunio, Mohammed M. Chowdhury, Ramzi Khamis, , Guillermo J. Tearney,
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41; doi:10.1161/atvbaha.120.315612

Abstract:
Objective: Near-infrared autofluorescence (NIRAF) of atherosclerosis associates with intraplaque hemorrhage and is detectable in living patients with coronary artery disease. However, further mechanisms underlying NIRAF generation have not been fully characterized. Here, we investigated the role of lipids and oxidative stress in NIRAF generation in atherosclerosis and in vitro in human macrophages. Approach and Results: In N=15 human carotid endarterectomy specimens, we investigated the spatial distribution of lipid, intraplaque hemorrhage, and NIRAF (ex/em 630/650 nm). Plaque NIRAF associated with both Sudan black-positive lipids ( r =0.53, P =0.023) and GPA (glycophorin A)-positive intraplaque hemorrhage ( r =0.48, P =0.043). Plaque NIRAF also localized with lipid and specifically insoluble lipid (ceroid) and iron. Intriguingly, some NIRAF-positive areas were Sudan black-positive but GPA-negative. Studies on human macrophages investigated further the role of lipids in NIRAF generation. OxLDL (Oxidized low-density lipoprotein) and hemoglobin, but not LDL, generated NIRAF in both THP-1 cells and monocyte-derived macrophages. In oxLDL-treated THP-1 cells, higher NIRAF, lipid peroxidation products, and intracellular oxidative stress markers evolved ( P <0.001 versus LDL). The antioxidants α-tocopherol and N-acetylcysteine suppressed NIRAF generation and oxidative stress. Conclusions: In human atherosclerosis and human macrophages in vitro, NIRAF colocalizes with lipid and specifically insoluble lipid or ceroid. In vitro studies further show that oxidized LDL generates NIRAF, oxidative stress, and lipid peroxidation products. These results demonstrate a new pathway for NIRAF generation through oxidized lipid-driven oxidative stress and support ceroid as a source of NIRAF in human atherosclerosis. These findings may inform future clinical intracoronary NIRAF imaging studies of patients with coronary artery disease.
, Daniela T. Fuller, Raquel Fernandez, Xiaoqing Zhao, Robert Kutys, Elizabeth Binns-Roemer, Marco Delsante, Atsushi Sakamoto, Ka Hyun Paek, Yu Sato, et al.
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2201-2214; doi:10.1161/atvbaha.120.315788

Abstract:
Objective: Reported associations between kidney risk variants (G1 and G2) in APOL1 (apolipoprotein L1), encoding APOL1, and cardiovascular disease have been conflicting. We sought to explore associations of APOL1 risk variants with cause of sudden death using the CVPath Sudden Death Autopsy Registry. Approach and Results: APOL1 haplotypes and causes of sudden death, as determined through autopsy and histopathology, were obtained for 764 Black subjects. Genotyping revealed APOL1 risk alleles in 452 of 764 (59%) subjects with 347 (77%) subjects carrying one risk allele and 105 (23%) subjects harboring 2 risk alleles. APOL1 risk allele carrier status was associated with a significantly increased risk of coronary thrombosis due to plaque rupture, versus noncarriers (odds ratio for rupture, 1.655 [95% CI, 1.079–2.539]; P =0.021). Histological examinations showed coronary plaques in carriers of 2 APOL1 risk alleles had larger necrotic cores compared with noncarriers (necrotic core area/total plaque area: 46.79%±6.47% versus 20.57%±5.11%; P =0.0343 in ruptured plaques, and 41.48%±7.49% versus 18.93%±3.97%; P =0.0342 in nonruptured plaques), and immunohistochemical and immunofluorescent staining revealed APOL1-positive areas localized primarily to the necrotic core. Conclusions: APOL1 risk alleles were independently associated with an increased risk of thrombotic coronary death due to plaque rupture. Our results suggest that carriers of both 1 and 2 APOL1 risk alleles have greater accumulation of APOL1 protein within culprit plaques and greater necrotic core sizes than noncarriers. These findings suggest that APOL1 plays a role in determining plaque stability.
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2190-2200; doi:10.1161/atvbaha.120.315628

Abstract:
Objective: Macronutrients may relate differently with serum lipids depending on their source, and understanding this relationship is important for cardiovascular disease prevention. We aimed to investigate the associations between macronutrients and macronutrients from different sources with serum lipids in UK Biobank. Approach and Results: Serum lipids were obtained from serum collected at baseline in 24 639 participants with diet assessed using ≥2 twenty-four–hour dietary assessments completed at baseline and during follow-up. Multivariable linear regressions were conducted to calculate geometric mean concentrations of serum lipids by quintiles of macronutrients. We modeled the association between isoenergetic substitution of 5% energy intake from saturated fatty acids (SFA) with other macronutrients and serum lipids. Free sugar intake was positively associated with triglycerides (0.15 mmol/L geometric mean difference between highest and lowest quintile of intake [95% CI, 0.12–0.17 mmol/L]), whereas nonfree sugar intake was inversely associated with triglycerides (−0.08 [−0.10 to −0.05]). SFA intake was positively associated with LDL-C (low-density lipoprotein cholesterol; 0.17 [0.13–0.20]), omega-3 fatty acid intake was inversely associated with triglycerides (−0.15 [−0.17 to −0.12]). Modeled substitution of SFA with polyunsaturated fatty acids was associated with lower total cholesterol, LDL-C, and triglycerides. Conclusions: The relationship between carbohydrates and triglycerides may depend on their quality, and reducing free sugar intake may be important in cardiovascular disease prevention. Consistent with previous studies, SFA intake is associated with LDL-C and substitution of SFA intake with polyunsaturated fatty acids intake may be associated with a more favorable serum lipid profile.
Roy Jung, , Karen Dresser, Jennifer L. Cotton, Lloyd Hutchinson, Junhao Mao,
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2233-2235; doi:10.1161/atvbaha.121.316300

, Takashi Kubo, Yasushi Ino, Takeyoshi Kameyama, Kosei Terada, Stacie VanOosterhout, Abbey Mulder, Michael McNamara, Mohamad Kenaan, Soroush Samani, et al.
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2181-2189; doi:10.1161/atvbaha.120.315617

Abstract:
Objective: After percutaneous coronary intervention (PCI), it is unknown whether retained lipid content in the stented segment increases the risk of target lesion failure (TLF). This study evaluated the association between retained lipid content in the stented segment detected by post-PCI intracoronary near-infrared spectroscopy and TLF. Approach and Results: After the performance of PCI, post-PCI near-infrared spectroscopy–intravascular ultrasound images were acquired and analyzed by an independent core laboratory for retained lipid content in the stented segment, quantified by the maximum lipid core burden index in 4 mm (maxLCBI 4mm ). The primary outcome was TLF during follow-up, defined as a composite of cardiovascular death, target vessel myocardial infarction, and clinically driven target lesion revascularization. Among 202 patients with 209 target lesions treated by PCI and followed for 3.5±1.4 years, baseline post-PCI near-infrared spectroscopy–intravascular ultrasound images revealed a significantly greater maxLCBI 4mm in stented lesions with (297 [211, 401]) versus without (119 [9, 258]) TLF during follow-up ( P =0.006). By multivariate logistic regression, maxLCBI 4mm in the stented segment was independently associated with subsequent TLF (odds ratio, 1.6 [95% CI, 1.2–2.1] for every 100-unit increase, P =0.004). By receiver-operating characteristic analysis, the optimal residual maxLCBI 4mm threshold in the stented segment for subsequent TLF was 200. Stented lesions with a residual maxLCBI 4mm >200 had significantly greater TLF during follow-up than stented lesions with a maxLCBI 4mm ≤200 (15.0% versus 3.1%, P =0.002). Conclusions: Retained lipid content detected by near-infrared spectroscopy in the stented segment after PCI was associated with an increased risk of subsequent TLF.
Eirini Chatzopoulou, Hélène Rangé, Omar Deraz, , Marie-Cécile Perier, Catherine Guibout, Frédérique Thomas, Muriel Andrieu, Karine Bailly, Benoît Vedie, et al.
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2225-2232; doi:10.1161/atvbaha.121.316085

Abstract:
Objective: The mechanisms underlying the association between low number of masticatory units and cardiovascular disease remain unclear. Under a nutritional framework, we hypothesized that poor masticatory capacity could represent an early sign of elevated cardiovascular disease risk as evaluated by circulating markers of systemic inflammation and cardiomyocyte stress or damage. Approach and Results: In this cross-sectional analysis of the Paris Prospective Study III, a community-based observational study, 4837 adults aged 50 to 75 without cardiovascular disease history underwent a full-mouth clinical examination and plasma NTproBNP (N-terminal natriuretic propeptide), hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), hs-TNI (high-sensitivity troponin I) were measured using highly sensitive technics. Poor masticatory capacity was defined as <5 functional masticatory units, that is, pairs of opposing natural or prosthetically replaced posterior teeth. In linear regression analysis accounting for sociodemographic factors, cardiovascular disease risk factors, gingival inflammation, and body mass index, poor masticatory capacity was significantly associated with lower levels of NTproBNP (β=−0.11, P =0.045). The significant association between poor masticatory capacity and higher IL-6 in multivariable analysis was confounded by body mass index. There was no association between functional masticatory units and hs-TNI even in unadjusted analysis. Conclusions: The present findings support a nutritional pathway whereby diet alterations and the resulting abdominal obesity associated with poor masticatory capacity may contribute to the higher level of IL-6 and to the lower level of NTproBNP, respectively.
, Edward K. Duran, Martin Van Denburgh, Eunjung Kim, William G. Christen, , , Aruna D. Pradhan
Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 41, pp 2215-2224; doi:10.1161/atvbaha.121.316397

Abstract:
Objective: Case-control studies have identified plasma homocysteine as a risk marker for venous thromboembolism (VTE). Prospective data, particularly among women, are sparse. We examined whether plasma homocysteine associates with incident VTE in 2 large prospective cohorts of women. Approach and Results: In the WHS (Women’s Health Study), a prospective cohort study of 27 555 women ≥45 years old and free of cardiovascular disease and VTE, we assessed baseline homocysteine concentration along with other thrombotic biomarkers for association with future VTE (n=743), pulmonary embolism (n=363), and deep vein thrombosis (n=545). We used a second cohort of 2672 women (n=102 VTE events) in the WAFACS (Women’s Antioxidant and Folic Acid Cardiovascular Study) to corroborate our findings. In age-adjusted analyses, elevated homocysteine, hsCRP (high-sensitivity C-reactive protein), fibrinogen, and sICAM-1 (soluble intercellular adhesion molecule-1) were associated with incident VTE ( P for extreme quartile comparisons and P -trend <0.05). In multivariable models adjusting for body mass index and other traditional VTE risk factors, only the association for homocysteine persisted (HR Q4 , 1.31 [95% CI, 1.06–1.63]). Elevated homocysteine levels were associated with unprovoked pulmonary embolism (HR Q4 , 2.13 [95% CI, 1.30–3.51]) and deep vein thrombosis (HR Q4 , 1.59 [95% CI, 1.05–2.40]) but not provoked events. In WAFACS, elevated homocysteine levels were also associated with VTE events ( P -trend 0.023). Conclusions: Higher plasma homocysteine levels associate with VTE events in 2 cohorts of middle-aged and older women. Among VTE subtypes, homocysteine was associated with unprovoked, but not provoked, events. These data suggest a plausible biological role for homocysteine in the development of VTE. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000479, NCT00000541.
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