Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000017473.78775.F6
J. Bella, J. Maccluer, M. Roman, L. Almasy, K. North, T. Welty, Elisa Lee, R. Fabsitz, B. Howard, R. Devereux
Aortic root dilatation is a major pathophysiological mechanism for aortic regurgitation and predisposes the aortic root to dissection or rupture. However, only a small proportion of the variance of aortic root size can be explained by its known clinical and demographic correlates. The present study was undertaken to determine the heritability of echocardiographically derived aortic root diameter in the American Indian participants in the second Strong Heart Study examination. Echocardiograms were analyzed in 1373 SHS participants who had ≥1 family member in the cohort. Heritability calculations were performed by using variance component analysis as implemented in SOLAR, a computer analysis program. In a polygenic model, the variables entered and identified as covariates of larger aortic root diameter were older age, male sex, and center (P <0.001), which accounted for 35% of the overall variability of aortic root diameter. After simultaneous adjustment was made for these significant covariates, the proportion of phenotypic variance due to additive genetic contribution or residual heritability (h2) was 0.51 (SE=0.08, P <0.001). Additionally, simultaneous adjustment for height, weight, and systolic and diastolic BPs yielded slightly lower residual h2 of aortic root diameter (h2=0.44, SE=0.08, P <0.001), which accounted for 26% of the overall variance of aortic root size. Because center effects were identified as significant covariates in the analyses, h2 analyses were performed separately in Arizona, Oklahoma, and North/South Dakota centers, which confirmed that a significant proportion of the phenotypic variance of aortic root diameter is due to additive genetic contribution. Heredity explains a substantial proportion of the variability of aortic root size that is not accounted for by age, sex, body size, and blood pressure. Echocardiographic screening of family members with aortic root dilatation may identify other individuals predisposed to aortic dissection or rupture.
主动脉根部扩张是主动脉反流的主要病理生理机制，它使主动脉根部容易剥离或破裂。然而，只有一小部分主动脉根大小的差异可以用已知的临床和人口学相关因素来解释。本研究旨在确定美国印第安人参加第二次强心脏研究检查的超声心动图得出的主动脉根直径的遗传性。对1373名家庭成员≥1名的SHS参与者进行超声心动图分析。遗传力计算采用在SOLAR(一个计算机分析程序)中实现的方差成分分析。在多基因模型中，进入并确定为主动脉根直径较大协变量的变量是年龄较大、男性性别和中心(P <0.001)，占主动脉根直径总体变异性的35%。在对这些显著协变量进行同步调整后，由加性遗传贡献或剩余遗传力(h2)引起的表型变异比例为0.51 (SE=0.08, P <0.001)。此外，同时调整身高、体重、收缩期和舒张期血压，主动脉根部直径的剩余h2略低(h2=0.44, SE=0.08, P <0.001)，占主动脉根部大小总方差的26%。由于中心效应在分析中被确定为重要的协变量，因此在亚利桑那州、俄克拉荷马州和北达科他州/南达科他州的研究中心分别进行了h2分析，这证实了主动脉根直径表型变异的很大一部分是由于加性遗传贡献。遗传解释了主动脉根部大小变异的很大一部分，而这种变异与年龄、性别、体型和血压无关。超声心动图筛查有主动脉根部扩张的家庭成员可以识别其他易患主动脉夹层或破裂的个体。
{"title":"Genetic Influences on Aortic Root Size in American Indians: The Strong Heart Study","authors":"J. Bella, J. Maccluer, M. Roman, L. Almasy, K. North, T. Welty, Elisa Lee, R. Fabsitz, B. Howard, R. Devereux","doi":"10.1161/01.ATV.0000017473.78775.F6","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017473.78775.F6","url":null,"abstract":"Aortic root dilatation is a major pathophysiological mechanism for aortic regurgitation and predisposes the aortic root to dissection or rupture. However, only a small proportion of the variance of aortic root size can be explained by its known clinical and demographic correlates. The present study was undertaken to determine the heritability of echocardiographically derived aortic root diameter in the American Indian participants in the second Strong Heart Study examination. Echocardiograms were analyzed in 1373 SHS participants who had ≥1 family member in the cohort. Heritability calculations were performed by using variance component analysis as implemented in SOLAR, a computer analysis program. In a polygenic model, the variables entered and identified as covariates of larger aortic root diameter were older age, male sex, and center (P <0.001), which accounted for 35% of the overall variability of aortic root diameter. After simultaneous adjustment was made for these significant covariates, the proportion of phenotypic variance due to additive genetic contribution or residual heritability (h2) was 0.51 (SE=0.08, P <0.001). Additionally, simultaneous adjustment for height, weight, and systolic and diastolic BPs yielded slightly lower residual h2 of aortic root diameter (h2=0.44, SE=0.08, P <0.001), which accounted for 26% of the overall variance of aortic root size. Because center effects were identified as significant covariates in the analyses, h2 analyses were performed separately in Arizona, Oklahoma, and North/South Dakota centers, which confirmed that a significant proportion of the phenotypic variance of aortic root diameter is due to additive genetic contribution. Heredity explains a substantial proportion of the variability of aortic root size that is not accounted for by age, sex, body size, and blood pressure. Echocardiographic screening of family members with aortic root dilatation may identify other individuals predisposed to aortic dissection or rupture.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"16 1","pages":"1008-1011"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89198583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000019405.84384.9C
M. Ward, A. Agrotis, P. Kanellakis, John Hall, G. Jennings, A. Bobik
N (3,4-Dimethoxycinnamoyl) anthranilic acid (tranilast) prevents the synchronous upregulation of isoforms and receptors of the transforming growth factor (TGF)-&bgr; system after arterial injury and reduces restenosis after human coronary angioplasty. However, the effects of tranilast and the importance of the TGF-&bgr; system in stent restenosis, in which inward remodeling is unimportant but inflammatory cell stimulation of neointima formation is exaggerated, are uncertain. Boston minipigs, treated with tranilast or vehicle, were subjected to endoluminal stenting, and the expression of TGF-&bgr;1 and TGF-&bgr;3, the expression of their signaling receptors ALK-5 and T&bgr;R-II, leukocyte numbers around the stent struts, and neointima development were assessed over 28 days. Stenting greatly increased early (5-day) mRNA expression of the 2 TGF-&bgr; isoforms and their receptors. Immunohistochemical localization later showed that their concentrations were greatest in regions adjacent to stent struts, where leukocytes and collagen deposition were prevalent. Tranilast suppressed these elevations in TGF-&bgr; mRNAs and reduced their immunoreactive peptides detectable around stent struts. The accumulation of leukocytes and deposition of collagen in these regions was also greatly inhibited by tranilast. These effects were associated with a 48% reduction in maximal neointimal cross-sectional area and 43% reduction in mean neointimal cross-sectional area at 28 days (P <0.05). We conclude that tranilast suppresses neointima development after stenting, effects that can be at least partly attributed to its ability to attenuate the induction of the TGF-&bgr; system and leukocyte accumulation around stent struts.
{"title":"Tranilast Prevents Activation of Transforming Growth Factor-&bgr; System, Leukocyte Accumulation, and Neointimal Growth in Porcine Coronary Arteries After Stenting","authors":"M. Ward, A. Agrotis, P. Kanellakis, John Hall, G. Jennings, A. Bobik","doi":"10.1161/01.ATV.0000019405.84384.9C","DOIUrl":"https://doi.org/10.1161/01.ATV.0000019405.84384.9C","url":null,"abstract":"N (3,4-Dimethoxycinnamoyl) anthranilic acid (tranilast) prevents the synchronous upregulation of isoforms and receptors of the transforming growth factor (TGF)-&bgr; system after arterial injury and reduces restenosis after human coronary angioplasty. However, the effects of tranilast and the importance of the TGF-&bgr; system in stent restenosis, in which inward remodeling is unimportant but inflammatory cell stimulation of neointima formation is exaggerated, are uncertain. Boston minipigs, treated with tranilast or vehicle, were subjected to endoluminal stenting, and the expression of TGF-&bgr;1 and TGF-&bgr;3, the expression of their signaling receptors ALK-5 and T&bgr;R-II, leukocyte numbers around the stent struts, and neointima development were assessed over 28 days. Stenting greatly increased early (5-day) mRNA expression of the 2 TGF-&bgr; isoforms and their receptors. Immunohistochemical localization later showed that their concentrations were greatest in regions adjacent to stent struts, where leukocytes and collagen deposition were prevalent. Tranilast suppressed these elevations in TGF-&bgr; mRNAs and reduced their immunoreactive peptides detectable around stent struts. The accumulation of leukocytes and deposition of collagen in these regions was also greatly inhibited by tranilast. These effects were associated with a 48% reduction in maximal neointimal cross-sectional area and 43% reduction in mean neointimal cross-sectional area at 28 days (P <0.05). We conclude that tranilast suppresses neointima development after stenting, effects that can be at least partly attributed to its ability to attenuate the induction of the TGF-&bgr; system and leukocyte accumulation around stent struts.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"27 1","pages":"940-948"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90363503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000020007.25154.62
M. Acevedo, G. Pearce, K. Kottke-Marchant, D. Sprecher
Fibrinogen (Fib) plays an important role in platelet aggregation and thrombus formation, and homocysteine (tHcy) causes endothelial dysfunction and injury. Therefore, an interaction toward an enhanced risk of thrombotic events and consequent mortality might be expected in patients with both factors elevated. To determine whether patients exposed jointly to high Fib and high tHcy were at increased risk of mortality, we compared them with those with only one or neither risk factors elevated. Prevalence of coronary artery disease (cross-section) and short-term mortality (30±14 months) were assessed in 2084 patients with available baseline tHcy and Fib. Upper quartiles were used to define high tHcy (>14.2 &mgr;mol/L) and high Fib (>382 mg/dL). Cox models adjusting for Framingham risk score, creatinine, and coronary artery disease status were used to estimate the risk of high tHcy and high Fib and their combinations. Mean age of the patients was 56±12 years (35% women) with 71 (3.4%) recorded deaths. Risk-adjusted longitudinal models showed a hazard ratio of 2.14 (P =0.03) for isolated high tHcy, 2.28 (P =0.02) for isolated high Fib, and 3.29 (P <0.001) for both high tHcy and high Fib in comparison with neither risk factor high. Independence of each parameter and lack of synergism was found on longitudinal as well as cross-sectional analyses. Conjoint elevation of Fib and tHcy increased the risk of death by approximately 3-fold in three years. Although no significant interaction between Fib and tHcy was demonstrated, both provided independent information after adjustment for traditional risk factors.
{"title":"Elevated Fibrinogen and Homocysteine Levels Enhance the Risk of Mortality in Patients From a High-Risk Preventive Cardiology Clinic","authors":"M. Acevedo, G. Pearce, K. Kottke-Marchant, D. Sprecher","doi":"10.1161/01.ATV.0000020007.25154.62","DOIUrl":"https://doi.org/10.1161/01.ATV.0000020007.25154.62","url":null,"abstract":"Fibrinogen (Fib) plays an important role in platelet aggregation and thrombus formation, and homocysteine (tHcy) causes endothelial dysfunction and injury. Therefore, an interaction toward an enhanced risk of thrombotic events and consequent mortality might be expected in patients with both factors elevated. To determine whether patients exposed jointly to high Fib and high tHcy were at increased risk of mortality, we compared them with those with only one or neither risk factors elevated. Prevalence of coronary artery disease (cross-section) and short-term mortality (30±14 months) were assessed in 2084 patients with available baseline tHcy and Fib. Upper quartiles were used to define high tHcy (>14.2 &mgr;mol/L) and high Fib (>382 mg/dL). Cox models adjusting for Framingham risk score, creatinine, and coronary artery disease status were used to estimate the risk of high tHcy and high Fib and their combinations. Mean age of the patients was 56±12 years (35% women) with 71 (3.4%) recorded deaths. Risk-adjusted longitudinal models showed a hazard ratio of 2.14 (P =0.03) for isolated high tHcy, 2.28 (P =0.02) for isolated high Fib, and 3.29 (P <0.001) for both high tHcy and high Fib in comparison with neither risk factor high. Independence of each parameter and lack of synergism was found on longitudinal as well as cross-sectional analyses. Conjoint elevation of Fib and tHcy increased the risk of death by approximately 3-fold in three years. Although no significant interaction between Fib and tHcy was demonstrated, both provided independent information after adjustment for traditional risk factors.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"22 1","pages":"1042-1045"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81677095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000019732.25208.B8
M. Lincoff, J. Badimón, J. Delfin, M. Richard, E. Erhardtsen, M. Thomsen, A., E. Lev, J. Marmur, M. Zdravković, J. Osende, J. Robbins
FFR-rFVIIa is an inactivated recombinant factor VIIa (rFVIIa) that inhibits the binding of factor VIIa to tissue factor (TF). It has been shown to prevent TF-induced thrombosis in animals. The present study is a substudy of the Active Site Inhibited Seven (ASIS) trial and examines the antithrombotic effect of 3 doses of FFR-rFVIIa in 24 patients undergoing percutaneous coronary intervention (PCI). Group 1 (n=9) received 400 &mgr;g/kg FFR-rFVIIa and 40 to 50 U/kg heparin, group 2 (n=7) received 200 &mgr;g/kg FFR-rFVIIa and 100 U/kg heparin, and group 3 (n=8) received 50 &mgr;g/kg FFR-rFVIIa and 100 U/kg heparin. Blood thrombogenicity was assessed as total thrombus area and fibrin deposition on the perfusion chamber at shear rate conditions typical of mild-moderate coronary stenosis. Baseline blood thrombogenicity was evaluated a day before PCI, after heparin administration. A second perfusion chamber study was performed just before PCI, 15 minutes after the administration of heparin and FFR-rFVIIa. Thrombus formation at a high shear rate was markedly reduced in groups 1 and 2 after drug administration, by 79% to 84% and 76% to 87%, respectively (P <0.004 [group 1], P <0.04 [group 2]). In group 3, moderate thrombus reduction of 46% to 48% was achieved (P <0.04). Fibrin deposition in all 3 groups was nearly eliminated after drug administration. Our data demonstrate that FFR-rFVIIa has a potent antithrombotic effect at different shear rates and severe arterial injury conditions.
{"title":"Antithrombotic Effect of Tissue Factor Inhibition by Inactivated Factor VIIa: An Ex Vivo Human Study","authors":"M. Lincoff, J. Badimón, J. Delfin, M. Richard, E. Erhardtsen, M. Thomsen, A., E. Lev, J. Marmur, M. Zdravković, J. Osende, J. Robbins","doi":"10.1161/01.ATV.0000019732.25208.B8","DOIUrl":"https://doi.org/10.1161/01.ATV.0000019732.25208.B8","url":null,"abstract":"FFR-rFVIIa is an inactivated recombinant factor VIIa (rFVIIa) that inhibits the binding of factor VIIa to tissue factor (TF). It has been shown to prevent TF-induced thrombosis in animals. The present study is a substudy of the Active Site Inhibited Seven (ASIS) trial and examines the antithrombotic effect of 3 doses of FFR-rFVIIa in 24 patients undergoing percutaneous coronary intervention (PCI). Group 1 (n=9) received 400 &mgr;g/kg FFR-rFVIIa and 40 to 50 U/kg heparin, group 2 (n=7) received 200 &mgr;g/kg FFR-rFVIIa and 100 U/kg heparin, and group 3 (n=8) received 50 &mgr;g/kg FFR-rFVIIa and 100 U/kg heparin. Blood thrombogenicity was assessed as total thrombus area and fibrin deposition on the perfusion chamber at shear rate conditions typical of mild-moderate coronary stenosis. Baseline blood thrombogenicity was evaluated a day before PCI, after heparin administration. A second perfusion chamber study was performed just before PCI, 15 minutes after the administration of heparin and FFR-rFVIIa. Thrombus formation at a high shear rate was markedly reduced in groups 1 and 2 after drug administration, by 79% to 84% and 76% to 87%, respectively (P <0.004 [group 1], P <0.04 [group 2]). In group 3, moderate thrombus reduction of 46% to 48% was achieved (P <0.04). Fibrin deposition in all 3 groups was nearly eliminated after drug administration. Our data demonstrate that FFR-rFVIIa has a potent antithrombotic effect at different shear rates and severe arterial injury conditions.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"8 1","pages":"1036-1041"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78349169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000017703.87741.12
S. Tokuno, K. Hinokiyama, K. Tokuno, C. Löwbeer, L. Hansson, G. Valen
To investigate if spontaneous ischemic events in mice with severe multi-organ atherosclerosis could adapt to ischemia, apolipoprotein E/LDL receptor knockout mice were fed an atherogenic diet for 7 to 9 months. Signs of spontaneous ischemia occurred. One to two days later, hearts were excised, Langendorff-perfused with induced global ischemia, and compared with mice without signs of disease. In vivo heart or brain infarctions were verified by heart histology and/or increased serum levels of cardiac troponin T and S100B. Hearts of mice with spontaneous ischemic events had improved function and reduced Langendorff-induced infarctions. To investigate the remote preconditioning effect of brain ischemia, bilateral ligation of the internal carotid arteries was performed in C57BL6 mice. Twenty-four hours later, their isolated hearts were protected against induced global ischemia. A possible role of inducible NO synthase (iNOS) was studied in iNOS knock out mice, who were not preconditioned by induced brain ischemia. Cardiac iNOS was unchanged 24 hours after preconditioning, suggesting that NO is a trigger rather than a mediator of protection. These findings suggest that spontaneous ischemic events in the brain and heart adapt the heart to ischemia. This can be mimicked by induced brain ischemia, with iNOS as a key factor of protection.
{"title":"Spontaneous Ischemic Events in the Brain and Heart Adapt the Hearts of Severely Atherosclerotic Mice to Ischemia","authors":"S. Tokuno, K. Hinokiyama, K. Tokuno, C. Löwbeer, L. Hansson, G. Valen","doi":"10.1161/01.ATV.0000017703.87741.12","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017703.87741.12","url":null,"abstract":"To investigate if spontaneous ischemic events in mice with severe multi-organ atherosclerosis could adapt to ischemia, apolipoprotein E/LDL receptor knockout mice were fed an atherogenic diet for 7 to 9 months. Signs of spontaneous ischemia occurred. One to two days later, hearts were excised, Langendorff-perfused with induced global ischemia, and compared with mice without signs of disease. In vivo heart or brain infarctions were verified by heart histology and/or increased serum levels of cardiac troponin T and S100B. Hearts of mice with spontaneous ischemic events had improved function and reduced Langendorff-induced infarctions. To investigate the remote preconditioning effect of brain ischemia, bilateral ligation of the internal carotid arteries was performed in C57BL6 mice. Twenty-four hours later, their isolated hearts were protected against induced global ischemia. A possible role of inducible NO synthase (iNOS) was studied in iNOS knock out mice, who were not preconditioned by induced brain ischemia. Cardiac iNOS was unchanged 24 hours after preconditioning, suggesting that NO is a trigger rather than a mediator of protection. These findings suggest that spontaneous ischemic events in the brain and heart adapt the heart to ischemia. This can be mimicked by induced brain ischemia, with iNOS as a key factor of protection.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"157 1","pages":"995-1001"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75189041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000019729.39500.2F
E. Lutgens, M. Gijbels, M. Smook, P. Heeringa, P. Gotwals, V. Koteliansky, M. Daemen
The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-&bgr;, and a pivotal role for TGF-&bgr; in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-&bgr; inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-&bgr; receptor II (TGF&bgr;RII:Fc), which inhibits TGF-&bgr; signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 &mgr;g, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-&bgr; signaling treatment resulted in a prominent increase in CD3- and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGF&bgr;RII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGF&bgr;RII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-&bgr; in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.
{"title":"Transforming Growth Factor-&bgr; Mediates Balance Between Inflammation and Fibrosis During Plaque Progression","authors":"E. Lutgens, M. Gijbels, M. Smook, P. Heeringa, P. Gotwals, V. Koteliansky, M. Daemen","doi":"10.1161/01.ATV.0000019729.39500.2F","DOIUrl":"https://doi.org/10.1161/01.ATV.0000019729.39500.2F","url":null,"abstract":"The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-&bgr;, and a pivotal role for TGF-&bgr; in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-&bgr; inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-&bgr; receptor II (TGF&bgr;RII:Fc), which inhibits TGF-&bgr; signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 &mgr;g, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-&bgr; signaling treatment resulted in a prominent increase in CD3- and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGF&bgr;RII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGF&bgr;RII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-&bgr; in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"18 1","pages":"975-982"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85153817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000017728.55907.A9
E. Chavakis, S. Dimmeler
The process of angiogenesis plays an important role in many physiological and pathological conditions. Inhibition of endothelial cell (EC) apoptosis providing EC survival is thought to be an essential mechanism during angiogenesis. Many of the angiogenic growth factors inhibit EC apoptosis. In addition, the adhesion of ECs to the extracellular matrix or intercellular adhesion promotes EC survival. In contrast, increasing evidence suggests that the induction of EC apoptosis may counteract angiogenesis. In this review, we focus on the regulation of EC survival and apoptosis during angiogenesis and especially on the effects and intracellular signaling promoted by angiogenic growth factors, endogenous angiogenic inhibitors (such as angiostatin, endostatin, and thrombospondin-1), and the adhesion to the extracellular matrix. Furthermore, we discuss the effects of cross talk between adhesion molecules and growth factors. Understanding the molecular mechanisms involved in the regulation of EC survival and apoptosis may provide new targets for the development of new therapies to enhance angiogenesis in the case of tissue-ischemia (eg, the neovascularization of myocardium) or to inhibit angiogenesis in the case of neovascularization-dependent disease (eg, tumor, diabetic retinopathy).
{"title":"Regulation of Endothelial Cell Survival and Apoptosis During Angiogenesis","authors":"E. Chavakis, S. Dimmeler","doi":"10.1161/01.ATV.0000017728.55907.A9","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017728.55907.A9","url":null,"abstract":"The process of angiogenesis plays an important role in many physiological and pathological conditions. Inhibition of endothelial cell (EC) apoptosis providing EC survival is thought to be an essential mechanism during angiogenesis. Many of the angiogenic growth factors inhibit EC apoptosis. In addition, the adhesion of ECs to the extracellular matrix or intercellular adhesion promotes EC survival. In contrast, increasing evidence suggests that the induction of EC apoptosis may counteract angiogenesis. In this review, we focus on the regulation of EC survival and apoptosis during angiogenesis and especially on the effects and intracellular signaling promoted by angiogenic growth factors, endogenous angiogenic inhibitors (such as angiostatin, endostatin, and thrombospondin-1), and the adhesion to the extracellular matrix. Furthermore, we discuss the effects of cross talk between adhesion molecules and growth factors. Understanding the molecular mechanisms involved in the regulation of EC survival and apoptosis may provide new targets for the development of new therapies to enhance angiogenesis in the case of tissue-ischemia (eg, the neovascularization of myocardium) or to inhibit angiogenesis in the case of neovascularization-dependent disease (eg, tumor, diabetic retinopathy).","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"4 1","pages":"887-893"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84135498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000020400.25088.A7
E. Cottington, C. LaMantia, S. Stabler, R. Allen, A. Tangerman, C. Wagner, S. Zeisel, S. Mudd
The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer’s disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care.
{"title":"Adverse Event Associated With Methionine Loading Test: A Case Report","authors":"E. Cottington, C. LaMantia, S. Stabler, R. Allen, A. Tangerman, C. Wagner, S. Zeisel, S. Mudd","doi":"10.1161/01.ATV.0000020400.25088.A7","DOIUrl":"https://doi.org/10.1161/01.ATV.0000020400.25088.A7","url":null,"abstract":"The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer’s disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"28 1","pages":"1046-1050"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83482628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000017994.77066.75
D. Kuhel, B. Zhu, D. Witte, D. Hui
Five inbred strains of mice differing in susceptibility to diet-induced atherosclerosis were compared for neointimal hyperplasia after endothelial denudation with an epoxy resin–modified catheter probe. Results showed that all animals responded similarly to the arterial injury, with increased medial area and thickness after 14 days. In contrast, a significant strain-specific difference in neointimal formation after injury was observed. The atherosclerosis-susceptible C57L/J mice were also susceptible to injury-induced neointimal hyperplasia, and the C3H mice were resistant to both forms of vascular diseases. The 129/Sv mice, which displayed an intermediate level of diet-induced atherosclerosis, also displayed an intermediate level of injury-induced neointimal hyperplasia. Interestingly, the atherosclerosis-susceptible C57BL/6 mice were resistant to neointimal hyperplasia after endothelial denudation, whereas the atherosclerosis-resistant FVB/N mice were susceptible, displaying massive neointimal hyperplasia after arterial injury. All (C57L/J×C57BL/6)F1 hybrid mice were resistant to injury-induced neointimal hyperplasia. Moreover, N2 mice generated from backcrossing the F1 hybrid mice to the susceptible C57L/J mice displayed a range of arterial response to injury, spanning the most severe to the most resistant phenotype. These results indicate that injury-induced neointimal hyperplasia and diet-induced atherosclerosis are controlled by distinct sets of genes; the former appeared to be determined by recessive genes at ≥2 loci.
{"title":"Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice","authors":"D. Kuhel, B. Zhu, D. Witte, D. Hui","doi":"10.1161/01.ATV.0000017994.77066.75","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017994.77066.75","url":null,"abstract":"Five inbred strains of mice differing in susceptibility to diet-induced atherosclerosis were compared for neointimal hyperplasia after endothelial denudation with an epoxy resin–modified catheter probe. Results showed that all animals responded similarly to the arterial injury, with increased medial area and thickness after 14 days. In contrast, a significant strain-specific difference in neointimal formation after injury was observed. The atherosclerosis-susceptible C57L/J mice were also susceptible to injury-induced neointimal hyperplasia, and the C3H mice were resistant to both forms of vascular diseases. The 129/Sv mice, which displayed an intermediate level of diet-induced atherosclerosis, also displayed an intermediate level of injury-induced neointimal hyperplasia. Interestingly, the atherosclerosis-susceptible C57BL/6 mice were resistant to neointimal hyperplasia after endothelial denudation, whereas the atherosclerosis-resistant FVB/N mice were susceptible, displaying massive neointimal hyperplasia after arterial injury. All (C57L/J×C57BL/6)F1 hybrid mice were resistant to injury-induced neointimal hyperplasia. Moreover, N2 mice generated from backcrossing the F1 hybrid mice to the susceptible C57L/J mice displayed a range of arterial response to injury, spanning the most severe to the most resistant phenotype. These results indicate that injury-induced neointimal hyperplasia and diet-induced atherosclerosis are controlled by distinct sets of genes; the former appeared to be determined by recessive genes at ≥2 loci.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"408 1","pages":"955-960"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76627556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-06-01DOI: 10.1161/01.ATV.0000017461.79231.3D
K. Arakawa, K. Isoda, Toshimitu Ito, K. Nakajima, T. Shibuya, F. Ohsuzu
Vulnerable plaque generally contains a thin fibrous cap, lipid pools, and reduced internal plaque collagen. Arterial fluorescence analysis can differentiate atherosclerotic lesions from normal arteries; however, the contribution of the lipid core to atherosclerotic arterial fluorescence remains controversial. This study aimed to identify lipid core fluorophores and to differentiate the lipid core from normal artery and atheroma. The helium-cadmium laser–induced fluorescence spectra of cadaveric arteries and known chemical constituents were recorded. Lipid core fluorescence spectra exhibited marked red shifts and broadening compared with the fluorescence spectra of normal tissue and atheroma. Similar fluorescence spectra were obtained for lipid core and oxidized low density lipoprotein, for atheroma and collagen, and for normal artery and elastin. A classification based on collagen, elastin, and oxidized low density lipoprotein spectral decomposition could discriminate the lipid core (n=29), normal artery (n=74), atheroma (n=73), and preatheroma (n=10) with 86% accuracy. Fibrous cap thickness was correlated with the spectral collagen content index (r =0.65, P <0.0001), especially at a thickness of <200 &mgr;m. We conclude that a classification algorithm based on chemical spectral decomposition can accurately classify the fluorescence spectra of normal artery, atheroma, and lipid core and may be useful in identifying vulnerable atheroma in vivo.
易损斑块通常包含薄纤维帽、脂质池和减少的内部斑块胶原蛋白。动脉荧光分析可以区分动脉粥样硬化病变与正常动脉;然而，脂质核心对动脉粥样硬化动脉荧光的贡献仍然存在争议。本研究旨在鉴定脂质核心荧光团，并将脂质核心与正常动脉和动脉粥样硬化区分开。记录了氦镉激光诱导的尸体动脉和已知化学成分的荧光光谱。与正常组织和动脉粥样硬化组织相比，脂质核荧光光谱出现明显的红移和增宽。脂核和氧化低密度脂蛋白，动脉粥样硬化和胶原蛋白，正常动脉和弹性蛋白的荧光光谱相似。基于胶原蛋白、弹性蛋白和氧化低密度脂蛋白光谱分解的分类可以区分脂质核心(n=29)、正常动脉(n=74)、动脉粥样硬化(n=73)和动脉粥样硬化前期(n=10)，准确率为86%。纤维帽厚度与光谱胶原含量指数相关(r =0.65, P <0.0001)，特别是在纤维帽厚度<200 &mgr;m时。我们认为，基于化学光谱分解的分类算法可以准确地对正常动脉、动脉粥样硬化和脂质核心的荧光光谱进行分类，可能有助于识别体内易损动脉粥样硬化。
{"title":"Fluorescence Analysis of Biochemical Constituents Identifies Atherosclerotic Plaque With a Thin Fibrous Cap","authors":"K. Arakawa, K. Isoda, Toshimitu Ito, K. Nakajima, T. Shibuya, F. Ohsuzu","doi":"10.1161/01.ATV.0000017461.79231.3D","DOIUrl":"https://doi.org/10.1161/01.ATV.0000017461.79231.3D","url":null,"abstract":"Vulnerable plaque generally contains a thin fibrous cap, lipid pools, and reduced internal plaque collagen. Arterial fluorescence analysis can differentiate atherosclerotic lesions from normal arteries; however, the contribution of the lipid core to atherosclerotic arterial fluorescence remains controversial. This study aimed to identify lipid core fluorophores and to differentiate the lipid core from normal artery and atheroma. The helium-cadmium laser–induced fluorescence spectra of cadaveric arteries and known chemical constituents were recorded. Lipid core fluorescence spectra exhibited marked red shifts and broadening compared with the fluorescence spectra of normal tissue and atheroma. Similar fluorescence spectra were obtained for lipid core and oxidized low density lipoprotein, for atheroma and collagen, and for normal artery and elastin. A classification based on collagen, elastin, and oxidized low density lipoprotein spectral decomposition could discriminate the lipid core (n=29), normal artery (n=74), atheroma (n=73), and preatheroma (n=10) with 86% accuracy. Fibrous cap thickness was correlated with the spectral collagen content index (r =0.65, P <0.0001), especially at a thickness of <200 &mgr;m. We conclude that a classification algorithm based on chemical spectral decomposition can accurately classify the fluorescence spectra of normal artery, atheroma, and lipid core and may be useful in identifying vulnerable atheroma in vivo.","PeriodicalId":8418,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association","volume":"6 1","pages":"1002-1007"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77819327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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