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Nuclear Magnetic Resonance Spectroscopy of Lipoproteins and Risk of Coronary Heart Disease in the Cardiovascular Health Study
- Lewis Kuller,
- Alice Arnold,
- Russell Tracy,
- James Otvos,
- Greg Burke,
- Bruce Psaty,
- David Siscovick,
- David S. Freedman and
- Richard Kronmal
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 22, Issue 71 July 2002

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Objectives— Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis.Methods and Results— The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 “healthy” participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between “healthy” participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina.Conclusions— Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.
Inhibition of Renin-Angiotensin System Ameliorates Endothelial Dysfunction Associated With Aging in Rats
- Yasushi Mukai,
- Hiroaki Shimokawa,
- Midoriko Higashi,
- Keiko Morikawa,
- Tetsuya Matoba,
- Junko Hiroki,
- Ikuko Kunihiro,
- Hassan M.A. Talukder and
- Akira Takeshita
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 22, Issue 91 September 2002

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Objective— Endothelial vasodilator functions are progressively impaired with aging, which may account in part for the increased incidence of cardiovascular events in elderly people. We examined what treatment could ameliorate the endothelial dysfunction associated with aging in rats.Methods and Results— Aged (12-month-old) Wistar-Kyoto rats were treated with vehicle, temocapril, CS-866 (an angiotensin II type 1 receptor antagonist), cerivastatin, or hydralazine for 2 weeks. Endothelium-dependent relaxations (EDRs) of aortas from aged rats were markedly impaired compared with EDRs of aortas from young (3-month-old) rats. Indomethacin, NS-398 (a cyclooxygenase [COX]-2 inhibitor), and SQ-29548 (a thromboxane A₂/prostaglandin H₂ receptor antagonist) acutely restored EDRs in aged rats, suggesting an involvement of COX-2–derived vasoconstricting eicosanoids. Tiron, a superoxide scavenger, also partially improved EDRs, suggesting an involvement of superoxide. EDRs were significantly ameliorated in aged rats after long-term treatment with temocapril or CS-866 but not after treatment with cerivastatin or hydralazine. Indomethacin induced no further improvement of EDRs after treatment with temocapril or CS-866. COX-2 protein expression and superoxide production were increased in the aortas of aged rats and were also attenuated by treatment with temocapril or CS-866.Conclusions— These results demonstrate that long-term inhibition of the renin-angiotensin system ameliorates endothelial dysfunction associated with aging through the inhibition of the synthesis of COX-2–derived vasoconstricting factors and superoxide anions.
Retarded Intracellular Lipid Transport Associated With Reduced Expression of Cdc42, a Member of Rho-GTPases, in Human Aged Skin Fibroblasts: A Possible Function of Cdc42 in Mediating Intracellular Lipid Transport
- Kosuke Tsukamoto,
- Ken-ichi Hirano,
- Shizuya Yamashita,
- Naohiko Sakai,
- Chiaki Ikegami,
- Zhongyan Zhang,
- Fumihiko Matsuura,
- Hisatoyo Hiraoka,
- Akifumi Matsuyama,
- Masato Ishigami and
- Yuji Matsuzawa
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 22, Issue 111 November 2002

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Objective— Many cell types in atherosclerotic lesions are thought to have various biological abnormalities, such as impaired lipid homeostasis and slow cell proliferation, which may be related to senescence at cellular and individual levels. One of the common characteristics of senescent cells in vitro is the alteration of actin cytoskeletons, which have been reported to be involved in the intracellular transport of lipids. Recently, we raised the hypothesis that Cdc42, which is a member of the Rho-GTPase family and is known to play an important role in actin dynamics, might be important in cellular lipid transport.Methods and Results— In the present study, we found that the protein expression levels and GTP-binding activities of Cdc42 were decreased in aged human skin fibroblasts. Moreover, we found the intracellular kinetics of Golgi-associated lipids to be retarded in these cells, which was demonstrated by the fluorescence recovery after photobleaching (FRAP) technique and the use of N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminohexanoyl-d-erythro-sphingosine as a tracer. To correlate the decreased expression of Cdc42 with the retarded FRAP, we complemented the amount of wild-type c-myc–tagged Cdc42Hs (myc-Cdc42Hs-WT) by adenovirus-mediated gene transfer. We further tested the effect of the dominant-active form (myc-Cdc42Hs-DA, V12Cdc42Hs) or dominant-negative form (myc-Cdc42Hs-DN, N17Cdc42Hs) of Cdc42Hs on FRAP. Introduction of myc-Cdc42Hs-WT or myc-Cdc42Hs-DA recovered the retarded FRAP in the aged fibroblasts. Conversely, control fibroblasts infected with myc-Cdc42Hs-DN exhibited significantly retarded FRAP.Conclusions— These data clearly indicate that the expression of Cdc42, a small G protein, is decreased in the aged cells in close association with the retarded intracellular lipid transport. The present study demonstrates a possible function of Cdc42 in the mediation of intracellular lipid transport.
Role of p44/p42 MAP Kinase in the Age-Dependent Increase in Vascular Smooth Muscle Cell Proliferation and Neointimal Formation
- Giuseppa Gennaro,
- Catherine Ménard,
- Edith Giasson,
- Sophie-Élise Michaud,
- Maria Palasis,
- Sylvain Meloche and
- Alain Rivard
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 23, Issue 21 February 2003

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Objective— Age-dependent increase in vascular smooth muscle cell (VSMC) proliferation is thought to contribute to the pathology of atherosclerotic diseases. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) on VSMC proliferation and neointimal formation in the context of aging.Methods and Results— VSMCs were isolated from the aorta of young and old rabbits. The proliferative index after serum stimulation was significantly increased in old versus young VSMCs. This was associated with a significant and specific age-dependent increase in p44/p42 MAPK activation. Treatment with MEK inhibitor PD98059 successfully inhibited p44/p42 MAPK activities and VSMC proliferation. These results were confirmed in vivo using a model of balloon injury in rabbit iliac arteries. p44/p42 MAPK activities were rapidly induced by angioplasty in young and old animals. However, the levels of p44/p42 MAPK activities achieved in arteries of old rabbits were significantly higher than those of young rabbits. This was associated with a higher cellular proliferative index and a significant increase in neointimal formation in old animals. Local delivery of PD98059 in old rabbits successfully inhibited p44/p42 MAPK activities after angioplasty, which led to a significant reduction in cellular proliferation and neointimal formation in treated animals.Conclusions— Our study suggests for the first time that increased p44/p42 MAPK activation contributes to augmented VSMC proliferation and neointimal formation with aging. p44/p42 MAPK inhibition could represent a novel therapeutic avenue against atherosclerotic diseases.
White Cell Telomere Length and Risk of Premature Myocardial Infarction
- Scott Brouilette,
- Ravi K. Singh,
- John R. Thompson,
- Alison H. Goodall and
- Nilesh J. Samani
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 23, Issue 51 May 2003

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Objective— Biological age may be distinct from chronological age and contribute to the pathogenesis of age-related diseases. Mean telomeres lengths provide an assessment of biological age with shorter telomeres, indicating increased biological age. We investigated whether subjects with premature myocardial infarction (MI) had shorter leukocyte telomeres.Methods and Results— Mean terminal restriction fragment (TRF) length, a measure of average telomere size, was compared in leukocyte DNA of 203 cases with a premature MI (<50 years) and 180 controls. Age- and sex-adjusted mean TRF length of cases was significantly shorter than that of controls (difference 299.7±69.3 base pairs, P<0.0001) and on average equivalent to controls 11.3 years older. The difference in mean TRF length between cases and controls was not accounted for by other coronary risk factors. Compared with subjects in the highest quartile for telomere length, the risk of myocardial infarction was increased between 2.8- and 3.2-fold (P<0.0001) in subjects with shorter than average telomeres.Conclusions— The findings support the concept that biological age may play a role in the etiology of coronary heart disease and have potentially important implications for our understanding of its genetic etiology, pathogenesis, and variable age of onset.
Cross-Reactive B-Cell Epitopes of Microbial and Human Heat Shock Protein 60/65 in Atherosclerosis
- Hannes Perschinka,
- Manuel Mayr,
- Gunda Millonig,
- Christina Mayerl,
- Ruurd van der Zee,
- Sandra G. Morrison,
- Richard P. Morrison,
- Qingbo Xu and
- Georg Wick
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 23, Issue 61 June 2003

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Objective— Growing evidence suggests that immune reactions to heat shock protein 60 (HSP60) are involved in atherogenesis. Because of the high phylogenetic conservation between microbial and human HSP60, bacterial infections might be responsible for breaking the tolerance to self-HSP60, which is expressed on the surface of stressed arterial endothelial cells.Methods and Results— We purified serum antibodies to Escherichia coli HSP60 (GroEL), the 60-kD chlamydial HSP, and HSP65 of Mycobacterium tuberculosis by affinity chromatography from clinically healthy subjects with sonographically proven carotid atherosclerosis. Reactivity of the purified antibodies with overlapping human HSP60 peptides was measured, and 8 shared common epitopes, recognized by all anti-bacterial HSP60/65 antibodies, were identified. Antisera specific for these cross-reactive epitopes were produced by immunizing rabbits with peptides derived from human HSP60. By immunohistochemistry, the epitopes were found to be present in the arterial wall of young subjects during the earliest stages of the disease.Conclusions— Antibodies to microbial HSP60/65 recognize specific epitopes on human HSP60. These cross-reactive epitopes were shown to serve as autoimmune targets in incipient atherosclerosis and might provide further insights into the mechanisms of early atherogenesis.
Rat Aortic MCP-1 and Its Receptor CCR2 Increase With Age and Alter Vascular Smooth Muscle Cell Function
- Gaia Spinetti,
- Mingyi Wang,
- Robert Monticone,
- Jing Zhang,
- Di Zhao and
- Edward G. Lakatta
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 24, Issue 81 August 2004

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Objective— With age, rat arterial walls thicken and vascular smooth muscle cells (VSMCs) exhibit enhanced migration and proliferation. Monocyte chemotactic protein-1 (MCP-1) affects these VSMC properties in vitro. Because arterial angiotensin II, which induces MCP-1 expression, increases with age, we hypothesized that aortic MCP-1 and its receptor CCR2 are also upregulated and affect VSMC properties.Methods and Results— Both MCP-1 and CCR2 mRNAs and proteins increased in old (30-month) versus young (8-month) F344×BN rat aortas in vivo. Cellular MCP-1 and CCR2 staining colocalized with that of α-smooth muscle actin in the thickened aortas of old rats and were expressed by early-passage VSMCs isolated from old aortas, which, relative to young VSMCs, exhibited increased invasion, and the age difference was abolished by vCCI, an inhibitor of CCR2 signaling. MCP-1 treatment of young VSMCs induced migration and increased their ability to invade a synthetic basement membrane. The MCP-1–dependent VSMC invasiveness was blocked by vCCI. After MCP-1 treatment, migration and invasion capacities of VSMCs from young aortas no longer differed from those of VSMCs isolated from older rats.Conclusions— Arterial wall and VSMC MCP-1/CCR2 increase with aging. MCP-1 enhances VSMC migration and invasion, and thus, MCP-1/CCR2 signaling may play a role in age-associated arterial remodeling.This study demonstrates that MCP-1 and CCR2 are increased within the thickened aortas of older rats. In early-passage VSMCs from young rats, MCP-1 increased migration and invasion, imparting to these cells the characteristics of VSMCs from older rat aorta. Thus, MCP-1/CCR2 may be implicated in age-associated vascular remodeling.
Laminopathies and Atherosclerosis
- Khalid Z. Al-Shali and
- Robert A. Hegele
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 24, Issue 91 September 2004

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Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy [FPLD2] and Hutchinson-Gilford progeria syndrome [HGPS]) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes. In contrast, the premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits and probably reflects the generalized process of accelerated aging in HGPS. Although some common polymorphisms of LMNA have been associated with traits related to atherosclerosis, the monogenic diseases FPLD2 and HGPS are more likely to provide clues about new pathways for the general process of atherosclerosis.Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome are laminopathies caused by mutation in LMNA that feature atherosclerosis, which is related to proatherogenic metabolic disturbances and to the generalized process of accelerated aging, respectively. These monogenic diseases may provide clues about new pathways for atherogenesis.
TRL, IDL, and LDL Apolipoprotein B-100 and HDL Apolipoprotein A-I Kinetics as a Function of Age and Menopausal Status
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 25, Issue 81 August 2005

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Objective— To determine mechanisms contributing to the altered lipoprotein profile associated with aging and menopause, apolipoprotein B-100 (apoB-100) and apoA-I kinetic behavior was assessed.Methods and Results— Eight premenopausal (25±3 years) and 16 postmenopausal (65±6 years) women consumed for 6 weeks a standardized Western diet, at the end of which a primed-constant infusion of deuterated leucine was administered in the fed state to determine the kinetic behavior of triglyceride-rich lipoprotein (TRL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB-100, and high-density lipoprotein (HDL) apoA-I. Data were fit to a multicompartmental model using SAAM II to calculate fractional catabolic rate (FCR) and production rate (PR). Total cholesterol, LDL cholesterol (LDL-C), TRL-C, and triglyceride levels were higher (50%, 55%, 130%, and 232%, respectively) in the postmenopausal compared with the premenopausal women, whereas HDL-C levels were similar. Plasma TRL, IDL, and LDL-apoB-100 levels and pool sizes (PS) were significantly higher in the postmenopausal than premenopausal women. These differences were accounted for by lower TRL, IDL, and LDL apoB-100 FCR (P<0.05), with no difference in PR. There was no significant difference between groups in HDL-C levels or apoA-I kinetic parameters. Plasma TRL-C concentrations were negatively correlated with TRL apoB-100 FCR (r=−0.46; P<0.05) and positively correlated with PR (r=0.62; P<0.01). Plasma LDL-C concentrations were negatively correlated with LDL apoB-100 FCR (r=−0.70; P<0.001) but not PR.Conclusions— The mechanism for the increase in TRL and LDL apoB-100 PS observed in the postmenopausal women was determined predominantly by decreased TRL and LDL catabolism rather than increased production. No differences were observed in HDL apoA-I kinetics between groups.Postmenopausal women have higher VLDL-C and LDL-C levels compared with premenopausal women. To determine mechanism, apolipoprotein kinetic studies were conducted in 24 women. Postmenopausal women had higher TRL and LDL pool sizes, which were accounted for by lower TRL and LDL apoB-100 catabolic rates. No significant difference in plasma HDL-C levels or apoA-I kinetics parameters were observed between groups.
Degenerative Aortic Valve Stenosis, but not Coronary Disease, Is Associated With Shorter Telomere Length in the Elderly
- David J. Kurz,
- Barbara Kloeckener-Gruissem,
- Alexander Akhmedov,
- Franz R. Eberli,
- Ines Bühler,
- Wolfgang Berger,
- Osmund Bertel and
- Thomas F. Lüscher
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 26, Issue 61 June 2006

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Objective— The mechanisms responsible for the age-related increase in the incidence of calcific aortic valve stenosis (CAS) are unclear but may include telomere-driven cellular senescence. Because telomere length varies widely among individuals of the same age, we hypothesized that patients with shorter telomeres would be prone to develop CAS late in life.Methods and Results— Mean telomere length was measured in leukocytes from a cohort of 193 patients ≥70 years of age with and without CAS. Pilot experiments performed in 30 patients with CAS and controls pair-matched for age, sex, and presence or absence of coronary disease demonstrated significantly shorter telomeres in the CAS group both by Southern blot hybridization (5.75±0.55 kbp versus 6.27±0.7 kbp, P=0.0023) and by a quantitative polymerase chain reaction-based technique (relative telomere length 0.88±0.19 versus 1.0±0.19, P=0.01). This finding was then confirmed in the whole cohort (CAS n=64, controls n=129, relative telomere length=0.86±0.16 versus 0.94±0.12, P=0.0003). Both groups were comparable for potential confounding characteristics. Subgroup analysis according to the presence or absence of coronary disease demonstrated no association of this disorder with telomere length.Conclusions— In the elderly, calcific aortic stenosis, but not coronary disease, is associated with shorter leukocyte telomere length.The mechanisms responsible for the age-related increase in the incidence of calcific aortic valve stenosis (CAS) are unclear but may include telomere-driven cellular senescence. Because telomere length varies widely among individuals of the same age, we hypothesized that patients with shorter telomeres would be prone to develop CAS late in life. In the elderly, calcific aortic stenosis, but not coronary disease, is associated with shorter leukocyte telomere length.
Matrix Metalloproteinase 2 Activation of Transforming Growth Factor-β1 (TGF-β1) and TGF-β1–Type II Receptor Signaling Within the Aged Arterial Wall
- Mingyi Wang,
- Di Zhao,
- Gaia Spinetti,
- Jing Zhang,
- Li-Qun Jiang,
- Gianfranco Pintus,
- Robert Monticone and
- Edward G. Lakatta
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 26, Issue 71 July 2006

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Objective— To study matrix metalloproteinase 2 (MMP-2) effects on transforming growth factor-β1 (TGF-β1) activation status and downstream signaling during arterial aging.Methods and Results— Western blotting and immunostaining showed that latent and activated TGF-β1 are markedly increased within the aorta of aged Fisher 344 cross-bred Brown Norway (30 months of age) rats compared with adult (8 months of age) rats. Aortic TGF-β1–type II receptor (TβRII), its downstream molecules p-similar to mad-mother against decapentaplegic (SMAD)2/3 and SMAD4, fibronectin, and collagen also increased with age. Moreover, TGF-β1 staining is colocalized with that of activated MMP-2 within the aged arterial wall and vascular smooth muscle cell (VSMC) in vitro, and this physical association was confirmed by coimmunoprecipitation. Incubation of young aortic rings ex vivo or VSMCs in vitro with activated MMP-2 enhanced active TGF-β1, collagen, and fibronectin expression to the level of untreated old counterparts, and this effect was abolished via inhibitors of MMP-2. Interestingly, in old untreated rings or VSMCs, the increased TGF-β1, fibronectin, and collagen were also substantially reduced by inhibition of MMP-2.Conclusions— Active TGF-β1, its receptor, and receptor-mediated signaling increase within the aortic wall with aging. TGF-β1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity. Thus, MMP-2–activated TGF-β1, and subsequently TβRII signaling, is a novel molecular mechanism for arterial aging.We analyzed MMP-2 effects on TGF-β1 activation status and downstream signaling during age-associated arterial remodeling. MMP-2 increased TGF-β1 activity, collagen, and fibronectin within aortic rings or VSMCs from young rats to the levels that occur in old animals. All of these effects are substantially reduced by inhibition of MMP-2.
Aging in the Atherosclerosis Milieu May Accelerate the Consumption of Bone Marrow Endothelial Progenitor Cells
- Shoukang Zhu,
- Xialin Liu,
- Ying Li,
- Pascal J. Goldschmidt-Clermont and
- Chunming Dong
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 27, Issue 11 January 2007

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Objective— We have demonstrated that bone marrow cells from young and wild-type (WT), but not old apoE^−/−, mice are capable of preventing atherosclerosis. This study was performed to elucidate the numerical and functional changes underlying the efficacy difference between young and old bone marrow.Methods and Results— CD34⁺/VEGFR2⁺ conventional endothelial progenitor cells and lin⁻/cKit⁺/Sca-1⁺ hematopoietic stem cells did not differ numerically or functionally between young and old apoE^−/− bone marrow. Fluorescence- activated cell sorter analysis, however, showed that a group of cells (simple little cells or SLCs), characteristically located in the lower left quadrant of forward scatter/side scatter flow cytometric plot, were markedly decreased in old WT and apoE^−/− marrow, but abundantly present in young WT and apoE^−/− bone marrow. The SLC fraction was mainly composed of lin⁻/cKit⁻/Sca-1⁻ cells. In vitro differentiation assay demonstrated substantially more efficient endothelial differentiation of lin⁻/cKit⁻/Sca-1⁻ SLCs than other bone marrow fractions at a single cell level and en masse. Furthermore, old lin⁻/cKit⁻/Sca-1⁻ SLCs had a trend of decreased endothelial differentiation capability.Conclusions— Lin⁻/cKit⁻/Sca-1⁻ SLCs may represent a previously unrecognized cell population, enriched for endothelial progenitors. The identification of these cells may help improve the efficacy of cell therapy.A group of cells (simple little cells or SLCs) were markedly decreased in the marrow of old wild-type and apoE^−/− mice, relative to their young counterparts. Lineage negative cKit-/Sca-1- cells, the predominant cell type in the SLC population, displayed efficient conversion to a mature endothelial phenotype in vitro.
Hemostatic, Metabolic, and Androgenic Risk Factors for Coronary Heart Disease in Physically Active and Less Active Postmenopausal Women
- Edith T. Stevenson,
- Kevin P. Davy and
- Douglas R. Seals
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 15, Issue 51 May 1995

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Abstract Physically active postmenopausal women have a lower incidence of coronary heart disease (CHD) than their more sedentary peers, but little information is available concerning the responsible mechanisms. The primary aim of this study was to test the hypothesis that physically active postmenopausal women demonstrate more favorable levels of hemostatic, metabolic, and androgenic CHD risk factors than less active control subjects. If so, a secondary aim was to determine which of the characteristics associated with a physically active lifestyle, ie, low body fat, a high-carbohydrate/low-fat diet, high maximal aerobic capacity (aerobic fitness), and high levels of physical activity, are most closely related to this lower risk profile. To address these aims, we compared CHD risk factors in physically very active women (n=14; age, 55±2 years) with those in healthy, nonobese sedentary control subjects (n=17; age, 56±1 years). Maximal aerobic capacity (fitness) was 83% higher (P<.001) in the physically active women. Concentrations of plasminogen activator inhibitor type 1 activity and tissue plasminogen activator antigen were lower (more favorable) (P<.005) in the physically active women versus control subjects, whereas plasma fibrinogen levels did not differ. The physically active women had lower (P<.01) fasting plasma insulin and glucose concentrations as well as smaller responses to an oral glucose challenge. Both total-body and abdominal fat levels were lower (P<.001) and lipid and lipoprotein profiles were generally more favorable (P<.05) in the physically active women. Plasma sex hormone–binding globulin concentrations were higher (P<.01) in the physically active women, indicating a lower androgenicity-related CHD risk. In addition, the physically active women consumed a diet that was higher (P<.002) in carbohydrates and lower (P<.02) in fat and protein. Stepwise multiple regressions indicated that although a portion of the observed variability in these CHD risk factors can be explained by physical activity levels per se, the associated differences in total body and abdominal fat, dietary composition, and aerobic fitness also contribute in a significant but selective manner. Thirty percent to 40% of each group were on hormone replacement therapy, but its effects appeared to be minimal. These results demonstrate that physically active postmenopausal women exhibit favorable levels of hemostatic, metabolic, and androgenic CHD risk factors, which could contribute to their lower incidence of CHD.
Whole-Blood Platelet Aggregation Predicts In Vitro and In Vivo Primary Hemostatic Function in the Elderly
- Jonathan D. Emery,
- David W. Leifer,
- Glaci L. Moura,
- Patricia Southern,
- James H. Morrissey and
- Jeffry B. Lawrence
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 15, Issue 61 June 1995

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Abstract Increased platelet aggregation is associated with higher coronary artery disease mortality. Enhanced platelet aggregation in platelet-rich plasma has also been described in the elderly. To define age-related changes in primary hemostasis, we studied 37 elderly and 31 young blood donors. There were no significant age-related differences in whole-blood platelet aggregation, platelet adherence and thrombus formation on human umbilical artery segments, or bleeding time. Plasma fibrinogen was significantly higher in elderly men and women, whereas activated factor VII was elevated only in elderly women. Collagen-induced platelet aggregation was significantly correlated with platelet adherence to the subendothelium in elderly (r=.488, P=.002) but not in young donors. Accordingly, collagen-induced platelet aggregation showed a significant inverse correlation with bleeding time only in the elderly (r=−.401, P=.014). Arachidonic acid–induced platelet aggregation was significantly associated with platelet adherence to the subendothelium (r=.658, P=.003) and bleeding time (r=−.540, P=.021) only in elderly men. In young donors, ADP-induced platelet aggregation was significantly correlated with platelet adherence to the thrombogenic adventitial surface (r=.395, P=.031); in the elderly this association only approached significance (r=.315, P=.058). Whole-blood platelet aggregation in response to collagen and arachidonic acid may be more useful in predicting primary hemostatic function in the elderly than in the young. Furthermore, in the elderly, the correlation between platelet aggregation in whole blood and platelet–arterial wall interactions in vitro and in vivo may contribute to the ability of this test to predict coronary risk.
In Vivo LDL Receptor and HMG-CoA Reductase Regulation in Human Lymphocytes and Its Alterations During Aging
- Thomas M. Stulnig,
- Helmut Klocker,
- H. James Harwood,
- Günther Jürgens,
- Dieter Schönitzer,
- Elmar Jarosch,
- Lukas A. Huber,
- Albert Amberger and
- Georg Wick
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 15, Issue 71 July 1995

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Abstract The LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase play primary roles in the regulation of cellular cholesterol metabolism. To investigate the transcriptional regulation of lipid metabolism under physiological conditions ex vivo and its alterations during aging, we analyzed both the activity and mRNA concentration of the LDL receptor and HMG-CoA reductase in freshly isolated lymphocytes from healthy young and elderly donors. Data from fluorescent reverse transcriptase–polymerase chain reaction indicated that not only plasma LDL but also plasma HDL downregulates lymphocyte LDL receptor mRNA. Downregulation by HDL was three times more effective than that by LDL and presumably involved specific HDL binding sites. There was coordinate regulation of HMG-CoA reductase mRNA with LDL receptor mRNA that was independent of plasma lipoprotein concentrations. Despite elevated plasma concentrations of LDL, lymphocytes from elderly donors paradoxically expressed increased levels of the LDL receptor (P=.030) and HMG-CoA reductase mRNA (P=.062). The age-related dysregulation of the LDL receptor was predominantly due to impaired downregulation by plasma LDL rather than by HDL. Thus, not only LDL but also HDL and age significantly influences the transcriptional regulation of the LDL receptor in extrahepatic cells in vivo.
Absence of Age-Related Increase in Central Arterial Stiffness in Physically Active Women
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 18, Issue 11 January 1998

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Abstract—Increased arterial stiffness is thought to contribute to the increased incidence of cardiovascular disease with age. Little, however, is known about the influence of aging on central and peripheral arterial stiffness in females. Moreover, it is unknown whether physical activity status influences age-related increases in arterial stiffness in females. Arterial pulse wave velocity (PWV) and augmentation index (AI, applanation tonometry) were measured in 53 healthy females, including 10 premenopausal (Pre-S) and 18 postmenopausal (Post-S) sedentary women, and 9 premenopausal (Pre-PA) and 16 postmenopausal (Post-PA) physically active women. In the sedentary women, there were no age-related differences in arterial blood pressure, but aortic PWV and carotid AI (measures of central arterial stiffness) were higher (P<.01) in Post-S versus Pre-S (1065±110 versus 690±80 cm/sec and 16.5%±1.8% versus 0.3%±1.6%, respectively); however, there were no significant differences in leg and arm PWV (measures of peripheral arterial stiffness). Systolic and mean arterial blood pressures were higher (P<.05) in Post-PA versus Pre-PA. Despite this and in contrast to the sedentary women, aortic PWV and AI were not different in Post-PA versus Pre-PA. Stepwise multiple regression indicated that maximal oxygen consumption, plasma total cholesterol, and plasma LDL-cholesterol were significant independent predictors and together explained up to 50% of the variability in central arterial stiffness. We concluded that (1) central, but not peripheral, arterial stiffness increases with age in sedentary healthy females in the absence of age-related increases in arterial blood pressure; (2) significant age-related increases in central arterial stiffness are not observed in highly physically active women; and (3) aerobic fitness and plasma total cholesterol and LDL-cholesterol levels are significant independent physiological correlates of central arterial stiffness in this population.
Physical Activity Status and Adverse Age-Related Differences in Coagulation and Fibrinolytic Factors in Women
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 18, Issue 31 March 1998

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Abstract—Adverse changes in coagulation and fibrinolytic factors are thought to contribute to the increased risk of cardiovascular disease and atherothrombosis with age. We tested the hypothesis that such age-related changes in specific coagulation and fibrinolytic factors are absent in physically active women. Resting levels of plasma fibrinogen, tissue-type plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor-1 (PAI-1) antigen and activity, and fibrin d-dimer were measured in 24 healthy premenopausal women: 11 sedentary (aged 28±1 years; Pre-S) and 13 physically active (aged 30±1 years; Pre-PA) and in 27 healthy postmenopausal women: 14 sedentary (aged 61±1 years; Post-S) and 13 physically active (aged 58±1 years; Post-PA). Post-S had higher (P<.05) fibrinogen, t-PA antigen, PAI-1 antigen, PAI-1 activity, and fibrin d-dimer levels and lower t-PA activity than Pre-S. Post-PA demonstrated lower (P<.01) plasma fibrinogen, t-PA antigen, PAI-1 antigen, and PAI-1 activity and higher (P<.01) t-PA activity levels than Post-S. In addition, plasma fibrin d-dimer levels tended (P=.06) to be lower in Post-PA than in Post-S. Although plasma levels of fibrinogen and fibrin d-dimer in Post-PA were lower than in Post-S, they were higher (P<.05) than in Pre-PA. Importantly, however, the fibrinolytic profile of Post-PA did not differ from that of Pre-PA. The results of the present study demonstrate that the adverse age-associated differences in plasma fibrinogen concentrations and the endogenous fibrinolytic system in sedentary healthy women are either attenuated or absent in highly physically active women. The smaller or absent age-related differences in coagulation and fibrinolytic factors in women who habitually exercise may represent an important mechanism contributing to their lower age-related increase in both cardiovascular disease and atherothrombotic events. Future studies need to determine whether women who are moderately active would demonstrate the same favorable hemostatic profile.
Structural, Functional, and Hemodynamic Changes of the Common Carotid Artery With Age in Male Subjects
- Arno Schmidt-Trucksäss,
- Dominik Grathwohl,
- Andreas Schmid,
- Raffael Boragk,
- Christine Upmeier,
- Joseph Keul and
- Martin Huonker
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 19, Issue 41 April 1999

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Abstract—Aging of the common carotid artery (CCA) is associated with different principal structural, functional, and hemodynamic changes, which are often influenced by several atherosclerotic risk factors, so that it is difficult to estimate the exclusive effect of aging on this process. Studies dealing with vascular aging of the CCA usually assess only single, dimensional, or functional parameters, although it is likely that there are interactions and probably differences between them. Moreover, regional vascular blood flow characteristics are often not taken into consideration. Therefore, the aim of the study was to assess the age-related multiparametric changes of the CCA properties with ultrasound in 69 male subjects between the ages of 16 and 75 (42.4±16.5 years), who were screened for the absence of major atherosclerotic risk factors or existing vascular disease. As a result, the intima media thickness (0.052 mm/10 y) and diastolic diameter (0.17 mm/10 y) increased nearly linearly with age (r=0.60, P<0.001; and r=0.46, P<0.001, respectively). The absolute diastolic/systolic diameter change diminished by 0.10 mm/10 y (r=−0.73, P<0.001) and peak expansion velocity dropped by 0.12 cm/s per 10 years (r=−0.62, P<0.001) highly significantly with age. The peak blood flow velocity decreased continuously with age (r=−0.67, P<0.00) by 9.3 cm/s per 10 years. According to multiple regression analysis, peak blood flow velocity seems to reflect the changes of several structural and functional parameters in one; intima-media thickness was determined by diastolic arterial diameter and age as independent variables. The data indicate that a multiparametric assessment may contribute to a better understanding of vascular aging and might be the basis for further studies to evaluate the association of atherosclerotic risk factors and/or major vascular disease with local changes in the CCA.
Cholesterol and Lipoprotein Metabolism in Aging : Reversal of Hypercholesterolemia by Growth Hormone Treatment in Old Rats
- Paolo Parini,
- Bo Angelin and
- Mats Rudling
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 19, Issue 41 April 1999

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Abstract—Plasma cholesterol levels increase with age, as does the incidence of coronary heart disease. The mechanisms responsible for the age-related hypercholesterolemia are not well understood. An interesting hypothesis suggests that the relative deficiency in growth hormone (GH), which occurs with aging, contributes to the development of the age-related hypercholesterolemia, because GH has beneficial effects on cholesterol metabolism. In the present work, we tested this hypothesis by the administration of GH to normal rats of varying ages. Plasma lipids and hepatic cholesterol metabolism were characterized in 2-, 12-, and 18-month-old male Sprague-Dawley rats. In 2-month-old rats, GH specifically stimulated the hepatic low density lipoprotein (LDL) receptor expression in a dose-dependent way, both at the protein level and at the mRNA level. Concomitantly, plasma cholesterol increased by ≈30% within the large high density lipoprotein and LDL fractions. In 12-month-old animals, cholesterol 7α-hydroxylase (C7αOH) activity was reduced, whereas hepatic LDL receptors and plasma total cholesterol were unchanged. GH treatment (1 mg · kg⁻¹ · d⁻¹) normalized the activity of C7αOH and had effects on plasma cholesterol and LDL receptors similar to those seen in 2-month-old animals. In 18-month-old rats, plasma cholesterol was increased 2-fold, whereas hepatic LDL receptor expression and C7αOH activity were similar to those of the 12-month-old animals. Infusion of GH to 18-month-old rats had similar effects on hepatic C7αOH and LDL receptors as seen in 12-month-old rats. However, GH treatment strongly reduced the hypercholesterolemia in 18-month-old animals. We conclude that the age-dependent increase of plasma cholesterol in rats can be reversed by the administration of GH, presumably through the pleiotropic effects of this hormone on lipoprotein metabolism.
No Association Between Dehydroepiandrosterone Sulfate and Development of Atherosclerosis in a Prospective Population Study (Bruneck Study)
- Stefan Kiechl,
- Johann Willeit,
- Enzo Bonora,
- Siegfried Schwarz and
- Qingbo Xu
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 20, Issue 41 April 2000

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Abstract—Antiatherogenic properties of dehydroepiandrosterone (DHEA) have been postulated for >40 years. Large-scale epidemiological studies on this important issue, however, are still sparse, and those available have yielded contradictory results. The Bruneck Study involved a large random sample of men and women aged 40 to 79 years that were enrolled in 1990 and reevaluated 5 years later. Baseline DHEA sulfate (DHEAS) levels were measured in 867 subjects after an overnight fast. Development and progression of carotid atherosclerosis was monitored by high-resolution duplex ultrasound. DHEAS levels declined with advancing age (29% and 44% per decade in men and women) and showed a complex sex-specific association with various vascular risk attributes and factors conferring protection against atherosclerosis. Age- and sex-adjusted DHEAS baseline levels did not differ between subjects with or without incident/progressive atherosclerosis (geometric mean 1161 versus 1253 μg/L). After adjustment for vascular risk factors and potential confounders, the odds ratio of incident/progressive atherosclerosis comparing a 50% increase in DHEAS levels was 0.99 (95% CI 0.89 to 1.11). Lack of an association between DHEAS and atherogenesis was confirmed in sex-specific and a variety of supplementary analyses. Statistical power would be high enough to detect differences in DHEAS between outcome categories as low as 15% (α=0.05). This prospective community-based study does not support a role for endogenous DHEA(S) in the development of human atherosclerosis.

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