- Email: [email protected]
Th-W52:1 Vessel-aging and mechanisms of atherothrombosis
Thurs&ty, June 22, 2006: Workshop Th-W52 Agebtg
470
Results: A significant interaction was observed between sex and the MS (p<0.003 for the multiplicative interaction term). Compared to women without the MS, those with the syndrome had a 24% greater LV mass (49.54-12 vs 40.04-10 g/m2.7, p<0.001), while the difference was only 9% in men (50.34-12 vs 46.14-10 g/m 2'7, p=0.003). A greater prevalence of inappropriately high LV mass was found in women (28% vs 5%, p<0.001), but not in men (26% vs 16%, p=0.08), with the MS. After adjustment for the effect of age, body mass index, 24-hour systolic blood pressure, and several confounders, the MS was independently associated with a greater LV mass in women (regression coefficient 15.7 g, p<0.001), but not in men. Women with the MS also had a greater LV relative wall thickness (0.42 vs 0.39, p=0.004) and a depressed a£terload-corrected midwall fractional shortening (94.0% vs 101.0%, p<0.001) than women without the syndrome, while no differences emerged in men. Conclusions: In untreated hypertension, MS has a different impact on LV hypertrophy and function in men and women. The effect of MS is more pronounced in women, and is paxtly independent from the effect of several hemodynamic and non-hemodynamic determinants of LV mass.
I Th-W51:7 I NON-STEROIDAL ANTI-INFLAMMATORY DRUGS U P - R E G U L A T E N A D P H O X I D A S E E X P R E S S I O N IN S P O N T A N E O U S L Y H Y P E R T E N S I V E RATS H. Li I , M. Hortmann I , A. DaJber 2, M. Oelze 2, I. Brausch I , C. Mang I , P.M. Schwarz I , T. Munzel-, U. Forstermann 1 . 1Department of
Pharmacology, Johannes Gutenberg Universi~, Mainz, Germany: 21ntental Medicine II, Johannes Gutenberg Universi~, Mainz, Germany Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation. However, recent studies have associated selective inhibitors of cyclooxygenase 2 with an increased cardiovascular risk and there is concern that this increased risk may be a common feature of all NSAIDs, especially in risk patients. We hypothesized that the major superoxide-producing enzymes, the NADPH oxidases, may be involved in the pathomechanism. Methods: Spontaneously hypertensive rats were treated for two weeks with rofecoxib (10 mg/kg/d), celecoxib (30 mg/kg/d) or diclofenac (5 mg/kg/d). The mRNA expression of the NADPH oxidase subunits p22phox and gp91phox (NOX2), and the gp91phox homologs NOX1 and NOX4 was analysed using quantitative real-time RT-PCR. Superoxide was measured by chemiluminescence with lucigenin or Diogenes. Results: In aorta and heart, the mRNA expression of the NADPH oxidase subunits was markedly increased by the non-selective NSAID diclofenac. A moderate upregulation of NADPH oxidase subunits was also seen with rofecoxib or celecoxib. This expressional upregulation of NADPH oxidase by the NSAIDs was associated with increased superoxide production in aorta and heart. Accordingly, plasma lipid peroxides were increased in parallel. Conclusions: NSAIDs may increase the cardiovascular risk by upregulating NADPH oxidases and increasing oxidative stress. Coxibs produce less oxidative stress than the non-selective didofenac. F u n d i n g : This work was supported by the Collaborative Research Center SFB 553 from the DFG, Bonn, Germany.
Th-W52 Th-W52:l
AGEING
VESSEL-AGING AND MECHANISMS OF ATHEROTHROMBOSIS
E Holvoet. Atherosclerosis arm Metabolism Unit, Department of Molecular arm Cardiovascular Researeh, Katholieke Universiteit Leuven, Belgium Schematically one distinguishes two major types of modifications in the arterial wall: atheromatous plaque formation (atherosclerosis) and agingassociated increase of wall thickness and arterial stiffening (arteriosclerosis). Although epidemiological studies have revealed that high lipid levels, obesity, diabetes, hypertension, smoking, sedentary lifestyle, and genetic factors axe risk factors for CVD, advancing age unequivocally confers the major risk. One possible explanation for the dominant effect of age on the likelihood for CVD occurrence is that other defined risk factors co-vaxy in number or severity with increasing age and that increasing age contributes to an increased exposure time to these other age-dependent risk factors. For example, the prevalence and the severity of the metabolic syndrome increase with age and it amplifies the age-associated increases in vascular thickness and stiffness. A possible mechanism is the increase in oxidative stress.
Aging is also associated with alterations in a number of structural and functional properties of arteries, including diameter, wall thickness, wall stiffness, vasoconstrictor responses, endothelial function, apoptosis, oxidative stress, and inflammation. Over time, this aging process alters the substrate on which specific pathophysiological disease mechanisms linked toatherosclerosis, become superimposed. Vascular stiffening, for example, is exacerbated by common disorders such as hypertension and diabetes. Aging-associated arterial stiffening results from structural alterationsin the vascular media, including changes in concentration and metabolism of glycosaminoglycans, increase in amount and cross-link grade of collagen, increased thickness of collagen fibrils, reduced elastin content, increased elastin fractures, and calcification resulting in lower expansibility of the vessel. Prominent aging-associated arterial stiffening has been demonstrated in populations with little or no atherosclerosis, indicating that vascular stiffening can occur independently of atherosderosis. However, more recent data indicate that increased large vessel stiffening also occurs in the context of atherosderosis. The link may be that stiffness is governed not only by the structural changes within the matrix, as noted above, but also by endothelial dysfunction resulting in impaired regulation of vascular smooth muscle tone and of other aspects of vascular wall structure/function. Endothelial dysfunction occurs early on in the pathophysiology of atherosclerosis. Thus, there is evidence of a vicious cycle: altered mechanical properties of the vessel wall influence the development of atherosclerosis and the latter, via endothelial cell dysfunction and other mechanisms, influences vascular stiffness. Increased intimal thickening can thus be considered as a risk factor for atherosclerosis. Additional risk factors, including hypertension, smoking, dyslipidemia, diabetes, diet, and genetic factors, can then interact with vascular aging to activate an atherosclerotic plaque, explaining why plaque progression increases with age. Finally, aging is associated with impaired repair mechanisms attributable to exhaustion of bone marrow-derived vascular repair cells.
ITh-W52:21 SMEORRUTMA LCIHTOY LINE STTHE ER OELL DAENRDL YI N - H O S P I T A L R. Bernabei. Chair of Gerontology, Catholic Universi~ of the Sacred Heart,
Rome, Italy Objective: Total cholesterol levels correlate with long-term mortality from all causes among middle-aged persons; however, this association remains controversial in older persons. We studied whether total cholesterol levels predict all-cause in-hospital mortality, independent of frailty and comorbidity, or whether it serves only as a marker of health status, in a series of unselected hospitalized elderly patients. Methods: We analyzed data from a large collaborative observational study, the Italian Group of Phaxmacoepidemiology in the Elderly (GIFA), which collected data on about 34,000 hospitalized patients. A total of 6984 patients aged 65 years or older who had been admitted to 81 participating medical centers during four survey periods (from 1993 to 1998) were enrolled. Patients were divided into four groups based on total cholesterol levels at hospital admission: < 160 mg/dL (n = 2115), 160 to 199 mg/dL (n = 2210), 200 to 239 mg/dL (n = 1719), and _>240 mg/dL (n = 940). We ascertained in-hospital mortality; data about cause of death or death after hospitalization were not gathered. Drugs were coded according to the Anatomical Therapeutic and Chemical codes. Discharge diagnoses were coded according to the International Classification of Diseases, Ninth Edition, Clinical Modification. Comorbidity was quantified using the Charlson comorbidity index. Crude and adjusted odds ratios and 95% confidence intervals for mortality by cholesterol levels were calculated using logistic regression models. Variables considered for adjustment were age, sex, body mass index, smoking, alcohol consumption, Charlson comorbidity index, functional impairment, cognitive impairment, and serum albumin levels. We also performed logistic regression models that stratified the cohort by age and sex. To assess whether the association between serum cholesterol and mortality could be explained by inflammation, we performed an additional logistic regression model that included the erythrocyte sedimentation rate and fibrinogen level. Because the use of statins or any other lipid-lowering agent was very low within the study sample (1.7%), it was not included in our analyses. Results: Patients (mean age, 78 -4- 7) were hospitalized for an average of 15 -4- 10 days. The mean total cholesterol level was 186 -4- 49 mg/dL. A total of 202 patients died during hospitalization. Mortality was inversely related to cholesterol levels (< 160 mg/dL: 5.2% [110/2115]; 160-199 mg/dL: 2.2% [49/2210]; 200-239 mg/dL: 1.6% [27/1719]; and _>240 mg/dL: 1.7% [16/940]; P for linear trend <0.001). After adjustment for potential confounders (demographic characteristics, smoking, alcohol use, indicators of
XIV bztentational Symposium on Atheroscletosis, Rome, Italy, June 18-22, 2006
470
Results: A significant interaction was observed between sex and the MS (p<0.003 for the multiplicative interaction term). Compared to women without the MS, those with the syndrome had a 24% greater LV mass (49.54-12 vs 40.04-10 g/m2.7, p<0.001), while the difference was only 9% in men (50.34-12 vs 46.14-10 g/m 2'7, p=0.003). A greater prevalence of inappropriately high LV mass was found in women (28% vs 5%, p<0.001), but not in men (26% vs 16%, p=0.08), with the MS. After adjustment for the effect of age, body mass index, 24-hour systolic blood pressure, and several confounders, the MS was independently associated with a greater LV mass in women (regression coefficient 15.7 g, p<0.001), but not in men. Women with the MS also had a greater LV relative wall thickness (0.42 vs 0.39, p=0.004) and a depressed a£terload-corrected midwall fractional shortening (94.0% vs 101.0%, p<0.001) than women without the syndrome, while no differences emerged in men. Conclusions: In untreated hypertension, MS has a different impact on LV hypertrophy and function in men and women. The effect of MS is more pronounced in women, and is paxtly independent from the effect of several hemodynamic and non-hemodynamic determinants of LV mass.
I Th-W51:7 I NON-STEROIDAL ANTI-INFLAMMATORY DRUGS U P - R E G U L A T E N A D P H O X I D A S E E X P R E S S I O N IN S P O N T A N E O U S L Y H Y P E R T E N S I V E RATS H. Li I , M. Hortmann I , A. DaJber 2, M. Oelze 2, I. Brausch I , C. Mang I , P.M. Schwarz I , T. Munzel-, U. Forstermann 1 . 1Department of
Pharmacology, Johannes Gutenberg Universi~, Mainz, Germany: 21ntental Medicine II, Johannes Gutenberg Universi~, Mainz, Germany Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation. However, recent studies have associated selective inhibitors of cyclooxygenase 2 with an increased cardiovascular risk and there is concern that this increased risk may be a common feature of all NSAIDs, especially in risk patients. We hypothesized that the major superoxide-producing enzymes, the NADPH oxidases, may be involved in the pathomechanism. Methods: Spontaneously hypertensive rats were treated for two weeks with rofecoxib (10 mg/kg/d), celecoxib (30 mg/kg/d) or diclofenac (5 mg/kg/d). The mRNA expression of the NADPH oxidase subunits p22phox and gp91phox (NOX2), and the gp91phox homologs NOX1 and NOX4 was analysed using quantitative real-time RT-PCR. Superoxide was measured by chemiluminescence with lucigenin or Diogenes. Results: In aorta and heart, the mRNA expression of the NADPH oxidase subunits was markedly increased by the non-selective NSAID diclofenac. A moderate upregulation of NADPH oxidase subunits was also seen with rofecoxib or celecoxib. This expressional upregulation of NADPH oxidase by the NSAIDs was associated with increased superoxide production in aorta and heart. Accordingly, plasma lipid peroxides were increased in parallel. Conclusions: NSAIDs may increase the cardiovascular risk by upregulating NADPH oxidases and increasing oxidative stress. Coxibs produce less oxidative stress than the non-selective didofenac. F u n d i n g : This work was supported by the Collaborative Research Center SFB 553 from the DFG, Bonn, Germany.
Th-W52 Th-W52:l
AGEING
VESSEL-AGING AND MECHANISMS OF ATHEROTHROMBOSIS
E Holvoet. Atherosclerosis arm Metabolism Unit, Department of Molecular arm Cardiovascular Researeh, Katholieke Universiteit Leuven, Belgium Schematically one distinguishes two major types of modifications in the arterial wall: atheromatous plaque formation (atherosclerosis) and agingassociated increase of wall thickness and arterial stiffening (arteriosclerosis). Although epidemiological studies have revealed that high lipid levels, obesity, diabetes, hypertension, smoking, sedentary lifestyle, and genetic factors axe risk factors for CVD, advancing age unequivocally confers the major risk. One possible explanation for the dominant effect of age on the likelihood for CVD occurrence is that other defined risk factors co-vaxy in number or severity with increasing age and that increasing age contributes to an increased exposure time to these other age-dependent risk factors. For example, the prevalence and the severity of the metabolic syndrome increase with age and it amplifies the age-associated increases in vascular thickness and stiffness. A possible mechanism is the increase in oxidative stress.
Aging is also associated with alterations in a number of structural and functional properties of arteries, including diameter, wall thickness, wall stiffness, vasoconstrictor responses, endothelial function, apoptosis, oxidative stress, and inflammation. Over time, this aging process alters the substrate on which specific pathophysiological disease mechanisms linked toatherosclerosis, become superimposed. Vascular stiffening, for example, is exacerbated by common disorders such as hypertension and diabetes. Aging-associated arterial stiffening results from structural alterationsin the vascular media, including changes in concentration and metabolism of glycosaminoglycans, increase in amount and cross-link grade of collagen, increased thickness of collagen fibrils, reduced elastin content, increased elastin fractures, and calcification resulting in lower expansibility of the vessel. Prominent aging-associated arterial stiffening has been demonstrated in populations with little or no atherosclerosis, indicating that vascular stiffening can occur independently of atherosderosis. However, more recent data indicate that increased large vessel stiffening also occurs in the context of atherosderosis. The link may be that stiffness is governed not only by the structural changes within the matrix, as noted above, but also by endothelial dysfunction resulting in impaired regulation of vascular smooth muscle tone and of other aspects of vascular wall structure/function. Endothelial dysfunction occurs early on in the pathophysiology of atherosclerosis. Thus, there is evidence of a vicious cycle: altered mechanical properties of the vessel wall influence the development of atherosclerosis and the latter, via endothelial cell dysfunction and other mechanisms, influences vascular stiffness. Increased intimal thickening can thus be considered as a risk factor for atherosclerosis. Additional risk factors, including hypertension, smoking, dyslipidemia, diabetes, diet, and genetic factors, can then interact with vascular aging to activate an atherosclerotic plaque, explaining why plaque progression increases with age. Finally, aging is associated with impaired repair mechanisms attributable to exhaustion of bone marrow-derived vascular repair cells.
ITh-W52:21 SMEORRUTMA LCIHTOY LINE STTHE ER OELL DAENRDL YI N - H O S P I T A L R. Bernabei. Chair of Gerontology, Catholic Universi~ of the Sacred Heart,
Rome, Italy Objective: Total cholesterol levels correlate with long-term mortality from all causes among middle-aged persons; however, this association remains controversial in older persons. We studied whether total cholesterol levels predict all-cause in-hospital mortality, independent of frailty and comorbidity, or whether it serves only as a marker of health status, in a series of unselected hospitalized elderly patients. Methods: We analyzed data from a large collaborative observational study, the Italian Group of Phaxmacoepidemiology in the Elderly (GIFA), which collected data on about 34,000 hospitalized patients. A total of 6984 patients aged 65 years or older who had been admitted to 81 participating medical centers during four survey periods (from 1993 to 1998) were enrolled. Patients were divided into four groups based on total cholesterol levels at hospital admission: < 160 mg/dL (n = 2115), 160 to 199 mg/dL (n = 2210), 200 to 239 mg/dL (n = 1719), and _>240 mg/dL (n = 940). We ascertained in-hospital mortality; data about cause of death or death after hospitalization were not gathered. Drugs were coded according to the Anatomical Therapeutic and Chemical codes. Discharge diagnoses were coded according to the International Classification of Diseases, Ninth Edition, Clinical Modification. Comorbidity was quantified using the Charlson comorbidity index. Crude and adjusted odds ratios and 95% confidence intervals for mortality by cholesterol levels were calculated using logistic regression models. Variables considered for adjustment were age, sex, body mass index, smoking, alcohol consumption, Charlson comorbidity index, functional impairment, cognitive impairment, and serum albumin levels. We also performed logistic regression models that stratified the cohort by age and sex. To assess whether the association between serum cholesterol and mortality could be explained by inflammation, we performed an additional logistic regression model that included the erythrocyte sedimentation rate and fibrinogen level. Because the use of statins or any other lipid-lowering agent was very low within the study sample (1.7%), it was not included in our analyses. Results: Patients (mean age, 78 -4- 7) were hospitalized for an average of 15 -4- 10 days. The mean total cholesterol level was 186 -4- 49 mg/dL. A total of 202 patients died during hospitalization. Mortality was inversely related to cholesterol levels (< 160 mg/dL: 5.2% [110/2115]; 160-199 mg/dL: 2.2% [49/2210]; 200-239 mg/dL: 1.6% [27/1719]; and _>240 mg/dL: 1.7% [16/940]; P for linear trend <0.001). After adjustment for potential confounders (demographic characteristics, smoking, alcohol use, indicators of
XIV bztentational Symposium on Atheroscletosis, Rome, Italy, June 18-22, 2006