- Email: [email protected]
33 Enhanced lipid peroxidation and platelet activation as potential contributors to increased cardiovascular risk in the “low-HDL” phenotype
Abstracts XIXth National Congress, Italian SocieO, f o r the Study o f Athemsclerosis 1.01, 95% I.C. 1.0-1.03, p 0.05) and diastolic blood pressure (OR 0.96, 95% I.C. 0.93-0.99, p 0.035), whereas the MS was excluded (p > 0.9). Conclusions: In hypertension, the MS predicts a more advanced degree of CA, independently from age, sex, blood pressure total cholesterol and smoking. This effect is completely explained by HDL-cholesterol and fasting glucose levels.
['3-'~ FENOFIBRATE IMPROVES REVERSE CHOLESTEROL TRANSPORT IN HYPOALPHALIPOPROTEINEMIA C. Colombo 1 , E. Favari2, F. Bernini 2, L. Calabresi 1, C.R. Sirtori 1 , G. Franceschini 1. 1Center E. Grossi Paoletti, Department of Pha~vzacological
Sciences, Unic,ersiO, of Milan; 2Department of Pha~wzacological and Biological Sciences and Applied (;~emist~3,, Unic,ersi O, of Pa~vm, Ba!v E-mail: cinzia-colombo@ libero.it High density lipoproteins (HDL) are associated with decreased risk o f cardiovascular disease. The protective effect of HDL is mainly due to their major function in reverse cholesterol transport (RCT), the process by which excess cholesterol in peripheral tissues is transported to the liver for excretion. A randomized double-blind trial evaluated the effects of fenofibrate on RCT. Fifty-two patients with hypoalphalipoproteinemia (HDL < 40 mg/dl) were randomized to receive fenofibrate (160 mg/die) or simvastatin (40 mg/die) for 8 weeks. Fenofibrate significantly increased HDL-cholesterol by 29%; apo A-II increased by 7%, while apoA-I did not change. LpA-I decreased significantly and LpA-I:A-II increased by 23%. Simvastatin had no effects on HDL-C or on apoA-I and apoA-II concentrations, while LpA-I:A-II increased. Plasma LCAT concentrations increased significantly after fenofibrate treatment (10%); CETP concentrations significantly increased after both fenofibrate and simvastatin treatment (18% and 9%, respectively). Fenofibrate treatment increased the ability of serum to promote cellular cholesterol effiux in stimulated macrophages by 11%, while simvastatin significantly increased the efflux mediated by the SRB1 receptor by 10%. In conclusion, fenofibrate significantly increases plasma HDL and improves reverse cholesterol transport in H A patients, and is therefore indicated for the treatment o f isolated hypoalphalipoproteinemia.
[•
PHYSICAL ACTIVITY AND CARDIOVASCULAR DISEASE MORTALITY: THE BRISlGHELLA HEART STUDY (BHS)
S. D'Addato 1 , A. Dormi 2, R. Bernardi 1 , C. Borgh i2, A Gaddi 1 . 1 Unic,ersitv
of Bologna; 2please, proc,ide c~liation, Ba!v E-mail: sdaddat [email protected] Aims: to assess the relationship between PA, mad the cardiovascular disease mortality (CVD). Methods: the BHS is a prospective, population-based cohort study that began in 1972. We used data obtained from 1489 men and 1447 women. In the Study men and women were divided into two groups: adults (age ~>29 mad <65 years) and elderly (age ~>65 years). The data about the level of the physical activity intensity was based on the sweat produced by the subjects during daily activity. The PA was divided in two categories: mediumintense (MI) and scarce or nothing (SN). The follow-up was o f 10 years from 1973 to 1983. The role of the PA was studied with a Cox regression model (CRM) introducing the following parameters: age at death or age 10 years after the survey, systolic and diastolic blood pressure (SBP and DBS), body mass index, Total Cholesterol (CT), smoking habit mad PA. Results: During the Follow up for CVD 54 men and 20 women died. Dividing the population by sex and introducing the parameters in the CRM resulted significant for the men: SBR CT and PA, and for the women alone SBR The positive effects o f PA on CVD were observed only in the adult males (OR. 2.81; 95% IC: 1.29-6.10 p < 0.001).The CRM showed that PA is useful in predicting for CVD in the young adult subjects independently from CT and SBR The risk o f CVD death, increased by 29% for every 1 0 m m H g increase of SBP and by 9% for every 10mg/dl of CT, and decreased by 61% in subjects MI PA compared to the population SN PA. The protective effect was not confirmed in the other categories where the SBP (adult women), the DBP and the age (elderly women) and SBP (elderly men) played a prominent role. Conclusions: The study shows the effectiveness of PA in the prevention of CVD, particularly in the male adults.
[•
ENHANCED LIPID PEROXIDATION AND PLATELET ACTIVATION AS POTENTIAL CONTRIBUTORS TO INCREASED CARDIOVASCULAR RISK IN THE "LOW-HDL" PHENOTYPE
G. Davi 1 , E Santilli 1 , A. Ganci 2, C.M. Barbagallo2, L. Pescara 1 , "d Davi 2, A.B. Cefal/12 , S. LattaaazioI , D. Noto 2, G. Ciabattoni 1 , M. Averna2 . 1 ('enter of
$9
ventions aimed at increasing HDL cholesterol levels prevent the progression o f CHD (Whitney EL Ann Intern Med 2005). Anti-atherogenic properties have been recognized for HDL, including protection of low-density lipoproteins from oxidation, thereby minimizing the deleterious consequences o f this process. Our study is aimed at examining whether HDL levels are related to in vivo oxidative stress and platelet activation, as potential contributors to increased cardiovascular risk. Urinary 8-iso-prostaglaaadin (PG)F2alpha and 11-dehydrothromboxane (TX)B2, in vivo markers o f oxidative stress and platelet activation, respectively, were measured in 45 CHD patients with HDL < 35 mg/dL (9 F, 36 M, aged 6 1 ± 9 yrs), compared to 30 CHD patients with HDL > 35 mg/dL (10F, 20 M, aged 6 1 ± 1 0 yrs). Patients with HDL < 35 mg/dL showed significantly higher levels o f 8-iso-PGF2alpha (301 ±163 pg/mg creatinine) and 11 -dehydroTXB2 (620±416 pg/mg creatinine) as compared to patients with high HDL (207±114 and 351±192 pg/mg creatinine, respectively). A significant direct correlation was found between urinary 8-iso- PGF2alpha and 11 -dehydro-TXB2 in both groups o f patients. We conclude that a low HDL phenotype is associated with increased lipid peroxidation and platelet activation, thus providing novel insight into the mechanisms linking low HDL and occurrence of cardiovascular disease.
[ ' ~ INVESTIGATION ON MECHANISM OF CHOLESTEROL EFFLUX IN HUMAN MONOCYTES/MACROPHAGES THP-1 C. Degirolamo 1 , E. Favaxi1 , F. Zimetti 1 , M.R Adorni 1 , I. Zanotti 1 , G.H. Rothblat 2, E Bernini 1 . 1Dip. Scienze Fa~vz. Biol. e (;~im. Appl.,
Unic,ersit?t di Parma; 2please, proc,ide reference, Ball, E-maih [email protected] The reverse cholesterol transport is the process in which excess cholesterol from peripheral tissues is delivered to the liver for its removal from the body. Cholesterol efflux from cells to extracellular acceptors, such as HDL or apolipoproteins, represents the first step o f this process.Cellular cholesterol effiux occurs through different pathways among which ATP-binding cassette transporter (ABCA1)-mediated process and the scavenger receptor B type I (SR-BI)-mediated efflux. This investigation evaluated the contributions given by these two mechanisms to cellular choelsterol effiux in human monocytes/macrophages THP-1, a human cellular model still poorly characterized.Incubation with HDL, an SR-BI acceptors, induced three-fold cholesterol effiux. The pre-treatment o f cells with BLT-1, an SR-BI-specific inhibitor induced a 23% partial inhibition o f efflux. Incubation with apolipoprotein-AI (apoAI), an ABCAl-specific acceptor, induced an 1.5 2-fold increase of effiux in the presence o f the association 22-OH/9cRA. In the same experimental conditions, pre-treatment with probucol, an ABCAl-specific inhibitor, determined a partialinhibition by 20 30%.These results suggest that THP-1 can express an efflux mechanism independent on both ABCA1 and SR-BI.
[•
FLOW MEDIATED DILATION, AORTIC STIFFNESS AND MICROCIRCULATION REHACTIVITY IN RHEUMATOID ARTHRITIS
S. De Marchi, A. Rigoni, M. Prior, E. Arosio. Unit?l Operatic,a di Riabilitazione
Uardioc,ascolare, Unic,ersiO~ of ~'~rona, Ba!v E-maih riabvasc @mail.univr.it Introduction: increased cardiovascular morbidity and mortality is associated with Rheumatoid arthitis (RA). We aimed to study forearm haemodynamics, arterial stiffness and microcirculatory reactivity in patients suffering from rheumatoid arthritis. Materials and Methods: 34 females affected from R A (DAS 3.7±1.1) underwent the tests: laserdoppler (rest and post-ischemic), endothelial-dependent vasodilation measurement and calculation of pulse wave velocity, 34 healthy subjects were matched. Results: microcircolatory flux was reduced in RA (112±45 vs 2 2 0 ± 6 5 UP; p < 0.005), post ischemic flow was lower in R A (235±65 vs 329±76 UP; p < 0 . 0 5 ) ; percentage increase was higher in R A respect healthy subjects (153±12 vs 6 5 ± 1 8 UP; p < 0 . 0 5 ) . Endothelium dependent dilation at humeral artery was impaired in A R (8.2±2 vs 12.5±3%; p < 0 . 0 5 ) . P W V was higher in RA (9.3±0.2 vs 8.4±0.4m/s; p < 0.05). Conclusions: These results suggest the presence o f decrease acral microcirculatory function and reactivity, endothelial dysfunction and increased arterial stiffness. Alterations in vascular bed are extended and can explain the increased incidence of cardiovascular events in these patients.
~ ' ] ORAL ACETYLCYSTEINE INDUCES HAEMODYNAMICS MODIFICATIONS IN DIABETICS WITH PERIPHERAL ARTERIAL DISEASE S. De Maxchi, M. Prior, A. Rigoni, G. Cacici, A. Lechi, E. Arosio. Unit?l
Evcellence on Aging, Unic,ersiO, of (;~ieti "G. D'Atmunzio" and; 2Department of hzte~vml Medicine, Faculo~ of Medicine, Unic,ersiO~ of Pale~vzo, BaO~ E-mail: [email protected]
Operatic,a di Riabilitazione (~trdioc,ascolare, Unic,ersit~'t di ~'~rona, Balv E-maih riabvasc @mail.univr.it
Low levels of high-density lipoprotein (HDL) cholesterol are now identified as a major independent risk factor for coronary heart disease (CHD) and inter-
Introduction: acetylcysteine (ACS) is a molecule with scavenger activity on reactive oxygen species and is involved in glntathione synthesis. We aimed
['3-'~ FENOFIBRATE IMPROVES REVERSE CHOLESTEROL TRANSPORT IN HYPOALPHALIPOPROTEINEMIA C. Colombo 1 , E. Favari2, F. Bernini 2, L. Calabresi 1, C.R. Sirtori 1 , G. Franceschini 1. 1Center E. Grossi Paoletti, Department of Pha~vzacological
Sciences, Unic,ersiO, of Milan; 2Department of Pha~wzacological and Biological Sciences and Applied (;~emist~3,, Unic,ersi O, of Pa~vm, Ba!v E-mail: cinzia-colombo@ libero.it High density lipoproteins (HDL) are associated with decreased risk o f cardiovascular disease. The protective effect of HDL is mainly due to their major function in reverse cholesterol transport (RCT), the process by which excess cholesterol in peripheral tissues is transported to the liver for excretion. A randomized double-blind trial evaluated the effects of fenofibrate on RCT. Fifty-two patients with hypoalphalipoproteinemia (HDL < 40 mg/dl) were randomized to receive fenofibrate (160 mg/die) or simvastatin (40 mg/die) for 8 weeks. Fenofibrate significantly increased HDL-cholesterol by 29%; apo A-II increased by 7%, while apoA-I did not change. LpA-I decreased significantly and LpA-I:A-II increased by 23%. Simvastatin had no effects on HDL-C or on apoA-I and apoA-II concentrations, while LpA-I:A-II increased. Plasma LCAT concentrations increased significantly after fenofibrate treatment (10%); CETP concentrations significantly increased after both fenofibrate and simvastatin treatment (18% and 9%, respectively). Fenofibrate treatment increased the ability of serum to promote cellular cholesterol effiux in stimulated macrophages by 11%, while simvastatin significantly increased the efflux mediated by the SRB1 receptor by 10%. In conclusion, fenofibrate significantly increases plasma HDL and improves reverse cholesterol transport in H A patients, and is therefore indicated for the treatment o f isolated hypoalphalipoproteinemia.
[•
PHYSICAL ACTIVITY AND CARDIOVASCULAR DISEASE MORTALITY: THE BRISlGHELLA HEART STUDY (BHS)
S. D'Addato 1 , A. Dormi 2, R. Bernardi 1 , C. Borgh i2, A Gaddi 1 . 1 Unic,ersitv
of Bologna; 2please, proc,ide c~liation, Ba!v E-mail: sdaddat [email protected] Aims: to assess the relationship between PA, mad the cardiovascular disease mortality (CVD). Methods: the BHS is a prospective, population-based cohort study that began in 1972. We used data obtained from 1489 men and 1447 women. In the Study men and women were divided into two groups: adults (age ~>29 mad <65 years) and elderly (age ~>65 years). The data about the level of the physical activity intensity was based on the sweat produced by the subjects during daily activity. The PA was divided in two categories: mediumintense (MI) and scarce or nothing (SN). The follow-up was o f 10 years from 1973 to 1983. The role of the PA was studied with a Cox regression model (CRM) introducing the following parameters: age at death or age 10 years after the survey, systolic and diastolic blood pressure (SBP and DBS), body mass index, Total Cholesterol (CT), smoking habit mad PA. Results: During the Follow up for CVD 54 men and 20 women died. Dividing the population by sex and introducing the parameters in the CRM resulted significant for the men: SBR CT and PA, and for the women alone SBR The positive effects o f PA on CVD were observed only in the adult males (OR. 2.81; 95% IC: 1.29-6.10 p < 0.001).The CRM showed that PA is useful in predicting for CVD in the young adult subjects independently from CT and SBR The risk o f CVD death, increased by 29% for every 1 0 m m H g increase of SBP and by 9% for every 10mg/dl of CT, and decreased by 61% in subjects MI PA compared to the population SN PA. The protective effect was not confirmed in the other categories where the SBP (adult women), the DBP and the age (elderly women) and SBP (elderly men) played a prominent role. Conclusions: The study shows the effectiveness of PA in the prevention of CVD, particularly in the male adults.
[•
ENHANCED LIPID PEROXIDATION AND PLATELET ACTIVATION AS POTENTIAL CONTRIBUTORS TO INCREASED CARDIOVASCULAR RISK IN THE "LOW-HDL" PHENOTYPE
G. Davi 1 , E Santilli 1 , A. Ganci 2, C.M. Barbagallo2, L. Pescara 1 , "d Davi 2, A.B. Cefal/12 , S. LattaaazioI , D. Noto 2, G. Ciabattoni 1 , M. Averna2 . 1 ('enter of
$9
ventions aimed at increasing HDL cholesterol levels prevent the progression o f CHD (Whitney EL Ann Intern Med 2005). Anti-atherogenic properties have been recognized for HDL, including protection of low-density lipoproteins from oxidation, thereby minimizing the deleterious consequences o f this process. Our study is aimed at examining whether HDL levels are related to in vivo oxidative stress and platelet activation, as potential contributors to increased cardiovascular risk. Urinary 8-iso-prostaglaaadin (PG)F2alpha and 11-dehydrothromboxane (TX)B2, in vivo markers o f oxidative stress and platelet activation, respectively, were measured in 45 CHD patients with HDL < 35 mg/dL (9 F, 36 M, aged 6 1 ± 9 yrs), compared to 30 CHD patients with HDL > 35 mg/dL (10F, 20 M, aged 6 1 ± 1 0 yrs). Patients with HDL < 35 mg/dL showed significantly higher levels o f 8-iso-PGF2alpha (301 ±163 pg/mg creatinine) and 11 -dehydroTXB2 (620±416 pg/mg creatinine) as compared to patients with high HDL (207±114 and 351±192 pg/mg creatinine, respectively). A significant direct correlation was found between urinary 8-iso- PGF2alpha and 11 -dehydro-TXB2 in both groups o f patients. We conclude that a low HDL phenotype is associated with increased lipid peroxidation and platelet activation, thus providing novel insight into the mechanisms linking low HDL and occurrence of cardiovascular disease.
[ ' ~ INVESTIGATION ON MECHANISM OF CHOLESTEROL EFFLUX IN HUMAN MONOCYTES/MACROPHAGES THP-1 C. Degirolamo 1 , E. Favaxi1 , F. Zimetti 1 , M.R Adorni 1 , I. Zanotti 1 , G.H. Rothblat 2, E Bernini 1 . 1Dip. Scienze Fa~vz. Biol. e (;~im. Appl.,
Unic,ersit?t di Parma; 2please, proc,ide reference, Ball, E-maih [email protected] The reverse cholesterol transport is the process in which excess cholesterol from peripheral tissues is delivered to the liver for its removal from the body. Cholesterol efflux from cells to extracellular acceptors, such as HDL or apolipoproteins, represents the first step o f this process.Cellular cholesterol effiux occurs through different pathways among which ATP-binding cassette transporter (ABCA1)-mediated process and the scavenger receptor B type I (SR-BI)-mediated efflux. This investigation evaluated the contributions given by these two mechanisms to cellular choelsterol effiux in human monocytes/macrophages THP-1, a human cellular model still poorly characterized.Incubation with HDL, an SR-BI acceptors, induced three-fold cholesterol effiux. The pre-treatment o f cells with BLT-1, an SR-BI-specific inhibitor induced a 23% partial inhibition o f efflux. Incubation with apolipoprotein-AI (apoAI), an ABCAl-specific acceptor, induced an 1.5 2-fold increase of effiux in the presence o f the association 22-OH/9cRA. In the same experimental conditions, pre-treatment with probucol, an ABCAl-specific inhibitor, determined a partialinhibition by 20 30%.These results suggest that THP-1 can express an efflux mechanism independent on both ABCA1 and SR-BI.
[•
FLOW MEDIATED DILATION, AORTIC STIFFNESS AND MICROCIRCULATION REHACTIVITY IN RHEUMATOID ARTHRITIS
S. De Marchi, A. Rigoni, M. Prior, E. Arosio. Unit?l Operatic,a di Riabilitazione
Uardioc,ascolare, Unic,ersiO~ of ~'~rona, Ba!v E-maih riabvasc @mail.univr.it Introduction: increased cardiovascular morbidity and mortality is associated with Rheumatoid arthitis (RA). We aimed to study forearm haemodynamics, arterial stiffness and microcirculatory reactivity in patients suffering from rheumatoid arthritis. Materials and Methods: 34 females affected from R A (DAS 3.7±1.1) underwent the tests: laserdoppler (rest and post-ischemic), endothelial-dependent vasodilation measurement and calculation of pulse wave velocity, 34 healthy subjects were matched. Results: microcircolatory flux was reduced in RA (112±45 vs 2 2 0 ± 6 5 UP; p < 0.005), post ischemic flow was lower in R A (235±65 vs 329±76 UP; p < 0 . 0 5 ) ; percentage increase was higher in R A respect healthy subjects (153±12 vs 6 5 ± 1 8 UP; p < 0 . 0 5 ) . Endothelium dependent dilation at humeral artery was impaired in A R (8.2±2 vs 12.5±3%; p < 0 . 0 5 ) . P W V was higher in RA (9.3±0.2 vs 8.4±0.4m/s; p < 0.05). Conclusions: These results suggest the presence o f decrease acral microcirculatory function and reactivity, endothelial dysfunction and increased arterial stiffness. Alterations in vascular bed are extended and can explain the increased incidence of cardiovascular events in these patients.
~ ' ] ORAL ACETYLCYSTEINE INDUCES HAEMODYNAMICS MODIFICATIONS IN DIABETICS WITH PERIPHERAL ARTERIAL DISEASE S. De Maxchi, M. Prior, A. Rigoni, G. Cacici, A. Lechi, E. Arosio. Unit?l
Evcellence on Aging, Unic,ersiO, of (;~ieti "G. D'Atmunzio" and; 2Department of hzte~vml Medicine, Faculo~ of Medicine, Unic,ersiO~ of Pale~vzo, BaO~ E-mail: [email protected]
Operatic,a di Riabilitazione (~trdioc,ascolare, Unic,ersit~'t di ~'~rona, Balv E-maih riabvasc @mail.univr.it
Low levels of high-density lipoprotein (HDL) cholesterol are now identified as a major independent risk factor for coronary heart disease (CHD) and inter-
Introduction: acetylcysteine (ACS) is a molecule with scavenger activity on reactive oxygen species and is involved in glntathione synthesis. We aimed