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Atorvastatin inhibits CD40 ligand expression by human platelets
318 ATORVASTATIN INHIBITS H U M A N PLATELETS
XVII S.I.S.A. National Congress CD40 LIGAND EXPRESSION
BY
V Sanguigni*z P P i g n a t e l l i * * , L L e n t i * * , A Bellia*, M Tesauro*, R Lauro* and F V i o l i * *
RELATIONSHIP BETWEEN SOLUBLE CD40 LIGAND (sCD4OL)zOXIDANT STRESS AND CLOTTING A C T I V A T I O N I N PATIENTS AFFECTED BY HYPERCHOLESTEROLEMIA V Sanguigni*, D F e r r o , P Pignatalli ,G A l e s s a n d r o , M L o n g o , F Violi
Dipartimento di Medicina Interne, Universi~ di Rome "Tor Vergata*. Dipartimento di Medicina Sperimentale e Patologia Universit~di Roma "La Sapienza"**.
~Universit~Tor Vergata; Universit~La Sapienza. Rome
Introduction: CD40 ligand is a surface-bound protein, expressed by leucocytes and platelets, that elicits a series of proinflammatory and prothrombotic responses implicated in the atherosclerotic process. Previous studies reported that stetins may have antiinflammatory effect .We performed an in vitro and in vivo study to assess if atorvastatin directly affects CD40 ligand expression by platelets. Methods: Cytofluorimetric analysis of CD40 ligand expression was performed in collagen-stimulated platelets with or without scalar(0.1-10 mM) concentrations of atorvastetin. Clinical trial consisted in randomly assigning 24 patients, affected by polygenic hypercholesterolemia, to diet or atorvastatin 10mg /day. At baseline and after 3 days of treatment serum lipids and collagen-induced platelet CD40 ligand expression were analysed Results: In vitro study demonstrated that atorvastatin dose-dependently inhibited the platelet expression of CD40 ligand induced by collagen. In patients assigned to diet alone no changes of serum lipids and platelet CD40 ligand expression were observed. In atorvastatin-assigned patients no changes of serum lipids but a significant decrease (- 71%, p<0,001) of platelet CD40 ligand expression was detected. Conclusions: This finding provides evidence that inhibition of CD40L by atorvastatin is an early phenomenon, that is independent of its lowering effect.
Previous studies showed in hypercholesterolemic patients elevated circulating levels of sCD40L, a soluble form of a transmembrane protein with proinflammatory and prothrombotic activity. As previous reports demonstrated that CD40L shows proinflammatory activity, via increased expression of oxygen free radicals, the aim of this study was to evaluate in vivo the relation between sCD4OL plasmatic values, oxidative stress, and clotting activation in hypercholesterolemia. We studied 40 subjects (22 males, 18 females, age 41-68 years) affected by type IIa hypercholesterolemia and 20 healthy subjects matched for age and sex. In each subject we evaluated sCD40L (Quantikine CD4O ligand, R&D Systems, Minneapolis, USA), 8-hydroxy-2'-deoxyguanosine (8-OHdG) (Bioxytech 8-OHdG-EIATM Kit), a marker of oxidative stress and plasmatic levels and prothrombin fragment 1+2 ( F l + 2 ) (Enzygnost F1+2, Behringwerke, Marburg, Germany), a marker of thrombin generation. Compared to controls, hypercholesterolemic patients had significantly higher sCD4OL(3.94-0.3 vs. 2.34-0.3 ng/ml; p<0.0og), 8OHdG (3.24-0.5 vs. 1.44-0.5 ng/ml; p < 0.05) and F:[+2 (1.724-0.8 vs. 1.024-0.6 nM; p<0.O03) respect to controls. A significant correlation between sCD40L and 8-OHdG values (R=0.87; p
PROGNOSTIC SIGNIFICANCE OF THE METABOLIC SYNDROME I N ESSENTIAL HYPERTENSION G Schillaci, M Pirro, F Gemelli, G Vaudo, S Marchesi, C PorcellaU, E Mannarino Medicina Interna, Angiologia e Malaltie da Arteriosclerosi, Universit~ degli Studi di Perugia Background: the metabolic syndrome (MS) carries an adverse prognostic significance in the general population, but no prospective data are available in the hypertensive population. Methods: in the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale Study, we followed for up to 11 years (average 4.2 years) 1742 patients with initially untreated essential hypertension without prevalent cardiovascular or renal disease. MS was defined following the NCEP ATP III guidelines. Since waist circumference was not available for all subjects, a body mass index >=28.6 Kg/m2 (M) and >=27.5 Kg/m2 (W) was selected as an index of adiposity, which in our population corresponds to a waist circumference of >=102 cm (M) and >=88 cm (W). Results: the prevalence of MS (hypertension + at least 2 metabolic factors) was 34.9%. During follow-up 162 major cardiovascular events occurred. Event rate was nearly doubled in patients with MS (3.30 vs 1.72 per 100 pt-yrs). Cardiovascular morbidity increased progressively in hypertensive patients with 1, 2, 3, 4 and 5 factors of the MS (1.48, 1.93, 2.83, 3.96, and 4.87 per 100 ptyrs). In a Cox analysis, after adjustment for age, sex, LDL cholesterol, smoking, 24-hour systolic blood pressure, left ventricular hypertrophy, and serum creatinine (all p<0.05), MS was associated to an increased event rate (odds ratio 1.70, 95% CI 1.24-2.34, p<0.OOl). Conclusions: in uncomplicated essential hypertension, MS is an important predictor of cardiovascular morbidity. Such association is independent from the effect of several risk factors and target organ markers.
HIGH INCIDENCE OF PREMATURE CORONARY HEART DISEASE I N FH W I T H CLASS IT MUTATIONS AND POOR RESPONSE TO STATIN TREATMENT R Valente 2, S Martini 1, L Previatolf G Maraglino 2, P Zucchetta 3, MC Marzola3r G Mazzetto 1, I Cortella ~, D Dal Porto ;, A Calabr6t, B Sabini ~, G Crepaldi z. Clinica Medica I ~, Cardiologia 2, Ospedaliera di Padova.
Medicina
Nucleare
13, Azienda
FH depending on Class I I b mutations, FH Padova 1 (D200G) and FH Padova 4 (681-682ins18Ex4) is frequently observed in the Veneto region. In a recent survey on 60 carriers of these mutations (age 454-14 years) we showed premature asymptomatic CHD in 36% of subjects (stress-rest myocardial perfusion SPET) and carotid artery atherosclerosis (IMT > l . 0 m m or carotid plaques) in 63% of subjects (echo-color-Doppler ultrasonography). During two years of follow-up statin treatment (up to 40 rag/day of simvastatin or atorvastatin) failed to achieve ATP I I I goal levels in 90% of cases. Control stress-rest myocardial perfusion SPET has been performed in 15 subjects up to now. About one half of myocardial ischemic areas at baseline disappeared at follow-up ; in the remaining cases ischemic areas were still present. Surprisingly, the most part of subjects with normal baseline myocardial perfusion showed the appearance of an ischemic area after two years. In 4 out of 6 subjects with impairment at control test we found a poor response to statin treatment with total cholesterol levels >300 mg/dl, while in a young female an ischemic area appeared after successful pregnancy. Of the 5 subjects showing disappearance of ischemic areas at control 3 showed a strong decrease of LDL cholesterol during follow-up, one stopped smoking and the other started antihypertensive treatment. These preliminary results suggest the opportunity of careful follow-up, aggressive lipid lowering and treatment of associated risk factors in FH with class 2b mutations.
XVII S.I.S.A. National Congress CD40 LIGAND EXPRESSION
BY
V Sanguigni*z P P i g n a t e l l i * * , L L e n t i * * , A Bellia*, M Tesauro*, R Lauro* and F V i o l i * *
RELATIONSHIP BETWEEN SOLUBLE CD40 LIGAND (sCD4OL)zOXIDANT STRESS AND CLOTTING A C T I V A T I O N I N PATIENTS AFFECTED BY HYPERCHOLESTEROLEMIA V Sanguigni*, D F e r r o , P Pignatalli ,G A l e s s a n d r o , M L o n g o , F Violi
Dipartimento di Medicina Interne, Universi~ di Rome "Tor Vergata*. Dipartimento di Medicina Sperimentale e Patologia Universit~di Roma "La Sapienza"**.
~Universit~Tor Vergata; Universit~La Sapienza. Rome
Introduction: CD40 ligand is a surface-bound protein, expressed by leucocytes and platelets, that elicits a series of proinflammatory and prothrombotic responses implicated in the atherosclerotic process. Previous studies reported that stetins may have antiinflammatory effect .We performed an in vitro and in vivo study to assess if atorvastatin directly affects CD40 ligand expression by platelets. Methods: Cytofluorimetric analysis of CD40 ligand expression was performed in collagen-stimulated platelets with or without scalar(0.1-10 mM) concentrations of atorvastetin. Clinical trial consisted in randomly assigning 24 patients, affected by polygenic hypercholesterolemia, to diet or atorvastatin 10mg /day. At baseline and after 3 days of treatment serum lipids and collagen-induced platelet CD40 ligand expression were analysed Results: In vitro study demonstrated that atorvastatin dose-dependently inhibited the platelet expression of CD40 ligand induced by collagen. In patients assigned to diet alone no changes of serum lipids and platelet CD40 ligand expression were observed. In atorvastatin-assigned patients no changes of serum lipids but a significant decrease (- 71%, p<0,001) of platelet CD40 ligand expression was detected. Conclusions: This finding provides evidence that inhibition of CD40L by atorvastatin is an early phenomenon, that is independent of its lowering effect.
Previous studies showed in hypercholesterolemic patients elevated circulating levels of sCD40L, a soluble form of a transmembrane protein with proinflammatory and prothrombotic activity. As previous reports demonstrated that CD40L shows proinflammatory activity, via increased expression of oxygen free radicals, the aim of this study was to evaluate in vivo the relation between sCD4OL plasmatic values, oxidative stress, and clotting activation in hypercholesterolemia. We studied 40 subjects (22 males, 18 females, age 41-68 years) affected by type IIa hypercholesterolemia and 20 healthy subjects matched for age and sex. In each subject we evaluated sCD40L (Quantikine CD4O ligand, R&D Systems, Minneapolis, USA), 8-hydroxy-2'-deoxyguanosine (8-OHdG) (Bioxytech 8-OHdG-EIATM Kit), a marker of oxidative stress and plasmatic levels and prothrombin fragment 1+2 ( F l + 2 ) (Enzygnost F1+2, Behringwerke, Marburg, Germany), a marker of thrombin generation. Compared to controls, hypercholesterolemic patients had significantly higher sCD4OL(3.94-0.3 vs. 2.34-0.3 ng/ml; p<0.0og), 8OHdG (3.24-0.5 vs. 1.44-0.5 ng/ml; p < 0.05) and F:[+2 (1.724-0.8 vs. 1.024-0.6 nM; p<0.O03) respect to controls. A significant correlation between sCD40L and 8-OHdG values (R=0.87; p
PROGNOSTIC SIGNIFICANCE OF THE METABOLIC SYNDROME I N ESSENTIAL HYPERTENSION G Schillaci, M Pirro, F Gemelli, G Vaudo, S Marchesi, C PorcellaU, E Mannarino Medicina Interna, Angiologia e Malaltie da Arteriosclerosi, Universit~ degli Studi di Perugia Background: the metabolic syndrome (MS) carries an adverse prognostic significance in the general population, but no prospective data are available in the hypertensive population. Methods: in the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale Study, we followed for up to 11 years (average 4.2 years) 1742 patients with initially untreated essential hypertension without prevalent cardiovascular or renal disease. MS was defined following the NCEP ATP III guidelines. Since waist circumference was not available for all subjects, a body mass index >=28.6 Kg/m2 (M) and >=27.5 Kg/m2 (W) was selected as an index of adiposity, which in our population corresponds to a waist circumference of >=102 cm (M) and >=88 cm (W). Results: the prevalence of MS (hypertension + at least 2 metabolic factors) was 34.9%. During follow-up 162 major cardiovascular events occurred. Event rate was nearly doubled in patients with MS (3.30 vs 1.72 per 100 pt-yrs). Cardiovascular morbidity increased progressively in hypertensive patients with 1, 2, 3, 4 and 5 factors of the MS (1.48, 1.93, 2.83, 3.96, and 4.87 per 100 ptyrs). In a Cox analysis, after adjustment for age, sex, LDL cholesterol, smoking, 24-hour systolic blood pressure, left ventricular hypertrophy, and serum creatinine (all p<0.05), MS was associated to an increased event rate (odds ratio 1.70, 95% CI 1.24-2.34, p<0.OOl). Conclusions: in uncomplicated essential hypertension, MS is an important predictor of cardiovascular morbidity. Such association is independent from the effect of several risk factors and target organ markers.
HIGH INCIDENCE OF PREMATURE CORONARY HEART DISEASE I N FH W I T H CLASS IT MUTATIONS AND POOR RESPONSE TO STATIN TREATMENT R Valente 2, S Martini 1, L Previatolf G Maraglino 2, P Zucchetta 3, MC Marzola3r G Mazzetto 1, I Cortella ~, D Dal Porto ;, A Calabr6t, B Sabini ~, G Crepaldi z. Clinica Medica I ~, Cardiologia 2, Ospedaliera di Padova.
Medicina
Nucleare
13, Azienda
FH depending on Class I I b mutations, FH Padova 1 (D200G) and FH Padova 4 (681-682ins18Ex4) is frequently observed in the Veneto region. In a recent survey on 60 carriers of these mutations (age 454-14 years) we showed premature asymptomatic CHD in 36% of subjects (stress-rest myocardial perfusion SPET) and carotid artery atherosclerosis (IMT > l . 0 m m or carotid plaques) in 63% of subjects (echo-color-Doppler ultrasonography). During two years of follow-up statin treatment (up to 40 rag/day of simvastatin or atorvastatin) failed to achieve ATP I I I goal levels in 90% of cases. Control stress-rest myocardial perfusion SPET has been performed in 15 subjects up to now. About one half of myocardial ischemic areas at baseline disappeared at follow-up ; in the remaining cases ischemic areas were still present. Surprisingly, the most part of subjects with normal baseline myocardial perfusion showed the appearance of an ischemic area after two years. In 4 out of 6 subjects with impairment at control test we found a poor response to statin treatment with total cholesterol levels >300 mg/dl, while in a young female an ischemic area appeared after successful pregnancy. Of the 5 subjects showing disappearance of ischemic areas at control 3 showed a strong decrease of LDL cholesterol during follow-up, one stopped smoking and the other started antihypertensive treatment. These preliminary results suggest the opportunity of careful follow-up, aggressive lipid lowering and treatment of associated risk factors in FH with class 2b mutations.