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804 EPICARDIAL FAT AND A RISK OF CORONARY ATHEROSCLEROSIS
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
802 SAFETY AND EFFICACY OF NCX 6560, A NITRIC OXIDE (NO)DONATING ATORVASTATIN, IN A FIRST-INTO-MAN RANDOMISED, DOUBLE-BLIND, PLACEBO- AND ACTIVE-CONTROLLED STUDY P. Pfister1 , J. Djian1 , T. Ferreira1 , R. Maucci2 , J. Croizier1 , P. Tocchetti2 , L. Gheyle3 , S. Mesens3 . 1 NicOx SA, Sophia-Antipolis, France, 2 NicOx Research Institute, Bresso, Italy, 3 SGS Life Science Services, Antwerpen, Belgium NCX 6560, a novel compound releasing both NO and atorvastatin (ATV), was as effective as equimolar atorvastatin on lipid lowering but more effective on anti-thrombotic, anti-inflammatory properties and endothelial function in animal models. The aim of this FIM study was to assess the safety, tolerability, and pharmacokinetics of NCX 6560 and its pharmacodynamic effects on lipids. Multiple ascending oral doses of NCX 6560 (24, 48, 96 and 144 mg od), ATV 40 mg od and placebo were administered for 2 weeks to 48 male healthy subjects with high LDL-C (between 130–180 mg/dL). Subjects were randomized as follows: 8 on active, 2 on control and 2 on placebo in each cohort. Doses were escalated after evaluation of safety, tolerability and pharmacokinetics. Treatment with NCX 6560 was safe and well tolerated and no SAEs or severe AEs were reported. No significant increase in liver enzymes or CK was observed even at the highest dose. A dose-related decrease from baseline in LDL-C (up to 57%), total cholesterol (up to 45%), and Apo B levels (up to 49%) was observed, with 48 mg NCX 6560 and 40 mg ATV showing equiefficacy. The pharmacokinetic profile of ATV following NCX 6560 administration was dose proportional up to 96 mg. After 48 mg NCX 6560, the bioavailability of ATV and its active metabolites was around 50% of the bioavailability following 40 mg ATV. NCX 6560 had the same lipid-lowering effect of equimolar ATV despite a lower exposure to ATV and its active metabolites. 803 ADDITIONAL EFFECTIVENESS OF EZETIMIBE CO ADMINISTERED WITH ATORVASTATIN IN HIGH RISK PATIENTS WITH CORONARY HEART DISEASE AND HYPERCHOLESTEROLEMIA K.A. Nadaraia1 , N.N. Kipshidze2 , T.A. Gegenava1 . 1 Ischemic Heart Diseases, 2 Academician Nodar Kipshidze National Center of Therapy, Tbilisi, Georgia Objective: The aim of our study was to evaluate the additional effectiveness of Ezetimibe add-on therapy in high risk patients with documented coronary heart disease who were not at goals with previous statin therapy. Methods: The including criteria of 127 patients, enrolled in the study were the presence of established CHD, type 2 diabetes and/or other major risk factors, LDL-C >100 mg/dl and <200 mg/dl, high triglycerides (TG) <400 mg/dl. Patients had to have been receiving a stable dose of baseline statin, for at least 4 weeks. At randomization, patients were assigned to switch to ezetimibe/atorvastatin 10 mg/10 mg (Gr.1, 62 patients) or to continue statin therapy with atorvastatin 20 mg (Gr.2, 65 patients). Results: After 16 week follow up the study showed that 72.6% of patients (45 from 62) in Gr.1 achieved LDL-C <100 mg/dl vs 27.7% of patients (18 from 65) in Gr.2 (P < 0.001). 29.0% of patients (18 from 62) from Gr.1 reached more lower LDL-C goal <70 mg/dl vs 4.6% (3 from 65) of patients in Gr.2 (P < 0.01). Patients from Gr.1 experienced statistically significant (P < 0.01) an additional LDL-C, total cholesterol and total cholesterol/HDL-C ratio reductions after 16 weeks of treatment compared with Gr.2: 29.2%, 18.9% and 14.7% vs 12.3%, 7.8% and 6.9%, respectively. Conclusion: According to our study we conclude that for high risk patients with CHD who did not achieve LDL-C goals on their previous statin therapy, ezetimibe 10 mg/atorvastatin 10 mg combination provided superior lipid-lowering efficacy vs the atorvastatin 20 mg monotherapy after 16 weeks of treatment. 804 EPICARDIAL FAT AND A RISK OF CORONARY ATHEROSCLEROSIS G. Chumakova1,2 , N. Veselovskaya2,3 , A. Kozarenko1,2 , O. Gritsenko1 . 1 Internal Medicine, Altay State Medical University, Barnaul, 2 Multifocal Atherosclerosis, Science Research Institute of Complex Problems of Cardiovascular Diseases SD RAMS, Kemerovo, 3 Cardiologycal, Altay Regional Cardiology Dispensaries, Barnaul, Russia Objective: To study the correlation between the thickness of epicardial fat (TEF) with neurohumoral activity of visceral fat and coronary atherosclerosis. Materials and Methods: The study included 80 patients with angina. All patients were measured level of leptin, adiponectin, resistin. TEF was assessed by echocardiography. Group 1 − (38 attendees) with TEF more than 7 mm, Group 2 − (42 attendees) with TEF less than 7 mm. Results: TEF in group 1 was 9.5±1.3 mm and waist circumference (WC) 106±4.3 cm; in group 2 TEF was 5.4±0.5 mm and WC 99±5.1 cm. In group 1 resistin levels were 78.3±3.1, in group 2 − 61.3±2.1 ng/ml, the levels of resistin − 11.8±1.6 and 8.2±0.6 ng/ml, respectively, levels of adiponectin − 4.1±0.2 and 7.1±0.5 mkg/mmol. All differences are significant with p < 0.05. Correlation analysis showed that TEF in group 1 had correlation with the levels of leptin and resistin (r = 0.68; p < 0.01 and r = 0.61; p < 0.01) and adiponectin
169
(r = −0.56; p < 0.01). Correlation of these indices with WC were less close, and not always reliable (r = 0.23; p < 0.05; r = 0.18; p > 0.05; r = −0.27; p < 0.05 respectively). Revealed that patients with damage of the single coronary artery TEF was 5.6±0.3 mm, two arteries − 7.8±0.5 mm, and three arteries − 10.1±0.4 mm (p < 0.05). Average of WC in the group with a 3-coronary vascular lesions was 104±8.1 cm, with a 2-vascular lesions 102±7.8 cm, with 1-vascular 101±5.5 cm (p > 0.05). Thus, Perhaps increasing of hormonal activity of EF may be one of the key links in the progression of coronary atherosclerosis. 805 CANNABINOID RECEPTOR 1 DOES NOT CORRELATE WITH PERIADVENTITIAL FAT ADIPONECTIN AND VISFATIN EXPRESSION IN AORTIC AND CORONARY ATHEROSCLEROTIC LESIONS S.G. Spiroglou1 , C.G. Kostopoulos1 , P.P. Keryttopoulos2 , J.N. Varakis1 , H.H. Papadaki1 . 1 University of Patras, Patras, 2 General Hospital of Veroia, Veroia, Greece Introduction: The endocannabinoid system influence on cardiovascular function is being extensively investigated. Its actions through cannabinoid receptor 1 (CB1) on adipokine expression and the atherosclerotic process are of special interest. We investigated the expression of CB1, adiponectin and visfatin in periaortic and pericoronary fat, correlations among them, as well as with aortic and coronary atherosclerosis. Methods: Paraffin embedded samples of human abdominal aortas (n = 41) and left coronary arteries (n = 41), including periadventitial fat, were evaluated for CB1, adiponectin and visfatin expression using immunohistochemistry. Atherosclerosis was assessed using the AHA classification. SPSS for Windows was used for statistical analysis. Results: CB1 was expressed in 36/41 and 30/41 periaortic and pericoronary adipose tissue samples, respectively. Adiponectin was expressed in 37/41 and 39/41 periaortic and pericoronary fat samples, respectively, while visfatin was expressed in 40/41 and 41/41 samples, respectively. No statistically significant correlation was found between CB1 and adiponectin and visfatin expression in periadventitial fat. Atherosclerosis was detected in 35/41 abdominal aortas and in 37/41 coronary arteries. CB1 was not correlated with aortic and coronary atherosclerosis. Adiponectin expression in periaortic and pericoronary fat was negatively correlated with aortic (r = −0.705, p < 0.001) and coronary (r = −0.385, p = 0.013) atherosclerosis, respectively. Visfatin expression was positively correlated with aortic (r = 0.568, p < 0.001) and coronary (r = 0.321, p = 0.040) atherosclerosis. Conclusions: Local adiponectin expression in periadventitial fat is negatively correlated with atherosclerosis, while visfatin expression is positively correlated with atherosclerosis. CB1 expression in periadventitial fat does not correlate either with adiponectin and visfatin expression or atherosclerosis itself. Further studies are required to elucidate the role of the endocannabinoid system on adipokine expression and atherosclerosis. 806 VALUE OF THE HYPERURICAEMIA IN PATIENTS WITH CHRONIC HEART FAILURE V. Larina, B. Bart. Outpatient, Russian State Medical University, Moscow, Russia Aim: This study investigates whether hyperuricaemia (defined as serum UA level 360 mcmol/l for women and 418 mcmol/l for men) extends its clinical and prognostic value on population of elderly patients with CHF. Methods: We studied 211 consecutive adult outpatients above age 60 years with stable CHF (135 men, age: 69 (65−75) years, NYHA class II/III/IV: 76/95/40, LVEF: 46.5 (34−57)%). All patients were under optimal therapy with ACEinhibitor, beta-blockers, diuretics, and digoxin when necessary. Results: Serum UA level (median: 400 (337–490) mcmol/l, range: 131–714 mcmol/l) increased in parallel to CHF severity expressed as NYHA class (366 (313–421) vs. 400 (335–489) vs. 483 (397–540) mcmol/l NYHA II vs. III vs. IV; NYHA II, III vs. IV, p = 0.006, c2 = 7.47) and inversely correlated with LVEF (r = −0.26, p < 0.001), current admission for cardiovascular diseases (r = 0.23, p < 0.001), but not with age (r = 0.04, p = 0.614), glucose serum (r = 0.04, p = 0.614) and renal function (expressed as creatinine clearance calculated from Cockcroft-Gault formula; r = −0.102, p = 0.139). Hyperuricaemia was detected in 111 (52%) patients. During follow-up of median 1.6 (0.8−4.3) years 35% patients with hyperuricaemia and 22% patients without hyperuricaemia died (p = 0.035, c2 = 4.42, HR = 1.82). Kaplan-Meier analysis revealed that uric acid levels effectively risk stratified elderly CHF patients for cardiac events. Conclusion: In elderly patients with CHF hyperuricaemia related to poor prognosis and current admission for cardiovascular diseases. These findings suggest that measurement of uric acid levels in elderly CHF patients may add valuable prognostic information to predict cardiac events.
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
802 SAFETY AND EFFICACY OF NCX 6560, A NITRIC OXIDE (NO)DONATING ATORVASTATIN, IN A FIRST-INTO-MAN RANDOMISED, DOUBLE-BLIND, PLACEBO- AND ACTIVE-CONTROLLED STUDY P. Pfister1 , J. Djian1 , T. Ferreira1 , R. Maucci2 , J. Croizier1 , P. Tocchetti2 , L. Gheyle3 , S. Mesens3 . 1 NicOx SA, Sophia-Antipolis, France, 2 NicOx Research Institute, Bresso, Italy, 3 SGS Life Science Services, Antwerpen, Belgium NCX 6560, a novel compound releasing both NO and atorvastatin (ATV), was as effective as equimolar atorvastatin on lipid lowering but more effective on anti-thrombotic, anti-inflammatory properties and endothelial function in animal models. The aim of this FIM study was to assess the safety, tolerability, and pharmacokinetics of NCX 6560 and its pharmacodynamic effects on lipids. Multiple ascending oral doses of NCX 6560 (24, 48, 96 and 144 mg od), ATV 40 mg od and placebo were administered for 2 weeks to 48 male healthy subjects with high LDL-C (between 130–180 mg/dL). Subjects were randomized as follows: 8 on active, 2 on control and 2 on placebo in each cohort. Doses were escalated after evaluation of safety, tolerability and pharmacokinetics. Treatment with NCX 6560 was safe and well tolerated and no SAEs or severe AEs were reported. No significant increase in liver enzymes or CK was observed even at the highest dose. A dose-related decrease from baseline in LDL-C (up to 57%), total cholesterol (up to 45%), and Apo B levels (up to 49%) was observed, with 48 mg NCX 6560 and 40 mg ATV showing equiefficacy. The pharmacokinetic profile of ATV following NCX 6560 administration was dose proportional up to 96 mg. After 48 mg NCX 6560, the bioavailability of ATV and its active metabolites was around 50% of the bioavailability following 40 mg ATV. NCX 6560 had the same lipid-lowering effect of equimolar ATV despite a lower exposure to ATV and its active metabolites. 803 ADDITIONAL EFFECTIVENESS OF EZETIMIBE CO ADMINISTERED WITH ATORVASTATIN IN HIGH RISK PATIENTS WITH CORONARY HEART DISEASE AND HYPERCHOLESTEROLEMIA K.A. Nadaraia1 , N.N. Kipshidze2 , T.A. Gegenava1 . 1 Ischemic Heart Diseases, 2 Academician Nodar Kipshidze National Center of Therapy, Tbilisi, Georgia Objective: The aim of our study was to evaluate the additional effectiveness of Ezetimibe add-on therapy in high risk patients with documented coronary heart disease who were not at goals with previous statin therapy. Methods: The including criteria of 127 patients, enrolled in the study were the presence of established CHD, type 2 diabetes and/or other major risk factors, LDL-C >100 mg/dl and <200 mg/dl, high triglycerides (TG) <400 mg/dl. Patients had to have been receiving a stable dose of baseline statin, for at least 4 weeks. At randomization, patients were assigned to switch to ezetimibe/atorvastatin 10 mg/10 mg (Gr.1, 62 patients) or to continue statin therapy with atorvastatin 20 mg (Gr.2, 65 patients). Results: After 16 week follow up the study showed that 72.6% of patients (45 from 62) in Gr.1 achieved LDL-C <100 mg/dl vs 27.7% of patients (18 from 65) in Gr.2 (P < 0.001). 29.0% of patients (18 from 62) from Gr.1 reached more lower LDL-C goal <70 mg/dl vs 4.6% (3 from 65) of patients in Gr.2 (P < 0.01). Patients from Gr.1 experienced statistically significant (P < 0.01) an additional LDL-C, total cholesterol and total cholesterol/HDL-C ratio reductions after 16 weeks of treatment compared with Gr.2: 29.2%, 18.9% and 14.7% vs 12.3%, 7.8% and 6.9%, respectively. Conclusion: According to our study we conclude that for high risk patients with CHD who did not achieve LDL-C goals on their previous statin therapy, ezetimibe 10 mg/atorvastatin 10 mg combination provided superior lipid-lowering efficacy vs the atorvastatin 20 mg monotherapy after 16 weeks of treatment. 804 EPICARDIAL FAT AND A RISK OF CORONARY ATHEROSCLEROSIS G. Chumakova1,2 , N. Veselovskaya2,3 , A. Kozarenko1,2 , O. Gritsenko1 . 1 Internal Medicine, Altay State Medical University, Barnaul, 2 Multifocal Atherosclerosis, Science Research Institute of Complex Problems of Cardiovascular Diseases SD RAMS, Kemerovo, 3 Cardiologycal, Altay Regional Cardiology Dispensaries, Barnaul, Russia Objective: To study the correlation between the thickness of epicardial fat (TEF) with neurohumoral activity of visceral fat and coronary atherosclerosis. Materials and Methods: The study included 80 patients with angina. All patients were measured level of leptin, adiponectin, resistin. TEF was assessed by echocardiography. Group 1 − (38 attendees) with TEF more than 7 mm, Group 2 − (42 attendees) with TEF less than 7 mm. Results: TEF in group 1 was 9.5±1.3 mm and waist circumference (WC) 106±4.3 cm; in group 2 TEF was 5.4±0.5 mm and WC 99±5.1 cm. In group 1 resistin levels were 78.3±3.1, in group 2 − 61.3±2.1 ng/ml, the levels of resistin − 11.8±1.6 and 8.2±0.6 ng/ml, respectively, levels of adiponectin − 4.1±0.2 and 7.1±0.5 mkg/mmol. All differences are significant with p < 0.05. Correlation analysis showed that TEF in group 1 had correlation with the levels of leptin and resistin (r = 0.68; p < 0.01 and r = 0.61; p < 0.01) and adiponectin
169
(r = −0.56; p < 0.01). Correlation of these indices with WC were less close, and not always reliable (r = 0.23; p < 0.05; r = 0.18; p > 0.05; r = −0.27; p < 0.05 respectively). Revealed that patients with damage of the single coronary artery TEF was 5.6±0.3 mm, two arteries − 7.8±0.5 mm, and three arteries − 10.1±0.4 mm (p < 0.05). Average of WC in the group with a 3-coronary vascular lesions was 104±8.1 cm, with a 2-vascular lesions 102±7.8 cm, with 1-vascular 101±5.5 cm (p > 0.05). Thus, Perhaps increasing of hormonal activity of EF may be one of the key links in the progression of coronary atherosclerosis. 805 CANNABINOID RECEPTOR 1 DOES NOT CORRELATE WITH PERIADVENTITIAL FAT ADIPONECTIN AND VISFATIN EXPRESSION IN AORTIC AND CORONARY ATHEROSCLEROTIC LESIONS S.G. Spiroglou1 , C.G. Kostopoulos1 , P.P. Keryttopoulos2 , J.N. Varakis1 , H.H. Papadaki1 . 1 University of Patras, Patras, 2 General Hospital of Veroia, Veroia, Greece Introduction: The endocannabinoid system influence on cardiovascular function is being extensively investigated. Its actions through cannabinoid receptor 1 (CB1) on adipokine expression and the atherosclerotic process are of special interest. We investigated the expression of CB1, adiponectin and visfatin in periaortic and pericoronary fat, correlations among them, as well as with aortic and coronary atherosclerosis. Methods: Paraffin embedded samples of human abdominal aortas (n = 41) and left coronary arteries (n = 41), including periadventitial fat, were evaluated for CB1, adiponectin and visfatin expression using immunohistochemistry. Atherosclerosis was assessed using the AHA classification. SPSS for Windows was used for statistical analysis. Results: CB1 was expressed in 36/41 and 30/41 periaortic and pericoronary adipose tissue samples, respectively. Adiponectin was expressed in 37/41 and 39/41 periaortic and pericoronary fat samples, respectively, while visfatin was expressed in 40/41 and 41/41 samples, respectively. No statistically significant correlation was found between CB1 and adiponectin and visfatin expression in periadventitial fat. Atherosclerosis was detected in 35/41 abdominal aortas and in 37/41 coronary arteries. CB1 was not correlated with aortic and coronary atherosclerosis. Adiponectin expression in periaortic and pericoronary fat was negatively correlated with aortic (r = −0.705, p < 0.001) and coronary (r = −0.385, p = 0.013) atherosclerosis, respectively. Visfatin expression was positively correlated with aortic (r = 0.568, p < 0.001) and coronary (r = 0.321, p = 0.040) atherosclerosis. Conclusions: Local adiponectin expression in periadventitial fat is negatively correlated with atherosclerosis, while visfatin expression is positively correlated with atherosclerosis. CB1 expression in periadventitial fat does not correlate either with adiponectin and visfatin expression or atherosclerosis itself. Further studies are required to elucidate the role of the endocannabinoid system on adipokine expression and atherosclerosis. 806 VALUE OF THE HYPERURICAEMIA IN PATIENTS WITH CHRONIC HEART FAILURE V. Larina, B. Bart. Outpatient, Russian State Medical University, Moscow, Russia Aim: This study investigates whether hyperuricaemia (defined as serum UA level 360 mcmol/l for women and 418 mcmol/l for men) extends its clinical and prognostic value on population of elderly patients with CHF. Methods: We studied 211 consecutive adult outpatients above age 60 years with stable CHF (135 men, age: 69 (65−75) years, NYHA class II/III/IV: 76/95/40, LVEF: 46.5 (34−57)%). All patients were under optimal therapy with ACEinhibitor, beta-blockers, diuretics, and digoxin when necessary. Results: Serum UA level (median: 400 (337–490) mcmol/l, range: 131–714 mcmol/l) increased in parallel to CHF severity expressed as NYHA class (366 (313–421) vs. 400 (335–489) vs. 483 (397–540) mcmol/l NYHA II vs. III vs. IV; NYHA II, III vs. IV, p = 0.006, c2 = 7.47) and inversely correlated with LVEF (r = −0.26, p < 0.001), current admission for cardiovascular diseases (r = 0.23, p < 0.001), but not with age (r = 0.04, p = 0.614), glucose serum (r = 0.04, p = 0.614) and renal function (expressed as creatinine clearance calculated from Cockcroft-Gault formula; r = −0.102, p = 0.139). Hyperuricaemia was detected in 111 (52%) patients. During follow-up of median 1.6 (0.8−4.3) years 35% patients with hyperuricaemia and 22% patients without hyperuricaemia died (p = 0.035, c2 = 4.42, HR = 1.82). Kaplan-Meier analysis revealed that uric acid levels effectively risk stratified elderly CHF patients for cardiac events. Conclusion: In elderly patients with CHF hyperuricaemia related to poor prognosis and current admission for cardiovascular diseases. These findings suggest that measurement of uric acid levels in elderly CHF patients may add valuable prognostic information to predict cardiac events.