- Email: [email protected]
Role of nitric oxide in patients with established coronary artery disease
74
Bernini
were genotyped for three SNPs in the IL-6 promoter and IL-6 serum concentrations were measured. MI risk was higher with increasing quartiles of IL-6, with high compared to low levels giving an odds-ratio (OR) of 3.4 [95%CI 2.34.1]) for men, with the effects of high IL-6 levels being lesser for women. The risks for men were stronger, and independent from, the effects of CRP which were associated with low ORs. Synergistic interaction, further increasing the MI risks, were found between high IL-6 levels and several metabolic risk factors including smoking. The -598A and -573C alleles were frequent in the population and the -573C was rare with only five homozygous subjects being identified in this study. The -598A allele was significantly associated with lower serum-insulin levels in the male control group but none of these genetic variants influenced MI risk or IL-6 levels. In conclusion, elevated IL-6 is an important risk-marker for MI in men and synergistic interaction with other important riskfactors enhances this effect further.
are on-going. The recent Adult Treatment Panel III (ATP-III) suggests LDLcholesterol as the primary target with a goal <2.6 mmol/1 (<100 mg/dl). A secondary goal is non-HI)L-cholesterol <3.3 mmol/1 (130 mg/dl) in patients where LDL-cholesterol is to goal but plasma triglycerides remain >2.3 mmol/1 (200 mg/dl). This requires intensified statin therapy together with addition of fibrate or nicotinic acid in some cases, with appropriate safety monitoring.
•4--•
ROLE OF VARIOUS ADHESION AND ACTIVATION MOLECULES IN PATIENTS W I T H CORONARY ARTERY DISEASE
G. Dwivedi 1, R. Vijayvergiya 1, A. Grover1, Y.P. Sharma 1, A. Bhatna~ar2, S. Majumdar2. ]Department of Cardiology, 2Department of Experimental
Medicine, PGIMER, Chandigarh, India
•
PLEIOTROPIC ANTIATHEROSCLEROTIC EFFECT OF LIPOPHILIC CALCIUM ANTAGONISTS IN MACROPHAGES E B e r n i n i 1 , N . B a l d i n i 1 , I. Z a n o t t i 1 , M . C a n a v e s i 2, E. Favari 1 , S. Bellosta 2.
1University of Parma," 2University of Milan, Italy Cholesterol esterification and matrix metalloproteinases (MMPs) secretion by macrophages play a major role in plaque composition and stability. Lipophilic calcium antagonists (CA) such as lacidipine and lercanidipine, but not nifedipine, reduce cholesterol esterification and MMPs secretion in cultured macrophages and in vivo animal models. Moreover, cellular functions of activated macrophages may influence atheroma formation. In our studies lercanidipine (10 7 to 1 0 4 M) inhibited from 20 to 50% the release of nitric oxide (NO) produced by iNOS in mouse peritoneal macrophages activated with LPS and interferon y. Lipophilic CA show an high tropism for cellular membranes which provide them with a long lasting pharmacological activity. Consistently we observed that lacidipine and lercanidipine maintain their effect on macrophages after 72h of wash out. In our experiments we tested whether after chronic treatment of ceils the inhibitory effects of these drugs could be observed at concentrations comparable with those observed in man. Our results indicate more than 80% inhibition of cholesterol esterification after incubation of macrophages for nine days with lacidipine or lercanidipine at concentration as low as 10 9 M. At similar concentrations MMPs activity was reduced about 50%. In the same experimental conditions inhibition of NO and TNF-c~ secretion was obtained with drugs concentration of 10 8 and 1 0 ~ M respectively, without signs of toxicity. All together our results support the hypothesis that lipophilic calcium antagonists may have pleiotropic antiatherosclerotic properties potentially relevant in man. Recently the results of ELSA study with lacidipine supported this hypothesis in a clinical setting. ~-~
STATINS: OLD DRUGS AND NEW DEVELOPMENTS THE ROLE OF STATINS IN DIABETIC DYSLIPIDAEMIA
D.J. Betteridge. University College London, UK
Chronic inflammation is the underlying pathologic process in development of atherosclerotic coronary artery disease (CAD). Chronic inflammatory response is associated with the generation of cytokines, which results in increased expression of various adhesion and activation molecules. We estimated levels of various adhesion and activation molecules in peripheral and coronary sinus blood samples in angiographically proven CAD cases and compared it with normal coronary arteries controls. M e t h o d s : Various molecules like CD3 (T cell surface receptor), CDll (receptor for ICAM), CD19 (B cell surface receptor), CD25 (Interleukin-2 Receptor), CD54 (Intercellular adhesion molecule-l), and CD69 (Early activation marker), were estimated in peripheral and coronary sinus blood samples in 20 cases and compared it with 20 controls. Both groups were matched for demographics and conventional CAD risk factors. R e s u l t s : Significant elevation of CD3, CDllb, CD25, CD54 and CD69 were found both in coronary sinus and peripheral blood samples in cases compared to controls (p<0.05). No significant difference was noted for CDlla, C D l l c and CD19 (p>0.1). Only CDllb, CDllc, CD54 and CD69 were elevated in coronary sinus compared to peripheral blood in cases (p<0.05), while in controls CDlla, CD1 lb, CD25, CD54 and CD69 were elevated in coronary sinus compared to peripheral blood (p<0.05). C o n c l u s i o n : Adhesion and activation molecules like CD25, CD54, CD69, CD3, and C D l l b were elevated in CAD patients. There is not much of incremental benefit in estimating various molecules in coronary sinus compared to peripheral blood. Background:
•4-•
ROLE OF NITRIC OXIDE IN PATIENTS W I T H ESTABLISHED CORONARY ARTERY DISEASE
G. Dwivedi 1, R. Vijayvergiya 1, A. Grover1, Y.P. Sharma 1, A. Bhatna~ar2, S. Majumdar2. ]Department of Cardiology, 2Department of Experimental
Medicine, PGIMER, Chnandigarh, India Endothelial dysfunction, which is basically impairment of nitric oxide (NO) dependant vasodilatation, plays an important role in the ischemic manifestation of coronary artery disease (CAD). We estimated level of NO byproducts Reactive Nitrogen Intermediates (RNI) and citrulline in peripheral and coronary sinus blood samples in angiographically proven CAD cases and compared it with normal coronary arteries controls. M e t h o d s : RNI and citrulline levels were estimated in peripheral and coronary sinus blood samples in 20 cases and compared it with 20 controls. Both groups were matched for demographics and conventional CAD risk factors. R e s u l t s : RNI levels were 29.52+20.27 nmol/ml and 27.80+19.89 nmol/ml in coronary and peripheral blood samples respectively in cases (p>0.1). Its levels in controls were 16.18+14.35 nmol/ml and 14.85+13.56 nmol/ml in coronary and peripheral blood samples respectively (p>0.1). Significantly higher value was found both in coronary sinus and peripheral blood samples in cases compared to controls (p<0.05). Citrulline level was 2.42+3.54 mmol/ml and 1.78+1.33 mmol/ml in coronary and peripheral blood samples respectively in cases (p>0.1). Its level in controls was 1.51+0.31 mmol/ml and 1.42+0.28 mmol/ml in coronary and peripheral blood samples respectively (p<0.05). Insignificant higher values were found in cases compared to controls in both coronary and peripheral blood (p>0.1). C o n c l u s i o n : Citrulline and RNI levels were elevated in CAD patients, which is suggestive of endothelial dysfunction. There is no incremental benefit of estimating coronary sinus compared to peripheral blood levels in CAD patients. Background:
Type 2 diabetes is associated with high risk of premature morbidity and mortality from atherosclerosis-related disease. Diabetic dyslipidaemia contributes to this increased risk and is open to therapeutic intervention with lifestyle and lipid-lowering drugs. The major characteristics of the dyslipidaemia are moderate hypertriglyceridaemia and low HI)L-cholesterol with total and LDL-cholesterol similar to non-diabetic subjects. Perhaps statins in the past would not necessarily have been an automatic firstchoice therapy for this type of dyslipidaemia. However qualitative lipoprotein changes in diabetes; the preponderance of small dense LDL such that there are increased numbers of LDL particles and the accumulation of remnant particles are likely to respond to statin therapy. The effect of statin therapy on lipoprotein fractions measured by NMR spectroscopy in type 2 diabetes will be discussed. The major statin trials in secondary prevention point to benefits for diabetic patients on subgroup analysis. The recent Heart Protection Study supports these findings and extends information to primary prevention. In the fibrate secondary prevention trials VAHIT with gemfibrozil was positive whereas BIP was negative. VAHIT contained large numbers of subjects with the metabolic syndrome and type 2 diabetes which may help explain the positive result. Further information on lipid-lowering in specific diabetes populations will be available from CARDS (atorvastatin), ASPEN (atorvastatin) and FIELD (fenofibrate). Perhaps a combination of fibrate therapy (reduction in C-III, increase in lipoprotein lipase and A-I) and statin therapy would be the best approach but no such end-point studies
73rd EAS Congress
Bernini
were genotyped for three SNPs in the IL-6 promoter and IL-6 serum concentrations were measured. MI risk was higher with increasing quartiles of IL-6, with high compared to low levels giving an odds-ratio (OR) of 3.4 [95%CI 2.34.1]) for men, with the effects of high IL-6 levels being lesser for women. The risks for men were stronger, and independent from, the effects of CRP which were associated with low ORs. Synergistic interaction, further increasing the MI risks, were found between high IL-6 levels and several metabolic risk factors including smoking. The -598A and -573C alleles were frequent in the population and the -573C was rare with only five homozygous subjects being identified in this study. The -598A allele was significantly associated with lower serum-insulin levels in the male control group but none of these genetic variants influenced MI risk or IL-6 levels. In conclusion, elevated IL-6 is an important risk-marker for MI in men and synergistic interaction with other important riskfactors enhances this effect further.
are on-going. The recent Adult Treatment Panel III (ATP-III) suggests LDLcholesterol as the primary target with a goal <2.6 mmol/1 (<100 mg/dl). A secondary goal is non-HI)L-cholesterol <3.3 mmol/1 (130 mg/dl) in patients where LDL-cholesterol is to goal but plasma triglycerides remain >2.3 mmol/1 (200 mg/dl). This requires intensified statin therapy together with addition of fibrate or nicotinic acid in some cases, with appropriate safety monitoring.
•4--•
ROLE OF VARIOUS ADHESION AND ACTIVATION MOLECULES IN PATIENTS W I T H CORONARY ARTERY DISEASE
G. Dwivedi 1, R. Vijayvergiya 1, A. Grover1, Y.P. Sharma 1, A. Bhatna~ar2, S. Majumdar2. ]Department of Cardiology, 2Department of Experimental
Medicine, PGIMER, Chandigarh, India
•
PLEIOTROPIC ANTIATHEROSCLEROTIC EFFECT OF LIPOPHILIC CALCIUM ANTAGONISTS IN MACROPHAGES E B e r n i n i 1 , N . B a l d i n i 1 , I. Z a n o t t i 1 , M . C a n a v e s i 2, E. Favari 1 , S. Bellosta 2.
1University of Parma," 2University of Milan, Italy Cholesterol esterification and matrix metalloproteinases (MMPs) secretion by macrophages play a major role in plaque composition and stability. Lipophilic calcium antagonists (CA) such as lacidipine and lercanidipine, but not nifedipine, reduce cholesterol esterification and MMPs secretion in cultured macrophages and in vivo animal models. Moreover, cellular functions of activated macrophages may influence atheroma formation. In our studies lercanidipine (10 7 to 1 0 4 M) inhibited from 20 to 50% the release of nitric oxide (NO) produced by iNOS in mouse peritoneal macrophages activated with LPS and interferon y. Lipophilic CA show an high tropism for cellular membranes which provide them with a long lasting pharmacological activity. Consistently we observed that lacidipine and lercanidipine maintain their effect on macrophages after 72h of wash out. In our experiments we tested whether after chronic treatment of ceils the inhibitory effects of these drugs could be observed at concentrations comparable with those observed in man. Our results indicate more than 80% inhibition of cholesterol esterification after incubation of macrophages for nine days with lacidipine or lercanidipine at concentration as low as 10 9 M. At similar concentrations MMPs activity was reduced about 50%. In the same experimental conditions inhibition of NO and TNF-c~ secretion was obtained with drugs concentration of 10 8 and 1 0 ~ M respectively, without signs of toxicity. All together our results support the hypothesis that lipophilic calcium antagonists may have pleiotropic antiatherosclerotic properties potentially relevant in man. Recently the results of ELSA study with lacidipine supported this hypothesis in a clinical setting. ~-~
STATINS: OLD DRUGS AND NEW DEVELOPMENTS THE ROLE OF STATINS IN DIABETIC DYSLIPIDAEMIA
D.J. Betteridge. University College London, UK
Chronic inflammation is the underlying pathologic process in development of atherosclerotic coronary artery disease (CAD). Chronic inflammatory response is associated with the generation of cytokines, which results in increased expression of various adhesion and activation molecules. We estimated levels of various adhesion and activation molecules in peripheral and coronary sinus blood samples in angiographically proven CAD cases and compared it with normal coronary arteries controls. M e t h o d s : Various molecules like CD3 (T cell surface receptor), CDll (receptor for ICAM), CD19 (B cell surface receptor), CD25 (Interleukin-2 Receptor), CD54 (Intercellular adhesion molecule-l), and CD69 (Early activation marker), were estimated in peripheral and coronary sinus blood samples in 20 cases and compared it with 20 controls. Both groups were matched for demographics and conventional CAD risk factors. R e s u l t s : Significant elevation of CD3, CDllb, CD25, CD54 and CD69 were found both in coronary sinus and peripheral blood samples in cases compared to controls (p<0.05). No significant difference was noted for CDlla, C D l l c and CD19 (p>0.1). Only CDllb, CDllc, CD54 and CD69 were elevated in coronary sinus compared to peripheral blood in cases (p<0.05), while in controls CDlla, CD1 lb, CD25, CD54 and CD69 were elevated in coronary sinus compared to peripheral blood (p<0.05). C o n c l u s i o n : Adhesion and activation molecules like CD25, CD54, CD69, CD3, and C D l l b were elevated in CAD patients. There is not much of incremental benefit in estimating various molecules in coronary sinus compared to peripheral blood. Background:
•4-•
ROLE OF NITRIC OXIDE IN PATIENTS W I T H ESTABLISHED CORONARY ARTERY DISEASE
G. Dwivedi 1, R. Vijayvergiya 1, A. Grover1, Y.P. Sharma 1, A. Bhatna~ar2, S. Majumdar2. ]Department of Cardiology, 2Department of Experimental
Medicine, PGIMER, Chnandigarh, India Endothelial dysfunction, which is basically impairment of nitric oxide (NO) dependant vasodilatation, plays an important role in the ischemic manifestation of coronary artery disease (CAD). We estimated level of NO byproducts Reactive Nitrogen Intermediates (RNI) and citrulline in peripheral and coronary sinus blood samples in angiographically proven CAD cases and compared it with normal coronary arteries controls. M e t h o d s : RNI and citrulline levels were estimated in peripheral and coronary sinus blood samples in 20 cases and compared it with 20 controls. Both groups were matched for demographics and conventional CAD risk factors. R e s u l t s : RNI levels were 29.52+20.27 nmol/ml and 27.80+19.89 nmol/ml in coronary and peripheral blood samples respectively in cases (p>0.1). Its levels in controls were 16.18+14.35 nmol/ml and 14.85+13.56 nmol/ml in coronary and peripheral blood samples respectively (p>0.1). Significantly higher value was found both in coronary sinus and peripheral blood samples in cases compared to controls (p<0.05). Citrulline level was 2.42+3.54 mmol/ml and 1.78+1.33 mmol/ml in coronary and peripheral blood samples respectively in cases (p>0.1). Its level in controls was 1.51+0.31 mmol/ml and 1.42+0.28 mmol/ml in coronary and peripheral blood samples respectively (p<0.05). Insignificant higher values were found in cases compared to controls in both coronary and peripheral blood (p>0.1). C o n c l u s i o n : Citrulline and RNI levels were elevated in CAD patients, which is suggestive of endothelial dysfunction. There is no incremental benefit of estimating coronary sinus compared to peripheral blood levels in CAD patients. Background:
Type 2 diabetes is associated with high risk of premature morbidity and mortality from atherosclerosis-related disease. Diabetic dyslipidaemia contributes to this increased risk and is open to therapeutic intervention with lifestyle and lipid-lowering drugs. The major characteristics of the dyslipidaemia are moderate hypertriglyceridaemia and low HI)L-cholesterol with total and LDL-cholesterol similar to non-diabetic subjects. Perhaps statins in the past would not necessarily have been an automatic firstchoice therapy for this type of dyslipidaemia. However qualitative lipoprotein changes in diabetes; the preponderance of small dense LDL such that there are increased numbers of LDL particles and the accumulation of remnant particles are likely to respond to statin therapy. The effect of statin therapy on lipoprotein fractions measured by NMR spectroscopy in type 2 diabetes will be discussed. The major statin trials in secondary prevention point to benefits for diabetic patients on subgroup analysis. The recent Heart Protection Study supports these findings and extends information to primary prevention. In the fibrate secondary prevention trials VAHIT with gemfibrozil was positive whereas BIP was negative. VAHIT contained large numbers of subjects with the metabolic syndrome and type 2 diabetes which may help explain the positive result. Further information on lipid-lowering in specific diabetes populations will be available from CARDS (atorvastatin), ASPEN (atorvastatin) and FIELD (fenofibrate). Perhaps a combination of fibrate therapy (reduction in C-III, increase in lipoprotein lipase and A-I) and statin therapy would be the best approach but no such end-point studies
73rd EAS Congress