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Total plasma apolipoprotein B-100 levels: a possible efficacy marker for lipid lowering therapy in patients with familial combined hyperlipidemia
Posters II. Lipid Lowering Drugs/Nooel
88
IPl66
KINETICS OF INHIBITION OF HMGCoA REDUCTASE BY A NEW STATIN, ROSWASTATIN
G.A. Hold te W.H.J. Ward, R.G. Davidson, M. Thornton, R. March, + E cTaggart. AstraZeneca. Mereside, Alder& SK10 4TG. UK
Park, Macclesjield,
Cheshire
Therapeutic agents of the statin class lower the circulating levels of atherogenie lipoproteins and thereby retard or possibly reverse the progression of atherosclerosis. These compounds act by inhibition of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoAR), which is a highly regulated enzyme on the biosynthetic pathway to cholesterol and other products. Rosuvastatin is a promising new HMG-CoAR inhibitor, which is currently nearing completion of phase III clinical trials. Here, we describe the characteristics of inhibition of a catalytic fragment of human HMG-CoAR by rosuvastatin. Like other statins, there is “slow binding inhibition”, in that catalytic activity decreases over several minutes in assays started by addition of the enzyme. Inhibition follows competitive kinetics with respect to HMG-CoA and non-competitive kinetics when the other substrate, NADPH, is varied. Rosuvastatin has a high aSinity for HMGCoAR, with an overall inhibition constant (Kt’) of approximately lo-” M. This tight binding reflects a slow regain of enzyme activity (half-life around 5.3 min) after removal of free inhibitor. We have measured the concentrations of statins required to give 50% inhibition (ICsa) of HMG-CoAR in the presence of a fixed concentration of competing HMG-CoA. Rosuvastatin has an ICsc = 5 x 10m9M. This is at least as potent as atorvastatin, cerivastatin and simvaatatin (I& = 8 to 11 x 10e9 M), and more potent than fluvastatin or pravastatin (I& = 28 to 44 x 1O-9 M). Around 6% of the UK population is heterozygotic for a polymorphism where the amino-acid residue IIe-638 of HMG-CoAR is replaced by VaI. We have shown that this change has no significant effect on the kinetics of substrate utilisation, or inhibition by rosuvastatin. We conclude that the characteristics of inhibition by rosuvastatin of both polymorphic variants of human HMG-CoAR favour its choice for treatment of elevated plasma cholesterol levels in patients who are at risk from coronary disease. 1P167 TOTAL PLASMA APOLH’OPROTEIN
B-100 LEVELS: A POSSIBLE EFFICACY MARKER FOR LIPID LOWERING THERAPY IN PATIENTS WITH FAMILIAL COMBINED HYPERLIPIDEMIA
129), pravastatin + ciprofibrate (n = 132), and simvaatatin + ciprofibrate (n = 129). The mortality and morbidity rates, although indicative, could be considered remarkably low: during the S-year period, only 27 patients had a major coronary event which led to coronary death, non-fatal myocardial infarction or revascularization procedures. In these patients (n = 27), the mean percent change in apo B-100 was significantly less than that of LDL cholesterol (-27% vs -36%, p < O.Ol), the mean apo B values were above 150 mgdl (159 f 9 mg/dl) and they remained sigrmicantly higher (p < 0.001) than those of patients without any CAD related event (n = 498) during the 5-year follow-up period (141&8 mg/dl). This was also the case for triglycerides (186 f 12 mg/dl vs 175f9 mg/dl, p < O.Ol), while mean values of LDL cholesterol (138flO mg/dl vs 135f8 mg!dl) and high density lipoprotein cholesterol (4 1f3 mg/dl vs 42*3 mg/dl) were not significantly different in the two groups 0, = NS) during the 5.year follow-up period. The data suggest that total plasma apo B-100 levels with “low” LDL-C concentrations, could be additionally used, not only as a stratification tool at baseline, as suggested by other studies, but as a drug efficacy parameter and treatment goal as well, at least in patients with FCHL which exhibit a high prevalence of hyperapobetalipoproteinemia. This might lead to the use of regimens more effective in inducing both quantitative and qualitative changes in LDL and to a more global approach to CAD risk reduction. Ip1681 DO STATINS IMPROVE HEART RATE VXRIABILITY IN PATIENTS WITH A PREVIOUS MYOCARDIAL INFARCTION? S. Riahi J.H. Christensen, E. Taft, H.A. Skou, E.B. Schmidt. Department -9 of Cardiology, Aalboorg Hospital, Hobrwej, 9000 Aalborg, Denmark
The purpose of the study was to investigate whether statin treatment may have an impact on heart rate variability (HRV). Statins decrease mortality in patients with coronary artery disease (CAD), and the mechanism(s) behind this has not been totally delineated. A decreased HRV is associated with increased risk of future coronary events and sudden cardiac death in patients with CAD. Three hundred and four patients (age 59.9f8.6 years) referred for elective coronary angiography due to suspected CAD were included. Seventy three of the patients (age 61.3~t8.4 years) had a previous myocardial infarction (MI). A 24-h Holter recording was obtained from all patients in order to analyze HRV In patients with a previous MI, HRV was significantly higher in those treated with statins compared to patients not given statins [standard deviation of all normal RR intervals in 24 hours (SDNN) = 131.3 (f24.3 ms) and SDNN = 110.6 (+c30.8 ms), respectively, p = 0.005]. A matching of the patients with respect to serum cholesterol levels also revealed a higher SDNN in patients who had a previous MI and who were on statin treatment [n = 15 pairs, SDNN = 129.3 (f23.1 ms) compared to SDNN = 105.7 (f26.3 ms), p = 0.012). Similar results were seen by matching for serum LDL-cholesterol level [n = 15 pairs, SDNN = 129.7 (f29.5 ms) compared to SDNN = 106.8 (f25.1 ms), p = 0.0261. HRV in patients without previous MI was not affected by statin therapy. In conclusion, the data suggest, that statins might have a beneficial impact on HRV in patients with a previous MI. This could in part explain the reduction in clinical events observed after statin therapy.
VG. Athyros, A.A. Papageorgiou, D.S. Demitriadis, I.G. Minovgidis, A.G. Kontopoulos. Lipid Out-patient Clinic, Division of Cardioiogv, 2nd Prop. Department of Internal Medicine, Aristotelian University, Hippocmtion Hospital, Thessaloniki, Greece
Ip1691 EFFECTS OF SOLUBLE FIBER (ZSPAGHULA HUSK) ON PLASMA LIPIDS. LIPOPROTEINS AND APOLIPOPROTEINS IN MEN WITH ISCHEMIC HEART DISEASE
The estimate of coronary artery disease (CAD) risk based predominantly on low density lipoprotein (LDL) cholesterol levels, which do not provide any information about LDL particle size-atherogenicity, might no longer be enough to stratify dyslipidemic patients at baseline or to be used as the main treatment goal for hypolipidemic treatment in clinical practice. Purpose of the present study was to investigate the possible use of apolipoprotein (apo) B-100 as a marker of hypolipidemic drug treatment efficacy, during long-term (S-year) statin-fibrate co-administration in patients with familial combined hyperlipidemia (FCHL). The study included 525 primary (n = 273, 52%) and secondary (n = 252,48%) CAD prevention patients with FCHL treated for a 5-year period (mean) with four different statin-fibrate combinations (simvastatin 20 mgday or pravastatin 20 mgday plus gemfibrozil 1,200 mgday or ciprofibrate 100 mgday). Distribution of patients assigned to each drug combination was as follows: pravaatatin + gemtibrozil (n = 135), simvastatin + gemfibrozil (n =
R. Solh G. Godas, J.L. Richard, M. Heras, S. Olive, A. Anguera, J. Salas, -, L. Masana. Unitat de Li$ids i Arteriosclerosi, Hospital Universitari de Sant Joan, Facultat de Medicina. Universitat Rovira i Virgili, IRCIS, C/Sant Lloreng 21; 43201- REUS, Spain
Dietary fiber appears to protect against cardiovascular disease (1). Fiber type may affect cardiovascular risk factors such as plasma lipoprotein (1). However, the effect that fiber type has on plasma lipids in high-risk individuals of ischemic heart disease is unknown. To determine the effects of soluble fiber, Ispaghula husk, on plasma lipids, when used in conjunction with a low-fat diet, in men with ischemic heart disease and LDL cholesterol concentration lower than 130 mg/dL. In a randomised, crossover study, we assigned 28 patients (mean&SD age; 61.4f8.6 years) with ischemic heart disease to follow two diets, each for 8 wk: one of the diets contained 10.5 g/day of Ispaghula husk and
72nd EAS Congress
88
IPl66
KINETICS OF INHIBITION OF HMGCoA REDUCTASE BY A NEW STATIN, ROSWASTATIN
G.A. Hold te W.H.J. Ward, R.G. Davidson, M. Thornton, R. March, + E cTaggart. AstraZeneca. Mereside, Alder& SK10 4TG. UK
Park, Macclesjield,
Cheshire
Therapeutic agents of the statin class lower the circulating levels of atherogenie lipoproteins and thereby retard or possibly reverse the progression of atherosclerosis. These compounds act by inhibition of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoAR), which is a highly regulated enzyme on the biosynthetic pathway to cholesterol and other products. Rosuvastatin is a promising new HMG-CoAR inhibitor, which is currently nearing completion of phase III clinical trials. Here, we describe the characteristics of inhibition of a catalytic fragment of human HMG-CoAR by rosuvastatin. Like other statins, there is “slow binding inhibition”, in that catalytic activity decreases over several minutes in assays started by addition of the enzyme. Inhibition follows competitive kinetics with respect to HMG-CoA and non-competitive kinetics when the other substrate, NADPH, is varied. Rosuvastatin has a high aSinity for HMGCoAR, with an overall inhibition constant (Kt’) of approximately lo-” M. This tight binding reflects a slow regain of enzyme activity (half-life around 5.3 min) after removal of free inhibitor. We have measured the concentrations of statins required to give 50% inhibition (ICsa) of HMG-CoAR in the presence of a fixed concentration of competing HMG-CoA. Rosuvastatin has an ICsc = 5 x 10m9M. This is at least as potent as atorvastatin, cerivastatin and simvaatatin (I& = 8 to 11 x 10e9 M), and more potent than fluvastatin or pravastatin (I& = 28 to 44 x 1O-9 M). Around 6% of the UK population is heterozygotic for a polymorphism where the amino-acid residue IIe-638 of HMG-CoAR is replaced by VaI. We have shown that this change has no significant effect on the kinetics of substrate utilisation, or inhibition by rosuvastatin. We conclude that the characteristics of inhibition by rosuvastatin of both polymorphic variants of human HMG-CoAR favour its choice for treatment of elevated plasma cholesterol levels in patients who are at risk from coronary disease. 1P167 TOTAL PLASMA APOLH’OPROTEIN
B-100 LEVELS: A POSSIBLE EFFICACY MARKER FOR LIPID LOWERING THERAPY IN PATIENTS WITH FAMILIAL COMBINED HYPERLIPIDEMIA
129), pravastatin + ciprofibrate (n = 132), and simvaatatin + ciprofibrate (n = 129). The mortality and morbidity rates, although indicative, could be considered remarkably low: during the S-year period, only 27 patients had a major coronary event which led to coronary death, non-fatal myocardial infarction or revascularization procedures. In these patients (n = 27), the mean percent change in apo B-100 was significantly less than that of LDL cholesterol (-27% vs -36%, p < O.Ol), the mean apo B values were above 150 mgdl (159 f 9 mg/dl) and they remained sigrmicantly higher (p < 0.001) than those of patients without any CAD related event (n = 498) during the 5-year follow-up period (141&8 mg/dl). This was also the case for triglycerides (186 f 12 mg/dl vs 175f9 mg/dl, p < O.Ol), while mean values of LDL cholesterol (138flO mg/dl vs 135f8 mg!dl) and high density lipoprotein cholesterol (4 1f3 mg/dl vs 42*3 mg/dl) were not significantly different in the two groups 0, = NS) during the 5.year follow-up period. The data suggest that total plasma apo B-100 levels with “low” LDL-C concentrations, could be additionally used, not only as a stratification tool at baseline, as suggested by other studies, but as a drug efficacy parameter and treatment goal as well, at least in patients with FCHL which exhibit a high prevalence of hyperapobetalipoproteinemia. This might lead to the use of regimens more effective in inducing both quantitative and qualitative changes in LDL and to a more global approach to CAD risk reduction. Ip1681 DO STATINS IMPROVE HEART RATE VXRIABILITY IN PATIENTS WITH A PREVIOUS MYOCARDIAL INFARCTION? S. Riahi J.H. Christensen, E. Taft, H.A. Skou, E.B. Schmidt. Department -9 of Cardiology, Aalboorg Hospital, Hobrwej, 9000 Aalborg, Denmark
The purpose of the study was to investigate whether statin treatment may have an impact on heart rate variability (HRV). Statins decrease mortality in patients with coronary artery disease (CAD), and the mechanism(s) behind this has not been totally delineated. A decreased HRV is associated with increased risk of future coronary events and sudden cardiac death in patients with CAD. Three hundred and four patients (age 59.9f8.6 years) referred for elective coronary angiography due to suspected CAD were included. Seventy three of the patients (age 61.3~t8.4 years) had a previous myocardial infarction (MI). A 24-h Holter recording was obtained from all patients in order to analyze HRV In patients with a previous MI, HRV was significantly higher in those treated with statins compared to patients not given statins [standard deviation of all normal RR intervals in 24 hours (SDNN) = 131.3 (f24.3 ms) and SDNN = 110.6 (+c30.8 ms), respectively, p = 0.005]. A matching of the patients with respect to serum cholesterol levels also revealed a higher SDNN in patients who had a previous MI and who were on statin treatment [n = 15 pairs, SDNN = 129.3 (f23.1 ms) compared to SDNN = 105.7 (f26.3 ms), p = 0.012). Similar results were seen by matching for serum LDL-cholesterol level [n = 15 pairs, SDNN = 129.7 (f29.5 ms) compared to SDNN = 106.8 (f25.1 ms), p = 0.0261. HRV in patients without previous MI was not affected by statin therapy. In conclusion, the data suggest, that statins might have a beneficial impact on HRV in patients with a previous MI. This could in part explain the reduction in clinical events observed after statin therapy.
VG. Athyros, A.A. Papageorgiou, D.S. Demitriadis, I.G. Minovgidis, A.G. Kontopoulos. Lipid Out-patient Clinic, Division of Cardioiogv, 2nd Prop. Department of Internal Medicine, Aristotelian University, Hippocmtion Hospital, Thessaloniki, Greece
Ip1691 EFFECTS OF SOLUBLE FIBER (ZSPAGHULA HUSK) ON PLASMA LIPIDS. LIPOPROTEINS AND APOLIPOPROTEINS IN MEN WITH ISCHEMIC HEART DISEASE
The estimate of coronary artery disease (CAD) risk based predominantly on low density lipoprotein (LDL) cholesterol levels, which do not provide any information about LDL particle size-atherogenicity, might no longer be enough to stratify dyslipidemic patients at baseline or to be used as the main treatment goal for hypolipidemic treatment in clinical practice. Purpose of the present study was to investigate the possible use of apolipoprotein (apo) B-100 as a marker of hypolipidemic drug treatment efficacy, during long-term (S-year) statin-fibrate co-administration in patients with familial combined hyperlipidemia (FCHL). The study included 525 primary (n = 273, 52%) and secondary (n = 252,48%) CAD prevention patients with FCHL treated for a 5-year period (mean) with four different statin-fibrate combinations (simvastatin 20 mgday or pravastatin 20 mgday plus gemfibrozil 1,200 mgday or ciprofibrate 100 mgday). Distribution of patients assigned to each drug combination was as follows: pravaatatin + gemtibrozil (n = 135), simvastatin + gemfibrozil (n =
R. Solh G. Godas, J.L. Richard, M. Heras, S. Olive, A. Anguera, J. Salas, -, L. Masana. Unitat de Li$ids i Arteriosclerosi, Hospital Universitari de Sant Joan, Facultat de Medicina. Universitat Rovira i Virgili, IRCIS, C/Sant Lloreng 21; 43201- REUS, Spain
Dietary fiber appears to protect against cardiovascular disease (1). Fiber type may affect cardiovascular risk factors such as plasma lipoprotein (1). However, the effect that fiber type has on plasma lipids in high-risk individuals of ischemic heart disease is unknown. To determine the effects of soluble fiber, Ispaghula husk, on plasma lipids, when used in conjunction with a low-fat diet, in men with ischemic heart disease and LDL cholesterol concentration lower than 130 mg/dL. In a randomised, crossover study, we assigned 28 patients (mean&SD age; 61.4f8.6 years) with ischemic heart disease to follow two diets, each for 8 wk: one of the diets contained 10.5 g/day of Ispaghula husk and
72nd EAS Congress