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B-mode detection of subclinical atherosclerosis
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INFLUENCE OF LDL RECEPTOR GENE POLYMORPHISMS ON SERUM LIPID LEVELS AND RESPONSE TO ATORVASTATIN IN SUBJECTS W I T H FAMILIAL AND NON FAMILIAL HYPERCHOLESTEROLEMIA
L.A. Salazar tS, M.H. Hirata 1, S.A. Cavalli 1, E.R. Nakandakare 2, N.A. Forti3, J. Diament 3, S. Giannini3, M.C. Bertolami4, R.D.C. Hirata 1.
JFaculty of Pharmaceutical Sciences, 2Endocrinology Service, 3Heart Institute (InCor), Medical School, University of Sao Paulo; 4Dante Pazzanese Cardiology Institute, Sgzo Paulo, SP, Brazil," SFaculty of Medicine, University of La Frontera, Temuco, Chile We have investigated the allele frequencies and the effect of HincII (exon 12), AvaII (exon 13), and PvuII (intron 15) polymorphisms at the LDL receptor (LDLR) gene on serum lipid levels of 300 white unrelated Brazilians subjects with primary hypercholesterolemia (PH) and 200 normolipidemic controls (NC) by PCR-RFLP. We have also evaluated the LDLR and HMGCoA reductase mRNA levels in mononuclear leukocytes by duplex RT-PCR assay and the response to atorvastatin therapy (10 mg/d, 4-weeks period) in 25 unrelated subjects with heterozygous familial hypercholesterolemia (FH). We found a high frequency ofA+A+(AvaII), H+H+(HincII) and P1PI(PvuII) LDLR homozygous genotypes in the PH subjects when compared to NC group. These genotypes were associated to high levels of total cholesterol and LDL-C in both PH and NC subjects. Atorvastatin significantly reduced serum LDL-C levels and increased LDLR and HMG-CoA reductase mRNA levels in 19 responder FH patients. Whereas, 6 FH patients showed lower LDL-C reduction (<15%), and lower LDLR and HMG-CoA reductase mRNA expression when compared to responders at week 0 and 4. In addition, FH subjects carrying the A+A+(AvaII) and P1PI(PvuII) LDLR genotypes exhibited lower LDLR mRNA expression and lower response to atorvastatin. In summary, this study confirms the significant contribution of the LDLR gene polymorphisms in determining interindividual differences in plasma cholesterol levels in normo and hypercholesterolemic subjects. It also demonstrates an important association between the lipid-lowering response to atorvastatin, LDLR mRNA levels in mononuclear leukocytes and polymorphisms at the LDLR gene in subjects with FH. Grant sponsors: CNPq (474905/01 2) and FAPESP (98/09759 8), Brazil.
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~ - - ~ INFLAMMATORY ENDOTHELIAL CELL MARKERS AND MORBIDITY IN ELDERLY H I G H RISK MEN E.M. Hierkinn , I. Seljeflot, I. Hjermann, H. Arnesen. Ullev&l University
Hospital, Oslo, Norway Circulating endothelial cell adhesion molecules (CAMs) are looked upon as inflammatory markers of endothelial function, and related to the process of athero sclero sis. In the present cross sectional study of 563 men characterized as hypercholesterolemics in 1970 72, we investigated the levels of CAMs as related to cardiovascular morbidity after 25 years. The CAMs measured were vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. The participants were 70 (±2.9) yrs, 34% were smokers. Morbidity was characterized as verified cardiovascular disease (CVD+) (28%), free of CVD (CVD-) and diabetes (15%). In the CVD+ group 56% were on statin treatment. Results (means, ng/mL): No differences in the levels of any CAMs in those presenting with or without CVD were observed: VCAM-I: 585 vs 562 (p-0.162), ICAM-I: 313 vs 307 (p-0.487), E-selectin: 48.5 vs 46.7 (p-0.321). There were also no differences in the levels of CAMs in the individuals on statin treatment compared to non-treated. In diabetics the levels of E-selectin were statistically significantly higher compared to nondiabetics (55.9 vs 45,7 p-0.000). Smokers had significantly elevated levels of ICAM-1 compared to non-smokers (331 vs 298, p-0.000), but lower levels of VCAM-1 (543 vs 583, p-0.011). Conclusion: In the present population of elderly high risk men, no differences in the levels of CAMs in individuals with and without CVD were observed, possibly influenced by the use of statins. Diabetics had significantly elevated levels of E-selectin, whereas smokers presented with elevated levels of ICAM-1, but lower levels of VCAM-1.
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B-MODE DETECTION OF SUBCLINICAL ATHEROSCLEROSIS
~ 7 - ~ RELATIONS BETWEEN CAROTID PLAQUES, INTIMA MEDIA THICKNESS AND MORBIDITY IN ELDERLY MEN W I T H LONGSTANDING HYPERCHOLESTEROLEMIA
H.N. Hodis, W.J. Mack. University of Southern California School of Medicine, Los Angeles, CA, USA
E.M. Hierkinn , L. Bergengen, I. Seljeflot, I. Hjermann, H. Arnesen. Ullevdl
Atherosclerosis is an intima-media process. Arterial wall thickening is the earliest detectable anatomical change in the development and progression of atherosclerosis. Autopsy findings demonstrate that carotid and coronary artery atherosclerosis are significantly correlated. Comparison with excised vessel segments demonstrates that ultrasonographic measurement of carotid IMT is accurate. High resolution B-mode ultrasonography focused on common carotid artery (CCA) IMT is useful for quantifying risk factor relationships to subclinical atherosclerosis. Epidemiological studies demonstrate an association of carotid IMT with cardiovascular risk factors in both men and women indicating that the association between coronary and carotid atherosclerosis depends in part, on exposure of both arterial beds to the same risk factors. Progression of CCA IMT significantly correlates with CAD progression measured by serial quantitative coronary angiography. Progression ofCCA IMT is predictive of clinical events, paralleling coronary atherosclerosis in which change in coronary artery percent diameter stenosis determined by sequential angiography over 2 years predicts future coronary events. The relation between events and progression of carotid IMT is as strong as the relation between events and progression of coronary atherosclerosis determined by angiography. Change in carotid IMT progression in intervention trials mirrors CVD events rates in morbidity/mortality trials. Taken together, data confirm the close association between carotid and coronary atherosclerosis and support the usefulness of B-mode ultrasound measurement of IMT for quantitation of subclinical atherosclerosis in the study of antiatherosclerosis therapies. High resolution B-mode ultrasonography can be performed at any frequency in any population with negligible risk to quantitate subclinical atherosclerosis changes. Over the past 10 years, carotid IMT has been the most robust, highly tested, utilized noninvasive end point for assessing antiatherosclerosis therapies. When high resolution B-mode ultrasound imaging is focused on CCA IMT, small changes in atherosclerosis can be measured. Repeated measurements of IMT as a quantitative variable greatly reduces sample size necessary for study when automated computerized edge detection methodology of image analysis is applied to B-mode images. As such, study duration and sample size required to conduct an intervention trial can be substantially reduced relative to trials that use clinical outcome.
University Hospital, Oslo, Norway Ultrasonic assessments of intima-media thickness (IMT) and atherosclerotic plaques (P1) in the carotid artery are widely used to grade atherosclerosis. In the present cross sectional study 563 men characterized in 1970 72 as hypercholesterolemic, we evaluated the levels of IMT and P1 as related to cardiovascular morbidity after 25 years. The participants were 70 (±2.9) yrs, 34% were smokers. Morbidity was characterized as verified cardiovascular disease (CVD+) and diabetes. Using Acuson 128 with linear transducer, IMT was assessed in the common carotid artery (CCA) (mean IMTCCA (m-IMT); maximum IMTCCA (M-IMT); maximum IMT-bulb). Pl-area, P1height and a Pl-score were also evaluated. Results (means, mm): Those presenting with CVD had higher IMT-bulb compared to those without (1.94 vs 1.84, p-0.053) and also higher Pl-height, Pl-area and the semiquantitative Pl-score (1.60 vs 1.34, p-0.013; 13.81 vs 11.47, p-0.035 and 3.36 vs 2.92, p-0.020, respectively). In diabetics, higher IMT-bulb was found compared to non-diabetics (2.01 vs 1.84, p-0.053) and higher Pl-height and Pl-area than in non-diabetics (1.65 vs 1.37, p-0.03 and 14.79 vs 11.66, p-0.09, respectively). Smokers, independent of the morbidity status, tended to higher M-IMT values compared to non-smokers (1.21 vs 1.15, p-0.079) and especially to higher Pl-area and Pl-score (13.36 vs 11.27, p-0.040 and 3.24 vs 2.91, p-0.045, respectively). In conclusion, in this male population with longstanding hypercholesterolemia, plaque evaluation showed that plaques height and area in addition to a semiquantative plaques score, were more related to CVD, diabetes and smoking than traditional IMT measurements in the carotid artery.
73rd EAS Congress
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INFLUENCE OF LDL RECEPTOR GENE POLYMORPHISMS ON SERUM LIPID LEVELS AND RESPONSE TO ATORVASTATIN IN SUBJECTS W I T H FAMILIAL AND NON FAMILIAL HYPERCHOLESTEROLEMIA
L.A. Salazar tS, M.H. Hirata 1, S.A. Cavalli 1, E.R. Nakandakare 2, N.A. Forti3, J. Diament 3, S. Giannini3, M.C. Bertolami4, R.D.C. Hirata 1.
JFaculty of Pharmaceutical Sciences, 2Endocrinology Service, 3Heart Institute (InCor), Medical School, University of Sao Paulo; 4Dante Pazzanese Cardiology Institute, Sgzo Paulo, SP, Brazil," SFaculty of Medicine, University of La Frontera, Temuco, Chile We have investigated the allele frequencies and the effect of HincII (exon 12), AvaII (exon 13), and PvuII (intron 15) polymorphisms at the LDL receptor (LDLR) gene on serum lipid levels of 300 white unrelated Brazilians subjects with primary hypercholesterolemia (PH) and 200 normolipidemic controls (NC) by PCR-RFLP. We have also evaluated the LDLR and HMGCoA reductase mRNA levels in mononuclear leukocytes by duplex RT-PCR assay and the response to atorvastatin therapy (10 mg/d, 4-weeks period) in 25 unrelated subjects with heterozygous familial hypercholesterolemia (FH). We found a high frequency ofA+A+(AvaII), H+H+(HincII) and P1PI(PvuII) LDLR homozygous genotypes in the PH subjects when compared to NC group. These genotypes were associated to high levels of total cholesterol and LDL-C in both PH and NC subjects. Atorvastatin significantly reduced serum LDL-C levels and increased LDLR and HMG-CoA reductase mRNA levels in 19 responder FH patients. Whereas, 6 FH patients showed lower LDL-C reduction (<15%), and lower LDLR and HMG-CoA reductase mRNA expression when compared to responders at week 0 and 4. In addition, FH subjects carrying the A+A+(AvaII) and P1PI(PvuII) LDLR genotypes exhibited lower LDLR mRNA expression and lower response to atorvastatin. In summary, this study confirms the significant contribution of the LDLR gene polymorphisms in determining interindividual differences in plasma cholesterol levels in normo and hypercholesterolemic subjects. It also demonstrates an important association between the lipid-lowering response to atorvastatin, LDLR mRNA levels in mononuclear leukocytes and polymorphisms at the LDLR gene in subjects with FH. Grant sponsors: CNPq (474905/01 2) and FAPESP (98/09759 8), Brazil.
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~ - - ~ INFLAMMATORY ENDOTHELIAL CELL MARKERS AND MORBIDITY IN ELDERLY H I G H RISK MEN E.M. Hierkinn , I. Seljeflot, I. Hjermann, H. Arnesen. Ullev&l University
Hospital, Oslo, Norway Circulating endothelial cell adhesion molecules (CAMs) are looked upon as inflammatory markers of endothelial function, and related to the process of athero sclero sis. In the present cross sectional study of 563 men characterized as hypercholesterolemics in 1970 72, we investigated the levels of CAMs as related to cardiovascular morbidity after 25 years. The CAMs measured were vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. The participants were 70 (±2.9) yrs, 34% were smokers. Morbidity was characterized as verified cardiovascular disease (CVD+) (28%), free of CVD (CVD-) and diabetes (15%). In the CVD+ group 56% were on statin treatment. Results (means, ng/mL): No differences in the levels of any CAMs in those presenting with or without CVD were observed: VCAM-I: 585 vs 562 (p-0.162), ICAM-I: 313 vs 307 (p-0.487), E-selectin: 48.5 vs 46.7 (p-0.321). There were also no differences in the levels of CAMs in the individuals on statin treatment compared to non-treated. In diabetics the levels of E-selectin were statistically significantly higher compared to nondiabetics (55.9 vs 45,7 p-0.000). Smokers had significantly elevated levels of ICAM-1 compared to non-smokers (331 vs 298, p-0.000), but lower levels of VCAM-1 (543 vs 583, p-0.011). Conclusion: In the present population of elderly high risk men, no differences in the levels of CAMs in individuals with and without CVD were observed, possibly influenced by the use of statins. Diabetics had significantly elevated levels of E-selectin, whereas smokers presented with elevated levels of ICAM-1, but lower levels of VCAM-1.
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B-MODE DETECTION OF SUBCLINICAL ATHEROSCLEROSIS
~ 7 - ~ RELATIONS BETWEEN CAROTID PLAQUES, INTIMA MEDIA THICKNESS AND MORBIDITY IN ELDERLY MEN W I T H LONGSTANDING HYPERCHOLESTEROLEMIA
H.N. Hodis, W.J. Mack. University of Southern California School of Medicine, Los Angeles, CA, USA
E.M. Hierkinn , L. Bergengen, I. Seljeflot, I. Hjermann, H. Arnesen. Ullevdl
Atherosclerosis is an intima-media process. Arterial wall thickening is the earliest detectable anatomical change in the development and progression of atherosclerosis. Autopsy findings demonstrate that carotid and coronary artery atherosclerosis are significantly correlated. Comparison with excised vessel segments demonstrates that ultrasonographic measurement of carotid IMT is accurate. High resolution B-mode ultrasonography focused on common carotid artery (CCA) IMT is useful for quantifying risk factor relationships to subclinical atherosclerosis. Epidemiological studies demonstrate an association of carotid IMT with cardiovascular risk factors in both men and women indicating that the association between coronary and carotid atherosclerosis depends in part, on exposure of both arterial beds to the same risk factors. Progression of CCA IMT significantly correlates with CAD progression measured by serial quantitative coronary angiography. Progression ofCCA IMT is predictive of clinical events, paralleling coronary atherosclerosis in which change in coronary artery percent diameter stenosis determined by sequential angiography over 2 years predicts future coronary events. The relation between events and progression of carotid IMT is as strong as the relation between events and progression of coronary atherosclerosis determined by angiography. Change in carotid IMT progression in intervention trials mirrors CVD events rates in morbidity/mortality trials. Taken together, data confirm the close association between carotid and coronary atherosclerosis and support the usefulness of B-mode ultrasound measurement of IMT for quantitation of subclinical atherosclerosis in the study of antiatherosclerosis therapies. High resolution B-mode ultrasonography can be performed at any frequency in any population with negligible risk to quantitate subclinical atherosclerosis changes. Over the past 10 years, carotid IMT has been the most robust, highly tested, utilized noninvasive end point for assessing antiatherosclerosis therapies. When high resolution B-mode ultrasound imaging is focused on CCA IMT, small changes in atherosclerosis can be measured. Repeated measurements of IMT as a quantitative variable greatly reduces sample size necessary for study when automated computerized edge detection methodology of image analysis is applied to B-mode images. As such, study duration and sample size required to conduct an intervention trial can be substantially reduced relative to trials that use clinical outcome.
University Hospital, Oslo, Norway Ultrasonic assessments of intima-media thickness (IMT) and atherosclerotic plaques (P1) in the carotid artery are widely used to grade atherosclerosis. In the present cross sectional study 563 men characterized in 1970 72 as hypercholesterolemic, we evaluated the levels of IMT and P1 as related to cardiovascular morbidity after 25 years. The participants were 70 (±2.9) yrs, 34% were smokers. Morbidity was characterized as verified cardiovascular disease (CVD+) and diabetes. Using Acuson 128 with linear transducer, IMT was assessed in the common carotid artery (CCA) (mean IMTCCA (m-IMT); maximum IMTCCA (M-IMT); maximum IMT-bulb). Pl-area, P1height and a Pl-score were also evaluated. Results (means, mm): Those presenting with CVD had higher IMT-bulb compared to those without (1.94 vs 1.84, p-0.053) and also higher Pl-height, Pl-area and the semiquantitative Pl-score (1.60 vs 1.34, p-0.013; 13.81 vs 11.47, p-0.035 and 3.36 vs 2.92, p-0.020, respectively). In diabetics, higher IMT-bulb was found compared to non-diabetics (2.01 vs 1.84, p-0.053) and higher Pl-height and Pl-area than in non-diabetics (1.65 vs 1.37, p-0.03 and 14.79 vs 11.66, p-0.09, respectively). Smokers, independent of the morbidity status, tended to higher M-IMT values compared to non-smokers (1.21 vs 1.15, p-0.079) and especially to higher Pl-area and Pl-score (13.36 vs 11.27, p-0.040 and 3.24 vs 2.91, p-0.045, respectively). In conclusion, in this male population with longstanding hypercholesterolemia, plaque evaluation showed that plaques height and area in addition to a semiquantative plaques score, were more related to CVD, diabetes and smoking than traditional IMT measurements in the carotid artery.
73rd EAS Congress