- Email: [email protected]
3WS20-6 Is liver the culprit of diabetic dyslipidemia?
190
Wednesday October 1, 2003: Workshop 3WS20 Diabetic Dyslipidemia
Methods and Results: For the micro-level, we obtained patient-level costs with components, and also used standardized fee data as proxy cost indicators. The costs of atherosclerosis-related diseases varied across cases even after casemix adjustment, and human resources occupied a large part of the cost. The macro-level healthcare expenditure is lower in Japan than other OECD countries, but efficiency parameters are poor, as hospital stay in Japan is extraordinarily longer. Contrarily, hospital employment per bed is 0.8 FTE in Japan, 3 to 7 times lower than others, likewise other resource parameters. Discussion and Conclusion: The current standards often require the more resources for the quality of care. A shortsighted policy relying on cutting cost and shortening hospital stay could deteriorate quality or impose net burden to the society through cost shifts, without balanced policy measures. The Japanese unique system could be resultant from well adaptation for efficiency; However, the causal mechanisms among long hospital stay, low resource level, micro-level quality and low macro-expenditure are still to be modeled and investigated. More harmonized efforts for health care cost and performance database is necessary for evidence-based policy discussion.
3WS20 DIABETIC DYSLIPIDEMIA 3WS20-1
Increased atherosclerosis in type 1 diabetes - Are lipids and lipoproteins irrelevant?
H. Colhoun. University College London, London, United Kingdom Type 1 diabetes is associated with a greatly increased coronary heart disease risk. Compared to the general population the relative risk is greater in women than men so that the sex difference in coronary heart disease is abolished in diabetes. Using electron beam CT measures of coronary artery atherosclerosis we have confirmed that this is an atherosclerotic phenomenon. Given that, in the absence of renal failure, the lipid profile is often normal in type 1 diabetes, other more subtle lipoprotein related abnormalities have been sought. We have shown that, whilst cholesteryl ester transfer protein (CETP) activity is increased in type 1 diabetes, the actual mass of cholesteryl esters transferred is not. However, type 1 diabetes is associated with a substantial increase in phospholipid transfer protein activity (PLTP) and to a lesser extent PLTP mass. There is also evidence that some anti-atherogenic lipoprotein changes in diabetic men (such as increased average LDL size) are not present in diabetic women. Other abnormalities such as decreased protection against LDL oxidation, as suggested by reduced paraoxonase activity, may also be important. The relevance of these to the increased risk of CHD in diabetes and the loss of the sex difference in CHD will be discussed. Finally the role of lipid lowering therapy in reducing this risk in type 1 diabetes will be reviewed. 3WS20-3
Postprandial lipemia and endothelial dysfunction in dyslipidemia and diabetes
A.L. Catapano. Dept. Pharmacological Sciences, Center for the Study of Atherosclerosis, Italy Several clinical and experimental data suggest that elevated postprandial lipemia is related to the presence of coronary artery disease (CAD) and is an independent risk factor for coronary atherosclerosis. The role of the endothelium in the pathogenesis of cardiovascular diseases is well recognised. A close correlation exists between the presence of cardiovascular risk factors and a decrease of the endothelial vasodilator function. Endothelial function is reduced in patients with myocardial ischemia, with CAD or presenting with diabetes. Furthermore endothelial dysfunction predicts the recurrence of cardiovascular events and progression of atherosclerotic disease. During the post prandial lipemia the endothelial function is transiently reduced in normocholesterolemic and in hyperlipidemic subjects. The lipoprotein fraction(s) that may be involved in determining such an effect are unknown. Fasting remant lipoprotein (RLPs) levels correlate directly with the endothelial dysfunction in peripheral and coronary arteries. Furthermore RLPs plasma levels are strongly associated with angiographically verified progression of focal coronary atherosclerosis and their lowering with gemfibrozil prevents vein graft stenosis. In addition RLPs levels are significantly increased after a fat loading. This burden of evidence prompted us to investigate whether changes in RLPs plasma levels during the postprandial phase affect endothelial function, a surrogate index of atherosclerotic disease. Our data suggest that remnant lipoproteins are one of the major determinants of endothelial dysfunction during the post prandial phase. Furthermore we addressed in vitro the effect of TG rich lipoproteins in the induction of specific genes in human endothelial cells
by using the microarray approach. The data indicate that VLDL induce some 170 genes, the most relevant to the atherosclerotic process will be discussed. 3WS20-4
Dyslipidaemia, inflammation and endothelial dysfunction in diabetes mellitus
K. Tan. Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR Endothelial dysfunction is an early event in atherogenesis and precedes the thickening of the intima and the formation of atherosclerotic plaques. Endothelial dysfunction has also been implicated in the pathogenesis of both microand macroangiopathy in diabetes and has been consistently demonstrated in patients with type 1 and type 2 diabetes mellitus. Markers of endothelial dysfunction (eg. von Willebrand Factor, vascular cell adhesion molecules) are elevated in patients with diabetes mellitus and vasodilation mediated by endothelium-derived nitric oxide is impaired. The aetiology of endothelial dysfunction in diabetes is complex and it has been shown that more than one mechanism is involved. We and others have demonstrated that diabetic dyslipidaemia plays a significant role. The increase in the concentration of small dense LDL, enhanced susceptibility of LDL to oxidation and exaggerated postprandial lipaemia found in patients with type 2 diabetes mellitus are associated with impairment of endothelium-dependent vasodilation. We have shown that treatment with atorvastatin improves but does not completely normalise endothelial function in patients with type 2 diabetes. In addition to lowering LDL cholesterol, atorvastatin also lowers C-reactive protein (CRP) levels. The magnitude of reduction in CRP correlates with the degree of improvement in endothelium-dependent vasodilation, suggesting that chronic low-grade inflammation may also be involved in causing endothelial dysfunction. Chronic inflammation is associated with activation of the endothelium and both dyslipidaemia and advanced glycation end products are important triggers for inflammation in diabetes mellitus. Hence, dyslipidaemia, chronic low-grade inflammation and endothelial dysfunction are interrelated and contribute to the high cardiovascular risk in subjects with diabetes. 3WS20-5
Insights into the mechanisms of HDL lowering in insulin resistant states and type 2 diabetes
G.F. Lewis, T. Watanabe, T. Sakaue. University of Toronto, Canada The typical dyslipidemia that is associated with insulin resistance and Type 2 diabetes is felt to play an important, although not exclusive, role in the accelerated atherosclerosis in affected individuals. Hypertriglyceridemia, low plasma concentrations of high density lipoproteins (HDL) and qualitative changes in low density lipoproteins (LDL) comprise the typical dyslipidemia of insulin resistant states. Low plasma concentrations of HDL-c and its major protein component, apolipoprotein A-I (apo A-I), are particularly powerful, independent risk factors for ASCD. Consequently, there is great interest in determining the mechanisms responsible for reduced HDL-c and apo A-I plasma concentrations, particularly in insulin resistant states. Although isolated low plasma HDL-c can occur in the absence of hypertriglyceridemia or any other features of insulin resistance (associated with abdominal obesity, glucose intolerance or Type 2 diabetes), it is a less prevalent clinical occurrence and may be attributed to the presence of rare genetic disorders that affect HDL metabolism. The majority of cases of low HDL-c, however, are closely linked with other clinical features of insulin resistance and hypertriglyceridemia. We and other investigators have postulated that hypertriglyceridemia, which is a frequent occurrence in insulin resistant conditions, combined with the action of hepatic lipase (HL), are driving forces in the reduction of HDL-c and apoA-I plasma concentrations. This presentation will focus on the metabolic alterations in insulin resistant states and Type 2 diabetes that contribute to the reduction of HDL-c and HDL-apoA-I plasma concentrations. Studies in the whole body, human and animal, will be highlighted to demonstrate how insights can be gained from integrative physiology research. 3WS20-6
Is liver the culprit of diabetic dyslipidemia?
M.-R. Taskinen. Dept. of Medicine, University of Helsinki, Finland Growing data evidence that hepatic steatosis is a feature of dyslipidemia and insulin resistance. Nonalcoholic fatty liver disease (NAFLD) associates closely with hypertriglyceridemia, low HDL cholesterol, hyperinsulinemia and insulin resistance and glucose intolerance. Liver fat can be quantitated in man by using proton spectroscopy or from the CT images calculating the attenuation index of the liver. Recently we have reported a close positive
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
Wednesday October 1, 2003: Workshop 3WS22 Scavenger Receptors correlation between fasting plasma triglycerides and liver fat quantitated by proton spectroscopy. Likewise we have observed a positive correlation between the response of VLDL 1 (Sf 60 – 400) triglyceride to a standard oral fat load and liver fat. The machinery driving VLDL assembly in the liver includes 1. impaired insulin signaling via PI3 kinase pathway that enhances lipid accumulation to “nascent” VLDL particles 2. Upregulation of sterol regulatory element binding protein (SREBP) 1C that stimulates denovo lipogenesis 3. excess availability of “fat” in hepatocytes that stabilizes apo B 100 and overexpression of microsomal transfer protein (MTP). Chronically elevated flux of FFAs to the liver increases the cytosolic triglyceride storage pool and promotes VLDL overproduction in face of reduced degradation of apo B and overexpression of MTP both associated with insulin resistance. In Type 2 diabetic subjects VLDL 1 apo B 100 and triglycerides production rates are increased as compared to non-diabetic subjects. There is a close correlation between the mean residence time of VLDL 1 particles and both VLDL 1 apo B 100 and VLDL 1 triglyceride production rates. Whether the amount of fat in the liver is the cause of VLDL1 overproduction remains an issue to be resolved. Another open question is whether the amount of fat in the liver is the cause of consequence of insulin resistance.
3WS21 POSTMENOPAUSAL WOMAN AND HRT: TO BE OR NOT TO BE? 3WS21-2
Can a healthy endothelium influence the cardiovascular effects of hormone replacement therapy?
K. Koh. Division of Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Republic of Korea Emerging clinical and observational evidences suggest that estrogen confers physiologic benefits that are receptor mediated and depend on the integrity and functional status of the endothelium within the coronary vasculature. In postmenopausal women, estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) regimens can enhance the lipoprotein panel; blunt the expression of numerous cytokines, chemokines, and other proinflammatory mediators of endothelial injury and vascular smooth muscle cell proliferation; up-regulate endothelial nitric oxide synthase activity and nitric oxide production; and augment fibrinolysis potential and vasodilator capacity (diminish arterial resistance). Advancing age and atherosclerotic injury to the vessel wall tend to deplete estrogen receptors, compromise endothelial function, promote thrombus formation, and thus potentially diminish the efficacy of ERT and HRT. Therefore, optimizing the clinical benefits of these regimens in postmenopausal women depends largely on promoting a healthy endothelium through life-style modifications that diminish coronary risk. 3WS21-3
E. Moriguchi, J.L. Vieira. Pontifical Catholic University of Rio Grande do Sul, Brazil Although experimental studies had shown antiatherogenic effects of estrogen in animal models and observational studies had suggested that hormone replacement therapy (HRT) could be an important weapon for preventing coronary heart diseases (CHD), no large clinical trials had been done to evaluate HRT protection against CHD until recently. In 1998, the Heart and Estrogen/progestin Replacement Study (HERS), a secondary prevention trial, showed no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, with higher rates of thromboembolic events and gallbladder disease for those assigned to estrogen/progestin. Even the apparent time trend of fewer CHD events in years 3 to 5 did not persist during additional follow-up. In 2000, the study Estrogen Replacement and Atherosclerosis (ERA) indicated no angiographic benefit on coronary lesion from either estrogen or estrogen/progestin HRT. In July 2002, the estrogen/progestin arm of the Women’s Health Initiative (WHI) trial was discontinued after 5.6 years of the planned 8.5-year trial because women in the hormone treated group were at increased risk for cardiovascular events and breast cancer, and these risks outweighed the benefits of HRT on colon cancer and fractures due to osteoporosis. The results have shown increased risk of CHD (HR, 1.29; 95% CI, 1.02-1.63), stroke (HR, 1.41; 95% CI, 1.07-1.85), and pulmonary embolism (HR, 2.13; 95% CI, 1.39-3.25). There are recent evidences from the WHI showing that HRT may also increase the risk for dementia.
Evidence-based medicine has demonstrated that the risk of cardiovascular disease in women can be reduced like in men with the use of beta-blockers, aspirin, statins and ACE inhibitors. The evidence cumulated in the last years is sufficient to warrant recommendation against the use of HRT as a preventive measure for cardiovascular disease both in primary or secondary prevention. 3WS21-4
Protection from coronary artery disease in women on hormone replacement therapy
E. Windler 1 , B.-C. Zyriax 1 , B. Eidenmueller 1 , H. Boeing 2 . 1 University Hospital Hamburg-Eppendorf, Hamburg; 2 Institute of Human Nutrition, Potsdam-Rehbrücke, Germany As to the effects of hormone replacement therapy (HRT) on atherosclerotic vascular disease data of observational and interventional trials are contradictory. Most observational trials have reported lower rates of coronary events in users of HRT, however, this has not been reproduced in randomized trials. We have evaluated the use of HRT in a case-control study, in which 200 women with incident CHD and 255 age-matched controls were enrolled. Significantly less cases than controls used HRT. No woman with CHD had started HRT within the preceding year. On average women on HRT had less vascular risk factors and a healthier lifestyle. However, those women that were on HRT and developed coronary heart disease comprised a subgroup characterized by unfavorable eating habits, a high rate of smoking, and an elevated waist-to-hip ratio with insulin resistance and consecutive risk factors. Low HDL-cholesterol and elevated lipoprotein(a) may be due to a lack of response to HRT. The results fit meta-analyses that suggest that the observed lower rates of vascular events in HRT-users may be entirely or partly due to a healthy user effect. Yet, they do not exclude a contribution of HRT to the lower risk. On the other hand, our results do not support the observation of HERS of an increased risk within the first year of HRT to be a common problem. However, they are in line with the suggestion by the subgroup of HERS treated with statins that correction of risk factors might mitigate any possible excess risk in women on HRT with CHD. These and the results of many other trials contradict the singular finding of one arm of WHI using combined HRT as to an increased vascular risk through HRT. In essence, HRT for perimenopausal symptoms can well be part of a healthy lifestyle including appropriate medical treatment, but HRT cannot compensate for gross deficits in the individual health care.
3WS22 SCAVENGER RECEPTORS 3WS22-1
Characterization of the HDL receptor SR-BI and its influence on lipoprotein metabolism and associated pathophysiology
M. Krieger. Massachusetts Institute of Technology, Cambridge, MA, USA Scavenger receptor class B type I, SR-BI, is a physiologically relevant, high affinity cell surface HDL receptor. It mediates selective lipid uptake of HDL cholesterol, a mechanism fundamentally different from that of classic receptor-mediated uptake via coated pits and vesicles. In mice, SR-BI plays a key role in determining the levels of plasma HDL cholesterol, in delivering HDL-cholesterol to steroidogenic tissues and the liver and bile, and in protecting against atherosclerosis. Mice with null mutations in both the SR-BI and apoE genes express many features of human coronary heart disease. These hypercholesterolemic/atherosclerotic animals exhibit extensive lipid-rich coronary artery occlusions, multiple myocardial infarctions, cardiac dysfunction (e.g., enlarged hearts, reduced ejection fraction and contractility, ECG abnormalities), and they all die prematurely (50% mortality at 6 weeks). Treatment with the lipid-lowering drug probucol corrects all early onset pathology in these mice and dramatically extends their lives. The structure, mechanism of action and pathophysiologic consequences of blocking the activity of SR-BI will be reviewed. 3WS22-2
Functional role and regulation of hepatic scavenger receptor class B type I (SR-BI)
A. Rigotti. Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Chile The scavenger receptor class B type I (SR-BI) was the first functional cell surface HDL receptor to be described. SR-BI is highly expressed in the liver, a key organ for HDL metabolism. Under basal conditions, hepatic SR-BI expression
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
WEDNESDAY
Hormone replacement therapy and atherosclerosis: The fallen myth of the cardiovascular protective effects of hormone replacement therapy
191
Wednesday October 1, 2003: Workshop 3WS20 Diabetic Dyslipidemia
Methods and Results: For the micro-level, we obtained patient-level costs with components, and also used standardized fee data as proxy cost indicators. The costs of atherosclerosis-related diseases varied across cases even after casemix adjustment, and human resources occupied a large part of the cost. The macro-level healthcare expenditure is lower in Japan than other OECD countries, but efficiency parameters are poor, as hospital stay in Japan is extraordinarily longer. Contrarily, hospital employment per bed is 0.8 FTE in Japan, 3 to 7 times lower than others, likewise other resource parameters. Discussion and Conclusion: The current standards often require the more resources for the quality of care. A shortsighted policy relying on cutting cost and shortening hospital stay could deteriorate quality or impose net burden to the society through cost shifts, without balanced policy measures. The Japanese unique system could be resultant from well adaptation for efficiency; However, the causal mechanisms among long hospital stay, low resource level, micro-level quality and low macro-expenditure are still to be modeled and investigated. More harmonized efforts for health care cost and performance database is necessary for evidence-based policy discussion.
3WS20 DIABETIC DYSLIPIDEMIA 3WS20-1
Increased atherosclerosis in type 1 diabetes - Are lipids and lipoproteins irrelevant?
H. Colhoun. University College London, London, United Kingdom Type 1 diabetes is associated with a greatly increased coronary heart disease risk. Compared to the general population the relative risk is greater in women than men so that the sex difference in coronary heart disease is abolished in diabetes. Using electron beam CT measures of coronary artery atherosclerosis we have confirmed that this is an atherosclerotic phenomenon. Given that, in the absence of renal failure, the lipid profile is often normal in type 1 diabetes, other more subtle lipoprotein related abnormalities have been sought. We have shown that, whilst cholesteryl ester transfer protein (CETP) activity is increased in type 1 diabetes, the actual mass of cholesteryl esters transferred is not. However, type 1 diabetes is associated with a substantial increase in phospholipid transfer protein activity (PLTP) and to a lesser extent PLTP mass. There is also evidence that some anti-atherogenic lipoprotein changes in diabetic men (such as increased average LDL size) are not present in diabetic women. Other abnormalities such as decreased protection against LDL oxidation, as suggested by reduced paraoxonase activity, may also be important. The relevance of these to the increased risk of CHD in diabetes and the loss of the sex difference in CHD will be discussed. Finally the role of lipid lowering therapy in reducing this risk in type 1 diabetes will be reviewed. 3WS20-3
Postprandial lipemia and endothelial dysfunction in dyslipidemia and diabetes
A.L. Catapano. Dept. Pharmacological Sciences, Center for the Study of Atherosclerosis, Italy Several clinical and experimental data suggest that elevated postprandial lipemia is related to the presence of coronary artery disease (CAD) and is an independent risk factor for coronary atherosclerosis. The role of the endothelium in the pathogenesis of cardiovascular diseases is well recognised. A close correlation exists between the presence of cardiovascular risk factors and a decrease of the endothelial vasodilator function. Endothelial function is reduced in patients with myocardial ischemia, with CAD or presenting with diabetes. Furthermore endothelial dysfunction predicts the recurrence of cardiovascular events and progression of atherosclerotic disease. During the post prandial lipemia the endothelial function is transiently reduced in normocholesterolemic and in hyperlipidemic subjects. The lipoprotein fraction(s) that may be involved in determining such an effect are unknown. Fasting remant lipoprotein (RLPs) levels correlate directly with the endothelial dysfunction in peripheral and coronary arteries. Furthermore RLPs plasma levels are strongly associated with angiographically verified progression of focal coronary atherosclerosis and their lowering with gemfibrozil prevents vein graft stenosis. In addition RLPs levels are significantly increased after a fat loading. This burden of evidence prompted us to investigate whether changes in RLPs plasma levels during the postprandial phase affect endothelial function, a surrogate index of atherosclerotic disease. Our data suggest that remnant lipoproteins are one of the major determinants of endothelial dysfunction during the post prandial phase. Furthermore we addressed in vitro the effect of TG rich lipoproteins in the induction of specific genes in human endothelial cells
by using the microarray approach. The data indicate that VLDL induce some 170 genes, the most relevant to the atherosclerotic process will be discussed. 3WS20-4
Dyslipidaemia, inflammation and endothelial dysfunction in diabetes mellitus
K. Tan. Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR Endothelial dysfunction is an early event in atherogenesis and precedes the thickening of the intima and the formation of atherosclerotic plaques. Endothelial dysfunction has also been implicated in the pathogenesis of both microand macroangiopathy in diabetes and has been consistently demonstrated in patients with type 1 and type 2 diabetes mellitus. Markers of endothelial dysfunction (eg. von Willebrand Factor, vascular cell adhesion molecules) are elevated in patients with diabetes mellitus and vasodilation mediated by endothelium-derived nitric oxide is impaired. The aetiology of endothelial dysfunction in diabetes is complex and it has been shown that more than one mechanism is involved. We and others have demonstrated that diabetic dyslipidaemia plays a significant role. The increase in the concentration of small dense LDL, enhanced susceptibility of LDL to oxidation and exaggerated postprandial lipaemia found in patients with type 2 diabetes mellitus are associated with impairment of endothelium-dependent vasodilation. We have shown that treatment with atorvastatin improves but does not completely normalise endothelial function in patients with type 2 diabetes. In addition to lowering LDL cholesterol, atorvastatin also lowers C-reactive protein (CRP) levels. The magnitude of reduction in CRP correlates with the degree of improvement in endothelium-dependent vasodilation, suggesting that chronic low-grade inflammation may also be involved in causing endothelial dysfunction. Chronic inflammation is associated with activation of the endothelium and both dyslipidaemia and advanced glycation end products are important triggers for inflammation in diabetes mellitus. Hence, dyslipidaemia, chronic low-grade inflammation and endothelial dysfunction are interrelated and contribute to the high cardiovascular risk in subjects with diabetes. 3WS20-5
Insights into the mechanisms of HDL lowering in insulin resistant states and type 2 diabetes
G.F. Lewis, T. Watanabe, T. Sakaue. University of Toronto, Canada The typical dyslipidemia that is associated with insulin resistance and Type 2 diabetes is felt to play an important, although not exclusive, role in the accelerated atherosclerosis in affected individuals. Hypertriglyceridemia, low plasma concentrations of high density lipoproteins (HDL) and qualitative changes in low density lipoproteins (LDL) comprise the typical dyslipidemia of insulin resistant states. Low plasma concentrations of HDL-c and its major protein component, apolipoprotein A-I (apo A-I), are particularly powerful, independent risk factors for ASCD. Consequently, there is great interest in determining the mechanisms responsible for reduced HDL-c and apo A-I plasma concentrations, particularly in insulin resistant states. Although isolated low plasma HDL-c can occur in the absence of hypertriglyceridemia or any other features of insulin resistance (associated with abdominal obesity, glucose intolerance or Type 2 diabetes), it is a less prevalent clinical occurrence and may be attributed to the presence of rare genetic disorders that affect HDL metabolism. The majority of cases of low HDL-c, however, are closely linked with other clinical features of insulin resistance and hypertriglyceridemia. We and other investigators have postulated that hypertriglyceridemia, which is a frequent occurrence in insulin resistant conditions, combined with the action of hepatic lipase (HL), are driving forces in the reduction of HDL-c and apoA-I plasma concentrations. This presentation will focus on the metabolic alterations in insulin resistant states and Type 2 diabetes that contribute to the reduction of HDL-c and HDL-apoA-I plasma concentrations. Studies in the whole body, human and animal, will be highlighted to demonstrate how insights can be gained from integrative physiology research. 3WS20-6
Is liver the culprit of diabetic dyslipidemia?
M.-R. Taskinen. Dept. of Medicine, University of Helsinki, Finland Growing data evidence that hepatic steatosis is a feature of dyslipidemia and insulin resistance. Nonalcoholic fatty liver disease (NAFLD) associates closely with hypertriglyceridemia, low HDL cholesterol, hyperinsulinemia and insulin resistance and glucose intolerance. Liver fat can be quantitated in man by using proton spectroscopy or from the CT images calculating the attenuation index of the liver. Recently we have reported a close positive
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
Wednesday October 1, 2003: Workshop 3WS22 Scavenger Receptors correlation between fasting plasma triglycerides and liver fat quantitated by proton spectroscopy. Likewise we have observed a positive correlation between the response of VLDL 1 (Sf 60 – 400) triglyceride to a standard oral fat load and liver fat. The machinery driving VLDL assembly in the liver includes 1. impaired insulin signaling via PI3 kinase pathway that enhances lipid accumulation to “nascent” VLDL particles 2. Upregulation of sterol regulatory element binding protein (SREBP) 1C that stimulates denovo lipogenesis 3. excess availability of “fat” in hepatocytes that stabilizes apo B 100 and overexpression of microsomal transfer protein (MTP). Chronically elevated flux of FFAs to the liver increases the cytosolic triglyceride storage pool and promotes VLDL overproduction in face of reduced degradation of apo B and overexpression of MTP both associated with insulin resistance. In Type 2 diabetic subjects VLDL 1 apo B 100 and triglycerides production rates are increased as compared to non-diabetic subjects. There is a close correlation between the mean residence time of VLDL 1 particles and both VLDL 1 apo B 100 and VLDL 1 triglyceride production rates. Whether the amount of fat in the liver is the cause of VLDL1 overproduction remains an issue to be resolved. Another open question is whether the amount of fat in the liver is the cause of consequence of insulin resistance.
3WS21 POSTMENOPAUSAL WOMAN AND HRT: TO BE OR NOT TO BE? 3WS21-2
Can a healthy endothelium influence the cardiovascular effects of hormone replacement therapy?
K. Koh. Division of Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Republic of Korea Emerging clinical and observational evidences suggest that estrogen confers physiologic benefits that are receptor mediated and depend on the integrity and functional status of the endothelium within the coronary vasculature. In postmenopausal women, estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) regimens can enhance the lipoprotein panel; blunt the expression of numerous cytokines, chemokines, and other proinflammatory mediators of endothelial injury and vascular smooth muscle cell proliferation; up-regulate endothelial nitric oxide synthase activity and nitric oxide production; and augment fibrinolysis potential and vasodilator capacity (diminish arterial resistance). Advancing age and atherosclerotic injury to the vessel wall tend to deplete estrogen receptors, compromise endothelial function, promote thrombus formation, and thus potentially diminish the efficacy of ERT and HRT. Therefore, optimizing the clinical benefits of these regimens in postmenopausal women depends largely on promoting a healthy endothelium through life-style modifications that diminish coronary risk. 3WS21-3
E. Moriguchi, J.L. Vieira. Pontifical Catholic University of Rio Grande do Sul, Brazil Although experimental studies had shown antiatherogenic effects of estrogen in animal models and observational studies had suggested that hormone replacement therapy (HRT) could be an important weapon for preventing coronary heart diseases (CHD), no large clinical trials had been done to evaluate HRT protection against CHD until recently. In 1998, the Heart and Estrogen/progestin Replacement Study (HERS), a secondary prevention trial, showed no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, with higher rates of thromboembolic events and gallbladder disease for those assigned to estrogen/progestin. Even the apparent time trend of fewer CHD events in years 3 to 5 did not persist during additional follow-up. In 2000, the study Estrogen Replacement and Atherosclerosis (ERA) indicated no angiographic benefit on coronary lesion from either estrogen or estrogen/progestin HRT. In July 2002, the estrogen/progestin arm of the Women’s Health Initiative (WHI) trial was discontinued after 5.6 years of the planned 8.5-year trial because women in the hormone treated group were at increased risk for cardiovascular events and breast cancer, and these risks outweighed the benefits of HRT on colon cancer and fractures due to osteoporosis. The results have shown increased risk of CHD (HR, 1.29; 95% CI, 1.02-1.63), stroke (HR, 1.41; 95% CI, 1.07-1.85), and pulmonary embolism (HR, 2.13; 95% CI, 1.39-3.25). There are recent evidences from the WHI showing that HRT may also increase the risk for dementia.
Evidence-based medicine has demonstrated that the risk of cardiovascular disease in women can be reduced like in men with the use of beta-blockers, aspirin, statins and ACE inhibitors. The evidence cumulated in the last years is sufficient to warrant recommendation against the use of HRT as a preventive measure for cardiovascular disease both in primary or secondary prevention. 3WS21-4
Protection from coronary artery disease in women on hormone replacement therapy
E. Windler 1 , B.-C. Zyriax 1 , B. Eidenmueller 1 , H. Boeing 2 . 1 University Hospital Hamburg-Eppendorf, Hamburg; 2 Institute of Human Nutrition, Potsdam-Rehbrücke, Germany As to the effects of hormone replacement therapy (HRT) on atherosclerotic vascular disease data of observational and interventional trials are contradictory. Most observational trials have reported lower rates of coronary events in users of HRT, however, this has not been reproduced in randomized trials. We have evaluated the use of HRT in a case-control study, in which 200 women with incident CHD and 255 age-matched controls were enrolled. Significantly less cases than controls used HRT. No woman with CHD had started HRT within the preceding year. On average women on HRT had less vascular risk factors and a healthier lifestyle. However, those women that were on HRT and developed coronary heart disease comprised a subgroup characterized by unfavorable eating habits, a high rate of smoking, and an elevated waist-to-hip ratio with insulin resistance and consecutive risk factors. Low HDL-cholesterol and elevated lipoprotein(a) may be due to a lack of response to HRT. The results fit meta-analyses that suggest that the observed lower rates of vascular events in HRT-users may be entirely or partly due to a healthy user effect. Yet, they do not exclude a contribution of HRT to the lower risk. On the other hand, our results do not support the observation of HERS of an increased risk within the first year of HRT to be a common problem. However, they are in line with the suggestion by the subgroup of HERS treated with statins that correction of risk factors might mitigate any possible excess risk in women on HRT with CHD. These and the results of many other trials contradict the singular finding of one arm of WHI using combined HRT as to an increased vascular risk through HRT. In essence, HRT for perimenopausal symptoms can well be part of a healthy lifestyle including appropriate medical treatment, but HRT cannot compensate for gross deficits in the individual health care.
3WS22 SCAVENGER RECEPTORS 3WS22-1
Characterization of the HDL receptor SR-BI and its influence on lipoprotein metabolism and associated pathophysiology
M. Krieger. Massachusetts Institute of Technology, Cambridge, MA, USA Scavenger receptor class B type I, SR-BI, is a physiologically relevant, high affinity cell surface HDL receptor. It mediates selective lipid uptake of HDL cholesterol, a mechanism fundamentally different from that of classic receptor-mediated uptake via coated pits and vesicles. In mice, SR-BI plays a key role in determining the levels of plasma HDL cholesterol, in delivering HDL-cholesterol to steroidogenic tissues and the liver and bile, and in protecting against atherosclerosis. Mice with null mutations in both the SR-BI and apoE genes express many features of human coronary heart disease. These hypercholesterolemic/atherosclerotic animals exhibit extensive lipid-rich coronary artery occlusions, multiple myocardial infarctions, cardiac dysfunction (e.g., enlarged hearts, reduced ejection fraction and contractility, ECG abnormalities), and they all die prematurely (50% mortality at 6 weeks). Treatment with the lipid-lowering drug probucol corrects all early onset pathology in these mice and dramatically extends their lives. The structure, mechanism of action and pathophysiologic consequences of blocking the activity of SR-BI will be reviewed. 3WS22-2
Functional role and regulation of hepatic scavenger receptor class B type I (SR-BI)
A. Rigotti. Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Chile The scavenger receptor class B type I (SR-BI) was the first functional cell surface HDL receptor to be described. SR-BI is highly expressed in the liver, a key organ for HDL metabolism. Under basal conditions, hepatic SR-BI expression
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
WEDNESDAY
Hormone replacement therapy and atherosclerosis: The fallen myth of the cardiovascular protective effects of hormone replacement therapy
191