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Acute phase reduction of Lp(a) predicts restenosis in patients with acute myocardial infarction performed primary percutaneous transluminal coronary angioplasty
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Fraunberger POSSIBLE ROLE OF STATINS AS AN ADJUVANT THERAPY IN CANCER
P. Fraunberger, B. Siegele, A. Helm, D. Seidel, A.K. Walli. Institute for Clinical Chemistry, Klinikum Grosshadern, Munich, Germany Hypocholesterolemia is often observed in cancer patients in pre-clinical stages. Tumor tissue has a higher requirement of cholesterol for growth; cell proliferation and this demand can be met either by circulating lipoproteins or by endogenous cholesterol synthesis. I contrast to solid tumors and leukemia; it is unlikely that small sized tumors can cause a drop in circulating cholesterol. We therefore investigated if cancer tissue or established tumor cell lines in culture release factors that increase cell proliferation and lipoprotein utilization in fibroblast from healthy volunteers. Furthermore because of pleiotropic effects of statins we also investigated if simvastatin was capable to modulate the release of stimulatory factors. Binding studies with 125I-LDL revealed increased LDL-receptor activity in membranes from cancer tissue of various origin (colon, liver, lung and kidney) compared to adjecent normal tissue. Conditioned medium from tumor tissue tumor cell lines in culture stimulated LDL receptor activity as well as cell proliferation in cultured fibroblasts. Antibodies specific to growth factors were able to inhibit this stimulatory effect of tumor-conditioned medium from colon carcinoma cell lines (PDGF) and renal carcinoma (FGF). The presence of these growth factors could also be confirmed by SDS-page and immunoblots. Pretreatment of tumor cells with statins caused an inhibition of growth factor production and reduced the humoral effects of tumor cell conditioned medium. Moreover statins caused decreased thymidine and BrdU-incorporation in tumor cells and increased percentage of apoptotic cells increased. Our data suggest that inhibition of HMG-CoA reductase with statins deserves attention as an adjuvant to usual cancer therapy since it reduces proliferation, growth signaling and increases apoptosis in tumor cells. ~
AUTONOMIC NERVOUS SYSTEM INFLUENCE ON PULSE PRESSURE IN MILD NON-TREATED HYPERTENSION
J. Freitas, R. Santos, M. Carvalho, A. Falcao De Freitas. Centro de Estudos da Funcao Autonomica, Faculdade de Medicina do Porto, Portugal Potential new cardiovascular risk factors (CRF) are emerging everyday. Pulse pressure and autonomic nervous system (ANTS) dysfunction are recent CRF that predict morbidity and mortality on hypertension and other cardiac diseases. The goal of this study was the assessment of CRY in hypertensive and their correlation. Thirty untreated patients with essential hypertension (It) and thirty aged-adjust normotensive (N) subjects underwent ABMP and ANTS evaluation at supine and tilt position. Pulse pressure (PP) was calculated either by ABMP (24h, day and night) and also by Finapres during 10 rain supine and 10 rain tilt position. FFT was used to access heart rate and systolic blood pressure variability. Baroreceptor gain (BR) was calculated by cross-spectral coherence (Alfa-index). Hemodynamics indexes using non-invasive modelflow analysis were calculated. PP of H in AMBP was 53(8), 52(7) and 53(10) mmHg on 24h, day and night. PP of N in ABMP was 47(6), 47(5) and 47(6) mmHg on 24h, day and night (p<0,01 between H and N). Systolic volume was 67(22) ml in H and 70(13) in N (ns). Total vascular resistances (TVR) was 2044(1185) dyn.s.cm-5 in H and 1410(359)dyn.s.cm-5 in N (p<0.01). HR was 79(9), 83(9) and 72(9) bpm on 24h, day and night in H. HR was 78(7), 83(8) and 65(7) bpm on 24h, day and night in N (p <0.01, only at night). BR was 6.7(3.4) ms/mmHg on H and 14.7(8.1) in N (p<0.01). H F R R (vagal tonus) was 219(181) ms2 in H and 1493(2909) in N (p <0.05) in supine and 85(82) ms2 in H and 323(295) in N (p<0.01) in orthostasis. LF SBP (sympathetic tonus) was 6.1(4.4) mmHg2 in H and 5.8(4.3) in N (ns). Twenty-four hour PP had correlation with VS (r-0,40 in H and r-0,64 in N). PP had a poor correlation with BR and only in H (r--0,21). PP had a weak negative correlation with vagal activity (r--0,14 in H and r--0,17 in N) and correlated with sympathetic vasomotor activity (r-0,33) only on H. In mild non-treated hypertension it seems that PP, ANTS and TPR are already impaired. These CRY had poor correlation. It is desirable to treat high blood pressure together with the other impaired cardiovascular risk factors. ~ROLE OF NUCLEAR RECEPTORS IN LIPOPROTEIN METABOLISM J.C. Fmchart. Institut Pasteur de Lille, INSERM U545, Universite de Lille II, France Extensive epidemiological, genetic, clinical and interventional data support that elevated plasma triglyceride (TG) and low HI)L-cholesterol levels
are important risk factors for coronary artery diseases (CAD). We have recently assessed the mode of action of the normolipidaemic drugs fibrates in the regulation of TG and ItDL metabolism. The mechanism of action occurs at the molecular level and involves the activation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARa) in the liver and in macrophages. PPARa agonists decrease TG plasma concentrations by increasing the expression of lipoprotein lipase and decreasing apolipoprotein C-III concentrations. Interestingly, we recently discovered a new apolipoprotein (apo AV). Apo AV gene has been shown in apo AV transgenic and knockout mice and human association studies to be important in determining plasma TG levels. We demonstrate that apo AV is a PPARa target gene and supporting its role as a major mediator for how fibrates reduce plasma triglycerides in humans and mice. The main hypothesis for the protective effect of ItDL against atherosclerosis is related to its key function in reverse cholesterol transport, a crucial process for body cholesterol balance. The recent discovery by our lab of the protective role of human apolipoprotein A-I containing particles (LpA-I, LpA-I:A-II) and the identification of novel ItDL receptors (CLA-1/SR-BI, ABC1) provide new avenues for treatment of atherosclerotic cardiovascular disease. Investigation on the mechanism of action of fibrates on ItDL metabolism revealed that they increase HI)L-cholesterol by increasing the expression of apo A-I and apo A-II through activation of PPARa. We have also investigated the expression of CLA-1/SR-BI in macrophages and its regulation by fenofibrate. Immunohistological analysis of human atherosclerosis lesions showed high CLA-1/SR-BI expression in resident macrophages in the lipid core of the plaque, colocalizing with specific PPARa staining. Activation of PPARa by fenofibrate resulted in the induction of CLA-1/SRBI protein expression in monocytes as well as in fully differentiated human macrophages. We have also showed that SR-BI protein expression was increased in aortic lesions of apo E null mice treated with fenofibrate. Very recently, we have found that the expression of ABC1 gene which encodes the 'cholesterol efflux regulatory protein' (CERP), is also up-regulated by fenofibrate through PPARa activation. Therefore, we postulate that fenofibrate therapy might facilitate cholesterol efflux and thus might reduce atherosclerotic lesion size by increasing CLA-1/SR-BI expression. Although PPARa activators have been in clinical use for the past 30 years, a special role of fibrate therapy has only recently been established. The Helsinki Heart Study showed for the first time that increasing HI)L-cholesterol concentrations was independently associated with a reduction in CItD events and the VA-HIT trial showed for the first time that treatment to increase a low HI)L-cholesterol in the presence of a low-risk LDL-cholesterol significantly decreases the incidence of major coronary heart disease events in men with a high prevalence of the insulin resistance syndrome, type 2 diabetes and typical diabetic dyslipidemia. Furthermore, the DAIS angiographic trial demonstrated for the first time that lipid therapy and fibrate can slow the progression of coronary atherosclerosis in patients with type 2 diabetes. ~ i - ~ ACUTE PHASE REDUCTION OF LP(A) PREDICTS RESTENOSIS IN PATIENTS W I T H ACUTE MYOCARDIAL INFARCTION PERFORMED PRIMARY PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY A. Fuiino 1, T. Watanabe 1, K. Taira 1, K. Ashikawa1, Y. Maruyama2. J Yonezawa City Hospital, Yonezawa, Yamagata; 2Fukushima Medical University, Fukushima, Japan Object: To examnine whether acute phase reduction of serum Lipoprotein(a) [Lp(a)] predicts restenosis after primary percutaneous transluminal coronary angioplasty (PTCA) in patients with acute myocardial infarction (AMI). Method: We examined serial change of serum Lp(a) in 101 cases [68 male, 33 female, mean age was 65.7 years old] at day 1, 3 in patients those underwent successful primary PTCA. Patients were devided to 2 groups such as no restenosis (N) group and restenosis (R) group according to the following criteria of restenosis. Restenosis was defined as more than 50% of stenosis at follow-up coronary angiogram evaluated using quantitative coronary angiography analysis. Results: Between two groups, age, gender, lesion characteristics, stents, and lipids showed no significant difference. In group R, serum Lp(a) decreased significantly at day 3 from 33.6 to 27.3 mg/dl, but in group N, serum Lp(a) increased significantly at day 3 from 28.8 to 38.5 mg/dl. We confirmed that diagnostic coronary angiography showed no significant serial change of serum Lp(a) at day 3. A hypothesis that acute phase reduction of serum Lp(a) at day 3 predicts restenosis after primary PTCA showed 88% of sensitivity and 97.4% of specificity. Conclusion: We conclude that serial measurement of serum Lp(a) is a useful clinical parameter which predicts restenosis after primary PTCA.
73rd EAS Congress
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Fraunberger POSSIBLE ROLE OF STATINS AS AN ADJUVANT THERAPY IN CANCER
P. Fraunberger, B. Siegele, A. Helm, D. Seidel, A.K. Walli. Institute for Clinical Chemistry, Klinikum Grosshadern, Munich, Germany Hypocholesterolemia is often observed in cancer patients in pre-clinical stages. Tumor tissue has a higher requirement of cholesterol for growth; cell proliferation and this demand can be met either by circulating lipoproteins or by endogenous cholesterol synthesis. I contrast to solid tumors and leukemia; it is unlikely that small sized tumors can cause a drop in circulating cholesterol. We therefore investigated if cancer tissue or established tumor cell lines in culture release factors that increase cell proliferation and lipoprotein utilization in fibroblast from healthy volunteers. Furthermore because of pleiotropic effects of statins we also investigated if simvastatin was capable to modulate the release of stimulatory factors. Binding studies with 125I-LDL revealed increased LDL-receptor activity in membranes from cancer tissue of various origin (colon, liver, lung and kidney) compared to adjecent normal tissue. Conditioned medium from tumor tissue tumor cell lines in culture stimulated LDL receptor activity as well as cell proliferation in cultured fibroblasts. Antibodies specific to growth factors were able to inhibit this stimulatory effect of tumor-conditioned medium from colon carcinoma cell lines (PDGF) and renal carcinoma (FGF). The presence of these growth factors could also be confirmed by SDS-page and immunoblots. Pretreatment of tumor cells with statins caused an inhibition of growth factor production and reduced the humoral effects of tumor cell conditioned medium. Moreover statins caused decreased thymidine and BrdU-incorporation in tumor cells and increased percentage of apoptotic cells increased. Our data suggest that inhibition of HMG-CoA reductase with statins deserves attention as an adjuvant to usual cancer therapy since it reduces proliferation, growth signaling and increases apoptosis in tumor cells. ~
AUTONOMIC NERVOUS SYSTEM INFLUENCE ON PULSE PRESSURE IN MILD NON-TREATED HYPERTENSION
J. Freitas, R. Santos, M. Carvalho, A. Falcao De Freitas. Centro de Estudos da Funcao Autonomica, Faculdade de Medicina do Porto, Portugal Potential new cardiovascular risk factors (CRF) are emerging everyday. Pulse pressure and autonomic nervous system (ANTS) dysfunction are recent CRF that predict morbidity and mortality on hypertension and other cardiac diseases. The goal of this study was the assessment of CRY in hypertensive and their correlation. Thirty untreated patients with essential hypertension (It) and thirty aged-adjust normotensive (N) subjects underwent ABMP and ANTS evaluation at supine and tilt position. Pulse pressure (PP) was calculated either by ABMP (24h, day and night) and also by Finapres during 10 rain supine and 10 rain tilt position. FFT was used to access heart rate and systolic blood pressure variability. Baroreceptor gain (BR) was calculated by cross-spectral coherence (Alfa-index). Hemodynamics indexes using non-invasive modelflow analysis were calculated. PP of H in AMBP was 53(8), 52(7) and 53(10) mmHg on 24h, day and night. PP of N in ABMP was 47(6), 47(5) and 47(6) mmHg on 24h, day and night (p<0,01 between H and N). Systolic volume was 67(22) ml in H and 70(13) in N (ns). Total vascular resistances (TVR) was 2044(1185) dyn.s.cm-5 in H and 1410(359)dyn.s.cm-5 in N (p<0.01). HR was 79(9), 83(9) and 72(9) bpm on 24h, day and night in H. HR was 78(7), 83(8) and 65(7) bpm on 24h, day and night in N (p <0.01, only at night). BR was 6.7(3.4) ms/mmHg on H and 14.7(8.1) in N (p<0.01). H F R R (vagal tonus) was 219(181) ms2 in H and 1493(2909) in N (p <0.05) in supine and 85(82) ms2 in H and 323(295) in N (p<0.01) in orthostasis. LF SBP (sympathetic tonus) was 6.1(4.4) mmHg2 in H and 5.8(4.3) in N (ns). Twenty-four hour PP had correlation with VS (r-0,40 in H and r-0,64 in N). PP had a poor correlation with BR and only in H (r--0,21). PP had a weak negative correlation with vagal activity (r--0,14 in H and r--0,17 in N) and correlated with sympathetic vasomotor activity (r-0,33) only on H. In mild non-treated hypertension it seems that PP, ANTS and TPR are already impaired. These CRY had poor correlation. It is desirable to treat high blood pressure together with the other impaired cardiovascular risk factors. ~ROLE OF NUCLEAR RECEPTORS IN LIPOPROTEIN METABOLISM J.C. Fmchart. Institut Pasteur de Lille, INSERM U545, Universite de Lille II, France Extensive epidemiological, genetic, clinical and interventional data support that elevated plasma triglyceride (TG) and low HI)L-cholesterol levels
are important risk factors for coronary artery diseases (CAD). We have recently assessed the mode of action of the normolipidaemic drugs fibrates in the regulation of TG and ItDL metabolism. The mechanism of action occurs at the molecular level and involves the activation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARa) in the liver and in macrophages. PPARa agonists decrease TG plasma concentrations by increasing the expression of lipoprotein lipase and decreasing apolipoprotein C-III concentrations. Interestingly, we recently discovered a new apolipoprotein (apo AV). Apo AV gene has been shown in apo AV transgenic and knockout mice and human association studies to be important in determining plasma TG levels. We demonstrate that apo AV is a PPARa target gene and supporting its role as a major mediator for how fibrates reduce plasma triglycerides in humans and mice. The main hypothesis for the protective effect of ItDL against atherosclerosis is related to its key function in reverse cholesterol transport, a crucial process for body cholesterol balance. The recent discovery by our lab of the protective role of human apolipoprotein A-I containing particles (LpA-I, LpA-I:A-II) and the identification of novel ItDL receptors (CLA-1/SR-BI, ABC1) provide new avenues for treatment of atherosclerotic cardiovascular disease. Investigation on the mechanism of action of fibrates on ItDL metabolism revealed that they increase HI)L-cholesterol by increasing the expression of apo A-I and apo A-II through activation of PPARa. We have also investigated the expression of CLA-1/SR-BI in macrophages and its regulation by fenofibrate. Immunohistological analysis of human atherosclerosis lesions showed high CLA-1/SR-BI expression in resident macrophages in the lipid core of the plaque, colocalizing with specific PPARa staining. Activation of PPARa by fenofibrate resulted in the induction of CLA-1/SRBI protein expression in monocytes as well as in fully differentiated human macrophages. We have also showed that SR-BI protein expression was increased in aortic lesions of apo E null mice treated with fenofibrate. Very recently, we have found that the expression of ABC1 gene which encodes the 'cholesterol efflux regulatory protein' (CERP), is also up-regulated by fenofibrate through PPARa activation. Therefore, we postulate that fenofibrate therapy might facilitate cholesterol efflux and thus might reduce atherosclerotic lesion size by increasing CLA-1/SR-BI expression. Although PPARa activators have been in clinical use for the past 30 years, a special role of fibrate therapy has only recently been established. The Helsinki Heart Study showed for the first time that increasing HI)L-cholesterol concentrations was independently associated with a reduction in CItD events and the VA-HIT trial showed for the first time that treatment to increase a low HI)L-cholesterol in the presence of a low-risk LDL-cholesterol significantly decreases the incidence of major coronary heart disease events in men with a high prevalence of the insulin resistance syndrome, type 2 diabetes and typical diabetic dyslipidemia. Furthermore, the DAIS angiographic trial demonstrated for the first time that lipid therapy and fibrate can slow the progression of coronary atherosclerosis in patients with type 2 diabetes. ~ i - ~ ACUTE PHASE REDUCTION OF LP(A) PREDICTS RESTENOSIS IN PATIENTS W I T H ACUTE MYOCARDIAL INFARCTION PERFORMED PRIMARY PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY A. Fuiino 1, T. Watanabe 1, K. Taira 1, K. Ashikawa1, Y. Maruyama2. J Yonezawa City Hospital, Yonezawa, Yamagata; 2Fukushima Medical University, Fukushima, Japan Object: To examnine whether acute phase reduction of serum Lipoprotein(a) [Lp(a)] predicts restenosis after primary percutaneous transluminal coronary angioplasty (PTCA) in patients with acute myocardial infarction (AMI). Method: We examined serial change of serum Lp(a) in 101 cases [68 male, 33 female, mean age was 65.7 years old] at day 1, 3 in patients those underwent successful primary PTCA. Patients were devided to 2 groups such as no restenosis (N) group and restenosis (R) group according to the following criteria of restenosis. Restenosis was defined as more than 50% of stenosis at follow-up coronary angiogram evaluated using quantitative coronary angiography analysis. Results: Between two groups, age, gender, lesion characteristics, stents, and lipids showed no significant difference. In group R, serum Lp(a) decreased significantly at day 3 from 33.6 to 27.3 mg/dl, but in group N, serum Lp(a) increased significantly at day 3 from 28.8 to 38.5 mg/dl. We confirmed that diagnostic coronary angiography showed no significant serial change of serum Lp(a) at day 3. A hypothesis that acute phase reduction of serum Lp(a) at day 3 predicts restenosis after primary PTCA showed 88% of sensitivity and 97.4% of specificity. Conclusion: We conclude that serial measurement of serum Lp(a) is a useful clinical parameter which predicts restenosis after primary PTCA.
73rd EAS Congress