Hyperlipidemias: Verhamme P

Clement D, Kolh P, Motte S, Sprynger M, Van Damme H, Verhamme P, Vermassen F, Wautrecht JC, Anonymous00147. · University of Ghent, Belgium. · Acta Chir Belg. · Pubmed #18277433 No free full text.

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Verreth W, De Keyzer D, Pelat M, Verhamme P, Ganame J, Bielicki JK, Mertens A, Quarck R, Benhabilès N, Marguerie G, Mackness B, Mackness M, Ninio E, Herregods MC, Balligand JL, Holvoet P. · Cardiovascular Research Unit of the Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Belgium. · Circulation. · Pubmed #15533870 links to  free full text

Abstract: BACKGROUND: Weight loss in obese insulin-resistant but not in insulin-sensitive persons reduces coronary heart disease risk. To what extent changes in gene expression are related to atherosclerosis and cardiovascular function is unknown. METHODS AND RESULTS: We studied the effect of diet restriction-induced weight loss on gene expression in the adipose tissue, the heart, and the aortic arch and on atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia, and insulin resistance are associated with hypertension, impaired left ventricular function, and accelerated atherosclerosis in those mice. Compared with lean mice, peroxisome proliferator-activated receptors (PPAR)-alpha and PPAR-gamma expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR-alpha and PPAR-gamma, and a change in the expression of genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress, and inflammation, most of which are under the transcriptional control of these PPARs. Changes in gene expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. PPAR-alpha and PPAR-gamma expression was inversely related to plaque volume and to oxidized LDL content in the plaques. CONCLUSIONS: Induction of PPAR-alpha and PPAR-gamma in adipose tissue, heart, and aortic arch is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight loss. Improved lipid metabolism and insulin signaling is associated with decreased tissue deposition of oxidized LDL that increases cardiovascular risk in persons with the metabolic syndrome.

Holvoet P, Harris TB, Tracy RP, Verhamme P, Newman AB, Rubin SM, Simonsick EM, Colbert LH, Kritchevsky SB. · Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit, Leuven, Belgium. · Arterioscler Thromb Vasc Biol. · Pubmed #12791672 links to  free full text

Abstract: OBJECTIVE: Although circulating oxidized LDL (oxLDL) is elevated in persons with coronary heart disease (CHD), whether oxLDL is elevated in persons with high CHD risk before any events is unknown. Therefore, we studied the association between high, predicted CHD risk and oxLDL in the Health ABC cohort. METHODS AND RESULTS: This cohort included 385 persons with CHD and 1183 persons at high risk; the latter were all persons with CHD risk equivalents: noncoronary forms of clinical atherosclerotic disease, diabetes, and a 10-year risk for CHD >20% by Framingham scoring. The remaining 1535 participants were at low risk. Levels of oxLDL were 1.18+/-0.61 mg/dL for low-risk persons, 1.50+/-0.81 mg/dL for high-risk persons without diagnosed CHD, and 1.32+/-0.83 mg/dL for persons with CHD (P<0.001). The odds ratio for high CHD risk in the highest quintile of oxLDL, compared with the lowest quintile and after adjusting for age, sex, race, LDL cholesterol, smoking status, and C-reactive protein, was 2.79 (P<0.001). CONCLUSIONS: The odds ratio for elevated oxLDL among persons with high CHD risk before any CHD events was higher than that among persons with established CHD. A likely explanation is that once CHD is diagnosed, individuals are frequently treated with a statin, which is associated with lowering of LDL cholesterol and oxLDL levels.

Mertens A, Verhamme P, Bielicki JK, Phillips MC, Quarck R, Verreth W, Stengel D, Ninio E, Navab M, Mackness B, Mackness M, Holvoet P. · Cardiovascular Research Unit at the Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Campus Gasthuisberg, O&N, Herestraat 49, B-3000 Leuven, Belgium. · Circulation. · Pubmed #12668499 links to  free full text

Abstract: BACKGROUND: Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B-containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice. METHODS AND RESULTS: LDL receptor knockout (LDLR-/-), leptin-deficient (ob/ob), double-mutant (LDLR-/-;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL (P<0.001) and HDL (P<0.01) cholesterol and of triglycerides (P<0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL (P<0.001). C57BL6 and ob/ob mice had no detectable lesions. Lesions covered 20% of total area of the thoracic abdominal aorta in double-mutant mice compared with 3.5% in LDLR-/- mice (P<0.01). Higher macrophage homing and accumulation of oxidized apolipoprotein B-100-containing lipoproteins were associated with larger plaque volumes in the aortic root of double-mutant mice (P<0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; P<0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% (P<0.01) and reduced the titer of autoantibodies by 40% (P<0.01) and plaque volume in the aortic root by 42% (P<0.05) at 6 weeks. CONCLUSIONS: Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.

Verhamme P, Quarck R, Hao H, Knaapen M, Dymarkowski S, Bernar H, Van Cleemput J, Janssens S, Vermylen J, Gabbiani G, Kockx M, Holvoet P. · Cardiovascular Research Unit, Center for Experimental Surgery and Anesthesiology, KU Leuven, Campus Gasthuisberg, O&N, Herestraat 49, Leuven, Belgium. · Cardiovasc Res. · Pubmed #12237174 links to  free full text

Abstract: OBJECTIVE: To study the effect of dietary cholesterol withdrawal on size and composition of LDL-hypercholesterolemia-induced coronary plaques in miniature pigs. METHODS: Pigs were on normal chow (control group), on a cholesterol-rich diet for 37 weeks (hypercholesterolemic group) or on a cholesterol-rich diet followed by normal chow for 26 weeks (cholesterol withdrawal group). Endothelial function was assessed with quantitative angiography after intracoronary infusion of acetylcholine, plaque load with intra-coronary ultrasound and plaque composition with image analysis of cross-sections. The effect of porcine serum on coronary smooth muscle cell (SMC) function was studied in vitro. RESULTS: Cholesterol-rich diet caused LDL-hypercholesterolemia, increased plasma levels of oxidized LDL (ox-LDL) and C-reactive protein (CRP), and induced endothelial dysfunction and coronary atherosclerosis. Dietary cholesterol withdrawal lowered LDL, ox-LDL and CRP. It restored endothelial function, did not affect plaque size but decreased lipid, ox-LDL and macrophage content. Smooth muscle cells and collagen accumulated within the plaque. Increased smoothelin-to-alpha-smooth muscle actin ratio indicated a more differentiated SMC phenotype. Cholesterol lowering reduced proliferation and apoptosis. In vitro, hypercholesterolemic serum increased SMC apoptosis and decreased SMC migration compared to non-hypercholesterolemic serum. CONCLUSIONS: Cholesterol lowering induced coronary plaque stabilization as evidenced by a decrease in lipids, ox-LDL, macrophages, apoptosis and cell proliferation, and an increase in differentiated SMC and collagen. Increased migration and decreased apoptosis of SMC may contribute to the disappearance of the a-cellular core after lipid lowering.

Theilmeier G, Verhamme P, Dymarkowski S, Beck H, Bernar H, Lox M, Janssens S, Herregods MC, Verbeken E, Collen D, Plate K, Flameng W, Holvoet P. · Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium. · Circulation. · Pubmed #12196342 links to  free full text

Abstract: BACKGROUND: Hypercholesterolemia induces functional and structural changes of the microvasculature and reduces coronary flow reserve in humans and experimental animals. The effect of hypercholesterolemia on left ventricular (LV) function in the absence of coronary stenosis is, however, unknown. Our objective was therefore to assess the effect of hypercholesterolemia and cholesterol withdrawal on LV function in the presence of advanced coronary plaques that do not cause stenosis. METHODS AND RESULTS: Twenty-eight minipigs on cholesterol diet for 34 weeks and 16 control pigs were studied. Seven hypercholesterolemic pigs were withdrawn from the diet for 26 weeks. LV function was assessed with cine-MRI, myocardial blood flow with colored microspheres, and capillary density with immunohistochemistry, and microvascular endothelial cell apoptosis with terminal dUTP nick-end labeling staining. Hypercholesterolemia (17+/-8 versus 268+/-150 versus 12+/-10 mg/dL LDL cholesterol, control versus hypercholesterolemic versus cholesterol withdrawal; P<0.001) induced atherosclerosis but not stenosis in the left coronary artery. Baseline cardiac output, ejection fraction, and stroke volume were similar in control and hypercholesterolemic pigs. In dobutamine stress test, cardiac output (P<0.05) and stroke volume (P<0.01) were lower in hypercholesterolemic pigs compared with controls. The impaired response to dobutamine was reversible by dietary cholesterol withdrawal. Hypercholesterolemia reduced endomyocardial coronary flow reserve (P<0.01) and capillary density (P<0.05) and induced capillary endothelial cell apoptosis. Hypercholesterolemic pigs failed to reduce vascular resistance in response to increased LV workload and pharmacological vasodilation. CONCLUSION: LDL hypercholesterolemia in minipigs impaired LV response to dobutamine stress in the absence of coronary stenosis.

Theilmeier G, Quarck R, Verhamme P, Bochaton-Piallat ML, Lox M, Bernar H, Janssens S, Kockx M, Gabbiani G, Collen D, Holvoet P. · Center for Molecular and Vascular Biology, Campus Gasthuisberg, O&N, Herestraat 49, B-3000, Leuven, Belgium. · Cardiovasc Res. · Pubmed #12123778 links to  free full text

Abstract: OBJECTIVE: To assess the effect of hypercholesterolemia on neointima formation and vascular remodelling after porcine coronary angioplasty. METHODS: Left anterior descending coronary angioplasty was carried out in five control and 16 age-matched hypercholesterolemic miniature pigs. Vascular remodelling was measured by intravascular ultrasound. Neointima size and composition were assessed by quantitative image analysis. Coronary smooth muscle cells (SMC) from control and diet pigs were collected 1 h after angioplasty for in vitro study of the effect of hypercholesterolemic serum on SMC migration and of macrophage-induced matrix degradation on SMC adhesion. RESULTS: Twenty-eight days after angioplasty, lumen increase was 0.08+/-1.7 mm(2) in diet and 2.7+/-2.7 mm(2) (P=0.016) in control pigs. Lumen increase correlated with vascular remodelling (IEL(post)/IEL(pre); R(2)=0.59; P<0.001) and with the circumferential gain relative to the neointima (R(2)=0.32; P<0.01) but not with neointimal area that was similar in control and diet pigs. Circumferential gain correlated with VSMC deposition at the site of the injury (R(2)=0.28; P<0.01) that correlated with organized collagen (R(2)=0.34; P<0.01). The VSMC and collagen content of neointima in diet pigs was lower whereas the macrophage content was higher. Hypercholesterolemic serum and oxidised LDL reduced migration of VSMC from diet pigs. Macrophage-induced degradation of VSMC extracellular matrix reduced VSMC adhesion (P=0.015). CONCLUSION: Hypercholesterolemia impairs vascular remodelling of balloon-treated coronary arteries. It decreases VSMC and collagen accumulation at the site of injury. Our in vitro data suggest that this decrease can be due to macrophage-induced matrix degradation and reduced VSMC adhesion and to impaired VSMC migration. Oxidised LDL mimics the inhibitory effect of hypercholesterolemic serum.