Hyperlipidemias: Rabelink TJ

Rabelink TJ. · University Medical Center Utrecht, Internal Medicine, Room G 02.228, PO Box 85500, 3508 GA Utrecht, The Netherlands. · Nephrol Dial Transplant. · Pubmed #14671033 links to  free full text

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Westerweel PE, Verhaar MC, Rabelink TJ. · Universitaire Medisch Centrum Utrecht, divisie Inwendige Geneeskunde en Dermatologie, afd. Vasculaire Geneeskunde, Utrecht. · Ned Tijdschr Geneeskd. · Pubmed #15326645 No free full text.

Abstract: Statins safely and effectively reduce the morbidity and mortality due to cardiovascular disease. In the trials conducted so far, which have been carried out predominantly on high-risk patients, the observed risk reduction is probably completely attributable to the reduction of the cholesterol level. However, statins also influence the atherosclerotic disease process in a lipid-independent way. This includes beneficial effects on the early pathogenetic components of atherosclerosis, such as endothelial dysfunction and inflammation. These effects are probably not visible in the large clinical trials that usually follow up cohorts of patients with late stages of atherosclerosis during a relatively short period of time. These cholesterol-independent effects do affect intermediate factors in the atherosclerotic process, such as endothelial dysfunction. In clinical practice, where not only short-term effects in patients with manifest vascular disease but also the prevention of the long-term complications of atherosclerosis in high-risk patients is an important goal, these so-called pleiotropic effects may contribute to risk reduction.

Prinsen BH, de Sain-van der Velden MG, de Koning EJ, Koomans HA, Berger R, Rabelink TJ. · Department of Vascular Medicine and Metabolism, University Medical Center Utrecht, Utrecht, The Netherlands. · Kidney Int Suppl. · Pubmed #12694325 No free full text.

Abstract: Cardiovascular disease (CVD) is a major cause of mortality in patients with chronic renal failure (CRF) caused by numerous factors defined as traditional and uremia-related risk factors. One of these risk factors, dyslipidemia, is often observed in patients with CRF, resulting in abnormal concentrations and composition of plasma lipoproteins. The prominent features of uremic dyslipidemia are an increase in plasma triglycerides and cholesterol in nearly all lipoproteins, and a reduction in high-density lipoprotein (HDL) cholesterol. Because of its direct contact with the circulating blood, the endothelium is preferentially subjected to the modulatory effects of these altered lipoproteins. Little is known about the mechanisms for hypertriglyceridemia in CRF. This review highlights several studies over the past years that have contributed to knowledge of hypertriglyceridemia, especially in combination with renal diseases and their dialysis treatment. The underlying mechanisms behind hypertriglyceridemia have not been fully clarified and may indeed be multifactorial. Hypertriglyceridemia may contribute to the progression of atherosclerosis. Therefore, it is essential to study the putative mechanisms for uremic dyslipidemia, since optimal treatment is essential for the prevention or delay of cardiovascular complications in patients with CRF.

van Oostrom AJ, Cabezas MC, Rabelink TJ. · Department of Vascular Medicine, University Hospital Utrecht, F02.126, PO Box 85500, 3508 GA Utrecht, The Netherlands. · J R Soc Med. · Pubmed #12216328 links to  free full text

Abstract: IRS is a complex disease consisting of a clustering of metabolic disorders, of which hyperglycaemia, hyper-insulinaemia and dyslipidaemia are the most important. Endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis. The effects of hyperinsulinaemia seem to depend on lipidaemia and glycaemia. Hyperglycaemia and hyperlipidaemia have detrimental effects on endothelial function in the fasting as well as the postprandial states. In both situations, the generation of ROS and vasoactive molecules plays a major role in interfering with the atheroprotective endothelium-dependent NO system. Treatment of IRS in regard to endothelial function should be focused initially on lifestyle improvement, such as stopping smoking and eating a balanced diet containing antioxidant vitamins, folic-acid, L-arginine and long-chain omega-3 unsaturated FA. Strict glucose control has shown to improve endothelial function and decrease microvascular complications. However, macrovascular complications, in line with endothelial functional improvement, have so far been reduced only when treatment was focused on other characteristics of the IRS syndrome, in particular dyslipidaemia. Other relevant treatments include ACE inhibitors and thiazolidinediones, and probably tetrahydrobiopterin and folic acid supplementation. Future studies should address the effects of therapeutic neovascularization on endothelial dysfunction.

van Oostrom AJ, Plokker HW, van Asbeck BS, Rabelink TJ, van Kessel KP, Jansen EH, Stehouwer CD, Cabezas MC. · Department of Internal Medicine, University Medical Center Utrecht, The Netherlands. · Atherosclerosis. · Pubmed #16098531 No free full text.

Abstract: We investigated whether pro-inflammatory aspects of the postprandial phase can be modulated by rosuvastatin in premature coronary artery disease (CAD) patients. Herefore standardized 8 h oral fat loading tests were performed off-treatment and after rosuvastatin 40 mg/d in 20 male CAD patients (50 +/- 4 years). The expression of leukocyte activation markers CD11a, CD11b, CD62L and CD66b was studied using flowcytometry. Migration of isolated neutrophils towards chemoattractants was determined in a fluorescence-based assay. Rosuvastatin did not affect baseline leukocyte counts nor the postprandial neutrophil increment (maximum mean increase +10% pre- and +14% post-treatment, P < 0.01 for each). Rosuvastatin reduced baseline platelets (from 266 +/- 78 to 225 +/- 74 x 10(9) cells/L, P < 0.001) and blunted the postprandial platelet count change (maximum mean increase +6%, P = 0.01, and 0%, respectively). The baseline expression of CD11a, CD11b and CD62L increased on most types of leukocytes by rosuvastatin, whereas the postprandial responses were unaffected. Pretreatment, postprandial neutrophil migration increased dose-dependently, but there were no postprandial changes after rosuvastatin. The latter effect was unrelated to changes in lipoprotein concentrations. In conclusion, in CAD patients postprandial pro-inflammatory and pro-coagulant changes can be modified by rosuvastatin. These apparently lipid-lowering independent effects may render protection against atherosclerosis.

Verhaar MC, Wever RM, Kastelein JJ, van Loon D, Milstien S, Koomans HA, Rabelink TJ. · Department of Nephrology, University Hospital Utrecht, The Netherlands. · Circulation. · Pubmed #10421591 links to  free full text

Abstract: BACKGROUND: Folates have been suggested to be of benefit in reducing cardiovascular risk. The present study was designed to examine whether oral folic acid supplementation could improve endothelial function as an intermediate end point for cardiovascular risk in patients with increased risk of atherosclerosis due to familial hypercholesterolemia (FH). METHODS AND RESULTS: In a prospective, randomized, double-blind, placebo-controlled study with crossover design, we evaluated the effects of 4 weeks of treatment with oral folic acid (5 mg PO) on endothelial function in FH. In 20 FH patients, forearm vascular function was assessed at baseline, after 4 weeks of folic acid treatment, and after 4 weeks of placebo treatment by venous occlusion plethysmography, with serotonin and sodium nitroprusside used as endothelium-dependent and -independent vasodilators. In addition, we examined the vasoconstrictor response to the NO synthase inhibitor N(G)-monomethyl-L-arginine to assess basal NO activity. In FH patients, folic acid supplementation restored the impaired endothelium-dependent vasodilation, whereas it did not significantly influence endothelium-independent vasodilation or basal forearm vasomotion. There was a trend toward improvement in basal NO activity. CONCLUSIONS: These data demonstrate that oral supplementation of folic acid can improve endothelial function in patients with increased risk of atherosclerotic disease due to hypercholesterolemia, without changes in plasma lipids.

van Etten RW, de Koning EJ, Honing ML, Stroes ES, Gaillard CA, Rabelink TJ. · Department of Vascular Medicine and Diabetes, University Medical Center, Utrecht, the Netherlands. · Arterioscler Thromb Vasc Biol. · Pubmed #12006393 links to  free full text

Abstract: Cardiovascular disease is the most important cause of morbidity and mortality in patients with type 2 diabetes. Endothelial dysfunction predicts cardiovascular outcome. Type 2 diabetes is characterized by endothelial dysfunction, which may be caused by dyslipidemia. Statin therapy restores endothelial function in hyperlipidemic patients. Therefore, we hypothesize a beneficial effect of atorvastatin on NO-dependent vasodilation in patients with type 2 diabetes and mild dyslipidemia (low density lipoproteins >4.0 mmol/L and/or triglycerides >1.8 mmol/L). We evaluated the effect of intensive lipid lowering (4 weeks of 80 mg atorvastatin once daily) on vasoreactivity in 23 patients with type 2 diabetes by using venous occlusion plethysmography. Twenty-one control subjects were matched for age, sex, body mass index, blood pressure, and smoking habits. The ratio of blood flows in the infused (measurement [M]) and noninfused (control [C]) arm was calculated for each recording (M/C ratio), and M/C% indicates the percentage change from the baseline M/C ratio. Serotonin-induced NO-dependent vasodilation was significantly blunted (52+/-30 versus 102+/-66 M/C%, P<0.005), and nitroprusside-induced endothelium-independent vasodilation was modestly reduced (275+/-146 versus 391+/-203 M/C%, P<0.05) in patients with type 2 diabetes compared with control subjects. Despite significant reduction of total cholesterol, low density lipoproteins, and triglycerides (5.8+/-1.0 to 3.2+/-0.6 [P<0.0001], 4.1+/-1.1 to 1.8+/-0.7 [P<0.0001], and 2.2+/-1.3 to 1.4+/-0.5 [P<0.05] mmol/L, respectively), no effect on NO-dependent (59+/-44 M/C%) and endothelium-independent (292+/-202 M/C%) vasodilation was demonstrated. These data suggest that intensive lipid lowering by atorvastatin has no effect on NO availability in forearm resistance arteries in type 2 diabetic patients. Other factors, such as hyperglycemia, may be a more important contributing factor regarding impaired vasoreactivity in this patient group.

Joles JA, Kunter U, Janssen U, Kriz W, Rabelink TJ, Koomans HA, Floege J. · Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands. · J Am Soc Nephrol. · Pubmed #10752526 links to  free full text

Abstract: Hyperlipidemia in conjunction with uninephrectomy leads to renal injury in rats. It is unknown whether this is due to mesangial cell or podocyte injury and whether the injuries induced by hypercholesterolemia and hypertriglyceridemia share a similar pathogenesis. Therefore, renal effects of hypercholesterolemia were studied in male rats with dietary hypercholesterolemia compared with rats on a regular diet. Renal effects of hypertriglyceridemia were studied in female Nagase analbuminemic rats (NAR). Hypertriglyceridemia was reduced in NAR by ovariectomy. Both models were studied after uninephrectomy or sham operation. Dietary hypercholesterolemia had little effect on plasma triglycerides, whereas ovariectomy in the NAR had no effect on plasma cholesterol. However, an increase in intermediate density lipoprotein cholesterol was common to both models. Dietary hypercholesterolemia and uninephrectomy separately induced a similar increase in proteinuria after 13 wk, which was additive when these interventions were combined. At this stage, only a minimal increase was present in glomerular alpha-smooth muscle actin staining, a marker of mesangial cell activation, or in mesangial matrix expansion. Moreover, platelet-derived growth factor-B chain, a marker of mesangial cell proliferation, was not increased. However, podocyte injury was prominent as evidenced by podocytic de novo expression of desmin and ultrastructural changes. Glomerular macrophage counts were increased by hypercholesterolemia but not by uninephrectomy, and were not related to the level of proteinuria. Hypertriglyceridemia and uninephrectomy in female NAR induced an increase in proteinuria after 24 wk, which was also associated with an increase in podocyte desmin expression without any mesangial activation and proliferation or matrix accumulation. Hypertriglyceridemia, proteinuria, and the increase in desmin staining were largely prevented by ovariectomy. Interstitial myofibroblast activation and tubulointerstitial injury accompanied proteinuria in both models. These findings indicate that both hypercholesterolemia and hypertriglyceridemia aggravate renal injury primarily via podocyte rather than via mesangial cell damage. Such podocyte injury is accompanied by tubulointerstitial cell activation and injury.

Verhaar MC, Honing ML, van Dam T, Zwart M, Koomans HA, Kastelein JJ, Rabelink TJ. · Department of Nephrology and Hypertension, University Hospital, Utrecht, Netherlands. · Cardiovasc Res. · Pubmed #10533616 links to  free full text

Abstract: OBJECTIVE: Dihydropyridine calcium antagonists have been shown to retard atherogenesis in animal models and to prevent the development of early angiographic lesions in human coronary arteries. Endothelial dysfunction is an early event in the pathogenesis of cardiovascular disease. We investigated whether nifedipine could improve endothelial function in hypercholesterolemia, independently of changes in blood pressure or plasma lipids. METHODS: First, we compared in vivo forearm vascular responses to the endothelium-dependent and independent vasodilators serotonin (5-HT) and sodium nitroprusside (SNP) in 11 patients with familial hypercholesterolemia before and after 6-weeks treatment with nifedipine GITS (60 mg, OD) and in 12 matched controls. In a subgroup of six control subjects forearm vascular function was also assessed before and after 6-weeks nifedipine GITS treatment. In vitro, we subsequently explored possible mechanisms underlying the effect of nifedipine on endothelial function. We investigated the effects of nifedipine on both NO production by recombinant endothelial NO synthase (eNOS) and endothelial cells, using 3H-arginine conversion, as well as on superoxide generation by endothelial cell lysates, using lucigenin enhanced chemiluminescence. RESULTS: In hypercholesterolemia 5-HT-induced vasodilation was impaired (47 +/- 9% increase in forearm bloodflow vs. 99 +/- 8% in controls). Treatment with nifedipine completely restored 5-HT-induced vasodilation (113 +/- 13%), whereas it did not influence basal forearm vasomotion or SNP-induced vasodilation. Nifedipine did not alter forearm vascular responses in control subjects and did not alter blood pressure or plasma lipids. In vitro, we found no direct effect of nifedipine on NO production by recombinant eNOS or endothelial cells. However, we did observe a reduction in endothelial superoxide generation. CONCLUSIONS: Our data show that nifedipine improves endothelial function in hypercholesterolemia. It is suggested from our in vitro experiments that this effect is due to reduced NO degradation.

Vuong TD, Stroes ES, Willekes-Koolschijn N, Rabelink TJ, Koomans HA, Joles JA. · Department of Nephrology and Hypertension, Utrecht University, Utrecht, The Netherlands. · Kidney Int. · Pubmed #10027937 links to  free full text

Abstract: BACKGROUND: A phospholipid, lysophosphatidylcholine (LPC), is the major determinant of the atherosclerotic properties of oxidized low-density lipoprotein (LDL). Under normal circumstances most LPC is bound to albumin. We hypothesized that lipoprotein LPC concentrations are increased in hypoalbuminemic patients with the nephrotic syndrome, irrespective of their lipid levels. To test this hypothesis, we selected nephrotic and control subjects with matched LDL cholesterol levels. METHODS: Lipoproteins and the albumin-rich lipoprotein-deficient fractions were separated by ultracentrifugation and their phospholipid composition was analyzed by thin-layer chromatography. RESULTS: Nephrotic subjects (albumin 23 +/- 2 g/liter and LDL cholesterol 3.1 +/- 0.2 mmol/liter) had a LDL LPC concentration that was increased (P < 0.05) to 66 +/- 7 vs. 35 +/- 6 micromol/liter in matched controls (albumin 42 +/- 5 g/liter and LDL cholesterol 3.1 +/- 0.2 mmol/liter). LPC in very low-density lipoprotein plus intermediate-density lipoprotein (VLDL + IDL) in these subjects was also increased to 33 +/- 7 vs. 9 +/- 2 micromol/liter in controls (P < 0.05). Conversely, LPC was decreased to 19 +/- 4 micromol/liter in the albumin-containing fraction of these hypoalbuminemic patients, as compared to 46 +/- 10 micromol/liter in the controls (P < 0.05). LPC was also low (14 +/- 4 micromol/liter) in the albumin-containing fraction of hypoalbuminemic, hypocholesterolemic patients with nonrenal diseases. In hyperlipidemic nephrotic subjects (albumin 21 +/- 2 g/liter and LDL cholesterol 5.7 +/- 0.5 mmol/liter) the LPC levels in LDL and VLDL + IDL were further increased, to 95 +/- 20 and 56 +/- 23 micromol/liter, respectively (P < 0.05). CONCLUSION: These findings suggest that in the presence of hypoalbuminemia in combination with proteinuria, LPC shifts from albumin to VLDL, IDL and LDL. This effect is independent of hyperlipidemia. Increased LPC in lipoproteins may be an important factor in the disproportionate increase in cardiovascular disease in nephrotic patients with hypoalbuminemia.