• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Effects of Rosuvastatin on Endothelial Function in Patients With Familial Combined Hyperlipidaemia (FCH)

Posted on: Saturday, 15 October 2005, 03:00 CDT

By Avest, Ewoud ter; Abbink, Evertine J; Holewijn, Suzanne; de Graaf, Jacqueline; Et al

Key words: Endothelial function - Familial combined hyperlipidaemia - Flow mediated dilation - Forearm blood flow - Rosuvastatin

ABSTRACT

Objective: Although several studies have reported a positive effect of statins on endothelial vasoreactivity, most studies performed in subjects with type 2 diabetes mellitus report no effect at all. This lack of effect may be related to the existence of insulin resistance, or to insufficient lowering of atherogenic (apo)lipoproteins. Therefore, we tested in this study whether treatment of insulin resistant familial combined hyperlipidaemia (FCH) patients with a high dose (40 mg/day) of the potent rosuvastatin was able to improve endothelial function, without necessarily improving insulin sensitivity.

Research design and methods: In a double-blind randomised crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean [standard deviation] age 54 [7] years) underwent a 4-week run-in period after which they were randomised to treatment with placebo once daily for 12 weeks, followed by rosuvastatin 40 mg/day for 12 weeks or vice versa. Endothelial function was determined after 8 and 12 weeks of both treatment periods, respectively, by measurement of flow-mediated vasodilation (FMD) using high-resolution ultrasound and by measurement of vasodilator response to intrabrachial acetylcholine (Ach) by venous occlusion plethysmography (forearm blood flow [FBF]).

Results: Plasma levels of lipids, (apo)lipoproteins and high- sensitivity C-reactive protein (hsCRP) improved significantly after rosuvastatin therapy compared to placebo. However, rosuvastatin had no effect on homeostasis model assessment (HOMA)-indices or on vasodilator responses to intra-brachial acetylcholine-infusion (FBF- ratio increased from a mean of 1.28 [SD: 0.46] to 5.82 [3.44] after rosuvastatin and from 1.33 [0.67] to 5.99 [3.89] after placebo, p = 0.35). Endothelium-dependent FMD was also unchanged (1.6% [3.1%] vs. 3.2% [3.5]%, p= 0.56 rosuvastatin vs. placebo, respectively).

Conclusion: In patients with FCH, a 12-week treatment of rosuvastatin 40mg/day did not improve endothelial function (either in large conduit vessels or in resistance vessels), despite significant improvements in plasma lipids, (apo)lipoproteins. and low-grade inflammation.

Introduction

Familial combined hyperlipidaemia (FCH) is the most frequent inherited disorder of lipid metabolism, with an estimated prevalence in Western populations of 1%1. The FCH-phenotype is characterised by elevated levels of serum total cholesterol, triglycerides and/or apolipoprotein B. In addition, other traits of FCH that have been proposed to contribute to accelerated atherosclerosis in vivo are a decreased high-density lipoprotein (HDL)-cholesterol, the presence of small dense low-density lipoprotein (LDL) particles, increased high-sensitivity C-reactive protein (hsCRP) levels and a decreased insulin sensitivity1-5. Finally, FCH-subjects have an impaired endothelial vasoreactivity6. This disturbance in endothelial vasoreactivity is viewed as an early stage of the gradually developing atherosclerotic process, and has been shown to predict future cardiovascular events in other populations7.

Many studies have been carried out to investigate whether modification of risk factors that predispose to endothelial dysfunction can improve endothelial vasoreactivity, and thereby prevent cardiovascular events. In this respect, much attention has been paid to the hydroxymethylglutaryl CoA-reductase inhibitors (statins). Cellular and animal investigations have demonstrated that statins may induce an upregulation of endothelial nitric oxide synthase (eNOS)8. However, the results of prospective studies of statins on endothelial vasoreactivity in vivo are conflicting and the methods used to quantify endothelium-dependent vasodilation are diverse. While in healthy subjects and hypercholesterolaemic patients almost all studies find a positive effect of statins on endothelium-dependent vasodilation6,9-16, in subjects with type 2 diabetes, the majority of the studies report no effect at all, with a few exceptions17-21. This may be related to the existence of insulin resistance, which itself is associated with endothelial dysfunction22. Perhaps endothelial dysfunction in insulin resistant subjects is only reversed when insulin sensitivity improves. On the other hand, the decrease in lipid levels in these studies may not have been large enough to induce a beneficial effect on endothelial function. Therefore, we tested in this study whether treatment with a high dose of the potent rosuvastatin was able to improve endothelial function without necessarily improving insulin sensitivity. Subjects with FCH provide an excellent model to test this hypothesis, since they are insulin resistant, but do not have overt diabetes23. Such an approach would also avoid the possibility of irreversible vessel damage characteristic of the diabetic state and probably resulting in a lack of effect of statins on endothelial function. To obtain comprehensive information about the effect of statin treatment on endothelial function in both conductance vessels and on resistance vessels, we assessed endothelial function by two different methods: measurement of flow mediated dilation of the brachial artery by high resolution ultrasound and measurement of the vasodilator response to intrabrachial acetylcholine by venous occlusion plethysmography.

Methods

Study population

All studies were performed in 18 FCH patients. FCH diagnosis was based on the nomogram as published recently by our group5. Plasma triglyceride and total cholesterol levels, adjusted for age and gender, as well as absolute apolipoprotein B levels, were applied to the nomogram, to calculate a probability of being affected by FCH. In short, in the nomogram for each of the three variables the corresponding number of points is read from a scale and then summed to give a total point score, which is translated into a probability of being affected by FCH. If the subject has a probability of > 60% then they are defined as affected by FCH when the diagnostic phenotype is present in at least one first-degree relative, and premature cardiovascular disease (CVD), before the age of 60 years, is present in at least one individual in the family.

In addition, all participants met the following criteria: age 30- 70 years; liver enzymes analysis (alkaline phosphatase [AP], aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤ 1.5 upper limit of normal reference values; and calculated creatinine clearance > 100 mL/min. Females had to be post- menopausal or taking oral contraceptive agents. Exclusion criteria were: diabetes mellitus (fasting glucose level > 7.0 mmol/L), overt coronary heart disease (CHD), smoking and pregnancy or lactation. The investigation conforms with the principles outlined in the declaration of Helsinki and the Medical Ethics Committee of the Radboud University Medical Centre Nijmegen approved the study protocol.

Protocol

The study was designed as a single-centre, double blind, randomised, placebo-controlled cross-over investigation (Figure 1). Eligibility of recruited subjects for participation in the study was determined in a screening visit. During this visit a physical examination was performed, an electrocardiogram (ECG) was recorded and venous blood was drawn for determination of glucose and lipid levels. If used, lipid lowering medication was discontinued (five patients). Concomitant cardiovascular medication consisted of: β-blockers (3), thiazide-diuretic (1) and a fixed dose combination of angiotensin-II-receptor antagonist with a thiazide diuretic (1). These medications remained unchanged during the study. No vitamin supplements were used. The patients were instructed to follow the same diet throughout the whole study period.

After a 4-week run-in phase, fasting lipid levels, apolipoprotein B (apoB) and liver enzymes (AP, AST and ALT) were measured and patients were randomised to treatment with either placebo once daily for 12 weeks, followed by rosuvastatin 40 mg for 12 weeks (both manufactured by AstraZeneca, Alderley Park, Macclesfield, UK) or vice versa. During each treatment period, participants visited the outpatient clinic at 4, 8 and 12 weeks of treatment. During these visits, weight, waist-hip ratio, blood pressure and heart rate were measured and fasting venous blood samples were taken for determination of liver enzymes, creatinine kinase (CK) and creatinine. At the end of both 12-weeks treatment periods, hsCRP and fasting glucose and insulin levels were measured and lipids and lipoproteins were analysed (total cholesterol [TC], triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C], very low density lipoprotein- cholesterol and -triglycerides [VLDL-C/TG] and apoB). After 8 weeks of each respective treatment period, endothelial function was assessed by high-resolution ultrasound of the brachial artery (measurement of flow mediated dilatation, FMD), and after 12 weeks by venous occlusion plethysmography (measurement of forearm blood flow, FBF).

Experimental procedures

For all measurements, patients abstained from caffeine- containing beverages and alcohol forat least 24 hours before the experiments. Experiments were performed in the morning after an overnight fast with the patient supine in a quiet temperature- controlled room (23-24C).

Figure 1. Study design

Plethysmography

Vasodilator responses to rosuvastatin were measured invasively at the end of each 12-week treatment period, using mercury-in-silastic strain-gauge venous occlusion plethysmography (Hokanson EC4, D.E. Hokanson, Inc., Issaquah, Washington, USA), as previously described24,25. Forearm volume was measured by the water displacement method. Subsequently, a 20 gauge cannula (Angiocath, 20 gauge, Deseret Medical Inc., Becton Dickinson and Comp., Sandy, Utah, USA) was inserted under local anaesthesia (lidocaine 2%) into the brachial artery of the left (experimental) arm, and connected to a Hewlett Packard monitor (type 78353B, Hewlett Packard GmbH, Bblingen, Germany) for blood pressure measurement and for intra- arterial drug administration by an automated syringe infusion pump (Type STC-521, Terumo Corp., Tokyo, Japan). After measurement of baseline forearm blood flow (FBF), vasodilator responses to three increasing dosages (0.5, 2.0 and 8.0 g*min^sup -1^*dL^sup -1^ of forearm volume) of the endothelial-dependent vasodilator acetylcholine (Ach) were recorded. After an equilibration period of 45 minutes, baseline levels were recorded again, after which three increasing dosages (0.06, 0.2 and 0.6 g* min^sup -1^*dL^sup -1^ of forearm volume) of the endothelium-independent vasodilator sodium nitroprusside (SNP) were infused. Each dose of Ach or SNP was infused for 5 minutes at a fixed volume rate of 100 l*min^sup -1^ *dL^sup -1^ forearm volume, and FBF was measured at both the experimental and the control arm. The FBF-ratio (ratio of the FBF in the experimental arm divided by the FBF in the control arm) was calculated to adjust for potential systemic changes. To take into account irreversible endothelial damage at baseline, also the Ach/ SNP-ratio was calculated by dividing the endothelium-dependent vasodilation during Ach-infusion by the endothelium-independent vasodilation during SNP-infusion.

High-resolution ultrasound

Vasodilator responses to rosuvastatin were measured non- invasively after 8 weeks of each treatment period by recording flow mediated dilation (FMD) of the brachial artery, using a 7.5 MHz linear-array transducer of an AU5 ultrasound system (Esaote Biomedica, Genova, Italy), connected to a computer with a data acquisition board. For image optimization we used a stereostatic arm with a holder for the probe and a water bath to prevent compression of the artery. Dedicated software (Wall Track System 2.0; Pie Medical, Maastricht, the Netherlands and AIM-WTS software, University Hospital Groningen, the Netherlands) was used to measure and analyse changes in vessel diameter. All measurements were performed by trained technicians, and analysed off-line by an independent analyst.

FMD was measured by the method of Celermajer et al.26. First, basal vessel diameter was measured. Subsequently, a pneumatic tourniquet, placed around the forearm was inflated to 50 mmHg above systolic blood pressure for 4 minutes. After deflation, vessel diameter was recorded continuously in 4-second frames every 15 seconds for at least 4 minutes to detect changes in vessel diameter (endothelium-dependent vasodilation). Thereafter, 15 minutes were allowed for vessel recovery, and a second baseline vessel diameter was measured. Sublingual GTN spray (Nitrolingual 400 g per dose, Tramedico BV, Weesp, the Netherlands) was administered, and from 2- 10 minutes after administration, endothelium-independent vasodilation was measured by the last series of scans.

FMD was calculated as the difference between the maximum diameter post-occlusion and the average baseline diameter, relative to the average baseline diameter, and expressed as a percentage. To take into account irreversible endothelial damage at baseline, the FMD/ GTN-ratio was calculated by dividing the endothelium-dependent vasodilation after reactive hyperaemia by the endothelium- independent vasodilation after GTN administration.

Laboratory measurements

TC and TG concentrations were determined using commercially available enzymatic reagents (Hitachi 747, Roche, Almere, the Netherlands). HDL-C was determined by the polyethylene glycol 6000 method27. LDL-C was determined after ultracentrifugation and separation of d = 1.006 g/mL. For measurement of oxidized LDL we used a commercial non-competitive ELISA (Mercodia, Uppsala, Sweden)28. Total plasma apoB concentration was determined by immunonephelometry29 and hsCRP by ELISA (Imtec Immundiagnostica, Berlin, Germany). Plasma glucose was determined by a commercially available glucose oxidation method (GOD-PAP, Hitachi 747; Roche Molecular Biochemicals, Indianapolis). Plasma insulin concentrations was assessed by radioimmunoassay (inhouse RIA [inter-assay coefficient of variation (CV), 10.3%])30. AP, AST, ALT, CK and creatinine were assessed by commercially available enzymatic reagents (Hitachi 747, Roche, Almere, The Netherlands; reference values < 120 U/L, < 40 U/L, < 45 U/L, < 200 U/L, 60-110 mol/L [male] / 50-90 mol/L [female]). Homeostasis model assessment (HOMA)-index was calculated using the formula: HOMA = fasting insulin (mU/L) fasting glucose (mmol/L) / 22.5(31).

Calculations and statistics

According to our experience, the standard deviation (SD) in acetylcholine-induced increase in forearm blood flow is approximately 3 mL*min^sup -1^*dL^sup -1^ of forearm tissue. A difference between rosuvastatin versus placebo of > 3.5 mL*min^sup - 1^*dL^sup -1^ was considered to be of significant relevance. To be able to detect such a difference, at a power of 90% at a two-sided significance level of 5%, power calculations revealed a sample size of 16 participants.

All data sets were tested for normal distribution by the Kolmogorov-Smirnov test. HOMA-indices and FMD-values were not normally distributed and were log-transformed before analysis. Data at the end of the two respective treatment periods were considered as representative for rosuvastatin or placebo and were compared using Student's t-test. To investigate the effect of increasing dosages of Ach and SNP on the FBF-ratio between the two treatments, the dose-to-group interaction was calculated by two-way repeated- measures ANOVA. Correlations were calculated using Pearson's r or Spearman's rho as appropriate. Unless stated otherwise, all variables are expressed as mean (SD). For all tests, statistical significance was accepted at the 95% confidence level (p < 0.05). Statistical analyses were performed using SPSS 12.0.1 for windows (SPSS Inc., Chicago Illinois, USA).

Results

Baseline characteristics

Twenty-three patients were originally included in the study. They were all of Caucasian origin. Five patients did not meet the inclusion criteria after the 4-week wash-out period. As a result, 18 patients (11 male, seven female) completed the study, and all results presented refer to this group. According to the International Diabetes Federation (IDF) criteria for Europeans, 10 of the 18 FCH patients fulfilled the criteria for the metabolic syndrome (http://www.idf.org/webdata/ docs/ IDF_Metasyndrome_definition.pdf). Baseline characteristics (after 4- weeks wash-out of lipid lowering medication) for age, anthropometric measurements, systolic- and diastolic blood pressures and plasma lipids and apolipoproteins are shown in Table 1.

Effects of rosuvastatin on plasma lipids, apolipoproteins, hsCRP and insulin sensitivity

Rosuvastatin treatment lowered plasma TC (-44%), LDL-C (-50%), TG (-28%), VLDL-C (-56%), VLDL-TG (-39%) and ApoB (-45%) levels significantly compared to placebo, and it decreased both median plasma level of hsCRP (-16%) and oxLDL (-55%) significantly. However, insulin sensitivity was not significantly improved. After 12 weeks placebo mean (SD) HOMA-index was 2.27 (0.91) versus 2.11 (0.94) after rosuvastatin, p = 0.46 placebo versus rosuvastatin.

Effects on endothelial function

Baseline FBF-measurements during venous occlusion plethysmography in both treatment periods were not significantly different, and both Ach and SNP produced a dose dependent increase in FBF in both treatment periods (Table 2).

The mean arterial pressure (MAP), as recorded during the FBF- measurements, was not significantly affected by infusion of either drug, and therefore changes in FBF-ratio represent changes in vascular tone. Twelve weeks of rosuvastatin had no effect on vasodilator responses to either Ach or SNP. After endothelium- dependent vasodilation (Ach-infusion) FBF-ratio increased from 1.28 (0.46) to 5.82 (3.44) (mean [SD] increase 499% [307%]) during rosuvastatin treatment and from 1.33 (0.67) to 5.99 (3.89) (increase 435% [199%]) during placebo-treatment, p = 0.35 rosuvastatin versus placebo (Figure 2A). Also endothelium-independent vasodilation was unaffected: after SNP-infusion, FBF-ratio increased from 1.44 (0.49) to 7.28 (3.78) (increase 564% [405%]) during rosuvastatin treatment and from 1.51 (0.69) to 7.53 (4.24) (increase 520% [284%]) during placebo-treatment, p = 0.56 rosuvastatin versus placebo (Figure 2B). As a result, the ratio of endothelium-dependent over -independent vasodilation (Ach/SNP-ratio) did not change during rosuvastatin- therapy (0.85 [0.33] vs. 0.85 [0.36] rosuvastatin compared to placebo, p = 0.76).

Non-invasive endothelial-function assessment with high- resolution ultrasound of the brachial artery yielded similar results. After 8 weeks of rosuvastatin treatment, mean (SD) baseline diameter of the brachial artery was 4.93mm (0.58 mm), compared to 4.94 mm (0.62 mm) after placebo, p = 0.95, and baseline diameters after both treatment-periods were highly correlated (r = 0.74, p < 0.001). Mean endothelium-dependent FMD was 1.6% (3.1%) after rosuvastatin compared to 3.2% (3.5%) after placebo treatment, p = 0.56. Median G\TN-mediated vasodilation was 12.6% (6.6%) after rosuvastatin and 14.3% (4.9%) after placebo, p = 0.29. Furthermore, the ratio of endothelium-dependent compared to -independent vasodilation (FMD/ GTN-ratio) did not change during rosuvastatin- therapy (0.15 [0.25] vs. 0.13 [0.51], rosuvastatin compared to placebo, p = 0.80).

Table 1. Baseline characteristics (mean [SD]) for age, anthropometric measurements, blood pressures, plasma lipids and (apo)liproproteins (n = 18)

Table 2. Effect of 12 weeks treatment with rosuvastatin (40 mg/ day) in patients with FCH on mean (SD) forearm blood flow (FBF) in the experimental arm before and during infusion of three increasing doses of acetylcholine (Ach) and sodium nitroprusside (SNP) (n = 17)

Figure 2. Effect of 12 weeks treatment with rosuvastatin (40 mg/ day) in patients with FCH on change in mean ( SEM) FBF ratio during (A) acetylcholine infusion (endothelium-dependent vasodilation) and [B) after nitroprusside infusion (endothelium-independent vasodilation (n = 17). Ach = acetylcholine; SNP = sodium nitroprusside; FBF-ratio = the ratio of forearm blood flow in the experimental arm divided by that in the control arm

No significant correlation was found for the endothelium- dependent responses to acetylcholine (plethysmography) and hyperaemia (high resolution ultrasound) for the same treatment- period (rho = 0.04, p = 0.83), nor did we find an association for the endothelium-independent responses to nitrates as measured with plethysmography and high-resolution ultrasound. (rho = 0.11, p = 0.55).

Effect on safety parameters.

Rosuvastatin was well tolerated; AST, AP and creatinine-levels remained unchanged during therapy. Although mean ALT and CK increased slightly (both p < 0.01), ALT and CK remained well below safety limits (ALT > 3 upper limit of normal (ULN), or CK > 10 ULN).

Discussion .

The present study demonstrates that in patients with FCH, despite significant improvements in plasma lipids, apolipoproteins and low- grade inflammation, a 12 week treatment of rosuvastatin 40 mg/day was not able to improve endothelial dependent vasodilation (as tested both by FMD and by vasodilator response to Ach) significantly.

At first sight, our results may seem to contradict earlier reports. From large statin-intervention studies, it has been suggested that the beneficial effect on cardiovascular morbidity and mortality may extend beyond the lipid-lowering effect of statins32,33. So called pleiotropic effects, including a decrease in vascular low-grade inflammation, increased plaque stability and improvement in endothelial function are held responsible for this additional beneficial effect. However, earlier prospective studies concerning the effect of statins on endothelial function have yielded conflicting results. While several studies report a positive effect on NO-dependent vasodilation, including one with rosuvastatin6,9-16,34,35, other studies report no effect at all17- 20,36. Especially in subjects with type 2 diabetes mellitus, the effect is controversial, with only two studies reporting a positive effect34,37.

One possible explanation for the observed differences in effects of statins between the various studies could be the variation in the methods used to assess endothelial vasoreactivity. The vasodilator response to acetylcholine measures the effect of treatment on forearm resistance vessels, while high-resolution ultrasound of the brachial artery during reactive hyperaemia focuses on the large conduit vessels19. In these different vascular tissue beds, the stimuli that trigger NO-production and release may vary (i.e. the effect of shear-stress on NO-release is supposed to be larger in large conduit vessels), leading to a different effect on NO- release. Therefore, in our study, we used both techniques to measure endothelium-dependent vasoreactivity. Nonetheless, the lack of effect of rosuvastatin on endothelium-dependent vasodilation was consistent across both measurement methods. No significant differences in FMD and FBF-ratio were observed after 12 weeks rosuvastatin therapy. Interestingly, there was also no significant correlation between the endothelium-dependent vasodilator response to acetylcholine and the flow-induced hyperaemic response (nor between both endothelium-independent responses to nitrates). It is unlikely that this lack of correlation is due to technical difficulties during the measurements. We have recently performed extensive reproducibility studies and reported a good medium-term (weeks) reproducibility of both FMD and FBF measurements with the currently used methods38,39. In addition, there is an excellent correlation of brachial artery diameters (as measured with high resolution ultrasonography) across both treatment periods of our study. The lack of correlation between FMD and Ach-induced vasodilation could rather be explained by the fact that during reactive hyperaemia, apart from nitric oxide (NO), several other factors (like adenosine, prostaglandins and ATP-sensitive potassium- channels) also play a role in the vasodilatory response40. Furthermore, the lack of correlation between the endothelium- independent responses suggests that the amount of endothelial damage (NO-generating capacity) and/or the smooth-muscle responsiveness to NO is unequal in both types of vascular tissue beds. These findings are in line with an earlier report by Monnink et al.41, and have to be kept in mind when performing intervention studies, since the effect of an intervention on endothelial function does not necessarily have to be equal in the different vascular tissue beds.

A potential explanation for the lack of effect of rosuvastatin on endothelial vasoreactivity in the present study is pre-existing irreversible endothelial damage, resulting in an impairment of both endotheliumdependent and -independent vasodilation. Although this could be an explanation for the lack of effect of various statins on endothelial function in subjects with type 2 diabetes (where irreversible endothelial damage may be the result of persistent hyperglycaemia and the presence of autonomic neuropathy20,42), it cannot explain the lack of effect of rosuvastatin in our study. Although endotheliumdependent vasoreactivity was decreased in comparison with a group of healthy younger subjects38, endotheliumindependent vasoreactivity was comparable with results in healthy subjects43, thereby rejecting the hypothesis that endothelial damage (decreased NO-generating capacity and/or a decreased smooth-muscle responsiveness to NO) could be responsible for the observed lack of effect.

It is unlikely that the absence of an effect of rosuvastatin on endothelial vasoreactivity is the result of a type II statistical error, since power calculations revealed that we should have been able to detect a clinical relevant difference in forearm vasodilator response of 3.SmLmin^sup -1^-dL^sup -1^. Still, the number of subjects in the current study was relatively small and the study- duration was relatively short. Therefore, we cannot rule out the possibility of missing a delayed onset-vasoactive effect, although the chance of missing such a late-onset effect is small because other studies have demonstrated that a beneficial effect of statins could be detected as early as hours after administration12.

An alternative explanation for the lack of effect of rosuvastatin on endothelial function may be the fact that rosuvastatin had no effect on insulin sensitivity in FCH-subjects. In previous studies, a decreased insulin sensitivity has been associated with a marked endothelial dysfunction22. The mechanism(s) by which insulin resistance could affect endothelial function are not yet fully elucidated. Blunted activity of the phosphatidyl inositol-3 kinase (PI3K)-pathway might be a possible explanation, since this leads to a combined defect in insulin-mediated glucose transport and in (insulin stimulated) endothelial vasodilation44. Alternatively, there might be a shared (more proximal) disorder in FCH-patients, responsible for the parallel development of both insulin resistance and endothelial dysfunction (as suggested by the 'foetal insulin hypothesis'45) that was not affected by rosuvastatin treatment.

In conclusion, our study demonstrates that in patients with FCH, a 12-week treatment of rosuvastatin 40 mg/ day did not improve endothelial function (neither in large conduit vessels, nor in resistance vessels), despite significant improvements in plasma lipids, (apo)lipoproteins and low-grade inflammation. Perhaps the fact that insulin resistance was not reversed may relate to these findings.

Acknowledgements

Declaration of interest: This study was funded by an unrestricted grant from Astra Zeneca. Dr C. Tack is a recipient of a clinical fellowship of the Dutch Diabetes Foundation.

Drs E. ter Avest and E. Abbink contributed equally to this study. We especially thank the patients who participated in this study. The help of Ms T. Terburg, research nurse, is gratefully acknowledged. We thank Mrs M. Beelen and Mr R. Praster for all FMD measurements, and Mrs H. Lemmers, Mrs H. Toenhake, Ms M. Hectors and Mrs E. Bolat for technical assistance.

References

1. de Graaf J, Veerkamp MJ, Stalenhoef AF. Metabolic pathogenesis of familial combined hyperlipidaemia with emphasis on insulin resistance, adipose tissue metabolism and free fatty acids. J R Soc Med 2002;95(Suppl 42):46-53

2. Bredie SJ, Tack CJ, Smits P, et al. Nonobese patients with familial combined hyperlipidemia are insulin resistant compared with their nonaffected relatives. Arterioscler Thromb Vase Biol 1997;17:1465-71

3. Bredie SJ, Demacker PN, Stalenhoef AF. Metabolic and genetic aspects of familial combined hyperlipidaemia with emphasis on low- density lipoprotein heterogeneity. Eur J Clin Invest 1997;27:802-11

4. de Graaf J, Stalenhoef AF. Defects of lipoprotein metabolism in familial combined hyperlipidaemia. Curr Opin Lipidol1998;9:189- 96

5. Veerkamp MJ, de Graaf J, Hendriks JC, et al. Nomogram to diagnose familial combined hyperlipidemia on the basis of results of a 5-year follow-up study. Circulation 2004;109:2980-5

6. Stroes E, de Bruin T, de VaIk H, et al. NO activity in familial combined hyperlipidemia: potential role of cholesterol remnants. Cardiovasc Res 1997;36:445-52

7. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899-906

8. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy3- methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vase Biol 2001 ;21:1712-9

9. Beckman JA, Liao JK, Hurley S, et al. Atorvastatin restores endothelial function in normocholesterolemic smokers independent of changes in low-density lipoprotein. Circ Res 2004;95:217-23

10. Marchesi S, Lupattelli G, Siepi D, et al. Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women. J Cardiovasc Pharmacol 2000;36:617-21

11. O'driscoll G, Green D, Taylor RR. Simvastatin, an HMGcoenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997;95:1126-31

12. Omori H, Nagashima H, Tsurumi Y, et al. Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol 2002;54:395-9

13. Perticone F, Ceravolo R, Maio R, et al. Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients. Atherosclerosis 2000;152:511-8

14. Sakabe K, Fukuda N, Wakayama K, et al. Time course differences for statin-induced pleiotropic effects in hypercholesterolemic patients. Int J Cardiol 2004;94:111-7

15. Vogel RA, Corretti MC, Plotnick GD. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men. Am J Cardiol 1996;77:37-40

16. Wassmann S, Ribaudo N, Paul A, et al. Effect of atorvastatin 80 mg on endothelial cell function (forearm blood flow) in patients with pretreatment serum low-density lipoprotein cholesterol levels < 130mg/dL. Am J Cardiol 2004;93:84-8

17. Sheu WH, Juang BL, Chen YT, et al. Endothelial dysfunction is not reversed by Simvastatin treatment in type 2 diabetic patients with hypercholesterolemia. Diabetes Care 1999;22:1224-5

18. van de Ree MA, Huisman MV, de Man FH, et al. Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of Simvastatin. Cardiovasc Res 2001;52:299-305

19. van Etten RW, de Koning EJ, Honing ML, et al. Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. Arterioscler Thromb Vase Biol 2002;22:799-804

20. van Venrooij FV, van de Ree MA, Bots ML, et al. Aggressive lipid lowering does not improve endothelial function in type 2 diabetes: the Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized, double-blind, placebo-controlled trial. Diabetes Care 2002;25:1211-6

21. Paniagua JA, Lopez-Miranda J, Escribano A, et al. Cerivastatin improves insulin sensitivity and insulin secretion in early-state obese type 2 diabetes. Diabetes 2002; 51:2596-603

22. Baron AD. Insulin resistance and vascular function. J Diabetes Complications 2002;16:92-102

23. Veerkamp MJ, de Graaf J, Stalenhoef AF. Role of insulin resistance in familial combined hyperlipidemia. Arterioscler Thromb Vase Biol 2005;25:1026-31

24. Bijlstra PJ, den Arend JA, Lutterman JA, et al. Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans. Diabetologia 1996;39:1562-8

25. Bijlstra PJ, Lutterman JA, Russel FG, et al. Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans. Diabetologia 1996;39:1083-90

26. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:llll-5

27. Demacker PN, Hijmans AG, Vos-Janssen HE, et al. A study of the use of polyethylene glycol in estimating cholesterol in highdensity lipoprotein. Clin Chem 1980;26:1775-9

28. van Tits LJ, van Himbergen TM, Lemmers HL, et al. Proportion of oxidized LDL relative to plasma apolipoprotein B does not change during statin therapy in patients with heterozygous familial hypercholesterolemia. Atherosclerosis 2005;Jul 7; [Epub ahead of print; doi:10.1016/j.atherosclerosis.2005.06.006]

29. Demacker PN, Veerkamp MJ, Bredie SJ, et al. Comparison of the measurement of lipids and lipoproteins versus assay of apolipoprotein B for estimation of coronary heart disease risk: a study in familial combined hyperlipidemia. Atherosclerosis 2000;153:483-90

30. de Galan BE, Tack CJ, Lenders JW, et al. Theophylline improves hypoglycemia unawareness in type 1 diabetes. Diabetes 2002;51:790-6

31. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9

32. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990;322:1700-7

33. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7

34. Tsunekawa T, Hayashi T, Kano H, et al. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 2001; 104:376-9

35. Lu TM, Ding YA, Leu HB, et al. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol 2004;94:157-61

36. Parnell MM, Chin-Dusting JP, Starr J, et al. Low-dose atorvastatin therapy does not augment endothelial function in active hypercholesterolaemic males. Br J Clin Pharmacol 2003;55:212-5

37. Economides PA, caselli A, Tiani E, et al. The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes. J CHn Endocrinol Metab 2004;89:740-7

38. ter Avest E, Holewijn S, Stalenhoef AF, et al. Variation in noninvasive measurements of vascular function in healthy volunteers during daytime. CIm Sci (Lond) 2005; 108:425-31

39. Thijssen DH, Bleeker MW, Smits P, et al. Reproducibility of blood flow and post-occlusive reactive hyperaemia as measured by venous occlusion plethysmography. CHn Sci (Lond) 2005;108:151-7

40. Carlsson I, Sollevi A, Wennmalm A. The role of myogenic relaxation, adenosine and prostaglandins in human forearm reactive hyperaemia. J Physiol 1987;389:147-61

41. Monnink SH, van Haelst PL, van Boven AJ, et al. Endothelial dysfunction in patients with coronary artery disease: a comparison of three frequently reported tests. J Investig Med 2002; 50:19-24

42. Henry RM, Ferreira I, Kostense PJ, et al. Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not; The Hoorn Study. Atherosclerosis 2004; 174:49-56

43. Hijmering ML, Stroes ES, Pasterkamp G, et al. Variability of flow mediated dilation: consequences for clinical application. Atherosclerosis 2001; 157:369-73

44. Hsueh WA, Quinones MJ. Role of endothelial dysfunction in insulin resistance. Am J Cardiol 2003;92:10J-17

45. Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999;353:1789-2

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3121J,, Accepted for publication: 02 August 2005

Published Online: OO August 2005

doi:10.1185/030079905X61910

Ewoud ter Avest(a), Evertine J. Abbink(a), Suzanne Holewijn(a,b), Jacqueline de Graaf(a), Cees J. Tack(a) and Anton F. H. Stalenhoef(a)

a Department of Medicine, Division of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

b Vascular Laboratory, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Address for correspondence: A. F. H. Stalenhoef, MD, PhD, Professor of Medicine, 541 Department of Internal Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101,6500HB Nijmegen, The Netherlands. Tel.: +31-243-616552; Fax: +31-243-541734; email: a.stalenhoef@aig.umcn.nl

Copyright Librapharm Sep 2005

Source: Current Medical Research and Opinion

More News in this Category