Mieke D. Trip

Toll‐like receptor‐4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolaemia

Backgroundu2002 Toll‐like receptor‐4 (TLR4) is a major receptor for inflammatory stimuli potentially involved in the pathogenesis of atherosclerosis, such as lipopolysaccharide (LPS) and heat‐shock proteins. The Asp299Gly polymorphism of the TLR4 gene has been associated with a reduced intima‐media thickness (IMT) of the common carotid artery in healthy individuals. We have investigated whether the presence of the Asp299Gly polymorphism in patients with familial hypercholesterolaemia (FH) has a similar protective effect, and whether it influences the effects of HMG‐CoA reductase treatment.

Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.

BACKGROUNDnFamilial hypercholesterolemia (FH) has been associated with increased cardiovascular risk when untreated or when normal LDL-C concentrations are not reached. Some patients with FH do not reach LDL-C goals despite intensive combination therapy.nnnOBJECTIVEnThis study assessed the efficacy and tolerability of colesevelam added to maximally tolerated, stable-dose combination treatment with a statin + ezetimibe.nnnMETHODSnThis Phase IV, multicenter, randomized, double-blind, placebo-controlled trial enrolled patients aged 18 to 75 years with FH and an LDL-C concentration >2.5 mmol/L who were receiving a maximally tolerated and stable regimen of a statin + ezetimibe. Patients were randomly assigned to receive colesevelam 3.75 g/d or placebo added to the statin + ezetimibe for 12 weeks. The primary efficacy outcome was the difference in LDL-C between the colesevelam and placebo groups after 6 weeks. Secondary efficacy outcomes were between-group differences in LDL-C, total cholesterol (TC), HDL-C, triglyceride (Tg), apolipoprotein (apo) B, and apoA-I concentrations, as well as apoB/apoA-I ratio after 12 weeks. Tolerability was assessed based on the prevalences of adverse events by organ system class in each treatment group.nnnRESULTSnEighty-six patients were randomized (45 colesevelam, 41 placebo), of whom 84 (44 colesevelam, 40 placebo) were included in the primary analysis. The mean (SD) age of the participants was 52.8 (10.8) years, and 51 (59%) were men. The difference (95% CI) in LDL-C between colesevelam and placebo after 6 weeks was -18.5% (-25.3 to -11.8). Between-group differences in LDL-C, TC, HDL-C, Tg, and apoB/apoA-I ratio after 12 weeks were -12.0% (-17.8 to -6.3), -7.3% (-12.0 to -2.6), +3.3% (-2.4 to +9.0), +2.8% (-10.4 to +15.9), and -12.2% (-20.2 to -4.2), respectively. Colesevelam was generally well tolerated, with gastrointestinal adverse events in 12 of 45 patients (27%) versus 7 of 40 (18%) in the placebo group (P = NS).nnnCONCLUSIONnIn these patients with FH, colesevelam added to a combination of a statin + ezetimibe was associated with significantly improved LDL-C concentrations compared with placebo during the 12-week study period and was generally well tolerated.

Rationale, Design and Baseline Characteristics of a Clinical Trial Comparing the Effects of Robust vs Conventional Cholesterol Lowering and Intima Media Thickness in Patients with Familial Hypercholesterolaemia : The Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) Study.

AbstractObjective: Hypercholesterolaemia is strongly associated with increased vessel wall thickness as measured by ultrasound. The question is whether aggressive cholesterol lowering with high-dose atorvastatin can alter intima media thickening to a greater extent than conventional therapy in patients with familial hypercholesterolaemia (FH). The baseline characteristics of a double-blind, randomised trial are described to determine whether two active treatments (high-dose atorvastatin 80mg versus conventional dose simvastatin 40mg), administered over a period of 2 years, may retard the process of intima media thickening in the carotid and femoral arteries of patients with FH.n Design and Patients: 325 patients with FH were randomised. Patients entered an 8-week placebo period in which all lipid-lowering medication was discontinued. Thereafter, baseline measurements of lipoprotein parameters and intima media thickness (IMT) of carotid and femoral artery were performed.n Results: Baseline low density lipoprotein (LDL) cholesterol (±SD) levels were 8.11 ± 1.92 mmol/L (312 ± 73 mg/dl) in men and 8.22 ± 1.91 mmol/L (316 ± 73 mg/dl) in women, respectively. Mean posterior wall IMT in the left common carotid artery (CCA) was significantly greater in men (0.94 ± 0.29mm) compared with women (0.85 ± 0.20) [p < 0.05]. A similar difference was found for the internal carotid artery (ICA). In the carotid bifurcation, IMT was 1.20 ± 0.50mm in men and 1.1 ± 0.54mm in women. The IMT of the common femoral artery (CFA) was 2.03 ± 0.88mm in men with cardiovascular disease (CVD) and 1.63 ± 0.70mm in men without CVD (p < 0.05). Strikingly, plaques were present in all men and 95% of the women with CVD. The cholesterol-year score and HDL cholesterol levels partially explained the variation in IMT in the carotid bifurcation, whereas gender and smoking contributed to the variation in IMT in the CFA in this group of patients.n Conclusion: The patients participating in the Atorvastatin and Simvastatin on Atherosclerosis Progression (ASAP) trial constitute the largest well-documented FH population exhibiting marked increases in IMT of both carotid and femoral arteries and a very high prevalence of plaques, indicating extreme CVD risk. Since lipid-lowering therapy provides the highest benefit in precisely such patients, the ASAP trial will help assess whether aggressive LDL cholesterol intervention leads to retardation of subclinical atherosclerosis progression, as estimated with ultrasonographically assessed IMT.

Current and Future Pharmacologic Options for the Management of Patients Unable to Achieve Low-Density Lipoprotein-Cholesterol Goals with Statins

Low-density lipoprotein-cholesterol (LDL-C) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk. HMG-CoA reductase inhibitors (statins) are currently the most effective LDL-C-lowering drugs. However, a substantial number of patients do not reach treatment targets with statins. Therefore, an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels, either by monotherapy or combination therapy. Upregulation of the LDL receptor with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat (TAK-475) has recently been discontinued. Ezetimibe combined with statins allowed significantly more patients to reach their LDL-C targets. Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate (FM-VP4) and bile acid transport inhibitors have shown positive results in early development trials, whereas the prospect of acyl coenzyme A: cholesterol acyltransferase inhibition in cardiovascular prevention is dire. Selective inhibition of messenger RNA (mRNA) by antisense oligonucleotides is a new approach to modify cholesterol levels. The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium (ISIS 301012) has shown striking results in phase II studies both as monotherapy as well as in combination with statins.

Genome-Wide Association Studies in Atherosclerosis

Cardiovascular disease remains the major cause of worldwide morbidity and mortality. Its pathophysiology is complex and multifactorial. Because the phenotype of cardiovascular disease often shows a marked heritable pattern, it is likely that genetic factors play an important role. In recent years, large genome-wide association studies have been conducted to decipher the molecular mechanisms underlying this heritable and prevalent phenotype. The emphasis of this review is on the recently identified 17 susceptibility loci for coronary artery disease. Implications of their discovery for biology and clinical medicine are discussed. A description of the landscape of human genetics in the near future in the context of next-generation sequence technologies is provided at the conclusion of this review.

Long-term LDL-c lowering in heterozygous familial hypercholesterolemia normalizes carotid intima-media thickness

OBJECTIVEnWe investigated the effectiveness of statins in daily practice in reducing the arterial wall thicknesses by comparing the carotid intima-media thickness (cIMT) between statin-treated familial hypercholesterolemia (FH) patients and their unaffected spouses.nnnMETHODSnFH subjects treated with LDL-c lowering medication for at least 5 years and their unaffected spouses were included in this observational study. Clinical data and carotid intima-media thickness (cIMT) as surrogate marker for atherosclerosis were acquired.nnnRESULTSnIn total 40 FH patients, age 48.4±4.2 years, and their 40 unaffected spouses, age 47.4±3.9 years, were included. Pre-treatment total cholesterol levels of FH patients were on average 9.3±2.0 mmol/L. Treated FH patients and unaffected spouses exhibited similar LDL-c (3.8±1.5 vs. 3.5±1.1 mmol/L; p=0.25) and total cholesterol levels (5.8±1.6 vs. 5.6±1.1 mmol/L; p=0.56). Also, in a multivariate model cIMT adjusted for age and sex did not differ between affected and spouses (95% CI: -0.032 to 0.092 mm; p=0.34).nnnCONCLUSIONnLong-term statin treatment normalizes cIMT in severe FH patients and therefore it is likely that the extreme risk of cardiovascular disease in FH patients is significantly reduced by this therapy.

Prognostic value of myocardial perfusion scintigraphy in type 2 diabetic patients with mild, stable angina pectoris

AimTo determine the prognostic value of reversible myocardial perfusion defects on myocardial perfusion scintigraphy (MPS) in patients with type 2 diabetes mellitus and mild anginal complaints.Methods and resultsIn the MERIDIAN trial, patients with diabetes mellitus type 2, stable, mild anginal symptoms (Canadian Cardiovascular Society classification (CCS) I-II/IV) and reversible perfusion defects were randomized to either continued pharmacological treatment or early invasive treatment. In this sub analysis, the severity of the myocardial perfusion defect was related to the occurrence of cardiac death and non-fatal myocardial infarction, in 319 patients (63% male, 65xa0±xa09xa0years). During follow-up (2.2xa0±xa00.6xa0years), 14 patients had a cardiac event: 3 in 171 patients without myocardial ischemia and 11 in 148 patients with myocardial ischemia. Annual event rates rose from 0.8% to 5.8% with increasing severity of myocardial ischemia. Multivariable analysis identified the presence of severe myocardial ischemia (hazard ratio (HR) 5.45, 95%CI 1.89-15.71) and insulin use (HR 4.00, 95%CI 1.25-12.75) as independent predictors of cardiac events.ConclusionsType 2 diabetics with mild anginal symptoms with no or moderate myocardial ischemia have a low annual cardiac event rate. In patients with severe myocardial ischemia event rate increased 3-6 fold.

Efficacy and safety of disodium ascorbyl phytostanol phosphates in men with moderate dyslipidemia

ObjectiveThis study investigated the efficacy, safety, tolerability, and pharmacokinetics of a novel cholesterol absorption inhibitor, FM-VP4, comprising disodium ascorbyl sitostanol phosphate (DASP) and disodium ascorbyl campestanol phosphate (DACP).MethodsIn phase 1, 30 men received a single dose of 100, 200, 400, 800, 1,600, or 2,000xa0mg FM-VP4 or placebo. In phase 2, 100 men were treated with 100, 200, 400, or 800xa0mg/day of FM-VP4 or placebo for 4xa0weeks.ResultsThe drug was well tolerated at each single or multiple dose level. After 4 weeks of treatment, low-density lipoprotein cholesterol (LDL-C) levels changed by 2.7% in the placebo group and by 2.9%, −4.2%, and −4.6% in the 100, 200, and 800xa0mg/day groups, respectively, which was not statistically significant. However, 400xa0mg/day of FM-VP4 significantly decreased LDL-C by 6.5% (p=0.02). Phase 1 showed that DACP and DASP were absorbed into plasma with a median tmax of 12xa0h for both components, and clearance was slow with a mean t1/2λ of 57xa0h. During 4xa0weeks of treatment, steady state was reached by approximately 8xa0days.ConclusionThis study demonstrated that up to 800xa0mg/day of FM-VP4 is safe and well tolerated for at least 4xa0weeks. Furthermore, the higher doses significantly reduced LDL-C by 7% compared with baseline or by 10% compared with placebo, with the maximum effect reached at 400xa0mg/day.

Prevalence of myocardial ischaemia as assessed with myocardial perfusion scintigraphy in patients with diabetes mellitus type 2 and mild anginal symptoms

PurposeTo determine the prevalence and predictors of reversible myocardial perfusion defects, indicative of myocardial ischaemia, in patients with mild, stable anginal complaints [Canadian Cardiovascular Society classification (CCS) I–II/IV] and diabetes mellitus type 2 (T2DM).MethodsA total of 329 patients with T2DM and stable, mild anginal symptoms (CCS I–II/IV) underwent myocardial perfusion scintigraphy. Perfusion images were assessed using a five-point (semi)-quantitative scoring system according to a 17-segment myocardial model.ResultsOne-hundred and fifty-six (47%) patients showed reversible myocardial perfusion defects defined as a summed difference score of ≥3. Male gender [odds ratio (OR) 2.28, 95% CI 1.4–3.71, p=0.001], previous myocardial infarction (MI) without revascularisation (OR 3.04, 95% CI 1.28–7.24, p=0.01), and the use of two or more classes of anti-anginal medication (OR 2.36, 95% CI 1.48–3.76, p<0.001) were independent predictors for the presence of reversible defects. By contrast, lipid-lowering therapy reduced the possibility of reversible perfusion defects (OR 0.56, 95% CI 0.33–0.95, p=0.03).ConclusionApproximately half of the patients with mild, stable angina pectoris and T2DM showed evidence of myocardial ischaemia. Male gender, previous MI and the use of anti-anginal medication were positive predictors and lipid-lowering therapy was a negative predictor for the results of the scintigraphic stress test.