LDL cholesterol targets rarely achieved in familial hypercholesterolemia patients: A sex and gender-specific analysis.

BACKGROUND AND AIMS: Despite lipid lowering therapy (LLT), reaching LDL-C targets in patients with familial hypercholesterolemia (FH) remains challenging. Our aim was to determine attainment of LDL-C target levels and reasons for not reaching these in female and male FH patients. METHODS: We performed a cross-sectional study of heterozygous FH patients in five hospitals in the Netherlands and Norway. Clinical characteristics and information about LLT, lipid levels and reasons for not being on LDL-C treatment target were retrospectively collected from electronic medical records. RESULTS: We studied 3178 FH patients (53.9% women), median age 48.0 (IQR 34.0-59.9) years. Median LDL-C before treatment and on-treatment was higher in women compared to men (6.2 (IQR 5.1-7.3) and 6.0 (IQR 4.9-7.2) mmol/l (p=0.005) and 3.0 (IQR 2.4-3.8) and 2.8 (IQR 2.3-3.5) mmol/L (p<0.001)), respectively. A minority of women (26.9%) and men (28.9%) reached LDL-C target. In patients with CVD, 17.2% of women and 25.8% of men reached LDL-C target. Women received less often high-intensity statins and ezetimibe. Most common reported reasons for not achieving the LDL-C target were insufficient effect of maximum LLT (women 17.3%, men 24.3%) and side effects (women 15.2%, men 8.6%). CONCLUSIONS: In routine practice, only a minority of women and men with FH achieved their LDL-C treatment target. Extra efforts have to be made to provide FH patients with reliable information on the safety of statins and their long-term effects on CVD risk reduction. If statin treatment is insufficient, alternative lipid lowering therapies such as ezetimibe or PCSK9-inhibitors should be considered.

The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown. OBJECTIVES: The aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD. METHODS: In this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables. RESULTS: We randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: -0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: -0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (-205.6 pmol/L; 95% CI: -255.8, -155.3 pmol/L). No adverse events were reported. CONCLUSION: MK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

Elastic compression stockings one year after DVT diagnosis: Who might discontinue?

BACKGROUND: Elastic compression stockings (ECS) are uncomfortable to wear but may prevent post-thrombotic syndrome (PTS). The ability to predict PTS may help clinical decision making regarding the optimal duration of ECS after deep vein thrombosis (DVT). AIMS: Predefined endpoint analysis of the Octavia study that randomized patients who compliantly used ECS up to one year after DVT to continue or discontinue ECS treatment. Primary aim was to identify predictors of PTS. METHODS: Patient characteristics were collected and ultrasonography was performed to assess reflux, residual thrombosis and persistent thrombus load 12 months after DVT. Multivariable analyses were performed to identify factors related to PTS. RESULTS: Thrombus score ≥ 3, BMI ≥ 26, duration of symptoms before DVT diagnosis ≥ 8 days and a Villalta score of 2-4 points were statistically significant predictors of PTS. The predictive value for PTS for the assessed variables was not different between the 2 treatment groups. In the stop ECS group, 3.2% (95%CI 0.08-18) of patients without any predictors for PTS were diagnosed with mild PTS during follow-up, and none with severe PTS, for a sensitivity of 98% (95% CI 89-100), a specificity of 14% (95% CI 10-20), a positive predictive value of 20% (95% CI 19-22), and a negative predictive value of 97% (95% CI 81-100). CONCLUSION: We identified 4 predictors of PTS occurring in the 2nd year after DVT. Our findings may be used to decide on whether to continue ECS treatment for an additional year, after one year of compliant ECS use, keeping in mind that patients with none of the predictors will have the lowest PTS incidence.

Predicting Post-Thrombotic Syndrome with Ultrasonographic Follow-Up after Deep Vein Thrombosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Post-thrombotic syndrome (PTS) is a common and potential severe complication of deep venous thrombosis (DVT). Elastic compression stocking therapy may prevent PTS if worn on a daily basis, but stockings are cumbersome to apply and uncomfortable to wear. Hence, identification of predictors of PTS may help physicians to select patients at high risk of PTS. AIMS: This article identifies ultrasonography (US) parameters assessed during or after treatment of DVT of the leg, that predict PTS. METHODS: This is a systematic review and meta-analysis study. Databases were searched for prospective studies including consecutive patients with DVT who received standardized treatment, had an US during follow-up assessing findings consistent with vascular damage after DVT and had a follow-up period of at least 6 months for the occurrence of PTS assessed by a standardized protocol. RESULTS: The literature search revealed 1,156 studies of which 1,068 were irrelevant after title and abstract screening by three independent reviewers. After full-text screening, 12 relevant studies were included, with a total of 2,684 analysed patients. Two US parameters proved to be predictive of PTS: residual vein thrombosis, for a pooled odds ratio (OR) of 2.17 (95% confidence interval [CI], 1.79-2.63) and venous reflux at the popliteal level, for a pooled OR of 1.34 (95% CI, 1.03-1.75). CONCLUSION: The US features reflux and residual thrombosis measured at least 6 weeks after DVT predict PTS. Whether these features may be used to identify patients who may benefit from compression therapy remains to be assessed in further studies.

Consideration of hypertensive retinopathy as an important end-organ damage in patients with hypertension.

Longstanding and therapy-resistant hypertension may cause cerebral, renal, cardiac and retinal end-organ damage (EOD). Retinal hypertensive abnormalities are correlated with an increased risk of cardiovascular (CV) disease in general but are not included in CV risk assessment tools. Research into prevalence and determinants of retinal organ damage, such as hypertensive retinopathy (HR), is scarce. We evaluated the prevalence of HR and the association with other signs of EOD in patients with hypertension. A retrospective observational study was performed in all hypertensive patients referred by a general practitioner to the hypertension clinic at the Diakonessenhuis, Utrecht and Zeist, the Netherlands between 2011 and 2013. A screening of risk factors, albuminuria, left-ventricular hypertrophy (LVH) and retinal fundoscopy was performed. In all, 44% (123/280) of patients referred to the clinic were diagnosed with HR, while 15 and 11% were diagnosed with LVH and microalbuminuria, respectively. Patients with isolated HR consisted of 31% of all patients. When HR was added as a form of EOD, the percentage of patients with a treatment indication increased from 3 to 14%. Patients who were already on treatment goal exhibited a high prevalence of HR (28%), warranting treatment intensification. HR is prevalent in a third of hypertensive patients referred to our clinic, and isolated HR accounts for the majority of (end-) organ damages. Fundoscopy in the evaluation of hypertension might improve the indication for therapy. Furthermore, diagnosing HR could be helpful in selecting patients with hypertension on treatment goal in need of more aggressive treatment.

One versus two years of elastic compression stockings for prevention of post-thrombotic syndrome (OCTAVIA study): randomised controlled trial.

OBJECTIVE:  To study whether stopping elastic compression stockings (ECS) after 12 months is non-inferior to continuing them for 24 months after proximal deep venous thrombosis. DESIGN:  Multicentre single blind non-inferiority randomised controlled trial. SETTING:  Outpatient clinics in eight teaching hospitals in the Netherlands, including one university medical centre. PARTICIPANTS:  Patients compliant with compression therapy for 12 months after symptomatic, ultrasound proven proximal deep venous thrombosis of the leg. INTERVENTIONS:  Continuation or cessation of ECS 12 months after deep venous thrombosis. MAIN OUTCOME MEASURES:  The primary outcome was the incidence of post-thrombotic syndrome 24 months after diagnosis of deep venous thrombosis, as assessed by the standardised Villalta scale in an intention to treat analysis. The predefined non-inferiority margin was 10%. The main secondary outcome was quality of life (VEINES-QOL/Sym). RESULTS:  518 patients compliant with ECS and free of post-thrombotic syndrome were randomised one year after diagnosis of deep venous thrombosis to stop or continue ECS therapy for another year. In the stop-ECS group, 51 of 256 patients developed post-thrombotic syndrome, with an incidence of 19.9% (95% confidence interval 16% to 24%). In the continue-ECS group, 34 of 262 patients developed post-thrombotic syndrome (incidence 13.0%, 9.9% to 17%), of whom 85% used ECS six or seven days a week during the study period, for an absolute difference of 6.9% (95% confidence interval upper limit 12.3%). Because the upper limit of the 95% confidence interval exceeds the predefined margin of 10%, non-inferiority was not reached. The number needed to treat to prevent one case of post-thrombotic syndrome by continuing ECS was 14 (95% confidence interval lower limit 8). Quality of life did not differ between the two groups. CONCLUSION:  Stopping ECS after one year in compliant patients with proximal deep venous thrombosis seemed not to be non-inferior to continuing ECS therapy for two years in this non-inferiority trial. TRIAL REGISTRATION:  Netherlands Trial Register NTR1442.

Optimal drug therapy after aspirin-induced upper gastrointestinal bleeding.

Upper gastrointestinal bleeding is a common adverse effect of chronic aspirin treatment. Traditionally, most physicians might tend to discontinue aspirin therapy after related gastrointestinal bleeding. However, recent studies have shown that continuation of aspirin is beneficial because of a decrease of cardiovascular complications and only a relatively small increase of recurrent peptic ulcer bleeding when combined with a proton pump inhibitor. There might be individual cases where the burden of recurrent gastrointestinal complications outweighs the risk of vascular events. In these cases the physician needs to carefully consider other precipitating factors for the recurrent gastrointestinal symptoms. At the moment, alternative antiplatelet therapy does not lead to lower gastrointestinal risks. In the near future, therapies with a more favorable profile might emerge.

Is extensive screening for cancer in idiopathic venous thromboembolism warranted?

BACKGROUND: Patients with a first episode of idiopathic venous thromboembolism (IVTE) have an estimated 10% incidence of cancer within 12 months after diagnosis. However, the utility of screening for cancer in this population is controversial. METHODS: In this prospective concurrently controlled cohort study, limited and extensive cancer screening strategies were compared. All 630 patients underwent baseline screening consisting of history, physical examination, basic laboratory tests and chest X-ray. In the extensive screening group abdominal and chest CT scan and mammography were added. Outcomes were incidence and curability of cancer, and cancer-related and overall mortality. RESULTS: In 12 of the 342 (3.5%) patients in the extensive screening group malignancy was diagnosed at baseline compared with 2.4% (seven of 288 patients) in the limited screening group. Extensive screening detected six additional cancers (2.0%; 95% CI, 0.74-4.3), of which three were potentially curable. During a median 2.5 years of follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. In the extensive screening group 26 patients (7.6%) died compared with 24 (8.3%) in the limited screening group; adjusted hazard ratio 1.22 (95% CI, 0.69-2.22). Of these deaths 17 (5.0%) in the extensive screening group and 8 (2.8%) in the limited screening group were cancer related; adjusted hazard ratio 1.79 (95% CI, 0.74-4.35). CONCLUSIONS: The low yield of extensive screening and lack of survival benefit do not support routine screening for cancer with abdominal and chest CT scan and mammography in patients with a first episode of IVTE.

The use of D-dimer in specific clinical conditions: a narrative review.

The use of D-dimer in combination with a clinical decision rule has been widely investigated in pulmonary embolism and deep venous thrombosis. Although it has been shown to be safe in excluding venous thromboembolism, the clinician is often faced with specific situations in which the use of D-dimer is controversial. We review the best available evidence on these patients. We conclude that it is not safe to use D-dimer testing in patients with symptoms of a venous thromboembolism for over 14 days, patients receiving therapeutic heparin treatment and patients with suspected deep venous thrombosis during oral anticoagulant therapy. In these populations the levels of D-dimer can be lower then expected giving rise to false-negative results. It is safe to use D-dimer testing in combination with a clinical decision rule in patients of all ages, patients presenting with a suspected recurrent venous thromboembolism or inpatients with suspected pulmonary embolism. As patients with recurrent venous thromboembolism, elderly patients and inpatients have higher levels of D-dimer, D-dimer testing has a low specificity and the need for additional radiological testing is increased.

Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis.

BACKGROUND: The evidence on the optimal duration of treatment in patients with an idiopathic venous thromboembolic event (VTE) is inconclusive. d-dimer testing to predict recurrent VTE has been evaluated in several studies. OBJECTIVES: We performed a meta-analysis of studies of patients with idiopathic VTE treated with oral anticoagulation therapy (OAT) to assess the prognostic value of elevated D-dimer levels 1 month after discontinuation of OAT for VTE recurrence. PATIENTS/METHODS: The MEDLINE, EMBASE and Cochrane databases were searched to identify relevant studies. Studies were eligible for inclusion if they included patients with idiopathic VTE and in addition reported results for this group separately, had measured D-dimer approximately 1 month after discontinuation of OAT and had reported on recurrence of VTE. A random-effects model was used to pool study results. RESULTS: Data from four studies (1539 patients) were included in the current analysis. All studies reported on the number of recurrent events in the normal and elevated D-dimer groups. Overall, 125 of 751 patients (16.6%) with elevated D-dimer levels experienced recurrent VTE during the period of follow-up compared with 57 of 788 patients (7.2%) with normal D-dimer levels. Elevated D-dimer levels were significantly associated with recurrent VTE (odds ratio , 2.36; 95% CI, 1.65 to 3.36). CONCLUSIONS: Elevated d-dimer levels measured 1 month after discontinuation of OAT identify patients with idiopathic VTE at higher risk of recurrence.

Decrease of hemostatic cardiovascular risk factors by aggressive vs. conventional atorvastatin treatment in patients with Type 2 diabetes mellitus.

BACKGROUND: Patients with Type 2 diabetes mellitus have increased levels of hemostatic risk variables for cardiovascular disease, such as fibrinogen, von Willebrand factor (VWF), factor (F)VIIa, d-dimer and plasminogen activator inhibitor-1 (PAI-1). OBJECTIVES: To evaluate the effect of aggressive vs. standard dose atorvastatin on hemostatic cardiovascular risk factors in patients with Type 2 diabetes mellitus. PATIENTS AND METHODS: The effect of 30 weeks of treatment with atorvastatin 10 and 80 mg on hemostatic cardiovascular risk factors was assessed in a randomized double-blind placebo-controlled trial on 217 patients with Type 2 diabetes mellitus and dyslipidemia. RESULTS AND CONCLUSIONS: Atorvastatin 10 and 80 mg dose-dependently reduced d-dimer (7.4% and 8.5%, respectively, P for trend = 0.004) and PAI-1 antigen levels (9.0% and 18%, respectively, P for trend = 0.021). Levels of fibrinogen, VWF, tissue-type plasminogen activator and FVIIa were not influenced by atorvastatin. In conclusion, in patients with Type 2 diabetes mellitus, atorvastatin dose-dependently improved the levels of the hemostatic risk variables d-dimer and PAI-1.

Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus.

OBJECTIVE: Statins are known to reduce CRP concentrations, but whether high doses are more effective is not known. METHODS: In a prospective double-blind multicenter study in 186 DM2 patients without manifest coronary artery disease and with dyslipidemia, the effect of a 30-week treatment with 10 and 80 mg atorvastatin or placebo on the reduction of hs-CRP levels was measured. RESULTS: Median CRP levels increased with 6.6% in the placebo group and were reduced by 15 and 47%, respectively, with atorvastatin 10 and 80 mg (P<0.001; significantly different from 10 mg atorvastatin and from placebo (P<0.001). Variation in IL-6 and plasma lipids associated for 21 and 8%, respectively, with variation in CRP levels (P<0.001 and P=0.01). Of patients with a baseline CRP level above an arbitrary threshold of 3.0 mg/l, 56% in the 80 mg atorvastatin group reached a level of less than 3.0 mg/l, versus 23% randomized to 10 mg atorvastatin (P<0.01) and 17% in the placebo group (P<0.005). CONCLUSIONS: In DM2 patients high dose atorvastatin induced a strong reduction in CRP levels. The decrease in CRP was mainly independent of effects on lipid lowering and changes in IL-6 levels. The pleiotropic effect of high-dose atorvastatin on inflammation could add to its cardioprotective effect in high-risk patients.

Statins in type 2 diabetes mellitus: target on lipids and vascular wall function.

The typical dyslipidaemia in type 2 diabetes mellitus shows high levels of triglycerides, low levels of highdensity lipoprotein cholesterol (HDL-c) and small dense low-density lipoprotein (LDL) particles. In these patients low-dose atorvastatin (10 mg) results in a significant and relevant reduction in triglycerides and LDL-c. High-dose atorvastatin (80 mg) results in a better LDL-c reduction. The endothelial dysfunction is likely to be caused by factors related to insulin resistance and not by dyslipidaemia alone. The results from the DALI study (Diabetes Atorvastatin Lipid Intervention) on lipids and endothelial function are discussed, together with two invasive endothelial function studies in diabetics and hypertriglyceridaemic patients. The subgroup of diabetics in the large secondary prevention trials using statins are analysed with respect to total cholesterol lowering and death due to coronary heart disease and nonfatal myocardial infarction.

Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia.

OBJECTIVES: To infer the relative impact of elevated triglyceride levels and insulin resistance on endothelial dysfunction in patients with chronic hypertriglyceridemia (HTG). METHODS: Endothelial function was studied in 11 HTG patients and 16 normolipidemic controls. Cumulative-dose infusions of 5-hydroxytryptamine (5HT) and sodium nitroprusside were infused locally into the brachial artery to study endothelium-dependent and endothelium-independent vasodilation, respectively. Data of the HTG patients were dichotomized around the median of insulin resistance, calculated as HOMA-index, forming HTG groups with mild (HTG-MIR) and severe insulin resistance (HTG-SIR). RESULTS: HTG patients had higher triglyceride levels and smaller LDL particle size than controls (both P< or =0.001), whereas these parameters did not differ between both HTG groups. Insulin resistance was higher in both HTG groups than in controls (11.1 (7.0-14.5) and 4.9 (4.0-6.7) vs. 2.4 (4.9-5.2), respectively, both P<0.001). Similarly, free fatty acid levels, another indicator of insulin resistance, were highest in the HTG-SIR group, followed by those in the HTG-MIR and control group (0.7 (0.6-0.8), 0.5 (0.4-0.6) and 0.4 (0.3-0.4) mmol/l, respectively, all P<0.05). Endothelial-dependent vasodilation was similar in HTG-MIR and controls. In contrast, the response to 5HT was attenuated in the HTG-SIR group compared to controls (low and high dose by, respectively, -60 and -44%, both P<0.01), and tended to be lower than in the HTG-MIR group (-43%, P=0.068 and -41%, P=0.100, respectively). Endothelium-independent vasodilation did not differ between the three groups. CONCLUSION: These findings indicate that chronic hypertriglyceridemia per se is not associated with endothelial dysfunction. In contrast, the presence of insulin resistance, characterized by hyperinsulinemia and FFA elevation, contributes to the induction of endothelial dysfunction in chronic HTG.

Impaired endothelium-dependent vasodilation in type 2 diabetes mellitus and the lack of effect of simvastatin.

OBJECTIVE: Although type 2 diabetes is recognized as an independent risk factor for cardiovascular disease and cardiovascular disease is associated with endothelial dysfunction, the influence of type 2 diabetes per se on the endothelial function is controversial. HMG-CoA-reductase inhibitors have been shown to have short-term beneficial effects on endothelial dysfunction among patients with dyslipidemia or cardiovascular disease. The effect of HMG-CoA reductase inhibitors on the endothelial function in diabetes is largely unknown. METHODS: Seventeen patients with type 2 diabetes, free of cardiovascular disease and no other cardiovascular risk factors, except for dyslipidemia, were studied together with ten healthy volunteers. The effect of 5-hydroxytryptamine, as an endothelium-dependent vasodilator, and sodium nitroprusside, as an endothelium-independent vasodilator, on the forearm blood flow was measured using venous occlusion plethysmography. RESULTS: 5-Hydroxytryptamine and sodium nitroprusside, infused in the brachial artery, caused a dose-dependent vasodilation. The vasodilator response to 5-hydroxytryptamine was significantly lower among the diabetic patients, 42 and 56%, than among the controls, 73 and 103%, at a dose of 0.3 and 0.9 ng/kg/min, respectively (P<0.05 and P<0.001). Vasodilator responses to sodium nitroprusside were comparable among the diabetic patients and controls. A 6-week treatment with simvastatin 40 mg once daily did not change the vasodilator responses to 5-hydroxytryptamine or sodium nitroprusside among the patients with diabetes. CONCLUSIONS: The results of this study indicate that the endothelial function is impaired in type 2 diabetes and is not restored after a 6-week treatment period with simvastatin 40 mg.

Monitoring renal function in obese patients with type 2 diabetes mellitus in daily practice.

BACKGROUND: Endogenous creatinine clearance (GFR(24-hr)) and the Cockcroft formula (GFR(Cockcroft)) are used for the assessment of the glomerular filtration rate (GFR) in daily practice. The influence of extreme obesity in Type 2 diabetes mellitus (T2DM) on the Cockcroft formula was evaluated. METHODS: We compared GFR as calculated by GFR(Cockcroft) to GFR as determined by GFR(24-hr) in 210 patients with T2DM and normal serum creatinine levels. The influence of body mass index (BMI) on the difference between both methods was evaluated. RESULTS: GFR(Cockcroft) was an overall good predictor for GFR(24-hr), but a large individual difference between both methods was observed. A significant correlation was found between the two methods (r=0.962, p<0.001). In T2DM patients with a BMI>35 kg/m2, mean GFR(Cockcroft) was 18% greater than GFR(24-hr). For every unit BMI in this patient group the GFR(Cockcroft) increased by 7.9% relative to the GFR(24-hr). CONCLUSIONS: The major limitation of this evaluation is the lack of a gold standard for GFR measurement. This evaluation of daily practice shows the GFR estimation by the Cockcroft formula and the 24-hr creatinine clearance are in agreement, although a large individual variation was found between both methods making the interchangeability questionable. In view of the influence of BMI on the Cockcroft formula, this should not be used to estimate the GFR in T2DM patients with extreme obesity.

[Higher prevalence of familial hypercholesterolemia than expected in adult patients of four family practices in Netherlands]. / Prevalentie van familiaire hypercholesterolemie onder volwassenen in vier huisartsenpraktijken hoger dan werd aangenomen.

OBJECTIVE: To determine the prevalence of familial hypercholesterolaemia (FH). DESIGN: Patient record screening, questionnaire and if necessary, case finding. METHODS: Over the period mid-1990-mid-1992 (approximately 2.5 years) 8,800 adult individuals (age 18 years and over) in 4 general practices in Hoofddorp, the Netherlands, were screened for risk factors for coronary artery disease and invited for further analysis. Of the 3,289 selected and invited individuals 2,719 (83%) were investigated. Total cholesterol concentrations were investigated 3 times and if the mean value was above 8.0 mmol/l patients were referred to a lipid clinic to investigate the possible existence of FH. RESULTS: 114 patients were eligible for referral to a lipid clinic of whom 92 (81%) were indeed referred. Of these, 38 patients were diagnosed with FH: 23 men and 15 women, with a mean age of 47.7 years (range: 21-74). CONCLUSION: The prevalence of FH in this investigated population was at least 1:232. This is more than 1:500, the estimated number of FH patients in the Dutch population.

Detection of the Pro664-Leu mutation in the low-density lipoprotein receptor and its relation to lipoprotein(a) levels in patients with familial hypercholesterolemia of Dutch ancestry from The Netherlands and Canada.

From a large cohort of hyperlipidemic patients, who attended the Lipid Research Clinic in Amsterdam, The Netherlands and in Vancouver, Canada, 915 consecutive patients with familial hypercholesterolemia (FH) of Dutch descent, were selected. This group of FH patients was screened for the presence of a cytosine to thymidine nucleotide substitution in exon 14 of the LDL-receptor gene, in order to determine the frequency of this mutation in patients of Dutch descent and to investigate the relationship between the mutation and the level of lipoprotein(a). The mutation was detected in seven individuals. All patients with this mutation shared the same haplotype, which is suggestive of an ancient mutation. The index patients and a large kindred with this mutation were further analyzed at the biochemical and clinical level. Except for total and LDL-cholesterol, there was no statistically significant difference in biochemical parameters between family members with and without FH. In contrast to previous reports, there was no difference in plasma levels of lipoprotein(a) between patients with the mutation in exon 14 and unaffected individuals.