Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.

AIMS: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands. METHODS AND RESULTS: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be ∼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event. CONCLUSION: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.

Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.

Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.

Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society.

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. METHODS AND RESULTS: Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. CONCLUSION: This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.

Familial combined hyperlipidemia: from molecular insights to tailored therapy.

PURPOSE OF REVIEW: This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL). RECENT FINDINGS: A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment. SUMMARY: Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.

Combining risk markers improves cardiovascular risk prediction in women.

Cardiovascular risk stratification could be improved by adding measures of atherosclerosis to current risk scores, especially in intermediate-risk individuals. We prospectively evaluated the additive value of different non-invasive risk markers (both individual and combined) for gender-specific cardiovascular risk stratification on top of traditional risk factors in a middle-aged population-based cohort. Carotid-plaques, IMT (intima-media thickness), ABI (ankle-brachial index), PWV (pulse-wave velocity), AIx (augmentation index), CAP (central augmented pressure) and CSP (central-systolic pressure) were measured in 1367 CVD (cardiovascular disease)-free participants aged 50-70 years old. Cardiovascular events were validated after a mean follow-up of 3.8 years. AUC (area-under-the-curve) and NRI (net reclassification improvement) analyses (total-NRI for all and clinical-NRI for intermediate-risk groups) were used to determine the additive value of individual and combined risk markers. Cardiovascular events occurred in 32 women and 39 men. Traditional cardiovascular risk factors explained 6.2% and 12.5% of the variance in CVD in women and men respectively. AUCs did not substantially increase by adding individual or combined non-invasive risk markers. Individual risk markers only improved reclassification in intermediate-risk women and more than in men; clinical-NRIs ranged between 48.0 and 173.1% in women and 8.9 and 20% in men. Combined non-invasive-risk markers improved reclassification in all women and even more in those at intermediate risk; 'IMT-presence-thickness-of-plaques' showed largest reclassification [total-NRI=33.8%, P=0.012; IDI (integrated-discrimination-improvement)=0.048, P=0.066; clinical-NRI=168.0%]. In men, combined non-invasive risk markers improved reclassification only in those at intermediate risk; 'PWV-AIx-CSP-CAP-IMT' showed the largest reclassification (total-NRI=14.5%, P=0.087; IDI=0.016, P=0.148; clinical-NRI=46.0%). In all women, cardiovascular risk stratification improved by adding combinations and in women at intermediate risk also by adding individual non-invasive risk markers. The additive value of individual and combined non-invasive risk markers in men is limited to men at intermediate risk only, and to a lesser extent than in women.

Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.

AIMS: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). METHODS AND RESULTS: Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. CONCLUSION: Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies.

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to 'lipid and lipid-like molecules', 'organic acids and derivatives' and 'organoheterocyclic compounds'. In pathway analysis, perturbed 'vitamin B1 (thiamin) metabolism', 'de novo fatty acid biosynthesis', 'bile acid biosynthesis' and 'pentose phosphate pathway' were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry.

Towards a role of interleukin-32 in atherosclerosis.

BACKGROUND: IL-32 has been previously shown to promote inflammation in rheumatoid arthritis patients and to contribute to IL-1ß-induced ICAM-1 as well as other proinflammatory cytokines synthesis in human umbilical endothelial cells (HUVECs). Given the high rate of atherosclerosis in RA, these observations suggest that IL-32 may be involved in the inflammatory pathways of atherosclerosis. METHODS: mRNA and protein levels of IL-32 were determined in human atherosclerotic arterial vessel wall tissue by quantitative real-time PCR and immunohistochemistry. HUVEC and M1/M2 macrophages were stimulated with proinflammatory cytokines and TLR ligands to assess IL-32 mRNA induction. Human THP1 macrophages were transduced with AdIL-32γ, to investigate induction of several proatherosclerotic mediators. Finally, aortas from IL-32γ transgenic mice were studied and compared with aortas from age-matched wild-type mice. RESULTS: IL-32 expression was detectable in human atherosclerotic arterial vessel wall, with the expression of IL-32ß and IL-32γ mRNA significantly enhanced. TLR3-ligand Poly I:C in combination with IFNγ were the most potent inducers of IL-32 mRNA expression in both HUVEC and M1/M2 macrophages. Adenoviral overexpression of IL-32γ in human THP1 macrophages resulted in increased production of CCL2, sVCAM-1, MMP1, MMP9, and MMP13. The IL-32γ transgenic mice chow a normal fat diet exhibited vascular abnormalities resembling atherosclerosis. CONCLUSIONS: IL-32 acts as a proinflammatory factor and may be implicated in the inflammatory cascade contributing to atherosclerosis. By promoting the synthesis of matrix metalloproteinases, it may further contribute to plaque instability. Further studies are warranted to investigate whether IL-32 may serve as a potential therapeutic target in fighting atherosclerosis.

Simvastatin with or without ezetimibe in familial hypercholesterolemia.

BACKGROUND: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. METHODS: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. RESULTS: The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. CONCLUSIONS: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].).

Application and validation of a diagnostic algorithm for the atherogenic apoB dyslipoproteinemias: ApoB dyslipoproteinemias in a Dutch population-based study.

BACKGROUND: We applied a diagnostic algorithm using apolipoprotein B (apoB) in combination with triglycerides (TG) and total cholesterol to determine the prevalence of dyslipoproteinemias in the general population. We also characterized the overall cardiovascular (CV) risk profiles, including arterial structure and function as measured with a panel of noninvasive parameters. DESIGN: Clinical and biochemical characteristics and noninvasive measurements of atherosclerosis (NIMA) were determined in 1517 individuals, aged 50-70 years. RESULTS: In general, all dyslipoproteinemias were characterized by a worse CV risk profile and deteriorated outcomes of NIMA compared to those with normal apolipoprotein B (< 1·2 g L(-1)) and TG (< 1·5 mM) levels. The prevalence of hyperapoB-hyperTG was 15·1%, and these individuals showed the most abnormal atheroma-related parameters: reduced ankle-brachial-index at rest (-3·5%) and after exercise (-9·8%), increased intima-media thickness (+5·5%) and more carotid plaques (+39·1%). The prevalence of normoapoB-hyperTG because of increased VLDL was 18·1% and 2·3% because of increased chylomicrons and VLDL, and in these groups, the parameters related to stiffness (e.g. pulse-wave-velocity +7·6% and +5·2%, respectively) were most abnormal. Adjustment for apolipoprotein B (apoB) reduced differences in NIMA in the hyperapoB-hyperTG group, whereas adjustment for TG reduced differences in NIMA in the normoapoB-hyperTG group. CONCLUSIONS: The overall prevalence of dyslipoproteinemias according to the algorithm was approximately 40% in the Dutch population. The different dyslipoproteinemias showed a less favourable CV risk profile and deteriorated NIMA parameters, reflecting increased subclinical atherosclerosis. Furthermore, different effects on different NIMA parameters were observed in the different dyslipoproteinemias.

Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway.

OBJECTIVE: Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride, and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members. METHODS AND RESULTS: Plasma levels of squalene, desmosterol, and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol, and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (P<0.001) and 51% (P<0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR. CONCLUSIONS: Our data indicate that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.

Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus.

PURPOSE OF REVIEW: Familial combined hyperlipidemia (FCHL) and type 2 diabetes mellitus (T2DM) are prevalent entities that share many features of the metabolic syndrome. Recent findings suggest that FCHL and T2DM are less distinct than initially anticipated, which could offer new insights for their therapeutic approach. RECENT FINDINGS: Genetic association studies have provided evidence for a common genetic background (upstream transcription factor 1, activating transcription factor 6, transcription factor 7-like 2 and hepatocyte nuclear factor 4 alpha) between FCHL and T2DM. The metabolic overlap can be illustrated by the presence of ectopic fat accumulation and insulin resistance (muscle, adipose tissue and liver). We have shown that FCHL patients are at increased risk to develop T2DM. This indicates that both entities are not static, but instead the former is able to migrate to the latter as insulin resistance progresses. Given these new findings, it can be anticipated that FCHL patients could also benefit from insulin-sensitizing therapy such as pioglitazone and metformin. Indeed, pilot studies have demonstrated that pioglitazone might be advantageous in FCHL patients. SUMMARY: Recent studies suggest that FCHL patients have an increased risk to develop T2DM, which has important clinical implications. Further studies are necessary to evaluate whether FCHL patients can be protected from new-onset T2DM and premature cardiovascular events with insulin-sensitizing therapy.

The benefit of statins in non-cardiac vascular surgery patients.

There is overwhelming evidence that statins reduce morbidity and mortality in patients with coronary disease. Statins have also been shown to reduce the risk of (recurrent) stroke. Low-density lipoprotein (LDL)-cholesterol, which plays a causal role in the development of atherosclerotic disease, is the primary lipid target in prevention, and is effectively reduced by these agents. In this review, studies are summarized addressing the issues whether statins also directly influence the atherosclerotic process in peripheral arterial disease, carotid artery stenosis, and growth of abdominal aortic aneurysms, and whether statins have an effect on perioperative outcomes in vascular surgery patients. It appears that the evidence of statins on peripheral arterial disease is scarce and its effect on perioperative outcome inconclusive. Prospective randomized trials to answer these questions cannot be performed anymore, however, because all vascular patients should receive statin treatment as secondary prevention of cardiovascular disease.

Evaluation of PubMed filters used for evidence-based searching: validation using relative recall.

OBJECTIVES: The research sought to determine the value of PubMed filters and combinations of filters in literature selected for systematic reviews on therapy-related clinical questions. METHODS: References to 35,281 included and 48,514 excluded articles were extracted from 2,629 reviews published prior to January 2008 in the Cochrane Database of Systematic Reviews and sent to PubMed with and without filters. Sensitivity, specificity, and precision were calculated from the percentages of unfiltered and filtered references retrieved for each review and averaged over all reviews. RESULTS: Sensitivity of the Sensitive Clinical Queries filter was reasonable (92.7%, 92.1-93.3); specificity (16.1%, 15.1-17.1) and precision were low (49.5%, 48.5-50.5). The Specific Clinical Queries and the Single Term Medline Specific filters performed comparably (sensitivity, 78.2%, 77.2-79.2 vs. 78.0%; 77.0-79.0; specificity, 52.0%, 50.8-53.2 vs. 52.3%, 51.1-53.5; precision, 60.4%, 59.4-61.4 vs. 60.6%, 59.6-61.6). Combining the Abridged Index Medicus (AIM) and Single Term Medline Specific (65.2%, 63.8-66.6), Two Terms Medline Optimized (64.2%, 62.8-65.6), or Specific Clinical Queries filters (65.0%, 63.6-66.4) yielded the highest precision. CONCLUSIONS: Sensitive and Specific Clinical Queries filters used to answer questions about therapy will result in a list of clinical trials but cannot be expected to identify only methodologically sound trials. The Specific Clinical Queries filters are not suitable for questions regarding therapy that cannot be answered with randomized controlled trials. Combining AIM with specific PubMed filters yields the highest precision in the Cochrane dataset.

Haplotype analyses of the APOA5 gene in patients with familial combined hyperlipidemia.

BACKGROUND: Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined. MATERIALS AND METHODS: The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (-1131T>C and S19W) were genotyped. RESULTS: Haplotype analysis of APOA5 showed an association with FCH (p=0.029), total cholesterol (p=0.031), triglycerides (p<0.001), apolipoprotein B (p=0.011), HDL-cholesterol (p=0.013), small dense LDL (p=0.010) and remnant-like particle cholesterol (p=0.001). Compared to S19 homozygotes, 19W carriers had an increased risk of FCH (OR=1.6 [1.0-2.6]; p=0.026) and a more atherogenic lipid profile, reflected by higher triglyceride (+22%) and apolipoprotein B levels (+5%), decreased HDL-cholesterol levels (-7%) and an increased prevalence of small dense LDL (16% vs. 26%). In carriers of the -1131C allele, small dense LDL was more prevalent than in -1131T homozygotes (29% vs. 16%). No association of the APOA5 gene with IMT and CVD was evident. CONCLUSION: In Dutch FCH families, variants in the APOA5 gene are associated with FCH and an atherogenic lipid profile.

Adiponectin multimer distribution in patients with familial combined hyperlipidemia.

Adiponectin is secreted from adipocytes in different multimers, of which the high molecular weight (HMW) form is supposed to mediate favorable metabolic and anti-atherogenic effects. We determined adiponectin multimers in 29 female and 22 male patients with familial combined hyperlipidemia (FCH) and 51 age-, gender-, and BMI-matched controls in relation to cardiovascular disease (CVD). We observed a clear sexual dimorphism of total adiponectin and its multimers. Female, but not male, FCH patients had significant lower total adiponectin and both HMW and low molecular weight (LMW) adiponectin than controls. The adiponectin sensitivity index (ASI), reflected by HMW/total adiponectin, and the LMW/HMW adiponectin ratio did not differ significantly between FCH females and control females. However, FCH females with CVD exhibited significantly lower ASI (34.2+/-10.1% vs 46.0+/-7.1%) and higher LMW/HMW ratio (1.5+/-0.8 vs 0.7+/-0.3) compared to FCH females without CVD, reflecting a more atherogenic adiponectin multimer distribution.

Answers to questions posed during daily patient care are more likely to be answered by UpToDate than PubMed.

BACKGROUND: UpToDate and PubMed are popular sources for medical information. Data regarding the efficiency of PubMed and UpToDate in daily medical care are lacking. OBJECTIVE: The purpose of this observational study was to describe the percentage of answers retrieved by these information sources, comparing search results with regard to different medical topics and the time spent searching for an answer. METHODS: A total of 40 residents and 30 internists in internal medicine working in an academic medical center searched PubMed and UpToDate using an observation portal during daily medical care. The information source used for searching and the time needed to find an answer to the question were recorded by the portal. Information was provided by searchers regarding the topic of the question, the situation that triggered the question, and whether an answer was found. RESULTS: We analyzed 1305 patient-related questions sent to PubMed and/or UpToDate between October 1, 2005 and March 31, 2007 using our portal. A complete answer was found in 594/1125 (53%) questions sent to PubMed or UpToDate. A partial or full answer was obtained in 729/883 (83%) UpToDate searches and 152/242 (63%) PubMed searches (P < .001). UpToDate answered more questions than PubMed on all major medical topics, but a significant difference was detected only when the question was related to etiology (P < .001) or therapy (P = .002). Time to answer was 241 seconds (SD 24) for UpToDate and 291 seconds (SD 7) for PubMed. CONCLUSIONS: Specialists and residents in internal medicine generally use less than 5 minutes to answer patient-related questions in daily care. More questions are answered using UpToDate than PubMed on all major medical topics.

Analysis of queries sent to PubMed at the point of care: observation of search behaviour in a medical teaching hospital.

BACKGROUND: The use of PubMed to answer daily medical care questions is limited because it is challenging to retrieve a small set of relevant articles and time is restricted. Knowing what aspects of queries are likely to retrieve relevant articles can increase the effectiveness of PubMed searches. The objectives of our study were to identify queries that are likely to retrieve relevant articles by relating PubMed search techniques and tools to the number of articles retrieved and the selection of articles for further reading. METHODS: This was a prospective observational study of queries regarding patient-related problems sent to PubMed by residents and internists in internal medicine working in an Academic Medical Centre. We analyzed queries, search results, query tools (Mesh, Limits, wildcards, operators), selection of abstract and full-text for further reading, using a portal that mimics PubMed. RESULTS: PubMed was used to solve 1121 patient-related problems, resulting in 3205 distinct queries. Abstracts were viewed in 999 (31%) of these queries, and in 126 (39%) of 321 queries using query tools. The average term count per query was 2.5. Abstracts were selected in more than 40% of queries using four or five terms, increasing to 63% if the use of four or five terms yielded 2-161 articles. CONCLUSION: Queries sent to PubMed by physicians at our hospital during daily medical care contain fewer than three terms. Queries using four to five terms, retrieving less than 161 article titles, are most likely to result in abstract viewing. PubMed search tools are used infrequently by our population and are less effective than the use of four or five terms. Methods to facilitate the formulation of precise queries, using more relevant terms, should be the focus of education and research.

High plasma level of remnant-like particles cholesterol in familial combined hyperlipidemia.

CONTEXT: The traditional lipid and lipoprotein levels in patients with familial combined hyperlipidemia (FCH) are relatively mildly elevated and do not fully explain the increased risk of cardiovascular disease (CVD). In other populations, high remnant-like particles cholesterol (RLP-C) levels are an independent risk factor for CVD. OBJECTIVE: The objective of the study was to investigate whether plasma RLP-C concentrations are elevated in patients with FCH and contribute to the increased prevalence of CVD. DESIGN, SETTING, PARTICIPANTS: In this cross-sectional study, we studied RLP-C levels in 37 FCH families comprising 582 subjects, of whom 134 subjects were diagnosed FCH based on total cholesterol, triglyceride, and apolipoprotein-B levels. Plasma RLP-C concentrations were determined using an immune-separation technique. RESULTS: For both men and women, the mean plasma RLP-C concentration (mmol/liter) was 2-fold elevated in FCH patients [0.59 (0.54-0.66) and 0.40 (0.37-0.43), respectively] compared with both normolipidemic relatives [0.27 (0.26-0.29) in male and 0.22 (0.21-0.23) in female, all P<0.000]; and spouses [0.27 (0.23-0.31) in male and 0.24 (0.21-0.27) in female, all P<0.000]. Plasma RLP-C levels above the 90th percentile predicted prevalent CVD, independently of nonlipid cardiovascular risk factors [odds ratio 2.18 (1.02-4.66)] and triglyceride levels [odds ratio 2.35 (1.15-4.83)]. However, in both FCH patients and controls, RLP-C did not provide additional information about prevalent CVD over and above non-high-density lipoprotein cholesterol levels. CONCLUSIONS: Patients with FCH have 2-fold elevated plasma RLP-C levels, which add to the atherogenic lipid profile and contribute to the increased risk for CVD. However, for clinical practice, non-high-density lipoprotein cholesterol is the best predictor of prevalent CVD.