Familial hypercholesterolemia in children and the importance of early treatment.

PURPOSE OF REVIEW: Familial hypercholesterolemia leads to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth onwards due to a pathogenetic variation in genes in cholesterol metabolism. Early screening to identify and subsequently treat children with familial hypercholesterolemia is crucial to reduce the risk of premature atherosclerotic cardiovascular disease (ASCVD). This review focuses on recent insights in the field of pediatric familial hypercholesterolemia. RECENT FINDINGS: Screening in childhood and early initiation of optimal lipid-lowering therapy (LLT) have shown promising outcomes in the prevention of ASCVD. In addition, cost-effectiveness research has demonstrated highly favorable results. With the availability of novel therapies, familial hypercholesterolemia has become a well treatable disease. SUMMARY: Children with familial hypercholesterolemia benefit from early detection and optimal treatment of their elevated LDL-C levels.

Lipid metabolism during pregnancy: consequences for mother and child.

PURPOSE OF REVIEW: Accommodating fetal growth and development, women undergo multiple physiological changes during pregnancy. In recent years, several studies contributed to the accumulating evidence about the impact of gestational hyperlipidemia on cardiovascular risk for mother and child. This review aims to provide a comprehensive overview of the current research on lipid profile alterations during pregnancy and its associated (cardiovascular) outcomes for mother and child from a clinical perspective. RECENT FINDINGS: In a normal pregnancy, total and LDL-cholesterol levels increase by approximately 30-50%, HDL-cholesterol by 20-40%, and triglycerides by 50-100%. In some women, for example, with familial hypercholesterolemia (FH), a more atherogenic lipid profile is observed. Dyslipidemia during pregnancy is found to be associated with adverse (cardiovascular) outcomes for the mother (e.g. preeclampsia, gestational diabetes, metabolic syndrome, unfavorable lipid profile) and for the child (e.g. preterm birth, large for gestational age, preatherosclerotic lesions, unfavorable lipid profile). SUMMARY: The lipid profile of women during pregnancy provides a unique window of opportunity into the potential future cardiovascular risk for mother and child. Better knowledge about adverse outcomes and specific risk groups could lead to better risk assessment and earlier cardiovascular prevention. Future research should investigate implementation of gestational screening possibilities.

The association between lipoprotein(a) levels and ischemic stroke in children: A case-control study.

BACKGROUND: Pediatric arterial ischemic stroke (AIS) is a rare disorder, associated with severe morbidity. In adults, elevated lipoprotein(a) (Lp(a)), a cholesterol-like particle, is associated with ischemic stroke. However, data on Lp(a) and pediatric AIS are scarce. Therefore, we evaluated the association between Lp(a) levels and pediatric AIS. METHODS: We included children who suffered an AIS (≤18 years) and were treated in a tertiary center in Amsterdam, the Netherlands. Two groups of children with AIS were identified: (i) neonates and (ii) children older than 29 days. A case-control study was performed, with the latter group as cases and children without AIS as control group. Cases and controls were matched for age of Lp(a) testing and sex. Multivariable logistic regression models were used. RESULTS: Thirteen neonates and 23 children were included. Mean (SD) age of AIS was 0.6 (2.0) days and 9.2 (6.3) years, respectively. Children with AIS were matched to 62 controls. Lp(a) levels of greater than 50 mg/dL were more prevalent in children with AIS compared to controls (21.7% vs. 3.2%, p = .02). A significant association was found between Lp(a) and AIS (odds ratio [OR] adjusted for age at Lp(a) testing, body mass index [BMI], measurement assay: 1.36 per 10 mg/dL increase of Lp(a), 95% confidence interval [CI]: 1.02-1.82, p = .041). CONCLUSIONS: In this study, Lp(a) levels were positively associated with the risk of AIS in children, suggesting that high Lp(a) might be an independent risk factor for AIS. This underlines the importance of Lp(a) measurement in children with AIS.

Familial hypercholesterolemia care by Dutch pediatricians-mind the gaps.

PURPOSE: Familial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Since the first functional and morphologic changes of the arterial wall occur in childhood, treatment should start early in childhood to mitigate the elevated risk of ASCVD. Pediatricians play an important role in the detection and care of children with FH. In this study, we aim to explore potential gaps in FH care amongst Dutch pediatricians, in order to enhance their knowledge and awareness of detecting and treating children with FH. METHODS: An anonymous online survey, deployed using Google Forms, including 26 closed and semi-closed questions on FH care in children was distributed by the Dutch Association of Pediatrics via a newsletter to which the majority of the practicing Dutch pediatricians subscribe. In addition, we requested that the pediatric departments of all Dutch hospitals in the Netherlands distribute this survey personally among their employed pediatricians. Respondents were instructed to answer the questions without any help or use of online resources. RESULTS: Between September 1st, 2023 and November 1st, 2023, 158 (an estimated 11% response rate) Dutch pediatricians completed the survey. They reported a median (IQR) of 15.0 (6.0-22.0) years of experience as a pediatrician, and 34 (21.5%) were working in academic hospitals. The majority (76.6%) of pediatricians correctly identified a typical FH lipid profile but 68 (43.0%) underestimated the true prevalence of FH (1:300). Underestimation and unawareness of the increased risk of FH patients for ASCVD were reported by 37.3% and 25.9% of pediatricians, respectively. Although 70.9% of the pediatricians correctly defined FH, only 67 (42.4%) selected statins and ezetimibe to treat severe hypercholesterolemia. CONCLUSIONS: The results of this study suggest significant gaps in knowledge and awareness of FH in children among Dutch pediatricians. FH care in children needs improvement through educational and training initiatives to mitigate the life-long risk of ASCVD from early life. WHAT IS KNOWN: • Familial hypercholesterolemia (FH) leads to elevated LDL-cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). • The process of atherosclerosis starts in childhood • Pediatricians play an important role in the detection and treatment of children with FH. WHAT IS NEW: • Our results highlight significant gaps in care for children with FH amongst pediatricians and this may lead to suboptimal detection and treatment. • FH care in children needs improvement by educational initiatives to ultimately prevent ASCVD in adulthood.

Lipoprotein(a) levels in children with suspected familial hypercholesterolaemia: a cross-sectional study.

AIMS: Familial hypercholesterolaemia (FH) predisposes children to the early initiation of atherosclerosis and is preferably diagnosed by DNA analysis. Yet, in many children with a clinical presentation of FH, no mutation is found. Adult data show that high levels of lipoprotein(a) [Lp(a)] may underlie a clinical presentation of FH, as the cholesterol content of Lp(a) is included in conventional LDL cholesterol measurements. As this is limited to adult data, Lp(a) levels in children with and without (clinical) FH were evaluated. METHODS AND RESULTS: Children were eligible if they visited the paediatric lipid clinic (1989-2020) and if Lp(a) measurement and DNA analysis were performed. In total, 2721 children (mean age: 10.3 years) were included and divided into four groups: 1931 children with definite FH (mutation detected), 290 unaffected siblings/normolipidaemic controls (mutation excluded), 108 children with probable FH (clinical presentation, mutation not detected), and 392 children with probable non-FH (no clinical presentation, mutation not excluded). In children with probable FH, 32% were found to have high Lp(a) [geometric mean (95% confidence interval) of 15.9 (12.3-20.6) mg/dL] compared with 10 and 10% [geometric means (95% confidence interval) of 11.5 (10.9-12.1) mg/dL and 9.8 (8.4-11.3) mg/dL] in children with definite FH (P = 0.017) and unaffected siblings (P = 0.002), respectively. CONCLUSION: Lp(a) was significantly higher and more frequently elevated in children with probable FH compared with children with definite FH and unaffected siblings, suggesting that high Lp(a) may underlie the clinical presentation of FH when no FH-causing mutation is found. Performing both DNA analysis and measuring Lp(a) in all children suspected of FH is recommended to assess possible LDL cholesterol overestimation related to increased Lp(a).

A Systematic Review and Meta-analysis of Dietary Interventions Modulating Gut Microbiota and Cardiometabolic Diseases-Striving for New Standards in Microbiome Studies.

BACKGROUND & AIMS: Cardiometabolic diseases (CMDs) have shared properties and causes. Insulin resistance is a risk factor and characteristic of CMDs and has been suggested to be modulated by plasma metabolites derived from gut microbiota (GM). Because diet is among the most important modulators of GM, we performed a systematic review of the literature to assess whether CMDs can be modulated via dietary interventions targeting the GM. METHODS: A systematic review of the literature for clinical studies was performed on Ovid MEDLINE and Ovid Embase. Studies were assessed for risk of bias and patterns of intervention effects. A meta-analysis with random effects models was used to evaluate the effect of dietary interventions on clinical outcomes. RESULTS: Our search yielded 4444 unique articles, from which 15 randomized controlled trials and 6 nonrandomized clinical trials were included. The overall risk of bias was high in all studies. In general, most dietary interventions changed the GM composition, but no consistent effect could be found. Results of the meta-analyses showed that only diastolic blood pressure is decreased across interventions compared with controls (mean difference: -3.63 mm Hg; 95% confidence interval, -7.09 to -0.17; I2 = 0%, P = .04) and that a high-fiber diet was associated with reduced triglyceride levels (mean difference: -0.69 mmol/L; 95% confidence interval, -1.36 to -0.02; I2 = 59%, P = .04). Other CMD parameters were not affected. CONCLUSIONS: Dietary interventions modulate GM composition, blood pressure, and circulating triglycerides. However, current studies have a high methodological heterogeneity and risk of bias. Well-designed and controlled studies are thus necessary to better understand the complex interaction between diet, microbiome, and CMDs. PROSPERO: CRD42020188405.

Use of the National Early Warning Score for predicting deterioration of patients with acute pulmonary embolism: a post-hoc analysis of the YEARS Study.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are validated scores for mortality prediction in patients with pulmonary embolism (PE). National Early Warning Score (NEWS) is a general prognostic risk score for multiple clinical settings. We investigated whether the NEWS had a comparable performance with the PESI and sPESI, for predicting intensive care unit (ICU) admission and death in patients with acute PE. METHODS: In haemodynamically stable patients with confirmed PE from the YEARS Study (2013-2015), we evaluated the performance of the NEWS, PESI and sPESI for predicting 7-day ICU admission and 30-day mortality. Receiver operating characteristic curves were plotted and the area under the curve (AUC) was calculated. RESULTS: Of 352 patients, 12 (3.4%) were admitted to the ICU and 5 (1.4%) died. The AUC of the NEWS for ICU admission was 0.80 (95% CI 0.66 to 0.94) and 0.92 (95% CI 0.82 to 1.00) for 30-day mortality. At a threshold of 3 points, NEWS yielded a sensitivity and specificity of 92% and 53% for ICU admission and 100% and 52% for 30-day mortality. The AUC of the PESI was 0.64 (95% CI 0.48 to 0.79) for ICU admission and 0.94 (95% CI 0.87 to 1.00) for mortality. At a threshold of 66 points, PESI yielded a sensitivity of 75% and a specificity of 38% for ICU admission. For mortality, these were 100% and 37%, respectively. The performance of the sPESI was similar to that of PESI. CONCLUSION: In comparison with PESI and sPESI, NEWS adequately predicted 7-day ICU admission as well as 30-day mortality, supporting its potential relevance for clinical practice.

20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce. METHODS: We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima-media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. RESULTS: Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter) - a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter [2.59 mmol per liter]) were achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings (mean difference adjusted for sex, -0.0001 mm per year; 95% confidence interval, -0.0010 to 0.0008). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs. 26% and 0% vs. 7%, respectively). CONCLUSIONS: In this study, initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. (Funded by the AMC Foundation.).

Ideal cardiovascular health at age 5-6 years and cardiometabolic outcomes in preadolescence.

BACKGROUND: The American Heart Association (AHA) developed a definition of ideal cardiovascular health (ICH) based on the presence of both ideal health behaviours (diet, physical activity, weight status and smoking) and ideal health factors (glucose, total cholesterol and blood pressure levels). However, research of ICH in the paediatric population is scarce. We aimed to study ICH at age 5-6 years by extending the original ICH score with the health behaviours: sleep duration, screen time and prenatal smoke exposure, and to evaluate its association with cardiometabolic outcomes at age 11-12. METHODS: A total of 1666 children aged 5-6 years were selected from the database of the ABCD-study, a prospective cohort study on the health and development of children born in Amsterdam, the Netherlands. Of these, 846 (50.8%) were boys and 1460 (87.6%) had a healthy weight. Data on self-reported health behaviours and health factors were used to calculate the ICH scores (original and extended) by adding the frequency of scoring 'healthy' on each indicator, based on international cut-offs. The children were followed up for 6 years and cardiometabolic outcomes (carotid intima-media thickness (CIMT), blood pressure, glucose and lipids) were measured. Associations between ICH (both original and extended) and cardiometabolic outcomes were examined using multivariable regression models. RESULTS: At age 5-6 years, 11% scored poor (score 1-5), 56% intermediate (score 6-7) and 33% good (score 8-9) on extended ICH. Healthy diet and normal total cholesterol concentrations were the least prevalent. Neither the original nor the extended ICH scores were associated with CIMT at age 11-12. A higher score on the extended ICH was associated with lower total cholesterol (p for trend < 0.001), lower systolic (p for trend = 0.012) and diastolic blood pressure (p for trend = 0.011), and lower body mass index (BMI) (p < 0.001) at age 11-12. The original ICH score was associated with lower total cholesterol (p < 0.001) and BMI (p < 0.001) only. CONCLUSION: Our findings suggest that extending the ICH score in young children with additional health behaviours improves prediction of some cardiometabolic outcomes, but not CIMT in preadolescence, compared to the original ICH score. We would recommend other researchers to incorporate objective measures of health behaviours and longer follow-up to find out whether associations persist into adulthood.

Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS: We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS: All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION: Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION: Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY: Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING: The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

Clinical Consequences of Antibody Formation, Serum Concentrations, and HLA-Cw6 Status in Psoriasis Patients on Ustekinumab.

BACKGROUND: Ustekinumab for the treatment of psoriasis is currently administered in a standard dosing regimen. However, some patients tend to benefit from alternative dosing regimens, a step toward personalized medicine. METHODS: To investigate the role of ustekinumab serum concentrations, anti-ustekinumab antibodies [AUA] and HLA-Cw6 status as tools for optimizing ustekinumab treatment, a multicenter prospective cohort study was conducted at an academic hospital with affiliated nonacademic hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2 and 3). Patients with plaque-type psoriasis were eligible if treated with ustekinumab for ≥16 weeks. Serum samples and Psoriasis Area and Severity Index scores were obtained at baseline, week 16, 28, 40, 52, and/or ≥64 of ustekinumab treatment. RESULTS: A total of 137 patients with 229 observations for serum concentrations and AUA and 61 observations for HLA-Cw6 status were included. Presence of AUA (prevalence of 8.7%) was significantly associated with a diminished clinical response (P = 0.032). The median ustekinumab trough concentration was 0.3 mcg/mL (<0.02-3.80). No differences in serum concentrations were observed between moderate to good responders and nonresponders (P = 0.948). Serum trough concentrations were not affected by methotrexate comedication. Prevalence of HLA-Cw6 positivity was 41% with no statistically significant difference in clinical response between HLA-Cw6-positive and HLA-Cw6-negative patients (P = 0.164). CONCLUSIONS: The presence of AUA was associated with treatment failure in this patient population; measurement of AUA may therefore be a candidate marker for personalized pharmacotherapy. The clinical utility of ustekinumab serum trough concentrations or HLA-Cw6 status determination remains less clear. Further exploration on the potential of measuring ustekinumab serum concentrations and other biomarkers in predicting therapy outcomes should be encouraged.

Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label).

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in children with HeFH. METHODS: Children with HeFH (age, 6-<18 years) and low-density lipoprotein cholesterol >4.9 mmol/L or >4.1 mmol/L in combination with other risk factors received rosuvastatin for 2 years, starting at 5 mg once daily, with uptitration to 10 mg (age, 6-<10 years) or 20 mg (age, 10-<18 years). Carotid IMT was assessed by ultrasonography at baseline and 12 and 24 months in all patients and in age-matched unaffected siblings. Carotid IMT was measured at 3 locations (common carotid artery, carotid bulb, internal carotid artery) in both the left and right carotid arteries. A linear mixed-effects model was used to evaluate differences in carotid IMT between children with HeFH and the unaffected siblings. P values were adjusted for age, sex, carotid artery site, and family relations. RESULTS: At baseline, mean±SD carotid IMT was significantly greater for the 197 children with HeFH compared with the 65 unaffected siblings (0.397±0.049 and 0.377±0.045 mm, respectively; P=0.001). During 2 years of follow-up, the change in carotid IMT was 0.0054 mm/y (95% confidence interval, 0.0030-0.0082) in children with HeFH and 0.0143 mm/y (95% confidence interval, 0.0095-0.0192) in unaffected siblings (P=0.002). The end-of-study difference in mean carotid IMT between children with HeFH and unaffected siblings after 2 years was no longer significant (0.408±0.043 and 0.402±0.042 mm, respectively; P=0.2). CONCLUSIONS: In children with HeFH who were ≥6 years of age, carotid IMT was significantly greater at baseline compared with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with HeFH than untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin. These findings support the value of early initiation of statin treatment for low-density lipoprotein cholesterol reduction in children with HeFH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01078675.

Regional assessment of carotid artery pulse wave velocity using compressed sensing accelerated high temporal resolution 2D CINE phase contrast cardiovascular magnetic resonance.

BACKGROUND: Cardiovascular magnetic resonance (CMR) allows for non-invasive assessment of arterial stiffness by means of measuring pulse wave velocity (PWV). PWV can be calculated from the time shift between two time-resolved flow curves acquired at two locations within an arterial segment. These flow curves can be derived from two-dimensional CINE phase contrast CMR (2D CINE PC CMR). While CMR-derived PWV measurements have proven to be accurate for the aorta, this is more challenging for smaller arteries such as the carotids due to the need for both high spatial and temporal resolution. In this work, we present a novel method that combines retrospectively gated 2D CINE PC CMR, high temporal binning of data and compressed sensing (CS) reconstruction to accomplish a temporal resolution of 4 ms. This enables accurate flow measurements and assessment of PWV in regional carotid artery segments. METHODS: Retrospectively gated 2D CINE PC CMR data acquired in the carotid artery was binned into cardiac frames of 4 ms length, resulting in an incoherently undersampled ky-t-space with a mean undersampling factor of 5. The images were reconstructed by a non-linear CS reconstruction using total variation over time as a sparsifying transform. PWV values were calculated from flow curves by using foot-to-foot and cross-correlation methods. Our method was validated against ultrasound measurements in a flow phantom setup representing the carotid artery. Additionally, PWV values of two groups of 23 young (30 ± 3 years, 12 [52%] women) and 10 elderly (62 ± 10 years, 5 [50%] women) healthy subjects were compared using the Wilcoxon rank-sum test. RESULTS: Our proposed method produced very similar flow curves as those measured using ultrasound at 1 ms temporal resolution. Reliable PWV estimation proved possible for transit times down to 7.5 ms. Furthermore, significant differences in PWV values between healthy young and elderly subjects were found (4.7 ± 1.0 m/s and 7.9 ± 2.4 m/s, respectively; p < 0.001) in accordance with literature. CONCLUSIONS: Retrospectively gated 2D CINE PC CMR with CS allows for high spatiotemporal resolution flow measurements and accurate regional carotid artery PWV calculations. We foresee this technique will be valuable in protocols investigating early development of carotid atherosclerosis.

Can a laparoscopic Roux-en-Y gastric bypass be safely performed by surgical residents in a bariatric center-of-excellence? The learning curve of surgical residents in bariatric surgery.

BACKGROUND: A learning curve (LC) is a graphic display of the number of consecutive procedures performed necessary to reach competence and is defined by complications and duration of surgery (DOS). There is little evidence on the LC of surgical residents in bariatric surgery. Aim of the study is to evaluate whether the laparoscopic Roux-en-Y gastric bypass (LRYGB) can be safely performed by surgical residents, to evaluate the LC of surgical residents for LRYGB and to assess whether surgical residents fit in the LC of the bariatric center which has been established by their proctors. METHODS: Records of all 3389 consecutive primary LRYGB patients, operated between December 2007 and January 2016 in a bariatric center-of-excellence in Amsterdam, were reviewed. Differences in DOS were assessed by means of a linear regression model. Differences in complications (classified as Clavien-Dindo ≥ 2) were evaluated with the χ 2 or the Fisher exact test. Cases were clustered in groups of 70 for comparison and reported for residents with ≥70 cases as primary surgeon. RESULTS: Four surgeons (S1-4) and three residents (R1-3) performed 2690 (88.2%) and 361 (11.8%) of 3051 LRYGBs, respectively. Median (IQR) DOS was 52.0 (42.0-65.0) min for S1-4 versus 53.0 (46.0-63.0) min for R1-3 (p = 0.52). The LC of R1-3 in their first 70 cases (n = 210) differs significantly from the individual (n = 70) LCs of surgeon 1, 2, and 3, with remarkably shorter DOS for the residents (adjusted p < 0.0001; p < 0.001 and p = 0.0002, respectively) and the same amount of surgical complications 5.1% (137/2690) for S1-4 versus 3.0% (11/361) for R1-3 (p = 0.089). CONCLUSION: Laparoscopic Roux-en-Y gastric bypass can be safely performed by surgical residents under supervision of experienced bariatric surgeons. Surgical residents benefit from the experience of their proctors and they fit faultlessly in the LC of the surgical team, as set out by their proctors in a large bariatric center-of-excellence.

Selection of individuals for genetic testing for familial hypercholesterolaemia: development and external validation of a prediction model for the presence of a mutation causing familial hypercholesterolaemia.

AIMS: Familial hypercholesterolaemia (FH) is an autosomal dominant disease that warrants early diagnosis to prevent premature cardiovascular disease (CVD). However, genetic testing to make a definite diagnosis is costly, and careful selection of eligible subjects is important. Unfortunately, accuracy of current diagnostic criteria is poor, especially in young individuals. We therefore developed and validated a model to predict the presence of an FH causing mutation in persons referred by general practitioners. METHODS AND RESULTS: All participants in the Dutch FH screening programme from 1994 to 2014 were included in the development cohort. The validation cohort consisted of consecutive patients, suspected for FH, attending the outpatient lipid clinic in Saguenay (Quebec) from 1993 to 2014. Cross-sectional data were available on medical history, lipid profile, and DNA analysis. Multivariable logistic regression analysis was used for model development. The primary outcome was the presence of a deleterious FH mutation. The development cohort comprised 26 167 FH patients and 37 939 unaffected relatives. Our final model included age; sex; levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides; history and age of CVD; use of statins; smoking; alcohol; and presence of hypertension. The area under the receiver operating characteristic curve (AUC) was 85.4% (95% CI: 85.0-85.9). The calibration slope was 1.02 (where 1.00 is optimal). In the validation cohort (1436 FH patients and 1767 unaffected persons), the AUC was 95.4% (95% CI: 94.7-96.1%) and the calibration slope 1.06. CONCLUSION: Our model showed good discrimination and calibration. We specifically expect our model to be of added value for young persons set against current diagnostic criteria, since LDL-C and age are now used as continuous predictors. The equation will be available as an online calculator to estimate the probability of the presence of an FH mutation in individual patients. This tool might aid physicians in the decision for referral of patients for molecular testing.

Benefits and harms of 4-factor prothrombin complex concentrate for reversal of vitamin K antagonist associated bleeding: a systematic review and meta-analysis.

Prothrombin complex concentrate (PCC) is used for reversal of vitamin K antagonists (VKA) in patients with bleeding complications. This study aims to assess benefits and harms of 4-factor PCC compared to fresh frozen plasma (FFP) or no treatment in VKA associated bleeding. PubMed, EMBASE and CENTRAL were searched from 1945 to August 2015. Studies reporting 4-factor PCC use for VKA associated bleeding and providing data on INR normalization, mortality or thromboembolic (TE) complications were eligible. Two authors screened titles and full articles for inclusion, extracted data, and assessed risk of bias. Mortality data were pooled using Mantel-Haenszel random effects meta-analysis. Nineteen studies were included (N = 2878); 18 cohort studies and one RCT. Six studies had good methodological quality, 9 moderate and 4 poor. Baseline INR values ranged from 2.2 to >20. The INR within 1 h after PCC administration ranged from 1.4 to 1.9, and after FFP administration from 2.2 to 12. PCC reduced the time to reach INR correction in comparison with FFP or no treatment. The observed mortality rate ranged from 0 to 43% (mean 17%) in the PCC, 4.8-54% (mean 16%) in the FFP and 23-69% (mean 51%) in the no treatment group. Meta-analysis of mortality data resulted in an OR of 0.64 (95% confidence interval [CI] 0.27-1.5) for PCC versus FFP and an OR 0.41 (95% CI 0.13-1.3) for PCC versus no treatment. TE complications were observed in 0-18% (mean 2.5%) of PCC and in 6.4% of FFP recipients. Four-factor PCC is an effective and safe option in reversal of VKA bleeding events.

In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate.

Four-factor prothrombin complex concentrate (PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double-blind, crossover, placebo-controlled study, we compared the effects of PCC 37.5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice-daily rivaroxaban 15 mg for 2.5 days. Fifteen min after infusion of PCC 37.5 iu/kg, ETP increased from 47 ± 16% to 64 ± 22% (P = 0.03; pre-rivaroxaban ETP: 92 ± 14%) and remained higher than after placebo over 24 h (P = 0.001). PCC 25 iu/kg did not modify ETP within 15 min (53 ± 11% to 59 ± 12%; P = 0.14) and was not different from placebo over 24 h (P = 0.31). ETP reached pre-rivaroxaban levels within 6 h after PCC 37.5 iu/kg infusion and within 12-24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15 min (P < 0.001). Placebo did not have an effect on coagulation parameters. 37.5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37.5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels.

Carotid intima-media thickness in children with familial hypercholesterolemia.

RATIONALE: Familial hypercholesterolemia (FH) predisposes patients to premature cardiovascular disease, with the process of atherosclerosis initiated in early childhood. OBJECTIVE: As part of an ongoing trial to assess the efficacy and safety of rosuvastatin in children with FH aged 6 to 17 years, we report the differences in carotid intima-media thickness (cIMT) at baseline between children with FH and their unaffected siblings. METHODS AND RESULTS: B-mode ultrasound measurements of the carotid artery were made in 196 children with FH and 64 of their siblings. Mean (±SE) cIMT in children with FH was significantly greater than that of unaffected siblings (0.398±0.052 versus 0.377±0.045 mm; P<0.001). A significantly greater cIMT value was observed before the age of 8 years. Multivariable analyses showed that age, male sex, and presence of FH were independent predictors of cIMT. CONCLUSIONS: The difference in mean cIMT between children with FH and their unaffected siblings may be significant as early as age 8 years. This study confirms the need for early cholesterol lowering in this high-risk population. These patients participating in a carefully monitored study will help assess the long-term efficacy on cIMT and safety of statin therapy in young children.

Current novel-gene-finding strategy for autosomal-dominant hypercholesterolaemia needs refinement.

AIMS: Autosomal-dominant hypercholesterolaemia (ADH) is a heterogeneous common disorder, and uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research. However, despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful and are largely challenged by phenotypic and genetic heterogeneity of this disease. We aimed to investigate the impact of this phenotypic heterogeneity on successfully finding new genes that are involved in ADH. METHODS AND RESULTS: For the ADH phenotype, subjects are considered as affected according to plasma cholesterol levels above the 95th percentile for age and gender. The disease penetrance is generally set at 0.9. These parameters were evaluated in 10000 carriers of true pathogenic APOB and LDLR mutations and 20000 relatives negative for the familial mutations. Application of the above parameters in almost a thousand families included in this study would have identified the causal variant in only 38% of all families. An average penetrance of 0.9 or higher, with a cut-point at the 95th percentile, was only observed for LDLR nonsense mutations. For APOB and LDLR missense mutations, a disease penetrance of 0.9 or higher is only expected, when total cholesterol and low-density lipoprotein cholesterol cut-points between the 75th and 90th percentile are used to determine an individual's disease status. CONCLUSIONS: Although pathogenic LDLR and APOB mutations do follow Mendelian patterns of inheritance, the extensive variation in genotype and phenotype for well-known ADH-causing mutations emphasises that current criteria and strategies indeed are likely to hamper the identification of novel genes related to ADH. These findings provide a basis for the revision of our assessment on who is affected and who is not and emphasise the essence of pedigree information and mapping data before exome sequencing is applied in order to increase success rates of finding new genes related to ADH.