Efficacy of statins in familial hypercholesterolaemia: a long term cohort study

Objective To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia

Clinical and genetic factors influencing cardiovascular risk in patients with familial hypercholesterolemia

Patients with familial hypercholesterolemia (FH) have high levels of LDL-C, owing to defective uptake of these particles by LDL receptors in the liver. Consequently, FH patients have a high risk of cardiovascular disease (CVD). However, among these patients, there is marked variance in age of onset of CVD and a proportion of untreated patients do not develop CVD at all. Statin treatment can greatly reduce risk, and since it is not yet possible to precisely predict which FH patients will develop CVD, all patients initiate treatment once the diagnosis has been made. The purpose of this article is to provide an update of clinical and genetic risk factors influencing CVD risk in FH patients, and to discuss future lines of research that could uncover improved methods of treatment for heterozygous FH patients

Determining the minimal important change of the 6-minute walking test in Multiple Sclerosis patients using a predictive modelling anchor-based method

Background: The minimal important change (MIC) of the 6-minute walk test (6MWT) is not clear for patients with Multiple Sclerosis (MS), hampering treatment evaluation. The aim of our study was therefore to determine the MIC of the 6MWT in MS patients. Methods: MS patients did the 6MWT using the instruction to walk at comfortable speed twice with approximately one year in between. After the second 6MWT they completed 3-point anchor question. The MICadjusted with a 95% confidence interval (CI) was calculated with the predictive modelling method with bootstrapping. Results: 118 MS patients (mean age 48.2 years, 23.7% men) were included between September 2018 and October 2019. Mean 6MWT distance was 468 ± 112 m at baseline and 469 ± 115 m one year later. Twenty-three (19.5%) patients answered their walking distance improved, 43 (36.4%) answered it worsened. A MICadjusted for improvement of 19.7 m (95%CI 9.8–30.9 m) was found, and for deterioration of 7.2 m (95%CI -3.3–18.2 m). Conclusions: Using the most sophisticated statistical method, the MICadjusted of the 6MWT in MS patients was 19.7 m for improvement, and 7.2 m for deterioration. This knowledge allows physiotherapists and physicians to evaluate if their treatment has led to a meaningful improvement for their MS patients or if walking of their patients has deteriorated

Translation and cross-cultural adaptation of the ICHOM standard set for stroke: the Dutch version

Abstract Introduction The International Consortium for Health Outcomes Measurement (ICHOM) developed a standard set of patient-centered outcome measures for use in stroke patients. In addition to the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health, it is comprised of 25 questions that are not part of a specific questionnaire. This study aimed to translate these 25 single questions into Dutch. Methods Two native Dutch-speaking translators independently translated the original ICHOM questions into Dutch. A consensus translation was made by these translators and a third person. This translation was subsequently translated back to English independently by two native English-speaking translators. Afterwards a pre-final version was made by consensus of a committee. After field-testing among 30 stroke patients, a final version was made. Results The forward and backward translations led to eight cross-cultural adaptations. Based on the interviews with stroke patients, 12 questions were changed to enhance comprehensibility leading to a final Dutch translation of the 25 single questions. Conclusions A Dutch translation of the 25 single questions of the ICHOM Standard Set for Stroke was developed. Now a complete ICHOM Standard Set for Stroke can be used in Dutch populations allowing comparison and improvement of stroke care

5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia

Background: Tendon xanthomas are characteristic for familial hypercholesterolemia (FH), and are associated with a higher risk of coronary heart disease (CHD). They often present with local inflammation. Inflammation may therefore be involved in their pathogenesis, as it is in the pathogenesis of CHD. A key role in the inflammatory pathway is played by the 5-lipoxygenase activating protein (ALOX5AP), which is known to influence the risk of CHD in FH. To test our hypothesis that ALOX5AP contributes to the development of xanthomas, we studied whether variants in the ALOX5AP gene influence the risk of xanthomas. Methods: We examined 945 patients with genetically confirmed heterozygous FH to determine whether they had tendon xanthomas. We genotyped seven polymorphisms in the ALOX5AP gene and constructed haplotypes of these polymorphisms. Results: The A allele of the rs9551963 polymorphism was associated with an increased risk of xanthomas (OR 1.52, 95% CI 1.11-2.07, p=0.01), while the A allele of rs17222842 was protective (OR 0.62, 95% Cl 0.43-0.90, p = 0.01). These two polymorphisms fully explained the risk estimates of all haplotypes. Individual haplotypes, however, were not significantly associated with xanthomas. Conclusion: Variants in the ALOX5AP gene are associated with the presence of xanthomas in FH patients. This result supports our hypothesis that inflammation is a pathogenetic factor of xanthomas. (C) 2009 Elsevier Ireland Ltd. All rights reserve

Efficacy of statins in familial hypercholesterolaemia: A long term cohort study

Objective: To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. Design: Cohort study with a mean follow-up of 8.5 years. Setting: 27 outpatient lipid clinics. Subjects: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. Main outcome measures: Risk of coronary heart disease in treated and "untreated" (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. Results: In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of myocardial infarction in these statin treated patients was not significantly greater than that in an age-matched sample from the general population (hazard ration 1.44 (0.80 to 2.60), P=0.23). Conclusion: Lower statin doses than those currently advised reduced the risk of coronary heart disease to a greater extent than anticipated in patients with familial hypercholesterolaemia. With statin treatment, such patients no longer have a risk of myocardial infarction significantly different from that of the general population

Aging With Cerebral Palsy: A Photovoice Study Into Citizenship

Background: Adults with cerebral palsy (CP) may experience an increasing impact of their disability on daily life and this may interfere with their citizenship. Citizenship is a layered construct. Next to formal and theoretical significations, and civil rights acts such as the UN Convention on the Rights for Persons with Disabilities (CRPD), the meaning of citizenship is formed by the person themselves. The present study aimed to gain insight into what citizenship means for adults with CP 40 years or older and what is needed to support and pursue their citizenship to improve person-centered rehabilitation which can facilitate this process.Methods: Adults with CP (>40 years) without intellectual disability were recruited from medical records of a large rehabilitation center to participate in a qualitative study using the photovoice method. Participants were asked to take photos of objects or life situations that constituted citizenship for them; these photos were then the prompts for the semi-structured interviews that were held face-to-face at their homes. Background and clinical characteristics were gathered using a short face-to-face questionnaire. Data were analyzed through inductive thematic analysis.Results: Nineteen adults participated [mean age (SD) 57.8 (9.4) years (range 44-79), six men]. From the analysis four themes emerged: (a) Meanings of citizenship; (b) Citizenship: Facilitator and barriers; (c) Paradoxes of support and participation; and (d) Future. Furthermore, next to the ability to participate in society without restrictions, sense of belonging was reported to be an important aspect of "meanings of citizenship." The physiotherapist was perceived as an important health professional to maintain physical activity and deal with the impact of aging with CP on daily activities. Complex healthcare and support services regulations and aging affected citizenship negatively.Conclusion: Middle-aged and older adults with CP view citizenship as the ability to participate and belong in society. To optimize their citizenship the challenges and individual needs must be seen and supported by person-centered rehabilitation and support services. Simplification of complex healthcare and services regulations can further improve citizenship

Low-density lipoprotein receptor mutations generate synthetic genome-wide associations

Genome-wide association (GWA) studies have discovered multiple common genetic risk variants related to common diseases. It has been proposed that a number of these signals of common polymorphisms are based on synthetic associations that are generated by rare causative variants. We investigated if mutations in the low-density lipoprotein receptor (LDLR) gene causing familial hypercholesterolemia (FH, OMIM #143890) produce such signals. We genotyped 480 254 polymorphisms in 464 FH patients and in 5945 subjects from the general population. A total of 28 polymorphisms located up to 2.4 Mb from the LDLR gene were genome-wide significantly associated with FH (P<10-8). We replicated the 10 top signals in 2189 patients with a clinical diagnosis of FH and in 2157 subjects of a second sample of the general population (P<0.000087). Our findings confirm that rare variants are able to cause synthetic genome-wide significant associations, and that they exert this effect at relatively large distances from the causal mutation.European Journal of Human Genetics advance online publication, 12 September 2012; doi:10.1038/ejhg.2012.207

Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia

Aims: Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD. Methods and results: We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01-1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07-1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06-1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15-1.69, P < 0.001). Conclusion: We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD