Aortic stenosis in homozygous familial hypercholesterolaemia: a paradigm shift over a century.

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is an orphan disease defined by extreme elevations in low-density lipoprotein cholesterol, cutaneous xanthomas, and pre-mature atherosclerotic cardiovascular disease. Survival has more than doubled over the past three decades. Aortic stenosis (AS) [supravalvular aortic stenosis (SVAS) or valvular aortic stenosis (VAS)] is commonly encountered. There are no medical treatments available and complex high-risk surgeries represent the only available option in severe cases. A systematic review was performed to summarize the current evidence on AS in HoFH and to determine whether pharmacological treatment (statins) have had an impact on clinical presentation, phenotype and clinical course over the past nine decades (PROSPERO CRD42021250565). METHODS AND RESULTS: MEDLINE, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, PubMed, AfricaWide, and Scopus were searched from inception to 10 November 2021. Searches identified 381 publications, of which 19 were retained; they were cross-sectional or retrospective studies. Separately, 108 individual case reports were described. Within the 424 HoFH cases, AS was identified in 57% of patients in the pre-statin era vs. 35% in patients reported more recently (>2000, long-term statin period). With an increase in longevity due to statins and lipoprotein apheresis, a change in the proportion of patients with SVAS and VAS with a SVAS:VAS ratio of 47:53 and 10:90 for HoFH patients not on statin and on long-term statin, respectively, was noted. CONCLUSION: These data suggest that SVAS and VAS are frequent in HoFH and that the phenotype has shifted towards calcific VAS as statins and lipoprotein apheresis improve survival in these patients.

Health-related quality of life in homozygous familial hypercholesterolemia: A systematic review and meta-analysis.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by extreme elevations of low-density lipoprotein cholesterol (LDL-C) and extremely premature atherosclerotic cardiovascular disease. To date, impacts of HoFH and its treatment on the psychosocial wellbeing of patients have been poorly characterized. OBJECTIVES: We performed a systematic review of the association between HoFH and health-related quality of life (HRQL). METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) consensus guidelines. We searched MEDLINE, Embase, The Cochrane Controlled Register of Trials (CENTRAL), Pubmed, Scopus, AfricaWide (via EBSCO), and six trial registries and grey-literature databases from inception to May 2021 for published English-language literature examining HRQL and its determinants in HoFH. Studies were eligible if they included patients with confirmed HoFH and evaluated HRQL using validated tools. We performed a narrative synthesis of qualitative findings from included studies and, where data permitted, random-effects meta-analysis reporting standardized mean differences (SMD) and 95% confidence intervals (CIs). RESULTS: Our review identified seven eligible studies examining HRQL in HoFH participants. Pooling data from two included studies, we found that relative to the general population, HoFH patients demonstrated significantly poorer HRQL in multiple dimensions of the 36-item Short-Form Health Survey (SF-36) with lower scores in physical functioning (SMD -0.37; 95% CI: -0.60, -0.15), role limitations due to physical health (SMD -0.63; 95% CI: -1.24, -0.02), social functioning (SMD -0.61; 95% CI: -1.19, -0.03), bodily pain (SMD -0.24; 95% CI: -0.46, -0.01), and general health (SMD -1.55; 95% CI: -1.80, -1.31). No differences were observed in domains of energy and vitality, mental health and emotional well-being, or role limitations due to emotional problems. Patients suffered high treatment burdens related to lipoprotein apheresis that compromised educational attainment and employment. However, few patients received psychological support in navigating their treatment challenges. No studies evaluated the association of HoFH with incident anxiety, depression, or other psychopathology. CONCLUSIONS: Limited data are available on quality of life for patients with HoFH. The available data suggest that these patients may suffer disease-related impairments in quality of life. Future work should aim to elucidate relationships between HoFH and mental health outcomes and develop interventions to improve quality of life in this population.

Major adverse cardiovascular events in homozygous familial hypercholesterolaemia: a systematic review and meta-analysis.

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a genetic condition characterized by extremely elevated levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease and death. Due to its rarity, accurate assessment of cardiovascular outcomes associated with HoFH and how they have changed over time has been challenging. The goal of this study was to assess the prevalence and age-of-onset of major adverse cardiovascular events (MACE) among patients with HoFH. METHODS AND RESULTS: We searched MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Scopus, Africa-Wide, Google Scholar, Open Grey, and various clinical trial registries from inception to February 2020 to identify studies reporting on MACE in HoFH patients. We determined the pooled prevalence and mean age-of-onset of MACE outcomes individually using a random effects inverse variance model. We identified 94 studies that met our eligibility criteria. Myocardial infarction and coronary revascularization were common with a prevalence of 15.1% [95% confidence interval (95% CI) 10.7-20.0] and 28.3% (95% CI 22.5-34.3), respectively. The mean age-of-onset was 24.5 (95% CI 19.2-29.8) years for myocardial infarction and 32.2 (95% CI 26.6-37.8) years for revascularization. Sub-group analyses based on the year of publication revealed significant delays in the onset of MACE outcomes post-1990 compared to pre-1990. Egger's regression suggested possible bias, likely due to small study effects. CONCLUSIONS: Atherosclerotic cardiovascular disease is common among HoFH patients and occurs at a young age. Age-of-onset of myocardial infarction was delayed by more than a decade from pre-1990 to post-1990, likely attributable to widespread use of statins and other therapies, reflecting substantial progress in the management of this rare but severe disorder.

Lomitapide for treatment of homozygous familial hypercholesterolemia: The Québec experience.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is an orphan disease, most often caused by bi-allelic mutations of the LDLR gene. Patients with HoFH have elevated LDL-C levels >13 mmol/L, tendinous xanthomata and severe, premature atherosclerotic cardiovascular disease (ASCVD). Untreated, most HoFH patients die of ASCVD in youth. New therapeutic modalities include lomitapide, an inhibitor of microsomal triglyceride transfer protein that lowers hepatic LDL-C production. We have recently identified 79 Canadian patients with HoFH. Here, we describe our experience with lomitapide in the province of Quebec, a geographic area known to have a high prevalence of HoFH. METHODS: This is a retrospective case series of 12 HoFH patients followed at three lipidology centers in the province of Quebec. RESULTS: Mean age of the patients was 44 ± 18 years; age at time of HoFH diagnosis ranged from 2 to 59 years. All patients were on a statin and ezetimibe 10 mg/day and five patients were treated with LDL apheresis. Treatment with lomitapide reduced LDL-C levels by 38% (intention-to-treat). Intolerable gastrointestinal side effects were observed in 3/12 patients and were the main reason for treatment discontinuation. Three patients tolerated lomitapide at doses ranging between 5 and 30 mg/day without major side effects. Downwards drug titration was necessary in the 6 remaining patients because of gastrointestinal side effects (n = 5) and elevated liver enzymes (n = 1), and 2 of them finally discontinued treatment. CONCLUSIONS: Lomitapide may be used to further decrease LDL-C in HoFH patients; gastrointestinal side effects and hepatic toxicity may limit adherence.

Evidence for improved survival with treatment of homozygous familial hypercholesterolemia.

PURPOSE OF REVIEW: Homozygous familial hypercholesterolemia (HoFH) is an orphan disease caused by biallelic mutations at the LDL receptor (LDLR) gene, with a prevalence estimated at 1 : 250 000 to 1 : 630 000. HoFH is characterized by extremely elevated plasma levels of LDL-C greater than 10 mmol/l (>387 mg/dl), tendinous and cutaneous xanthomas in youth and premature atherosclerotic cardiovascular disease (ASCVD). The expected prevalence varies from country to country depending on the presence of founder effects, genetic probability and life expectancy. Untreated, HoFH is a fatal condition before age 30. Plasma levels of LDL-C are the major cause of mortality and the therapeutic target. Statin therapy led to a remarkable improvement in survival but is of limited use in loss-of-function LDLR gene variants or 'null' mutations. Inhibitors of PCSK9 are a useful adjunct in patients with LDLR mutations with residual activity. Extracorporeal LDL filtration has improved survival since its introduction three decades ago. RECENT FINDINGS: Novel therapies, not dependent on a functioning LDLR include lomitapide and mipomersen, which decrease hepatic apolipoprotein B secretion, and evinacumab, directed at the angiopoietin like-3 protein (ANGPLT-3). SUMMARY: Over the past 3-4 decades, the survival of patients with HoFH has increased markedly. New therapeutic options offer new hope.

The Lifelong Burden of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor gene. It is diagnosed in children or youth who present with extensive tendinous and cutaneous xanthomas and extreme elevation of low-density lipoprotein cholesterol. Untreated, premature coronary artery disease develops in the teenage years or earlier and survival to ages older than 30 years is rare. Herein we describe the clinical course of a patient with homozygous familial hypercholesterolemia treated according to the standards of care and experimental approaches. Despite aggressive therapies, atherosclerosis in all vascular beds progressed, leading to the patient's demise at age 59 years, highlighting the importance of early diagnosis and appropriate follow-up.

Simplified Canadian Definition for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal codominant lipoprotein disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease. Definitions for FH rely on complex algorithms that are on the basis of levels of total or LDL-C, clinical features, family history, and DNA analysis that are often difficult to obtain. We propose a novel simplified definition for FH. Definite FH includes: (1) elevated LDL-C (≥ 8.50 mmol/L); or (2) LDL-C ≥ 5.0 mmol/L (for age 40 years or older; ≥ 4.0 mmol/L if age younger than 18 years; and ≥ 4.5 mmol/L if age is between 18 and 39 years) when associated with at least 1 of: (1) tendon xanthomas; or (2) causal DNA mutation in the LDLR, APOB, or PCSK9 genes in the proband or first-degree relative. Probable FH is defined as subjects with an elevated LDL-C (≥ 5.0 mmol/L) and the presence of premature atherosclerotic cardiovascular disease in the patient or a first-degree relative or an elevated LDL-C in a first-degree relative. LDL-C cut points were determined from a large database comprising > 3.3 million subjects. To compare the proposed definition with currently used algorithms (ie, the Simon Broome Register and Dutch Lipid Clinic Network), we performed concordance analyses in 5987 individuals from Canada. The new FH definition showed very good agreement compared with the Simon Broome Register and Dutch Lipid Clinic Network criteria (κ = 0.969 and 0.966, respectively). In conclusion, the proposed FH definition has diagnostic performance comparable to existing criteria, but adapted to the Canadian population, and will facilitate the diagnosis of FH patients.

Knockdown of angiopoietin-like 2 mimics the benefits of intermittent fasting on insulin responsiveness and weight loss.

Angiopoietin-like 2 (ANGPTL2) is an inflammatory adipokine linking obesity to insulin resistance. Intermittent fasting, on the other hand, is a lifestyle intervention able to prevent obesity and diabetes but difficult to implement and maintain. Our objectives were to characterize a link between ANGPTL2 and intermittent fasting and to investigate whether the knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight gain and insulin responsiveness in knockdown and wild-type littermates mice. Intermittent fasting, access to food ad libitum once every other day, was initiated at the age of three months and maintained for four months. Intermittent fasting decreased by 63% (p < 0.05) gene expression of angptl2 in adipose tissue of wild-type mice. As expected, intermittent fasting improved insulin sensitivity (p < 0.05) and limited weight gain (p < 0.05) in wild-type mice. Knockdown mice fed ad libitum, however, were comparable to wild-type mice following the intermittent fasting regimen: insulin sensitivity and weight gain were identical, while intermittent fasting had no additional impact on these parameters in knockdown mice. Energy intake was similar between both wild-type fed intermittent fasting and ANGPTL2 knockdown mice fed ad libitum, suggesting that intermittent fasting and knockdown of ANGPTL2 equally lower feeding efficiency. These results suggest that the reduction of ANGPTL2 could be a useful and promising strategy to prevent obesity and insulin resistance, although further investigation of the mechanisms linking ANGPTL2 and intermittent fasting is warranted. Impact statement Intermittent fasting is an efficient diet pattern to prevent weight gain and improve insulin sensitivity. It is, however, a difficult regimen to follow and compliance is expected to be very low. In this work, we demonstrate that knockdown of ANGPTL2 in mice fed ad libitum mimics the beneficial effects of intermittent fasting on weight gain and insulin sensitivity in wild-type mice. ANGPTL2 is a cytokine positively associated with fat mass in humans, which inactivation in mice improves resistance to a high-fat metabolic challenge. This study provides a novel pathway by which IF acts to limit obesity despite equivalent energy intake. The development of a pharmacological ANGPTL2 antagonist could provide an efficient tool to reduce the burden of obesity.

Aortic Calcification Progression in Heterozygote Familial Hypercholesterolemia.

BACKGROUND: Patients with homozygous and heterozygous familial hypercholesterolemia (HeFH) develop severe aortic calcifications in an age- and gene dosage-dependent manner. The purpose of this study was to determine the rate of progression of aortic calcification in patients with HeFH. METHODS: We performed thoracoabdominal computed tomography scans and quantified aortic calcium (AoCa) score in 16 HeFH patients, all with the null low-density lipoprotein (LDL) receptor DEL15Kb mutation. Patients (12 men, 4 women) were rescanned an average of 8.2 ± 0.8 years after the first scan. RESULTS: Mean LDL cholesterol (LDL-C) during treatment was 2.53 mmol/L; all patients were receiving high-dose statin/ezetimibe; 5 of 16 were receiving evolocumab. Baseline LDL-C was 7.6 ± 1.3 mmol/L. Aortic calcifications increased in all patients in an exponential fashion with respect to age. Age was the strongest correlate of AoCa score. Cholesterol, LDL-C, or age × cholesterol did not correlate with AoCa score or its progression. Control patients (n = 31; 8 male, 23 female; mean age 61 ± 11 years) who underwent virtual colonoscopy were rescanned over the same period and showed an abdominal AoCa score of 1472 ± 2489 compared with 7916 ± 7060 Agatston U (P < 0.001) in patients with HeFH during treatment (mean age, 60 ± 14 years). The rate of progression was 159 vs 312 Agatston U/y in control participants vs those with HeFH. CONCLUSIONS: HeFH patients exhibit accelerated aortic calcification that increases exponentially with age. LDL-C at baseline or during treatment seems to have little effect on the rate of progression of AoCa score. Strategies to prevent aortic calcifications with statins have not met with clinical success and novel approaches are required; statins might also contribute to the process of arterial calcification.

Crash avoidance in response to challenging driving events: The roles of age, serialization, and driving simulator platform.

We examined the crash avoidance behaviors of older and middle-aged drivers in reaction to six simulated challenging road events using two different driving simulator platforms. Thirty-five healthy adults aged 21-36 years old (M=28.9±3.96) and 35 healthy adults aged 65-83 years old (M=72.1±4.34) were tested using a mid-level simulator, and 27 adults aged 21-38 years old (M=28.6±6.63) and 27 healthy adults aged 65-83 years old (M=72.7±5.39) were tested on a low-cost desktop simulator. Participants completed a set of six challenging events varying in terms of the maneuvers required, avoiding space given, directional avoidance cues, and time pressure. Results indicated that older drivers showed higher crash risk when events required multiple synchronized reactions. In situations that required simultaneous use of steering and braking, older adults tended to crash significantly more frequently. As for middle-aged drivers, their crashes were attributable to faster driving speed. The same age-related driving patterns were observed across simulator platforms. Our findings support the hypothesis that older adults tend to react serially while engaging in cognitively challenging road maneuvers.

Near peripheral motion detection threshold correlates with self-reported failures of attention in younger and older drivers.

Motion contrast thresholds for 0.4cycle/degree drifting Gabor stimuli were assessed at 15 degrees eccentricity in the right and left visual fields for 16 younger drivers (ages 24-42), and 15 older drivers (ages 65-84), using a temporal two-alternative forced choice staircase procedure. Two self-report questionnaires that assess failures of attention while driving-the Driver Perception Questionnaire (DPQ5), and an abridged Aging Driver Questionnaire (ADQ15)-were administered. The three UFOV((R)) subtests of attention and processing speed were also administered. Mean peripheral motion contrast threshold (PMCT) of older drivers was significantly higher than that of younger drivers. When controlling for age, PMCT thresholds correlated significantly with both DPQ5 and ADQ15 while the UFOV((R)) subtests were found not to correlate with PMCT results. The potential value of the PMCT as an assessment of drivers' hazard detection capacity is discussed.

Capturing the serial nature of older drivers' responses towards challenging events: a simulator study.

Older drivers' ability to trigger simultaneous responses in reaction to simulated challenging road events was examined through crash risk and local analyses of acceleration and direction data provided by the simulator. This was achieved by segregating and averaging the simulator's primary measures according to six short time intervals, one before and five during the challenging events. Twenty healthy adults aged 25-45 years old (M=29.5+/-4.32) and 20 healthy adults aged 65 and older (M=73.4+/-5.17) were exposed to five simulated scenarios involving sudden, complex and unexpected maneuvres. Participants were also administered the Useful Field of View (UFOV), single reaction time and choice reaction time tests, a visual secondary task in the simulator, and a subjective workload evaluation (NASA-TLX). Results indicated that the challenging event that required multiple synchronized reactions led to a higher crash rate in older drivers. Acceleration and orientation data analyses confirmed that the drivers who crashed limited their reaction. The other challenging events did not generate crashes because they could be anticipated and one response (braking) was sufficient to avoid crash. Our findings support the proposal (Hakamies-Blomqvist, L., Mynttinen, S., Backman, M., Mikkonen, V., 1999. Age-related differences in driving: are older drivers more serial? International Journal of Behavioral Development 23, 575-589) that older drivers have more difficulty activating car controls simultaneously putting them at risk when facing challenging and time pressure road events.

Organizational cultural competence in community health and social service organizations: how to conduct a self-assessment.

OBJECTIVES: In an effort to address the significant socio-cultural changes in the population demographics of the United States (US) and Canada, organizations are increasingly seeking ways of improving their level of cultural competence. Evaluating organizational cultural competence is essential to address the needs of ethnic and cultural minorities. Yet, research related to organizational cultural competence is relatively new. The purpose of this paper is to review the extant literature with a specific focus on: (1) identifying the key standards that define culturally competent community health and social service organizations; and (2) outlining the core elements for evaluating cultural competence in a health and social service organization. Furthermore, issues related to choosing self-assessment tools and conducting an evaluation will be explored.

Preserved LTP and water maze learning in hyperglycaemic-hyperinsulinemic ZDF rats.

Previous investigations have demonstrated that cognitive deficits as well as hippocampal dysfunctions are generated in animals presenting manifestations of Type 1 diabetes (T1D) mellitus. The present study examined whether such deficits can also be reproduced in the Zucker Diabetic Fatty (ZDF) rats after they developed symptoms of Type 2 diabetes (T2D). Learning and memory assessments were performed using the Morris water maze 5 weeks after the animals presented symptoms of Type 1 diabetes for Experiment 1 (Exp 1) and after 8 weeks for Experiment 2 (Exp 2). Testing in the water maze revealed that ZDF rats learned the task normally, although control rats were found to swim significantly faster after 5 or 8 weeks of untreated diabetes. From an electrophysiological perspective, we observed that the integrity of synaptic function was also preserved in ZDF rats as no alterations in long-term potentiation (LTP) were observed in the area CA1 of hippocampal slices. It is concluded that hyperglycaemia is not the only factor influencing water maze learning and LTP in this animal model of Type 2 diabetes (T2D). The experiments suggest that the resistance of ZDF rats to cognitive and electrophysiological dysfunctions might be related to the protective action of hyperinsulinemia. Indeed, measurements of the plasma insulin level at the end of testing were significantly superior in ZDF rats in comparison to control rats.