Preventive Lipid-Lowering Therapy and Interactions With Health Care in Patients Who Develop Premature Coronary Artery Disease.

Background: Rates of premature coronary artery disease (CAD) are stagnant, and the prevalence of cardiovascular risk factors in young and middle-aged adults is increasing. Lipid-lowering therapy (LLT) is effective in preventing CAD but is underutilized in younger patients. The reasons for and consequences of this underutilization are not fully understood.

Cardiovascular risk and subclinical atherosclerosis in first-degree relatives of patients with premature cardiovascular disease.

Background: Screening first-degree relatives (FDRs) of patients with premature coronary artery disease (CAD) is recommended but not routinely performed.

Objectives: To assess the diagnostic yield and impact on clinical management of a clinical and imaging-based screening program of FDRs delivered in the setting of routine clinical care.

Methods: We recruited FDRs of patients with premature CAD with no personal history of CAD and prospectively assessed for: 1) cardiovascular risk and presence of significant subclinical atherosclerosis (SA) defined as plaque on carotid ultrasound, stenosis >50% or extensive atherosclerosis on coronary computed tomography angiography, or coronary artery calcium scores >100 Agatston units or >75% percentile for age and sex; 2) utilization of preventive medications and lipid levels prior enrolment and after completion of the assessment.

Longitudinal Control of Lipid Levels in Patients With Premature Coronary Artery Disease.

Background: Lipid-lowering therapy (LLT) is a central aspect of the treatment of patients with coronary artery disease (CAD), and the benefits of LLT accrue over time. However, there are limited real-world data on longitudinal lipid control in patients with premature CAD.

Objectives: The purpose of this study was to assess longitudinal attainment of guideline-recommended lipid goals and outcomes in a contemporary cohort of patients with premature CAD.

The Importance of Nontraditional and Sex-Specific Risk Factors in Young Women With Vasomotor Nonobstructive vs Obstructive Coronary Syndromes.

Background: Heart disease is the leading cause of premature death for women in Canada. Ischemic heart disease is categorized as myocardial infarction (MI) with no obstructive coronary artery disease (MINOCA), ischemia with no obstructive coronary arteries (INOCA), and atherosclerotic obstructive coronary artery disease (CAD) with MI (MI-CAD) or without MI (non-MI-CAD). This study aims to study the prevalence of traditional and nontraditional ischemic heart disease risk factors and their relationships with (M)INOCA, compared to MI-CAD and non-MI-CAD in young women.

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial.

Importance: Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.

Objective: To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.

Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation.

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or -thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors.

Clinical characteristics and treatment experience of individuals with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE): Findings from an online caregiver survey.

Purpose: SCN8A developmental epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset developmental delay, cognitive impairment, and intractable seizures. SCN8A gene variants are associated with a broad phenotypic spectrum and variable disease severity. A caregiver survey, solicited by the advocacy group The Cute Syndrome Foundation (TCSF), was conducted to gather information on the demographics/disease presentation, seizure history, and treatment of patients with SCN8A-related epilepsies.

NBI-921352, a first-in-class, Na1.6 selective, sodium channel inhibitor that prevents seizures in gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na1.6 channels. Such a molecule provides a precision-medicine approach to target -related epilepsy syndromes (-RES), where gain-of-function (GoF) mutations lead to excess Na1.

Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia.

Background And Aims: Familial combined hyperlipidemia (FCHL) is one of the most common inherited lipid phenotypes, characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. The genetic inheritance of FCHL remains poorly understood. The goals of this study were to investigate the polygenetic architecture and cardiovascular risk associated with FCHL.

Familial Hypercholesterolemia, Familial Combined Hyperlipidemia, and Elevated Lipoprotein(a) in Patients With Premature Coronary Artery Disease.

Background: Familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), and elevated lipoprotein (a) (Lp[a]) increase risk of premature coronary artery disease (CAD). The objective of this study was to assess the prevalence of FH, FCHL, elevated Lp(a) and their impact on management in patients with premature CAD.

Methods: We prospectively recruited men ≤ 50 years and women ≤ 55 with obstructive CAD.

Lipid-lowering therapy for primary prevention of premature atherosclerotic coronary artery disease: Eligibility, utilization, target achievement, and predictors of initiation.

Objectives: Despite advances in screening and prevention, rates of premature coronary artery disease (CAD) have been stagnant. The goals of this study were to investigate the barriers to early risk detection and preventive treatment in patients with premature CAD. In particular, we: 1) assessed the performance of the latest versions of major international guidelines in detection of risk of premature CAD and eligibility for preventive treatment; and, 2) investigated real-life utilization of primary prevention with lipid-lowering therapies in these patients.

Capturing seizures in clinical trials of antiseizure medications for -DEE.

Literature review of patients with developmental and epileptic encephalopathy (-DEE) reveals, based on 16 reports including 139 patients, a clinical phenotype that includes age- and disease-specific stereotyped seizures. The typical seizure type of -DEE, focal tonic, starts within 0-5 days of life and is readily captured by video-electroencephalography VEEG for clinical and genetic diagnosis. After initial identification, -DEE seizures are clinically apparent and can be clearly identified without the use of EEG or VEEG.

Priorities for Services in Young Patients With Atherosclerotic Cardiovascular Disease and Their Family Members: An Exploratory Mixed-Methods Study.

Background: Optimal design of clinical programs for patients with premature atherosclerotic cardiovascular disease (ASCVD) (men aged ≤ 50 years, women aged ≤ 55 years) requires an understanding of their priorities. We aimed to explore patient and family priorities for services in clinical programs.

Methods: We co-designed this study with a Patient Partner Committee using a sequential exploratory mixed-methods design.

TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101.

Objective: Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy.

Premature Atherosclerotic Cardiovascular Disease: Trends in Incidence, Risk Factors, and Sex-Related Differences, 2000 to 2016.

Background The incidence of atherosclerotic cardiovascular disease has declined in the past 2 decades. However, these benefits may not extend to young patients. The objective of this work was to assess temporal trends in the incidence, risk profiles, sex-related differences, and outcomes in a contemporary population of young patients presenting with coronary artery disease ( CAD ) in British Columbia, Canada.

The design and rationale of SAVE BC: The Study to Avoid CardioVascular Events in British Columbia.

Atherosclerotic cardiovascular disease (ASCVD) is highly heritable, particularly when it occurs at a young age. The screening of individuals with premature ASCVD, although often recommended, is not routinely performed. Strategies to address this gap in care are essential.

Identification of Cadherin 2 () Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families.

Methods And Results: Whole exome sequencing was performed on 2 cousins with ARVC.

Safety and Efficacy of a Topical Sodium Channel Inhibitor (TV-45070) in Patients With Postherpetic Neuralgia (PHN): A Randomized, Controlled, Proof-of-Concept, Crossover Study, With a Subgroup Analysis of the Nav1.7 R1150W Genotype.

Objective: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism.

Materials And Methods: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial.

Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.

We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development.

Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker.

Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli.

Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.

Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes.

Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes.

Objective: The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study.

Methods: The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders.

Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates.

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.

Allelic variation in the promoter region of the LDL receptor gene: analysis of an African-specific variant in the FP2 cis-acting regulatory element.

DNA samples of 2303 individuals from nine different population groups were screened for variant -175g-->t in the promoter region of the low-density lipoprotein receptor (LDLR) gene. The -175g-->t variant detected at carrier frequencies of 3-10% in different African population groups was absent in the Caucasian and Asian (Chinese) individuals studied. In contrast to previous findings in Black South Africans where this polymorphism predominated in patients with familial hypercholesterolaemia (FH), it occurred at a significantly lower frequency in hypercholesterolaemics from the recently admixed Coloured population of South Africa compared with population-matched controls (P<0.