Queen Elizabeth II Health Sciences Centre

BackgroundHomozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extreme elevations in low-density lipoprotein cholesterol levels and premature cardiovascular disease.ObjectivesThe objective of this study was to assess the prevalence, clinical presentation, and current therapeutic approaches for aortic stenosis in Canadian patients with HoFH.MethodsDemographic data, lipid profiles, and genetic testing results for patients with HoFH were collected prospectively since 2008. Reports from echocardiography, cardiac catheterization, and surgical or transcatheter interventions involving the aortic valve and/or ascending aorta were retrieved from medical records.ResultsData were available for 63 patients with either a clinical diagnosis (n = 14, 22.2%) or genetic confirmation (n = 49, 77.8%) of HoFH. The median age at diagnosis was 14.0 years (Q1-Q3: 6.0 to 31.0), the median highest recorded low-density lipoprotein cholesterol level was 13.0 mmol/L (Q1-Q3: 10.6-16.3), and 17 patients (27.0%) developed moderate-to-severe aortic stenosis. Extensive calcification of the aortic valve and ascending aorta, combined with severe valvular and/or supravalvular stenosis and coronary ostial stenosis, necessitated complex and often consecutive surgical procedures. Six transcatheter aortic valve replacements were performed in 4 patients, 4 of which failed. Thirteen patients (20.6%) underwent at least 1 surgical aortic valve procedure. Patients developed aortic stenosis at a young age despite intensive treatment, including lipoprotein apheresis started at an early age.ConclusionsModerate-to-severe aortic stenosis was observed in 27.0% of patients in the Canadian HoFH Registry, with 20.6% requiring invasive intervention. The severe aortic phenotype associated with HoFH requires complex, multidisciplinary surgical management in specialized centers with appropriate expertise.

The long-term effects of catheter ablation (CA) compared with medical therapy on cardiovascular outcomes for atrial fibrillation (AF) remain undetermined. Using a population-based cohort, we sought to determine what the association between CA and medical therapy was on these outcomes. By use of Alberta administrative data, patients with AF as the primary diagnosis during hospitalization, emergency department visit, or physician visit were included between October 1, 2008, and March 31, 2018. Based on therapy received, patients were assigned to categories of CA, rate control, or rhythm control with medication. The association of treatment with the primary composite outcome of all-cause death, hospitalization for heart failure, or stroke was examined after adjustment for age, sex, comorbidities, and baseline medications. Of 39,966 treated AF patients, 2077 (5.2%), 29,467 (73.7%), and 8422 (21.1%) were treated with CA, rate control, and rhythm control with medication, respectively. Patients in the CA group had a lower incidence of the primary outcome (4.0/100 person-years) compared with the rate control group (8.7/100 person-years) or the rhythm control with medication group (6.8/100 person-years) during a median follow-up of 6.3 years. In multivariable analysis, compared with CA, both rate control (hazard ratio, 1.28; 95% confidence interval, 1.09-1.50) and rhythm control with medication (hazard ratio, 1.21; 95% confidence interval, 1.03-1.43) were associated with a higher risk of the primary outcome. In this cohort study, patients who received CA demonstrated a reduction in the risk of long-term adverse cardiovascular outcomes compared with medical therapy in patients with AF, providing some data to indicate the effects of CA in the long-term.

Chronic lymphocytic leukemia (CLL) is the most common low-grade B-cell neoplasm worldwide. While diagnostic criteria are well established, prognostication and management of this disease are an evolving field, owing to the biological and clinical heterogeneity of CLL. Molecular, cytogenetic, and immunogenetic workup are key in the management of CLL, and include evaluation for specific gene variants, copy number variants (CNVs), and detailed analysis of the immunoglobulin heavy chain variable region (IGHV) with respect to somatic hypermutation (SHM) status and the presence of recurrent stereotyped IGHV subsets. IGHV status has significant prognostic, predictive, and therapeutic implications in CLL and has been incorporated into multiple risk stratification systems. The advent of both next-generation sequencing (NGS) and novel targeted therapies has added further complexity to immunogenetic analysis in CLL. Owing to the necessity and growing complexity of IGHV analysis, the European Research Initiative on CLL (ERIC) developed guidelines to standardize methods for immunogenetic analysis and provide recommendations for interpretation of challenging cases (including multiple productive IGHV clones and discordant SHM status) and has published multiple updates, revising recommendations and raising new questions. This review discusses the biology and clinical significance of IGHV status in CLL as well as laboratory methodology in immunogenetic analysis, the evolution of the ERIC recommendations leading into the era of NGS, and recent advances and emerging strategies in this field.