👤 Robert Lyle

Cardiovascular disease (CVD) is the leading cause of mortality in the United States and globally. This review describes changes in CVD lipid and lipoprotein biomarker measurements that occurred in line with the evolution of clinical practice guidelines for CVD risk assessment and treatment. It also discusses the level of comparability of these biomarker measurements in clinical practice. Comparable and reliable measurements are achieved through assay standardization, which not only depends on correct test calibration but also on factors such as analytical sensitivity, selectivity, susceptibility to factors that can affect the analytical measurement process, and the stability of the test system over time. The current status of standardization for traditional and newer CVD biomarkers is discussed, as are approaches to setting and achieving standardization goals for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG), lipoprotein(a) (Lp(a)), apolipoproteins (apo) A-I and B, and non-HDL-C. Appropriate levels of standardization for blood lipids are maintained by the Centers for Disease Control and Prevention's (CDC) CVD Biomarkers Standardization Program (CDC CVD BSP) using the analytical performance goals recommended by the National Cholesterol Education Program. The level of measurement agreement that can be achieved is dependent on the characteristics of the analytes and differences in measurement principles between reference measurement procedures and clinical assays. The technical and analytical limitations observed with traditional blood lipids are not observed with apolipoproteins. Additionally, apoB and Lp(a) may more accurately capture CVD risk and residual CVD risk, respectively, than traditional lipids, thus prompting current guidelines to recommend apolipoprotein measurements. This review further discusses CDC's approach to standardization and describes the analytical performance of traditional blood lipids and apoA-I and B observed over the past 11 years. The reference systems for apoA-I and B, previously maintained by a single laboratory, no longer exist, thus requiring the creation of new systems, which is currently underway. This situation emphasizes the importance of a collaborative network of laboratories, such as CDC's Cholesterol Reference Methods Laboratory Network (CRMLN), to ensure standardization sustainability. CDC is supporting the International Federation of Clinical Chemistry and Laboratory Medicine's (IFCC) work to establish such a network for lipoproteins. Ensuring comparability and reliability of CVD biomarker measurements through standardization remains critical for the effective implementation of clinical practice guidelines and for improving patient care. Utilizing experience gained over three decades, CDC CVD BSP will continue to improve the standardization of traditional and emerging CVD biomarkers together with stakeholders. Show less

Hypertrophic cardiomyopathy (HCM) is a heterogeneous autosomal dominant cardiac disorder with a prevalence of 1 in 500. Over 450 different pathogenic mutations in at least 16 genes have been identified so far. The large allelic and genetic heterogeneity of HCM requires high-throughput, rapid, and affordable mutation detection technologies to efficiently integrate molecular screening into clinical practice. We developed a custom DNA resequencing array that contains both strands of all coding exons (160), splice-site junctions, and 5'UTR regions of 12 genes that have been clearly implicated in HCM (MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC, TNNC1, and PRKAG2). We analyzed a first series of 38 unrelated patients with HCM (17 familial, 21 sporadic). A total of 953,306 bp across the 38 patients were sequenced with a mean nucleotide call rate of 96.92% (range: 93-99.9%). Pathogenic mutations (single nucleotide substitutions) in MYH7, MYBPC3, TNNI3, and MYL3 (six known and six novel) were identified in 60% (10/17) of familial HCM and 10% of sporadic cases (2/21). The high-throughput HCM resequencing array is the most rapid and cost-effective tool for molecular testing of HCM to date; it thus has considerable potential in diagnostic and predictive testing, and prognostic stratification. Show less