👤 Robert G Weintraub

Familial hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C), leading to a high risk of early onset atherosclerotic cardiovascular disease (ASCVD). This document provides an update to the National Lipid Association's 2011 clinical guidance, summarizing the remarkable progress in the field. With a global prevalence of approximately 1 in 311, FH remains severely underdiagnosed. This guidance reviews current diagnostic criteria, including the expanding role of genetic testing to complement diagnosis and to facilitate cascade screening, and emphasizes a thorough differential diagnosis. It provides recommendations for universal pediatric screening and systematic cascade screening in families to improve detection. Management strategies include intensified LDL-C treatment goals for both primary and secondary prevention of ASCVD. A stepwise approach to optimal therapy is outlined, beginning with lifestyle interventions and pharmacotherapy with maximally tolerated statins and ezetimibe. This update incorporates newer agents, including proprotein convertase subtilisin/kexin type 9 inhibitors and bempedoic acid. Additional therapies, such as lomitapide and evinacumab for homozygous FH and lipoprotein apheresis for heterozygous and homozygous FH, are discussed. Further topics include cardiovascular imaging for risk stratification, management in specific populations and circumstances, such as planning for and during pregnancy and in pediatrics, and recognition of health disparities. This guidance equips clinicians with evidence-based strategies to improve the identification and care of patients with FH, ultimately reducing the high morbidity and mortality associated with this condition. Show less

Elevated lipoprotein(a) (Lp[a]) is an independent risk factor for the development of atherosclerotic cardiovascular disease. Despite National Lipid Association guidelines recommending one-time Lp(a) screening in adults aged 18 years and older, Lp(a) testing remains underutilized. A novel gamified ambulatory curriculum educating internal medicine residents on Lp(a) was implemented at a single academic internal medicine residency program. A total of 108 residents received a Lp(a) lecture in either a gamified format using KAHOOT! or slide-based traditional format. Learning outcomes including Likert scale ratings of confidence utilizing and interpreting Lp(a) results and a 10-question knowledge assessment were collected prior to the didactic, immediately following, and after 3 months. Screening rates prior to and following intervention were assessed. The Lp(a) curriculum significantly improved resident knowledge following the lecture (8.5 out of 10 questions post-test vs 3.9 pretest, P < .0001) and at 3-month follow up (5.8 3-month vs 3.9 pretest, P = .0001). Learning outcomes in the gamified group were similar to the traditional group (8.5 post-test traditional vs 8.6 post-test gamified, P = .978; 6.3 3-month traditional vs 5.8 3-month gamified, P = .466). In the 3 months following the didactic, there was a significant increase in resident Lp(a) screening among patients who had a lipid panel assessed compared to baseline (3.11% vs 1.21%, P < .0001). Both internal medicine resident Lp(a) knowledge and confidence improved following either a gamified or traditional lecture-based didactic. Addressing gaps in resident knowledge led to a modest increase in Lp(a) screening rates in our resident clinic among patients for whom a lipid panel was assessed. Show less

To evaluate whether epidural analgesia is an independent risk factor for OASIS. A population-based cohort study including all women who delivered by spontaneous vaginal delivery or by instrumental delivery beyond 24 weeks gestation was conducted. Deliveries occurred between 1988 and 2016 at a large university tertiary medical center. Women with multiple gestations and those lacking prenatal care were excluded from the analysis. During the study period, 252,542 women delivered at the Soroka University Medical Center and met the inclusion criteria. Of these, 583 (0.23%) were diagnosed with OASIS. Women with OASIS were more likely to be younger, nulliparous, with suspected fetal macrosomia, had higher rates of labor induction and vacuum extraction delivery, higher rates of conceiving after infertility treatments, more advanced gestational age at delivery, higher mean birth weight, higher rates of post-partum hemorrhage and need for blood transfusions. Use of epidural analgesia during pregnancy was significantly high among the OASIS group. Rates of episiotomy were not significantly different between the groups. Using a multimodal logistic regression model, after controlling for vacuum delivery, large for gestational age, nulliparity, gestational age, ethnicity, maternal age, induction of labor, fertility treatments, non-reassuring fetal heart rate and non-progressive second stage of labor, epidural analgesia was found to be significantly associated with OASIS. Epidural analgesia was found to be an independent risk factor for OASIS in our population. Show less

There is an incomplete understanding of the burden of splice-disrupting variants in definitively associated inherited heart disease genes and whether these genes can amplify from blood RNA to support functional confirmation of splicing outcomes. We performed burden testing of rare splice-disrupting variants in people with inherited heart disease and sudden unexplained death compared to 125,748 population controls. ClinGen definitively disease-associated inherited heart disease genes were amplified using RNA extracted from fresh blood, derived cardiomyocytes, and myectomy tissue. Variants were functionally assessed and classified for pathogenicity. We found 88 in silico-predicted splice-disrupting variants in 128 out of 1242 (10.3%) unrelated participants. There was an excess burden of splice-disrupting variants in PKP2 (5.9%), FLNC (2.7%), TTN (2.8%), MYBPC3 (8.2%) and MYH7 (1.3%), in distinct cardiomyopathy subtypes, and KCNQ1 (3.6%) in long QT syndrome. Blood RNA supported the amplification of 21 out of 31 definitive disease-associated inherited heart disease genes. Our functional studies confirmed altered splicing in six variants. Eleven variants of uncertain significance were reclassified as likely pathogenic based on functional studies and six were used for cascade genetic testing in 12 family members. Our study highlights that splice-disrupting variants are a significant cause of inherited heart disease, and that analysis of blood RNA confirms splicing outcomes and supports variant pathogenicity classification. Show less

Copy-number variant (CNV) analysis is increasingly performed in genetic diagnostics. We leveraged recent gene curation efforts and technical standards for interpretation and reporting of CNVs to characterize clinically relevant CNVs in patients with inherited heart disease and sudden cardiac death. Exome sequencing data were analyzed for CNVs using eXome-Hidden Markov Model tool in 48 established disease genes. CNV breakpoint junctions were characterized. CNVs were classified using the American College of Medical Genetics and Genomics technical standards. We identified eight CNVs in 690 unrelated probands (1.2%). Characterization of breakpoint junctions revealed nonhomologous end joining was responsible for four deletions, whereas one duplication was caused by nonallelic homologous recombination between duplicated sequences in MYH6 and MYH7. Identifying the precise breakpoint junctions determined the genomic involvement and proved useful for interpreting the clinical relevance of CNVs. Three large deletions involving TTN, MYBPC3, and KCNH2 were classified as pathogenic in three patients. Haplotype analysis of a deletion in ACTN2, found in two families, suggests the deletion was caused by an ancestral event. CNVs infrequently cause inherited heart diseases and should be investigated when standard genetic testing does not reveal a genetic diagnosis. Show less