👤 Marina Cuchel

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

Effective lipid lowering therapies are essential for the prevention of atherosclerosis and cardiovascular disease. Available treatments have evolved in both their efficacy and their frequency of administration, and currently include monoclonal antibodies, antisense oligonucleotides and siRNA approaches. However, an unmet need remains for more effective and long-lasting therapeutics. Gene editing permanently alters endogenous gene expression and has the potential to revolutionize disease treatment. Despite the existence of several gene editing approaches, the CRISPR/Cas9 system has emerged as the preferred technology because of its high efficiency and relative simplicity. This review provides a general overview of this promising technology and an update on the progress made towards the development of treatments of dyslipidemia. The recently started phase 1b gene editing clinical trial targeting PCSK9 in patients with heterozygous familial hypercholesterolemia and cardiovascular disease highlights how gene editing may become available to treat not only patients affected by rare disorders of lipid metabolism, but also patients that are difficult-to-treat or at high risk. Other targets like ANGPTL3, LDLR, and APOC3 are on track for further pre-clinical development. The identification of novel targets using electronic health record-linked biobanks and human sequencing studies will continue to expand the potential target pool, and clinical assessment of treated patients will provide essential efficacy and safety information on current strategies. Gene editing of genes regulating lipid metabolism holds promise as an exciting new therapeutic approach. However, since gene editing permanently alters a patient's genome, its therapeutic application in humans will require careful safety assessment and ethical considerations. Show less

Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden. Show less