Current opinion in lipidology最新文献

Purpose of review: To summarize the recent literature on the effectiveness and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing low-density lipoprotein cholesterol (LDL-C) and mitigating atherosclerotic cardiovascular disease (ASCVD) risk.

Recent findings: PCSK9i demonstrated considerable benefits in patients with acute myocardial infarction (AMI). Within an intensive lipid-lowering strategy ("strike early-strike strong"), these agents were associated with improved outcomes, primarily through LDL-C reductions and atheromatous plaque regression and stabilization, particularly in multivessel disease. In heterozygous familial hypercholesterolemia, significant LDL-C reductions were noted for alirocumab (-43.3%) and lerodalcibep (-58.6%), while in homozygous hypercholesterolemia, lerodalcibep (-4.9%) and inclisiran (-1.68%) were ineffective, with evolocumab demonstrating a superior -10.3% LDL-C reduction. PCSK9i exhibit a favorable safety profile and high adherence rates; nevertheless, concerns have been raised in patients with respiratory comorbidities and during pregnancy. Additionally, challenges like high costs and complex authorization procedures limit their widespread implementation. Clinicians should also be mindful of the potential discontinuation of concurrent lipid-lowering therapies following PCSK9i initiation.

Summary: PCSK9i remain integral in ASCVD risk reduction, given their potent LDL-C-lowering effects, all while maintaining a favorable safety profile. The greatest benefits are observed in patients with AMI, particularly in multivessel disease. Despite high adherence, broader utilization is hindered by persistent challenges, including costs and complex authorization processes.

Purpose of review: Myocardial infarction survivors are at a high risk of a recurrent event despite receiving guideline preventive therapy. There is accumulated evidence that persistent atherosclerotic plaque inflammation contributes to this risk. Oxidized low-density lipoprotein (LDL) is widely recognized as a key factor in plaque inflammation and instability; however, no therapies that directly target oxidized LDL are to date available for clinical use. We will here review recent observations indicating that treatment with the anti-oxidized LDL antibody orticumab specifically inhibits plaque inflammation.

Recent findings: The effect of orticumab on coronary inflammation in a randomized, double-blind, placebo-controlled pilot phase 2a trial in subjects with moderate to severe psoriasis is a new and recent finding. Coronary inflammation was assessed by calculation of the fat attenuation index (FAI)-Score in the pericoronary adipose tissue in coronary computed tomography angiograms. After 15 weeks of treatment the mean FAI-Score of the three main coronary arteries was significantly reduced in the orticumab group while no change occurred in the placebo group. The effect of orticumab was most pronounced in those with most inflammation at baseline.

Summary: Treatment with orticumab represents a new and plaque-specific way to reduce arterial inflammation.

Purpose of review: To summarize and comment recent analyses from the Seven Countries Study of Cardiovascular Diseases (SCS) on the role of Atherogenicity (ATI) and Thrombogenicity (THI) indexes (created by combining several types of dietary fatty acids) in predicting major cardiovascular disease (CVD) and mainly coronary heart disease (CHD) mortalities in a long follow-up observation of ecological procedures involving 16 cohorts of middle-aged men.

Recent findings: In a chain of steps, a dietary score [Mediterranean Adequacy Index (MAI)] was inversely correlated with the ATI ( R  = -0.91). ATI directly correlated with serum cholesterol ( R  = +0.73) and serum cholesterol directly correlated with 50-year CHD mortality ( R  = +0.78). Moreover, MAI was inversely correlated ( R  = -0.91) and ATI was directly correlated with CHD mortality ( R  = +0.93). THI produced comparable results. In 10 cohorts reaching the extinction after 60 years of follow-up, results were similar. The same dietary and metabolic indicators were instead unrelated to other major types of CVD fatalities (heart diseases of uncertain etiology and stroke) or even inverse.

Summary: ATI and THI indices assembled by pooling several types of dietary fatty acids are strongly associated with long-term CHD mortality but not with other major CVD types.

Purpose of review: Doubts about whether high-density lipoprotein-cholesterol (HDL-C) levels are causally related to atherosclerotic cardiovascular disease (CVD) risk have stimulated research on identifying HDL-related metrics that might better reflect its cardioprotective functions. HDL is made up of different types of particles that vary in size, protein and lipid composition, and function. This review focuses on recent findings on the specific roles of HDL subpopulations defined by size in CVD.

Recent findings: Small HDL particles are more effective than larger particles at promoting cellular cholesterol efflux because apolipoprotein A-I on their surface better engages ABCA1 (ATP binding cassette subfamily A member 1). In contrast, large HDL particles bind more effectively to scavenger receptor class B type 1 on endothelial cells, which helps prevent LDL from moving into the artery wall. The specific role of medium-sized HDL particles, the most abundant subpopulation, is still unclear.

Summary: HDL is made up of subpopulations of different sizes of particles, with selective functional roles for small and large HDLs. The function of HDL may depend more on the size and composition of its subpopulations than on HDL-C levels. Further research is required to understand how these different HDL subpopulations influence the development of CVD.

Purpose of review: As the primary guardians at the air-surface interface, the functional profile of alveolar macrophages (AM) is wide-ranging from establishment of the alveolar niche, homeostatic maintenance of surfactant levels, to pathogen clearance and resolution and repair processes. Alveolar lipid homeostasis is disturbed in chronic lung diseases and contributes to disease pathogenesis through extracellular localization in the alveolar lumen or intracellular accumulation in AM. This review aims to provide a focused overview of the state of knowledge of AM, their ontogeny and development during health and disease, and how dysregulated AM lipids play a key role in disease processes, from initiation to resolution.

Recent findings: While lipid-laden macrophages are observed across a broad spectrum of lung diseases, their occurrence has largely been considered consequential. Recent advances in lipidomic profiling of single cell types has revealed that disturbances to lipid homeostasis occur early in disease in tissue-resident cells. Comparisons between inflammatory and fibrotic injury models reveal specific alveolar macrophage subsets with different lipid utilization that contribute to the disease process.

Summary: Understanding the intricate web of AM population seeding and development and how this niche is perturbed by lipid disturbances may help provide leverage for new interventions.

Purpose of review: Hypertriglyceridemia (HTG), which arises from defects in triglyceride-rich lipoprotein (TRL) metabolism, is associated with increased morbidity and mortality from pancreatitis and atherosclerotic cardiovascular disease. Traditional therapies, including fibrates and omega-3 fatty acids, have shown limited efficacy in controlling triglyceride (TG) levels and cardiovascular risk. This review explores the role of emerging therapies that target TG and TRL metabolism via novel biochemical pathways.

Recent findings: Apolipoprotein C-III inhibitors appear most effective for patients with variants of severe HTG, particularly multifactorial and familial chylomicronemia syndromes, by enhancing TRL metabolism through both lipoprotein lipase-dependent and independent mechanisms. Angiopoeitin-like proteins 3 and 4 inhibitors appear most useful for mixed hyperlipidemia, with favorable effects across the entire spectrum of apoB-containing atherogenic lipoproteins. For patients with HTG and concomitant complications of insulin resistance, including metabolic associated steatotic liver disease and type 2 diabetes mellitus, fibroblast growth factor-21 analogs may provide significant benefit.

Summary: HTG is a diverse condition. Apolipoprotein C-III inhibitors, angiopoeitin-like proteins 3 and 4 inhibitors, and fibroblast growth factor-21 analogs represent significant advancements in the treatment of HTG, offering new hope for effectively managing this condition across its full spectrum of disease.

Purpose of review: Chylomicron biosynthesis plays a vital role in supplying essential lipids and lipid soluble vitamins to peripheral tissues for various functions. Despite this, the intracellular synthesis, trafficking, and secretion of chylomicrons remains only partly understood. The purpose of this review is to summarize the role of established proteins in this process and bring attention to recently identified proteins to provide an up-to-date model of chylomicron biosynthesis.

Recent findings: Recently, several proteins have been shown to play a role in the initial formation and lipidation of chylomicrons at the endoplasmic reticulum (ER), which include: TM6SF2, PLA2G12B, PRAP1, and SURF4. In addition, mitochondria have been implicated in chylomicron metabolism, but mechanistic insight is missing. The trafficking of chylomicrons from the ER to the Golgi, and the subsequent trafficking from the Golgi to the basolateral side of enterocytes, however, remains a mystery.

Summary: Progress in the chylomicron biosynthesis field is largely associated with findings in VLDL biosynthesis. In addition, increased insight in events after prechylomicrons leave the ER is needed. Given the important role of chylomicron biosynthesis in whole-body lipid metabolism, further research into the molecular mechanisms is warranted.

Purpose of review: Elevated lipoprotein(a) [Lp(a)] is a genetically determined independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Current guidelines recommend universal testing of Lp(a) once in an individual's lifetime, with risk factor management intensification for those with elevated levels. However, there is a paucity of real-world data about how patients with elevated Lp(a) are managed and about their associated cardiovascular risk. The purpose of this review is to discuss recent progress in the establishment of registries of patients with elevated Lp(a).

Recent findings: Multiple registries that include patients with elevated Lp(a) have been established in various countries. These studies will provide a snapshot of the global burden of this condition and the current patterns of treatment of this patient population.

Summary: Elevated Lp(a) is a common but underdiagnosed risk factor for ASCVD. National and international registries are needed to expand our understanding and improve the treatment of this condition.

Purpose of review: Individuals with familial hypercholesterolemia (FH), particularly those with homozygous FH (HoFH) who have markedly elevated LDL-cholesterol (LDL-C) levels from birth, present with unique complications during pregnancy. This review explores the complexities of FH care during pregnancy.

Recent findings: The worldwide burden of FH is much greater than previously thought. Still, underdiagnosis and undertreatment are substantial, necessitating increased awareness, genetic screening efforts, and better access to diagnostic tools. Although there is guidance for implementing best practices in the care of FH, including pregnancy, currently, there are no evidence-based guidelines that address HoFH at the time of pregnancy planning or during pregnancy and lactation.

Summary: FH management in pregnancy requires a reasonable balance between fetal safety and maternal LDL-C control. Discontinuing lipid-lowering medication during pregnancy and the postpartum period needs to be considered, and in severe cases, lipoprotein apheresis may be an appropriate substitute. Comprehensive patient care requires coordination by genetic counselors, cardiologists, lipidologists, and obstetricians. The management of HoFH in pregnancy requires further research efforts, enhancement of public knowledge, and worldwide cooperation. By focusing on these areas, we can make significant progress in diagnostics and develop efficient management plans for improving outcomes among pregnant women with HoFH.