Current opinion in lipidology最新文献

Purpose of review: A review of recent publications demonstrating the important role of the intestine in the pathogenesis of cardiovascular disease.

Recent findings: At baseline (≥ 6 months since myocardial infarction), the pattern of fecal microbiota and blood LPS levels after a meal predicted risk for new major adverse cardiovascular events over the next 7 years. In intestine, tryptophan is metabolized primarily by the kynurenine pathway, which is regulated by the enzyme indoleamine-2,3-dioxygenase 1 (IDO1). Tryptophan flow into the kynurenine pathway limits its availability for the formation of microbiota-derived indole derivatives including butyrate, and limits availability of tryptophan for the 5-hydroxytryptamine (5-HT or serotonin) pathway. Feeding Ldlr-/- mice a high-fat high-cholesterol diet (HFD+HCD) increased intestinal IDO1 activity, decreased levels of tryptophan, fecal butyrate, and 5-HT. Ldlr-/- mice deficient in intestinal Ido1  ( Ldlr-/-Ido1-/- ) on HFD+HCD had increased intestinal levels of 5-HT, increased gut permeability, increased gut inflammation, increased LPS, and increased aortic atherosclerosis. Ldlr-/- mice fed HFD+HCD and treated with a 5-HT pathway inhibitor had increased fecal indole levels, improved gut-barrier, increased antimicrobial peptide levels, and decreased aortic atherosclerosis without a change in plasma cholesterol.

Summary: These studies demonstrate the importance of microbiota-derived products and intestinal tryptophan metabolism in atherosclerosis.

Purpose of review: Peripheral artery disease (PAD) is a major cause of global health burden, including amputation and impaired quality of life. This review examines the evidence implicating lipoprotein(a) [Lp(a)] in PAD, which is timely as novel therapies lowering Lp(a) are currently being tested in several clinical trials.

Recent findings: Human observational studies demonstrate strong associations between elevated Lp(a) levels and increased risk of PAD incidence, severity of chronic limb-threatening ischemia, and major adverse limb events. Emerging therapies including small interfering RNA, antisense oligonucleotides, proprotein convertase subtilisin-kexin type 9 inhibitors and lipoprotein apheresis demonstrate significant Lp(a)-lowering effects. However, whether these treatments benefit patients with PAD is currently unknown.

Summary: Lp(a) may be involved in PAD pathogenesis. Lp(a)-lowering therapies may significantly reduce PAD-related events and improve outcomes. Future studies are needed to test Lp(a)-lowering therapies in people with PAD and to explore how the association of Lp(a) varies in different sexes and ethnicities and understand mechanisms by which Lp(a) may contribute to limb ischemia.

Purpose of review: Macrophages can accumulate lipid droplets in their cytoplasm resulting in the foamy appearance seen in various diseases, especially atherosclerosis. This review assesses new insights from single cell analyses into the role of different human macrophage subpopulations and genetic risk in atherosclerotic disease.

Recent findings: Single cell transcriptomic studies have identified TREM2hi foamy macrophages as a key population in both human and mouse atherosclerotic plaques. In addition, a TREM1hi/PLIN2hi population in human plaques has pro-inflammatory properties. Combined single cell transcriptomic and epigenetic multiomic profiling identified a population of CD52hi lipid-handling macrophages that are enriched for heritability of atherosclerotic disease. Molecular mechanisms have been identified linking gene-regulatory effects of disease-associated polymorphisms to the macrophage response to ox-LDL.

Summary: Recent studies have used singe cell approaches to provide new insights into macrophage subsets, their interactions with lipid species and their role in mediating genetic influences on disease risk.

Purpose of review: Remnant cholesterol is receiving increasing attention as a target to reduce residual atherosclerotic cardiovascular disease (ASCVD) risk in individuals already treated with statins. New therapeutic options as antisense oligonucleotides, small interfering RNA, and monoclonal antibodies allow specific targeting of genes and proteins to counter pathological pathways promoted by these genes. Identifying genetic determinants of remnant cholesterol and relating these to risk of ASCVD is thus an appealing path to identifying and evaluating new and existing drug targets.

Recent findings: Human genetic epidemiology has identified several genetic variants in genes involved in lipoprotein metabolism with effect on plasma concentrations of remnant cholesterol. Lipoprotein lipase (LPL) is central to the metabolism of remnant lipoproteins and plasma concentrations of remnant cholesterol, and several genes, including APOC3 , ANGPTL3 and ANGPTL4 , whose gene products regulate activity of LPL, are important determinants of remnant cholesterol.

Summary: Current opinion is that remnant cholesterol is a likely causal factor in the development of ASCVD. Human genetic studies have identified several genes, many involved in LPL function, affecting remnant cholesterol concentrations, some of which are already used as therapeutic targets, and others which are subject to investigation of their remnant cholesterol and triglyceride-lowering effect in clinical trials.

Purpose of review: Lipoprotein(a) [Lp(a)] is a significant player in cardiovascular disease (CVD) and type 2 diabetes (T2D). While Lp(a) contributes to residual cardiovascular risk in T2D, lower levels paradoxically increase the risk of developing T2D. This review explores Lp(a)'s dual role in cardiometabolic disease, its association with T2D, and emerging Lp(a)-lowering therapies.

Recent findings: Large-scale studies confirm Lp(a) as a potent risk factor for cardiovascular events in T2D, with lower Lp(a) thresholds increasing risk compared to nondiabetic individuals. Observational and genetic studies reveal an inverse relationship between Lp(a) and T2D risk, linked to insulin dynamics, Kringle IV-type-2 repeat variants, and metabolic pathways. Emerging evidence suggests a connection between Lp(a), nonalcoholic fatty liver disease, and statin use. However, Mendelian randomization analyses have yielded conflicting results, leaving key mechanistic questions unresolved.

Summary: Lp(a) plays a complex role in cardiometabolic health, acting as both a cardiovascular hazard and a potential metabolic marker in T2D. The paradoxical association of low Lp(a) with increased T2D risk challenges conventional perspectives and raises concerns regarding Lp(a)-lowering interventions. Further research is needed to clarify causality, refine risk stratification, and guide clinical decisions for Lp(a) modulation in T2D patients.

Purpose of review: Small dense low-density lipoprotein cholesterol (sdLDL-C) is recognized for its strong atherosclerogenic potential. However, its direct measurement remains impractical in clinical settings due to its high cost, time constraints, and labor-intensive nature. This review discusses the benefits and limitations of estimating sdLDL-C using conventional lipid fractions, highlighting recent advancements in estimation methods.

Recent findings: Sampson et al. proposed a novel equation for estimating sdLDL-C based on conventional lipid parameters, offering a more accessible alternative to direct measurement. Recent studies, including ours, demonstrated that this estimation method achieves sufficiently high accuracy for overall application. However, its accuracy can be improved by incorporating machine learning. Furthermore, sdLDL-C estimated by Sampson's equation has been shown to be a superior risk marker for hypertension, an intermediate phenotype of atherosclerosis, and ischemic heart disease, a major cardiovascular event, compared to conventional lipid profiles alone, although further research is needed to determine whether estimated sdLDL-C is equivalent to directly measured sdLDL-C in risk assessment.

Summary: Estimated sdLDL-C presents a promising alternative to direct measurement. While estimated sdLDL-C levels can serve a risk marker for cardiovascular diseases, further research is needed to refine estimation models and explore their integration into clinical practice.

Purpose of review: Achilles tendon thickness is one of the most specific physical findings of familial hypercholesterolemia (FH), and thus it is used as one of the clinical diagnostic criteria. However, the objective assessment using imaging has not been used for a long time. We review the recent topic of this matter and discuss how this important assessment should be implemented in clinical settings.

Recent findings: Achilles tendon thickness assessed via X-ray or ultrasound can be used not only for diagnostic criteria but also as a useful biomarker for risk stratification. In addition, relying upon physical examination alone to detect the presence of tendon xanthoma may lead to underdiagnosis of FH.

Summary: The use of noninvasive imaging, such as X-ray or ultrasound appears to be quite useful for FH diagnosis as well as risk stratification. These objective assessments are currently adopted by a clinical guideline only in Japan; however, much attention should be paid to specific situation in FH around the world.

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.