PURPOSE OF REVIEW:Despite aggressive cholesterol lowering, many patients continue to experience cardiovascular events ("residual risk"), emphasizing the need for novel risk reduction strategies. This review highlights recent advances in studying atherosclerosis resolution, with a focus on the key role played by plaque inflammation. RECENT FINDINGS:Preclinical studies demonstrate that while atherosclerosis resolution can involve plaque size reductions, more important are changes in plaque remodeling, as measured by necrotic core, CD68 area, and collagen content. Resolution can be partially achieved with cholesterol lowering, inflammation resolution alone, or better yet, combination approaches. This review evaluates lipid-lowering strategies, as well as inflammation-targeting pathways involving efferocytosis, pro-resolving macrophages, platelets, and caloric restriction. Translational studies and clinical trials targeting inflammatory pathways, including interleukin (IL)-1β, IL-6, NLRP3, and pro-resolving mediators further support inflammation modulation as a therapeutic strategy. SUMMARY:Many preclinical models of atherosclerosis resolution promote significant plaque remodeling by lipid-lowering, inflammation resolution, or combination approaches. Many recent and currently recruiting clinical trials are testing the benefits of inflammation resolution to further reduce cardiovascular risk in at-risk patients.
PURPOSE OF REVIEW:Endothelial-to-mesenchymal transition (EndMT) has been implicated in the development of cardiovascular disease, including atherosclerosis. EndMT is a complex continuum with multiple involved pathways, each with different pathophysiologic implications depending on the driving regulators. RECENT FINDINGS:In this brief review, we will focus on the latest studies that have helped elucidate the role of lipids and related factors in the initiation of EndMT in the setting of atherosclerosis, with particular attention to atherosclerotic plaque stability and sex specific differences of disease. SUMMARY:We explore potential therapeutic strategies, including the impact that lipid modulation has on EndMT and the effects of EndMT-specific approaches on lipid deposition. Overall, this will inform future areas of research on EndMT modulation.
PURPOSE OF REVIEW:Lipids and lipoproteins have established roles in calcific atherosclerosis, but there is less awareness of their role in calcific aortic valve disease (CAVD). Clinical studies link CAVD with severe hypercholesterolemia, and genetic studies consistently link it with lipoprotein little (a) [Lp(a)], a major carrier of oxidized phospholipids. Given the remarkable similarities between calcific atherosclerotic plaques and calcific aortic valves, lipids are incriminated. Hence, lipid-lowering therapies used for atherosclerosis have been tested in CAVD, but results have been inexplicably disappointing. New evidence for the importance of lipids, despite failure of lipid-lowering, and new concepts in diagnostic and therapeutic approaches are discussed. RECENT FINDINGS:Evidence supports a key role of Lp(a) levels in CAVD. Potential diagnostic advances include pH-sensitive-fluorescence probes for visualizing lipid droplets in valves and identification of natural antibodies to modified LDL that associate inversely with CAVD. Potential therapeutic advances include Lp(a) lowering, SGLT2 inhibition, and reactivation of soluble guanylate cyclase. Trial outcomes currently remain mixed. SUMMARY:Recent studies clarify the mechanisms by which lipids, lipoproteins, and Lp(a) contribute to CAVD. New potential diagnostic techniques include screening for natural antibodies and visualizing lipid deposits. New therapeutic agents include oligonucleotides and nanoparticles. New clinical trials are underway.
PURPOSE OF REVIEW:It has become clear that elevated HDL-C is not a reliable marker of protection against inflammation and cardiovascular disease (CVD). This review summarizes recent advances in understanding how HDL function is affected by its associated proteins, demonstrating that this is a more appropriate lens through which to assess HDL's protective capacity. RECENT FINDINGS:Recent publications have demonstrated an inverse relationship between ApoM and clinical outcomes in chronic kidney disease and its concomitant cardiovascular indications. Mechanistic studies show that ApoM's regulation of mitochondrial function and autophagy are likely contributors to this effect. Additionally, ApoA-I, serum amyloid albumin (SAA), and SR-B1 have recently been highlighted as key regulators of atherogenesis through their ability to prevent LDL transcytosis and arterial entrapment by proteoglycans. Lastly, a novel mechanism is described wherein HDL-bound endotoxin is degraded through the endosome-lysosome pathway in an SR-B1-dependent manner, attenuating IL-1β activation. In the same study, inhibition of CETP (cholesterol ester transfer protein) increased HDL and improved mortality in a mouse model of sepsis, highlighting this pathway's importance and therapeutic potential of CETP inhibition, which is currently in key clinical trials. SUMMARY:HDL regulates inflammation and CVD through a variety of mechanisms independent of reverse cholesterol transport, including autophagy, LDL deposition, endotoxin clearance.
PURPOSE OF REVIEW:Biallelic loss-of-function (LOF) variants in any of five canonical genes - LPL, GPIHBP1, APOA5, APOC2 , and LMF1 - cause familial chylomicronemia syndrome (FCS), a rare and severe Mendelian disorder. Heterozygosity for these same variants is far more common but its clinical implications have only recently come into focus. Here, the past 18months of evidence on the monoallelic carrier state across the FCS genes is synthesized. RECENT FINDINGS:Longitudinal studies of LPL and APOA5 heterozygotes have demonstrated that triglyceride phenotypes vary widely both between individuals and within the same individual over time, ranging from completely normal levels to severe hypertriglyceridemia. Heterozygosity contributes to 15-25% of multifactorial chylomicronemia syndrome (MCS) cases. Mechanistic data implicate dominant-negative effects for some truncating variants and saturation of compromised lipolytic reserve as unifying explanations, rather than simple haploinsufficiency. Common intermediate-effect risk alleles such as LPL p.D36N and p.N318S, and APOA5 p.S19W and p.G185C, behave differently and should not be conflated with rare LOF variants. SUMMARY:The phenotype of FCS-gene heterozygotes is best understood as a complex trait modulated by polygenic background and secondary factors. This understanding has practical implications for cascade screening, counseling, and selection of patients who may benefit from emerging apolipoprotein C-III-targeted therapies, particularly those in the refractory MCS subgroup.
PURPOSE OF THE REVIEW:Premature atherosclerotic cardiovascular disease (ASCVD) is increasingly recognized as a major public health challenge in the Middle East and North Africa (MENA) region, where cardiovascular events occur at younger ages than in Western populations. Despite ongoing policy reforms and improvements in healthcare infrastructure, premature ASCVD remains underrecognized and insufficiently addressed. This review summarizes the epidemiology, economic burden, policy initiatives, and current barriers related to premature ASCVD in MENA, while proposing targeted interventions to support policymakers and improve health outcomes. RECENT FINDINGS:Recent evidence demonstrates that premature ASCVD occurs approximately 10-12 years earlier in MENA populations than in Western countries. The high prevalence of traditional risk factors, including dyslipidemia, obesity, diabetes, hypertension, smoking, and physical inactivity, together with genetic predisposition and familial hypercholesterolemia, contributes substantially to earlier disease onset. Available economic data indicate a considerable burden associated with ischemic heart disease, stroke, and acute coronary syndromes across the region. Multiple initiatives have focused on cardiovascular risk reduction through screening programs, tobacco taxation, trans-fat elimination policies, and strengthening acute care systems. However, significant barriers persist, including healthcare inequities, fragmented health-information systems, workforce limitations, financing constraints, and insufficient implementation of preventive strategies. SUMMARY:Premature ASCVD represents an underrecognized and growing challenge in the MENA region. Addressing this burden requires integrated policy reforms emphasizing early screening, aggressive risk-factor management, strengthened primary healthcare systems, improved digital health infrastructure, expanded workforce capacity, and sustainable financing strategies. Coordinated regional efforts are essential to reduce the long-term clinical and economic consequences of premature ASCVD.
PURPOSE OF REVIEW:Atherosclerotic cardiovascular disease (ACVD) causes more than 17 million deaths annually, and traditional risk scores capture only part of individual risk. Metabolomic and lipidomic profiling has emerged as a route to better risk stratification and to mechanistic insight into how diet shapes atherogenesis. This narrative review summarizes the most replicated circulating biomarkers of ACVD and the dietary patterns that modulate them. RECENT FINDINGS:Eight metabolite classes - trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAGln), short-chain fatty acids (SCFAs), lysophosphatidylcholines (LPC), ceramides, branched-chain amino acids (BCAAs), acylcarnitines, and bile acids - show consistent associations with coronary artery disease, plaque burden, and adverse cardiovascular events across recent cohort and case-control studies. Mediterranean-style and DASH dietary patterns are associated with favorable shifts in these biomarkers, including reductions in TMAO, ceramides, and BCAAs, and increases in SCFAs. SUMMARY:Metabolomic biomarkers add biological depth to cardiovascular risk assessment and provide a measurable readout of dietary exposure. Standardized analytical protocols, validated clinical thresholds, and prospective interventional studies are needed before these markers can be used routinely for risk stratification or disease monitoring.
PURPOSE OF REVIEW:This review examines whether high high-density lipoprotein cholesterol (HDL-C) is protective, harmful, or simply misleading in relation to atherosclerotic cardiovascular disease (ASCVD), with emphasis on recent mechanistic, epidemiologic, genetic, and trial evidence. RECENT FINDINGS:HDL is biologically important and multifunctional, but HDL-C is an imperfect surrogate for HDL function. Recent cohort studies show nonlinear associations, with very high HDL-C not consistently protective and in some settings associated with increased mortality. Mendelian randomization studies do not support HDL-C as a causal protective factor, and randomized trials of HDL-C-raising strategies have generally failed to reduce ASCVD events. These findings have shifted attention from HDL quantity to HDL quality, including cholesterol efflux capacity, particle characteristics, and pathway-specific biology. At the same time, modern cholesteryl ester transfer protein (CETP) inhibition has renewed interest in whether benefit, if any, relates to Apolipoprotein B-lowering rather than HDL-C elevation itself. SUMMARY:HDL biology remains highly relevant, but HDL-C alone should not be interpreted as a reliable marker of atheroprotection or as a therapeutic target. Very high HDL-C should not be used to downplay established causal risk factors. Future research should prioritize functional HDL metrics, deeper phenotyping, and mechanism-aligned trials to determine whether improving HDL quality, rather than simply raising HDL-C, can reduce ASCVD risk.
PURPOSE OF REVIEW:Risk assessment in patients with familial hypercholesterolemia (FH) remains an important clinical challenge. The polygenic susceptibility for plasma lipoprotein traits or coronary artery disease (CAD) can be assessed by polygenic risk scores (PRS). The purpose of this review is to discuss the potential roles of PRS in the context of FH management. RECENT FINDINGS:Recent studies suggested that a high PRS for lipoprotein(a) falsely explains the phenotype in a fifth of variant-negative FH patients, whereas a larger proportion can be explained by high low-density lipoprotein cholesterol (LDL-C) PRS. The cardiovascular risk, but also the risk of type 2 diabetes, is different in patients with polygenic hypercholesterolemia compared to monogenic FH. Lastly, it has been shown that a PRS for CAD, but not for LDL-C or lipoprotein(a), was associated with increased lifelong incidence of cardiovascular disease in patients with monogenic FH, independently of clinical variables. SUMMARY:Several studies have explored the potential clinical relevance of PRS in FH, including for diagnostic purpose and in cardiovascular risk stratification. Prior to implementation in clinical practice for cardiovascular risk stratification, future studies in FH should determine whether the polygenic information offers incremental predictive value over conventional clinical variables.
PURPOSE OF REVIEW:Although therapies for hyperlipidemia and hypertension have been shown to be highly effective, they have not sufficiently mitigated overall cardiovascular disease risk. Endothelial cells (ECs) are an integral mediator in the development and progression of atherosclerotic cardiovascular disease. The purpose of this review is to provide an update on the current state of endothelial lipid metabolism research, with particular emphasis on atherosclerosis. RECENT FINDINGS:Although it has been known that elevated palmitic acid (PA) levels were linked to metabolic dysfunction, inflammation and cardiovascular diseases, more recent studies presented here elucidate the mechanisms behind the negative effects induced by PA. Palmitoylation was found to be detrimental in the case of pyruvate kinase isozyme M2 (PKM2) activity, but also vital for the normal functioning of endothelial ciliation and cell health. Endothelial cholesterol metabolism and hemodynamic forces have also been further confirmed to be key regulators in vessel development and endothelial homeostasis. Perturbations in these pathways promote endothelial dysfunction and maladaptive lipid accumulation. SUMMARY:Although atherosclerosis remains a complex, multifactorial disease that arises from the coordinated dysfunction across multiple vascular and immune cell types, substantial advances have been made in identifying mechanisms behind dysfunctional endothelial lipid metabolism. Despite this, further investigation is necessary to identify high impart therapeutic targets aimed at reducing overall cardiovascular disease risk.
PURPOSE OF REVIEW:Advances in the management of lipid disorders have expanded therapeutic options for hypercholesterolemia and beyond. We review the current advances in RNA interference (RNAi) therapies as small interfering RNA (siRNA) drugs, critically assess their clinical positioning, and explore their potential role in reshaping lipid management over the next years. RECENT FINDINGS:RNAi enables targeted, durable suppression of key lipid-regulating proteins at the mRNA level. Inclisiran, the first approved RNAi therapy for hypercholesterolemia, achieves about 50% sustained LDL-c reduction with long-interval maintenance dosing, offering an alternative to monoclonal antibodies. Beyond LDL-c lowering, multiple RNAi drugs are in advanced development targeting lipoprotein(a), apolipoprotein C-III, and angiopoietin-like protein 3, aiming to address residual cardiovascular risk. Early safety and adherence data are encouraging, yet pivotal outcome trials and cost-effectiveness analyses are still pending. SUMMARY:RNAi is a naturally occurring gene-silencing mechanism that can be harnessed therapeutically through siRNA molecules. In lipidology, siRNA-based therapies represent a disruptive technology with the potential to transform both prevention and treatment of atherosclerotic cardiovascular disease. If ongoing trials confirm cardiovascular benefit and safety, RNAi agents could become foundational in personalized lipid management, moving the field toward long-acting, target-specific, and potentially combination-based regimens. The coming years will determine whether RNAi fulfills its promise as the future standard of care in lipid disorders.
PURPOSE OF REVIEW:Elevated concentrations of both low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) [Lp(a)] is probably the most detrimental lipid profile in terms of cardiovascular health. Our primary objective was to review the reports published before January 2026 pertaining to the metabolism of lipoprotein(a) and associated cardiovascular disease (CVD) risk specifically in familial hypercholesterolemia. RECENT FINDINGS:Lp(a) has consistently been found elevated in familial hypercholesterolemia (FH) cohorts. To a large extent, this results from the fact that elevated Lp(a) increases the likelihood for a patient to be clinically diagnosed as FH. For long, increases in Lp(a) concentrations observed in FH patients have been regarded as the consequence of impaired Lp(a) plasma clearance by the LDL receptor. However, recent studies strongly advocate against a significant role for the LDL receptor in mediating Lp(a) hepatic uptake. The molecular mechanisms by which Lp(a) is cleared from blood still remain elusive. Finally, mounting clinical evidence indicates that lowering LDL-C pharmacologically will not offset the specific cardiovascular risk stemming from elevated Lp(a) in FH. SUMMARY:It is highly recommended to systematically measure Lp(a) in FH patients. These patients should be treated with high-dose statins, when necessary, in combination with a proprotein convertase subtilisin/kexin type 9 inhibitor to reach LDL-C therapeutic goals. Hopefully, the Lp(a) lowering therapies currently under development will prove instrumental for adequate treatment of FH patients with concomitantly elevated Lp(a) in coming years.
PURPOSE OF REVIEW:Growth differentiation factor-15 (GDF15) is widely described as a hormone that conveys somatic distress to the brain, yet this framework does not explain why GDF15 is elevated in many common metabolic states. Recent work shows that GDF15 rises most consistently when fatty acid availability exceeds mitochondrial and endoplasmic reticulum capacity. This review synthesizes emerging evidence that positions GDF15 as an endocrine sensor of lipid load rather than a general stress signal. RECENT FINDINGS:Across acute dietary lipid exposure, endogenous lipolysis during fasting, chronic overnutrition, ketogenic feeding, and mitochondrial dysfunction, free fatty acids activate lipid-sensitive transcriptional pathways that induce GDF15 expression in kidney, liver, intestine, and adipose tissue macrophages. Once elevated, GDF15 engages hindbrain glial-cell-derived neurotrophic factor family receptor α-like (GFRAL) signaling to increase sympathetic outflow, promote whole-body fatty acid oxidation, redistribute lipid burden, and improve metabolic flexibility. These effects occur independently of reduced food intake and reflect coordinated actions across liver, adipose tissue, and skeletal muscle. SUMMARY:Viewing GDF15 as a lipid-responsive hormonal signal reshapes our understanding of its physiological role and provides new insight into metabolic adaptations to lipid overload. This pattern suggests that GDF15 is part of a feedback system that attempts to match fatty acid oxidation with supply, analogous to how carbohydrate ingestion stimulates insulin to promote glucose oxidation and suppress hepatic glucose production to restore euglycemia. Within this framework, individual tissues respond in complementary ways to reduce lipid burden and maintain metabolic balance. Understanding this coordinated lipid-responsive network highlights opportunities to target the GDF15 pathway in disorders characterized by impaired fatty acid handling including obesity, type 2 diabetes, cardiovascular disease, cancer cachexia and metabolic dysfunction-associated steatotic liver disease (MASLD).
PURPOSE OF REVIEW:Familial hypercholesterolemia is a monogenic Mendelian disorder characterized by elevated LDL cholesterol and premature atherosclerotic cardiovascular disease. It is caused by pathogenic variants in LDLR , APOB , and PCSK9 , with rarer involvement of LDLRAP1 and APOE . Despite advances in molecular diagnostics, no causative variant is identified in approximately 25-75% of clinically diagnosed cases. RECENT FINDINGS:Familial hypercholesterolemia is currently defined as an autosomal semi-dominant disorder with a gene-dosage effect, whereby biallelic pathogenic variants result in markedly more severe phenotypes than heterozygous variants. Terminology for homozygous familial hypercholesterolemia has been refined. Former terms such as 'true homozygote', 'compound heterozygote', and 'double heterozygotes' have been replaced by monogenic biallelic forms, with identical or different variants, and digenic biallelic forms involving two familial hypercholesterolemia-associated genes. Polygenic risk score (PRS) and lipoprotein(a) measurement help explain familial hypercholesterolemia-like phenotypes in patients without a monogenic cause and enable determination of polygenic severe hypercholesterolemia and/or hyperlipoproteinemia(a). Although advances in molecular genetics have improved variant detection, interpretation remains challenging. Integration of case-level data and functional studies, including high-throughput LDLR assays and APOB structural analyses, has enhanced variant pathogenicity classification. SUMMARY:Combining monogenic variant detection, PRS determination and lipoprotein(a) assessment enables comprehensive diagnosis, tailored risk stratification, and personalized familial hypercholesterolemia management.
PURPOSE OF REVIEW:Our understanding of the genetic regulation of lipoprotein(a) [Lp(a)] is hindered by the complex structure of the LPA gene, limited non-European datasets and its elusive cellular receptor(s). This review summarizes recent efforts and advances providing new insights on its genetic architecture, variability across ancestries and regulators beyond the LPA gene. RECENT FINDINGS:Impressive advances in DNA sequencing and bioinformatics now resolve LPA variants and kringle IV-type 2 copy number at scale. This provides new reference datasets and enables tools that unlock hidden variation also from already available sequencing datasets. In parallel, genetic studies broaden our understanding of the regulation of Lp(a) across ancestries and improve genetic risk scores. Finally, while recent studies implicate new mechanisms for Lp(a) uptake, upcoming genome-wide gene knockout screens allow comprehensive, agnostic scans for regulators and receptors. Puzzlingly, this still converges on the LDL receptor, whose exact role in Lp(a) uptake remains enigmatic. SUMMARY:Technological advances establish a foundation for more accurate genetic risk assessment across ancestries. These advances are enhancing our understanding of Lp(a) regulation and build a framework for future integrative genetic studies, which may shed new light on the evolution of the Lp(a) trait, adding important context for its physiological and clinical relevance.
PURPOSE OF REVIEW:More than 95% of human genes undergo alternative pre-mRNA processing based on cell type, developmental stages, and environmental stimuli, among other factors. Not all alternatively spliced mRNAs are translated to proteins, and some of the noncoding mRNA isoforms play vital roles in cellular homeostasis. This review summarizes protein coding and noncoding RNA isoforms reported for key genes involved in lipoprotein metabolism, and emerging technologies that can be exploited to specifically induce a desired isoform. RECENT FINDINGS:As sequencing technologies become more accessible, more variations in gene transcripts are being detected. Publicly available databases collate these as they arise, but not all of them are captured. Additionally, the function, if any, of many of these alternatively spliced transcripts is currently unknown. Novel strategies to investigate specific transcripts are also continuously evolving. SUMMARY:Most human genes are alternatively spliced, generating various mRNAs and protein isoforms. Any cis or trans factors that alter the balance of these isoforms can have deleterious effects. The fundamental knowledge on the role of each isoform in maintaining cellular health is currently lacking. Emerging technologies which allow modulation of natural mRNA splicing can be used to further our understanding of natural isoform expression and function.
PURPOSE OF REVIEW:The purpose of this report is to summarize evidence supporting the use of nonfasting lipid testing for cardiovascular risk assessment, the potential reasons nonfasting lipid testing predicts cardiovascular risk better than fasting measurement, and to provide a preliminary survey of the status of adoption of nonfasting lipid testing by individual physicians and patients. RECENT FINDINGS:There is increased awareness of the importance of remnant lipoprotein cholesterol, which is increased after eating, as a key factor predicting risk for ischemic vascular disease. Nonfasting lipid measurement is now recommended in guidelines and consensus statements worldwide, but has not yet been adopted in many countries. Preliminary evidence suggests physician's practice of requesting a fasting glucose along with a lipid profile is decreasing over time, but still limits implementation of nonfasting lipid testing. Patient's perception of the optimal conditions for lipid testing as well as their preferred time of day to perform the test may also be limiting adoption of nonfasting measurements. SUMMARY:Nonfasting testing is now accepted as the preferred method of lipid measurement for cardiovascular risk prediction and lipid target achievement. Further acceptance of nonfasting lipid testing requires increased awareness by physicians and patients of the rationale for this recommendation.
PURPOSE OF REVIEW:Lipoprotein(a), Lp(a), is a genetically determined, lifelong risk factor for atherosclerotic cardiovascular disease (ASCVD). Despite broad guideline support for universal one-time testing, Lp(a) measurement remains rare in clinical practice. This review summarizes recent advances in machine learning-based strategies that can enhance the efficiency, yield, and equity of Lp(a) screening. RECENT FINDINGS:To date, three studies have developed and validated machine learning models to identify individuals with elevated Lp(a) using routinely available clinical variables. The ARISE framework, derived from the UK Biobank and validated across multiple US cohorts, reduced the number needed to test by more than 50% while maintaining consistent discrimination across demographic subgroups. Additional studies have confirmed the feasibility of decision-tree and neural network models to improve case finding for elevated Lp(a) in both clinical and population-based settings. SUMMARY:Machine learning-based strategies provide a scalable means of operationalizing universal Lp(a) testing recommendations within health systems. When developed using unbiased data, externally validated, and assessed for fairness and interpretability, these models can support systematic identification of individuals with elevated Lp(a) and integration of Lp(a) measurement into routine cardiovascular risk assessment.
PURPOSE OF REVIEW:Greenlanders differ from other populations in terms of traditional lifestyle and genetic architecture. This might have a great impact on lipid levels in the population and the spectrum of genetic variants associated with lipid traits. Here, we review recent advances in lipid genetics in Greenlanders and highlight the potential of moving from single lipid trait analyses to more comprehensive lipidomic profiling. RECENT FINDINGS:Genetic association studies in the Greenlandic population have identified variants, including PCSK9 (rs12117661), LDLR (rs730882082), and SI (rs781470490), associated with large effects on triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and total cholesterol (TC) levels, as well as altered risk of cardiovascular disease (CVD). These variants are common in the Greenlandic population and explain more lipid variation than variants observed in Europeans. Accordingly, European-derived polygenic scores (PGSs) underperform in Greenlanders, but including the Greenlandic variants increases the performance of lipid PGSs. Lipidomic profiling has the potential to reveal strong cardiometabolic-risk signatures. SUMMARY:The Greenlandic population harbors high-impact variants in PCSK9 , LDLR , and SI, particularly affecting the levels of TG, LDL-C, and TC. Obtaining information on these variants could facilitate earlier detection and potentially prevention of CVD, and advance precision medicine for Greenlanders.
