Current opinion in lipidology最新文献

Purpose of review: In recent years, studies have shed light on the concept of risk heterogeneity among patients with severe hypertriglyceridemia (HTG). Several clinical risk factors for acute pancreatitis have been identified in this population, but the importance of different genetic factors above and beyond triglyceride concentration remains unclear. This review endeavours to summarize recent developments in this field.

Recent findings: Recent studies suggest that the molecular basis of severe HTG (polygenic susceptibility vs. rare pathogenic variants) can modulate the risk of acute pancreatitis independently of triglyceride level. Furthermore, a pancreatitis polygenic risk score has been developed and validated using data from the largest GWAS meta-analysis of acute pancreatitis published to date. In patients with severe HTG, a high polygenic susceptibility for pancreatitis was associated with a three-fold increased risk of acute pancreatitis compared with those with a lower polygenic risk score.

Summary: In the past months, there have been substantial advances in understanding the prediction of acute pancreatitis in patients with severe HTG. However, further efforts at developing risk-stratification strategies and predictive models may help identifying the patients who would benefit most from early and effective interventions to reduce the risk of pancreatitis, including treatment with APOC3 inhibitors.

Purpose of review: Genetic testing has become an integral component of clinical care when an inherited condition is suspected. However, the interpretation of variants identified with this testing can be nuanced. Variants of uncertain significance (VUS) are variants for which there is not enough data currently available to determine if the variant is causal for disease (i.e. pathogenic) or is benign. VUS can exist on a spectrum with some leaning towards suspected pathogenicity and others leaning towards likely benign. Clinician understanding of variant interpretation can improve clinical care by providing more context around how suspicious a VUS is, determining whether additional steps should be taken to further evaluate the variant in question, and ensuring patient understanding of these results.

Recent findings: Research on this topic highlights the complexities around VUS interpretation and counseling. VUS are not static: interpretations of pathogenicity change as new information is uncovered.

Summary: This review aims to summarize this literature and provide insight into variant interpretation, practical steps clinicians can take to further assess a VUS, and considerations when counseling patients on these results.

Purpose of review: For many years, inflammation has been a major concept in basic research on atherosclerosis and in the development of potential diagnostic tools and treatments. The purpose of this review is to assess the performance of this concept with an emphasis on recent clinical trials. In addition, contemporary literature may help identify new therapeutic targets, particularly in the context of the treatment of early, rather than end-stage, arterial disease.

Recent findings: Newly reported clinical trials cast doubt on the efficacy of colchicine, the sole anti-inflammatory agent currently approved for use in patients with atherosclerotic cardiovascular disease (ASCVD). New analyses also challenge the hypothesis that residual ASCVD event risk after optimal management of lipids, blood pressure, and smoking arises primarily from residual inflammatory risk. Current clinical practice to initiate interventions so late in the course of atherosclerotic arterial disease may be a better explanation. Lipid-lowering therapy in early atherosclerosis, possibly combined with novel add-on agents to specifically accelerate resolution of maladaptive inflammation, may be more fruitful than the conventional approach of testing immunosuppressive strategies in end-stage arterial disease. Also discussed is the ongoing revolution in noninvasive technologies to image the arterial wall. These technologies are changing screening, diagnosis, and treatment of atherosclerosis, including early and possibly reversable disease.

Summary: The burden of proof that the Big Idea of inflammation in atherosclerosis has clinical value remains the responsibility of its advocates. This responsibility requires convincing trial data but still seems largely unmet. Unfortunately, the focus on inflammation as the source of residual ASCVD event risk has distracted us from the need to screen and treat earlier.

Purpose of review: Since its discovery, most research on fibroblast growth factor 21 (FGF21) has focused on its antihyperglycemia properties. However, attention has recently shifted towards elucidating the ability of FGF21 to lower circulating lipid levels and ameliorate liver inflammation and steatosis. We here discuss the physiology of FGF21 and its role in lipid metabolism, with a focus on genetics, which has up until now not been fully appreciated.

Recent findings: New developments have uncovered associations of common small-effect variants of the FGF21 gene, such as the single nucleotide polymorphisms rs2548957 and rs838133, with numerous physiological, biochemical and behavioural phenotypes linked to energy metabolism and liver function. In addition, rare loss-of-function variants of the cellular receptors for FGF21 have been recently associated with severe endocrine and metabolic phenotypes. These associations corroborate the findings from basic studies and preliminary clinical investigations into the therapeutic potential of FGF21 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia. Furthermore, recent breakthrough research has begun to dissect mechanisms of a potential FGF21 brain-adipose axis. Such inter-organ communication would be comparable to that seen with other potent metabolic hormones. A deeper understanding of FGF21 could prove to be further beneficial for drug development.

Summary: FGF21 is a potent regulator of lipid and energy homeostasis and its physiology is currently at the centre of investigative efforts to develop agents targeting hypertriglyceridemia and MASLD.

Purpose of review: The study of naturally occurring genetic variation in human populations has laid the foundation for proprotein converts subtilisin/kexin type 9 inhibitors, and more recently new classes of lipid-lowering drugs such as lipoprotein(a) inhibitors and lipoprotein lipase pathway activators. These emerging therapies lower plasma lipoprotein-lipid levels that are not adequately managed by traditional low-density lipoprotein (LDL) cholesterol-lowering medications. By targeting different risk factors, these therapies could help manage the important residual cardiovascular risk of LDL cholesterol medications.

Recent findings: We review the latest insights into the pharmacological and genetic modulation of these new therapeutic targets. We highlight that the drugs remarkably recapitulate the lipid effects observed in genetic studies. In addition to lowering lipoprotein-lipid levels, robust genetic evidence support that these drugs may prevent cardiometabolic outcomes.

Summary: Emerging lipid-lowering therapies could launch a new era for preventive medicine in which treatments are optimally tailored to patient's lipoprotein-lipid profiles.

Purpose of review: Familial hypercholesterolemia is a treatable genetic disorder of cholesterol metabolism. Genetic testing is the most specific method for diagnosing familial hypercholesterolemia, but it remains underutilized. Implementation science aims to bridge the gap between evidence and practice and, thereby, support improved familial hypercholesterolemia care. This review presents the current evidence on the use of implementation science to improve the use of genetic testing for familial hypercholesterolemia.

Recent findings: Recent research has focused on developing implementation strategies to improve the use of genetic testing, particularly cascade testing of at-risk blood relatives of known familial hypercholesterolemia cases. Stakeholder informed strategies aimed at improving communication between families and detection of familial hypercholesterolemia in primary care have been developed and implemented. Findings demonstrate implementation science methods can help remove barriers and improve the uptake of cascade genetic testing.

Summary: Significant gaps in familial hypercholesterolemia care emphasize the importance of practical and realistic approaches to improve the detection of this preventable cause of premature heart disease, and recent efforts using implementation science have shown some promising results. More implementation science studies are needed that address the considerable gaps in familial hypercholesterolemia care, including the underutilization of genetic testing, so that all individuals receive the best clinical care.

Purpose of review: Cognitive decline and late-onset dementia pose significant challenges in aging societies, and many dementia cases could be prevented or delayed through modification of associated risk factors, many of which are tied to cardiovascular and metabolic dysfunction. As individuals age, the blood-brain barrier becomes more permeable, easing the exchange of molecules between the bloodstream and the brain. Consequently, blood-based biological markers (so-called biomarkers) provide a minimally invasive and accessible means of accessing molecular changes associated with aging and neurodegeneration.

Recent findings: Circulating free fatty acids, also called nonesterified fatty acids (NEFAs), and sphingolipids are associated with cardiovascular disease, insulin resistance, and diabetes; thus, could be promising candidates as biomarkers for cognitive decline and dementia.

Summary: The opportunity to study such minimally invasive biomarkers further opens up potential new avenues for improved understanding of the underlying biology of diseases of the brain.

Purpose of review: Despite reductions in low-density lipoprotein (LDL) cholesterol (LDLc), residual cardiovascular risk remains due to factors beyond lipoprotein levels, such as LDL particle count, size, electronegativity and modifications. Technological advances allow detailed profiling of LDL particles, offering potential biomarkers for diagnosis, prognosis, and treatment of cardiovascular disease (CVD). The aim of this review is to provide an updated overview of the state of knowledge in the field of LDL atherosclerotic role, which is evolving rapidly due to technological advances in biomarker measurement and applications.

Recent findings: While small dense LDL has been linked to increased CVD risk, current approaches favor a comprehensive evaluation of all lipoprotein subtypes, as this is a more feasible and standardized method. The atherogenic potential of circulating oxidized LDL (oxLDL) may be the key factor in the onset and progression of atherosclerosis. Thus, elevated oxLDL levels are recognized as a marker of increased CVD risk in both general and high-risk populations, although further research is needed to clarify some conflicting findings. The oxidized LDL receptor 1 (LOX-1) has emerged as a promising target for immunotherapy and innovative drug delivery strategies to modulate atherosclerosis.

Summary: A panel of biomarkers related to LDL atherogenicity may help predict future ischemic events. An atheroprotective diet and increased physical activity could improve LDL oxidation. OxLDL has become a target for immunomodulatory antiatherosclerosis therapy and delivering LDL-based nanocarriers holds promise for both imaging and therapeutics.