People who maintain ideal cardiovascular heath have a low lifetime risk of cardiovascular disease. Therefore, encouraging people to achieve ideal cardiovascular health represents an important ...opportunity to improve the prevention of cardiovascular disease. However, preventing cardiovascular disease by promoting ideal cardiovascular health requires shifting the focus from treating disease after it develops to preventing cardiovascular events before they happen by slowing the progression of atherosclerosis. Because atherogenic lipoproteins play a central causal role in the initiation and progression of atherosclerosis, maintaining optimal lipid levels is necessary to achieve ideal cardiovascular health. This review describes the cumulative effect of lipid-carrying lipoproteins on the risk of cardiovascular disease, estimates the magnitude of the clinical benefit that can be achieved by maintaining optimal lipid levels, identifies the most effective timing for implementing strategies designed to achieve optimal lipid levels, and provides a clinical pathway to help people achieve the lipid levels necessary for ideal cardiovascular health.
Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy ...of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.
We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks.
The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients 78.5% in the bempedoic acid group and 584 of 742 78.7% in the placebo group) and serious adverse events (216 patients 14.5% and 104 14.0%, respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients 10.9% vs. 53 7.1%), as was the incidence of gout (18 patients 1.2% vs. 2 0.3%). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy.
In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).
This narrative review aims to discuss the more relevant evidence on the role of linoleic acid (LA), a n-6 essential fatty acid that constitutes the predominant proportion of dietary polyunsaturated ...fatty acids (PUFA), in cardiovascular health. Although LA can be metabolized into Arachidonic Acid (AA), a 20 carbon PUFA which is the precursor of eicosanoids, including some with proinflammatory or prothrombotic-vasoconstrictor action, the large majority of experimental and clinical studies have assessed the potential benefit of increasing dietary intake of LA. Overall, data from clinical studies and meta-analyses suggest an association between high dietary intakes or tissue levels of n-6 PUFA, and specifically LA, and the improvement of cardiovascular risk (mainly of the plasma lipid profile), as well as long-term glycaemic control and insulin resistance. Most observational data show that elevated/increased dietary intake or tissue levels of LA is associated with a reduced incidence of cardiovascular diseases (mainly coronary artery diseases) and of new onset metabolic syndrome or type 2 diabetes. The effects of LA (or n-6 PUFA) in other physio-pathological areas are less clear. High quality clinical trials are needed to assess both the actual amplitude and the underlying mechanisms of the health effects related to dietary intake of this essential fatty acid.
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•Linoleic acid (LA) is an essential18-carbon n-6 polyunsaturated fatty acid.•An adequate dietary supply of LA is crucial for human health.•LA intakes/blood levels are inversely correlated with cardiovascular disease risk.•LA intakes should be increased in most western countries.
Global epidemiology of dyslipidaemias Pirillo, Angela; Casula, Manuela; Olmastroni, Elena ...
Nature reviews cardiology,
10/2021, Letnik:
18, Številka:
10
Journal Article
Recenzirano
Dyslipidaemias are alterations to the plasma lipid profile that are often associated with clinical conditions. Dyslipidaemias, particularly elevated plasma LDL-cholesterol levels, are major risk ...factors for cardiovascular disease, but some forms, such as hypertriglyceridaemia, are associated with severe diseases in other organ systems, including non-alcoholic fatty liver disease and acute pancreatitis. Dyslipidaemias can be genetically determined (primary or familial dyslipidaemias) or secondary to other conditions (such as diabetes mellitus, obesity or an unhealthy lifestyle), the latter being more common. Hypercholesterolaemia is the most common form of dyslipidaemia and is associated with an increased risk of cardiovascular disease, with elevated plasma LDL-cholesterol levels being the 15th leading risk factor for death in 1990, rising to 11th in 2007 and 8th in 2019. The global burden of dyslipidaemias has increased over the past 30 years. Furthermore, the combination of high triglyceride levels and low HDL-cholesterol levels (together with the presence of small, dense LDL particles), referred to as atherogenic dyslipidaemia, is highly prevalent in patients with diabetes or metabolic syndrome and increases their risk of cardiovascular disease. Given the increasing prevalence of diabetes worldwide, treating lipid abnormalities in these patients might reduce their risk of cardiovascular disease.
Emerging therapies in dyslipidaemias Catapano, Alberico L.
Vascular pharmacology,
December 2023, 2023-12-00, 20231201, Letnik:
153
Journal Article
Recenzirano
Odprti dostop
Several observations have shown that elevated levels of low-density lipoprotein cholesterol (LDL-C) are a cause of cardiovascular disease. Lowering LDL-C is a key strategy for reducing cardiovascular ...risk, with a continuous linear correlation between LDL-C reduction and cardiovascular benefit. Based on these observations, current guidelines have further lowered LDL-C goals and call for the use of more effective therapeutic interventions. In addition to statins, ezetimibe and the monoclonal antibodies targeting PCSK9, several new lipid-lowering agents are currently in phase 3 clinical trials to evaluate their clinical effects, and more are in development. The use of combination therapies targeting different pathways can increase the effectiveness of treatment.
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Apolipoprotein C-III (apoC-III) has a critical role in the metabolism of triglyceride (TG)-rich lipoproteins (TRLs). Animal models lacking the APOC3 gene exhibit reduced plasma TG levels, whereas the ...overexpression of APOC3 leads to increased TG levels. In humans, loss-of-function mutations in APOC3 are associated with reduced plasma TG levels and reduced risk for ischemic vascular disease and coronary heart disease. Several hypolipidemic agents have been shown to reduce apoC-III, including fibrates and statins, and antisense technology aimed at inhibiting APOC3 mRNA to decrease the production of apoC-III is currently in Phase III of clinical development. Here, we review the pathophysiological role of apoC-III in TG metabolism and the evidence supporting this apolipoprotein as an emerging target for hypertriglyceridemia (HTG) and associated cardiovascular disorders.
Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with ...hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted.
Graphical Abstract
Graphical Abstract
The great complexity of HDL. High-density lipoprotein (HDL) particles carry a large number of proteins and lipids, which contribute to define their compositional ...and functional complexity. HDLs exert multiple protective activities, essentially by three major mechanisms. HDLs, however, can lose their protective functions and even gain adverse functions in chronic diseases or during infections. U-shaped relationships between HDL-cholesterol (HDL-C) levels and several conditions have been reported, being both low and extremely high HDL-C levels associated with an increased risk of several pathologies and mortality. LCAT, lecithin:cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; PONI, paraoxonase 1; S1P, sphingosine-1-phosphate; ASCVD, atherosclerotic cardiovascular disease; LDL, low-density lipoprotein; SAA, serum amyloid A; OxPL, oxidized phospholipids
Abstract
Previous interest in high-density lipoproteins (HDLs) focused on their possible protective role in atherosclerotic cardiovascular disease (ASCVD). Evidence from genetic studies and randomized trials, however, questioned that the inverse association of HDL-cholesterol (HDL-C) is causal. This review aims to provide an update on the role of HDL in health and disease, also beyond ASCVD. Through evolution from invertebrates, HDLs are the principal lipoproteins, while apolipoprotein B-containing lipoproteins first developed in vertebrates. HDLs transport cholesterol and other lipids between different cells like a reusable ferry, but serve many other functions including communication with cells and the inactivation of biohazards like bacterial lipopolysaccharides. These functions are exerted by entire HDL particles or distinct proteins or lipids carried by HDL rather than by its cholesterol cargo measured as HDL-C. Neither does HDL-C measurement reflect the efficiency of reverse cholesterol transport. Recent studies indicate that functional measures of HDL, notably cholesterol efflux capacity, numbers of HDL particles, or distinct HDL proteins are better predictors of ASCVD events than HDL-C. Low HDL-C levels are related observationally, but also genetically, to increased risks of infectious diseases, death during sepsis, diabetes mellitus, and chronic kidney disease. Additional, but only observational, data indicate associations of low HDL-C with various autoimmune diseases, and cancers, as well as all-cause mortality. Conversely, extremely high HDL-C levels are associated with an increased risk of age-related macular degeneration (also genetically), infectious disease, and all-cause mortality. HDL encompasses dynamic multimolecular and multifunctional lipoproteins that likely emerged during evolution to serve several physiological roles and prevent or heal pathologies beyond ASCVD. For any clinical exploitation of HDL, the indirect marker HDL-C must be replaced by direct biomarkers reflecting the causal role of HDL in the respective disease.