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Global Heart 2022Atherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death,... (Review)
Review
BACKGROUND
Atherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death, disability and healthcare expenditure globally. Preventing the accumulation of cholesterol-containing atherogenic lipoproteins in the vessel wall is central to any healthcare strategy to prevent ASCVD. Advances in current concepts about reducing cumulative exposure to apolipoprotein B (apo B) cholesterol-containing lipoproteins and the emergence of novel therapies provide new opportunities to better prevent ASCVD. The present update of the World Heart Federation Cholesterol Roadmap provides a conceptual framework for the development of national policies and health systems approaches, so that potential roadblocks to cholesterol management and thus ASCVD prevention can be overcome.
METHODS
Through a review of published guidelines and research papers since 2017, and consultation with a committee composed of experts in clinical management of dyslipidaemias and health systems research in low-and-middle income countries (LMICs), this Roadmap identifies (1) key principles to effective ASCVD prevention (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMICs; and (4) potential strategies for overcoming these.
RESULTS
Reducing the future burden of ASCVD will require diverse approaches throughout the life-course. These include: a greater focus on primordial prevention; availability of affordable cholesterol testing; availability of universal cholesterol screening for inherited dyslipidaemias; risk stratification moving beyond 10-year risk to look at lifetime risk with adequate risk estimators; wider availability of affordable cholesterol-lowering therapies which should include statins as essential medications globally; use of adequate doses of potent statin regimens; and combination therapies with ezetimibe or other therapies in order to attain and maintain robust reductions in LDL-C in those at highest risk. Continuing efforts are needed on health literacy for both the public and healthcare providers, utilising multi-disciplinary teams in healthcare and applications that quantify both ASCVD risk and benefits of treatment as well as increased adherence to therapies.
CONCLUSIONS
The adverse effects of LDL-cholesterol and apo B containing lipoprotein exposure are cumulative and result in ASCVD. These are preventable by implementation of different strategies, aimed at efficiently tackling atherosclerosis at different stages throughout the human life-course. Preventive strategies should therefore be updated to implement health policy, lifestyle changes and when needed pharmacotherapies earlier with investment in, and a shift in focus towards, early preventive strategies that preserve cardiovascular health rather than treat the consequences of ASCVD.
Topics: Humans; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dyslipidemias; Atherosclerosis; Lipoproteins; Apolipoproteins B; Cardiovascular Diseases
PubMed: 36382159
DOI: 10.5334/gh.1154 -
Journal of Clinical Lipidology 2021A diet high in saturated fatty acids (SFA) is a suspected contributor to atherosclerotic cardiovascular disease (ASCVD) risk, in large part because of an effect to raise...
A diet high in saturated fatty acids (SFA) is a suspected contributor to atherosclerotic cardiovascular disease (ASCVD) risk, in large part because of an effect to raise the low-density lipoprotein cholesterol (LDL-C) concentration. Most dietary guidance from health authorities advocates limiting intake of SFA, particularly for people with clinical ASCVD, dyslipidemia, or diabetes mellitus. However, recent reviews have highlighted controversies regarding SFA intake and cardiovascular health. This brief editorial commentary includes a discussion of the evidence regarding SFA intake and cardiovascular health, outlines gaps in the available evidence, and proposes tentative conclusions based on what is known today about SFA consumption and ASCVD risk. Results from observational studies demonstrate that dietary patterns with lower average intakes of SFA are associated with favorable cardiovascular outcomes. Additionally, although the number of randomized controlled trials testing the effects of reducing SFA intake on ASCVD outcomes is limited, the available evidence supports the view that replacing SFA with unsaturated fatty acids, particularly polyunsaturated fatty acids, may reduce ASCVD risk. Beyond raising LDL-C and atherogenic lipoprotein particle concentrations, higher intakes of SFA may influence pathways affecting inflammation, cardiac rhythm, hemostasis, apolipoprotein CIII production, and high-density lipoprotein function. However, the impacts of these effects on ASCVD risk remain uncertain. In the authors' view, the totality of the evidence supports the current recommendation to limit SFA intake to <10% of total daily energy for the general healthy population and further (e.g., to 5-6% of total daily energy) for patients with hypercholesterolemia.
Topics: Apolipoproteins B; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Cholesterol, LDL; Dietary Fats; Fatty Acids; Humans; Lipoproteins, HDL; Risk Factors
PubMed: 34649831
DOI: 10.1016/j.jacl.2021.09.049 -
Current Opinion in Lipidology Aug 2021The 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular... (Review)
Review
PURPOSE OF REVIEW
The 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular risk and a better guide to the adequacy of lipid lowering than low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (HDL-C). Also, they stated that apoB can be measured more accurately than LDL-C or non-HDL-C. This strong endorsement of the central role of apoB contrasts with the limited endorsement of apoB by the 2018 American College of Cardiology/American Heart Association Multisociety Guidelines. Nevertheless, both retained LDL-C as the primary metric to guide statin/ezetimibe/Proprotein convertase subtilisin/kexin type 9 (PCSK9) therapy.
RECENT FINDINGS
This essay will review the most important recent advances in knowledge about apoB with particular emphasis on the results of Mendelian randomization studies and a new discordance analysis in subjects on statin therapy. We will also lay out why using LDL-C to guide the adequacy of lipid lowering therapy represents an interpretive error of the results of the statin/ezetimibe/PCSK9 inhibitor randomized clinical trials and therefore why apoB should be the primary metric to guide statin/ezetimibe/PCSK9 therapy.
SUMMARY
There is now a robust body of evidence demonstrating the superiority of apoB over LDL-C and non-HDL-C as a clinical marker of cardiovascular risk. LDL-C is not the appropriate marker to assess the benefits of statin/ezetimibe/PCSK9 therapy.
Topics: Apolipoproteins B; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Mendelian Randomization Analysis
PubMed: 33870931
DOI: 10.1097/MOL.0000000000000754 -
Journal of the American College of... May 2023Lipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and...
BACKGROUND
Lipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and OxPLs predict coronary artery disease (CAD) severity and outcomes in a contemporary, statin-treated cohort is not well established.
OBJECTIVES
This study sought to evaluate the relationships between Lp(a) particle concentration and OxPLs associated with apolipoprotein B (OxPL-apoB) or apolipoprotein(a) (OxPL-apo[a]) with angiographic CAD and cardiovascular outcomes.
METHODS
Among 1,098 participants referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study, Lp(a), OxPL-apoB, and OxPL-apo(a) were measured. Logistic regression estimated the risk of multivessel coronary stenoses by Lp(a)-related biomarker level. Cox proportional hazards regression estimated the risk of major adverse cardiovascular events (MACEs) (coronary revascularization, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) in follow-up.
RESULTS
Median Lp(a) was 26.45 nmol/L (IQR: 11.39-89.49 nmol/L). Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated (Spearman R ≥0.91 for all pairwise combinations). Lp(a) and OxPL-apoB were associated with multivessel CAD. Odds of multivessel CAD per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.10 (95% CI: 1.03-1.18; P = 0.006), 1.18 (95% CI: 1.03-1.34; P = 0.01), and 1.07 (95% CI: 0.99-1.16; P = 0.07), respectively. All biomarkers were associated with cardiovascular events. HRs for MACE per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.08 (95% CI: 1.03-1.14; P = 0.001), 1.15 (95% CI: 1.05-1.26; P = 0.004), and 1.07 (95% CI: 1.01-1.14; P = 0.02), respectively.
CONCLUSIONS
In patients undergoing coronary angiography, Lp(a) and OxPL-apoB are associated with multivessel CAD. Lp(a), OxPL-apoB, and OxPL-apo(a) are associated with incident cardiovascular events. (Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).
Topics: Humans; Coronary Artery Disease; Lipoprotein(a); Cardiovascular Diseases; Phospholipids; Apolipoproteins B; Apolipoproteins A; Biomarkers; Apoprotein(a); Oxidation-Reduction
PubMed: 37137588
DOI: 10.1016/j.jacc.2023.02.050 -
Nature Biotechnology Nov 2023The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound...
The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB and MTTP organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Drug Evaluation, Preclinical; Hepatocytes; Lipid Metabolism; Apolipoproteins B; Liver
PubMed: 36823355
DOI: 10.1038/s41587-023-01680-4 -
Science (New York, N.Y.) Sep 2023Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively...
Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively associated with atherogenic apoB-lipoprotein cholesterol levels in humans, but the mechanisms are unknown. We found that tPA, partially through the lysine-binding site on its Kringle 2 domain, binds to the N terminus of apoB, blocking the interaction between apoB and microsomal triglyceride transfer protein (MTP) in hepatocytes, thereby reducing very-low-density lipoprotein (VLDL) assembly and plasma apoB-lipoprotein cholesterol levels. Plasminogen activator inhibitor 1 (PAI-1) sequesters tPA away from apoB and increases VLDL assembly. Humans with PAI-1 deficiency have smaller VLDL particles and lower plasma levels of apoB-lipoprotein cholesterol. These results suggest a mechanism that fine-tunes VLDL assembly by intracellular interactions among tPA, PAI-1, and apoB in hepatocytes.
Topics: Humans; Apolipoproteins B; Atherosclerosis; Hepatocytes; Lipoproteins, VLDL; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator; Animals; Mice; Mice, Inbred C57BL
PubMed: 37651538
DOI: 10.1126/science.adh5207 -
International Journal of Molecular... Apr 2022Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during... (Review)
Review
Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.
Topics: Apolipoproteins B; Heart Atria; Humans; Lipoproteins, VLDL; Liver; Metabolic Syndrome; Triglycerides
PubMed: 35457118
DOI: 10.3390/ijms23084300 -
Journal of the American College of... Mar 2021Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol... (Review)
Review
Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)-lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C-induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients.
Topics: Apolipoproteins B; Cholesterol, LDL; Humans; Hypercholesterolemia; Hyperlipoproteinemias
PubMed: 33766264
DOI: 10.1016/j.jacc.2020.11.079 -
Clinica E Investigacion En... May 2021Hypolipoproteinemias are characterized by a decrease in the plasma concentration of lipoproteins. Within them, we find two groups: hypobetalipoproteinemias (HBL), due to... (Review)
Review
Hypolipoproteinemias are characterized by a decrease in the plasma concentration of lipoproteins. Within them, we find two groups: hypobetalipoproteinemias (HBL), due to a decrease in the plasma concentration of lipoproteins containing apolipoprotein B, and hypoalphalipoproteinemias. Hypolipoproteinemias can be classified according to their origin, into primary and secondary. Primary HBLs are rare entities produced by mutations in different genes. So far, more than 140 mutations have been identified in the APOB, PCSK9, ANGPTL3, MTTP, and SAR1 genes. Early diagnosis and treatment are essential to avoid the development of serious complications. In this review we address the diagnosis and treatment of HBL, especially those in which there is hypotriglyceridemia.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Apolipoproteins B; Humans; Hypobetalipoproteinemias; Hypolipoproteinemias; Mutation; Proprotein Convertase 9
PubMed: 34006356
DOI: 10.1016/j.arteri.2020.12.011 -
Nutrients Dec 2022Accumulating observational studies suggested that hypercholesterolemia is associated with vascular dementia (VaD); however, the causality between them remains unclear....
Accumulating observational studies suggested that hypercholesterolemia is associated with vascular dementia (VaD); however, the causality between them remains unclear. Hence, the aim of this study is to infer causal associations of circulating lipid-related traits [including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB)] with VaD jointly using univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR methods. Then, the summary-data-based MR (SMR) and two-sample MR analysis were conducted to investigate the association of lipid-lowering drugs target genes expression (including HMGCR, PCSK9, NPC1L1, and APOB) and LDL-C level mediated by these target genes with VaD. The results of forward MR analyses found that genetically predicted HDL-C, LDL-C, TG, apoA-I, and apoB concentrations were not significantly associated with the risk of VaD (all p > 0.05). Notably, there was suggestive evidence for a causal effect of genetically predicted VaD on HDL-C via reverse MR analysis [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.994−0.999; p = 0.022]. On the contrary, the MR results showed no significant relationship between VaD with LDL-C, TG, apoA-I, and apoB. The results for the SMR method found that there was no evidence of association for expression of HMGCR, PCSK9, NPC1L1, and APOB gene with risk of VaD. Furthermore, the result of MR analysis provided evidence for the decreased LDL-C level mediated by gene HMGCR reduced the risk of VaD (OR, 18.381; 95% CI, 2.092−161.474; p = 0.009). Oppositely, none of the IVW methods indicated any causal effects for the other three genes. Using genetic data, this study provides evidence that the VaD risk may cause a reduction of HDL-C level. Additionally, the finding supports the hypothesis that lowering LDL-C levels using statins may be an effective prevention strategy for VaD risk, which requires clinical trials to confirm this result in the future.
Topics: Humans; Proprotein Convertase 9; Cholesterol, LDL; Apolipoprotein A-I; Dementia, Vascular; Mendelian Randomization Analysis; Hypolipidemic Agents; Cholesterol, HDL; Triglycerides; Apolipoproteins B; Polymorphism, Single Nucleotide
PubMed: 36615727
DOI: 10.3390/nu15010069