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Triglycerides and Triglyceride-Rich Lipoproteins in the Causal Pathway of Cardiovascular Disease

2016; Elsevier BV; Volume: 118; Issue: 1 Linguagem: Inglês

10.1016/j.amjcard.2016.04.004

ISSN

1879-1913

Autores

Matthew J. Budoff,

Tópico(s)

Diabetes, Cardiovascular Risks, and Lipoproteins

Resumo

Epidemiologic and clinical studies suggest that elevated triglyceride levels are a biomarker of cardiovascular (CV) risk. Consistent with these findings, recent genetic evidence from mutational analyses, genome-wide association studies, and Mendelian randomization studies provide robust evidence that triglycerides and triglyceride-rich lipoproteins are in the causal pathway for atherosclerotic CV disease, indicating that they may play a pathogenic role, much like low-density lipoprotein cholesterol (LDL-C). Although statins are the cornerstone of dyslipidemia management, high triglyceride levels may persist in some patients despite statin therapy. Several triglyceride-lowering agents are available, including fibrates, niacin, and omega-3 fatty acids, of which prescription omega-3 fatty acids have the best tolerability and safety profile. In clinical studies, omega-3 fatty acids have been shown to reduce triglyceride levels, but products containing both eicosapentaenoic acid and docosahexaenoic acid may increase LDL-C levels. Icosapent ethyl, a high-purity eicosapentaenoic acid–only product, does not raise LDL-C levels and also reduces triglyceride, non–high-density lipoprotein cholesterol, and triglyceride-rich lipoprotein levels. In conclusion, omega-3 fatty acids are currently being evaluated in large CV outcome studies in statin-treated patients; these studies should help to elucidate the causative role of triglycerides in atherosclerotic CV disease. Epidemiologic and clinical studies suggest that elevated triglyceride levels are a biomarker of cardiovascular (CV) risk. Consistent with these findings, recent genetic evidence from mutational analyses, genome-wide association studies, and Mendelian randomization studies provide robust evidence that triglycerides and triglyceride-rich lipoproteins are in the causal pathway for atherosclerotic CV disease, indicating that they may play a pathogenic role, much like low-density lipoprotein cholesterol (LDL-C). Although statins are the cornerstone of dyslipidemia management, high triglyceride levels may persist in some patients despite statin therapy. Several triglyceride-lowering agents are available, including fibrates, niacin, and omega-3 fatty acids, of which prescription omega-3 fatty acids have the best tolerability and safety profile. In clinical studies, omega-3 fatty acids have been shown to reduce triglyceride levels, but products containing both eicosapentaenoic acid and docosahexaenoic acid may increase LDL-C levels. Icosapent ethyl, a high-purity eicosapentaenoic acid–only product, does not raise LDL-C levels and also reduces triglyceride, non–high-density lipoprotein cholesterol, and triglyceride-rich lipoprotein levels. In conclusion, omega-3 fatty acids are currently being evaluated in large CV outcome studies in statin-treated patients; these studies should help to elucidate the causative role of triglycerides in atherosclerotic CV disease. Epidemiologic studies have demonstrated that elevated triglyceride levels are independently associated with increased cardiovascular (CV) risk.1Boullart A.C. de G.J. Stalenhoef A.F. Serum triglycerides and risk of cardiovascular disease.Biochim Biophys Acta. 2012; 1821: 867-875Crossref PubMed Scopus (108) Google Scholar Consistent with the epidemiologic data, clinical studies have shown that reaching target triglyceride levels correlates with reduced CV risk.2Miller M. Stone N.J. Ballantyne C. Bittner V. Criqui M.H. Ginsberg H.N. Goldberg A.C. Howard W.J. 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Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics.Arterioscler Thromb Vasc Biol. 2015; 35: e3-e9Crossref PubMed Scopus (49) Google Scholar Lipoprotein lipase (LPL) promotes hydrolysis of the core triglycerides in VLDL and chylomicrons, producing VLDL remnants and chylomicron remnants, both of which are enriched in cholesterol relative to triglycerides.4Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am J Physiol Endocrinol Metab. 2009; 297: E271-E288Crossref PubMed Scopus (574) Google Scholar Some of these particles may be taken up by the liver and cleared; those that remain in circulation are further modified by LPL and hepatic lipase, resulting in formation of cholesterol-enriched LDL particles.3Khetarpal S.A. Rader D.J. 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As with LDL particles, VLDL remnants and chylomicron remnants can be taken up by macrophages in the arterial wall, where they may contribute to vascular inflammation and atherosclerotic plaque development and progression; however, unlike LDL particles, remnant particles do not require oxidative modification for this to occur.3Khetarpal S.A. Rader D.J. Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics.Arterioscler Thromb Vasc Biol. 2015; 35: e3-e9Crossref PubMed Scopus (49) Google Scholar Several apolipoproteins (Apos) are components of VLDL and chylomicrons and are important in TRL metabolism. ApoC-II is a cofactor necessary for full activation of LPL,4Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am J Physiol Endocrinol Metab. 2009; 297: E271-E288Crossref PubMed Scopus (574) Google Scholar whereas ApoA-V appears to enhance LPL activity, possibly by facilitating interactions between LPL and TRLs. 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