Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies
Abstract
:1. Introduction
2. What Are Triglycerides?
3. Triglycerides and ASCVD
4. Lessons from Extreme Cases (Severe Hypertriglyceridemia)
5. Interventions for Hypertriglyceridemia
6. Fasting State or Post-prandial (Non-fasting) State?
7. Residual Risk Factor for ASCVD
8. LPL Pathway and ASCVD
9. Conclusion
Author Contributions
Funding
Conflicts of Interest
References
- Trialists, C.T. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010, 376, 1670–1681. [Google Scholar]
- Cannon, C.P.; Blazing, M.A.; Giugliano, R.P.; McCagg, A.; White, J.A.; Theroux, P.; Darius, H.; Lewis, B.S.; Ophuis, T.O.; Jukema, J.W.; et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 2015, 372, 2387–2397. [Google Scholar] [CrossRef] [PubMed]
- Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 2017, 376, 1713–1722. [Google Scholar] [CrossRef] [PubMed]
- Varbo, A.; Nordestgaard, B.G. Remnant cholesterol and triglyceride-rich lipoproteins in atherosclerosis progression and cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 2133–2135. [Google Scholar] [CrossRef] [PubMed]
- Tada, H.; Kawashiri, M.A.; Nomura, A.; Yoshimura, K.; Itoh, H.; Komuro, I.; Yamagishi, M. Serum triglycerides predict first cardiovascular events in diabetic patients with hypercholesterolemia and retinopathy. Eur. J. Prev. Cardiol. 2018, 25, 1852–1860. [Google Scholar] [CrossRef] [PubMed]
- Madsen, C.M.; Varbo, A.; Nordestgaard, B.G. Unmet need for primary prevention in individuals with hypertriglyceridaemia not eligible for statin therapy according to European Society of Cardiology/European Atherosclerosis Society guidelines: A contemporary population-based study. Eur. Heart J. 2018, 39, 610–619. [Google Scholar] [CrossRef] [PubMed]
- Lampe, M.A.; Burlingame, A.L.; Whitney, J.; Williams, M.L.; Brown, B.E.; Roitman, E.; Elias, P.M. Human stratum corneum lipids: Characterization and regional variations. J. Lipid Res. 1983, 24, 120–130. [Google Scholar] [PubMed]
- Proctor, S.D.; Mamo, J.C. Intimal retention of cholesterol derived from apolipoprotein B100- and apolipoprotein B48-containing lipoproteins in carotid arteries of Watanabe heritable hyperlipidemic rabbits. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 1595–1600. [Google Scholar] [CrossRef] [PubMed]
- Chung, B.H.; Segrest, J.P.; Smith, K.; Griffin, F.M.; Brouillette, C.G. Lipolytic surface remnants of triglyceride-rich lipoproteins are cytotoxic to macrophages but not in the presence of high density lipoprotein. A possible mechanism of atherogenesis? J. Clin. Investig. 1989, 83, 1363–1374. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tomono, S.; Kawazu, S.; Kato, N.; Ono, T.; Ishii, C.; Ito, Y.; Shimizu, M.; Shimoyama, M.; Nakano, T.; Nakajima, K. Uptake of remnant like particles (RLP) in diabetic patients from mouse peritoneal macrophages. J. Atheroscler. Thromb. 1994, 1, 98–102. [Google Scholar] [CrossRef] [PubMed]
- Tada, H.; Kawashiri, M.A.; Nohara, A.; Sakata, K.; Inazu, A.; Mabuchi, H.; Yamagishi, M.; Hayashi, K. Remnant-like particles and coronary artery disease in familial hypercholesterolemia. Clin. Chim. Acta 2018, 482, 120–123. [Google Scholar] [CrossRef] [PubMed]
- Tada, H.; Kawashiri, M.A.; Yamagishi, M. Comprehensive genotyping in dyslipidemia: Mendelian dyslipidemias caused by rare variants and Mendelian randomization studies using common variants. J. Hum. Genet. 2017, 62, 453–458. [Google Scholar] [CrossRef] [PubMed]
- Do, R.; Willer, C.J.; Schmidt, E.M.; Sengupta, S.; Gao, C.; Peloso, G.M.; Gustafsson, S.; Kanoni, S.; Ganna, A.; Chen, J.; et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 2013, 45, 1345–1352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khera, A.V.; Won, H.H.; Peloso, G.M.; O’Dushlaine, C.; Liu, D.; Stitziel, N.O.; Natarajan, P.; Nomura, A.; Emdin, C.A.; Gupta, N.; et al. Association of Rare and Common Variation in the lipoprotein lipase gene with coronary artery disease. JAMA 2017, 317, 937–946. [Google Scholar] [CrossRef] [PubMed]
- Liu, D.J.; Peloso, G.M.; Yu, H.; Butterworth, A.S.; Wang, X.; Mahajan, A.; Saleheen, D.; Emdin, C.; Alam, D.; Alves, A.C.; et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 2017, 49, 1758–1766. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tada, H.; Kawashiri, M.A. Genetic variations, triglycerides, and atherosclerotic disease. J. Atheroscler. Thromb. 2018, 19, 31. [Google Scholar] [CrossRef] [PubMed]
- Tada, H.; Kawashiri, M.A.; Nakahashi, T.; Yagi, K.; Chujo, D.; Ohbatake, A.; Mori, Y.; Mori, S.; Kometani, M.; Fujii, H.; et al. Clinical characteristics of Japanese patients with severe hypertriglyceridemia. J. Clin. Lipidol. 2015, 9, 519–524. [Google Scholar] [CrossRef] [PubMed]
- Teramoto, R.; Tada, H.; Kawashiri, M.A.; Nohara, A.; Nakahashi, T.; Konno, T.; Inazu, A.; Mabuchi, H.; Yamagishi, M.; Hayashi, K. Molecular and functional characterization of familial chylomicronemia syndrome. Atherosclerosis 2018, 269, 272–278. [Google Scholar] [CrossRef] [PubMed]
- Appel, L.J.; Sacks, F.M.; Carey, V.J.; Obarzanek, E.; Swain, J.F.; Miller, E.R., 3rd; Conlin, P.R.; Erlinger, T.P.; Rosner, B.A.; Laranjo, N.M.; et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: Results of the OmniHeart randomized trial. JAMA 2005, 294, 2455–2464. [Google Scholar] [CrossRef] [PubMed]
- Miller, M.; Stone, N.J.; Ballantyne, C.; Bittner, V.; Criqui, M.H.; Ginsberg, H.N.; Goldberg, A.C.; Howard, W.J.; Jacobson, M.S.; Kris-Etherton, P.M.; et al. Triglycerides and cardiovascular disease: A scientific statement from the American Heart Association. Circulation 2011, 123, 2292–2333. [Google Scholar] [CrossRef] [PubMed]
- Rimm, E.B.; Appel, L.J.; Chiuve, S.E.; Djoussé, L.; Engler, M.B.; Kris-Etherton, P.M.; Mozaffarian, D.; Siscovick, D.S.; Lichtenstein, A.H.; American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; et al. Seafood Long-Chain n-3 polyunsaturated fatty acids and cardiovascular Disease: A Science Advisory From the American Heart Association. Circulation 2018, 138, e35–e47. [Google Scholar] [CrossRef] [PubMed]
- Frick, M.H.; Elo, O.; Haapa, K.; Heinonen, O.P.; Heinsalmi, P.; Helo, P.; Huttunen, J.K.; Kaitaniemi, P.; Koskinen, P.; Manninen, V.; et al. Helsinki Heart Study.Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 1987, 317, 1237–1245. [Google Scholar] [CrossRef] [PubMed]
- Bezafibrate Infarction Prevention (BIP) Study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000, 102, 21–27. [Google Scholar] [CrossRef]
- Rubins, H.B.; Robins, S.J.; Collins, D.; Nelson, D.B.; Elam, M.B.; Schaefer, E.J.; Faas, F.H.; Anderson, J.W. Diabetes, plasma insulin, and cardiovascular disease: Subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch. Intern. Med. 2002, 162, 2597–2604. [Google Scholar] [CrossRef] [PubMed]
- Sullivan, D.; Forder, P.; Simes, J.; Whiting, M.; Kritharides, L.; Merrifield, A.; Donoghoe, M.; Colman, P.G.; Graham, N.; Haapamäki, H.; et al. Associations between the use of metformin, sulphonylureas, or diet alone and cardiovascular outcomes in 6005 people with type 2 diabetes in the FIELD study. Diabetes Res. Clin. Pract. 2011, 94, 284–290. [Google Scholar] [CrossRef] [PubMed]
- ACCORD Study Group; Ginsberg, H.N.; Elam, M.B.; Lovato, L.C.; Crouse, J.R., 3rd; Leiter, L.A.; Linz, P.; Friedewald, W.T.; Buse, J.B.; Gerstein, H.C.; et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 2010, 362, 1563–1574. [Google Scholar] [PubMed]
- Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: The Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001, 357, 905–910. [Google Scholar] [CrossRef]
- Fruchart, J.C. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator for management of atherogenic dyslipidaemia. Cardiovasc. Diabetol. 2017, 16, 124. [Google Scholar] [CrossRef] [PubMed]
- Arai, H.; Yamashita, S.; Yokote, K.; Araki, E.; Suganami, H.; Ishibashi, S.; K-877 Study Group. Efficacy and safety of Pemafibrate Versus fenofibrate in patients with high triglyceride and low HDL cholesterol levels: A multicenter, placebo-controlled, double-blind, randomized trial. J. Atheroscler. Thromb. 2018, 25, 521–538. [Google Scholar] [CrossRef] [PubMed]
- Abdelhamid, A.S.; Martin, N.; Bridges, C.; Brainard, J.S.; Wang, X.; Brown, T.J.; Hanson, S.; Jimoh, O.F.; Ajabnoor, S.M.; Deane, K.H.; et al. Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2018, 7, CD012345. [Google Scholar] [CrossRef] [PubMed]
- TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute; Crosby, J.; Peloso, G.M.; Auer, P.L.; Crosslin, D.R.; Stitziel, N.O.; Lange, L.A.; Lu, Y.; Tang, Z.Z.; Zhang, H.; et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 2014, 371, 22–31. [Google Scholar]
- Gaudet, D.; Alexander, V.J.; Baker, B.F.; Brisson, D.; Tremblay, K.; Singleton, W.; Geary, R.S.; Hughes, S.G.; Viney, N.J.; Graham, M.J.; et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 2015, 373, 438–447. [Google Scholar] [CrossRef] [PubMed]
- Martin, S.S.; Blaha, M.J.; Elshazly, M.B.; Toth, P.P.; Kwiterovich, P.O.; Blumenthal, R.S.; Jones, S.R. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013, 310, 2061–2068. [Google Scholar] [CrossRef] [PubMed]
- Freiberg, J.J.; Tybjaerg-Hansen, A.; Jensen, J.S.; Nordestgaard, B.G. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008, 300, 2142–2152. [Google Scholar] [CrossRef] [PubMed]
- Bansal, S.; Buring, J.E.; Rifai, N.; Mora, S.; Sacks, F.M.; Ridker, P.M. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007, 298, 309–316. [Google Scholar] [CrossRef] [PubMed]
- Sever, P.S.; Dahlöf, B.; Poulter, N.R.; Wedel, H.; Beevers, G.; Caulfield, M.; Collins, R.; Kjeldsen, S.E.; Kristinsson, A.; McInnes, G.T.; et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (Ascot-LLA): A multicentre randomised controlled trial. Lancet 2003, 361, 1149–1158. [Google Scholar] [PubMed]
- SEARCH Study Collaborative Group; Bowman, L.; Armitage, J.; Bulbulia, R.; Parish, S.; Collins, R. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): Characteristics of a randomized trial among 12064 myocardial infarction survivors. Am. Heart J. 2007, 154, 815–823. [Google Scholar] [PubMed]
- Stone, N.J.; Robinson, J.G.; Lichtenstein, A.H.; Bairey Merz, C.N.; Blum, C.B.; Eckel, R.H.; Goldberg, A.C.; Gordonz, D.; Levy, D.; Lloyd-Jones, D.M.; et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014, 63, 2889–2934. [Google Scholar] [CrossRef] [PubMed]
- Borén, J.; Matikainen, N.; Adiels, M.; Taskinen, M.R. Postprandial hypertriglyceridemia as a coronary risk factor. Clin. Chim. Acta 2014, 431, 131–142. [Google Scholar] [CrossRef] [PubMed]
- Tada, H.; Kawashiri, MA.; Tanaka, A.; Nakano, T.; Nakajima, K.; Inoue, T.; Noguchi, T.; Nakanishi, C.; Konno, T.; Hayashi, K.; et al. Post-prandial remnant lipoprotein metabolism in autosomal recessive hypercholesterolaemia. Eur. J. Clin. Investig. 2012, 42, 1094–1099. [Google Scholar] [CrossRef] [PubMed]
- Tada, H.; Nomura, A.; Nohara, A.; Inazu, A.; Mabuchi, H.; Yamagishi, M.; Kawashiri, M.A. Post-prandial Remnant Lipoprotein Metabolism in Sitosterolemia. J. Atheroscler. Thromb. 2018. [Google Scholar] [CrossRef] [PubMed]
- Reith, C.; Armitage, J. Management of residual risk after statin therapy. Atherosclerosis 2016, 245, 161–170. [Google Scholar] [CrossRef] [PubMed]
- Schwartz, G.G.; Abt, M.; Bao, W.; DeMicco, D.; Kallend, D.; Miller, M.; Mundl, H.; Olsson, A.G. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J. Am. Coll. Cardiol. 2015, 65, 2267–2275. [Google Scholar] [CrossRef] [PubMed]
- Sato, K.; Okajima, F.; Miyashita, K.; Imamura, S.; Kobayashi, J.; Stanhope, K.L.; Havel, P.J.; Machida, T.; Sumino, H.; Murakami, M.; et al. The majority of lipoprotein lipase in plasma is bound to remnant lipoproteins: A new definition of remnant lipoproteins. Clin. Chim. Acta 2016, 461, 114–125. [Google Scholar] [CrossRef] [PubMed]
- Do, R.; Stitziel, N.O.; Won, H.H.; Jørgensen, A.B.; Duga, S.; Angelica Merlini, P.; Kiezun, A.; Farrall, M.; Goel, A.; Zuk, O.; et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015, 518, 102–106. [Google Scholar] [CrossRef] [PubMed]
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Tada, H.; Nohara, A.; Kawashiri, M.-a. Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies. Nutrients 2018, 10, 1789. https://doi.org/10.3390/nu10111789
Tada H, Nohara A, Kawashiri M-a. Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies. Nutrients. 2018; 10(11):1789. https://doi.org/10.3390/nu10111789
Chicago/Turabian StyleTada, Hayato, Atsushi Nohara, and Masa-aki Kawashiri. 2018. "Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies" Nutrients 10, no. 11: 1789. https://doi.org/10.3390/nu10111789
APA StyleTada, H., Nohara, A., & Kawashiri, M.-a. (2018). Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies. Nutrients, 10(11), 1789. https://doi.org/10.3390/nu10111789