Genetic Risk Stratification Will Enhance Primary Prevention of Coronary Artery Disease
Main Article Content
Abstract
Coronary artery disease, the number one cause of death in the world, is highly amenable to primary and secondary prevention. Primary prevention is limited because of lack of biomarkers to detect CAD in its asymptomatic phase. Conventional risk factors such as hypertension, are not evident until the 6th or 7th decade, which may be late for primary prevention particularly in males. The recent discovery of genetic risk variants for CAD has the potential through risk stratification to detect individuals most appropriate for primary prevention. First, genetic risk accounts for about 50% of predisposition to CAD; second, it is determined at conception and not influenced by age since DNA does not change in one’s lifetime. Thirdly, genetic risk can be determined at any time from birth onward which is close to ideal for early primary prevention. A review of the literature show genetic risk can be summarized in a single number, referred to as polygenic risk score (PRS), and used to risk stratify for CAD. The PRS has been evaluated in over 1 million individuals and those in the top 20% exhibit a one-to-four-fold greater risk for CAD than those in the bottom 20%. More importantly, clinical studies have shown that decreasing plasma LDL-C or modifying lifestyle decreases the genetic risk for CAD by 50%. The polygenic risk score, obtained from a single blood sample, does not need to be repeated in one’s lifetime. Furthermore, the genetic risk captured by the PRS is relatively independent of the conventional risk factors including family history. The current PRS was determined primarily in individuals of European decent which can be a limitation to its use in other ethnic groups. However, results of trials ongoing in several ethnic groups will soon be available. We propose primary prevention to be initiated early in life in individuals in the top 20% of the PRS. The test is relatively inexpensive and generic drug therapy is also inexpensive. The use of the PRS to risk stratify for CAD would be a paradigm shift for implementation of early primary prevention of CAD.
Article Details
How to Cite
ROBERTS, Robert; ACUNA, Esperanza.
Genetic Risk Stratification Will Enhance Primary Prevention of Coronary Artery Disease.
Medical Research Archives, [S.l.], v. 11, n. 7.1, july 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4063>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v11i7.1.4063.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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4. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. The Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5
5. Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013;369(5):448–57.
6. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29-322. doi:10.1161/CIR.0000000000000152
7. Navar-Boggan AM, Peterson ED, D’Agostino RB, Neely B, Sniderman AD, Pencina MJ. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation. 2015;131(5):451-458. doi:10.1161/CIRCULATIONAHA.114.012477
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9. Grundy Scott M., Stone Neil J., Bailey Alison L., et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
10. Roberts R, Fair J. A Less than Provocative Approach for the Primary Prevention of CAD. J Cardiovasc Transl Res. Published online June 14, 2021. doi:10.1007/s12265-021-10144-6
11. Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors. J Am Coll Cardiol. 2017;70(24):2979-2991. doi:10.1016/j.jacc.2017.10.024
12. Peters SAE, Colantonio LD, Zhao H, et al. Sex Differences in High-Intensity Statin Use Following Myocardial Infarction in the United States. J Am Coll Cardiol. 2018;71(16):1729-1737. doi:10.1016/j.jacc.2018.02.032
13. Chan L, Boerwinkle E. Gene-environment interactions and gene therapy in atherosclerosis. Cardiology in Review. 1994; 2: 130-137.
14. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316(5830):1488-1491. doi:10.1126/science.1142447
15. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007 Jun 8;316(5830):1491-3.
16. Erdmann J, Kessler T, Munoz Venegas L, Schunkert H. A decade of genome-wide association studies for coronary artery disease: the challenges ahead. Cardiovasc Res. 2018;114(9):1241-1257. doi:10.1093/cvr/cvy084
17. Assimes TL, Roberts R. Genetics: Implications for Prevention and Management of Coronary Artery Disease. J Am Coll Cardiol. 2016;68(25):2797-2818. doi:10.1016/j.jacc.2016.10.039
18. Roberts R, Chavira J, Acuna E. Therapeutic Implications of Genetic Risk Stratification for CAD. Int J Fam Med Prim Care. 2022; 3(1): 1059..
19. Khera AV, Chaffin M, Zekavat SM, et al. Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. Circulation. 2019;139(13):1593-1602. doi:10.1161/CIRCULATIONAHA.118.035658
20. Inouye M, Abraham G, Nelson CP, Wood AM, Sweeting MJ, Dudbridge F, et al. Genomic risk prediction of coronary artery disease in 480,000 adults. J Am Coll Cardiol 2018;72(16):1883–93.
21. Khera AV, Chaffin M, Aragam KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018;50(9):1219-1224. doi:10.1038/s41588-018-0183-z
22. Mega JL, Stitziel NO, Smith JG, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet Lond Engl. 2015;385(9984):2264-2271. doi:10.1016/S0140-6736(14)61730-X
23. Natarajan P, Young R, Stitziel NO, et al. Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting. Circulation. 2017;135(22):2091-2101. doi:10.1161/CIRCULATIONAHA.116.024436
24. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
25. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174
26. Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 2016;375(24):2349–58.].
27. Tikkanen E, Gustafsson S, Ingelsson E. Associations of fitness, physical activity, strength, and genetic risk with cardiovascular disease: longitudinal analyses in the UK Biobank study. Circulation 2018;137(24):2583–91.
28. 1. AK Jiang T, Goel A, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. 2022;54(12):1803-1815. doi:10.1038/s41588-022-01233-6
29. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-2330. doi:10.1093/eurheartj/ehz962
30. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144
31. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet Lond Engl. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5
32. Luo F, Das A, Khetarpal SA, et al. ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases. Trends Cardiovasc Med. 2023;(23):S1050-1738. doi:10.1016/j.tcm.2023.01.008
33. Roberts R. Genetics keeps on giving: A possible vaccine for heart disease. Trends Cardiovasc Med. 2023;(23):S1050-1738. doi:10.1016/j.tcm.2023.02.008
34. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489
35. Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62(13):1154-1162. doi:10.1016/j.jacc.2013.05.050
36. Cohen DE. Balancing cholesterol synthesis and absorption in the gastrointestinal tract. J Clin Lipidol. 2008;2(2):S1-S3. doi:10.1016/j.jacl.2008.01.004
37. Tabas I. Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. J Clin Invest. 2002;110(7):905-911. doi:10.1172/JCI16452
38. Ference BA, Cannon CP, Landmesser U, Lüscher TF, Catapano AL, Ray KK. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018;39(27):2540-2545. doi:10.1093/eurheartj/ehx450
39. Cannon CP. Low-Density Lipoprotein Cholesterol. J Am Coll Cardiol. 2020;75(17):2119. doi:10.1016/j.jacc.2020.03.033
40. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. The Lancet. 2017;390(10106):1962-1971. doi:10.1016/S0140-6736(17)32290-0
41. Grundy Scott M., Cleeman James I., Merz C. Noel Bairey, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110(2):227-239. doi:10.1161/01.CIR.0000133317.49796.0E
42. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504. doi:10.1056/NEJMoa040583
43. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-1435. doi:10.1056/NEJMoa050461
44. Authors/Task Force Members, ESC Committee for Practice Guidelines (CPG), ESC National Cardiac Societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis. 2019;290:140-205. doi:10.1016/j.atherosclerosis.2019.08.014
45. Murphy SA, Cannon CP, Blazing MA, et al. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol. 2016;67(4):353-361. doi:10.1016/j.jacc.2015.10.077
46. Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial. JAMA Cardiol. 2019;4(7):613-619. doi:10.1001/jamacardio.2019.0886
47. Szarek M, White HD, Schwartz GG, et al. Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol. 2019;73(4):387-396. doi:10.1016/j.jacc.2018.10.039
48. Fujita H, Okada T, Inami I, et al. Low-density lipoprotein profile changes during the neonatal period. J Perinatol Off J Calif Perinat Assoc. 2008;28(5):335-340. doi:10.1038/jp.2008.8
49. Pac-Kozuchowska E. Evaluation of lipids, lipoproteins and apolipoproteins concentrations in cord blood serum of newborns from rural and urban environments. Ann Agric Environ Med 2007;14(1):25–9.
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Orig Publ Vol 2 Issue 8934. 1994;344(8934):1383-1389. doi:10.1016/S0140-6736(94)90566-5
3. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet Lond Engl. 2005;366(9493):1267-1278. doi:10.1016/S0140-6736(05)67394-1
4. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. The Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5
5. Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013;369(5):448–57.
6. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29-322. doi:10.1161/CIR.0000000000000152
7. Navar-Boggan AM, Peterson ED, D’Agostino RB, Neely B, Sniderman AD, Pencina MJ. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation. 2015;131(5):451-458. doi:10.1161/CIRCULATIONAHA.114.012477
8. Ference BA, Yoo W, Alesh I, et al. Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease. J Am Coll Cardiol. 2012;60(25):2631. doi:10.1016/j.jacc.2012.09.017
9. Grundy Scott M., Stone Neil J., Bailey Alison L., et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
10. Roberts R, Fair J. A Less than Provocative Approach for the Primary Prevention of CAD. J Cardiovasc Transl Res. Published online June 14, 2021. doi:10.1007/s12265-021-10144-6
11. Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors. J Am Coll Cardiol. 2017;70(24):2979-2991. doi:10.1016/j.jacc.2017.10.024
12. Peters SAE, Colantonio LD, Zhao H, et al. Sex Differences in High-Intensity Statin Use Following Myocardial Infarction in the United States. J Am Coll Cardiol. 2018;71(16):1729-1737. doi:10.1016/j.jacc.2018.02.032
13. Chan L, Boerwinkle E. Gene-environment interactions and gene therapy in atherosclerosis. Cardiology in Review. 1994; 2: 130-137.
14. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316(5830):1488-1491. doi:10.1126/science.1142447
15. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007 Jun 8;316(5830):1491-3.
16. Erdmann J, Kessler T, Munoz Venegas L, Schunkert H. A decade of genome-wide association studies for coronary artery disease: the challenges ahead. Cardiovasc Res. 2018;114(9):1241-1257. doi:10.1093/cvr/cvy084
17. Assimes TL, Roberts R. Genetics: Implications for Prevention and Management of Coronary Artery Disease. J Am Coll Cardiol. 2016;68(25):2797-2818. doi:10.1016/j.jacc.2016.10.039
18. Roberts R, Chavira J, Acuna E. Therapeutic Implications of Genetic Risk Stratification for CAD. Int J Fam Med Prim Care. 2022; 3(1): 1059..
19. Khera AV, Chaffin M, Zekavat SM, et al. Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. Circulation. 2019;139(13):1593-1602. doi:10.1161/CIRCULATIONAHA.118.035658
20. Inouye M, Abraham G, Nelson CP, Wood AM, Sweeting MJ, Dudbridge F, et al. Genomic risk prediction of coronary artery disease in 480,000 adults. J Am Coll Cardiol 2018;72(16):1883–93.
21. Khera AV, Chaffin M, Aragam KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018;50(9):1219-1224. doi:10.1038/s41588-018-0183-z
22. Mega JL, Stitziel NO, Smith JG, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet Lond Engl. 2015;385(9984):2264-2271. doi:10.1016/S0140-6736(14)61730-X
23. Natarajan P, Young R, Stitziel NO, et al. Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting. Circulation. 2017;135(22):2091-2101. doi:10.1161/CIRCULATIONAHA.116.024436
24. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
25. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174
26. Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 2016;375(24):2349–58.].
27. Tikkanen E, Gustafsson S, Ingelsson E. Associations of fitness, physical activity, strength, and genetic risk with cardiovascular disease: longitudinal analyses in the UK Biobank study. Circulation 2018;137(24):2583–91.
28. 1. AK Jiang T, Goel A, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. 2022;54(12):1803-1815. doi:10.1038/s41588-022-01233-6
29. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-2330. doi:10.1093/eurheartj/ehz962
30. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144
31. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet Lond Engl. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5
32. Luo F, Das A, Khetarpal SA, et al. ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases. Trends Cardiovasc Med. 2023;(23):S1050-1738. doi:10.1016/j.tcm.2023.01.008
33. Roberts R. Genetics keeps on giving: A possible vaccine for heart disease. Trends Cardiovasc Med. 2023;(23):S1050-1738. doi:10.1016/j.tcm.2023.02.008
34. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489
35. Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62(13):1154-1162. doi:10.1016/j.jacc.2013.05.050
36. Cohen DE. Balancing cholesterol synthesis and absorption in the gastrointestinal tract. J Clin Lipidol. 2008;2(2):S1-S3. doi:10.1016/j.jacl.2008.01.004
37. Tabas I. Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. J Clin Invest. 2002;110(7):905-911. doi:10.1172/JCI16452
38. Ference BA, Cannon CP, Landmesser U, Lüscher TF, Catapano AL, Ray KK. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018;39(27):2540-2545. doi:10.1093/eurheartj/ehx450
39. Cannon CP. Low-Density Lipoprotein Cholesterol. J Am Coll Cardiol. 2020;75(17):2119. doi:10.1016/j.jacc.2020.03.033
40. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. The Lancet. 2017;390(10106):1962-1971. doi:10.1016/S0140-6736(17)32290-0
41. Grundy Scott M., Cleeman James I., Merz C. Noel Bairey, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110(2):227-239. doi:10.1161/01.CIR.0000133317.49796.0E
42. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504. doi:10.1056/NEJMoa040583
43. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-1435. doi:10.1056/NEJMoa050461
44. Authors/Task Force Members, ESC Committee for Practice Guidelines (CPG), ESC National Cardiac Societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis. 2019;290:140-205. doi:10.1016/j.atherosclerosis.2019.08.014
45. Murphy SA, Cannon CP, Blazing MA, et al. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol. 2016;67(4):353-361. doi:10.1016/j.jacc.2015.10.077
46. Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial. JAMA Cardiol. 2019;4(7):613-619. doi:10.1001/jamacardio.2019.0886
47. Szarek M, White HD, Schwartz GG, et al. Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol. 2019;73(4):387-396. doi:10.1016/j.jacc.2018.10.039
48. Fujita H, Okada T, Inami I, et al. Low-density lipoprotein profile changes during the neonatal period. J Perinatol Off J Calif Perinat Assoc. 2008;28(5):335-340. doi:10.1038/jp.2008.8
49. Pac-Kozuchowska E. Evaluation of lipids, lipoproteins and apolipoproteins concentrations in cord blood serum of newborns from rural and urban environments. Ann Agric Environ Med 2007;14(1):25–9.