Atherosclerosis—Know Your Risk—Is it Time for a Paradigm Shift?

US Endocrinology, 2014;10(2):105–10 DOI: http://doi.org/10.17925/USE.2014.10.02.105

Abstract:

Atherosclerosis is a form of arteriosclerosis characterized by the deposition of atheromatous plaques containing cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries. People with atherosclerosis have a higher risk for cardiovascular disease (CVD) and stroke. Modification of traditional risk factors, such as smoking cessation, decreasing blood pressure, and lowering of cholesterol in high-risk individuals, has resulted in reducing CVD and stroke remarkably. However, the current standard of care using traditional modifiable risk factors alone is frequently inadequate to identify some individuals with atherosclerosis. Therefore, it is important to not rely solely on risk factor modification when assessing for CVD, but also to incorporate a disease platform. A new paradigm focusing on the disease itself (atherosclerosis) is necessary. This article will review the tools necessary to identify disease and will examine why it is critical to know the cause of the disease and to develop a treatment plan to eradicate it.
Keywords: Atherosclerosis, lumenology, arteriology, genetic testing, inflammatory biomarkers, insulin resistance, heart failure, periodontal disease, plant sterols
Disclosure: Claude K Lardinois, MD, FACP, MACN, FACE, has no conflicts of interest to declare. No funding was received for the publication of this article
Received: July 02, 2014 Accepted September 19, 2014
Correspondence: Claude K Lardinois, MD, FACP, MACN, FACE, 1700 Aquila Avenue, Reno, Nevada, US. E: Lardinois@sbcglobal.net

Atherosclerosis continues to be the number one cause of death in the US. Annually, 1,000,000 people will suffer a myocardial infarction (MI): one-third of those will occur in people who have already suffered an event.1 Despite treatment of major modifiable risk factors proved to reduce CVD,2,3 the high recurrence rate raises serious questions that the current standard of care using modifiable risk factors to reduce MI is inadequate and that it is critical to start looking beyond the status quo. Framingham and Reynolds Risk Scores fail to identify the majority of people who will have an event.4 Most MIs are caused by nonobstructing plaques of less than 50 % of the arterial lumen.5,6 Traditional cardiology focuses on stress testing and angiography to assess MI risk (‘lumenology’—is the lumen open?) The pitfall is that many people will still have atherosclerosis and be at high risk for a MI despite having a normal stress test or angiogram. A new paradigm (‘arteriology’—is disease present?) using noninvasive tools such as carotid intima media thickness (cIMT), carotid and aortic ultrasound, and coronary calcium score (CCS) is necessary. If disease (atherosclerosis) is discovered, a comprehensive evaluation and treatment plan must be implemented to reduce the high recurrence rate of MI.

Arteriology—Is Disease Present?

Direct examination of the endothelium is important to determine if disease (atherosclerosis) is present or not. Patient identification is categorized as primary, secondary, or tertiary (see Figure 1). Primary means no disease is present; secondary means that disease is present but the patient has not had an MI or stroke; tertiary means the patient has suffered an MI or stroke. cIMT is an excellent tool to detect and monitor plaque.1 cIMT thickness and presence or absence of plaque improves prediction of CVD risk.7,8 cIMT is noninvasive, inexpensive, repeatable without adverse effects, adds prognostic power to conventional risk stratification tools, and can be used to monitor the disease (atherosclerotic) process. CCS is another excellent tool to document the presence of atherosclerosis and identify patients at increased risk for CVD and stroke.9–11 The calcium scale is a linear scale with 4 calcium score categories that correlate directly with risk for events and likelihood of obstructive CVD: <11 none; 11–99 mild; 100– 400 moderate; >400 severe. CCS adds prognostic power to conventional risk stratification tools, alters therapeutic goals and improves compliance.

References:
1. Go AS, Mozaffarian D, Roger VL, et al., Heart disease and stroke statistics—2013 update. A report from the American Heart Association, Circulation, 2013;127:e6–e245.
2. Yusuf S, Hawken S, Ôunpuu S, et al., INTERHEART Study Investigators: Effects of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study, Lancet, 2004;364:937– 52.
3. Lardinois CK, No more heart disease: Addressing major modifiable risk factors in type 2 diabetes, US Endocrinology, 2011;7:16–22.
4. Nancy R, Cook NR, Paynter NP, et al., Comparison of the Framingham and Reynolds Risk scores for global cardiovascular risk prediction in the multiethnic Women’s Health Initiative, Circulation, 2012;125:1748–56.
5. Falk E, Shah PK, Fuster V, Coronary plaque disruption, Circulation, 1995;92:657–71.
6. Virmani R, Burke AP, Farb A, Kolodgie FD, Pathology of the vulnerable plaque, J Am Coll Cardiol, 2006;47:C13–C18.
7. Nambi V, Chambless L, Folsom A, et al., Carotid intimamedia thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk in Communities) study, J Am Coll Cardiol, 2010;55:1600–7.
8. Polak JF, Pencina MJ, Pencina KM, et al., Carotid-wall intima– media thickness and cardiovascular events, N Engl J Med, 2011;365:213–21.
9. Nasir K, Rubin J, Blaha MJ, Interplay of coronary artery calcification and traditional risk factors for the prediction of all-cause mortality in asymptomatic individuals, Circ Cardiovasc Imaging, 2012;5:467–73.
10. Hermann DM, Gronewold J, Lehmann N, et al., Coronary artery calcification is an independent stroke predictor in the general population, Stroke, 2013;44:1008–13.
11. Polonsky TS, McClelland RL, Jorgensen NW, et al., Coronary artery calcium score and risk classification for coronary heart disease prediction, JAMA, 2010;303:1610–6.
12. Minihane AM, Khan S, Leigh-Firbank EC, et al., ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype, Arterioscler Thromb Vasc Biol, 2000;20:1990–7.
13. Masson LF, McNeill G, Avenell A, Genetic variation and the lipid response to dietary intervention: a systematic review, Am J Clin Nutr, 2003;77:1098–111.
14. Moreno JA, Perez-Jimenez F, Marin C, et al., The effect of dietary fat on LDL size is influenced by apolipoprotein E genotype in healthy subjects, J Nutr, 2004;134:2517–22.
15. Corella D, Tucker K, Lahoz C, et al., Alcohol drinking determines the effect of the APOE locus on LDL-cholesterol concentrations in men: the Framingham Offspring Study, Am J Clin Nutr, 2001;73:736–45.
16. Angelopoulos T, Lowndes J, ApoE genotype: impact on health, fitness and nutrition, World Rev Nutr Diet, 2008;98:77–93.
17. Katzel LI, Fleg JL, Paidi M, et al., ApoE4 polymorphism increases the risk for exercise-induced silent myocardial ischemia in older men, Arterioscler Thromb Vasc Biol, 1993;13:1495–1500.
18. Iakoubova OA, Tong CH, Rowland CM, et al., Association of the Trp719Arg polymorphism in kinesis-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials, J Am Coll Cardiol, 2008;51:435–43.
19. Iakoubova OA, Sabatine MS, Rowland CM, et al., Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE It-TIMI 22 study, J Am Coll Cardiol, 2008;51:449–55.
20. Ridker PM, MacFadyen JG, Glynn RJ, Chasman DI, Kinesin-like protein 6 (KIF6) polymorphism and the efficacy of rosuvastatin in primary prevention, Circ Cardiovasc Genet, 2011;4:312–7.
21. Arsenault BJ, Boekholdt SM, Hovingh GK, et al., The 719Arg variant of KIF6 and cardiovascular outcomes in statin-treated, stable coronary patients of the treating to new targets and incremental decrease in end points through aggressive lipid-lowering prospective studies, Circ Cardiovascular Genet, 2012;5:51–7.
22. Hopewell JC, Parish S, Clarke R, et al., No impact of KIF6 genotype on vascular risk and statin response among 18,348 randomized patients in the Heart Protection Study, J Am Coll Cardiol, 2011;57:2000–7.
23. Ference BA, Yoo W, Flack JM, Clarke M, A common KIF6 polymorphism increases vulnerability to low-density lipoprotein cholesterol: two meta-analyses and a meta-regression analysis, PloS One, 2011;6:1–10.
24. Assimes TL, Holm H, Kathiresan S, et al., Lack of association between the Trp719Arg polymorphism in Kinesin-Like Protein-6 and coronary artery disease in 19 case-control studies, J Am Coll Cardiol, 2010;56:1552–63.
25. Sever PS, Dahlof B, Poulter NR, 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 multicenter randomized controlled trial, Lancet, 2003;361:1149–58.
26. Helgadottir A, Thorleifsson G, Magnusson KP, et al., The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm, Nature Genetics, 2008;40;217–24.
27. Helgadottir A, Thorleifsson G, Manolescu A, et al., A common variant on chromosome 9p21 affects the risk of myocardial infarction, Science, 2007:1491–3.
28. Zhang W, Chen Y, Liu P, et al., Variants on chromosome 9p21.3 correlated with ANRIL expression contribute to stroke risk and recurrence in a large prospective stroke population, Stroke, 2012;43:14–21.
29. Clarke R, Peden JF, Hopewell JC, et al., Genetic variants associated with Lp(a) lipoprotein level and coronary disease, N Engl J Med, 2009;361:2518–28.
30. Luke MM, Kane JP, Liu DM et al., A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease, Arterioscler Thromb Vasc Biol, 2007;27:2030–6.
31. Chasman DI, Shiffman D, Zee RY, et al., Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy, Atherosclerosis, 2009;203:371–6.
32. Shiffman D, Chasman DI, Ballantyne CM, et al., Coronary heart disease risk, aspirin use, and apolipoprotein(a) 4399Met allele in the Atherosclerosis Risk in Communities (ARIC) study, Thromb Haemost, 2009;102:179–80.
33. Davies SS, Roberts LJ, F2-Isoprostanes as an indicator and risk factor for coronary heart disease, Free Radic Biol Med, 2011;50:559–66.
34. Schwedhelm E, Bartling A, Lenzen H, et al., Urinary 8-isoProstaglandin F2{alpha} as a risk marker in patients with coronary heart disease: A matched case-control study, Circulation, 2004;109:843–8.
35. Shishehbor MH, Zhang R, Medina H, et al., Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease, Free Radic Biol Med, 2006;41:1678–83.
36. Hindorff LA, Rice KM, Lange LA, et al., Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study, Atherosclerosis, 2008;197:922–30.
37. Ridker PM, Cushman M, Stampfer MJ, et al., Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men, N Engl J Med, 1997;336:973–9.
38. Ridker PM, Buring JE, Nancy NR, et al., C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events an 8-year follow-up of 14 719 initially healthy American women, Circulation, 2003;107:391–7.
39. Dehghan A, Dupuis J, Barbalic M, et al., Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels, Circulation, 2011;123:731–8.
40. Gerstein HC, Mann JF, Yi Q, et al., Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals, JAMA, 2001;286:421–6.
41. Gross JL, De Azevedo MJ, Silveiro SP, et al., Diabetic nephropathy: diagnosis, prevention, and treatment, Diabetes Care, 2005;28:176–88.
42. Dahlöf B, Devereux RB, Kjeldsen SE, et al., Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol, Lancet, 2002;359:995–1003.
43. Mann JF, Gerstein HC, Pogue J, et al., Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial, Ann Intern Med, 2001;134:629–36.
44. Hallan S, Astor B, Romundstad S, et al., Association of kidney function and albuminuria with cardiovascular mortality in older vs. younger individuals: The HUNT II Study, Arch Intern Med, 2007;167:2490–6.
45. Arnllow J, Evans JC, Meigs JB, et al., Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals, The Framingham Heart Study, Circulation, 2005;112:969–75.
46. Carr C, Myzak MC, Stocker R, et al., Myeloperoxidase binds to low-density lipoprotein: potential implications for atherosclerosis, FEBS Letters, 2000;487;176–30. lipoprotein modified by myeloperoxidase in inflammatory pathways and clinical studies, Mediators of Inflammation, Volume 2013 (2013), Article ID 971579, 18 pages.
48. Ansell BJ, Watson KE, Fogelman AM, et al., High-density lipoprotein function recent advances, J Am Coll Cardiol, 2005;46:1792–8.
49. Fogelman AM, When good cholesterol goes bad, Nat Med, 2004;10:902–3.
50. Ishida K, Cucchiara B, Therapeutic options to reduce Lp-PLA2 levels and the potential impact on vascular risk reduction, Curr Treat Options Cardiovasc Med, 2013;15:313–21.
51. Oei HH, van der Meer IM, Hofman A, et al., Lipoproteinassociated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study, Circulation, 2005;111:570–5.
52. Ridker PM, MacFadyen JG, Wolfert RL, et al., Relationship of lipoprotein-associated phospholipase A(2) mass and activity with incident vascular events among primary prevention patients allocated to placebo or to statin therapy: an analysis from the JUPITER trial, Clin Chem, 2012;58:877–86.
53. Rosenson RS, Stafforini DM, Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2, J Lipid Res, 2012;53:1767–82.
54. White H, Held C, Stewart R, et al., Study design and rationale for the clinical outcomes of the STABILITY Trial (Stabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease, Am Heart J, 2010;160:655–61.
55. O’Donoghue ML, Braunwald E, White HD, et al., Study design and rationale for the Stabilization of pLaques usIng DarapladibThrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome, Am Heart J, 2011;162:613–9.
56. White HD; STABILITY investigators, Darapladib for preventing ischemic events in stable coronary heart disease, N Engl J Med, 2014;370:1702–11.
57. O’Donoghue ML, Braunwald E, White HD, et al., Effect of darapladib on major coronary events after an acute coronary syndrome, JAMA, 2014;312:1006–15.
58. Danesh J, Lewington S, Thompson SG, et al., Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality. An individual participant meta-analysis, JAMA, 2005;294:1799–1809.
59. Meisinger C, Baumert J, Khuseyinova N, et al., Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease. Events in apparently healthy, middle-aged men from the general population, Circulation, 2005;112:651–7.
60. Holvoet P, Lee D-H, Steffes M, et al., Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome, JAMA, 2008;299:2287–93.
61. Veeranna V, Zalawayiya S, Niraj A, et al., Homocysteine and reclassification of cardiovascular disease risk, J Am Coll Cardiol, 2011;58:1025–33.
62. Bonora E, Insulin resistance as an independent risk factor for cardiovascular disease: clinical assessment and therapy approaches, Av Diabetol, 2005;21:255–61.
63. Mozaffarian D, Marfisi R, Levantesi G, et al., Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors, Lancet, 2007;370:667–75.
64. Rundek T, Gardener H, Xu Q, et al., Insulin resistance and risk of ischemic stroke among nondiabetic individuals from the northern Manhattan Study, Arch Neurol, 2010;67:1195–200.
65. Abdul-Ghani M, Stern MP, Lyssenko V, et al., Minimal contribution of fasting hyperglycemia to the incidence of type 2 diabetes in subjects with normal 2-h plasma glucose, Diabetes Care, 2010;33:557–61.
66. Bhalla V, Willis S, Maisel AS, B-type natriuretic peptide: The level and the drug—partners in the diagnosis and management of congestive heart failure, Congest Heart Fail, 2004;10(Suppl. 1):3–27.
67. Betti I, Castelli G, Barchielli A, et al., The role of N-terminal PRObrain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF Study, J Cardiac Fail, 2009;15:377–84.
68. McMurray J, McGuire D, Fisher BM, EASD/ESC Symposium: heart failure and diabetes: a deadly intersection, presented at EASD 49th Annual Meeting, 26 September 2013, Barcelona, Spain. Available at: http://www.easdvirtualmeeting.org/ contentsessions/259 (accessed February 11, 2014).
69. Drager LF, Polotsky VY, Lorenzi-Filho G, Obstructive sleep apnea. An emerging risk factor for atherosclerosis, Chest, 2011;140:534–42.
70. Lavie CJ, Lee JH, Milani RV, Vitamin D and cardiovascular disease. Will it live up to its hype, J Am Coll Cardiol, 2011:58:1547–56.
71. Ambrose JA, Barua RS, The pathophysiology of cigarette smoking and cardiovascular disease, J Am Coll Cardiol, 2004;43:1731–7.
72. Lockhart PB, Bolger AF, Papapanou PN, et al., Periodontal disease and atherosclerotic vascular disease: Does the evidence support an independent association?, Circulation, 2012;125:2520–44.
73. Miettinen TA, Gylling H, Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large dose of statin treatment, Eur J Clin Invest, 2003;33:976–82.
74. van Himbergen TM, Matthan NR, Resteghini NA, et al., Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers, J Lipid Res, 2009;50:730–9.
75. Miettinen TA, Strandberg TE, Gylling H, Noncholesterol sterols and cholesterol lowering by long-term simvastatin treatment in coronary patients: relation to basal serum cholestanol, Arterioscler Thromb Vasc Biol, 2000;20:1340–6.
Keywords: Atherosclerosis, lumenology, arteriology, genetic testing, inflammatory biomarkers, insulin resistance, heart failure, periodontal disease, plant sterols