Non-Traditional Cardiovascular Risk Markers in the Era of Established Major Risk Factors and Multiple Guidelines

Author(s): Thomas F. Whayne*.

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

The non-traditional cardiovascular (CV) risk factors that appear to be of most clinical interest include: apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-sensitivity C-Reactive protein (hsCRP), homocysteine, interleukin 1 (IL1), lipoprotein (a) [Lp(a)], the density of low-density lipoprotein (LDL) particles, the LDL particle number, tissue/tumor necrosis factor-α (TNF-α) and uric acid. These non-traditional risk factors may be of value in adding further confirmation and attention to suspected significant CV risk. They can also provide a better understanding of current concepts of atherogenesis (e.g. various potential mechanisms associated with inflammation) as an etiology and in guiding current plus future therapies. In the mid-20th century, atherosclerosis and CV disease were considered mechanistic occurrences with essentially no attention to possible metabolic and molecular etiologies. Therefore, the only treatments then centered around mainly surgical procedures to try to improve blood flow, first with peripheral arterial disease (PAD) and later coronary artery disease (CAD). Now, failure to treat CV risk factors, especially where there is good evidence-based medicine, as in the case of statins for high CV risk patients, is considered medical negligence. Nevertheless, many problems remain to be solved regarding atherosclerosis prevention and treatment.

Keywords: Anti-inflammatory medications, cardiovascular risk, high-sensitivity C-reactive protein, interleukin-1, nontraditional risk markers, LDL-C.

[1]
Stone NJ, Robinson JG, Lichtenstein AH, 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: 2889-934.
[2]
Whayne TF Jr. Is there an ideal low-density lipoprotein cholesterol level? confusion regarding lipid guidelines, low-density lipoprotein cholesterol targets, and medical management. Int J Angiol 2017; 26: 73-7.
[3]
Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: Part 1 - executive summary. J Clin Lipidol 2014; 8: 473-88.
[4]
Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias: The task force for the management of dyslipidaemias of the European society of cardiology (ESC) and the European atherosclerosis society (EAS). Eur Heart J 2011; 32: 1769-818.
[5]
Jellinger PS, Handelsman Y, Rosenblit PD, et al. American association of clinical endocrinologists and american college of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017; 23: 1-87.
[6]
American Diabetes Association. Standards of medical care in diabetes-2017. J Clin Appl Res Educ 2017; 40(Supp 1): 1-133.
[7]
Whayne TF. Low-density lipoprotein cholesterol (LDL-C): how low? Curr Vasc Pharmacol 2017; 15: 374-9.
[8]
Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003; 289: 2560-72.
[9]
Eagle KA, Ginsburg GS, Musunuru K, et al. Identifying patients at high risk of a cardiovascular event in the near future: current status and future directions: report of a national heart, lung, and blood institute working group. Circulation 2010; 121: 1447-54.
[10]
Kannel WB, Dawber TR, Kagan A, et al. Factors of risk in the development of coronary heart disease six-year follow-up experience. The Framingham study. Ann Intern Med 1961; 55: 33-50.
[11]
Bergmann K. Non-HDL cholesterol and evaluation of cardiovascular disease risk. EJIFCC 2010; 21: 64-7.
[12]
Libby P. Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of cantos and beyond. J Am Coll Cardiol 2017; 70: 2278-89.
[13]
van Holten TC, Waanders LF, de Groot PG, et al. Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One 2013; 8: e62080.
[14]
Gilotra TS, Geraci SA. C-Reactive protein as an independent cardiovascular risk predictor in HIV+ patients: A focused review of published studies. J Clin Med Res 2017; 9: 891-9.
[15]
Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103: 1813-8.
[16]
Popa C, Netea MG, van Riel PL, et al. The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res 2007; 48: 751-62.
[17]
Yang ZS, Lin NN, Li L, et al. The effect of TNF inhibitors on cardiovascular events in psoriasis and psoriatic arthritis: an updated meta-analysis. Clin Rev Allergy Immunol 2016; 51: 240-7.
[18]
Vlachopoulos C, Gravos A, Georgiopoulos G, et al. The effect of TNF-a antagonists on aortic stiffness and wave reflections: a meta-analysis. Clin Rheumatol 2017; 37(2): 515-26.
[19]
Turner MD, Nedjai B, Hurst T, et al. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta 2014; 1843: 2563-82.
[20]
Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 2045-51.
[21]
Nidorf SM, Eikelboom JW, Budgeon CA, et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013; 61: 404-10.
[22]
Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995; 91: 2844-50.
[23]
Vogel RA, Forrester JS. Cooling off hot hearts: a specific therapy for vulnerable plaque? J Am Coll Cardiol 2013; 61: 411-2.
[24]
Steffens S, Winter C, Schloss MJ, et al. Circadian control of inflammatory processes in atherosclerosis and its complications. Arterioscler Thromb Vasc Biol 2017; 37: 1022-8.
[25]
Gutierrez J, Albuquerque ALA, Falzon L. HIV infection as vascular risk: A systematic review of the literature and meta-analysis. PLoS One 2017; 12: e0176686.
[26]
Friis-Moller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients--association with antiretroviral therapy. Results from the DAD study. AIDS 2003; 17: 1179-93.
[27]
Nsagha DS, Assob JC, Njunda AL, et al. Risk factors of cardiovascular diseases in HIV/AIDS patients on HAART. Open AIDS J 2015; 9: 51-9.
[28]
Grunfeld C, Pang M, Doerrler W, et al. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992; 74: 1045-52.
[29]
Thompson GR, Seed M. Lipoprotein(a): the underestimated cardiovascular risk factor. Heart 2014; 100: 534-5.
[30]
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.
[31]
Tsimikas S. A test in context: Lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol 2017; 69: 692-711.
[32]
Cao J, Steffen BT, Budoff M, et al. Lipoprotein(a) levels are associated with subclinical calcific aortic valve disease in white and black individuals: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 2016; 36: 1003-9.
[33]
Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302: 412-23.
[34]
Gurdasani D, Sjouke B, Tsimikas S, et al. Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol 2012; 32: 3058-65.
[35]
Nozue T, Michishita I, Mizuguchi I. Effects of ezetimibe on remnant-like particle cholesterol, lipoprotein (a), and oxidized low-density lipoprotein in patients with dyslipidemia. J Atheroscler Thromb 2010; 17: 37-44.
[36]
Klingel R, Heibges A, Fassbender C. Lipoprotein apheresis for Lp(a)-hyperlipoproteinemia with progressive cardiovascular disease--Additional particular aspects of the Pro(a)LiFe multicenter trial. Atheroscler Suppl 2015; 18: 35-40.
[37]
Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016; 37: 2999-58.
[38]
Kronenberg F. Lipoprotein(a): there’s life in the old dog yet. Circulation 2014; 129: 619-21.
[39]
Katsiki N, Al-Rasadi K, Mikhailidis DP. Lipoprotein (a) and Cardiovascular Risk: The show must go on. Curr Med Chem 2017; 24: 989-1006.
[40]
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA 2003; 290: 2292-300.
[41]
Whayne TF, Alaupovic P, Curry MD, et al. Plasma apolipoprotein B and VLDL-, LDL-, and HDL-cholesterol as risk factors in the development of coronary artery disease in male patients examined by angiography. Atherosclerosis 1981; 39: 411-24.
[42]
Mora S. Advanced lipoprotein testing and subfractionation are not (yet) ready for routine clinical use. Circulation 2009; 119: 2396-404.
[43]
Slyper AH. Low-density lipoprotein density and atherosclerosis. Unraveling the connection. JAMA 1994; 272: 305-8.
[44]
Mikhailidis DP, Elisaf M, Rizzo M, et al. European panel on low density lipoprotein (LDL) subclasses: a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses: executive summary. Curr Vasc Pharmacol 2011; 9: 531-2.
[45]
Mikhailidis DP, Elisaf M, Rizzo M, et al. European panel on low density lipoprotein (LDL) subclasses: a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr Vasc Pharmacol 2011; 9: 533-71.
[46]
Cziraky MJ. Management of dyslipidemia in patients with metabolic syndrome. J Am Pharm Assoc 2004; 44: 478-88.
[47]
Takagi H, Niwa M, Mizuno Y, et al. Effects of rosuvastatin versus atorvastatin on small dense low-density lipoprotein: a meta-analysis of randomized trials. Heart Vessels 2014; 29: 287-99.
[48]
Daniels TF, Killinger KM, Michal JJ, et al. Lipoproteins, cholesterol homeostasis and cardiac health. Int J Biol Sci 2009; 5: 474-88.
[49]
Katsiki N, Athyros VG, Karagiannis A, et al. High-density lipoprotein, vascular risk, cancer and infection: a case of quantity and quality? Curr Med Chem 2014; 21: 2917-26.
[50]
Watts GF, Barrett PH. High-density lipoprotein metabolism in familial hypercholesterolaemia: significance, mechanisms, therapy. Nutr Metab Cardiovasc Dis 2002; 12: 36-41.
[51]
Whayne TF. Falsely elevated plasma triglycerides occasionally lead to unnecessary treatment: important awareness of a rare disorder. J Ky Med Assoc 2011; 109: 89-91.
[52]
Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr 2006; 136: 1636-40.
[53]
Eikelboom JW, Lonn E, Genest J, et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999; 131: 363-75.
[54]
Stanger O, Herrmann W, Pietrzik K, et al. DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. Clin Chem Lab Med 2003; 41: 1392-403.
[55]
Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 1578-88.
[56]
Liu Y, Tian T, Zhang H, et al. The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: a meta-analysis of randomized controlled trials. Atherosclerosis 2014; 235: 31-5.
[57]
Christen WG, Ajani UA, Glynn RJ, et al. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med 2000; 160: 422-34.
[58]
Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 2011; 34: 75-81.
[59]
Xiao Y, Su X, Huang W, et al. Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism. Int J Biochem Cell Biol 2015; 67: 158-66.
[60]
Ebbing M, Bleie O, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA 2008; 300: 795-804.
[61]
Armitage JM, Bowman L, Clarke RJ, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 2010; 303: 2486-94.
[62]
Andras A, Stansby G, Hansrani M. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts. Cochrane Database Syst Rev 2013; CD003285.
[63]
Wald DS, Law M, Morris JK. The dose-response relation between serum homocysteine and cardiovascular disease: implications for treatment and screening. Eur J Cardiovasc Prev Rehabil 2004; 11: 250-3.
[64]
Miller ER, Juraschek S, Pastor-Barriuso R, et al. Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. Am J Cardiol 2010; 106: 517-27.
[65]
Debreceni B, Debreceni L. Why do homocysteine-lowering B vitamin and antioxidant E vitamin supplementations appear to be ineffective in the prevention of cardiovascular diseases? Cardiovasc Ther 2012; 30: 227-33.
[66]
Sahebkar A, Pirro M, Reiner Z, et al. A systematic review and meta-analysis of controlled trials on the effects of statin and fibrate therapies on plasma homocysteine levels. Curr Med Chem 2016; 23: 4490-503.
[67]
Hou X, Chen X, Shi J. Genetic polymorphism of MTHFR C677T and premature coronary artery disease susceptibility: A meta-analysis. Gene 2015; 565: 39-44.
[68]
Whayne TF Jr. Methylenetetrahydrofolate reductase C677T polymorphism, venous thrombosis, cardiovascular risk, and other effects. Angiology 2015; 66: 401-4.
[69]
Katsiki N, Perez-Martinez P, Mikhailidis DP. Homocysteine and non-cardiac vascular disease. Curr Pharm Des 2017; 23: 3224-32.
[70]
Braga F, Pasqualetti S, Ferraro S, et al. Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis. Clin Chem Lab Med 2016; 54: 7-15.
[71]
Wang R, Song Y, Yan Y, et al. Elevated serum uric acid and risk of cardiovascular or all-cause mortality in people with suspected or definite coronary artery disease: A meta-analysis. Atherosclerosis 2016; 254: 193-9.
[72]
Xu Q, Zhang M, Abeysekera IR, et al. High serum uric acid levels may increase mortality and major adverse cardiovascular events in patients with acute myocardial infarction. Saudi Med J 2017; 38: 577-85.
[73]
Huang H, Huang B, Li Y, et al. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail 2014; 16: 15-24.
[74]
Zhang EY, Kou L, Li M, et al. High uric acid level predicts left atrial thrombus or spontaneous echo contrast detected by transesophageal echocardiography: Meta-analysis and systematic review. Chronic Dis Transl Med 2016; 2: 27-33.
[75]
Maharani N, Kuwabara M, Hisatome I. Hyperuricemia and atrial fibrillation. Int Heart J 2016; 57: 395-9.
[76]
Karagiannis A, Mikhailidis DP, Tziomalos K, et al. Serum uric acid as an independent predictor of early death after acute stroke. Circ J 2007; 71: 1120-7.
[77]
Zhang T, Pope JE. Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis. Rheumatology (Oxford) 2017; 56: 1144-53.
[78]
Akkineni R, Tapp S, Tosteson AN, et al. Treatment of asymptomatic hyperuricemia and prevention of vascular disease: a decision analytic approach. J Rheumatol 2014; 41: 739-48.
[79]
Guedes M, Esperanca A, Pereira AC, et al. What is the effect on cardiovascular events of reducing hyperuricemia with allopurinol? An evidence-based review. Rev Port Cardiol 2014; 33: 727-32.
[80]
Xin W, Mi S, Lin Z. Allopurinol therapy improves vascular endothelial function in subjects at risk for cardiovascular diseases: a meta-analysis of randomized controlled trials. Cardiovasc Ther 2016; 34: 441-9.
[81]
Derosa G, Maffioli P, Sahebkar A. Plasma uric acid concentrations are reduced by fenofibrate: A systematic review and meta-analysis of randomized placebo-controlled trials. Pharmacol Res 2015; 102: 63-70.
[82]
Toulis KA, Goulis DG, Mintziori G, et al. Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome. Hum Reprod Update 2011; 17: 741-60.
[83]
Macut D, Panidis D, Glisic B, et al. Lipid and lipoprotein profile in women with polycystic ovary syndrome. Can J Physiol Pharmacol 2008; 86: 199-204.
[84]
Dregan A, Charlton J, Chowienczyk P, et al. Chronic inflammatory disorders and risk of type 2 diabetes mellitus, coronary heart disease, and stroke: a population-based cohort study. Circulation 2014; 130: 837-44.
[85]
Amaya-Amaya J, Sarmiento-Monroy JC, Mantilla RD, et al. Novel risk factors for cardiovascular disease in rheumatoid arthritis. Immunol Res 2013; 56: 267-86.
[86]
de La Forest Divonne M, Gottenberg JE, Salliot C. Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers. Joint Bone Spine 2017; 84: 133-40.
[87]
Kotani K, Miyamoto M, Ando H. The effect of treatments for rheumatoid arthritis on endothelial dysfunction evaluated by flow-mediated vasodilation in patients with rheumatoid arthritis. Curr Vasc Pharmacol 2017; 15: 10-8.
[88]
Barron E, Lara J, White M, et al. Blood-borne biomarkers of mortality risk: systematic review of cohort studies. PLoS One 2015; 10: e0127550.
[89]
Balta S, Celik T, Mikhailidis DP, et al. The relation between atherosclerosis and the neutrophil-lymphocyte ratio. Clin Appl Thromb Hemost 2016; 22: 405-11.
[90]
Vezzoli G, Arcidiacono T, Rainone F, et al. Hyperparathyroidism as a cardiovascular risk factor in chronic kidney disease: an update from a biological-cellular perspective. G Ital Nefrol 2011; 28: 383-92.
[91]
Katsiki N, Wierzbicki AS, Mikhailidis DP. Erectile dysfunction and coronary heart disease. Curr Opin Cardiol 2015; 30: 416-21.
[92]
Smith-Palmer J, Bae JP, Boye KS, et al. Traditional and non-traditional risk factors for cardiovascular disease in type 2 diabetes: systematic review of longitudinal studies. Value Health 2014; 17: A478.
[93]
Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA 2013; 310: 1711-20.
[94]
Artenjak A, Lakota K, Frank M, et al. Antiphospholipid antibodies as non-traditional risk factors in atherosclerosis based cardiovascular diseases without overt autoimmunity. A critical updated review. Autoimmun Rev 2012; 11: 873-82.
[95]
Balagopal PB, de Ferranti SD, Cook S, et al. Nontraditional risk factors and biomarkers for cardiovascular disease: mechanistic, research, and clinical considerations for youth: a scientific statement from the American heart association. Circulation 2011; 123: 2749-69.
[96]
Stec JJ, Silbershatz H, Tofler GH, et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the framingham offspring population. Circulation 2000; 102: 1634-8.
[97]
George A, Movahed A. Coronary artery calcium scores: current thinking and clinical applications. Open Cardiovasc Med J 2008; 2: 87-92.
[98]
Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American heart association/american college of cardiology foundation scientific statement from the American heart association council for high blood pressure research professional education committee, council on clinical cardiology, stroke council, and council on cardiovascular nursing. In collaboration with the national heart, lung, and blood institute national center on sleep disorders research (National Institutes of Health). Circulation 2008; 118: 1080-111.
[99]
Katsiki N, Athyros VG, Karagiannis A, et al. Should we expand the concept of coronary heart disease equivalents? Curr Opin Cardiol 2014; 29: 389-95.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 17
ISSUE: 3
Year: 2019
Page: [270 - 277]
Pages: 8
DOI: 10.2174/1570161116666180123112956
Price: $58

Article Metrics

PDF: 52
HTML: 2
EPUB: 1
PRC: 1