Download PDF
Thromb Haemost 2017; 117(02): 231-237
DOI: 10.1160/TH16-10-0770
Perspective
Schattauer GmbH

Atherosclerosis revisited from a clinical perspective: still an inflammatory disease?

Donato Santovito
1   Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
,
Christian Weber
1   Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
2   German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
› Author Affiliations Financial support: The work of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB1123, A1/B4).
Further Information

Publication History

Received:10 October 2016

Accepted after minor revision:10 November 2016

Publication Date:
13 November 2017 (online)

    Permissions and Reprints

Summary

Compelling experimental results have substantiated the immune-driven inflammatory nature of atherosclerosis. Most of the scientific advances over the past decades have been achieved by relying on transgenic animal models that have been employed with increasing levels of sophistication. However, recent failures in translating various anti-inflammatory therapeutic strategies for use in humans might raise some skepticism with regards to an inflammatory causality underlying human atherosclerosis. By applying a dialectical approach, this Perspective aims to challenge and deduce the nature of atherosclerosis by reviewing results exclusively derived from human studies and recent clinical trials, as “things may not always be, what they appear”.

Note: The review process for this manuscript was fully handled by Gregory Y. H. Lip, Editor in Chief.

Keywords

inflammation - atherosclerosis - atherothrombosis
 

  • References

  • 1 Ross R.. Atherosclerosis--an inflammatory diseas. N Engl J Med 1999; 340: 115-126.
    CrossrefPubMedGoogle Scholar
  • 2 Weber C, Noels H.. Atherosclerosis: current pathogenesis and therapeutic option. Nat Med 2011; 17: 1410-1422.
    CrossrefPubMedGoogle Scholar
  • 3 Santovito D, Egea V, Weber C.. Small but smart: MicroRNAs orchestrate atherosclerosis development and progressio. Biochim Biophys Acta 2016; 1861: 2075-2086.
    CrossrefPubMedGoogle Scholar
  • 4 Levula M, Oksala N, Airla N. et al. Genes involved in systemic and arterial bed dependent atherosclerosis-Tampere Vascular study. PLoS ONE 2012; 07: e33787.
    CrossrefPubMedGoogle Scholar
  • 5 Bidzhekov K, Gan L, Denecke B. et al. microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans. Thromb Haemost 2012; 107: 619-625.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Santovito D, Mezzetti A, Cipollone F.. Cyclooxygenase and prostaglandin synthases: roles in plaque stability and instability in human. Curr Opin Lipidol 2009; 20: 402-408.
    CrossrefPubMedGoogle Scholar
  • 7 Mandolini C, Santovito D, Marcantonio P. et al. Identification of microRNAs 758 and 33b as potential modulators of ABCA1 expression in human atherosclerotic plaques. Nutr Metab Cardiovasc Dis 2015; 25: 202-209.
    CrossrefPubMedGoogle Scholar
  • 8 Kaptoge S, Seshasai SRK, Gao P. et al. Inflammatory cytokines and risk of coronary heart disease: New prospective study and updated meta-analysis. Eur Heart J 2014; 35: 578-589.
    CrossrefPubMedGoogle Scholar
  • 9 Emerging Risk Factors Collaboration Kaptoge S, Di Angelantonio. E. et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132-140.
    CrossrefPubMedGoogle Scholar
  • 10 Ridker PM, Paynter NP, Rifai N. et al. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation 2008; 118: 2243-2251.
    CrossrefPubMedGoogle Scholar
  • 11 Defilippis AP, Young R, Carrubba CJ. et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Ann Intern Med 2015; 162: 266-275.
    CrossrefPubMedGoogle Scholar
  • 12 Hegel G.. System der Wissenschaft: Erster Theil, die Phänomenologie des Geiste. Bamberg and Würzburg: Joseph Anton Goebhardt eds 1807.
    PubMedGoogle Scholar
  • 13 Popper K.. Objective Knowledg. An Evolutionary Approach Oxford: Clarendon Press; 1972.
    Google Scholar
  • 14 Stitziel NO, Stirrups KE, Masca NGD. et al. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 2016; 374: 1134-1144.
    CrossrefPubMedGoogle Scholar
  • 15 Nikpay M, Goel A, Won H-H. et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47: 1121-1130.
    CrossrefPubMedGoogle Scholar
  • 16 Pekkanen J, Linn S, Heiss G. et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990; 322: 1700-1707.
    CrossrefPubMedGoogle Scholar
  • 17 Raal FJ, Santos RD.. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatmen. Atherosclerosis 2012; 223: 262-268.
    CrossrefPubMedGoogle Scholar
  • 18 Nicholls SJ, Ballantyne CM, Barter PJ. et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011; 365: 2078-2087.
    CrossrefPubMedGoogle Scholar
  • 19 Fulcher J, O’Connell R, Voysey M. et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials. Lancet 2015; 385: 1397-1405.
    CrossrefPubMedGoogle Scholar
  • 20 Cannon CP, Blazing MA, Giugliano RP. et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372: 2387-2397.
    CrossrefPubMedGoogle Scholar
  • 21 Sabatine MS, Giugliano RP, Wiviott SD. et al. Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015; 372: 1500-1509.
    CrossrefPubMedGoogle Scholar
  • 22 McGettigan P, Henry D.. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase . J Am Med Assoc 2006; 296: 1633-1644.
    CrossrefPubMedGoogle Scholar
  • 23 Solomon SD, McMurray JJV, Pfeffer MA. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071-1080.
    CrossrefPubMedGoogle Scholar
  • 24 Vaithianathan R, Hockey PM, Moore TJ. et al. Iatrogenic effects of COX-2 inhibitors in the US population: findings from the Medical Expenditure Panel Survey. Drug Saf 2009; 32: 335-343.
    CrossrefPubMedGoogle Scholar
  • 25 Mallat Z, Lambeau G, Tedgui A.. Lipoprotein-associated and secreted phospholipases A2 in cardiovascular disease: roles as biological effectors and biomarker. Circulation 2010; 122: 2183-2200.
    CrossrefPubMedGoogle Scholar
  • 26 O’donoghue ML, Braunwald E, White HD. et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. J Am Med Assoc 2014; 312: 1006-1015.
    CrossrefPubMedGoogle Scholar
  • 27 White HD, Held C, Stewart R. et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med 2014; 370: 1702-1711.
    CrossrefPubMedGoogle Scholar
  • 28 Nicholls SJ, Kastelein JJP, Schwartz GG. et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. J Am Med Assoc 2014; 311: 252-262.
    CrossrefPubMedGoogle Scholar
  • 29 Lehrer-Graiwer J, Singh P, Abdelbaky A. et al. FDG-PET imaging for oxidized LDL in stable atherosclerotic disease: a phase II study of safety, tolerability, and anti-inflammatory activity. JACC Cardiovasc Imaging 2015; 08: 493-494.
    CrossrefPubMedGoogle Scholar
  • 30 O’donoghue ML, Glaser R, Cavender MA. et al. Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial. J Am Med Assoc 2016; 315: 1591-1599.
    CrossrefPubMedGoogle Scholar
  • 31 Hauser TH, Salastekar N, Schaefer EJ. et al. Effect of Targeting Inflammation With Salsalate: The TINSAL-CVD Randomized Clinical Trial on Progression of Coronary Plaque in Overweight and Obese Patients Using Statins. J Am Med Assoc Cardiol 2016; 01: 413-423.
    PubMedGoogle Scholar
  • 32 Morton AC, Rothman AMK, Greenwood JP. et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J 2015; 36: 377-384.
    CrossrefPubMedGoogle Scholar
  • 33 Nidorf SM, Eikelboom JW, Budgeon CA. et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013; 61: 404-410.
    CrossrefPubMedGoogle Scholar
  • 34 Patti G, Pasceri V, Colonna G. et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention - Results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49: 1272-1278.
    CrossrefPubMedGoogle Scholar
  • 35 Everett BM, Smith RJ, Hiatt WR.. Reducing LDL with PCSK9 Inhibitors--The Clinical Benefit of Lipid Drug. N Engl J Med 2015; 373: 1588-1591.
    CrossrefPubMedGoogle Scholar
  • 36 Dinarello CA.. Anti-inflammatory Agents: Present and Future. Cel. 2010; 140: 935-950.
    PubMedGoogle Scholar
  • 37 Ridker PM, Danielson E, Fonseca FAH. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein (JUPITER). N Engl J Med 2008; 359: 2195-2207.
    CrossrefPubMedGoogle Scholar
  • 38 Braunwald E.. Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trial. Eur Heart J 2012; 33: 430-432.
    CrossrefPubMedGoogle Scholar
  • 39 Pearson TA, Ballantyne CM, Veltri E. et al. Pooled analyses of effects on C-reactive protein and low density lipoprotein cholesterol in placebo-controlled trials of ezetimibe monotherapy or ezetimibe added to baseline statin therapy. Am J Cardiol 2009; 103: 369-374.
    CrossrefPubMedGoogle Scholar
  • 40 Colantonio LD, Bittner V, Reynolds K. et al. Association of Serum Lipids and Coronary Heart Disease in Contemporary Observational Studies. Circulation 2016; 133: 256-264.
    CrossrefPubMedGoogle Scholar
  • 41 Leibowitz M, Karpati T, Cohen-Stavi CJ. et al. Association between achieved low-density lipoprotein levels and major adverse cardiac events in patients with stable ischemic heart disease taking statin treatment. J Am Med Assoc Intern Med 2016; 176: 1105-1113.
    PubMedGoogle Scholar
  • 42 Sahebkar A, Di Giosia P, Stamerra CA. et al. Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms. Br J Clin Pharmacol 2016; 81: 1175-1190.
    CrossrefPubMedGoogle Scholar
  • 43 Walley KR, Thain KR, Russell JA. et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med 2014; 06 (258) ra 143.
    PubMedGoogle Scholar
  • 44 Norata GD, Tavori H, Pirillo A. et al. Biology of proprotein convertase subtilisin kexin 9:beyond low-density lipoprotein cholesterol lowerin. Cardiovasc Res 2016; 112: 429-442.
    CrossrefPubMedGoogle Scholar
  • 45 Rader DJ, Kastelein JJP.. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemi. Circulation 2014; 129: 1022-1032.
    CrossrefPubMedGoogle Scholar
  • 46 Rungoe C, Nyboe Andersen N, Jess T.. Inflammatory bowel disease and risk of coronary heart diseas. Trends Cardiovasc Med 2015; 25: 699-704.
    CrossrefPubMedGoogle Scholar
  • 47 Ogdie A, Yu Y, Haynes K. et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis 2015; 74: 326-332.
    CrossrefPubMedGoogle Scholar
  • 48 van Sijl AM, Peters MJ, Knol DK. et al. Carotid Intima Media Thickness in Rheumatoid Arthritis as Compared to Control Subjects: A Meta-Analysis. Semin Arthritis Rheum 2011; 40: 389-397.
    CrossrefPubMedGoogle Scholar
  • 49 Karpouzas GA, Malpeso J, Choi T-Y. et al. Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann Rheum Dis 2014; 73: 1797-1804.
    CrossrefPubMedGoogle Scholar
  • 50 Myasoedova E, Crowson CS, Kremers HM. et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis 2011; 70: 482-487.
    CrossrefPubMedGoogle Scholar
  • 51 Ridker PM, Cannon CP, Morrow D. et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20-28.
    CrossrefPubMedGoogle Scholar
  • 52 Bohula EA, Giugliano RP, Cannon CP. et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation 2015; 132: 1224-1233.
    CrossrefPubMedGoogle Scholar
  • 53 Puri R, Nissen SE, Libby P. et al. C-Reactive Protein, but not Low-Density Lipoprotein Cholesterol Levels, Associate With Coronary Atheroma Regression and Cardiovascular Events After Maximally Intensive Statin Therapy. Circulation 2013; 128: 2395-2403.
    CrossrefPubMedGoogle Scholar
  • 54 Pedersen TR.. The Success Story of LDL Cholesterol Lowerin. Circ Res 2016; 118: 721-731.
    CrossrefPubMedGoogle Scholar
  • 55 Marnett LJ, DuBois RN.. COX-2: A target for colon cancer preventio. Annu Rev Pharmacol Toxicol 2002; 42: 55-80.
    CrossrefPubMedGoogle Scholar
  • 56 Grosser T, Yu Y, FitzGerald GA.. Emotion recollected in tranquility: lessons learned from the COX-2 sag. Annu Rev Med 2010; 61: 17-33.
    CrossrefPubMedGoogle Scholar
  • 57 McAdam BF, Catella-Lawson F, Mardini IA. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2. the human pharmacology of a selective inhibitor of COX-. Proc Natl Acad Sci USA 1999; 96: 272-277.
    CrossrefPubMedGoogle Scholar
  • 58 Ross S, Eikelboom J, Anand SS. et al. Association of cyclooxygenase-2 genetic variant with cardiovascular disease. Eur Heart J 2014; 35: 2242-2248.
    CrossrefPubMedGoogle Scholar
  • 59 Cipollone F, Santovito D.. EP Receptors and Coxibs: Seeing the Light at the End of the Tunne. Circ Res 2013; 113: 91-93.
    CrossrefPubMedGoogle Scholar
  • 60 Santilli F, Boccatonda A, Davì G. et al. The Coxib case: Are EP receptors really guilty?. Atherosclerosis 2016; 249: 164-173.
    CrossrefPubMedGoogle Scholar
  • 61 Kleveland O, Kunszt G, Bratlie M. et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J 2016; 37: 2406-2413.
    CrossrefPubMedGoogle Scholar
  • 62 Gilbert J, Lekstrom-Himes J, Donaldson D. et al. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am J Cardiol 2011; 107: 906-911.
    CrossrefPubMedGoogle Scholar
  • 63 Koenen RR, Hundelshausen von P, Nesmelova IV. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15: 97-103.
    CrossrefPubMedGoogle Scholar
  • 64 Blanchet X, Cesarek K, Brandt J. et al. Inflammatory role and prognostic value of platelet chemokines in acute coronary syndrome. Thromb Haemost 2014; 112: 1277-1287.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 65 Piconi S, Pocaterra D, Rainone V. et al. Maraviroc Reduces Arterial Stiffness in PI-Treated HIV-infected Patients. Sci Rep 2016; 06: 28853.
    CrossrefPubMedGoogle Scholar