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Update on advances in atherothrombosis

Abstract

The study of atherothrombosis is a rapidly evolving field, and significant progress was achieved in various aspects of the disease during the past year. In the area of diagnostic imaging, MRI and multidetector CT were actively used to evaluate the characteristics of the arterial wall, including calcified and noncalcified lesions, and both in the coronary and extracoronary vascular territories. There was also extensive research into the application of imaging modalities to visualize cellular or molecular disease processes, known as molecular imaging. Considerable efforts were devoted to the identification of novel biomarkers that reflect different components of atherothrombosis, namely inflammation, thrombogenicity, oxidative stress and reparative ability, predicting the presence of early disease or the risk of clinical events. In the therapeutic arena, substantial evidence accumulated on the beneficial effects of several pharmacologic agents, most significantly statins. Finally, important advances were also made in the understanding of the roles of immunity and neovascularization in atherogenesis, including the development and progression of disease at different stages. Awareness of these recent advances and new lines of active research is fundamental for health professionals involved in the care of patients with atherothrombosis. In this Review we present an overview of data in these areas.

Key Points

  • Noninvasive coronary angiography in clinical practice can be performed with high accuracy in selected populations. MDCT is currently the modality of choice

  • Whole-body MRI coupled with vessel wall and molecular imaging promises to enable a comprehensive evaluation of the arterial system in one single examination, providing indices of burden of disease and plaque vulnerability

  • Apart from traditional risk factors, which account for a large proportion of cardiovascular risk, novel biomarkers of inflammation, procoagulability and oxidative stress provide additive prognostic information

  • Endogenous reparative mechanisms involving progenitor cells have an important role in cardiovascular homeostasis, and stem cell profile might be related to susceptibility of disease

  • Statin therapy to reduce LDL cholesterol below previously recommended levels provides increased cardiovascular protection, which could be partly mediated through anti-inflammatory actions. Augmentation of HDL cholesterol levels seems to be the next major therapeutic target

  • Further understanding of the mechanisms and significance of plaque neovascularization and immune modulation in atherogenesis could lead to improved tools for risk stratification and therapy of atherothrombosis

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Figure 1: 'Whole-heart' magnetic resonance angiography showing normal coronary arteries.
Figure 2: Molecular MRI of experimentally induced carotid thrombosis in a rabbit model.
Figure 3: Pooled estimation of the percentage of hard coronary events to occur during the next 10 years in men and women of different age groups in the US.
Figure 4: Differences in the cumulative incidence of major cardiovascular events in the Treating to New Targets (TNT) trial.
Figure 5: Activation of hypoxia inducible factor (HIF)1-α and its contribution to angiogenesis.
Figure 6: Role of coordinated angiogenesis and inflammation in plaque progression.

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References

  1. Arad Y et al. (2005) Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol 46: 158–165

    Article  CAS  Google Scholar 

  2. Vliegenthart R et al. (2005) Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation 112: 572–577

    Article  Google Scholar 

  3. Taylor AJ et al. (2005) Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) Project. J Am Coll Cardiol 46: 807–814

    Article  CAS  Google Scholar 

  4. Mollet NR et al. (2005) High-resolution spiral computed tomography coronary angiography in patients referred for diagnostic conventional coronary angiography. Circulation 112: 2318–2323

    Article  Google Scholar 

  5. Haberl R et al. (2005) Multislice spiral computed tomographic angiography of coronary arteries in patients with suspected coronary artery disease: an effective filter before catheter angiography? Am Heart J 149: 1112–1119

    Article  Google Scholar 

  6. Kaiser C et al. (2005) Limited diagnostic yield of non-invasive coronary angiography by 16-slice multi-detector spiral computed tomography in routine patients referred for evaluation of coronary artery disease. Eur Heart J 26: 1987–1992

    Article  Google Scholar 

  7. Leber AW et al. (2006) Accuracy of 64-slice computed tomography to classify and quantify plaque volumes in the proximal coronary system: a comparative study using intravascular ultrasound. J Am Coll Cardiol 47: 672–677

    Article  Google Scholar 

  8. Kefer J et al. (2005) Head-to-head comparison of three-dimensional navigator-gated magnetic resonance imaging and 16-slice computed tomography to detect coronary artery stenosis in patients. J Am Coll Cardiol 46: 92–100

    Article  Google Scholar 

  9. Schuijf JD et al. (2006) Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography. Am Heart J 151: 404–411

    Article  Google Scholar 

  10. Fuster V and Kim RJ (2005) Frontiers in cardiovascular magnetic resonance. Circulation 112: 135–144

    Article  Google Scholar 

  11. Sakuma H et al. (2005) Assessment of coronary arteries with total study time of less than 30 minutes by using whole-heart coronary MR angiography. Radiology 237: 316–321

    Article  Google Scholar 

  12. Cai J et al. (2005) In vivo quantitative measurement of intact fibrous cap and lipid-rich necrotic core size in atherosclerotic carotid plaque: comparison of high-resolution, contrast-enhanced magnetic resonance imaging and histology. Circulation 112: 3437–3444

    Article  Google Scholar 

  13. Takaya N et al. (2005) Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. Circulation 111: 2768–2775

    Article  Google Scholar 

  14. Viles-Gonzalez JF et al. (2005) Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition—a magnetic resonance imaging study. Eur Heart J 26: 1557–1561

    Article  CAS  Google Scholar 

  15. Corti R et al. (2005) Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging. J Am Coll Cardiol 46: 106–112

    Article  CAS  Google Scholar 

  16. Taniguchi H et al. (2004) In vivo magnetic resonance evaluation of associations between aortic atherosclerosis and both risk factors and coronary artery disease in patients referred for coronary angiography. Am Heart J 148: 137–143

    Article  Google Scholar 

  17. Khera A et al. (2006) Relationship between C-reactive protein and subclinical atherosclerosis. The Dallas Heart Study. Circulation 113: 38–43

    Article  CAS  Google Scholar 

  18. Spuentrup E et al. (2005) Molecular magnetic resonance imaging of coronary thrombosis and pulmonary emboli with a novel fibrin-targeted contrast agent. Circulation 111: 1377–1382

    Article  CAS  Google Scholar 

  19. Sirol M et al. (2005) Chronic thrombus detection with in vivo magnetic resonance imaging and a fibrin-targeted contrast agent. Circulation 112: 1594–1600

    Article  Google Scholar 

  20. Leong-Poi H et al. (2005) Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular imaging of integrin expression. Circulation 111: 3248–3254

    Article  CAS  Google Scholar 

  21. Kraitchman DL et al. (2005) Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 112: 1451–1461

    Article  Google Scholar 

  22. Hofmann M et al. (2005) Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111: 2198–2202

    Article  Google Scholar 

  23. Bhatt DL et al. (2006) International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 295: 180–189

    Article  CAS  Google Scholar 

  24. Ridker PM et al. (2005) Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA 294: 326–333

    Article  CAS  Google Scholar 

  25. Whincup PH et al. (2005) Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors. Circulation 112: 1789–1797

    Article  CAS  Google Scholar 

  26. Yusuf S et al. (2005) Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 366: 1640–1649

    Article  Google Scholar 

  27. Arnlov J et al. (2005) Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation 112: 969–975

    Article  Google Scholar 

  28. Ruttmann E et al. (2005) γ-Glutamyltransferase as a risk factor for cardiovascular disease mortality. An epidemiological investigation in a cohort of 163 944 Austrian adults. Circulation 112: 2130–2137

    Article  CAS  Google Scholar 

  29. Suleiman M et al. (2005) Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction. Diabetes 54: 2802–2806

    Article  CAS  Google Scholar 

  30. Reilly MP et al. (2005) Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 111: 932–939

    Article  CAS  Google Scholar 

  31. Cushman M et al. (2005) C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the Cardiovascular Health Study. Circulation 112: 25–31

    Article  CAS  Google Scholar 

  32. Schillinger M et al. (2005) Inflammation and Carotid Artery—Risk for Atherosclerosis Study (ICARAS). Circulation 111: 2203–2209

    Article  Google Scholar 

  33. Tzoulaki I et al. (2005) C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation 112: 976–983

    Article  CAS  Google Scholar 

  34. Maier W et al. (2005) Inflammatory markers at the site of ruptured plaque in acute myocardial infarction: locally increased interleukin-6 and serum amyloid A but decreased C-reactive protein. Circulation 111: 1355–1361

    Article  CAS  Google Scholar 

  35. Inoue T et al. (2005) Local release of C-reactive protein from vulnerable plaque or coronary arterial wall injured by stenting. J Am Coll Cardiol 46: 239–245

    Article  CAS  Google Scholar 

  36. Blaschke F et al. (2004) C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells. Circulation 110: 579–587

    Article  CAS  Google Scholar 

  37. Timpson NJ et al. (2005) C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet 366: 1954–1959

    Article  CAS  Google Scholar 

  38. O'Donoghue M et al. (2006) Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) Trial. Circulation 113: 1745–1752

    Article  CAS  Google Scholar 

  39. Tsimikas S et al. (2005) Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 353: 46–57

    Article  CAS  Google Scholar 

  40. Smith A et al. (2005) Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly Study. Circulation 112: 3080–3087

    Article  Google Scholar 

  41. Fibrinogen Studies Collaboration (2005) Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 294: 1799–1809

  42. Rittersma SZ et al. (2005) Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: a pathological thrombectomy study in primary percutaneous coronary intervention. Circulation 111: 1160–1165

    Article  Google Scholar 

  43. Ndrepepa G et al. (2005) Prognostic value of N-terminal pro-brain natriuretic peptide in patients with chronic stable angina. Circulation 112: 2102–2107

    Article  CAS  Google Scholar 

  44. Kistorp C et al. (2005) N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA 293: 1609–1616

    Article  CAS  Google Scholar 

  45. Zethelius B et al. (2006) Troponin I as a predictor of coronary heart disease and mortality in 70-year-old men: a community-based cohort study. Circulation 113: 1071–1078

    Article  CAS  Google Scholar 

  46. Mattace-Raso FUS et al. (2006) Arterial stiffness and risk of coronary heart disease and stroke: The Rotterdam Study. Circulation 113: 657–663

    Article  Google Scholar 

  47. Hutter R et al. (2004) Vascular endothelial growth factor regulates reendothelialization and neointima formation in a mouse model of arterial injury. Circulation 110: 2430–2435

    Article  CAS  Google Scholar 

  48. Werner N et al. (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353: 999–1007

    Article  CAS  Google Scholar 

  49. Lee IM et al. (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 294: 56–65

    Article  CAS  Google Scholar 

  50. Cannon CP et al. (2005) Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 352: 1646–1654

    Article  CAS  Google Scholar 

  51. Nissen SE et al. (2006) Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 354: 1253–1263

    Article  CAS  Google Scholar 

  52. LaRosa JC et al. (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 352: 1425–1435

    Article  CAS  Google Scholar 

  53. Nissen SE et al. (2006) Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: The ASTEROID Trial. JAMA 295: 1556–1565

    Article  CAS  Google Scholar 

  54. Ridker PM et al. (2005) C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352: 20–28

    Article  CAS  Google Scholar 

  55. Wibaut-Berlaimont V et al. (2005) Atorvastatin affects leukocyte gene expression in dyslipidemia patients: in vivo regulation of hemostasis, inflammation and apoptosis. J Thromb Haemost 3: 677–685

    Article  CAS  Google Scholar 

  56. Arnaud C et al. (2005) Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins. Arterioscler Thromb Vasc Biol 25: 1231–1236

    Article  CAS  Google Scholar 

  57. Robinson JG et al. (2005) Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 46: 1855–1862

    Article  CAS  Google Scholar 

  58. Birjmohun RS et al. (2005) Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 45: 185–197

    Article  CAS  Google Scholar 

  59. Kuivenhoven JA et al. (2005) Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol 95: 1085–1088

    Article  CAS  Google Scholar 

  60. Giugliano RP and Braunwald E (2006) The year in non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol 48: 386–395

    Article  Google Scholar 

  61. Dixon SR et al. (2006) The year in interventional cardiology. J Am Coll Cardiol 47: 1689–1706

    Article  Google Scholar 

  62. Ridker PM et al. (2005) A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 352: 1293–1304

    Article  CAS  Google Scholar 

  63. Berger JS et al. (2006) Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 295: 306–313

    Article  CAS  Google Scholar 

  64. Bhatt DL et al. (2006) Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354: 1706–1717

    Article  CAS  Google Scholar 

  65. Despres J-P et al. (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353: 2121–2134

    Article  CAS  Google Scholar 

  66. Hakonarson H et al. (2005) Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 293: 2245–2256

    Article  CAS  Google Scholar 

  67. Tuomisto T et al. (2005) Genetics, genomics and proteomics in atherosclerosis research. Ann Med 37: 323–332

    Article  CAS  Google Scholar 

  68. Seo D et al. (2006) Gene expression analysis of cardiovascular diseases. novel insights into biology and clinical applications. J Am Coll Cardiol 48: 227–235

    Article  CAS  Google Scholar 

  69. Methe H et al. (2005) Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation 111: 2654–2661

    Article  CAS  Google Scholar 

  70. Schoneveld AH et al. (2005) Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res 66: 162–169

    Article  CAS  Google Scholar 

  71. Frantz S et al. (2005) Innate immunity and angiogenesis. Circ Res 96: 15–26

    Article  CAS  Google Scholar 

  72. Fuster V et al. (2005) Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol 46: 937–954

    Article  Google Scholar 

  73. Asleh R et al. (2005) Haptoglobin genotype- and diabetes-dependent differences in iron-mediated oxidative stress in vitro and in vivo . Circ Res 96: 435–441

    Article  CAS  Google Scholar 

  74. Leppanen P et al. (2005) Gene transfers of vascular endothelial growth factor-A, vascular endothelial growth factor-B, vascular endothelial growth factor-C, and vascular endothelial growth factor-D have no effects on atherosclerosis in hypercholesterolemic low-density lipoprotein-receptor/apolipoprotein B48-deficient mice. Circulation 112: 1347–1352

    Article  Google Scholar 

  75. Fenchel M et al. (2005) Atherosclerotic disease: whole-body cardiovascular imaging with MR system with 32 receiver channels and total-body surface coil technology—initial clinical results. Radiology 238: 280–291

    Article  Google Scholar 

  76. Achenbach S et al. (2006) Contrast-enhanced coronary artery visualization by dual-source computed tomography—initial experience. Eur J Radiol 57: 331–335

    Article  Google Scholar 

  77. Frias JC et al. (2004) Recombinant HDL-like nanoparticles: a specific contrast agent for MRI of atherosclerotic plaques. J Am Chem Soc 126: 16316–16317

    Article  CAS  Google Scholar 

  78. Heeschen C et al. (2005) Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. J Am Coll Cardiol 45: 229–237

    Article  CAS  Google Scholar 

  79. Naik SU et al. (2006) Pharmacological activation of liver X Receptors promotes reverse cholesterol transport in vivo . Circulation 113: 90–97

    Article  CAS  Google Scholar 

  80. Duffy D and Rader DJ (2006) Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport. Circulation 113: 1140–1150

    Article  Google Scholar 

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Correspondence to Valentin Fuster.

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Sanz, J., Moreno, P. & Fuster, V. Update on advances in atherothrombosis. Nat Rev Cardiol 4, 78–89 (2007). https://doi.org/10.1038/ncpcardio0774

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