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01-02-2012 | Cardiac Molecular Imaging (F Jaffer, Section Editor)

FDG-PET-CT as a Biomarker for Aortic Valve Inflammation

Authors: Gagandeep S. Gurm, Ahmed Tawakol

Published in: Current Cardiovascular Imaging Reports | Issue 1/2012

Abstract

Calcific aortic stenosis (AS) is the most common heart valve disorder in the Western world. Invasive valve replacement (via surgery or percutaneously) is the sole therapy available at present in patients with symptomatic AS. In the past decade several animal and clinical studies have provided new insights into the pathogenesis of AS, suggesting it to be a consequence of an active inflammatory process similar to atherosclerosis. This knowledge has stimulated new hypotheses regarding a role for anti-inflammatory therapies in management of AS. Currently, anatomical imaging with echocardiography is the recommended modality for assessment and surveillance of AS. Biological imaging with newer molecular imaging techniques may be helpful in assessing valvular inflammation and may subsequently help in assessment of valvular effects of anti-inflammatory therapies. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an emerging tool for quantifying inflammation within an atherosclerotic plaque. In this review, we discuss the role of anti-inflammatory therapy with statin drugs in management of AS with a focus on FDG-PET as a possible biomarker for aortic inflammation.

Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation. 2006;114:e84–e231.PubMedCrossRef

Rajamannan NM, Bonow RO, Rahimtoola SH. Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med. 2007;4:254–62.PubMedCrossRef

Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005;111:920–5.PubMedCrossRef

Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiography study of a random population sample. J Am Coll Cardiol. 1993;21:1220–5.PubMedCrossRef

Otto CM, Lind BK, Kitzman DW, et al. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med. 1999;341:142–7.PubMedCrossRef

• Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997;29(3):630–4. Largest prospective study providing evidence that atherosclerosis and aortic valve disease have similar clinical risk factors.PubMedCrossRef

Taylor Jr HA, Clark BL, Garrison RJ, et al. Relation of aortic valve sclerosis to risk of coronary heart disease in African-Americans. Am J Cardiol. 2005;95(3):401.PubMedCrossRef

Agmon Y, Khandheria BK, Meissner I, et al. Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study. J Am Coll Cardiol. 2001;38(3):827.PubMedCrossRef

Pohle K, Mäffert R, Ropers D, et al. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation. 2001;104(16):1927.PubMedCrossRef

10.

Katz R, Wong ND, Kronmal R, et al. Features of the metabolic syndrome and diabetes mellitus as predictors of aortic valve calcification in the Multi-Ethnic Study of Atherosclerosis. Circulation. 2006;113(17):2113.PubMedCrossRef

11.

Otto CM, Kuusisto J, Reichenbach DD, et al. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies. Circulation. 1994;90:844–53.PubMed

12.

O’Brien KD, Reichenbach DD, Marcovina SM, et al. Apolipoprotein B, (a), and E accumulate in the morphologically early lesion of degenerative’ valvular aortic stenosis. Arterioscler Thromb Vasc Biol. 1996;16:523–32.PubMedCrossRef

13.

Olsson M, Thyberg J, Nilsson J. Presence of oxidised low density lipoprotein in nonrheumatic stenotic aortic valves. Arterioscler Thromb Vasc Biol. 1999;19:1218–22.PubMedCrossRef

14.

Mohler ER, Gannon F, Reynolds C, et al. Bone formation and inflammation in cardiac valves. Circulation. 2001;103:1522–8.PubMed

15.

Rajamannan NM, Subramaniam M, Rickard D, et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003;107:2181–4.PubMedCrossRef

16.

Peltier M, Trojette F, Sarano ME, et al. Relation between cardiovascular risk factors and nonrheumatic severe calcific aortic stenosis among patients with a three-cuspid aortic valve. Am J Cardiol. 2003;91:97–9.PubMedCrossRef

17.

Otto CM. Aortic stenosis. Clinical evaluation and optimal timing of surgery. Cardiol Clin. 1998;16:353–73. vii.PubMedCrossRef

18.

Otto CM, Burwash IG, Legget ME, et al. Prospective study of asymptomatic valvular aortic stenosis: clinical, echocardiographic, and exercise predictors of outcome. Circulation. 1997;95:2262–70.PubMed

19.

Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–9.

20.

The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–57.CrossRef

21.

Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–9.PubMedCrossRef

22.

Inoue I, Goto S, Awata T, et al. Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells. Life Sci. 2000;67:863–76.PubMedCrossRef

23.

Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet. 1999;353:983–4.PubMedCrossRef

24.

Laufs U, Marra D, Node K, et al. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem. 1999;274:21926–31.PubMedCrossRef

25.

Romano M, Diomede L, Sironi M, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest. 2000;80:1095–100.PubMedCrossRef

26.

Luan Z, Chase A, Newby AC. Statins inhibit secretion of metalloproteinases-1, -2, -3, and −9 from vascular smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol. 2003;23:769–75.PubMedCrossRef

27.

Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol. 2006;48:1825–31.PubMedCrossRef

28.

Callister TQ, Raggi P, Cooil B, et al. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med. 1998;339(27):1972–8.PubMedCrossRef

29.

Albert MA, Danielson E, Rifai N, et al., for the PRINCE investigators. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. J Am Med Assoc. 2001;286:64–70.CrossRef

30.

Ridker PM, Cannon CP, Morrow D, et al., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.PubMedCrossRef

31.

Rajamannan NM, Subramaniam M, Springett M, et al. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002;105:2660–5.PubMedCrossRef

32.

Rajamannan NM, Subramaniam M, Stock SR, et al. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart. 2005;91:806–10.PubMedCrossRef

33.

Aronow WS, Ahn C, Kronzon I, et al. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol. 2001;88:693–5.PubMedCrossRef

34.

Novaro GM, Tiong IY, Pearce GL, et al. Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation. 2001;104:2205–9.PubMedCrossRef

35.

Shavelle DM, Takasu J, Budoff MJ, et al. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet. 2002;359:1125–6.PubMedCrossRef

36.

Rosenhek R, Rader F, Loho N, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation. 2004;110:1291–5.PubMedCrossRef

37.

Bellamy MF, Pellikka PA, Klarich KW, et al. Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. J Am Coll Cardiol. 2002;40:1723–30.PubMedCrossRef

38.

Pohle K, Maffert R, Ropers D, et al. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation. 2001;104:1927–32.PubMedCrossRef

39.

Antonini-Canterin F, Popescu BA, Huang G, et al. Progression of aortic valve sclerosis and aortic valve stenosis: what is the role of statin treatment? Ital Heart J. 2005;6:119–24.PubMed

40.

Cowell SJ, Newby DE, Prescott RJ, et al., for the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005;352:2389–97.PubMedCrossRef

41.

Moura LM, Ramos SF, Somorano JL, et al. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol. 2007;49:554–61.PubMedCrossRef

42.

Rossebo AB, Pedersen TF, Boman, et al., for the SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.PubMedCrossRef

43.

•• Chan KL, Teo K, Dumesnil JG, et al., ASTRONOMER Investigators. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010;121(2):306–14. Trial studying the possible role of lipid-lowering therapy in regression of calcific aortic valve disease.PubMedCrossRef

44.

•• Rudd JHF, Narula J, Strauss HW, et al. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography. Ready for prime time? J Am Coll Cardiol. 2010;55:2527–35. This review highlights the important evidence establishing the role of FDG-PET in atherosclerotic plaque imaging.PubMedCrossRef

45.

Garedew A, Henderson SO, Moncada S. Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. Cell Death Differ. 2010;17:1540–50.PubMedCrossRef

46.

Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645–57.PubMedCrossRef

47.

Kubota R, Kubota K, Yamada S, et al. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med. 1994;35:104–12.PubMed

48.

Rodriguez-Prados JC, Traves PG, Cuenca J, et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol. 2010;185:605–14.PubMedCrossRef

49.

Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation. 2002;105:2708–11.PubMedCrossRef

50.

Tawakol A, Migrino RQ, Bashian GG, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol. 2006;48:1818–24.PubMedCrossRef

51.

Tawakol A, Migrino RQ, Hoffmann U, et al. Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography. J Nucl Cardiol. 2005;12:294–301.PubMedCrossRef

52.

Graebe M, Pedersen SF, Borgwardt L, et al. Molecular pathology in vulnerable carotid plaques: correlation with [18]-fluorodeoxyglucose positron emission tomography (FDG-PET). Eur J Vasc Endovasc Surg. 2009;37:714–21.PubMedCrossRef

53.

Pedersen SF, Graebe M, Fisker Hag AM, et al. Gene expression and 18FDG uptake in atherosclerotic carotid plaques. Nucl Med Commun. 2010;31:423–9.PubMed

54.

Bural GG, Torigian DA, Chamroonrat W, et al. FDG-PET is an effective imaging modality to detect and quantify age-related atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging. 2008;35:562–9.PubMedCrossRef

55.

Joly L, Djaballah W, Koehl G, et al. Aortic inflammation, as assessed by hybrid FDG-PET/CT imaging, is associated with enhanced aortic stiffness in addition to concurrent calcification. Eur J Nucl Med Mol Imaging. 2009;36:979–85.PubMedCrossRef

56.

Rudd JHF, Myers KS, Bansilal S, et al. 18Fluorodeoxyglucose Positron Emission Tomography Imaging of Atherosclerotic Plaque Inflammation Is Highly Reproducible Implications for Atherosclerosis Therapy Trials Journal of the American College of Cardiology. 2007;49.

57.

Kim TN, Kim S, Yang SJ, et al. Vascular inflammation in patients with impaired glucose tolerance and type 2 diabetes: analysis with 18F-fluorodeoxyglucose positron emission tomography. Circ Cardiovasc Imaging. 2010;3:142–8.PubMedCrossRef

58.

•• Rogers IS, Nasir K, Figueroa AL, et al. Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging. 2010;3:388–97. This study establishes the possible role of FDG-PET plaque imaging in differentiating unstable atherosclerotic plaques from stable atherosclerotic plaques.PubMedCrossRef

59.

• Rominger A, Saam T, Wolpers S, et al. 18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease. J Nucl Med. 2009;50:1611–20. This study establishes the possible role of FDG-PET plaque imaging in differentiating unstable atherosclerotic plaques from stable atherosclerotic plaques.PubMedCrossRef

60.

Paulmier B, Duet M, Khayat R, et al. Arterial wall uptake of fluorodeoxyglucose on PET imaging in stable cancer disease patients indicates higher risk for cardiovascular events. J Nucl Cardiol. 2008;15:209–17.PubMedCrossRef

61.

Tahara N, Kai H, Ishibashi M, et al. Simvastatin Attenuates Plaque Inflammation: Evaluation by Fluorodeoxyglucose Positron Emission Tomography. J Am Coll Cardiol. 2006;j.jacc.2006.03.069.

62.

Ishii H, Nishio M, Takahashi H, et al. Comparison of Atorvastatin 5 and 20 mg/d for Reducing F-18 Fluorodeoxyglucose Uptake in Atherosclerotic Plaques on Positron Emission Tomography/Computed Tomography: A Randomized, Investigator-Blinded, Open-Label, 6-Month Study in Japanese Adults Scheduled for Percutaneous Coronary Intervention. Clin Ther. 2010;32:2337–47.PubMedCrossRef

63.

•• Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. The Lancet 2011. This study uses molecular imaging by FDG-PET to study therapeutic effects of dalcetrapib on atherosclerotic burden.

64.

Olsson M, Dalsgaard CJ, Haegerstrand A, et al. Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol. 1994;23:1162–70.PubMedCrossRef

65.

Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111(24):3316–26.PubMedCrossRef

66.

Novaro GM, Katz R, Aviles RJ, et al. Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study. J Am Coll Cardiol. 2007;50:1992–8.PubMedCrossRef

67.

Stone PH. C-reactive protein to identify early risk for development of calcific aortic stenosis: right marker? Wrong time? J Am Coll Cardiol. 2007;50:1999–2001.PubMedCrossRef

68.

•• Marincheva-Savcheva G, Subramanian S, Qadir S, et al. Imaging of the aortic valve using fluorodeoxyglucose positron emission tomography increased valvular fluorodeoxyglucose uptake in aortic stenosis. J Am Coll Cardiol. 2011;57:2507–15. This is the first study to show feasibility of using FDG-PET imaging to quantify inflammation within the diseased aortic valve.PubMedCrossRef

69.

Aikawa E, Nahrendorf M, Figueiredo JL, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation. 2007;116:2841–50.PubMedCrossRef

70.

Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–26.PubMedCrossRef

71.

Gronholdt ML, Nordestgaard BG, Bentzon J, et al. Macrophages are associated with lipid-rich carotid artery plaques, echolucency on B-mode imaging, and elevated plasma lipid levels. J Vasc Surg. 2002;35:137–45.PubMed

72.

Wahlgren CM, Zheng W, Shaalan W, et al. Human carotid plaque calcification and vulnerability. Relationship between degree of plaque calcification, fibrous cap inflammatory gene expression and symptomatology. Cerebrovasc Dis. 2009;27:193–200.PubMedCrossRef

73.

Rudd JH, Myers KS, Bansilal S, et al. Relationships among regional arterial inflammation, calcification, risk factors, and biomarkers: a prospective fluorodeoxyglucose positron-emission tomography/computed tomography imaging study. Circ Cardiovasc Imaging. 2009;2:107–15.PubMedCrossRef

74.

Aikawa E, Nahrendorf M, Sosnovik D, et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007;115:377–86.PubMedCrossRef

75.

Sui SJ, Ren MY, Xu FY, et al. A high association of aortic valve sclerosis detected by transthoracic echocardiography with coronary arteriosclerosis. Cardiology. 2007;108:322–30.PubMedCrossRef

76.

Mazzone A, Epistolato MC, Gianetti J, et al. Biologic features (Inflammation and Neoangiogenesis) and atherosclerotic risk factors in carotid plaques and calcified aortic valve stenosis: two different sites of the same disease? Am J Clin Pathol. 2006;126:494–502.PubMedCrossRef

Title: FDG-PET-CT as a Biomarker for Aortic Valve Inflammation
Authors: Gagandeep S. Gurm
Ahmed Tawakol
Publication date: 01-02-2012
Publisher: Current Science Inc.
Published in: Current Cardiovascular Imaging Reports / Issue 1/2012
Print ISSN: 1941-9066
Electronic ISSN: 1941-9074
DOI: https://doi.org/10.1007/s12410-011-9117-1

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