LDL-Density-Theory: Clinical Trial Design for Aortic Valve Disease



The cellular mechanisms are evolving rapidly in the field of calcific aortic valve biology. The experimental studies will have future translational implications for the treatment of this disease process. This chapter provides the premise for the role of lipids to activate atherosclerosis within the heart to initiate the development of bone formation. Lessons from the experimental studies have evolved into a series of clinical parameters, which provide the foundation for an algorithm to treat aortic valve disease: the LDL-Density-Radius and the LDL-Density-Pressure Theories. The LDL Density Theories provides a premise for the translational role of the Lrp 5/6 receptor biology in the treatment of calcific aortic valve disease.


Aortic Valve Mitral Valve Aortic Stenosis Valvular Heart Disease Viscous Friction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was completed with the support of an American Heart Association Grant-in-Aid (0555714Z) and a grant from the National Institute of Health (5K08HL073927-04, 1R01HL085591-01A1). Nalini M. Rajamannan is an inventor on a patent for the use of statins in degeneration of aortic valve disease. This patent is owned by the Mayo Clinic and Dr. Rajamannan does not receive any royalties from this patent.


  1. Agmon Y, Khandheria BK, Meissner I, Sicks JR, O’Fallon WM, Wiebers DO, Whisnant JP, Seward JB, Tajik AJ. 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):827–34.PubMedCrossRefGoogle Scholar
  2. Aronow WS, Ahn C, Kronzon I. Association of mitral annular calcium with symptomatic peripheral arterial disease in older persons. Am J Cardiol. 2001;88(3):333–4.PubMedCrossRefGoogle Scholar
  3. Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PV, Robinson JA, Bhat B, Marzolf J, Moran RA, Bex F. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res. 2003;18(6):960–74.PubMedCrossRefGoogle Scholar
  4. Bernoulli D. Hydrodynamica sive de viribus et motibus fluidorum commentarrii. Strasbourg: Argentoratum; 1738. p. St.31.Google Scholar
  5. Boon A, Cheriex E, Lodder J, Kessels F. Cardiac valve calcification: characteristics of patients with calcifi­cation of the mitral annulus or aortic valve. Heart (British Cardiac Society). 1997;78(5):472–4.Google Scholar
  6. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513–21.PubMedCrossRefGoogle Scholar
  7. Brown SD, Twells RC, Hey PJ, Cox RD, Levy ER, Soderman AR, Metzker ML, Caskey CT, Todd JA, Hess JF. Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family. Biochem Biophys Res Commun. 1998;248(3):879–88.PubMedCrossRefGoogle Scholar
  8. Busseuil D, Shi Y, Mecteau M, Brand G, Kernaleguen AE, Thorin E, Latour JG, Rheaume E, Tardif JC. Regression of aortic valve stenosis by ApoA-I mimetic peptide infusions in rabbits. Br J Pharmacol. 2008;154(4):765–73.PubMedCrossRefGoogle Scholar
  9. Caira FC, Stock SR, Gleason TG, McGee EC, Huang J, Bonow RO, Spelsberg TC, McCarthy PM, Rahimtoola SH, Rajamannan NM. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006;47(8):1707–12.PubMedCrossRefGoogle Scholar
  10. Cowell SJ, Newby DE, Prescott RJ, Bloomfield P, Reid J, Northridge DB, Boon NA. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005;352(23):2389–97.PubMedCrossRefGoogle Scholar
  11. Dodge Jr JT, Brown BG, Bolson EL, Dodge HT. Lumen diameter of normal human coronary arteries. Influence of age, sex, anatomic variation, and left ventricular hypertrophy or dilation. Circulation. 1992;86(1):232–46.PubMedCrossRefGoogle Scholar
  12. Dong Y, Lathrop W, Weaver D, Qiu Q, Cini J, Bertolini D, Chen D. Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity. Biochem Biophys Res Commun. 1998;251(3):784–90.PubMedCrossRefGoogle Scholar
  13. Drolet MC, Arsenault M, Couet J. Experimental aortic valve stenosis in rabbits. J Am Coll Cardiol. 2003;41(7):1211–7.PubMedCrossRefGoogle Scholar
  14. Fujino T, Asaba H, Kang MJ, Ikeda Y, Sone H, Takada S, Kim DH, Ioka RX, Ono M, Tomoyori H, Okubo M, Murase T, Kamataki A, Yamamoto J, Magoori K, Takahashi S, Miyamoto Y, Oishi H, Nose M, Okazaki M, Usui S, Imaizumi K, Yanagisawa M, Sakai J, Yamamoto TT. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A. 2003;100(1):229–34.PubMedCrossRefGoogle Scholar
  15. Galante A, Pietroiusti A, Vellini M, Piccolo P, Possati G, De Bonis M, Grillo RL, Fontana C, Favalli C. C-reactive protein is increased in patients with degenerative aortic valvular stenosis. J Am Coll Cardiol. 2001;38(4):1078–82.PubMedCrossRefGoogle Scholar
  16. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML, Osteoporosis-Pseudoglioma Syndrome Collaborative G. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513–23.PubMedCrossRefGoogle Scholar
  17. Grande-Allen KJ, Calabro A, Gupta V, Wight TN, Hascall VC, Vesely I. Glycosaminoglycans and proteoglycans in normal mitral valve leaflets and chordae: association with regions of tensile and compressive loading. Glycobiology. 2004;14:621–33.PubMedCrossRefGoogle Scholar
  18. Grande-Allen KJ, Borowski AG, Troughton RW, Houghtaling PL, Dipaola NR, Moravec CS, Vesely I, Griffin BP. Apparently normal mitral valves in patients with heart failure demonstrate biochemical and structural derangements: an extracellular matrix and echocardiographic study [see comment]. J Am Coll Cardiol. 2005;45:54–61.PubMedCrossRefGoogle Scholar
  19. Gunduz H, Arinc H, Tamer A, Akdemir R, Ozhan H, Binak E, Uyan C. The relation between homocysteine and calcific aortic valve stenosis. Cardiology. 2005;103(4):207–11.PubMedCrossRefGoogle Scholar
  20. Hatle L, Brubakk A, Tromsdal A, Angelsen B. Noninvasive assessment of pressure drop in mitral stenosis by Doppler ultrasound. Br Heart J. 1978;40(2):131–40.PubMedCrossRefGoogle Scholar
  21. Hatle L, Angelsen BA, Tromsdal A. Non-invasive assessment of aortic stenosis by Doppler ultrasound. Br Heart J. 1980;43(3):284–92.PubMedCrossRefGoogle Scholar
  22. Hawse JR, Iwaniec UT, Bensamoun SF, Monroe DG, Peters KD, Ilharreborde B, Rajamannan NM, Oursler MJ, Turner RT, Spelsberg TC, Subramaniam M. TIEG-null mice display an osteopenic gender-specific phenotype. Bone. 2008;42(6):1025–31.PubMedCrossRefGoogle Scholar
  23. Hey PJ, Twells RC, Phillips MS, Yusuke N, Brown SD, Kawaguchi Y, Cox R, Guochun X, Dugan V, Hammond H, Metzker ML, Todd JA, Hess JF. Cloning of a novel member of the low-density lipoprotein receptor family. Gene. 1998;216(1):103–11.PubMedCrossRefGoogle Scholar
  24. Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML, Williams BO. Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res. 2004;19(12):2033–40.PubMedCrossRefGoogle Scholar
  25. Hsu SY, Hung KC, Chang SH, Wen MS, Hsieh IC. C-reactive protein in predicting coronary artery disease in subjects with aortic valve sclerosis before diagnostic coronary angiography. Am J Med Sci. 2006;331(5):264–9.PubMedCrossRefGoogle Scholar
  26. Jian B, Jones PL, Li Q, Mohler 3rd ER, Schoen FJ, Levy RJ. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. Am J Pathol. 2001;159(1):321–7.PubMedCrossRefGoogle Scholar
  27. Johnson ML, Summerfield DT. Parameters of LRP5 from a structural and molecular perspective. Crit Rev Eukaryot Gene Expr. 2005;15(3):229–42.PubMedCrossRefGoogle Scholar
  28. Kim DH, Inagaki Y, Suzuki T, Ioka RX, Yoshioka SZ, Magoori K, Kang MJ, Cho Y, Nakano AZ, Liu Q, Fujino T, Suzuki H, Sasano H, Yamamoto TT. A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. J Biochem. 1998;124(6):1072–6.PubMedCrossRefGoogle Scholar
  29. Kumar V, Abbas A, Fausto N, Richard N. Robbins basic pathology. 8th ed. Philadelphia: Saunders; 2007. p. 402.Google Scholar
  30. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70(1):11–9.PubMedCrossRefGoogle Scholar
  31. Makkena B, Salti H, Subramaniam M, Thennapan S, Bonow RH, Caira F, Bonow RO, Spelsberg TC, Rajamannan NM. Atorvastatin decreases cellular proliferation and bone matrix expression in the hypercholesterolemic mitral valve. J Am Coll Cardiol. 2005;45(4):631–3.PubMedCrossRefGoogle Scholar
  32. Mohler 3rd ER, Adam LP, McClelland P, Graham L, Hathaway DR. Detection of osteopontin in calcified human aortic valves. Arterioscler Thromb Vasc Biol. 1997;17(3):547–52.PubMedCrossRefGoogle Scholar
  33. Mohler 3rd ER, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation. 2001;103(11):1522–8.PubMedCrossRefGoogle Scholar
  34. Mohty D, Pibarot P, Despres JP, Cote C, Arsenault B, Cartier A, Cosnay P, Couture C, Mathieu P. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol. 2008;28(1):187–93.PubMedCrossRefGoogle Scholar
  35. Moura LM, Ramos SF, Zamorano JL, Barros IM, Azevedo LF, Rocha-Goncalves F, Rajamannan NM. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol. 2007;49(5):554–61.PubMedCrossRefGoogle Scholar
  36. Moura LM, Rocha-Goncalves F, Zamorano JL, Barros I, Bettencourt P, Rajamannan N. New cardiovascular biomarkers: clinical implications in patients with valvular heart disease. Expert Rev Cardiovasc Ther. 2008;6(7):945–54.PubMedCrossRefGoogle Scholar
  37. Newby DE, Cowell SJ, Boon NA. Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both? Heart (British Cardiac Society). 2006;92(6):729–34.CrossRefGoogle Scholar
  38. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071–80.PubMedCrossRefGoogle Scholar
  39. Novaro GM, Katz R, Aviles RJ, Gottdiener JS, Cushman M, Psaty BM, Otto CM, Griffin BP. Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the cardiovascular health study. J Am Coll Cardiol. 2007;50(20):1992–8.PubMedCrossRefGoogle Scholar
  40. O’Brien KD, Kuusisto J, Reichenbach DD, Ferguson M, Giachelli C, Alpers CE, Otto CM. Osteopontin is expressed in human aortic valvular lesions. Circulation. 1995;92(8):2163–8.PubMedCrossRefGoogle Scholar
  41. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arterioscler Thromb Vasc Biol. 1996;16(4):523–32.PubMedCrossRefGoogle Scholar
  42. Oh J, Seward J, Tajik A. The Echo Manual. Wolters Kluwer. 2006; 59–70, 189–201.Google Scholar
  43. Rajamannan NM, Sangiorgi G, Springett M, Arnold K, Mohacsi T, Spagnoli LG, Edwards WD, Tajik AJ, Schwartz RS. Experimental hypercholesterolemia induces apoptosis in the aortic valve. J Heart Valve Dis. 2001;10(3):371–4.PubMedGoogle Scholar
  44. Rajamannan NM, Subramaniam M, Springett M, Sebo TC, Niekrasz M, McConnell JP, Singh RJ, Stone NJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002;105(22):2260–5.CrossRefGoogle Scholar
  45. Rajamannan NM, Subramaniam M, Rickard D, Stock SR, Donovan J, Springett M, Orszulak T, Fullerton DA, Tajik AJ, Bonow RO, Spelsberg T. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003a;107(17):2181–4.PubMedCrossRefGoogle Scholar
  46. Rajamannan NM, Edwards WD, Spelsberg TC. Hypercholesterolemic aortic-valve disease. N Engl J Med. 2003b;349(7):717–8.PubMedCrossRefGoogle Scholar
  47. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation. 2005a;112(9 Suppl):I229–34.PubMedGoogle Scholar
  48. Rajamannan NM, Subramaniam M, Stock SR, Stone NJ, Springett M, Ignatiev KI, McConnell JP, Singh RJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart (British Cardiac Society). 2005b;91(6):806–10.CrossRefGoogle Scholar
  49. Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in severe asymptomatic aortic stenosis. NEJM. 2000;343:611–7.PubMedCrossRefGoogle Scholar
  50. Rosenhek R, Klaar U, Schemper M, Scholten C, Heger M, Gabriel H, Binder T, Maurer G, Baumgartner H. Mild and moderate aortic stenosis. Natural history and risk stratification by echocardiography. Eur Heart J. 2004;25(3):199–205.PubMedCrossRefGoogle Scholar
  51. Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E, Gohlke-Barwolf C, Holme I, Kesaniemi YA, Malbecq W, Nienaber CA, Ray S, Skjaerpe T, Wachtell K, Willenheimer R. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.PubMedCrossRefGoogle Scholar
  52. Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes ­cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005;115(5):1210–20.PubMedGoogle Scholar
  53. Smith MD, Kwan OL, DeMaria AN. Value and limitations of continuous-wave Doppler echocardiography in estimating severity of valvular stenosis. JAMA. 1986;255(22):3145–51.PubMedCrossRefGoogle Scholar
  54. Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone diseases. Gene. 2004;341:19–39.PubMedCrossRefGoogle Scholar
  55. Whittaker P, Boughner DR, Perkins DG, Canham PB. Quantitative structural analysis of collagen in chordae tendineae and its relation to floppy mitral valves and proteoglycan infiltration. Br Heart J. 1987;57(3):264–9.PubMedCrossRefGoogle Scholar
  56. Williams BO, Insogna KL. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Miner Res. 2009;24(2):171–8.PubMedCrossRefGoogle Scholar
  57. Wooley CF, Baker PB, Kolibash AJ, Kilman JW, Sparks EA, Boudoulas H. The floppy, myxomatous mitral valve, mitral valve prolapse, and mitral regurgitation. Prog Cardiovasc Dis. 1991;33(6):397–433.PubMedCrossRefGoogle Scholar
  58. Yilmaz MB, Guray U, Guray Y, Cihan G, Caldir V, Cay S, Kisacik HL, Korkmaz S. Lipid profile of patients with aortic stenosis might be predictive of rate of progression. Am Heart J. 2004;147(5):915–8.PubMedCrossRefGoogle Scholar

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© Springer-Verlag London 2013

Authors and Affiliations

  1. 1.Department of Molecular Biology and BiochemistryMayo ClinicRochesterUSA
  2. 2.Department of Aerospace EngineeringUniversity of Notre DameSouth BendUSA

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