Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Potential drug targets for calcific aortic valve disease

Nature Reviews Cardiology volume 11, pages 218–231 (2014)Cite this article

Subjects

Key Points

  • Calcific aortic valve disease (CAVD) seems to be distinct from vascular calcification in terms of both disease mechanisms and progression, although some risk factors are shared

  • Valve-specific drug targets are likely to be required to prevent or treat CAVD, given that drug strategies for vascular disease have not proven successful when applied to CAVD

  • Ubiquitous targeting of the cytokines thought to lead to valve disease is not likely to be feasible or beneficial, because they are required for wound healing elsewhere in the body

  • Targeting specific combinations of G-protein-coupled receptors might simultaneously prevent myofibroblast activation and collagen accumulation, which are thought to be two of the main initiators of, and contributors to, CAVD

  • Functional blocking of cadherin-11 might be an effective target to prevent mechanotransduction between valve cells that is thought to exacerbate cytokine signalling and synergistically lead to calcification

  • Lipid lowering might be an effective strategy for CAVD treatment; however, a targeted approach centred on lowering the lipoprotein(a) level and increasing the HDL-cholesterol level might be required

Abstract

Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. Therefore, we discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure–function relationship in aortic valve biomechanics.
Figure 2: Biomechanical consequences of cardiovascular calcification.
Figure 3: Cardiovascular inflammation and calcification.
Figure 4: The evolution of in vitro calcific nodules.

Similar content being viewed by others

References

  1. Go, A. S. et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127, e6–e245 (2013).

    PubMed  Google Scholar 

  2. Nkomo, V. T. et al. Burden of valvular heart diseases: a population-based study. Lancet 368, 1005–1011 (2006).

    Article  PubMed  Google Scholar 

  3. Rajamannan, N. M. et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease—2011 update. Circulation 124, 1783–1791 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bach, D. S. Prevalence and characteristics of unoperated patients with severe aortic stenosis. J. Heart Valve Dis. 20, 284–291 (2011).

    PubMed  Google Scholar 

  5. Lindman, B. R., Bonow, R. O. & Otto, C. M. Current management of calcific aortic stenosis. Circ. Res. 113, 223–237 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Daneault, B. et al. Stroke associated with surgical and transcatheter treatment of aortic stenosis: a comprehensive review. J. Am. Coll. Cardiol. 58, 2143–2150 (2011).

    Article  PubMed  Google Scholar 

  7. Sacks, M. S. & Yoganathan, A. P. Heart valve function: a biomechanical perspective. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 1369–1391 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sacks, M. S., Smith, D. B. & Hiester, E. D. The aortic valve microstructure: effects of transvalvular pressure. J. Biomed. Mat. Res. 41, 131–141 (1998).

    Article  CAS  Google Scholar 

  9. Stella, J. A., Liao, J. & Sacks, M. S. Time-dependent biaxial mechanical behavior of the aortic heart valve leaflet. J. Biomech. 40, 3169–3177 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Schoen, F. J. Aortic valve structure-function correlations: role of elastic fibers no longer a stretch of the imagination. J. Heart Valve Dis. 6, 1–6 (1997).

    CAS  PubMed  Google Scholar 

  11. Stephens, E. H., Chu, C. K. & Grande-Allen, K. J. Valve proteoglycan content and glycosaminoglycan fine structure are unique to microstructure, mechanical load and age: relevance to an age-specific tissue-engineered heart valve. Acta Biomater. 4, 1148–1160 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Otto, C. M., Kuusisto, J., Reichenbach, D. D., Gown, A. M. & O'Brien, K. D. Characterization of the early lesion of 'degenerative' valvular aortic stenosis: histological and immunohistochemical studies. Circulation 90, 844–853 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Butcher, J. T. et al. Transcriptional profiles of valvular and vascular endothelial cells reveal phenotypic differences: influence of shear stress. Arterioscler. Thromb. Vasc. Biol. 26, 69–77 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Cucina, A. et al. Shear stress induces changes in the morphology and cytoskeleton organisation of arterial endothelial cells. Eur. J. Vasc. Endovasc. Surg. 9, 86–92 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Stamatas, G. N. & McIntire, L. V. Rapid flow-induced responses in endothelial cells. Biotechnol. Prog. 17, 383–402 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Butcher, J. T. & Nerem, R. M. Valvular endothelial cells and the mechanoregulation of valvular pathology. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 1445–1457 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sucosky, P., Balachandran, K., Elhammali, A., Jo, H. & Yoganathan, A. P. Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-β1-dependent pathway. Arterioscler. Thromb. Vasc. Biol. 29, 254–260 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Balachandran, K. et al. Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve. Proc. Natl Acad. Sci. USA 108, 19943–19948 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bischoff, J. & Aikawa, E. Progenitor cells confer plasticity to cardiac valve endothelium. J. Cardiovasc. Transl. Res. 4, 710–719 (2011).

    Article  PubMed  Google Scholar 

  20. Holliday, C. J., Ankeny, R. F., Jo, H. & Nerem, R. M. Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 301, H856–H867 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Simmons, C. A., Grant, G. R., Manduchi, E. & Davies, P. F. Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ. Res. 96, 792–799 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gould, S. T., Srigunapalan, S., Simmons, C. A. & Anseth, K. S. Hemodynamic and cellular response feedback in calcific aortic valve disease. Circ. Res. 113, 186–197 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Ankeny, R. F. et al. Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves—association with low BMP antagonists and SMAD6. PLoS ONE 6, e20969 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hergenreider, E. et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat. Cell Biol. 14, 249–256 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Butcher, J. T. & Nerem, R. M. Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Eng. 12, 905–915 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Tseng, H. et al. A three-dimensional co-culture model of the aortic valve using magnetic levitation. Acta Biomater. 10, 173–182 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Bosse, K. et al. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. J. Mol. Cell. Cardiol. 60, 27–35 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rabkin-Aikawa, E., Farber, M., Aikawa, M. & Schoen, F. J. Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. J. Heart Valve Dis. 13, 841–847 (2004).

    PubMed  Google Scholar 

  29. Filip, D. A., Radu, A. & Simionescu, M. Interstitial cells of the heart valves possess characteristics similar to smooth muscle cells. Circ. Res. 59, 310–320 (1986).

    Article  CAS  PubMed  Google Scholar 

  30. Chester, A. H. & Taylor, P. M. Molecular and functional characteristics of heart-valve interstitial cells. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 1437–1443 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807–1816 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mohler, E. R. 3rd et al. Bone formation and inflammation in cardiac valves. Circulation 103, 1522–1528 (2001).

    Article  PubMed  Google Scholar 

  33. Chen, J. H., Yip, C. Y., Sone, E. D. & Simmons, C. A. Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. Am. J. Pathol. 174, 1109–1119 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. New, S. E. & Aikawa, E. Cardiovascular calcification: an inflammatory disease. Circ. J. 75, 1305–1313 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Demer, L. L. & Tintut, Y. Vascular calcification: pathobiology of a multifaceted disease. Circulation 117, 2938–2948 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Freeman, R. V. & Otto, C. M. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 111, 3316–3326 (2005).

    Article  PubMed  Google Scholar 

  37. Ortlepp, J. R., Schmitz, F., Bozoglu, T., Hanrath, P. & Hoffmann, R. Cardiovascular risk factors in patients with aortic stenosis predict prevalence of coronary artery disease but not of aortic stenosis: an angiographic pair matched case–control study. Heart 89, 1019–1022 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Weiss, R. M., Miller, J. D. & Heistad, D. D. Fibrocalcific aortic valve disease: opportunity to understand disease mechanisms using mouse models. Circ. Res. 113, 209–222 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Miller, J. D., Weiss, R. M. & Heistad, D. D. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ. Res. 108, 1392–1412 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Adiguzel, E., Ahmad, P. J., Franco, C. & Bendeck, M. P. Collagens in the progression and complications of atherosclerosis. Vasc. Med. 14, 73–89 (2009).

    Article  PubMed  Google Scholar 

  41. Libby, P. The interface of atherosclerosis and thrombosis: basic mechanisms. Vasc. Med. 3, 225–229 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Newby, A. C. & Zaltsman, A. B. Fibrous cap formation or destruction—the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc. Res. 41, 345–360 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Libby, P. Collagenases and cracks in the plaque. J. Clin. Invest. 123, 3201–3203 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Libby, P. & Sasiela, W. Plaque stabilization: can we turn theory into evidence? Am. J. Cardiol. 98, 26P–33P (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Lin, T. C. et al. Mechanical response of a calcified plaque model to fluid shear force. Ann. Biomed. Eng. 34, 1535–1541 (2006).

    Article  PubMed  Google Scholar 

  46. Saremi, A., Bahn, G. & Reaven, P. D. Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 35, 2390–2392 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Houslay, E. S. et al. Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial. Heart 92, 1207–1212 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hjortnaes, J. et al. Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur. Heart J. 31, 1975–1984 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dweck, M. R. et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation 125, 76–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Dweck, M. R. et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J. Am. Coll. Cardiol. 59, 1539–1548 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Giachelli, C. M. Vascular calcification mechanisms. J. Am. Soc. Nephrol. 15, 2959–2964 (2004).

    Article  PubMed  Google Scholar 

  52. Goodman, W. G. et al. Vascular calcification in chronic kidney disease. Am. J. Kidney Dis. 43, 572–579 (2004).

    Article  PubMed  Google Scholar 

  53. Aikawa, E. et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 116, 2841–2850 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Aikawa, E. et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation 115, 377–386 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Carter, S. et al. Sirt1 inhibits resistin expression in aortic stenosis. PLoS ONE 7, e35110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mohty, D. et al. Age-related differences in the pathogenesis of calcific aortic stenosis: the potential role of resistin. Int. J. Cardiol. 142, 126–132 (2010).

    Article  PubMed  Google Scholar 

  57. New, S. E. et al. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ. Res. 113, 72–77 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rajamannan, N. M. et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation 107, 2181–2184 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Wallin, R., Wajih, N., Greenwood, G. T. & Sane, D. C. Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy. Med. Res. Rev. 21, 274–301 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Neven, E., De Schutter, T. M., De Broe, M. E. & D'Haese, P. C. Cell biological and physicochemical aspects of arterial calcification. Kidney Int. 79, 1166–1177 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Li, X., Yang, H. Y. & Giachelli, C. M. BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells. Atherosclerosis 199, 271–277 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dalfino, G. et al. Bone morphogenetic protein-2 may represent the molecular link between oxidative stress and vascular stiffness in chronic kidney disease. Atherosclerosis 211, 418–423 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Balderman, J. A. et al. Bone morphogenetic protein-2 decreases microRNA-30b and microRNA-30c to promote vascular smooth muscle cell calcification. J. Am. Heart Assoc. 1, e003905 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bertazzo, S. et al. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat. Mater. 12, 576–583 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kapustin, A. N. et al. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ. Res. 109, e1–e12 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Ferdous, Z., Jo, H. & Nerem, R. M. Differences in valvular and vascular cell responses to strain in osteogenic media. Biomaterials 32, 2885–2893 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Yip, C. Y., Chen, J. H., Zhao, R. & Simmons, C. A. Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arterioscler. Thromb. Vasc. Biol. 29, 936–942 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. O'Brien, K. D. et al. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis. Arterioscler. Thromb. Vasc. Biol. 16, 523–532 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Mohty, D. et al. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler. Thromb. Vasc. Biol. 28, 187–193 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Mahmut, A. et al. Lipoprotein lipase in aortic valve stenosis is associated with lipid retention and remodelling. Eur. J. Clin. Invest. 43, 570–578 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Nadlonek, N. A., Lee, J. H., Weyant, M. J., Meng, X. & Fullerton, D. A. ox-LDL induces PiT-1 expression in human aortic valve interstitial cells. J. Surg. Res. 184, 6–9 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Pohle, K. et al. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation 104, 1927–1932 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Aronow, W. S., Ahn, C., Kronzon, I. & Goldman, M. E. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am. J. Cardiol. 88, 693–695 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Moura, L. M. et al. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J. Am. Coll. Cardiol. 49, 554–561 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Novaro, G. M. et al. Effect of hydroxymethylglutaryl coenzyme A reductase inhibitors on the progression of calcific aortic stenosis. Circulation 104, 2205–2209 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Teo, K. K., Corsi, D. J., Tam, J. W., Dumesnil, J. G. & Chan, K. L. Lipid lowering on progression of mild to moderate aortic stenosis: meta-analysis of the randomized placebo-controlled clinical trials on 2344 patients. Can. J. Cardiol. 27, 800–808 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Gould, A. L., Rossouw, J. E., Santanello, N. C., Heyse, J. F. & Furberg, C. D. Cholesterol reduction yields clinical benefit: impact of statin trials. Circulation 97, 946–952 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Ray, K. K. et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch. Intern. Med. 170, 1024–1031 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Libby, P. & Aikawa, M. Mechanisms of plaque stabilization with statins. Am. J. Cardiol. 91, 4B–8B (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Libby, P. & Aikawa, M. Effects of statins in reducing thrombotic risk and modulating plaque vulnerability. Clin. Cardiol. 26 (Suppl. 1), I11–I14 (2003).

    Article  PubMed  Google Scholar 

  81. Benton, J. A., Kern, H. B., Leinwand, L. A., Mariner, P. D. & Anseth, K. S. Statins block calcific nodule formation of valvular interstitial cells by inhibiting alpha-smooth muscle actin expression. Arterioscler. Thromb. Vasc. Biol. 29, 1950–1957 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Bellamy, M. F., Pellikka, P. A., Klarich, K. W., Tajik, A. J. & Enriquez-Sarano, M. Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. J. Am. Coll. Cardiol. 40, 1723–1730 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Cowell, S. J. et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N. Engl. J. Med. 352, 2389–2397 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Rossebo, A. B. et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 359, 1343–1356 (2008).

    Article  PubMed  Google Scholar 

  85. Gerdts, E. et al. Impact of baseline severity of aortic valve stenosis on effect of intensive lipid lowering therapy (from the SEAS study). Am. J. Cardiol. 106, 1634–1639 (2010).

    Article  PubMed  Google Scholar 

  86. Chan, K. L., Teo, K., Dumesnil, J. G., Ni, A. & Tam, J. 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 121, 306–314 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Jassal, D. S. et al. Evaluating the effectiveness of rosuvastatin in preventing the progression of diastolic dysfunction in aortic stenosis: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study. Cardiovasc. Ultrasound 9, 5 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Stone, N. J. 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. http://dx.doi.org/10.1016/j.jacc.2013.11.002.

  89. Monzack, E. L. & Masters, K. S. A time course investigation of the statin paradox among valvular interstitial cell phenotypes. Am. J. Physiol. Heart Circ. Physiol. 303, H903–H909 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Capoulade, R. et al. Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy. J. Am. Coll. Cardiol. 60, 216–223 (2012).

    Article  PubMed  Google Scholar 

  91. Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jacobson, T. A. Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin. Proc. 88, 1294–1311 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Chu, Y. et al. Pioglitazone attenuates valvular calcification induced by hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 33, 523–532 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yontar, O. C. & Yilmaz, M. B. Importance of serum high-density lipoprotein levels to aortic valvular disease. Br. J. Pharmacol. 155, 1163 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Speidl, W. S. et al. Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model. Eur. Heart J. 31, 2049–2057 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Trapeaux, J. et al. Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice. Br. J. Pharmacol. 169, 1587–1599 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lommi, J. I. et al. High-density lipoproteins (HDL) are present in stenotic aortic valves and may interfere with the mechanisms of valvular calcification. Atherosclerosis 219, 538–544 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Towler, D. A. Molecular and cellular aspects of calcific aortic valve disease. Circ. Res. 113, 198–208 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Grinnell, F. & Ho, C. H. Transforming growth factor β stimulates fibroblast-collagen matrix contraction by different mechanisms in mechanically loaded and unloaded matrices. Exp. Cell Res. 273, 248–255 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Merryman, W. D. et al. Synergistic effects of cyclic tension and transforming growth factor-β1 on the aortic valve myofibroblast. Cardiovasc. Pathol. 16, 268–276 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Walker, G. A., Masters, K. S., Shah, D. N., Anseth, K. S. & Leinwand, L. A. Valvular myofibroblast activation by transforming growth factor-β: implications for pathological extracellular matrix remodeling in heart valve disease. Circ. Res. 95, 253–260 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Ghosh, J. et al. The role of transforming growth factor β1 in the vascular system. Cardiovasc. Pathol. 14, 28–36 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Jian, B., Narula, N., Li, Q. Y., Mohler, E. R. 3rd & Levy, R. J. Progression of aortic valve stenosis: TGF-β1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann. Thorac. Surg. 75, 457–465 (2003).

    Article  PubMed  Google Scholar 

  104. Fisher, C. I., Chen, J. & Merryman, W. D. Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent. Biomech. Model Mechanobiol. 12, 5–17 (2013).

    Article  PubMed  Google Scholar 

  105. Chen, J. H., Chen, W. L., Sider, K. L., Yip, C. Y. & Simmons, C. A. β-Catenin mediates mechanically regulated, transforming growth factor-β1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler. Thromb. Vasc. Biol. 31, 590–597 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Howe, P. H. in The Cytokine Handbook (eds Thomson, A. W. & Lotze, M. T.) 1119–1141 (Academic Press Inc., 2003).

    Book  Google Scholar 

  107. Zhang, Y. E. Non-Smad pathways in TGF-β signaling. Cell Res. 19, 128–139 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Galliher, A. J. & Schiemann, W. P. β3 Integrin and Src facilitate transforming growth factor-β mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res. 8, R42 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hutcheson, J. D., Ryzhova, L. M., Setola, V. & Merryman, W. D. 5-HT2B Antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation. J. Mol. Cell. Cardiol. 53, 707–714 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yanagawa, B. et al. miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis. J. Thorac. Cardiovasc. Surg. 144, 256–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Kaden, J. J. et al. Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J. Heart Valve Dis. 13, 560–566 (2004).

    PubMed  Google Scholar 

  112. Yang, X. et al. Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: role of Smad1 and extracellular signal-regulated kinase 1/2. J. Thorac. Cardiovasc. Surg. 138, 1008–1015 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Balachandran, K., Sucosky, P., Jo, H. & Yoganathan, A. P. Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. Am. J. Pathol. 177, 49–57 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kroeze, W. K., Sheffler, D. J. & Roth, B. L. G-protein-coupled receptors at a glance. J. Cell Sci. 116, 4867–4869 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Hutcheson, J. D., Setola, V., Roth, B. L. & Merryman, W. D. Serotonin receptors and heart valve disease—it was meant 2B. Pharmacol. Ther. 132, 146–157 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gustafsson, B. I., Hauso, O., Drozdov, I., Kidd, M. & Modlin, I. M. Carcinoid heart disease. Int. J. Cardiol. 129, 318–324 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Connolly, H. M. et al. Valvular heart disease associated with fenfluramine-phentermine. N. Engl. J. Med. 337, 581–588 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Fitzgerald, L. W. et al. Possible role of valvular serotonin 5-HT2B receptors in the cardiopathy associated with fenfluramine. Mol. Pharmacol. 57, 75–81 (2000).

    CAS  PubMed  Google Scholar 

  119. Rothman, R. B. et al. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102, 2836–2841 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Huang, X. P. et al. Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine2B receptor agonists: implications for drug safety assessment. Mol. Pharmacol. 76, 710–722 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Setola, V. et al. 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol. Pharmacol. 63, 1223–1229 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Launay, J. M. et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 8, 1129–1135 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Jaffré, F. et al. Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy. Circ. Res. 104, 113–123 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Helske, S. et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J. Am. Coll. Cardiol. 44, 1859–1866 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Brooke, B. S. et al. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N. Engl. J. Med. 358, 2787–2795 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cohn, R. D. et al. Angiotensin II type 1 receptor blockade attenuates TGF-β-induced failure of muscle regeneration in multiple myopathic states. Nat. Med. 13, 204–210 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Habashi, J. P. et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 332, 361–365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Olsen, M. H. et al. Effect of losartan versus atenolol on aortic valve sclerosis (a LIFE substudy). Am. J. Cardiol. 94, 1076–1080 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Côté, N., Couture, C., Pibarot, P., Després, J. -P. & Mathieu, P. Angiotensin receptor blockers are associated with a lower remodelling score of stenotic aortic valves. Eur. J. Clin. Inves. 41, 1172–1179 (2011).

    Article  CAS  Google Scholar 

  130. Nadir, M. A. et al. Impact of renin–angiotensin system blockade therapy on outcome in aortic stenosis. J. Am. Coll. Cardiol. 58, 570–576 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Capoulade, R. et al. Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis. Eur. J. Clin. Inves. 43, 1262–1272 (2013).

    Article  CAS  Google Scholar 

  132. Arishiro, K. et al. Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits. J. Am. Coll. Cardiol. 49, 1482–1489 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Judge, D. P., Rouf, R., Habashi, J. & Dietz, H. C. Mitral valve disease in Marfan syndrome and related disorders. J. Cardiovasc. Transl. Res. 4, 741–747 (2011).

    Article  PubMed  Google Scholar 

  134. Chang, S. K. et al. Cadherin-11 regulates fibroblast inflammation. Proc. Natl Acad. Sci. USA 108, 8402–8407 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Schneider, D. J. et al. Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-β production and epithelial to mesenchymal transition. FASEB J. 26, 503–512 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lee, D. M. et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006–1010 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Okazaki, M. et al. Molecular cloning and characterization of OB-cadherin, a new member of cadherin family expressed in osteoblasts. J. Biol. Chem. 269, 12092–12098 (1994).

    CAS  PubMed  Google Scholar 

  138. Hinz, B., Pittet, P., Smith-Clerc, J., Chaponnier, C. & Meister, J. J. Myofibroblast development is characterized by specific cell–cell adherens junctions. Mol. Biol. Cell 15, 4310–4320 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hutcheson, J. D. et al. Cadherin-11 regulates cell–cell tension necessary for calcific nodule formation by valvular myofibroblasts. Arterioscler. Thromb. Vasc. Biol. 33, 114–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Garg, V. et al. Mutations in NOTCH1 cause aortic valve disease. Nature 437, 270–274 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. Niessen, K. & Karsan, A. Notch signaling in cardiac development. Circ. Res. 102, 1169–1181 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Ladich, E., Nakano, M., Carter-Monroe, N. & Virmani, R. Pathology of calcific aortic stenosis. Future Cardiol. 7, 629–642 (2011).

    Article  PubMed  Google Scholar 

  143. Sun, L., Chandra, S. & Sucosky, P. Ex vivo evidence for the contribution of hemodynamic shear stress abnormalities to the early pathogenesis of calcific bicuspid aortic valve disease. PLoS ONE 7, e48843 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. de la Pompa, J. L. & Epstein, J. A. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev. Cell 22, 244–254 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Andersson, E. R., Sandberg, R. & Lendahl, U. Notch signaling: simplicity in design, versatility in function. Development 138, 3593–3612 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Tang, Y., Urs, S. & Liaw, L. Hairy-related transcription factors inhibit Notch-induced smooth muscle α-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site. Circ. Res. 102, 661–668 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sjolund, J. et al. The notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma. PLoS ONE 6, e23057 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Tang, Y. et al. Notch and transforming growth factor-β (TGFβ) signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J. Biol. Chem. 285, 17556–17563 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Masuda, S. et al. Notch1 oncoprotein antagonizes TGF-β /Smad-mediated cell growth suppression via sequestration of coactivator p300. Cancer Sci. 96, 274–282 (2005).

    Article  CAS  PubMed  Google Scholar 

  150. Sun, Y. et al. Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-β signaling. Oncogene 24, 5365–5374 (2005).

    Article  CAS  PubMed  Google Scholar 

  151. Fu, Y. et al. Differential regulation of transforming growth factor β signaling pathways by Notch in human endothelial cells. J. Biol. Chem. 284, 19452–19462 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kennard, S., Liu, H. & Lilly, B. Transforming growth factor-β (TGF-β1) down-regulates Notch3 in fibroblasts to promote smooth muscle gene expression. J. Biol. Chem. 283, 1324–1333 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Nigam, V. & Srivastava, D. Notch1 represses osteogenic pathways in aortic valve cells. J. Mol. Cell. Cardiol. 47, 828–834 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Nus, M. et al. Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL. Arterioscler. Thromb. Vasc. Biol. 31, 1580–1588 (2011).

    Article  CAS  PubMed  Google Scholar 

  155. Yang, X. et al. Pro-osteogenic phenotype of human aortic valve interstitial cells is associated with higher levels of Toll-like receptors 2 and 4 and enhanced expression of bone morphogenetic protein 2. J. Am. Coll. Cardiol. 53, 491–500 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Meng, X. et al. Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis. Am. J. Physiol. Cell Physiol. 294, C29–C35 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Zeng, Q. et al. Notch1 promotes the pro-osteogenic response of human aortic valve interstitial cells via modulation of ERK1/2 and nuclear factor-κB activation. Arterioscler. Thromb. Vasc. Biol. 33, 1580–1590 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Côté, N. et al. ATP acts as a survival signal and prevents the mineralization of aortic valve. J. Mol. Cell. Cardiol. 52, 1191–1202 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Mahmut, A. et al. Elevated expression of Lp-PLA2 in calcific aortic valve disease: implication for valve mineralization. J. Am. Coll. Cardiol. http://dx.doi.org/10.1016/j.jacc.2013.05.105.

  160. Osman, L., Chester, A. H., Amrani, M., Yacoub, M. H. & Smolenski, R. T. A novel role of extracellular nucleotides in valve calcification: a potential target for atorvastatin. Circulation 114 (Suppl.), I566–I572 (2006).

    PubMed  Google Scholar 

  161. Aikawa, E. et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 119, 1785–1794 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hinton, R. B. et al. Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model. Circ. Res. 107, 549–557 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Helske, S. et al. Increased expression of elastolytic cathepsins S, K, and V and their inhibitor cystatin C in stenotic aortic valves. Arterioscler. Thromb. Vasc. Biol. 26, 1791–1798 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Balachandran, K., Sucosky, P., Jo, H. & Yoganathan, A. P. Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. Am. J. Physiol. Heart Circ. Physiol. 296, H756–H764 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Aikawa, E. & Otto, C. M. Look more closely at the valve: imaging calcific aortic valve disease. Circulation 125, 9–11 (2012).

    Article  PubMed  Google Scholar 

  166. Aikawa, E. et al. Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113, 1344–1352 (2006).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Interdisciplinary Cardiovascular Sciences, 3 Blackfan Circle, 17th Floor, Center for Life Sciences Boston, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA

    Joshua D. Hutcheson

  2. Center for Excellence in Vascular Biology, 3 Blackfan Circle, 17th Floor, Center for Life Sciences Boston, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA

    Elena Aikawa

  3. Department of Biomedical Engineering, 2213 Garland Avenue, Vanderbilt University, Nashville, 37212, TN, USA

    W. David Merryman

Authors
  1. Joshua D. Hutcheson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Aikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. David Merryman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J. D. Hutcheson researched data for the article, and all the authors contributed substantially to discussion of its content. J. D. Hutcheson and W. D. Merryman wrote the manuscript, and all the authors revised/edited it before submission.

Corresponding author

Correspondence to W. David Merryman.

Ethics declarations

Competing interests

J. D. Hutcheson and W. D. Merryman declare that they have received grant support from the AHA. E. Aikawa and W. D. Merryman declare that they have received grant support from the NIH National Heart, Lung, and Blood Institute.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hutcheson, J., Aikawa, E. & Merryman, W. Potential drug targets for calcific aortic valve disease. Nat Rev Cardiol 11, 218–231 (2014). https://doi.org/10.1038/nrcardio.2014.1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2014.1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing