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Calcific Aortic Valve Disease: Part 1—Molecular Pathogenetic Aspects, Hemodynamics, and Adaptive Feedbacks

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Abstract

Aortic valvular stenosis (AVS), produced by calcific aortic valve disease (CAVD) causing reduced cusp opening, afflicts mostly older persons eventually requiring valve replacement. CAVD had been considered “degenerative,” but newer investigations implicate active mechanisms similar to atherogenesis—genetic predisposition and signaling pathways, lipoprotein deposits, chronic inflammation, and calcification/osteogenesis. Consequently, CAVD may eventually be controlled/reversed by lifestyle and pharmacogenomics remedies. Its management should be comprehensive, embracing not only the valve but also the left ventricle and the arterial system with their interdependent morphomechanics/hemodynamics, which underlie the ensuing diastolic and systolic LV dysfunction. Compared to even a couple of decades ago, we now have an increased appreciation of genomic and cytomolecular pathogenetic mechanisms underlying CAVD. Future pluridisciplinary studies will characterize better and more completely its pathobiology, evolution, and overall dynamics, encompassing intricate feedback processes involving specific signaling molecules and gene network cascades. They will herald more effective, personalized medicine treatments of CAVD/AVS.

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References

  1. Roberts, W. C., & Ko, J. M. (2005). 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, 111, 920–925.

    Article  PubMed  Google Scholar 

  2. Chambers, J. (2005). Aortic stenosis. Is common, but often unrecognised (Editorial). BMJ, 330, 801–802.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Aksoy, O., Cam, A., Agarwal, S., et al. (2014). Significance of aortic valve calcification in patients with low-gradient low-flow aortic stenosis. Clinical Cardiology, 37, 26–31.

    Article  PubMed  Google Scholar 

  4. Pasipoularides, A. (2015). Mechanotransduction mechanisms for intraventricular diastolic vortex forces and myocardial deformations: part 1. Journal of Cardiovascular Translational Research, 8, 76–87.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pasipoularides, A. (2015). Mechanotransduction mechanisms for intraventricular diastolic vortex forces and myocardial deformations: part 2. Journal of Cardiovascular Translational Research, 8, 293–318.

    Article  PubMed  Google Scholar 

  6. Rajamannan, N. M., Evans, F. J., Aikawa, E., et al. (2011). 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.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alexopoulos, A., Bravou, V., Peroukides, S., Kaklamanis, L., Varakis, J., Alexopoulos, D., & Papadaki, H. (2010). Bone regulatory factors NFATc1 and Osterix in human calcific aortic valves. International Journal of Cardiology, 139, 142–149.

    Article  PubMed  Google Scholar 

  9. Yutzey, K. E., Demer, L. L., Body, S. C., et al. (2014). Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 2387–2393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pasipoularides, A. (2014). Historical continuity in the methodology of modern medical science: Leonardo leads the way. International Journal of Cardiology, 171, 103–115.

    Article  PubMed  Google Scholar 

  11. Quiney, J. R., & Watts, G. B. (1989). Introduction. In J. R. Quiney & G. B. Watts (Eds.), Classic papers in hyperlipidemia. London: Science Press Limited.

    Google Scholar 

  12. Mönckeberg, J. G. (1904). Der normale histologische Bau und die Sklerose der Aortenklappen. Virchows Archiv für Pathologische Anatomie und Physiologie und für Klinische Medizin, 176, 472–514.

    Google Scholar 

  13. Pasipoularides, A. (2010). Heart’s vortex: intracardiac blood flow phenomena. Shelton: People’s Medical Publishing House. 960 p.

    Google Scholar 

  14. Rajamannan, N. M. (2011). Calcific aortic valve disease: cellular origins of valve calcification. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 2777–2778.

    Article  CAS  PubMed  Google Scholar 

  15. Schoen, F. J. (2008). Evolving concepts of cardiac valve dynamics: the continuum of development, functional structure, pathobiology, and tissue engineering. Circulation, 118, 1864–1880.

    Article  PubMed  Google Scholar 

  16. Rodriguez, K. J., & Masters, K. S. (2009). Regulation of valvular interstitial cell calcification by components of the extracellular matrix. Journal of Biomedical Materials Research. Part A, 90, 1043–1053.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Yip, C. Y., Chen, J. H., Zhao, R., & Simmons, C. A. (2009). Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 936–942.

    Article  CAS  PubMed  Google Scholar 

  18. Chen, J. H., Chen, W. L., Sider, K. L., Yip, C. Y., & Simmons, C. A. (2011). β-catenin mediates mechanically regulated, transforming growth factor-β1-induced myofibroblast differentiation of aortic valve interstitial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 590–597.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Rabkin, E., Aikawa, M., Stone, J. R., Fukumoto, Y., Libby, P., & Schoen, F. J. (2001). Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation, 104, 2525–2532.

    Article  CAS  PubMed  Google Scholar 

  21. Fondard, O., Detaint, D., Iung, B., et al. (2005). Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. European Heart Journal, 26, 1333–1341.

    Article  CAS  PubMed  Google Scholar 

  22. Coffey, S., Cox, B., & Williams, M. J. (2014). The prevalence, incidence, progression, and risks of aortic valve sclerosis: a systematic review and meta-analysis. Journal of the American College of Cardiology, 63, 2852–2861.

    Article  PubMed  Google Scholar 

  23. Cottignoli, V., Cavarretta, E., Salvador, L., Valfré, C., & Maras, A. (2015). Morphological and chemical study of pathological deposits in human aortic and mitral valve stenosis: a biomineralogical contribution. Pathology Research International, 2015, 342984. doi:10.1155/2015/342984.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gey, C., & Giannis, A. (2004). Small molecules, big plans—can low-molecular-weight compounds control human regeneration? Angewandte Chemie International Edition in English, 43, 3998–4000.

    Article  CAS  Google Scholar 

  25. Lee, S. J., Lee, H. K., Cho, S. Y., et al. (2008). Identification of osteogenic purmorphamine derivatives. Molecules and Cells, 26, 380–386.

    CAS  PubMed  Google Scholar 

  26. Leopold, J. A. (2012). Cellular mechanisms of aortic valve calcification. Circulation. Cardiovascular Interventions, 5, 605–614.

    Article  PubMed  PubMed Central  Google Scholar 

  27. New, S. E., & Aikawa, E. (2011). Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circulation Research, 108, 1381–1391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dweck, M. R., Boon, N. A., & Newby, D. E. (2012). Calcific aortic stenosis: a disease of the valve and the myocardium. Journal of the American College of Cardiology, 60, 1854–1863.

    Article  PubMed  Google Scholar 

  29. Smith, J. G., Luk, K., Schulz, C. A., et al. (2014). Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. JAMA, 312, 1764–1771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Miller, J. D., Weiss, R. M., Serrano, K. M., et al. (2009). Lowering plasma cholesterol levels halts progression of aortic valve disease in mice. Circulation, 119, 2693–2701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mathieu, P., Poirier, P., Pibarot, P., Lemieux, I., & Després, J. P. (2009). Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension, 53, 577–584.

    Article  CAS  PubMed  Google Scholar 

  32. Mathieu, P., Després, J., & Pibarot, P. (2007). The “valvulo-metabolic” risk in calcific aortic valve disease. Canadian Journal of Cardiology, 23(Suppl B), 32B–39B.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Caira, F. C., Stock, S. R., Gleason, T. G., et al. (2006). Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. Journal of the American College of Cardiology, 47, 1707–1712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mathieu, P., Bouchareb, R., & Boulanger, M. C. (2015). Innate and adaptive immunity in calcific aortic valve disease. Journal of Immunology Research, 2015, 851945. doi:10.1155/2015/851945.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rosenhek, R., Rader, F., Loho, N., et al. (2004). Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation, 110, 1291–1295.

    Article  CAS  PubMed  Google Scholar 

  36. Helske, S., Kupari, M., Lindstedt, K. A., & Kovanen, P. T. (2007). Aortic valve stenosis: an active atheroinflammatory process. Current Opinion in Lipidology, 18, 483–491.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Otto, C. M., & O’Brien, K. D. (2001). Why is there discordance between calcific aortic stenosis and coronary artery disease? Heart, 85, 601–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cowell, S. J., Newby, D. E., Prescott, R. J., et al. (2005). A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. New England Journal of Medicine, 352, 2389–2397.

    Article  CAS  PubMed  Google Scholar 

  40. Chan, K. L., Teo, K., Dumesnil, J. G., Ni, A., Tam, J., & ASTRONOMER Investigators. (2010). 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.

    Article  CAS  PubMed  Google Scholar 

  41. Pasipoularides, A. (2015). Linking genes to cardiovascular diseases: gene action and gene–environment interactions. Journal of Cardiovascular Translational Research, 8, 506–527.

    Article  PubMed  Google Scholar 

  42. Evangelou, E., & Ioannidis, J. P. (2013). Meta-analysis methods for genome-wide association studies and beyond. Nature Reviews Genetics, 14, 379–389.

    Article  CAS  PubMed  Google Scholar 

  43. Hindorff, L. A., Sethupathy, P., Junkins, H. A., et al. (2009). Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the United States of America, 106, 9362–9367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wray, N. R., Yang, J., Hayes, B. J., Price, A. L., Goddard, M. E., & Visscher, P. M. (2013). Pitfalls of predicting complex traits from SNPs. Nature Reviews Genetics, 14, 507–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pasipoularides, A. (2011). LV twisting and untwisting in HCM: ejection begets filling. Diastolic functional aspects of HCM. American Heart Journal, 162, 798–810.

    Article  PubMed  Google Scholar 

  46. Pasipoularides, A. (1990). Clinical assessment of ventricular ejection dynamics with and without outflow obstruction. Journal of the American College of Cardiology, 15, 859–882.

    Article  CAS  PubMed  Google Scholar 

  47. Pasipoularides, A., Murgo, J. P., Bird, J. J., & Craig, W. E. (1984). Fluid dynamics of aortic stenosis: mechanisms for the presence of subvalvular pressure gradients. American Journal of Physiology. Heart and Circulatory Physiology, 246, H542–H550.

    CAS  Google Scholar 

  48. Pasipoularides, A. (2011). Fluid dynamic aspects of ejection in hypertrophic cardiomyopathy. Hellenic Journal of Cardiology, 52, 416–426.

    PubMed  Google Scholar 

  49. Bird, J. J., Murgo, J. P., & Pasipoularides, A. (1982). Fluid dynamics of aortic stenosis: subvalvular gradients without subvalvular obstruction. Circulation, 66, 835–840.

    Article  CAS  PubMed  Google Scholar 

  50. Pasipoularides, A., Murgo, J. P., Bird, J. J., & Craig, W. E. (1984). Fluid dynamics of aortic stenosis: mechanisms for the presence of subvalvular pressure gradients. American Journal of Physiology, 246, H542–H550.

    CAS  PubMed  Google Scholar 

  51. Pasipoularides, A. D., Shu, M., Womack, M. S., Shah, A., von Ramm, O., & Glower, D. D. (2003). RV functional imaging: 3-D echo-derived dynamic geometry and flow field simulations. American Journal of Physiology. Heart and Circulatory Physiology, 284, H56–H65.

    Article  CAS  PubMed  Google Scholar 

  52. Cassar DeMarco, D., & Monaghan, M. J. (2014). The role of echocardiography in transcatheter aortic valve implantation. Interventional Cardiology (London), 6, 547–555.

    Article  Google Scholar 

  53. Attias, D., Macron, L., Dreyfus, J., et al. (2013). Relationship between longitudinal strain and symptomatic status in aortic stenosis. Journal of the American Society of Echocardiography, 26, 868–874.

    Article  PubMed  Google Scholar 

  54. Schueler, R., Sinning, J. M., Momcilovic, D., et al. (2012). Three-dimensional speckle-tracking analysis of left ventricular function after transcatheter aortic valve implantation. Journal of the American Society of Echocardiography, 25, 827–834.

    Article  PubMed  Google Scholar 

  55. Lang, R. M., Badano, L. P., Tsang, W., et al. (2012). EAE/ASE recommendations for image acquisition and display using three-dimensional echocardiography. Journal of the American Society of Echocardiography, 25, 3–46.

    Article  PubMed  Google Scholar 

  56. Baumgartner, H., Hung, J., Bermejo, J., et al. (2009). Echocardiographic assessment of valve stenosis: EAE/ ASE recommendations for clinical practice. Journal of the American Society of Echocardiography, 22, 1–23.

    Article  PubMed  Google Scholar 

  57. Ozkan, A., Kapadia, S., Tuzcu, M., & Marwick, T. H. (2011). Assessment of left ventricular function in aortic stenosis. Nature Reviews Cardiology, 8, 494–501.

    Article  PubMed  Google Scholar 

  58. Knebel, F., Schimke, I., Schroeckh, S., et al. (2009). Myocardial function in older male amateur marathon runners: assessment by tissue Doppler echocardiography, speckle tracking, and cardiac biomarkers. Journal of the American Society of Echocardiography, 22, 803–809.

    Article  PubMed  Google Scholar 

  59. Pasipoularides, A. (2013). Right and left ventricular diastolic pressure–volume relations: a comprehensive review. Journal of Cardiovascular Translational Research, 6, 239–252.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Baumgartner, H., Hung, J., Bernejo, J., et al. (2009). Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Journal of the American Society of Echocardiography, 22, 1–23.

    Article  PubMed  Google Scholar 

  61. Lloyd, T. R. (1992). Variation in Doppler-derived stenotic aortic valve area during ejection. American Heart Journal, 124, 529–532.

    Article  CAS  PubMed  Google Scholar 

  62. Kasprzak, J. D., Nosir, Y. F., Dall’Agata, A., et al. (1998). Quantification of the aortic valve area in three-dimensional echocardiographic data sets: analysis of orifice overestimation resulting from suboptimal cut-plane selection. American Heart Journal, 135, 995–1003.

    Article  CAS  PubMed  Google Scholar 

  63. Ng, A. C., Delgado, V., van der Kley, F., et al. (2010). Comparison of aortic root dimensions and geometries before and after transcatheter aortic valve implantation by 2- and 3-dimensional transesophageal echocardiography and multislice computed tomography. Circulation. Cardiovascular Imaging, 3, 94–102.

    Article  PubMed  Google Scholar 

  64. Lang, R. M., Tsang, W., Weinert, L., Mor-Avi, V., & Chandra, S. (2011). Valvular heart disease. The value of 3-dimensional echocardiography. Journal of the American College of Cardiology, 58, 1933–1944.

    Article  PubMed  Google Scholar 

  65. Michelena, H. I., Margaryan, E., Miller, F. A., et al. (2013). Inconsistent echocardiographic grading of aortic stenosis: is the left ventricular outflow tract important? Heart, 99, 921–931.

    Article  PubMed  Google Scholar 

  66. Bhatia, N., Dawn, B., Siddiqui, T. S., et al. (2015). Impact and predictors of noncircular left ventricular outflow tract shapes on estimating aortic stenosis severity by means of continuity equations. Texas Heart Institute Journal, 42, 16–24.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Nishimura, R. A., Otto, C. M., Bonow, R. O., et al. (2014). 2014 AHA/ACC guideline 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. Journal of the American College of Cardiology, 63, e57–e185.

    Article  PubMed  Google Scholar 

  68. Dahl, J. S., Eleid, M. F., Pislaru, S. V., et al. (2015). Development of paradoxical low-flow, low-gradient severe aortic stenosis. Heart, 101, 1015–1023.

    Article  PubMed  Google Scholar 

  69. Barone-Rochette, G., Pierard, S., Seldrum, S., et al. (2013). Aortic valve area, stroke volume, left ventricular hypertrophy, remodeling, and fibrosis in aortic stenosis assessed by cardiac magnetic resonance imaging: comparison between high and low gradient and normal and low flow aortic stenosis. Circulation. Cardiovascular Imaging, 6, 1009–1017.

    Article  PubMed  Google Scholar 

  70. Clavel, M. A., Ennezat, P. V., Marechaux, S., et al. (2013). Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF. JACC. Cardiovascular Imaging, 6, 175–183.

    Article  PubMed  Google Scholar 

  71. Tribouilloy, C., Rusinaru, D., Marechaux, S., et al. (2015). Low-gradient, low-flow severe aortic stenosis with preserved left ventricular ejection fraction: characteristics, outcome, and implications for surgery. Journal of the American College of Cardiology, 65, 55–66.

    Article  PubMed  Google Scholar 

  72. Hachicha, Z., Dumesnil, J. G., Bogaty, P., & Pibarot, P. (2007). Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation, 115, 2856–2864.

    Article  PubMed  Google Scholar 

  73. Clavel, M. A., Fuchs, C., Burwash, I. G., et al. (2008). Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study. Circulation, 118(14 Suppl), S234–S242.

    Article  PubMed  Google Scholar 

  74. Blais, C., Burwash, I. G., Mundigler, G., et al. (2006). Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low-flow, low-gradient aortic stenosis: the multicenter TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study. Circulation, 113, 711–721.

    Article  PubMed  Google Scholar 

  75. Magne, J., Lancellotti, P., & Piérard, L. A. (2014). Exercise testing in asymptomatic severe aortic stenosis. JACC. Cardiovascular Imaging, 7, 188–199.

    Article  PubMed  Google Scholar 

  76. Gomez, M., Ble, M., Cladellas, M., et al. (2015). Effect of correction of anemia on echocardiographic and clinical parameters in patients with aortic stenosis involving a three-cuspid aortic valve and normal left ventricular ejection fraction. American Journal of Cardiology, 116, 270–274.

    Article  PubMed  Google Scholar 

  77. Pawade, T. A., Newby, D. E., & Dweck, M. R. (2015). Calcification in aortic stenosis. Journal of the American College of Cardiology, 66, 561–577.

    Article  PubMed  Google Scholar 

  78. Pasipoularides, A., Murgo, J. P., Miller, J. W., & Craig, W. E. (1987). Nonobstructive left ventricular ejection pressure gradients in man. Circulation Research, 61, 220–227.

    Article  CAS  PubMed  Google Scholar 

  79. Isaaz, K., & Pasipoularides, A. (1991). Noninvasive assessment of intrinsic ventricular load dynamics in dilated cardiomyopathy. Journal of the American College of Cardiology, 17, 112–121.

    Article  CAS  PubMed  Google Scholar 

  80. Pasipoularides, A. (1992). Cardiac mechanics: basic and clinical contemporary research. Annals of Biomedical Engineering, 20, 3–17.

    Article  CAS  PubMed  Google Scholar 

  81. Georgiadis, J. G., Wang, M., & Pasipoularides, A. (1992). Computational fluid dynamics of left ventricular ejection. Annals of Biomedical Engineering, 20, 81–97.

    Article  CAS  PubMed  Google Scholar 

  82. Hampton, T., Shim, Y., Straley, C., & Pasipoularides, A. (1992). Finite element analysis of cardiac ejection dynamics: ultrasonic implications. American Society of Mechanical Engineers, Bioengineering Division (ASME BED) Advances Bioengineering, 22, 371–374.

    Google Scholar 

  83. Hampton, T., Shim, Y., Straley, C., Uppal, R., Smith, P. K., Glower, D., & Pasipoularides, A. (1992). Computational fluid dynamics of ventricular ejection on the CRAY Y-MP. IEEE Proceedings of the Computers in Cardiology, 19, 295–298.

    Article  Google Scholar 

  84. Pasipoularides, A. (2007). Complementarity and competitiveness of the intrinsic and extrinsic components of the total ventricular load: demonstration after valve replacement in aortic stenosis. American Heart Journal, 153, 4–6.

    Article  PubMed  Google Scholar 

  85. Laskey, W. K., & Kussmaul, W. G. (2001). Subvalvular gradients in patients with valvular aortic stenosis: prevalence, magnitude, and physiological importance. Circulation, 104, 1019–1022.

    Article  CAS  PubMed  Google Scholar 

  86. Schöbel, W. A., Voelker, W., Haase, K. K., & Karsch, K.-R. (1999). Extent, determinants and clinical importance of pressure recovery in patients with aortic valve stenosis. European Heart Journal, 20, 1355–1363.

    Article  PubMed  Google Scholar 

  87. Pasipoularides, A. (2013). Right and left ventricular diastolic flow field: why are measured intraventricular pressure gradients small? Revista Española de Cardiología, 66, 337–341.

    Article  PubMed  Google Scholar 

  88. Barki-Harrington, L., Perrino, C., & Rockman, H. A. (2004). Network integration of the adrenergic system in cardiac hypertrophy. Cardiovascular Research, 63, 391–402.

    Article  CAS  PubMed  Google Scholar 

  89. Mann, D. L., Kent, R. L., & Cooper, G. (1989). Load regulation of the properties of adult feline cardiocytes: growth induction by cellular deformation. Circulation Research, 64, 1079–1090.

    Article  CAS  PubMed  Google Scholar 

  90. Sadoshima, J., & Izumo, S. (1997). The cellular and molecular response of cardiac myocytes to mechanical stress. Annual Review of Physiology, 59, 551–571.

    Article  CAS  PubMed  Google Scholar 

  91. Yamazaki, T., Komuro, I., Nagai, R., & Yazaki, Y. (1996). Stretching the evidence in the case of cardiac growth. Cardiovascular Research, 31, 493–498.

    Article  CAS  PubMed  Google Scholar 

  92. Mirsky, I., & Pasipoularides, A. (1980). Elastic properties of normal and hypertrophied cardiac muscle. Federation Proceedings, 39, 156–161.

    CAS  PubMed  Google Scholar 

  93. Wee, K. B., Yio, W. K., Surana, U., & Chiam, K. H. (2012). Transcription factor oscillations induce differential gene expressions. Biophysical Journal, 102, 2413–2423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Guyton, A. C., Crowell, J. W., & Moore, J. W. (1956). Basic oscillating mechanism of Cheyne-Stokes breathing. American Journal of Physiology, 187, 395–398.

    PubMed  Google Scholar 

  95. Pasipoularides, A., Mirsky, I., Hess, O. M., Grimm, J., & Krayenbuehl, H. P. (1986). Muscle relaxation and passive diastolic properties in man. Circulation, 74, 991–1001.

    Article  CAS  PubMed  Google Scholar 

  96. Mirsky, I., & Pasipoularides, A. (1990). Clinical assessment of diastolic function. Progress in Cardiovascular Diseases, 32, 291–318.

    Article  CAS  PubMed  Google Scholar 

  97. Paulus, W. J., Grossman, W., Serizawa, T., Bourdillon, P. D., Pasipoularides, A., & Mirsky, I. (1985). Different effects of two types of ischemia on myocardial systolic and diastolic function. American Journal of Physiology. Heart and Circulatory Physiology, 248, H719–H728.

    CAS  Google Scholar 

  98. Pasipoularides, A., Palacios, I., Frist, W., Rosenthal, S., Newell, J. B., & Powell, W. J., Jr. (1985). Contribution of activation-inactivation dynamics to the impairment of relaxation in hypoxic cat papillary muscle. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 248, R54–R62.

    CAS  Google Scholar 

  99. Gelpi, R. J., Pasipoularides, A., Lader, A. S., Patrick, T. A., Chase, N., Hittinger, L., Shannon, R. P., Bishop, S. P., & Vatner, S. F. (1991). Changes in diastolic cardiac function in developing and stable perinephritic hypertension in conscious dogs. Circulation Research, 68, 555–567.

    Article  CAS  PubMed  Google Scholar 

  100. Komamura, K., Shannon, R. P., Pasipoularides, A., Ihara, T., Lader, A. S., Patrick, T. A., Bishop, S. P., & Vatner, S. F. (1992). Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure. Journal of Clinical Investigation, 89, 1825–1838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Laks, M. M., Garner, D., & Swan, H. J. C. (1967). Volumes and compliances measured simultaneously in the right and left ventricle of dog. Circulation Research, 20, 565–569.

    Article  CAS  PubMed  Google Scholar 

  102. Laks, M. M., Morady, F., Garner, D., & Swan, H. J. C. (1972). Relation of ventricular volume, compliance and mass in the normal and pulmonary arterial banded canine heart. Cardiovascular Research, 6, 187–198.

    Article  CAS  PubMed  Google Scholar 

  103. Laks, M. M., & Morady, F. (1976). Norepinephrine—the myocardial hypertrophy hormone? American Heart Journal, 91, 674–675.

    Article  CAS  PubMed  Google Scholar 

  104. Moss, R. L., & Fitzsimons, D. P. (2010). Regulation of contraction in mammalian striated muscles—the plot thickens. Journal of General Physiology, 136, 21–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Solaro, R. J., Sheehan, K. A., Lei, M., & Ke, Y. B. (2010). The curious role of sarcomeric proteins in control of diverse processes in cardiac myocytes. Journal of General Physiology, 136, 13–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pal, P. D., Dongre, P. M., & Chitre, A. V. (2014). “Is macromolecular crowding overlooked?”—Effects of volume exclusion on DNA-amino acids complexes and their reconstitutes. Journal of Fluorescence, 24, 1275–1284.

    Article  CAS  PubMed  Google Scholar 

  107. Kinjo, A. R., & Takada, S. (2003). Competition between protein folding and aggregation with molecular chaperones in crowded solutions: insight from mesoscopic simulations. Biophysical Journal, 85, 3521–3531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bernadó, P., García de la Torre, J., & Pons, M. (2004). Macromolecular crowding in biological systems: hydrodynamics and NMR methods. Journal of Molecular Recognition, 17, 397–407.

    Article  PubMed  CAS  Google Scholar 

  109. Ellis, R. J., & Minton, A. P. (2006). Protein aggregation in crowded environments. Biological Chemistry, 387, 485–497.

    Article  CAS  PubMed  Google Scholar 

  110. Pasipoularides, A. (2014). Galen, father of systematic medicine. An essay on the evolution of modern medicine and cardiology. International Journal of Cardiology, 172, 47–58.

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Authors and Affiliations

  1. Duke University School of Medicine, Durham, NC, USA

    Ares Pasipoularides

  2. Duke/NSF Research Center for Emerging Cardiovascular Technologies, Durham, NC, USA

    Ares Pasipoularides

  3. Duke University Graduate School, Durham, NC, 27710, USA

    Ares Pasipoularides

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  1. Ares Pasipoularides
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Correspondence to Ares Pasipoularides.

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Sources of Funding

Research support, for work from my Laboratory surveyed here, was provided by the National Heart, Lung, and Blood Institute, Grant No. R01 HL 050446; National Science Foundation, Grant No. CDR 8622201; and North Carolina Supercomputing Center and Cray Research. I declare that I have no conflict of interest, whatsoever.

Ethical Approval

All procedures performed in studies involving human participants that are reviewed here were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. All applicable international, national, and/or institutional guidelines for the care and use of animals in studies involving animals that are reviewed here were followed.

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Editor-in-Chief Jennifer L. Hall oversaw the review of this article

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Pasipoularides, A. Calcific Aortic Valve Disease: Part 1—Molecular Pathogenetic Aspects, Hemodynamics, and Adaptive Feedbacks. J. of Cardiovasc. Trans. Res. 9, 102–118 (2016). https://doi.org/10.1007/s12265-016-9679-z

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  • DOI: https://doi.org/10.1007/s12265-016-9679-z

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