Advertisement

Annals of Biomedical Engineering

, Volume 47, Issue 1, pp 138–153 | Cite as

A Computational Cardiac Model for the Adaptation to Pulmonary Arterial Hypertension in the Rat

  • Reza Avazmohammadi
  • Emilio A. Mendiola
  • João S. Soares
  • David S. Li
  • Zhiqiang Chen
  • Samer Merchant
  • Edward W. Hsu
  • Peter Vanderslice
  • Richard A. F. Dixon
  • Michael S. SacksEmail author
Article

Abstract

Pulmonary arterial hypertension (PAH) imposes pressure overload on the right ventricle (RV), leading to RV enlargement via the growth of cardiac myocytes and remodeling of the collagen fiber architecture. The effects of these alterations on the functional behavior of the right ventricular free wall (RVFW) and organ-level cardiac function remain largely unexplored. Computational heart models in the rat (RHMs) of the normal and hypertensive states can be quite valuable in simulating the effects of PAH on cardiac function to gain insights into the pathophysiology of underlying myocardium remodeling. We thus developed high-fidelity biventricular finite element RHMs for the normal and post-PAH hypertensive states using extensive experimental data collected from rat hearts. We then applied the RHM to investigate the transmural nature of RVFW remodeling and its connection to wall stress elevation under PAH. We found a strong correlation between the longitudinally-dominated fiber-level adaptation of the RVFW and the transmural alterations of relevant wall stress components. We further conducted several numerical experiments to gain new insights on how the RV responds both normally and in the post-PAH state. We found that the effect of pressure overload alone on the increased contractility of the RV is comparable to the effects of changes in the RV geometry and stiffness. Furthermore, our RHMs provided fresh perspectives on long-standing questions of the functional role of the interventricular septum in RV function. Specifically, we demonstrated that an inaccurate identification of the mechanical adaptation of the septum can lead to a significant underestimation of RVFW contractility in the post-PAH state. These findings show how integrated experimental–computational models can facilitate a more comprehensive understanding of the cardiac remodeling events during PAH.

Keywords

Pulmonary hypertension In silico biventricular model Fiber reorientation Wall stress Contractility 

Notes

Acknowledgments

We would like to thank Mr. Huan Nguyen at the University of Texas at Austin for assisting with part of simulations, and Dr. Lei Zhou at Texas Heart Institute for performing echocardiography of the rat hearts.

Funding

This work was supported by the US National Institutes of Health and American Heart Association awards (Nos. 5F32 HL132543-02 and 18CDA34110383, respectively) to R.A., the U.S. National Institutive of Healthy (Nos. T32EB007507 and F31HL139113) to D.S.L., and the W.A. Moncrief, Jr. SBES endowment to M.S.S.

Supplementary material

10439_2018_2130_MOESM1_ESM.pdf (90 kb)
Supplementary material (PDF 91 kb)

References

  1. 1.
    Anversa, P., R. Ricci, and G. Olivetti. Quantitative structural analysis of the myocardium during physiologic growth and induced cardiac hypertrophy: a review. J. Am. Coll. Cardiol. 7(5):1140–1149, 1986.CrossRefGoogle Scholar
  2. 2.
    Avazmohammadi, R., M. Hill, M. Simon, and M. Sacks. Transmural remodeling of right ventricular myocardium in response to pulmonary arterial hypertension. APL Bioeng. 1(1):016105, 2017.CrossRefGoogle Scholar
  3. 3.
    Avazmohammadi, R., M. R. Hill, M. A. Simon, W. Zhang, and M. S. Sacks. A novel constitutive model for passive right ventricular myocardium: evidence for myofiber–collagen fiber mechanical coupling. Biomech. Model. Mechanobiol. 16(2):561–581, 2017.CrossRefGoogle Scholar
  4. 4.
    Cantor, E. J., A. P. Babick, Z. Vasanji, N. S. Dhalla, and T. Netticadan. A comparative serial echocardiographic analysis of cardiac structure and function in rats subjected to pressure or volume overload. J. Mol. Cell. Cardiol. 38(5):777–786, 2005.CrossRefGoogle Scholar
  5. 5.
    de Man, F. S., M. L. Handoko, J. J. van Ballegoij, I. Schalij, S. J. Bogaards, P. E. Postmus, J. van der Velden, N. Westerhof, W. J. Paulus, and A. Vonk-Noordegraaf. Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension. Circ. Heart Fail. 5(1):97–105, 2011.CrossRefGoogle Scholar
  6. 6.
    Dohi, K., N. Yamada, and M. Ito. Right ventricular function. In: Diagnosis and Treatment of Pulmonary Hypertension. Springer, 2017, pp. 217–236.Google Scholar
  7. 7.
    Faber, M. J., M. Dalinghaus, I. M. Lankhuizen, P. Steendijk, W. C. Hop, R. G. Schoemaker, D. J. Duncker, J. M. Lamers, and W. A. Helbing. Right and left ventricular function after chronic pulmonary artery banding in rats assessed with biventricular pressure–volume loops. Am. J. Physiol. Heart Circ. Physiol. 291(4):H1580–H1586, 2006.CrossRefGoogle Scholar
  8. 8.
    Gomez, A. D., H. Zou, M. E. Bowen, X. Liu, E. W. Hsu, and S. H. McKellar. Right ventricular fiber structure as a compensatory mechanism in pressure overload: a computational study. J. Biomech. Eng. 139(8):081004, 2017.CrossRefGoogle Scholar
  9. 9.
    Gomez-Arroyo, J. G., L. Farkas, A. A. Alhussaini, D. Farkas, D. Kraskauskas, N. F. Voelkel, and H. J. Bogaard. The monocrotaline model of pulmonary hypertension in perspective. Am. J. Physiol. Lung Cell. Mol. Physiol. 302(4):L363–L369, 2011.CrossRefGoogle Scholar
  10. 10.
    Hadi, A. M., K. T. Mouchaers, I. Schalij, K. Grunberg, G. A. Meijer, A. Vonk-Noordegraaf, W. J. van der Laarse, and J. A. Belin. Rapid quantification of myocardial fibrosis: a new macro-based automated analysis. Cell. Oncol. 34(4):343–354, 2011.CrossRefGoogle Scholar
  11. 11.
    Healy, L. J., Y. Jiang, and E. W. Hsu. Quantitative comparison of myocardial fiber structure between mice, rabbit, and sheep using diffusion tensor cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 13(1):74, 2011.CrossRefGoogle Scholar
  12. 12.
    Hessel, M. H., P. Steendijk, B. den Adel, C. I. Schutte, and A. van der Laarse. Characterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat. Am. J. Physiol. Heart Circ. Physiol. 291(5):H2424–H2430, 2006.CrossRefGoogle Scholar
  13. 13.
    Hill, M. R., M. A. Simon, D. Valdez-Jasso, W. Zhang, H. C. Champion, and M. S. Sacks. Structural and mechanical adaptations of right ventricle free wall myocardium to pressure overload. Ann. Biomed. Eng. 42(12):2451–2465, 2014.CrossRefGoogle Scholar
  14. 14.
    Homsi, R., J. A. Luetkens, D. Skowasch, C. Pizarro, A. M. Sprinkart, J. Gieseke, H. H. Schild, and C. P. Naehle. Left ventricular myocardial fibrosis, atrophy, and impaired contractility in patients with pulmonary arterial hypertension and a preserved left ventricular function: a cardiac magnetic resonance study. J. Thorac. Imaging 32(1):36–42, 2017.CrossRefGoogle Scholar
  15. 15.
    Jang, S., R. R. Vanderpool, R. Avazmohammadi, E. Lapshin, T. N. Bachman, M. Sacks, and M. A. Simon. Biomechanical and hemodynamic measures of right ventricular diastolic function: translating tissue biomechanics to clinical relevance. J. Am. Heart Assoc. 6(9):e006084, 2017.CrossRefGoogle Scholar
  16. 16.
    Jiang, Y., K. Pandya, O. Smithies, and E. W. Hsu. Three-dimensional diffusion tensor microscopy of fixed mouse hearts. Magn. Reson. Med. 52(3):453–460, 2004.CrossRefGoogle Scholar
  17. 17.
    Manders, E., H. J. Bogaard, M. L. Handoko, M. C. van de Veerdonk, A. Keogh, N. Westerhof, G. J. Stienen, C. G. dos Remedios, M. Humbert, P. Dorfmüller, and E. Fadel. Contractile dysfunction of left ventricular cardiomyocytes in patients with pulmonary arterial hypertension. J. Am. Coll. Cardiol. 64(1):28–37, 2014.CrossRefGoogle Scholar
  18. 18.
    Marcus, J. T., C. T. J. Gan, J. J. M. Zwanenburg, A. Boonstra, C. P. Allaart, M. J. W. Götte, and A. Vonk-Noordegraaf. Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak shortening is related to right ventricular overload and left ventricular underfilling. J. Am. Coll. Cardiol. 51(7):750–757, 2008.CrossRefGoogle Scholar
  19. 19.
    Mekkaoui, C., I. Y. Chen, H. H. Chen, W. J. Kostis, F. Pereira, M. P. Jackowski, and D. E. Sosnovik. Differential response of the left and right ventricles to pressure overload revealed with diffusion tensor MRI tractography of the heart in vivo. J. Cardiovasc. Magn. Reson. 17(1):O3, 2015.CrossRefGoogle Scholar
  20. 20.
    Motoji, Y., H. Tanaka, Y. Fukuda, H. Sano, K. Ryo, T. Sawa, T. Miyoshi, J. Imanishi, Y. Mochizuki, K. Tatsumi, and K. Matsumoto. Association of apical longitudinal rotation with right ventricular performance in patients with pulmonary hypertension: insights into overestimation of tricuspid annular plane systolic excursion. Echocardiography 33(2):207–215, 2016.CrossRefGoogle Scholar
  21. 21.
    Nielsen, E., M. Smerup, P. Agger, J. Frandsen, S. Ringgard, M. Pedersen, P. Vestergaard, J. R. Nyengaard, J. B. Andersen, P. P. Lunkenheimer, and R. H. Anderson. Normal right ventricular three-dimensional architecture, as assessed with diffusion tensor magnetic resonance imaging, is preserved during experimentally induced right ventricular hypertrophy. Anat. Rec. 292(5):640–651, 2009.CrossRefGoogle Scholar
  22. 22.
    Phatak, N. S., S. A. Maas, A. I. Veress, N. A. Pack, E. V. Di Bella, and J. A. Weiss. Strain measurement in the left ventricle during systole with deformable image registration. Med. Image Anal. 13(2):354–361, 2009.CrossRefGoogle Scholar
  23. 23.
    Rabinovitch, M., C. Guignabert, M. Humbert, and M. R. Nicolls. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ. Res. 115(1):165–175, 2014.CrossRefGoogle Scholar
  24. 24.
    Rain, S., M. L. Handoko, P. Trip, C. T. J. Gan, N. Westerhof, G. J. Stienen, W. J. Paulus, C. A. Ottenheijm, J. T. Marcus, P. Dorfmller, and C. Guignabert. Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. Circulation 128(18):2016–2025, 2013.CrossRefGoogle Scholar
  25. 25.
    Sanz, J., A. García-Alvarez, L. Fernndez-Friera, A. Nair, J. G. Mirelis, S. T. Sawit, S. Pinney, and V. Fuster. Right ventriculo-arterial coupling in pulmonary hypertension: a magnetic resonance study. Heart 98:238–243, 2012.CrossRefGoogle Scholar
  26. 26.
    Spruijt, O. A., F. S. de Man, H. Groepenhoff, F. Oosterveer, N. Westerhof, A. Vonk-Noordegraaf, and H. J. Bogaard. The effects of exercise on right ventricular contractility and right ventricular-arterial coupling in pulmonary hypertension. Am. J. Respir. Crit. Care Med. 191(9):1050–1057, 2015.CrossRefGoogle Scholar
  27. 27.
    Tji-Joong, G. C., J. W. Lankhaar, J. T. Marcus, N. Westerhof, K. M. Marques, J. G. F. Bronzwaer, A. Boonstra, P. E. Postmus, and A. Vonk-Noordegraaf. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension. Am. J. Physiol. Heart Circ. Physiol. 290(4):H1528–H1533, 2006.CrossRefGoogle Scholar
  28. 28.
    Trip, P., E. J. Nossent, S. Frances, I.A. van den Berk, A. Boonstra, H. Groepenhoff, E. M. Leter, N. Westerhof, K. Grnberg, H. J. Bogaard, and A. V. Noordegraaf. Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur. Respir. J. 42(6):1575–1585, 2013.CrossRefGoogle Scholar
  29. 29.
    Trip, P., S. Rain, M. L. Handoko, C. Van der Bruggen, H. J. Bogaard, J. T. Marcus, A. Boonstra, N. Westerhof, A. Vonk-Noordegraaf, and S. Frances. Clinical relevance of right ventricular diastolic stiffness in pulmonary hypertension. Eur. Respir. J. 45(6):1603–1612, 2015.CrossRefGoogle Scholar
  30. 30.
    Valdez-Jasso, D., M. A. Simon, H. C. Champion, and M. S. Sacks. A murine experimental model for the mechanical behaviour of viable right-ventricular myocardium. J. Physiol. 590(18):4571–4584, 2012.CrossRefGoogle Scholar
  31. 31.
    Voelkel, N. F., R. Natarajan, J. I. Drake, and H. J. Bogaard. Right ventricle in pulmonary hypertension. Compr. Physiol. 1:525–540, 2011.Google Scholar
  32. 32.
    Vonk Noordegraaf, A., B. E. Westerhof, and N. Westerhof. The relationship between the right ventricle and its load in pulmonary hypertension. J. Am. Coll. Cardiol. 69(2):236–243, 2017.CrossRefGoogle Scholar
  33. 33.
    Wong, J., and E. Kuhl. Generating fibre orientation maps in human heart models using Poisson interpolation. Comput. Methods Biomech. Biomed. Eng. 17(11):1217–1226, 2014.CrossRefGoogle Scholar
  34. 34.
    Xi, C., C. Latnie, X. Zhao, J. Le Tan, S. T. Wall, M. Genet, L. Zhong, and L. C. Lee. Patient-specific computational analysis of ventricular mechanics in pulmonary arterial hypertension. J. Biomech. Eng. 138(11):111001, 2016.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2018

Authors and Affiliations

  • Reza Avazmohammadi
    • 1
  • Emilio A. Mendiola
    • 1
  • João S. Soares
    • 2
  • David S. Li
    • 1
  • Zhiqiang Chen
    • 3
  • Samer Merchant
    • 4
  • Edward W. Hsu
    • 4
  • Peter Vanderslice
    • 3
  • Richard A. F. Dixon
    • 3
  • Michael S. Sacks
    • 1
    Email author return OK on get
  1. 1.Willerson Center for Cardiovascular Modeling and Simulation, Institute for Computational Engineering and Sciences and the Department of Biomedical EngineeringThe University of Texas at AustinAustinUSA
  2. 2.Department of Mechanical & Nuclear EngineeringVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of Molecular CardiologyTexas Heart InstituteHoustonUSA
  4. 4.Department of Biomedical EngineeringUniversity of UtahSalt Lake CityUSA

Personalised recommendations