Annals of Biomedical Engineering

, Volume 43, Issue 6, pp 1335–1347 | Cite as

Computational Modeling of Pathophysiologic Responses to Exercise in Fontan Patients

  • Ethan Kung
  • James C. Perry
  • Christopher Davis
  • Francesco Migliavacca
  • Giancarlo Pennati
  • Alessandro Giardini
  • Tain-Yen Hsia
  • Alison MarsdenEmail author


Reduced exercise capacity is nearly universal among Fontan patients. Although many factors have emerged as possible contributors, the degree to which each impacts the overall hemodynamics is largely unknown. Computational modeling provides a means to test hypotheses of causes of exercise intolerance via precisely controlled virtual experiments and measurements. We quantified the physiological impacts of commonly encountered, clinically relevant dysfunctions introduced to the exercising Fontan system via a previously developed lumped-parameter model of Fontan exercise. Elevated pulmonary arterial pressure was observed in all cases of dysfunction, correlated with lowered cardiac output (CO), and often mediated by elevated atrial pressure. Pulmonary vascular resistance was not the most significant factor affecting exercise performance as measured by CO. In the absence of other dysfunctions, atrioventricular valve insufficiency alone had significant physiological impact, especially under exercise demands. The impact of isolated dysfunctions can be linearly summed to approximate the combined impact of several dysfunctions occurring in the same system. A single dominant cause of exercise intolerance was not identified, though several hypothesized dysfunctions each led to variable decreases in performance. Computational predictions of performance improvement associated with various interventions should be weighed against procedural risks and potential complications, contributing to improvements in routine patient management protocol.


Lumped-parameter model Dysfunction Single-ventricle Closed-loop Simulation Pulmonary pressure Regurgitation 



Abnormal pulmonary vascular response




1st degree AV block


AV valve insufficiency


Chronotropic insufficiency


Cardiac output in L/min


Disordered respiration


Diastolic dysfunction


Metabolic equivalent in units of 3.5 mL O2 kg−1 min−1


Pulmonary arterial


Pulmonary vascular resistance


Systolic dysfunction


Stroke volume



This work was supported by the Leducq Foundation as part of the Transatlantic Network of Excellence for Cardiovascular Research, a Burroughs Wellcome Fund Career award at the Scientific Interface, and an American Heart Association Postdoctoral Fellowship.

Conflict of Interest

No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Supplementary material

10439_2014_1131_MOESM1_ESM.docx (61 kb)
Supplementary material 1 (DOCX 62 kb)
10439_2014_1131_MOESM2_ESM.docx (3.2 mb)
Supplementary material 2 (DOCX 3234 kb)


  1. 1.
    Akagi, T., L. N. Benson, M. Green, J. Ash, D. L. Gilday, W. G. Williams, and R. M. Freedom. Ventricular performance before and after fontan repair for univentricular atrioventricular connection: angiographic and radionuclide assessment. J. Am. Coll. Cardiol. 20:920–926, 1992.PubMedCrossRefGoogle Scholar
  2. 2.
    Baretta, A., C. Corsini, A. L. Marsden, I. E. Vignon-Clementel, T.-Y. Hsia, G. Dubini, F. Migliavacca, and G. Pennati. Respiratory effects on hemodynamics in patient-specific cfd models of the fontan circulation under exercise conditions. Eur. J. Mech. B 35:61–69, 2012.CrossRefGoogle Scholar
  3. 3.
    Brooker, J., E. Alderman, and D. Harrison. Alterations in left-ventricular volumes induced by valsalva maneuver. Br. Heart J. 36:713–718, 1974.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Buda, A. J., M. R. Pinsky, N. B. Ingels, Jr., G. T. Daughters, E. B. Stinson, and E. L. Alderman. Effect of intrathoracic pressure on left ventricular performance. N. Engl. J. Med. 301:453–459, 1979.PubMedCrossRefGoogle Scholar
  5. 5.
    Damato, A. N., S. H. Lau, R. Helfant, E. Stein, R. D. Patton, B. J. Scherlag, and W. D. Berkowitz. A study of heart block in man using his bundle recordings. Circulation 39:297–305, 1969.PubMedCrossRefGoogle Scholar
  6. 6.
    Del Torso, S., M. J. Kelly, V. Kalff, and A. W. Venables. Radionuclide assessment of ventricular contraction at rest and during exercise following the fontan procedure for either tricuspid atresia or single ventricle. Am. J. Cardiol. 55:1127–1132, 1985.PubMedCrossRefGoogle Scholar
  7. 7.
    Diller, G., A. Giardini, K. Dimopoulos, G. Gargiulo, J. Muller, G. Derrick, G. Giannakoulas, S. Khambadkone, A. Lammers, F. Picchio, M. Gatzoulis, and A. Hager. Predictors of morbidity and mortality in contemporary fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur. Heart J. 31:3073–3083, 2010.PubMedCrossRefGoogle Scholar
  8. 8.
    Driscoll, D. J., G. K. Danielson, F. J. Puga, H. V. Schaff, C. T. Heise, and B. A. Staats. Exercise tolerance and cardiorespiratory response to exercise after the fontan operation for tricuspid atresia or functional single ventricle. J. Am. Coll. Cardiol. 7:1087–1094, 1986.PubMedCrossRefGoogle Scholar
  9. 9.
    Durongpisitkul, K., D. J. Driscoll, D. W. Mahoney, P. C. Wollan, C. D. Mottram, F. J. Puga, and G. K. Danielson. Cardiorespiratory response to exercise after modified fontan operation: determinants of performance. J. Am. Coll. Cardiol. 29:785–790, 1997.PubMedCrossRefGoogle Scholar
  10. 10.
    Gersony, W. Fontan operation after 3 decades - what we have learned. Circulation 117:13–15, 2008.PubMedCrossRefGoogle Scholar
  11. 11.
    Gewillig, M., S. C. Brown, B. Eyskens, R. Heying, J. Ganame, W. Budts, A. La Gerche, and M. Gorenflo. The fontan circulation: who controls cardiac output? Interact. CardioVasc. Thorac. Surg. 10:428–433, 2010.PubMedCrossRefGoogle Scholar
  12. 12.
    Gewillig, M. H., U. R. Lundström, C. Bull, R. K. Wyse, and J. E. Deanfield. Exercise responses in patients with congenital heart disease after fontan repair: patterns and determinants of performance. J. Am. Coll. Cardiol. 15:1424–1432, 1990.PubMedCrossRefGoogle Scholar
  13. 13.
    Goldman, L., and A. I. Schafer. Goldman’s Cecil Medicine, Chap. 5. Amsterdam: Elsevier, 2012.Google Scholar
  14. 14.
    Grigioni, F., M. Enriquez-Sarano, K. Zehr, K. Bailey, and A. Tajik. Ischemic mitral regurgitation - long-term outcome and prognostic implications with quantitative doppler assessment. Circulation 103:1759–1764, 2001.PubMedCrossRefGoogle Scholar
  15. 15.
    Grossi, E., G. Crooke, P. Digiorgi, C. Schwartz, U. Jorde, R. Applebaum, G. Ribakove, A. Galloway, J. Grau, and S. Colvin. Impact of moderate functional mitral insufficiency in patients undergoing surgical revascularization. Circulation 114:I573–I576, 2006.PubMedCrossRefGoogle Scholar
  16. 16.
    Hardt, S., S. Yazdi, A. Bauer, A. Filusch, G. Korosoglou, A. Hansen, R. Bekeredjian, P. Ehlermann, A. Remppis, H. Katus, and H. Kuecherer. Immediate and chronic effects of av-delay optimization in patients with cardiac resynchronization therapy. Int. J. Cardiol. 115:318–325, 2007.PubMedCrossRefGoogle Scholar
  17. 17.
    Hsia, T., S. Khambadkone, A. Redington, F. Migliavacca, J. Deanfield, and M. De Leval. Effects of respiration and gravity on infradiaphragmatic venous flow in normal and fontan patients. Circulation 102:148–153, 2000.Google Scholar
  18. 18.
    Koelling, T., K. Aaronson, R. Cody, D. Bach, and W. Armstrong. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am. Heart J. 144:524–529, 2002.PubMedCrossRefGoogle Scholar
  19. 19.
    Kung, E., A. Baretta, C. Baker, G. Arbia, G. Biglino, C. Corsini, S. Schievano, I. E. Vignon-Clementel, G. Dubini, G. Pennati, A. Taylor, A. Dorfman, A. M. Hlavacek, A. L. Marsden, T.-Y. Hsia, and F. Migliavacca. Predictive modeling of the virtual hemi-fontan operation for second stage single ventricle palliation: two patient-specific cases. J. Biomech. 46:423–429, 2013.PubMedCrossRefGoogle Scholar
  20. 20.
    Kung, E., G. Pennati, F. Migliavacca, T.-Y. Hsia, R. S. Figliola, A. Marsden, and A. Giardini. A simulation protocol for exercise physiology in fontan patients using a closed-loop lumped-parameter model. J. Biomech. Eng. 136(8):081007, 2014.CrossRefGoogle Scholar
  21. 21.
    Lamas, G., G. Mitchell, G. Flaker, S. Smith, B. Gersh, L. Basta, L. Moye, E. Braunwald, and M. Pfeffer. Clinical significance of mitral regurgitation after acute myocardial infarction. Circulation 96:827–833, 1997.PubMedCrossRefGoogle Scholar
  22. 22.
    Marsden, A. L., A. J. Bernstein, V. M. Reddy, S. C. Shadden, R. L. Spilker, F. P. Chan, C. A. Taylor, and J. A. Feinstein. Evaluation of a novel y-shaped extracardiac fontan baffle using computational fluid dynamics. J. Thorac. Cardiovasc. Surg. 137:394–403, 2009.PubMedCrossRefGoogle Scholar
  23. 23.
    Marsden, A. L., I. E. Vignon-Clementel, F. P. Chan, J. A. Feinstein, and C. A. Taylor. Effects of exercise and respiration on hemodynamic efficiency in cfd simulations of the total cavopulmonary connection. Ann. Biomed. Eng. 35:250–263, 2007.PubMedCrossRefGoogle Scholar
  24. 24.
    Migliavacca, F., R. Balossino, G. Pennati, G. Dubini, T. Y. Hsia, M. R. De Leval, and E. L. Bove. Multiscale modelling in biofluidynamics: application to reconstructive paediatric cardiac surgery. J. Biomech. 39:1010–1020, 2006.PubMedCrossRefGoogle Scholar
  25. 25.
    Morgan, B., W. Martin, T. Hornbein, and E. Crawford. Gunthero.Wg. Hemodynamic effects of intermittent positive pressure respiration. Anesthesiology 27:584–590, 1966.PubMedCrossRefGoogle Scholar
  26. 26.
    Paridon, S. M., P. D. Mitchell, S. D. Colan, R. V. Williams, A. Blaufox, J. S. Li, R. Margossian, S. Mital, J. Russell, J. Rhodes, and P. H. N. Investigators. A cross-sectional study of exercise performance during the first 2 decades of life after the fontan operation. J. Am. Coll. Cardiol. 52:99–107, 2008.PubMedCrossRefGoogle Scholar
  27. 27.
    Pekkan, K., B. Whited, K. Kanter, S. Sharma, D. De Zelicourt, K. Sundareswaran, D. Frakes, J. Rossignac, and A. P. Yoganathan. Patient-specific surgical planning and hemodynamic computational fluid dynamics optimization through free-form haptic anatomy editing tool (SURGEM). Med. Biol. Eng. Comput. 46:1139–1152, 2008.PubMedCrossRefGoogle Scholar
  28. 28.
    Reeves, J., J. Linehan, and K. Stenmark. Distensibility of the normal human lung circulation during exercise. Am. J. Physiol. Lung Cell. Mol. Physiol. 288:L419–L425, 2005.PubMedCrossRefGoogle Scholar
  29. 29.
    Sankaran, S., M. Moghadam, A. Kahn, E. Tseng, J. Guccione, and A. Marsden. Patient-specific multiscale modeling of blood flow for coronary artery bypass graft surgery. Ann. Biomed. Eng. 40:2228–2242, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Schroder, J., M. Williams, J. Hata, L. Muhlbaier, M. Swaminathan, J. Mathew, D. Glower, C. O’connor, P. Smith, and C. Milano. Impact of mitral valve regurgitation evaluated by intraoperative transesophageal echocardiography on long-term outcomes after coronary artery bypass grafting. Circulation 112:I293–I298, 2005.PubMedGoogle Scholar
  31. 31.
    Senzaki, H., C. Chen, and D. Kass. Single-beat estimation of end-systolic pressure-volume relation in humans - a new method with the potential for noninvasive application. Circulation 94:2497–2506, 1996.PubMedCrossRefGoogle Scholar
  32. 32.
    Stickland, M. K., R. C. Welsh, S. R. Petersen, J. V. Tyberg, W. D. Anderson, R. L. Jones, D. A. Taylor, M. Bouffard, and M. J. Haykowsky. Does fitness level modulate the cardiovascular hemodynamic response to exercise? J. Appl. Physiol. 100:1895–1901, 2006.PubMedCrossRefGoogle Scholar
  33. 33.
    Sundareswaran, K. S., K. Pekkan, L. P. Dasi, K. Whitehead, S. Sharma, K. R. Kanter, M. A. Fogel, and A. P. Yoganathan. The total cavopulmonary connection resistance: a significant impact on single ventricle hemodynamics at rest and exercise. Am. J. Physiol. Heart Circ. Physiol. 295:H2427–H2435, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Szabó, G., V. Buhmann, A. Graf, S. Melnitschuk, S. Bährle, C. F. Vahl, and S. Hagl. Ventricular energetics after the fontan operation: contractility-afterload mismatch. J. Thorac. Cardiovasc. Surg. 125:1061–1069, 2003.PubMedCrossRefGoogle Scholar
  35. 35.
    Takken, T., M. H. Tacken, A. C. Blank, E. H. Hulzebos, J. L. Strengers, and P. J. Helders. Exercise limitation in patients with fontan circulation: a review. J. Cardiovasc. Med. (Hagerstown) 8:775–781, 2007.CrossRefGoogle Scholar
  36. 36.
    Taylor, C. A., M. T. Draney, J. P. Ku, D. Parker, B. N. Steele, K. Wang, and C. K. Zarins. Predictive medicine: computational techniques in therapeutic decision-making. Comput. Aided Surg 4:231–247, 1999.PubMedCrossRefGoogle Scholar
  37. 37.
    Thavendiranathan, P., D. Phelan, P. Collier, J. D. Thomas, S. D. Flamm, and T. H. Marwick. Quantitative assessment of mitral regurgitation: how best to do it. JACC Cardiovasc. Imaging 5:1161–1175, 2012.PubMedCrossRefGoogle Scholar
  38. 38.
    Van De Bruaene, A., A. La Gerche, G. Claessen, P. De Meester, S. Devroe, H. Gillijns, J. Bogaert, P. Claus, H. Heidbuchel, M. Gewillig, and W. Budts. Sildenafil improves exercise hemodynamics in fontan patients. Circ. Cardiovasc. Imaging 7:265–273, 2014.CrossRefGoogle Scholar
  39. 39.
    Vignon-Clementel, I. E., A. L. Marsden, and J. A. Feinstein. A primer on computational simulation in congenital heart disease for the clinician. Prog. Pediatr. Cardiol. 30:3–13, 2010.CrossRefGoogle Scholar
  40. 40.
    Warburton, D. E., M. J. Haykowsky, H. A. Quinney, D. Blackmore, K. K. Teo, and D. P. Humen. Myocardial response to incremental exercise in endurance-trained athletes: influence of heart rate, contractility and the frank-starling effect. Exp. Physiol. 87:613–622, 2002.PubMedCrossRefGoogle Scholar
  41. 41.
    Whitehead, K. K., K. Pekkan, H. D. Kitajima, S. M. Paridon, A. P. Yoganathan, and M. A. Fogel. Nonlinear power loss during exercise in single-ventricle patients after the fontan: insights from computational fluid dynamics. Circulation 116:I165–I171, 2007.PubMedCrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2014

Authors and Affiliations

  • Ethan Kung
    • 1
    • 2
  • James C. Perry
    • 3
  • Christopher Davis
    • 3
  • Francesco Migliavacca
    • 4
  • Giancarlo Pennati
    • 4
  • Alessandro Giardini
    • 5
  • Tain-Yen Hsia
    • 5
  • Alison Marsden
    • 2
    Email author
  1. 1.Mechanical Engineering DepartmentClemson UniversityClemsonUSA
  2. 2.Mechanical and Aerospace Engineering DepartmentUniversity of California San DiegoLa JollaUSA
  3. 3.Rady Children’s Hospital/University of California San DiegoSan DiegoUSA
  4. 4.Department of Chemistry, Material and Chemical Engineering “Giulio Natta”Politecnico di MilanoMilanItaly
  5. 5.Great Ormond Street Hospital for ChildrenLondonUK

Personalised recommendations