Skip to main content
SpringerLink
Log in

Molecular Aspects of Right Ventricular Adaptation to Stress

  • Chapter
  • First Online:
Right Ventricular Physiology, Adaptation and Failure in Congenital and Acquired Heart Disease

  • 1117 Accesses

Abstract

The development of left ventricular (LV) hypertrophy and the progression to LV failure have been extensively studied and have provided valuable insight into the mechanisms of disease progression. However, there is minimal data on the right ventricular (RV) adaptation to pressure and volume loading. These hemodynamic stressors are commonly seen in children and adults after surgery for congenital heart disease (CHD), placing the RV at risk for progression to heart failure. Here, we will highlight some of similarities and differences in the molecular remodeling between the right and left ventricles when subjected to abnormal loading conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890–900.

    Article  PubMed  Google Scholar 

  2. Belmont JW. Recent progress in the molecular genetics of congenital heart defects. Clin Genet. 1998;54(1):11–9.

    Article  CAS  PubMed  Google Scholar 

  3. Lund O, Kristensen LH, Baandrup U, Hansen OK, Nielsen TT, Emmertsen K, et al. Myocardial structure as a determinant of pre- and postoperative ventricular function and long-term prognosis after valve replacement for aortic stenosis. Eur Heart J. 1998;19(7):1099–108.

    Article  CAS  PubMed  Google Scholar 

  4. Douglas PS, Reichek N, Hackney K, Ioli A, Sutton MG. Contribution of afterload, hypertrophy and geometry to left ventricular ejection fraction in aortic valve stenosis, pure aortic regurgitation and idiopathic dilated cardiomyopathy. Am J Cardiol. 1987;59(15):1398–404.

    Article  CAS  PubMed  Google Scholar 

  5. Kaufman BD, Desai M, Reddy S, Osorio JC, Chen JM, Mosca RS, et al. Genomic profiling of left and right ventricular hypertrophy in congenital heart disease. J Card Fail. 2008;14(9):760–7.

    Article  CAS  PubMed  Google Scholar 

  6. Buermans HP, Redout EM, Schiel AE, Musters RJ, Zuidwijk M, Eijk PP, et al. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics. 2005;21(3):314–23.

    Article  CAS  PubMed  Google Scholar 

  7. Gentles TL, Mayer JE Jr, Gauvreau K, Newburger JW, Lock JE, Kupferschmid JP, et al. Fontan operation in five hundred consecutive patients: factors influencing early and late outcome. J Thorac Cardiovasc Surg. 1997;4(3):376–91.

    Article  Google Scholar 

  8. Winter MM, Bouma BJ, Groenink M, Konings TC, Tijssen JG, van Veldhuisen DJ, et al. Latest insights in therapeutic options for systemic right ventricular failure: a comparison with left ventricular failure. Heart. 2009;95(12):960–3.

    Article  CAS  PubMed  Google Scholar 

  9. Szymanski P, Klisiewicz A, Hoffman P. Therapeutic options for systemic right ventricular failure. Heart. 2009;95(23):1950–1. Author reply 1.

    Article  CAS  PubMed  Google Scholar 

  10. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007;298(10):1171–9.

    Article  PubMed  Google Scholar 

  11. Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, et al. Enalapril in infants with single ventricle: results of a multicenter randomized trial. Circulation. 2010;122(4):333–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Buckberg GD, RESTORE Group. The ventricular septum: the lion of right ventricular function, and its impact on right ventricular restoration. Eur J Cardiothorac Surg. 2006;29(Suppl 1):S272–8.

    Article  PubMed  Google Scholar 

  13. Friedberg MK, Redington AN. Right versus left ventricular failure: differences, similarities, and interactions. Circulation. 2014;129(9):1033–44.

    Article  PubMed  Google Scholar 

  14. Kondo RP, Dederko DA, Teutsch C, Chrast J, Catalucci D, Chien KR, et al. Comparison of contraction and calcium handling between right and left ventricular myocytes from adult mouse heart: a role for repolarization waveform. J Physiol. 2006;571(Pt 1):131–46.

    Article  CAS  PubMed  Google Scholar 

  15. Piao L, Marsboom G, Archer SL. Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure. J Mol Med. 2010;88(10):1011–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Urashima T, Zhao M, Wagner R, Fajardo G, Farahani S, Quertermous T, et al. Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis. Am J Physiol Heart Circ Physiol. 2008;295(3):H1351–H68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Reddy S, Bernstein D. Molecular Mechanisms of Right Ventricular Failure. Circulation. 2015;132(18):1734–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Reddy S, Bernstein D. The vulnerable right ventricle. Curr Opin Pediatr. 2015;27(5):563–8.

    Article  PubMed  Google Scholar 

  19. Tsutsui H, Ide T, Hayashidani S, Suematsu N, Utsumi H, Nakamura R, et al. Greater susceptibility of failing cardiac myocytes to oxygen free radical-mediated injury. Cardiovasc Res. 2001;49(1):103–9.

    Article  CAS  PubMed  Google Scholar 

  20. Gomez-Arroyo J, Mizuno S, Szczepanek K, Van Tassell B, Natarajan R, dos Remedios CG, et al. Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail. 2013;6(1):136–44.

    Article  CAS  PubMed  Google Scholar 

  21. Ecarnot-Laubriet A, Rochette L, Vergely C, Sicard P, Teyssier JR. The activation pattern of the antioxidant enzymes in the right ventricle of rat in response to pressure overload is of heart failure type. Heart Dis. 2003;5(5):308–12.

    Article  CAS  PubMed  Google Scholar 

  22. Redout EM, van der Toorn A, Zuidwijk MJ, van de Kolk CW, van Echteld CJ, Musters RJ, et al. Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure. Am J Physiol Heart Circ Physiol. 2010;298(3):H1038–47.

    Article  CAS  PubMed  Google Scholar 

  23. Redout EM, Wagner MJ, Zuidwijk MJ, Boer C, Musters RJ, van Hardeveld C, et al. Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species. Cardiovasc Res. 2007;75(4):770–81.

    Article  CAS  PubMed  Google Scholar 

  24. Karamanlidis G, Bautista-Hernandez V, Fynn-Thompson F, Del Nido P, Tian R. Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease. Circ Heart Fail. 2011;4(6):707–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zong P, Tune JD, Downey HF. Mechanisms of oxygen demand/supply balance in the right ventricle. Exp Biol Med. 2005;230(8):507–19.

    Article  CAS  Google Scholar 

  26. Saito D, Tani H, Kusachi S, Uchida S, Ohbayashi N, Marutani M, et al. Oxygen metabolism of the hypertrophic right ventricle in open chest dogs. Cardiovasc Res. 1991;25(9):731–9.

    Article  CAS  PubMed  Google Scholar 

  27. Choi YH, Cowan DB, Nathan M, Poutias D, Stamm C, del Nido PJ, et al. Myocardial hypertrophy overrides the angiogenic response to hypoxia. PLoS One. 2008;3(12):e4042.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation. 2009;120(20):1951–60.

    Article  PubMed  Google Scholar 

  29. Zamir M. The physics of coronary blood flow. New York: Springer; 2005.

    Google Scholar 

  30. Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007;446(7134):444–8.

    Article  CAS  PubMed  Google Scholar 

  31. Partovian C, Adnot S, Eddahibi S, Teiger E, Levame M, Dreyfus P, et al. Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension. Am J Phys. 1998;275(6 Pt 2):H1948–56.

    CAS  Google Scholar 

  32. Setty S, Tune JD, Downey HF. Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle. Cardiovasc Res. 2004;64(3):431–6.

    Article  CAS  PubMed  Google Scholar 

  33. Tune JD, Richmond KN, Gorman MW, Feigl EO. Role of nitric oxide and adenosine in control of coronary blood flow in exercising dogs. Circulation. 2000;101(25):2942–8.

    Article  CAS  PubMed  Google Scholar 

  34. Piao L, Fang YH, Parikh KS, Ryan JJ, D’Souza KM, Theccanat T, et al. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation. 2012;126(24):2859–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Norozi K, Bahlmann J, Raab B, Alpers V, Arnhold JO, Kuehne T, et al. A prospective, randomized, double-blind, placebo controlled trial of beta-blockade in patients who have undergone surgical correction of tetralogy of Fallot. Cardiol Young. 2007;17(4):372–9.

    Article  PubMed  Google Scholar 

  36. Doughan AR, McConnell ME, Book WM. Effect of beta blockers (carvedilol or metoprolol XL) in patients with transposition of great arteries and dysfunction of the systemic right ventricle. Am J Cardiol. 2007;99(5):704–6.

    Article  CAS  PubMed  Google Scholar 

  37. Molenaar P, Bartel S, Cochrane A, Vetter D, Jalali H, Pohlner P, et al. Both beta(2)- and beta(1)-adrenergic receptors mediate hastened relaxation and phosphorylation of phospholamban and troponin I in ventricular myocardium of Fallot infants, consistent with selective coupling of beta(2)-adrenergic receptors to G(s)-protein. Circulation. 2000;102(15):1814–21.

    Article  CAS  PubMed  Google Scholar 

  38. Wang GY, McCloskey DT, Turcato S, Swigart PM, Simpson PC, Baker AJ. Contrasting inotropic responses to alpha1-adrenergic receptor stimulation in left versus right ventricular myocardium. Am J Physiol Heart Circ Physiol. 2006;291(4):H2013–7.

    Article  CAS  PubMed  Google Scholar 

  39. Wang GY, Yeh CC, Jensen BC, Mann MJ, Simpson PC, Baker AJ. Heart failure switches the RV alpha1-adrenergic inotropic response from negative to positive. Am J Physiol Heart Circ Physiol. 2010;298(3):H913–20.

    Article  CAS  PubMed  Google Scholar 

  40. Anand IS, Chandrashekhar Y, Ferrari R, Sarma R, Guleria R, Jindal SK, et al. Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery. Circulation. 1992;86(1):12–21.

    Article  CAS  PubMed  Google Scholar 

  41. Farber MO, Roberts LR, Weinberger MH, Robertson GL, Fineberg NS, Manfredi F. Abnormalities of sodium and H2O handling in chronic obstructive lung disease. Arch Intern Med. 1982;142(7):1326–30.

    Article  CAS  PubMed  Google Scholar 

  42. Schrier RW, Bansal S. Pulmonary hypertension, right ventricular failure, and kidney: different from left ventricular failure? Clin J Am Soc Nephrol. 2008;3(5):1232–7.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Maron BA, Leopold JA. The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series). Pulm Circ. 2014;4(2):200–10.

    Article  PubMed  PubMed Central  Google Scholar 

  44. van der Bom T, Winter MM, Bouma BJ, Groenink M, Vliegen HW, Pieper PG, et al. Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial. Circulation. 2013;127(3):322–30.

    Article  PubMed  Google Scholar 

  45. Dore A, Houde C, Chan KL, Ducharme A, Khairy P, Juneau M, et al. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial. Circulation. 2005;112(16):2411–6.

    Article  CAS  PubMed  Google Scholar 

  46. Robinson B, Heise CT, Moore JW, Anella J, Sokoloski M, Eshaghpour E. Afterload reduction therapy in patients following intraatrial baffle operation for transposition of the great arteries. Pediatr Cardiol. 2002;23(6):618–23.

    Article  CAS  PubMed  Google Scholar 

  47. Phillips D, Aponte AM, Covian R, Neufeld E, ZX Y, Balaban RS. Homogenous protein programming in the mammalian left and right ventricle free walls. Physiol Genomics. 2011;43(21):1198–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nagendran J, Gurtu V, Fu DZ, Dyck JR, Haromy A, Ross DB, et al. A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. J Thorac Cardiovasc Surg. 2008;136(1):168–78. 78 e1-3.

    Article  PubMed  Google Scholar 

  49. Kusachi S, Nishiyama O, Yasuhara K, Saito D, Haraoka S, Nagashima H. Right and left ventricular oxygen metabolism in open-chest dogs. Am J Phys. 1982;243(5):H761–6.

    CAS  Google Scholar 

  50. Do E, Baudet S, Verdys M, Touzeau C, Bailly F, Lucas-Heron B, et al. Energy metabolism in normal and hypertrophied right ventricle of the ferret heart. J Mol Cell Cardiol. 1997;29(7):1903–13.

    Article  CAS  PubMed  Google Scholar 

  51. Gunes Y, Guntekin U, Tuncer M, Sahin M. Improved left and right ventricular functions with trimetazidine in patients with heart failure: a tissue Doppler study. Heart Vessel. 2009;24(4):277–82.

    Article  Google Scholar 

  52. Gu Q, Chen XT, Xiao YB, Chen L, Wang XF, Fang J, et al. Identification of differently expressed genes and small molecule drugs for Tetralogy of Fallot by bioinformatics strategy. Pediatr Cardiol. 2014;35(5):863–9.

    Article  PubMed  Google Scholar 

  53. Rastogi S, Sharov VG, Mishra S, Gupta RC, Blackburn B, Belardinelli L, et al. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol. 2008;295(5):H2149–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Phan TT, Shivu GN, Choudhury A, Abozguia K, Davies C, Naidoo U, et al. Multi-centre experience on the use of perhexiline in chronic heart failure and refractory angina: old drug, new hope. Eur J Heart Fail. 2009;11(9):881–6.

    Article  CAS  PubMed  Google Scholar 

  55. Halbirk M, Norrelund H, Moller N, Schmitz O, Gotzsche L, Nielsen R, et al. Suppression of circulating free fatty acids with acipimox in chronic heart failure patients changes whole body metabolism but does not affect cardiac function. Am J Physiol Heart Circ Physiol. 2010;299(4):H1220–5.

    Article  CAS  PubMed  Google Scholar 

  56. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962–5.

    Article  CAS  PubMed  Google Scholar 

  57. O’Connor RD, Xu J, Ewald GA, Ackerman JJ, Peterson LR, Gropler RJ, et al. Intramyocardial triglyceride quantification by magnetic resonance spectroscopy: In vivo and ex vivo correlation in human subjects. Magn Reson Med. 2011;65(5):1234–8.

    Article  PubMed  Google Scholar 

  58. Reddy S, Zhao M, Hu DQ, Fajardo G, Katznelson E, Punn R, et al. Physiologic and molecular characterization of a murine model of right ventricular volume overload. Am J Physiol Heart Circ Physiol. 2013;304(10):H1314–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cordes KR, Srivastava D. MicroRNA regulation of cardiovascular development. Circ Res. 2009;104(6):724–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Callis TE, Wang DZ. Taking microRNAs to heart. Trends Mol Med. 2008;14(6):254–60.

    Article  CAS  PubMed  Google Scholar 

  61. El-Armouche A, Schwoerer AP, Neuber C, Emmons J, Biermann D, Christalla T, et al. Common microRNA signatures in cardiac hypertrophic and atrophic remodeling induced by changes in hemodynamic load. PLoS One. 2010;5(12):e14263.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Yang M, Yao Y, Eades G, Zhang Y, Zhou Q. MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism. Breast Cancer Res Treat. 2011;129(3):983–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Smith-Vikos T, Slack FJ. MicroRNAs and their roles in aging. J Cell Sci. 2012;125(Pt 1):7–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yu J, Li Q, Xu Q, Liu L, Jiang B. MiR-148a inhibits angiogenesis by targeting ERBB3. J Biomed Res. 2011;25(3):170–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Reddy S, Zhao M, Hu DQ, Fajardo G, Hu S, Ghosh Z, et al. Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics. 2012;44(10):562–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tabuchi T, Satoh M, Itoh T, Nakamura M. MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. Clin Sci (Lond). 2012;123(3):161–71.

    Article  CAS  Google Scholar 

  67. Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495(7439):107–10.

    Article  CAS  PubMed  Google Scholar 

  68. Potus F, Malenfant S, Graydon C, Mainguy V, Tremblay E, Breuils-Bonnet S, et al. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014;190(3):318–28.

    CAS  PubMed  Google Scholar 

  69. Thum T, Batkai S. MicroRNAs in right ventricular (dys)function (2013 Grover Conference series). Pulm Circ. 2014;4(2):185–90.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Paulin R, Sutendra G, Gurtu V, Dromparis P, Haromy A, Provencher S, et al. A miR-208-Mef2 axis drives the decompensation of right ventricular function in pulmonary hypertension. Circ Res. 2015;116(1):56–69.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Mingming Zhao, Dong-Qing Hu, and Giovanni Fajardo. NIH/NHLBI grant HL061535 (DB); Children’s Heart Foundation grant (DB and SR); Packard Children’s Hospital Pediatric Research Fund, Heart Center Research Fund and Reddy Foundation grant (SR); NIH/NHLBI 1K08HL127277 (SR). Department of Defense CMDRP in Congenital Heart Disease (DB and SR).

Author information

Authors and Affiliations

  1. Pediatric Cardiology, Lucile Packard Children’s Hospital, Stanford University, 750 Welch Rd, Ste 305, Palo Alto, CA, 94304, USA

    Sushma Reddy & Daniel Bernstein

Authors
  1. Sushma Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Bernstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sushma Reddy .

Editor information

Editors and Affiliations

  1. Paediatric Cardiology, Labatt Family Heart Center Hospital for Sick Children, Toronto, Ontario, Canada

    Mark K. Friedberg

  2. Heart Institute, Cincinnati Children’s Hosp Med Center, Cincinnati, Ohio, USA

    Andrew N. Redington

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Reddy, S., Bernstein, D. (2018). Molecular Aspects of Right Ventricular Adaptation to Stress. In: Friedberg, M., Redington, A. (eds) Right Ventricular Physiology, Adaptation and Failure in Congenital and Acquired Heart Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-67096-6_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-67096-6_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-67094-2

  • Online ISBN: 978-3-319-67096-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation