Skip to main content

Advertisement

Log in

Reverse Remodelling and Recovery from Heart Failure Are Associated with Complex Patterns of Gene Expression

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Combined left ventricular assist device (LVAD) support and pharmacological management of the failing heart can induce reversal of maladaptive cardiac remodelling leading to normalisation of cardiac structure and recovery of cardiac function. The purpose of this study was to compare the gene expression profiles of recovered and non-recovered LVAD patients in order to identify mechanisms underlying the recovery process and differences which may determine outcome. Myocardial expression of 54 genes chosen for their potential role in heart failure and tissue repair was measured using quantitative PCR at the time of LVAD implantation and again at explantation (recovery, n = 13) or transplantation (non-recovery, n = 5). Patients who went on to recover had higher levels of Giα2, EPAC2 and lower levels of IGF2 at the time of LVAD implant compared to patients who failed to recover. During recovery, expression of BNP, IL-1β, VWF and SFRP1 was decreased whilst RGS4 increased. Expression of IGF1 and pro-fibrotic genes was coordinated during recovery. Correlation analysis identified a novel co-regulation of SFRP1 and βMHC in myocardium. In summary, the gene expression profile underlying recovery is complex and comprises both regression and exacerbation of elements of the pathological gene program. Modulation of Giα2, EPAC2, RGS4 and SFRP1 indicates that inhibition of cAMP signalling may potentiate recovery prior to treatment whilst enhanced cAMP and Wnt signalling may underlie recovery during LVAD support.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Mann, D. L., & Bristow, M. R. (2005). Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation, 111, 2837–2849.

    Article  PubMed  Google Scholar 

  2. Frazier, O. H., & Myers, T. J. (1999). Left ventricular assist system as a bridge to myocardial recovery. The Annals of Thoracic Surgery, 68, 734–741.

    Article  PubMed  CAS  Google Scholar 

  3. Muller, J., Wallukat, G., Weng, Y. G., et al. (1997). Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy. Circulation, 96, 542–549.

    PubMed  CAS  Google Scholar 

  4. Mancini, D. M., Beniaminovitz, A., Levin, H., et al. (1998). Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation, 98, 2383–2389.

    PubMed  CAS  Google Scholar 

  5. Birks, E., & George, R. (2010). Molecular changes occurring during reverse remodelling following left ventricular assist device support. Journal of Cardiovascular Translational Research, 3, 635–642.

    Article  PubMed  Google Scholar 

  6. Razeghi, P., Myers, T. J., Frazier, O. H., & Taegtmeyer, H. (2002). Reverse remodeling of the failing human heart with mechanical unloading. Emerging concepts and unanswered questions. Cardiology, 98, 167–174.

    Article  PubMed  Google Scholar 

  7. Farrar, D. J., Holman, W. R., McBride, L. R., et al. (2002). Long-term follow-up of thoratec ventricular assist device bridge-to-recovery patients successfully removed from support after recovery of ventricular function. The Journal of Heart and Lung Transplantation, 21, 516–521.

    Article  PubMed  Google Scholar 

  8. Simon, M. A., Kormos, R. L., Murali, S., et al. (2005). Myocardial recovery using ventricular assist devices: prevalence, clinical characteristics, and outcomes. Circulation, 112, I-32.

    Google Scholar 

  9. Dandel, M., Weng, Y., Siniawski, H., et al. (2005). Long-term results in patients with idiopathic dilated cardiomyopathy after weaning from left ventricular assist devices. Circulation, 112, I37–I45.

    Article  PubMed  Google Scholar 

  10. Birks, E. J., Tansley, P. D., Hardy, J., et al. (2006). Left ventricular assist device and drug therapy for the reversal of heart failure. The New England Journal of Medicine, 355, 1873–1884.

    Article  PubMed  CAS  Google Scholar 

  11. Hall, J. L., Birks, E. J., Grindle, S., et al. (2007). Molecular signature of recovery following combination left ventricular assist device (LVAD) support and pharmacologic therapy. European Heart Journal, 28, 613–627.

    Article  PubMed  CAS  Google Scholar 

  12. Felkin, L. E., Taegtmeyer, A. B., & Barton, P. J. (2006). Real-time quantitative polymerase chain reaction in cardiac transplant research. Methods in Molecular Biology, 333, 305–330.

    PubMed  CAS  Google Scholar 

  13. Felkin, L. E., Lara-Pezzi, E., George, R., et al. (2009). Expression of extracellular matrix genes during myocardial recovery from heart failure after left ventricular assist device support. The Journal of Heart and Lung Transplantation, 28, 117–122.

    Article  PubMed  Google Scholar 

  14. Cullen, M. E., Yuen, A. H., Felkin, L. E., et al. (2006). Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation, 114, I16–I20.

    Article  PubMed  Google Scholar 

  15. Breckenridge, R. A., Zuberi, Z., Gomes, J., et al. (2009). Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice. Journal of Molecular and Cellular Cardiology, 47, 133–141.

    Article  PubMed  CAS  Google Scholar 

  16. Lara-Pezzi, E., Terracciano, C. M., Soppa, G. K., et al. (2009). A gene expression profile of the myocardial response to clenbuterol. Journal of Cardiovascular Translational Research, 2, 191–197.

    Article  PubMed  Google Scholar 

  17. Hudon-David, F., Bouzeghrane, F., Couture, P., & Thibault, G. (2007). Thy-1 expression by cardiac fibroblasts: lack of association with myofibroblast contractile markers. Journal of Molecular and Cellular Cardiology, 42, 991–1000.

    Article  PubMed  CAS  Google Scholar 

  18. Barton, P. J. R., Felkin, L. E., Birks, E. J., et al. (2005). Myocardial insulin-like growth factor-I gene expression during recovery from heart failure after combined left ventricular assist device and clenbuterol therapy. Circulation, 112, 46–I52.

    Google Scholar 

  19. Birks, E. J., Latif, N., Owen, V. J., et al. (2001). Quantitative myocardial cytokine expression and activation of the apoptotic pathway in patients who require left ventricular assist devices. Circulation, 104, I233–I240.

    Article  PubMed  CAS  Google Scholar 

  20. Kuhn, M., Voss, M., Mitko, D., et al. (2004). Left ventricular assist device support reverses altered cardiac expression and function of natriuretic peptides and receptors in end-stage heart failure. Cardiovascular Research, 64, 308–314.

    Article  PubMed  CAS  Google Scholar 

  21. Bruggink, A. H., de Jonge, N., van Oosterhout, M. F. M., et al. (2006). Brain natriuretic peptide is produced both by cardiomyocytes and cells infiltrating the heart in patients with severe heart failure supported by a left ventricular assist device. The Journal of Heart and Lung Transplantation, 25, 174–180.

    Article  PubMed  Google Scholar 

  22. Kawano, Y., & Kypta, R. (2003). Secreted antagonists of the Wnt signalling pathway. Journal of Cell Science, 116, 2627–2634.

    Article  PubMed  CAS  Google Scholar 

  23. Bergmann, M. W. (2010). Wnt signaling in adult cardiac hypertrophy and remodeling: lessons learned from cardiac development. Circulation Research, 107, 1198–1208.

    Article  PubMed  CAS  Google Scholar 

  24. Kaga, S., Zhan, L., Altaf, E., & Maulik, N. (2006). Glycogen synthase kinase-3β/β-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. Journal of Molecular and Cellular Cardiology, 40, 138–147.

    Article  PubMed  CAS  Google Scholar 

  25. Hahn, J. Y., Cho, H. J., Bae, J. W., et al. (2006). β-Catenin overexpression reduces myocardial infarct size through differential effects on cardiomyocytes and cardiac fibroblasts. The Journal of Biological Chemistry, 281, 30979–30989.

    Article  PubMed  CAS  Google Scholar 

  26. Mestdagt, M. (2006). Transactivation of MCP-1/CCL2 by β-catenin/TCF-4 in human breast cancer cells. International Journal of Cancer, 118, 35–42.

    Article  CAS  Google Scholar 

  27. Lowes, B. D., Minobe, W., Abraham, W. T., et al. (1997). Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. Journal of Clinical Investigation, 100, 2315–2324.

    Article  PubMed  CAS  Google Scholar 

  28. Birks, E. J., Hall, J. L., Barton, P. J. R., et al. (2005). Gene profiling changes in cytoskeletal proteins during clinical recovery following left ventricular assist device (LVAD) support. Circulation, 112, I57–I64.

    PubMed  Google Scholar 

  29. Latif, N., Yacoub, M. H., George, R., et al. (2007). Changes in sarcomeric and non-sarcomeric cytoskeletal proteins and focal adhesion molecules during clinical myocardial recovery after left ventricular assist device support. The Journal of Heart and Lung Transplantation, 26, 230–235.

    Article  PubMed  Google Scholar 

  30. Vischer, U. M. (2006). von Willebrand factor, endothelial dysfunction, and cardiovascular disease. Journal of Thrombosis and Haemostasis, 4, 1186–1193.

    Article  PubMed  CAS  Google Scholar 

  31. Miller, L. W. (2010). The development of the von Willebrand syndrome with the use of continuous flow left ventricular assist devices: a cause-and-effect relationship. Journal of the American College of Cardiology, 56, 1214–1215.

    Article  PubMed  Google Scholar 

  32. Owen, V. J., Burton, P. B. J., Mullen, A. J., et al. (2001). Expression of RGS3, RGS4 and Gi alpha 2 in acutely failing donor hearts and end-stage heart failure. European Heart Journal, 22, 1015–1020.

    Article  PubMed  CAS  Google Scholar 

  33. Tokudome, T., Kishimoto, I., Horio, T., et al. (2008). Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Circulation, 117, 2329–2339.

    Article  PubMed  CAS  Google Scholar 

  34. Wieland, T., & Mittmann, C. (2003). Regulators of G-protein signalling: multifunctional proteins with impact on signalling in the cardiovascular system. Pharmacology & Therapeutics, 97, 95–115.

    Article  CAS  Google Scholar 

  35. Takeishi, Y., Jalili, T., Hoit, B. D., et al. (2000). Alterations in Ca2+ cycling proteins and G α q signaling after left ventricular assist device support in failing human hearts. Cardiovascular Research, 45, 883–888.

    Article  PubMed  CAS  Google Scholar 

  36. Gloerich, M., & Bos, J. L. (2010). Epac: defining a new mechanism for cAMP action. Annual Review of Pharmacology and Toxicology, 50, 355–375.

    Article  PubMed  CAS  Google Scholar 

  37. Movsesian, M. A. (2004). Altered cAMP-mediated signalling and its role in the pathogenesis of dilated cardiomyopathy. Cardiovascular Research, 62, 450–459.

    Article  PubMed  CAS  Google Scholar 

  38. Musaro, A., Giacinti, C., Borsellino, G., et al. (2004). Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1. Proceedings of the National Academy of Sciences of the United States of America, 101, 1206–1210.

    Article  PubMed  CAS  Google Scholar 

  39. Santini, M. P., Tsao, L., Monassier, L., et al. (2007). Enhancing repair of the mammalian heart. Circulation Research, 100, 1732–1740.

    Article  PubMed  CAS  Google Scholar 

  40. Bruckner, B. A., Razeghi, P., Stetson, S., et al. (2004). Degree of cardiac fibrosis and hypertrophy at time of implantation predicts myocardial improvement during left ventricular assist device support. The Journal of Heart and Lung Transplantation, 23, 36–42.

    Article  PubMed  Google Scholar 

  41. Sharma, S., Ying, J., Razeghi, P., et al. (2006). Atrophic remodeling of the transplanted rat heart. Cardiology, 105, 128–136.

    Article  PubMed  Google Scholar 

  42. Bhavsar, P. K., Brand, N. J., Felkin, L. E., et al. (2010). Clenbuterol induces cardiac myocyte hypertrophy via paracrine signalling and fibroblast-derived IGF-1. Journal of Cardiovascular Translational Research, 3, 688–695.

    Article  PubMed  Google Scholar 

  43. Lara-Pezzi, E., Felkin, L. E., Birks, E. J., et al. (2008). Expression of follistatin-related genes is altered in heart failure. Endocrine, 149, 5822–5827.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Thoratec Corporation, The Royal Brompton and Harefield Charitable Trustees, the Magdi Yacoub Institute, Heart Research UK and by the National Institutes of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul J. R. Barton.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Online resource 1

Taqman assay details. (DOC 208 kb)

Online resource 2

Detailed analysis of the effect of segregating the recovery patients according to IGF1 gene expression at implant. qPCR was used to measure mRNA levels in left ventricular myocardium collected at the time of LVAD implant and explant in up to 13 recovery patients. The data were sub-grouped according to the patient's IGF1 status. Data are presented as the relative expression levels in individual patients at implant and explant and as the mean relative expression levels at implant and explant ± SEM. The significance of the change in expression in individual patients was assessed using a non-parametric paired t test (*p < 0.05), and differences in the mean implant and explant levels between the groups was tested using a non-parametric unpaired t test (#p < 0.05, ##p < 0.01) (DOC 60 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Felkin, L.E., Lara-Pezzi, E.A., Hall, J.L. et al. Reverse Remodelling and Recovery from Heart Failure Are Associated with Complex Patterns of Gene Expression. J. of Cardiovasc. Trans. Res. 4, 321–331 (2011). https://doi.org/10.1007/s12265-011-9267-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-011-9267-1

Keywords

Navigation