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A Multidisciplinary Assessment of Remote Myocardial Fibrosis After Reperfused Myocardial Infarction in Swine and Patients

Abstract

In extensive nonreperfused myocardial infarction (MI), remote fibrosis has been documented. Early reperfusion by primary angioplasty represents the gold standard method to minimize the extension of the infarction. We aimed to ascertain whether fibrosis also affects remote regions in reperfused MI in swine and patients. Swine were subjected to a transient occlusion of the left anterior descending artery followed by 1-week or 1-month reperfusion. Collagen content in the remote area macroscopically, microscopically, by magnetic resonance microimaging, and at the molecular level was similar to controls. In patients with previous MI, samples from autopsies displayed a significant increase in collagen content only in the infarct region. In patients with previous MI submitted to cardiac magnetic resonance-T1 mapping, the extracellular volume fraction in remote segments was similar to that for controls. In all scenarios, the remote region did not show a significant increase of collagen content in comparison with controls.

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Abbreviations

α-SMA:

Alpha-smooth muscle actin

CMR:

Cardiac magnetic resonance

COL1A1:

Collagen type I alpha 1

COL1A2:

Collagen type I alpha 2

COL3A1:

Collagen type III alpha 1

ECV:

Extracellular volume fraction

MI:

Myocardial infarction

TGF-β:

Transforming growth factor-β

TS:

Thioflavin-S

TTZ:

2,3,5-Triphenyltetrazolium chloride

References

  1. van den Borne, S. W. M., Diez, J., Blankesteijn, W. M., Verjans, J., Hofstra, L., & Narula, J. (2010). Myocardial remodeling after infarction: the role of myofibroblasts. Nature Reviews Cardiology, 7, 30–37.

    Article  PubMed  Google Scholar 

  2. Daskalopoulos, E. P., Janssen, B. J. A., & Blankesteijn, W. M. (2012). Myofibroblasts in the infarct area: concepts and challenges. Microscopy and Microanalysis, 18, 35–49.

    CAS  Article  PubMed  Google Scholar 

  3. Beltrami, C. A., Finato, N., Rocco, M., Feruglio, G. A., Puricelli, C., Cigola, E., Quaini, F., Sonnenblick, E. H., Olivetti, G., & Anversa, P. (1994). Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation, 89, 151–163.

    CAS  Article  PubMed  Google Scholar 

  4. Cleutjens, J. P. M., Verluyten, M. J. A., Smiths, J. F. M., & Daemen, M. J. A. P. (1995). Collagen remodeling after myocardial infarction in the rat heart. American Journal of Pathology, 147, 325–338.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Sun, Y., & Weber, K. T. (2000). Infarct scar: a dynamic tissue. Cardiovascular Research, 46, 250–256.

    CAS  Article  PubMed  Google Scholar 

  6. Sun, Y., Zhang, J. Q., Zhang, J., & Lamparter, S. (2000). Cardiac remodeling by fibrous tissue after infarction in rats. Journal of Laboratory and Clinical Medicine, 135, 316–323.

    CAS  Article  PubMed  Google Scholar 

  7. Sun, Y. (2009). Myocardial repair/remodelling following infarction: roles of local factors. Cardiovascular Research, 81, 482–490.

    CAS  Article  PubMed  Google Scholar 

  8. dos Santos, L., Gonçalves, G. A., Davel, A. P., Santos, A. A., Krieger, J. E., Rossoni, L. V., & Tucci, P. J. (2013). Cell therapy prevents structural, functional and molecular remodeling of remote non-infarcted myocardium. International Journal of Cardiology, 168, 3829–3836.

    Article  PubMed  Google Scholar 

  9. Hervas, A., de Dios, E., Forteza, M. J., Miñana, G., Nuñez, J., Ruiz-Sauri, A., Bonanad, C., Perez-Sole, N., Chorro, F. J., & Bodi, V. (2015). Intracoronary infusion of thioflavin-S to study microvascular obstruction in a model of myocardial infarction. Revista Española de Cardiología, 68, 928–934.

    Article  PubMed  Google Scholar 

  10. Hervas, A., Ruiz-Sauri, A., de Dios, E., Forteza, M. J., Minana, G., Nunez, J., Gomez, C., Bonanad, C., Perez-Sole, N., Gavara, J., Chorro, F. J., & Bodi, V. (2016). Inhomogeneity of collagen organization within the fibrotic scar after myocardial infarction: results in a swine model and in human samples. Journal of Anatomy, 228, 47–58.

    CAS  Article  PubMed  Google Scholar 

  11. Marijianowski, M. M. H., Teeling, P., & Becker, A. E. (1997). Remodeling after myocardial infarction in humans is not associated with interstitial fibrosis of noninfarcted myocardium. Journal of the American College of Cardiology, 30, 76–82.

    CAS  Article  PubMed  Google Scholar 

  12. Tarkia, M., Stark, C., Haavisto, M., Kentala, R., Vähäsilta, T., Savunen, T., Strandberg, M., Hynninen, V. V., Saunavaara, V., Tolvanen, T., Teräs, M., Rokka, J., Pietilä, M., Saukko, P., Roivainen, A., Saraste, A., & Knuuti, J. (2015). Cardiac remodeling in a new pig model of chronic heart failure: assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography. Journal of Nuclear Cardiology, 22, 655–665.

    Article  PubMed  Google Scholar 

  13. van den Borne, S. W. M., Isobe, S., Verjans, J. W., Petrov, A., Lovhaug, D., Li, P., Zandbergen, H. R., Ni, Y., Frederik, P., Zhou, J., Arbo, B., Rogstad, A., Cuthbertson, A., Chettibi, S., Reutelingsperger, C., Blankesteijn, W. M., Smits, J. F., Daemen, M. J., Zannad, F., Vannan, M. A., Narula, N., Pitt, B., Hofstra, L., & Narula, J. (2008). Molecular imaging of interstitial alterations in remodeling myocardium after myocardial infarction. Journal of the American College of Cardiology, 52, 2017–2028.

    Article  PubMed  Google Scholar 

  14. Prat-Vidal, C., Gálvez-Montón, C., Nonell, L., Puigdecanet, E., Astier, L., Solé, F., & Bayes-Genis, A. (2013). Identification of temporal and region-specific myocardial gene expression patterns in response to infarction in swine. PLoS ONE, 8, e54785.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Monreal, G., Nicholson, L. M., Han, B., Joshi, M. S., Phillips, A. B., Wold, L. E., Bauer, J. A., & Gerhardt, M. A. (2008). Cytoskeletal remodeling of desmin is a more accurate measure of cardiac dysfunction than fibrosis or myocyte hypertrophy. Life Sciences, 83, 786–794.

    CAS  Article  PubMed  Google Scholar 

  16. Frangogiannis, N. G. (2014). The inflammatory response in myocardial injury, repair and remodeling. Nature Reviews Cardiology, 11, 255–265.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Vilahur, G., Juan-Babot, O., Peña, E., Oñate, B., Casaní, L., & Badimon, L. (2011). Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction. Journal of Molecular and Cellular Cardiology, 50, 522–533.

    CAS  Article  PubMed  Google Scholar 

  18. Hao, J., Ju, H., Zhao, S., Junaid, A., Scammell-La Fleur, T., & Dixon, I. M. C. (1999). Elevation of expression of Smads 2, 3, and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. Journal of Molecular and Cellular Cardiology, 31, 667–678.

    CAS  Article  PubMed  Google Scholar 

  19. Willems, I. E. M. G., Havenith, M. G., De Mey, J. G. R., & Daemen, M. J. A. P. (1994). The alpha-smooth muscle actin-positive cells in healing human myocardial scars. American Journal of Pathology, 145, 868–875.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gonzalez-Segura, A., Morales, J. M., Gonzalez-Darder, J. M., Cardona-Marsal, R., Lopez-Gines, C., Cerda-Nicolas, M., & Monleon, D. (2011). Magnetic resonance microscopy at 14 Tesla and correlative histopathology of human brain tumor tissue. PLoS One, 6, e27442.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. White, S. K., Sado, D. M., Fontana, M., Banypersad, S. M., Maestrini, V., Flett, A. S., Piechnik, S. K., Robson, M. D., Hausenloy, D. J., Sheikh, A. M., Hawkins, P. N., & Moon, J. C. (2013). T1 mapping for myocardial extracellular volume measurement by CMR: bolus only versus primed infusion technique. JACC. Cardiovascular Imaging, 6, 955–962.

    Article  PubMed  Google Scholar 

  22. Ugander, M., Oki, A. J., Hsu, L. Y., Kellman, P., Greiser, A., Aletras, A. H., Sibley, C. T., Chen, M. Y., Bandettini, W. P., & Arai, A. E. (2012). Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology. European Heart Journal, 33, 1268–1278.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. de Souza, R. R. (2002). Aging of myocardial collagen. Biogerontology, 3, 325–335.

    Article  PubMed  Google Scholar 

  24. Olivetti, G., Melissari, M., Capasso, J. M., & Anversa, P. (1991). Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circulation Research, 68, 1560–1568.

    CAS  Article  PubMed  Google Scholar 

  25. Horn, M. A., & Trafford, A. W. (2015). Aging and the cardiac collagen matrix: novel mediators of fibrotic remodelling. Journal of Molecular and Cellular Cardiology. doi:10.1016/j.yjmcc.2015.11.005.

    PubMed Central  Google Scholar 

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Correspondence to Amparo Ruiz-Sauri or Vicente Bodi.

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Human Subjects Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees and conform to the ethical guidelines of the 1975 Declaration of Helsinki as revised in 2000.

Animal Studies Statement

The local Animal Care and Use Committee approved the study, and it conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1993).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Sources of Funding

This work was supported by the ‘Instituto de Salud Carlos III’ and co-funded by ‘FEDER’ [grant numbers PI14/00271, PIE15/00013] and by the ‘Generalitat Valenciana’ [grant number PROMETEO/2013/007].

Additional information

Associate Editor Enrique Lara-Pezzi oversaw the review of this article

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Online Resource 1

Expanded methodology used in the study. (PDF 443 kb)

Online Resource 2

Table of risk factors and baseline characteristics of controls and patients with previous myocardial infarcts submitted to cardiac magnetic resonance-T1 mapping. (PDF 53 kb)

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Hervas, A., Ruiz-Sauri, A., Gavara, J. et al. A Multidisciplinary Assessment of Remote Myocardial Fibrosis After Reperfused Myocardial Infarction in Swine and Patients. J. of Cardiovasc. Trans. Res. 9, 321–333 (2016). https://doi.org/10.1007/s12265-016-9698-9

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  • DOI: https://doi.org/10.1007/s12265-016-9698-9

Keywords

  • Myocardial infarction
  • Reperfusion
  • Remote fibrosis
  • Swine model