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Applying Fractal Dimension and Image Analysis to Quantify Fibrotic Collagen Deposition and Organization in the Normal and Hypertensive Heart

Published online by Cambridge University Press:  07 July 2014

Fouad A. Zouein ,
Mazen Kurdi ,
George W. Booz  and
John W. Fuseler
Fouad A. Zouein
Affiliation:
Department of Pharmacology and Toxicology, School of Medicine and the Center for Excellence in Cardiovascular-Renal Research and the Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
Mazen Kurdi
Affiliation:
Department of Pharmacology and Toxicology, School of Medicine and the Center for Excellence in Cardiovascular-Renal Research and the Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA Department of Chemistry and Biochemistry, Faculty of Sciences, Lebanese University, Rafic Hariri Educational Campus, Hadath, Lebanon
George W. Booz
Affiliation:
Department of Pharmacology and Toxicology, School of Medicine and the Center for Excellence in Cardiovascular-Renal Research and the Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
John W. Fuseler*
Affiliation:
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
*
*Corresponding author. [email protected]
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Abstract

Hearts of mice with reduction of function mutation in STAT3 (SA/SA) develop fibrotic collagen foci and reduced systolic function with hypertension. This model was used to determine if fractal dimension and image analysis can provide a quantitative description of myocardial fibrosis using routinely prepared trichome-stained material. Collagen was characterized by relative density [integrated optical density/area (IOD/A)] and fractal dimension (D), an index of complexity. IOD/A of collagen in wild type mice increased with hypertension while D decreased, suggesting tighter collagen packing that could eventually stiffen the myocardium as in diastolic heart failure. Reduced STAT3 function caused modest collagen fibrosis with increased IOD/A and D, indicating more tightly packed, but more disorganized collagen than normotensive and hypertensive controls. Hypertension in SA/SA mice resulted in large regions where myocytes were lost and replaced by fibrotic collagen characterized by decreased density and increased disorder. This indicates that collagen associated with reparative fibrosis in SA/SA hearts experiencing hypertension was highly disorganized and more space filling. Loss of myocytes and their replacement by disordered collagen fibers may further weaken the myocardium leading to systolic heart failure. Our findings highlight the utility of image analysis in revealing importance of a cellular protein for normal and reparative extracellular matrix deposition.

Keywords

fibrosiscollagenfractal analysiscardiac remodeling
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 20 , Issue 4 , August 2014 , pp. 1134 - 1144
Copyright
© Microscopy Society of America 2014 

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References

Amer, M.E., Heo, M.S., Brooks, S.L. & Benavides, E. (2012). Anatomical variations of trabecular bone structure in intraoral radiographs using fractal and particles count analyses. Imaging Sci Dent 42, 5–12.Google Scholar
Anderson, J.C., Babb, A.L. & Hlastala, M.P. (2005). A fractal analysis of the radial distribution of bronchial capillaries around large airways. J Appl Physiol 98, 850–855.Google Scholar
Basiouny, H.S., Salama, N.M., Maadawi, Z.M. & Farag, E.A. (2013). Effect of bone marrow derived mesenchymal stem cells on healing of induced full-thickness skin wounds in albino rat. Int J Stem Cells 6, 12–25.Google Scholar
Bowes, L.E., Jimenez, M.C., Hiester, E.D., Sacks, M.S., Brahmatewari, J., Mertz, P. & Eaglstein, W.H. (1999). Collagen fiber orientation as quantified by small angle light scattering in wounds treated with transforming growth factor-beta2 and its neutralizing antibody. Wound Repair Regen 7, 179–186.Google Scholar
Brodsky, B. & Ramshaw, J.A. (1994). Collagen organization in an oriented fibrous capsule. Int J Biol Macromol 16, 27–30.CrossRefGoogle Scholar
Brown, J.H., Gupta, V.K., Li, B.-L., Milne, B.T., Restrepo, C. & West, G.B. (2002). The fractal nature of nature: power laws, ecological complexity and biodiversity. Phil Trans R Soc Lond B 357, 619–626.Google Scholar
Caldwell, C.B., Moran, E.L. & Bogoch, E.R. (1998). Fractal dimension as a measure of altered trabecular bone in experimental inflammatory arthritis. J Bone Miner Res 13, 978–985.Google Scholar
Captur, G., Muthurangu, V., Cook, C., Flett, A.S., Wilson, R., Barison, A., Sado, D.M., Anderson, S., McKenna, W.J., Mohun, T.J., Elliott, P.M. & Moon, J.C. (2013). Quantification of left ventricular trabeculae using fractal analysis. J Cardiovasc Magn Reson 15, 36–46.CrossRefGoogle ScholarPubMed
Chen, J., Lee, S.K., Abd-Elgaliel, W.R., Liang, L., Galende, E.Y., Hajjar, R.J. & Tung, C.H. (2011). Assessment of cardiovascular fibrosis using novel fluorescent probes. PLoS One 6(4), e19097.Google Scholar
Chen, W., Rock, J.B., Yearsley, M.M., Ferrell, L.D. & Frankel, W.L. (2014). Different collagen types show distinct rates of increase from early to late stages of hepatitis C-related liver fibrosis. Hum Pathol 45, 160–165.CrossRefGoogle ScholarPubMed
Copley, S.J., Giannarou, S., Schmid, V.J., Hansell, D.M., Wells, A.U. & Yang, G.Z. (2012). Effect of aging on lung structure in vivo: Assessment with densitometric and fractal analysis of high-resolution computed tomography data. J Thorac Imaging 27, 366–371.Google Scholar
Creemers, E.E. & Pinto, Y.M. (2011). Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res 89, 265–272.CrossRefGoogle ScholarPubMed
de Jong, S., van Veen, T.A., de Bakker, J.M. & van Rijen, H.V. (2012). Monitoring cardiac fibrosis: A technical challenge. Neth Heart J 20, 44–48.Google Scholar
de Vries, H.J., Enomoto, D.N., van Marle, J., van Zuijlen, P.P., Mekkes, J.R. & Bos, J.D. (2000). Dermal organization in scleroderma: The fast Fourier transform and the laser scatter method objectify fibrosis in nonlesional as well as lesional skin. Lab Invest 80, 1281–1289.CrossRefGoogle ScholarPubMed
Di Ieva, A. (2012). Fractal analysis of microvascular networks in malignant brain tumors. Clin Neuropathol 31, 342–351.Google Scholar
Di Ieva, A., Grizzi, F., Ceva-Grimaldi, G., Russo, C., Gaetani, P., Aimar, E., Levi, D., Pisano, P., Tancioni, F., Nicola, G., Tschabitscher, M., Dioguardi, N. & Baena, R.R. (2007). Fractal dimension as a quantitator of the microvasculature of normal and adenomatous pituitary tissue. J Anat 211, 673–680.Google Scholar
Dioguardi, N., Grizzi, F., Fiamengo, B. & Russo, C. (2008). Metrically measuring liver biopsy: A chronic hepatitis B and C computer-aided morphologic description. World J Gastroenterol 14, 7335–7344.Google Scholar
Dioguardi, N., Grizzi, F., Franceschini, B., Bossi, P. & Russo, C. (2006). Liver fibrosis and tissue architectural change measurement using fractal-rectified metrics and Hurst’s exponent. World J Gastroenterol 12, 2187–2194.CrossRefGoogle ScholarPubMed
Doubal, F.N., MacGillivray, T.J., Patton, N., Dhillon, B., Dennis, M.S. & Wardlaw, J.M. (2010). Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke. Neurology 74, 1102–1107.CrossRefGoogle ScholarPubMed
Duerrschmid, C., Crawford, J.R., Reineke, E., Taffet, G.E., Trial, J., Entman, M.L. & Haudek, S.B. (2013). TNF receptor 1 signalling is critically involved in mediating angiotensin-II-induced cardiac fibrosis. J Mol Cell Cardiol 57, 59–67.Google Scholar
Farris, A.B., Adams, C.D., Brousaides, N., Della Pelle, P.A., Collins, A.B., Moradi, E., Smith, R.N., Grimm, P.C. & Colvin, R.B. (2011). Morphometric and visual evaluation of fibrosis in renal biopsies. J Am Soc Nephrol 22, 176–186.Google Scholar
Fuseler, J.W., Merrill, D.M., Rogers, J.A., Grisham, M.B. & Wolf, R.E. (2006). Analysis and quantitation of NF-kappaB nuclear translocation in tumor necrosis factor alpha (TNF-alpha) activated vascular endothelial cells. Microsc Microanal. 12, 269–276.Google Scholar
Fuseler, J.W., Bedenbaugh, A., Krishna, Y. & Baudino, T.A. (2010). Fractal and image analysis of the microvasculature in normal intestinal submucosa and intestinal polyps in ApcMin/+ mice. Microsc Microanal. 16, 73–79.CrossRefGoogle Scholar
Fuseler, J.W., Millette, C.F., Davis, J.M. & Carver, W. (2007). Fractal and image analysis of morphological changes in the actin cytoskeleton of neonatal cardiac fibroblasts in response to mechanical stretch. Microsc Microanal 13, 133–143.Google Scholar
Fuseler, J.W. & Valarmathi, M.T. (2012). Modulation of the migration and differentiation potential of adult bone marrow stromal stem cells by nitric oxide. Biomaterials 33, 1032–1043.Google Scholar
Grizzi, F. & Dioguardi, N. (1999). A fractal scoring system for quantifying active collagen synthesis during chronic liver disease. Int J Chaos Theo Appl 21, 262–266.Google Scholar
Grizzi, F., Russo, C., Colombo, P., Franceschini, B., Frezza, E.E., Cobos, E. & Chiriva-Internati, M. (2005). Quantitative evaluation and modelling of two-dimensional neovascular network complexity: The surface fractal dimension. BMC Cancer 5, 14–23.Google Scholar
Hilfiker-Kleiner, D., Hilfiker, A., Fuchs, M., Kaminski, K., Schaefer, A., Schieffer, B., Hillmer, A., Schmiedl, A., Ding, Z., Podewski, E., Podewski, E., Poli, V., Schneider, M.D., Schulz, R., Park, J.K., Wollert, K.C. & Drexler, H. (2004). Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 95, 187–195.CrossRefGoogle ScholarPubMed
Ho, C.Y. & Solomon, S.D. (2006). A clinician’s guide to tissue Doppler imaging. Circulation 113, e396–e398.Google Scholar
Hu, K., Meijer, J.H., Shea, S.A., vanderLeest, H.T., Pittman-Polletta, B., Houben, T., van Oosterhout, F., Deboer, T. & Scheer, F.A. (2012). Fractal patterns of neural activity exist within the suprachiasmatic nucleus and require extrinsic network interactions. PLoS One 7, e48927.Google Scholar
Jacoby, J.J., Kalinowski, A., Liu, M.G., Zhang, S.S., Gao, Q., Chai, G.X., Ji, L., Iwamoto, Y., Li, E., Schneider, M., Russell, K.S. & Fu, X.Y. (2003). Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci USA 100, 12929–12934.CrossRefGoogle ScholarPubMed
Jacquier, A., Thuny, F., Jop, B., Giorgi, R., Cohen, F., Gaubert, J.Y., Vidal, V., Bartoli, J.M., Habib, G. & Moulin, G. (2010). Measurement of trabeculated left ventricular mass using cardiac magnetic resonance imaging in the diagnosis of left ventricular non-compaction. Eur Heart J 31, 1098–1104.Google Scholar
Jelinek, H.F., Ristanović, D. & Milošević, N.T. (2011). The morphology and classification of α ganglion cells in the rat retinae: A fractal analysis study. J Neurosci Methods 201, 281–287.Google Scholar
Jiang, H.M., Wang, H.X., Yang, H., Zeng, X.J., Tang, C.S., Du, J. & Li, H.H. (2013). Role for granulocyte colony stimulating factor in angiotensin II-induced neutrophil recruitment and cardiac fibrosis in mice. Am J Hypertens. 26, 1224–1233.Google Scholar
Khorasani, H., Zheng, Z., Nguyen, C., Zara, J., Zhang, X., Wang, J., Ting, K. & Soo, C. (2011). A quantitative approach to scar analysis. Am J Pathol 178, 621–628.Google Scholar
Kido, S., Ikezoe, J., Naito, H., Tamura, S. & Machi, S. (1995). Fractal analysis of interstitial lung abnormalities in chest radiography. Radiographics 15, 1457–1464.CrossRefGoogle ScholarPubMed
Kurdi, M. & Booz, G.W. (2011). New take on the role of angiotensin II in cardiac hypertrophy and fibrosis. Hypertension 57, 1034–1038.CrossRefGoogle ScholarPubMed
Mandelbrot, B.B. (1982). The Fractal Geometry of Nature, 1st ed. New York: W. H. Freeman and Company.Google Scholar
Mir, S.A., Chatterjee, A., Mitra, A., Pathak, K., Mahata, S.K. & Sarkar, S. (2012). Inhibition of signal transducer and activator of transcription 3 (STAT3) attenuates interleukin-6 (IL-6)-induced collagen synthesis and resultant hypertrophy in rat heart. J Biol Chem 287, 2666–2677.CrossRefGoogle ScholarPubMed
Moledina, S., de Bruyn, A., Schievano, S., Owens, C.M., Young, C., Haworth, S.G., Taylor, A.M., Schulze-Neick, I. & Muthurangu, V. (2011). Fractal branching quantifies vascular changes and predicts survival in pulmonary hypertension: A proof of principle study. Heart 97, 1245–1249.CrossRefGoogle ScholarPubMed
Moreira, R.D., Moriel, A.R., Murta, L.O., Neves, L.A. & Godoy, M.F. (2011). Fractal dimension in quantifying the degree of myocardial cellular rejection after cardiac transplantation. Rev Bras Cir Cardiovasc 26, 155–163.Google Scholar
Nezadal, M., Zemeskal, O. & Buchnicek, M. (2001). The box-counting: Critical study, 4th Conference on Prediction, Synergetic and More, The Faculty of Management, Institute of Information Technologies, Faculty of Technology, Tomas Bata University in Zlin, HarFA software, October 25–26, p. 18.Google Scholar
Papavassiliu, T., Kühl, H.P., Schröder, M., Süselbeck, T., Bondarenko, O., Böhm, C.K., Beek, A., Hofman, M.M. & van Rossum, A.C. (2005). Effect of endocardial trabeculae on left ventricular measurements and measurement reproducibility at cardiovascular MR imaging. Radiology 236, 57–64.Google Scholar
Porter, K.E. & Turner, N.A. (2009). Cardiac fibroblasts: At the heart of myocardial remodeling. Pharmacol Ther 123, 255–278.Google Scholar
Qian, A.R., Li, D., Han, J., Gao, X., Di, S.M., Zhang, W., Hu, L.F. & Shang, P. (2012). Fractal dimension as a measure of altered actin cytoskeleton in MC3T3-E1 cells under simulated microgravity using 3-D/2-D clinostats. IEEE Trans Biomed Eng 59, 1374–1380.CrossRefGoogle ScholarPubMed
Reese, T.M., Brzoska, A., Yott, D.T. & Kelleher, D.J. (2012). Analyzing self-similar and fractal properties of the C. elegans neural network. PLoS One 7, e40483.Google Scholar
Rogers, J.A. & Fuseler, J.W. (2007). Regulation of NF-κB activation and nuclear translocation by exogenous nitric oxide (NO) donors in TNF-α activated vascular endothelial cells. Nitric Oxide 16, 379–391.CrossRefGoogle ScholarPubMed
Sedivy, R., Thurner, S., Budinsky, A.C., Köstler, W.J. & Zielinski, C.C. (2002). Short-term rhythmic proliferation of human breast cancer cell lines: Surface effects and fractal growth patterns. J Pathol 197, 163–169.Google Scholar
Segura, A.M., Frazier, O.H. & Buja, L.M. (2014). Fibrosis and heart failure. Heart Fail Rev 19, 173–185.Google Scholar
Servais, A., Meas-Yedid, V., Buchler, M., Morelon, E., Olivo-Marin, J.C., Lebranchu, Y., Legendre, C. & Thervet, E. (2007). Quantification of interstitial fibrosis by image analysis on routine renal biopsy in patients receiving cyclosporine. Transplantation 84, 1595–1601.CrossRefGoogle ScholarPubMed
Shen, Y., Schlessinger, K., Zhu, X., Meffre, E., Quimby, F., Levy, D.E. & Darnell, J.E. Jr. (2004). Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol 24, 407–419.CrossRefGoogle ScholarPubMed
Smith, T.G. Jr, Lange, G.D. & Marks, W.B. (1996). Fractal methods and results in cellular morphology—dimensions, lacunarity and multifractals. J Neurosci Methods 69, 123–136.Google Scholar
Souders, C.A., Bowers, S.L. & Baudino, T.A. (2009). Cardiac fibroblast: The renaissance cell. Circ Res 105, 1164–1176.CrossRefGoogle ScholarPubMed
Suvik, A. & Effendy, A.W.M. (2012). The use of modified Massion’s trichrome staining in collagen evaluation in wound healing study. Mal J Vet Res 3, 39–47.Google Scholar
Udhayakumar, G., Sujatha, C.M. & Ramakrishnan, S. (2013). Trabecular architecture analysis in femur radiographic images using fractals. Proc Inst Mech Eng H 227, 448–453.Google Scholar
Verhaegen, P.D., Res, E.M., van Engelen, A., Middelkoop, E. & van Zuijlen, P.P. (2010). A reliable, non-invasive measurement tool for anisotropy in normal skin and scar tissue. Skin Res Technol 16, 325–331.Google Scholar
Walter, R.J. Jr. & Berns, M.W. (1986). Digital image processing and analysis. In Video Microscopy, Inoue S. (Ed.), pp. 327–392. New York and London: Plenum Press.Google Scholar
Wick, N., Thurner, S., Paiha, K., Sedivy, R., Vietor, I. & Huber, L.A. (2003). Quantitative measurement of cell migration using time-lapse videomicroscopy and non-linear system analysis. Histochem Cell Bio 119, 15–20.CrossRefGoogle ScholarPubMed
Wolman, M. & Kasten, F.H. (1986). Polarized light microscopy in the study of the molecular structure of collagen and reticulin. Histochemistry 85, 41–49.Google Scholar
Wynn, T.A. (2007). Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117, 524–529.Google Scholar
Xue, B., Pamidimukkala, J. & Hay, M. (2005). Sex differences in the development of angiotensin II-induced hypertension in conscious mice. Am J Physiol Heart Circ Physiol 288, H2177–H2184.Google Scholar
Yoon, P.O., Lee, M.A., Cha, H., Jeong, M.H., Kim, J., Jang, S.P., Choi, B.Y., Jeong, D., Yang, D.K., Hajjar, R.J. & Park, W.J. (2010). The opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophy and fibrosis. J Mol Cell Cardiol. 49, 294–303.CrossRefGoogle ScholarPubMed
Zhang, L., Liu, J.Z., Dean, D., Sahgal, V. & Yue, G.H. (2006). A three-dimensional fractal analysis method for quantifying white matter structure in human brain. J Neurosci Methods 150, 242–253.Google Scholar
Zouein, F.A., de Castro Brás, L.E., de Costa, D.V., Lindsey, M.L., Kurdi, M. & Booz, G.W. (2013 a). Heart failure with preserved ejection fraction: Emerging drug strategies. J Cardiovasc Pharmacol 62, 13–21.CrossRefGoogle ScholarPubMed
Zouein, F.A., Kurdi, M. & Booz, G.W. (2013 b). Dancing rhinos in stilettos: The amazing saga of the genomic and nongenomic actions of STAT3 in the heart. JAKSTAT 2, e24352.Google Scholar
Zouein, F.A., Zgheib, C., Hamza, S., Fuseler, J.W., Hall, J.E., Soljancic, A., Lopez-Ruiz, A., Kurdi, M. & Booz, G.W. (2013 c). Role of STAT3 in angiotensin II-induced hypertension and cardiac remodeling revealed by mice lacking STAT3 serine 727 phosphorylation. Hypertens Res 36, 496–503.Google Scholar