Skip to main content
Top
Published in: Current Cardiovascular Imaging Reports 2/2012

01-04-2012 | Cardiac Magnetic Resonance (E Nagel, Section Editor)

Animal Models in Cardiovascular MRI Research: Value and Limitations

Published in: Current Cardiovascular Imaging Reports | Issue 2/2012

Login to get access

Abstract

This review will explore the interface between MRI, cardiovascular research, and animal models, with particular attention to values, limitations, and best practices. This includes the question of whether an animal model may be necessary or appropriate. Factors influencing the selection of small versus large animal models will be considered, including the features that distinguish mice from other animal models. MRI has proven extremely useful in studies of basic cardiovascular physiology, but its true utility lies in the acquisition of end points relevant to cardiovascular disease in preclinical and clinical investigations. Brief summaries will be presented of the many anatomic and functional parameters that can be assessed by cardiovascular MRI, along with its role in translational medicine. Finally, the predictive value and clinical relevance of animal models of cardiovascular disease will be explored, including steps that are recommended to maximize the predictive value of animal models in translational medicine.
Literature
1.
go back to reference Rogers Jr WJ, Shapiro EP, Weiss JL, Buchalter MB, Rademakers FE, Weisfeldt ML, et al. Quantification of and correction for left ventricular systolic long-axis shortening by magnetic resonance tissue tagging and slice isolation. Circulation. 1991;84(2):721–31.PubMed Rogers Jr WJ, Shapiro EP, Weiss JL, Buchalter MB, Rademakers FE, Weisfeldt ML, et al. Quantification of and correction for left ventricular systolic long-axis shortening by magnetic resonance tissue tagging and slice isolation. Circulation. 1991;84(2):721–31.PubMed
2.
go back to reference Mostbeck GH, Caputo GR, Higgins CB. MR measurement of blood flow in the cardiovascular system. AJR Am J Roentgenol. 1992;159(3):453–61.PubMed Mostbeck GH, Caputo GR, Higgins CB. MR measurement of blood flow in the cardiovascular system. AJR Am J Roentgenol. 1992;159(3):453–61.PubMed
3.
go back to reference Bennett KM, Shapiro EM, Sotak CH, Koretsky AP. Controlled aggregation of ferritin to modulate MRI relaxivity. Biophys J. 2008;95(1):342–51.PubMedCrossRef Bennett KM, Shapiro EM, Sotak CH, Koretsky AP. Controlled aggregation of ferritin to modulate MRI relaxivity. Biophys J. 2008;95(1):342–51.PubMedCrossRef
4.
go back to reference Harrison GJ, Cerniway RJ, Peart J, Berr SS, Ashton K, Regan S, et al. Effects of A(3) adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc Res. 2002;53(1):147–55.PubMedCrossRef Harrison GJ, Cerniway RJ, Peart J, Berr SS, Ashton K, Regan S, et al. Effects of A(3) adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc Res. 2002;53(1):147–55.PubMedCrossRef
5.
go back to reference Schuster A, Grunwald I, Chiribiri A, Southworth R, Ishida M, Hay G, et al. An isolated perfused pig heart model for the development, validation and translation of novel cardiovascular magnetic resonance techniques. J Cardiovasc Magn Reson. 2010;12:53.PubMedCrossRef Schuster A, Grunwald I, Chiribiri A, Southworth R, Ishida M, Hay G, et al. An isolated perfused pig heart model for the development, validation and translation of novel cardiovascular magnetic resonance techniques. J Cardiovasc Magn Reson. 2010;12:53.PubMedCrossRef
6.
go back to reference Goldberg AM, Zurlo J, Rudacille D. The three Rs and biomedical research. Science. 1996;272(5267):1403.PubMedCrossRef Goldberg AM, Zurlo J, Rudacille D. The three Rs and biomedical research. Science. 1996;272(5267):1403.PubMedCrossRef
7.
go back to reference Carmeliet P, Collen D. Transgenic mouse models in angiogenesis and cardiovascular disease. J Pathol. 2000;190(3):387–405.PubMedCrossRef Carmeliet P, Collen D. Transgenic mouse models in angiogenesis and cardiovascular disease. J Pathol. 2000;190(3):387–405.PubMedCrossRef
9.
go back to reference Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011;474(7351):337–42.PubMedCrossRef Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011;474(7351):337–42.PubMedCrossRef
10.
go back to reference Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420(6915):520–62. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420(6915):520–62.
11.
go back to reference Bockamp E, Sprengel R, Eshkind L, Lehmann T, Braun JM, Emmrich F, et al. Conditional transgenic mouse models: from the basics to genome-wide sets of knockouts and current studies of tissue regeneration. Regen Med. 2008;3(2):217–35.PubMedCrossRef Bockamp E, Sprengel R, Eshkind L, Lehmann T, Braun JM, Emmrich F, et al. Conditional transgenic mouse models: from the basics to genome-wide sets of knockouts and current studies of tissue regeneration. Regen Med. 2008;3(2):217–35.PubMedCrossRef
12.
go back to reference Huang G, Ashton C, Kumbhani DS, Ying Q-L. Genetic manipulations in the rat: progress and prospects. Curr Opin Nephrol Hypertens. 2011;20(4):391–9.PubMedCrossRef Huang G, Ashton C, Kumbhani DS, Ying Q-L. Genetic manipulations in the rat: progress and prospects. Curr Opin Nephrol Hypertens. 2011;20(4):391–9.PubMedCrossRef
13.
go back to reference Hasenfuss G. Animal models of human cardiovascular disease, heart failure and hypertrophy. Cardiovasc Res. 1998;39(1):60–76.PubMedCrossRef Hasenfuss G. Animal models of human cardiovascular disease, heart failure and hypertrophy. Cardiovasc Res. 1998;39(1):60–76.PubMedCrossRef
14.
go back to reference Decking UKM, Pai VM, Bennett E, Taylor JL, Fingas CD, Zanger K, et al. High-resolution imaging reveals a limit in spatial resolution of blood flow measurements by microspheres. Am J Physiol Heart Circ Physiol. 2004;287(3):H1132–40.PubMedCrossRef Decking UKM, Pai VM, Bennett E, Taylor JL, Fingas CD, Zanger K, et al. High-resolution imaging reveals a limit in spatial resolution of blood flow measurements by microspheres. Am J Physiol Heart Circ Physiol. 2004;287(3):H1132–40.PubMedCrossRef
15.
go back to reference Lawton J, Cupps B, Knutsen A, Ma N, Brady B, Reynolds L, et al. Magnetic resonance imaging detects significant sex differences in human myocardial strain. Biomed Eng Online. 2011;10(76):1–11. Lawton J, Cupps B, Knutsen A, Ma N, Brady B, Reynolds L, et al. Magnetic resonance imaging detects significant sex differences in human myocardial strain. Biomed Eng Online. 2011;10(76):1–11.
16.
go back to reference Spence AL, Naylor LH, Carter HH, Buck CL, Dembo L, Murray CP et al. A prospective randomised longitudinal MRI study of left ventricular adaptation to endurance and resistance exercise training in humans. J Physiol. 2011; Published online before print. Spence AL, Naylor LH, Carter HH, Buck CL, Dembo L, Murray CP et al. A prospective randomised longitudinal MRI study of left ventricular adaptation to endurance and resistance exercise training in humans. J Physiol. 2011; Published online before print.
17.
go back to reference Hockings P. Magnetic resonance imaging in pharmaceutical safety assessment. In: Vogel HG, editor. Drug discovery and evaluation: safety and pharmacokinetic assays. Berlin: Springer-Verlag; 2006. p. 385–408. Hockings P. Magnetic resonance imaging in pharmaceutical safety assessment. In: Vogel HG, editor. Drug discovery and evaluation: safety and pharmacokinetic assays. Berlin: Springer-Verlag; 2006. p. 385–408.
18.
go back to reference Franco F, Thomas GD, Giroir B, Bryant D, Bullock MC, Chwialkowski MC, et al. Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor alpha. Circulation. 1999;99(3):448–54.PubMed Franco F, Thomas GD, Giroir B, Bryant D, Bullock MC, Chwialkowski MC, et al. Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor alpha. Circulation. 1999;99(3):448–54.PubMed
19.
go back to reference Goetschalckx K, Rademakers F, Bogaert J. Right ventricular function by MRI. Curr Opin Cardiol. 2010;25(5):451–5.PubMedCrossRef Goetschalckx K, Rademakers F, Bogaert J. Right ventricular function by MRI. Curr Opin Cardiol. 2010;25(5):451–5.PubMedCrossRef
20.
go back to reference Kuppahally SS, Akoum N, Burgon NS, Badger TJ, Kholmovski EG, Vijayakumar S, et al. Left atrial strain and strain rate in patients with paroxysmal and persistent atrial fibrillation / Clinical Perspective. Circ Cardiovasc Imaging. 2010;3(3):231–9.PubMedCrossRef Kuppahally SS, Akoum N, Burgon NS, Badger TJ, Kholmovski EG, Vijayakumar S, et al. Left atrial strain and strain rate in patients with paroxysmal and persistent atrial fibrillation / Clinical Perspective. Circ Cardiovasc Imaging. 2010;3(3):231–9.PubMedCrossRef
21.
go back to reference Makowski M, Jansen C, Webb I, Chiribiri A, Nagel E, Botnar R, et al. First-pass contrast-enhanced myocardial perfusion MRI in mice on a 3-T clinical MR scanner. Magn Reson Med. 2010;64(6):1592–8.PubMedCrossRef Makowski M, Jansen C, Webb I, Chiribiri A, Nagel E, Botnar R, et al. First-pass contrast-enhanced myocardial perfusion MRI in mice on a 3-T clinical MR scanner. Magn Reson Med. 2010;64(6):1592–8.PubMedCrossRef
22.
go back to reference Zun Z, Wong EC, Nayak KS. Assessment of myocardial blood flow (MBF) in humans using arterial spin labeling (ASL): Feasibility and noise analysis. Magn Reson Med. 2009;62(4):975–83.PubMedCrossRef Zun Z, Wong EC, Nayak KS. Assessment of myocardial blood flow (MBF) in humans using arterial spin labeling (ASL): Feasibility and noise analysis. Magn Reson Med. 2009;62(4):975–83.PubMedCrossRef
23.
go back to reference Matheijssen NA, Baur LH, Reiber JH, van der Velde EA, van Dijkman PR, van der Geest RJ, et al. Assessment of left ventricular volume and mass by cine magnetic resonance imaging in patients with anterior myocardial infarction intra-observer and inter-observer variability on contour detection. Int J Card Imaging. 1996;12(1):11–9.PubMedCrossRef Matheijssen NA, Baur LH, Reiber JH, van der Velde EA, van Dijkman PR, van der Geest RJ, et al. Assessment of left ventricular volume and mass by cine magnetic resonance imaging in patients with anterior myocardial infarction intra-observer and inter-observer variability on contour detection. Int J Card Imaging. 1996;12(1):11–9.PubMedCrossRef
24.
go back to reference Bottini PB, Carr AA, Prisant LM, Flickinger FW, Allison JD, Gottdiener JS. Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens. 1995;8(3):221–8.PubMedCrossRef Bottini PB, Carr AA, Prisant LM, Flickinger FW, Allison JD, Gottdiener JS. Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens. 1995;8(3):221–8.PubMedCrossRef
25.
go back to reference Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2000;2(4):271–8.PubMedCrossRef Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2000;2(4):271–8.PubMedCrossRef
26.
go back to reference Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res. 1985;57(1):84–95.PubMed Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res. 1985;57(1):84–95.PubMed
27.
go back to reference Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. New Engl J Med. 1988;319(2):80–6.PubMedCrossRef Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. New Engl J Med. 1988;319(2):80–6.PubMedCrossRef
28.
go back to reference Pfeffer MA, Braunwald E, Moya LA, Basta L, Brown EJ, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med. 1992;327(10):669–77.CrossRef Pfeffer MA, Braunwald E, Moya LA, Basta L, Brown EJ, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med. 1992;327(10):669–77.CrossRef
29.
go back to reference Kloner RA, Forman MB, Gibbons RJ, Ross AM, Alexander RW, Stone GW. Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial. Eur Heart J. 2006;27(20):2400–5.PubMedCrossRef Kloner RA, Forman MB, Gibbons RJ, Ross AM, Alexander RW, Stone GW. Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial. Eur Heart J. 2006;27(20):2400–5.PubMedCrossRef
30.
go back to reference Maurer G. Adenosine as an adjunct to reperfusion in myocardial infarction. Eur Heart J. 2006;27(20):2376–7.PubMedCrossRef Maurer G. Adenosine as an adjunct to reperfusion in myocardial infarction. Eur Heart J. 2006;27(20):2376–7.PubMedCrossRef
31.
go back to reference • Desmet W, Bogaert J, Dubois C, Sinnaeve P, Adriaenssens T, Pappas C, et al. High-dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction. Eur Heart J. 2011;32(7):867–77. This report nicely illustrates the utility of combining T2-weighted and contrast-enhanced sequences to determine the myocardial salvage index for evaluating drug efficacy in the setting of acute MI.PubMedCrossRef • Desmet W, Bogaert J, Dubois C, Sinnaeve P, Adriaenssens T, Pappas C, et al. High-dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction. Eur Heart J. 2011;32(7):867–77. This report nicely illustrates the utility of combining T2-weighted and contrast-enhanced sequences to determine the myocardial salvage index for evaluating drug efficacy in the setting of acute MI.PubMedCrossRef
32.
go back to reference • Danhof M, Alvan G, Dahl SG, Kuhlmann J, Paintaud G. Mechanism-based pharmacokinetic-pharmacodynamic modeling: a new classification of biomarkers. Pharmaceut Res. 2005;22(9):1432–7. This article proposes a new classification scheme for biomarkers and discusses their application in mechanism-based PK/PD analysis for drug discovery and development.CrossRef • Danhof M, Alvan G, Dahl SG, Kuhlmann J, Paintaud G. Mechanism-based pharmacokinetic-pharmacodynamic modeling: a new classification of biomarkers. Pharmaceut Res. 2005;22(9):1432–7. This article proposes a new classification scheme for biomarkers and discusses their application in mechanism-based PK/PD analysis for drug discovery and development.CrossRef
33.
go back to reference Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med. 2003;348(14):1309–21.CrossRef Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med. 2003;348(14):1309–21.CrossRef
34.
go back to reference •• van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Med. 2010;7(3):e1000245. This review addresses the controversy surrounding the value of animal models in predicting the effectiveness of novel therapies in human trials and proposes practical strategies to improve their predictive value.PubMedCrossRef •• van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Med. 2010;7(3):e1000245. This review addresses the controversy surrounding the value of animal models in predicting the effectiveness of novel therapies in human trials and proposes practical strategies to improve their predictive value.PubMedCrossRef
35.
go back to reference Guerette B, Moisset PA, Huard C, Tardif F, Gravel C, Tremblay JP. Inflammatory damage following first-generation replication-defective adenovirus controlled by anti-LFA-1. J Leukoc Biol. 1997;61(4):533–8.PubMed Guerette B, Moisset PA, Huard C, Tardif F, Gravel C, Tremblay JP. Inflammatory damage following first-generation replication-defective adenovirus controlled by anti-LFA-1. J Leukoc Biol. 1997;61(4):533–8.PubMed
36.
go back to reference Bodenheimer T. Uneasy alliance - clinical investigators and the pharmaceutical industry. N Eng J Med. 2000;342(20):1539–44.CrossRef Bodenheimer T. Uneasy alliance - clinical investigators and the pharmaceutical industry. N Eng J Med. 2000;342(20):1539–44.CrossRef
37.
go back to reference Horrobin DF. Innovation in the pharmaceutical industry. JRSM. 2000;93(7):341–5. Horrobin DF. Innovation in the pharmaceutical industry. JRSM. 2000;93(7):341–5.
38.
go back to reference •• Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9(3):203–14. This review presents a detailed analysis of industry-wide data that characterizes the relative contributions of each step in the drug discovery/development pathway to overall productivity, then proposes specific strategies for improving that productivity.PubMed •• Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9(3):203–14. This review presents a detailed analysis of industry-wide data that characterizes the relative contributions of each step in the drug discovery/development pathway to overall productivity, then proposes specific strategies for improving that productivity.PubMed
39.
go back to reference Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711–6.PubMedCrossRef Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711–6.PubMedCrossRef
40.
go back to reference Yang Y, Adelstein SJ, Kassis AI. Target discovery from data mining approaches. Drug Discov Today. 2009;14(3–4):147–54.PubMedCrossRef Yang Y, Adelstein SJ, Kassis AI. Target discovery from data mining approaches. Drug Discov Today. 2009;14(3–4):147–54.PubMedCrossRef
41.
go back to reference Rudy Y, Ackerman MJ, Bers DM, Clancy CE, Houser SR, London B, et al. Systems approach to understanding electromechanical activity in the human heart. Circulation. 2008;118(11):1202–11.PubMedCrossRef Rudy Y, Ackerman MJ, Bers DM, Clancy CE, Houser SR, London B, et al. Systems approach to understanding electromechanical activity in the human heart. Circulation. 2008;118(11):1202–11.PubMedCrossRef
42.
go back to reference Phillips KA, Van Bebber S, Issa AM. Diagnostics and biomarker development: priming the pipeline. Nat Rev Drug Discov. 2006;5(6):463–9.PubMedCrossRef Phillips KA, Van Bebber S, Issa AM. Diagnostics and biomarker development: priming the pipeline. Nat Rev Drug Discov. 2006;5(6):463–9.PubMedCrossRef
Metadata
Title
Animal Models in Cardiovascular MRI Research: Value and Limitations
Publication date
01-04-2012
Published in
Current Cardiovascular Imaging Reports / Issue 2/2012
Print ISSN: 1941-9066
Electronic ISSN: 1941-9074
DOI
https://doi.org/10.1007/s12410-012-9128-6

Other articles of this Issue 2/2012

Current Cardiovascular Imaging Reports 2/2012 Go to the issue

Cardiac Magnetic Resonance (E Nagel, Section Editor)

Cost-Effectiveness of Cardiac Magnetic Resonance