**1. Introduction**

While cardiac mechanical function studies initially focused on large mammals and the human, the mouse emerged as the preferred animal species for such research in recent years [Collins 2003]. Despite the fact that evidence supports that bio-energetically and hemodynamically the mouse scales in a linear fashion with larger mammals and humans [Dobson 1995, Nielsen 1958], nevertheless, important physiological questions still remain [Kass 1998, Balaban 2001] on whether such a model is the most appropriate for extrapolation of conclusions to man [Schaper 1998, Balaban 2012]. With the complete characterization of the mouse and human genomes (a National Institutes of Health initiative) in 2002 and 2003 respectively [Collins 2003, Gregory 2002], a plethora of mouse studies emerged targeting the cardiovascular system in animals with genetic modifications [James 1998, Hoit 2001, Gehmann 2000, Ehmke 2003], marking the onset of the molecular physiology, proteomics, and (structural and functional) genomics era. Collectively, these studies [Milano 1994, Barbee 1994, MacGowan 2001] initially targeted six important areas of cardiac function including the: *(a) excitation-contraction cascade*; *(b) the beta-adrenergic system*; *(c) the cytosolic/structural system and the cytoskeleton*; *(d) the extracellular matrix and its coupling to important cytosolic elements that assist the mechanical force generation or propagation*; *(e) molecules that determine spatial-temporal mechanical changes (due to differential gene expression, phosphorylation, or recruitment of fetal development gene programs)*; and *(f) the energetic-metabolic status of the muscle*. Equally important in most of these studies was the non-invasive imaging of such animals for phenotypic and genotypic screening, often conducted under inhalational anesthesia [Erhart 1984, Hart 2001, Price 1980, Kober 2005, Constantinides\_ILAR 2011].

© 2012 Constantinides, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 Constantinides, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Despite the existence of a plethora of cardiac functional techniques for characterization of mechanical structure, function and dysfunction, a parallel need exists for development of invasive and non-invasive tools and techniques to describe the left ventricular (LV) tissue material properties as these relate to the: (a) mechanical pumping function of the LV; (b) myocardial oxygen demand defining myocyte metabolic status; (c) coronary blood flow and its auto-regulation; (d) arhythmogenic risk; (e) cell-signaling pathways responsible for growth and remodeling during development and disease. Reinforcing basic physiology work, invasive catheterization experiments [Georgakopoulos 1998] have also allowed determination of inotropic and lusitropic cardiac status, while Magnetic Resonance Imaging (MRI) experimentation, methodologies and technology advances have facilitated migration of such work to a non-invasive imaging platform, with tremendous potential for future basic science and translational research.

Study of the Murine Cardiac Mechanical Function Using Magnetic Resonance Imaging:

(RF), and gradient technologies) based on recent work and advances in miniature RF coils for imaging, state-of-the-art imaging techniques and pulse sequences based on rectilinear and non-cartesian sampling schemes, including functional MRI, atlas-based approaches for morphology assessment and four-dimensional (4D) motional variability, as well as regional cardiac functional characterization and quantification methods, Displacement Encoding with Stimulated Echoes (DENSE) [Aletras 1999], Harmonic Phase (HARP) [Osman 1999, Kuijer 2001], tagging and advanced imaging techniques. MRI-based, accurate threedimensional (3D) and 4D surface and finite element mesh model extractions, in association with advanced segmentation – seed-based or semi-automatic - and registration techniques – diffeomorphic or landmark-based, are shown to facilitate efficient mouse inter-strain cardiac hemodynamical comparisons of both right and left-ventricular chambers. Based on recently published DENSE human-mouse comparative studies, and findings from image-based regional functional quantifications, similar transmural motional patterns are observed in both species, lending additional support to long-standing hypotheses for the existence of allometric scaling in metabolism, energetics [Dobson 1995, Nielsen 1958, Phillips 2012], and

**Figure 1.** Hierarchical structure for studying human-animal pathology. Fundamental to the elucidation of pathological mechanisms is the detailed understanding of the structure and physiological function of tissues-organs as determined by their genetic background, or as influenced by the local environment.

The mouse emerged as an attractive animal research model following the rapid advances in experimental molecular biology techniques that allowed targeted mutagenesis in single genes [Capecchi 1989], in addition to the tremendous success for extraction, manipulation, and use of embryonic stem cells [Koller 1989]. Practical and ethical advantages were also associated with mice, such as their stable genetic lines, immune system, short gestation periods, low cost, and ease of use. Initial research strides were supported by US National initiatives including the Human and Mouse Genome projects administered through the National Institutes of Health (NIH) for cloning and mapping the entire human and mouse genomes [Collins 2003, Gregory 2002], efforts that were successfully completed in 2003.

**2. MRI of the mouse: Challenges for cardiac image-based mouse** 

mechanical function in mouse and man.

**2.1. The mouse as a research model** 

**phenotyping** 

The Current Status, Challenges, and Future Perspectives 345

Specifically, advances in MRI techniques (myocardial spin tagging [Zerhouni 1988, Axel 1989], DENSE [Aletras 1999], and harmonic phase imaging [Osman 1999]) have been introduced over the last decades to quantify cardiac function, allowing myocardial tracking, motion and strain quantification in normal and genetically engineered mice [Rockman 1991, Franco 1999, Brede 2001, Yang 2002, Engel 2004, Wilding 2005]. Critical to such work has been the validation of the underlying hypothesis of morphological and functional scaling from mouse to human (through consideration of global cardiac function, circulatory control, blood flow distribution, Ca2+ storage and cycling, myosin light chain distribution, and force frequency reserve), for comparative studies.

This chapter provides an overview of the major physiological issues and challenges for mouse MR imaging and discusses the most recent and major advances in conventional and new cardiac Magnetic Resonance imaging strategies, that ultimately allow quantification of motion, global, and regional cardiac function, strain, and elasticity, characterizing inotropic and lusitropic contractile function and dysfunction in humans and transgenic mice for image-based phenotyping.

Specifically, this chapter attempts a detailed reference to the mouse as a research model, focusing on its genetic background and homology with the human genome and to the developmental and morphological differences between mouse and man, thus addressing cellular and global organ similarities and differences. As a basic determinant of structure, cardiac functional differences are associated, justified by carefully-controlled indices that determine integrative physiological control and functional activities, including metabolism, perfusion, angiogenetic, collateral flow, and coronary reserve. The importance and impact of anesthesia for image-based phenotyping in patho-physiological status is addressed with brief references to the possible mechanisms and cellular and sub-cellular target sites of anesthesia action. The section is complemented with recent findings on heart rate variability (as a result of the widely used inhalational anesthesia use) under optimal anesthesia conditions using isoflurane and long term physiological stability elicited from the use of the balancing anesthetic, Nitrous Oxide.

A historical overview of the evolution of mouse cardiac MRI is also attempted (in direct correlation with the evolution and progress of human clinical cardiac MRI, radiofrequency (RF), and gradient technologies) based on recent work and advances in miniature RF coils for imaging, state-of-the-art imaging techniques and pulse sequences based on rectilinear and non-cartesian sampling schemes, including functional MRI, atlas-based approaches for morphology assessment and four-dimensional (4D) motional variability, as well as regional cardiac functional characterization and quantification methods, Displacement Encoding with Stimulated Echoes (DENSE) [Aletras 1999], Harmonic Phase (HARP) [Osman 1999, Kuijer 2001], tagging and advanced imaging techniques. MRI-based, accurate threedimensional (3D) and 4D surface and finite element mesh model extractions, in association with advanced segmentation – seed-based or semi-automatic - and registration techniques – diffeomorphic or landmark-based, are shown to facilitate efficient mouse inter-strain cardiac hemodynamical comparisons of both right and left-ventricular chambers. Based on recently published DENSE human-mouse comparative studies, and findings from image-based regional functional quantifications, similar transmural motional patterns are observed in both species, lending additional support to long-standing hypotheses for the existence of allometric scaling in metabolism, energetics [Dobson 1995, Nielsen 1958, Phillips 2012], and mechanical function in mouse and man.

**Figure 1.** Hierarchical structure for studying human-animal pathology. Fundamental to the elucidation of pathological mechanisms is the detailed understanding of the structure and physiological function of tissues-organs as determined by their genetic background, or as influenced by the local environment.
