The studies outlined in this application employ radiopaque marker technology in ovine experimental models to test hypotheses concerning the mechanisms for left ventricular (LV) remodeling leading to congestive heart failure (CHF) and/or chronic ischemic mitral regurgitation (CIMR). In addition to standard LV and valvular marker arrays, we have added LV transmural beadsets for simultaneous measurement of 4-D biomechanics of myofiber sheets and extracellular matrix. These studies focus on LV systolic torsion, LV diastolic torsional recoil, and transmural LV normal strains and shear strains. The knowledge derived should lead to improved surgical and medical therapies based on rational criteria for the lethal cascade culminating in CHF after a myocardial infarction (MI). We have recently discovered that LV torsion recoil, crucial to rapid early diastolic LV filling, is globally abolished by an MI causing CIMR, yet systolic torsion is preserved in all but the infarcted region. Elimination of LV torsion recoil may be an important initial CHF trigger in CIMR. To provide a mechanistic understanding of this phenomenon, we have developed a new and powerful technological capability (analysis of 3-D motion of transmural beadsets) which allows detailed examination of transmural LV normal strains and shear strains; these data can be transformed, using quantitative histologic information, to measure myofiber dynamics throughout the wall, throughout the entire cardiac cycle, and throughout the entire post-MI period of LV remodeling. We will test four global hypotheses: 1.) CIMR arises as a LV disease process whereby an inferior MI produces transmural strain abnormalities in the myofibers in remote, normally-perfused LV regions, which triggers a deleterious cascade that ultimately creates additional wall strain abnormalities in the remote viable regions; 2.) The CIMR disease process begins primarily as a diastolic mechanism involving limitation of normal fiber and chamber recoil mechanisms required to augment LV compliance rapidly in earliest diastole, thereby facilitating active LV filling at a low left atrial pressures; 3.) The MR observed in CIMR only reflects the severity of the underlying LV systolic dysfunction (reflecting LV dilatation and distortion of the valvular-ventricular apparatus sufficient to produce leaflet malcoaptation), and is not the central mechanism leading to CHF; and, 4.) Restriction of post-infarct mitral annular and LV dilatation favorably affects this remodeling cascade, as well as prevents CIMR. Testing these hypotheses will be possible using the unique capabilities of our measurement technology to track specific transmural LV wall, ventricular, annular, and leaflet anatomical sites on a beat-to-beat basis whenever desired as the LV remodeling process evolves over time. The knowledge gained should translate directly into more rational surgical as well as medical treatments for patients after an MI with CHF, CIMR, or both.
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| Stephens, Elizabeth H; Fahrenholtz, Monica M; Connell, Patrick S et al. (2015) Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction. Cardiovasc Eng Technol 6:151-9 |
| Stephens, Elizabeth H; Connell, Patrick S; Fahrenholtz, Monica M et al. (2015) Heterogeneity of Mitral Leaflet Matrix Composition and Turnover Correlates with Regional Leaflet Strain. Cardiovasc Eng Technol 6:141-50 |
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| Rausch, Manuel K; Famaey, Nele; Shultz, Tyler O'Brien et al. (2013) Mechanics of the mitral valve: a critical review, an in vivo parameter identification, and the effect of prestrain. Biomech Model Mechanobiol 12:1053-71 |
| Bothe, Wolfgang; Miller, D Craig; Doenst, Torsten (2013) Sizing for mitral annuloplasty: where does science stop and voodoo begin? Ann Thorac Surg 95:1475-83 |
| Rausch, Manuel K; Tibayan, Frederick A; Ingels Jr, Neil B et al. (2013) Mechanics of the mitral annulus in chronic ischemic cardiomyopathy. Ann Biomed Eng 41:2171-80 |
| Itoh, Akinobu; Stephens, Elizabeth H; Ennis, Daniel B et al. (2012) Contribution of myocardium overlying the anterolateral papillary muscle to left ventricular deformation. Am J Physiol Heart Circ Physiol 302:H180-7 |
| Tsamis, Alkiviadis; Cheng, Allen; Nguyen, Tom C et al. (2012) Kinematics of cardiac growth: in vivo characterization of growth tensors and strains. J Mech Behav Biomed Mater 8:165-77 |
| Rausch, Manuel K; Tibayan, Frederick A; Miller, D Craig et al. (2012) Evidence of adaptive mitral leaflet growth. J Mech Behav Biomed Mater 15:208-17 |
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