There are currently 5 million Americans with diagnosed heart failure (HF), and 550,000 new cases every year. The majority of HF cases is now the result of myocardial infarction (MI)-induced left ventricular (LV) remodeling. The lack of a well-established effective treatment has lead to a continually expanding list of medical and surgical options for the palliation of HF patients. Using our Myocardial Material Property Software Tool (MMPST;developed and validated during the initial funding period) and an ovine model of MI, we have provided cardiologists and cardiac surgeons with new insights into the mechanism of MI-induced HF by focusing their attention on changes that occur in the normally perfused myocardium immediately adjacent to the MI (the borderzone). Our MMPST demonstrates that borderzone (BZ) myocardial contractility is substantially reduced in comparison to that in LV regions remote from the MI. The overall goals of the proposed research are to validate clinical application of our MMPST and demonstrate a strong clinical correlation between regional myocardial contractility and disease state. There are five specific aims: (1) Using our MMPST, measure in-vivo regional myocardial contractility in patients before heart transplantation;(2) Measure ex-vivo regional myocardial contractility in skinned fiber preparation obtained from the hearts studied in Aim #1. We will use these direct active force measurements to validate clinical application of our MMPST; (3) Using diffusion MRI (dMRI), measure ex-vivo regional myofiber orientation in the hearts studied in Aim #1, as well as in normal human hearts and human hearts with an MI. If these clinically relevant measurements are not significantly different (as we previously discovered in normal versus infarcted sheep hearts), then clinical application of our MMPST does not require in-vivo dMRI;(4) Measure in-vivo regional myocardial contractility in patients after MI and compare BZ contractility with that in remote LV regions. If these clinical measurements also demonstrate significantly depressed BZ contractility, then procedures designed to restore a more normal LV geometry late in the remodeling process may be ineffective (as we also discovered in sheep with repaired LV aneurysm);(5) Measure in-vivo regional myocardial contractility in normal human subjects and compare these measurements with those obtained in Aim #1 and Aim #4. If these clinical measurements can be correlated to disease state and the potential effect of therapeutic intervention, then the cardiology community will be able to add a significant new methodology to its armamentarium regarding patient care protocols.

Public Health Relevance

Medical and/or surgical treatment of cardiovascular disease, especially heart failure, stands to vastly improve both the longevity and quality of life. Magnetic resonance imaging (MRI) with heart tissue tagging or cardiac tagged MRI combined with physics-based mathematical (finite element) modeling allows for non-invasive quantification of heart wall mechanical properties. If these mechanical properties can be correlated to disease state and the potential effect of therapeutic intervention, then the cardiology community will be able to add a significant new methodology to its armamentarium regarding patient care protocols.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077921-07
Application #
8434825
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (02))
Program Officer
Baldwin, Tim
Project Start
2006-04-15
Project End
2016-07-31
Budget Start
2013-09-01
Budget End
2014-07-31
Support Year
7
Fiscal Year
2013
Total Cost
$357,037
Indirect Cost
$125,945
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sack, Kevin L; Baillargeon, Brian; Acevedo-Bolton, Gabriel et al. (2016) Partial LVAD restores ventricular outputs and normalizes LV but not RV stress distributions in the acutely failing heart in silico. Int J Artif Organs 39:421-430
Kassab, Ghassan S; An, Gary; Sander, Edward A et al. (2016) Augmenting Surgery via Multi-scale Modeling and Translational Systems Biology in the Era of Precision Medicine: A Multidisciplinary Perspective. Ann Biomed Eng 44:2611-25
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Sack, Kevin L; Davies, Neil H; Guccione, Julius M et al. (2016) Personalised computational cardiology: Patient-specific modelling in cardiac mechanics and biomaterial injection therapies for myocardial infarction. Heart Fail Rev 21:815-826
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Genet, Martin; Chuan Lee, Lik; Ge, Liang et al. (2015) A Novel Method for Quantifying Smooth Regional Variations in Myocardial Contractility Within an Infarcted Human Left Ventricle Based on Delay-Enhanced Magnetic Resonance Imaging. J Biomech Eng 137:081009
Baillargeon, Brian; Costa, Ivan; Leach, Joseph R et al. (2015) Human Cardiac Function Simulator for the Optimal Design of a Novel Annuloplasty Ring with a Sub-valvular Element for Correction of Ischemic Mitral Regurgitation. Cardiovasc Eng Technol 6:105-16
Genet, M; Rausch, M K; Lee, L C et al. (2015) Heterogeneous growth-induced prestrain in the heart. J Biomech 48:2080-9
Lee, L C; Genet, M; Acevedo-Bolton, G et al. (2015) A computational model that predicts reverse growth in response to mechanical unloading. Biomech Model Mechanobiol 14:217-29

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