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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-E (02))
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Baldwin, Tim
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University of California San Francisco
Schools of Medicine
San Francisco
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Dabiri, Yaghoub; Sack, Kevin L; Shaul, Semion et al. (2018) Relationship of Transmural Variations in Myofiber Contractility to Left Ventricular Ejection Fraction: Implications for Modeling Heart Failure Phenotype With Preserved Ejection Fraction. Front Physiol 9:1003
Sack, K L; Aliotta, E; Choy, J S et al. (2018) Effect of intra-myocardial Algisyl-LVRâ„¢ injectates on fibre structure in porcine heart failure. J Mech Behav Biomed Mater 87:172-179
Sack, Kevin L; Aliotta, Eric; Ennis, Daniel B et al. (2018) Construction and Validation of Subject-Specific Biventricular Finite-Element Models of Healthy and Failing Swine Hearts From High-Resolution DT-MRI. Front Physiol 9:539
Choy, Jenny S; Leng, Shuang; Acevedo-Bolton, Gabriel et al. (2018) Efficacy of intramyocardial injection of Algisyl-LVR for the treatment of ischemic heart failure in swine. Int J Cardiol 255:129-135
Sack, Kevin L; Dabiri, Yaghoub; Franz, Thomas et al. (2018) Investigating the Role of Interventricular Interdependence in Development of Right Heart Dysfunction During LVAD Support: A Patient-Specific Methods-Based Approach. Front Physiol 9:520
Genet, M; Lee, L C; Baillargeon, B et al. (2016) Modeling Pathologies of Diastolic and Systolic Heart Failure. Ann Biomed Eng 44:112-27
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
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
Lee, L C; Kassab, G S; Guccione, J M (2016) Mathematical modeling of cardiac growth and remodeling. Wiley Interdiscip Rev Syst Biol Med 8:211-26
Burkhoff, Daniel; Guccione, Julius (2016) A New Twist on Mitral Regurgitation. JACC Basic Transl Sci 1:203-206

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