Heart failure (HF) is a worldwide epidemic that contributes considerably to the overall cost of health care in developed nations. The number of people afflicted with this complex disease is increasing at an alarming pace-a trend that is likely to continue for many years to come. The overall goal of our proposed research is to optimize a therapy for HF that involves percutaneous injection of a hydrogel (Algisyl-LVR) in the failing myocardium. Given the cardiovascular system's complexity, a multi-disciplinary expertise across experimental and computational domains is required to fully investigate this novel HF therapy. The three specific aims include the following: First, we will validate mathematical (finite element models of failing left ventricles that have been treated with Algisyl-LVR + coronary artery bypass grafting or Algisyl-LVR alone. The finite element models will have realistic 3D geometries based on magnetic resonance imaging and validated with in-vivo myocardial strain versus left and right ventricular pressure measurements. Additionally, ex-vivo 3D myofiber orientation and direct force measurements in skinned fiber preparations will be made. Second, we will use the validated finite element models and our method for automatically optimizing medical devices for treating HF to design the optimal Algisyl-LVR injection pattern and test it in swine with systolic HF. Lastly, we will deliver Algisyl-LVR percutaneously, using the optimal injection pattern determined in Aim 2, and test it in swine with systolic HF. The proposed approach and methodologies are innovative in simulation of animal-specific device therapy that holds very significant promise for treatment of the epidemic of HF.

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 and in particular the surgical treatment of heart failure as is the focus of this proposa.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Lee, Albert
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Northern California Institute Research & Education
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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