Cardiac left ventricular remodeling is responsible for over 250,000 heart failure deaths each year in the United States. Myocardial infarct expansion, progressive thinning and deposition of non-contractile fibrotic tissue can result in compensatory dilatation of the nonischemic borderzone segments. Ultimately, cardiac output cannot be sustained under such progressive heart enlargement. The long term project goals are to noninvasively detect myocardial infarction edema, fibrosis and infarct stability using magnetic resonance imaging techniques based on endogenous 1H contrast generated by nuclear magnetic relaxation. The hypothesis is that the primary biological changes occurring within the first 8 weeks following myocardial infarction, particularly myocyte apoptosis, recruitment of cytokines and deposition of fibrotic scar tissue, have a significant effect on the magnetic environment of 1H nuclei in water molecules. The 1H magnetic environment changes can be detected using novel T1A magnetic resonance imaging (MRI) techniques developed by Dr. Witschey during graduate school. 1H T1A relaxation is sensitive to low frequency fluctuations of water molecules including the overall apparent exchange rate between free water 1Hs and proteins and macromolecules at low exchange frequencies and changes in total water mobility. In preliminary investigations performed on swine, T1A was shown to detect changes to the overall apparent exchange rate and rate of relaxation caused by rotational modulation of the magnetic dipole-dipole interaction at 8 weeks following ligation of the second and third branches of the circumflex artery. These findings present an opportunity to overcome limitations of current methods of endogenous contrast MRI based on T2 relaxation measurements. In this proposal, research will be performed to develop methods to overcome magnetic field heterogeneity (static and RF fields) and motion artifacts associated specifically with T1A cardiac imaging. During the independent phase, experiments will be carried out to (1) serially examine the effect of apparent 1H exchange rates and rotational modulation of magnetic dipole-dipole coupling on 1H T1A relaxation times from the moment of initial ischemia throughout the period of cardiac remodeling to 8 weeks in swine and (2) determine whether 1H T1A methods provide different information regarding biochemistry from perfusion based MRI techniques. Extensive additional training is proposed during the K99 phase to include didactic training, participation at conferences, seminars and workshops, biannual meetings of a career development committee, and hands-on training in the creation of animals models of cardiac dysfunction, state-of-the-art imaging and technique development, analysis, and development of research career skills. This training will prepare Dr. Witschey to achieve his career goals to advance our understanding and treatment of cardiac disease through novel and interdisciplinary techniques combined with basic science research.

Public Health Relevance

Left ventricular remodeling is a deadly condition during which the heart undergoes structural, functional and biochemical changes following myocardial infarction (MI). The initial and long-term macroscopic changes, edema, cell apoptosis, and deposition of collagen, are hypothesized to influence the nuclear magnetic relaxation of 1Hs in water. The implications are that the remodeling process can be noninvasively followed without expensive and potentially hazardous exogenous contrast based methods using magnetic resonance imaging (MRI).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-P (O2))
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Carlson, Drew E
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University of Pennsylvania
Schools of Medicine
United States
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Witschey, Walter R T; Pouch, Alison M; McGarvey, Jeremy R et al. (2014) Three-dimensional ultrasound-derived physical mitral valve modeling. Ann Thorac Surg 98:691-4
Witschey, Walter R T; Contijoch, Francisco; McGarvey, Jeremy R et al. (2014) Real-time magnetic resonance imaging technique for determining left ventricle pressure-volume loops. Ann Thorac Surg 97:1597-603
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Weber, Hans; Gallichan, Daniel; Schultz, Gerrit et al. (2013) Excitation and geometrically matched local encoding of curved slices. Magn Reson Med 69:1317-25
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Koomalsingh, Kevin J; Witschey, Walter R T; McGarvey, Jeremy R et al. (2013) Optimized local infarct restraint improves left ventricular function and limits remodeling. Ann Thorac Surg 95:155-62
Witschey, Walter R T; Zsido, Gerald A; Koomalsingh, Kevin et al. (2012) In vivo chronic myocardial infarction characterization by spin locked cardiovascular magnetic resonance. J Cardiovasc Magn Reson 14:37
Ferrari, Victor A; Witschey, Walter R T; Zhou, Rong (2011) Cardiac magnetic resonance assessment of myocardial fibrosis: honing new clinical tools. Circ Cardiovasc Imaging 4:604-6

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