The applicant's overarching goal is to become an independently funded investigator in the field of interdisciplinary biomedical imaging science, with particular focus on MRI-based assessment of cardiovascular health. The central core of the training will involve closing the gap between the applicant's physics background and his limited exposure to pathophysiology and clinical research in order to enhance understanding of the clinical implications and biomedical needs of quantitative MRI toward translating imaging methodology to the clinic. The anticipated career development and training activities will include didactic coursework, one-on-one training with mentors, participation in conferences and regular interactions with other investigators, collaborators and trainees. The applicant will build upon hi successful NRSA T32 Postdoctoral Fellowship in quantitative MR imaging, and will continue to develop his skills within a multi-disciplinary, intellectually rich environment under mentors and collaborators who have a broad understanding of the multiple facets of the applicant's research, ranging from physics and engineering to physiology and cardiology. The overall project involves further development and evaluation of a non-invasive quantitative MRI protocol for measuring multiple parameters, as part of a single one-hour examination, to detect early signs of endothelial dysfunction (EDF). Early detection of EDF is vital as it promotes pathogenesis of atherosclerosis, a primary contributor to CVD. Current non-invasive screening techniques provide only a single physiological parameter to capture EDF, which is a complex systemic disorder, as opposed to a spectrum of measures. The central hypothesis of the proposed research is that a spectrum of MRI-derived parameters of central and peripheral vascular reactivity is able to detect the early signs of endothelial dysfunction in smokers without clinical symptoms of CVD. Smoking is chosen as a covariate because it is the most important preventable risk factor of CVD. Methods currently under development for translation to the clinic are comprised of techniques for simultaneous mapping of time-resolved velocity in the femoral artery and for quantifying the time-course of blood oxygen resaturation in the femoral vein during hyperemia, referred to as "dynamic oximetry." A third technique, presently under development, allows rapid quantification of regional PWV from central to peripheral arteries. The central hypothesis will be addressed with the following specific objectives: 1) Further develop a triple-procedure MRI protocol at 3T field strength for quantifying multiple surrogate markers of EDF, consisting of the following elements: (i) rapid peripheral PWV quantification, (ii) ungated time-resolved arterial blood velocimetry and (iii) dynamic oximetry, 2) evaluate systematic errors, both theoretically and experimentally, and assess intra- and inter-observer reproducibility of the MRI protocol in Aim 1 in human subjects, and 3) apply the integrated MRI protocol in Aim 1 to an observational pilot study involving healthy subjects, ages 30-39 years, without a history of CVD, partitioned equally into smokers and non-smokers, to evaluate the hypothesis that smoking promotes EDF and specifically that in smokers, compared to their non-smoking peers, matched for possible co-variates, a) the time-course of the blood oxygenation during hyperemia will have increased washout time of oxygen-depleted blood, reduced resaturation rate and overshoot, b) the relative increase in the shear rate from baseline will be modulated and the transient blood flow will be prolonged with reduced peak velocity, and c) the central PWV will be elevated and the difference in PWV between central and peripheral arteries will be reduced. The expected outcome is a novel integrated MRI protocol for detecting early signs of EDF by quantifying multiple surrogate measures in a single one-hour examination.

Public Health Relevance

Cardiovascular diseases (CVD) account for over one-third of all deaths in the United States. This burden is expected to increase due to the difficulty of controlling traditional CVD risk factors, such as smoking. To reduce morbidity and mortality while also curbing healthcare costs, a reproducible, accurate and noninvasive technique for quantifying early stages of CVD is needed to allow preventive intervention, including changes in lifestyle, before the onset of symptoms. The goal of this research is to further develop and evaluate a non- invasive MRI procedure as part of a single one-hour examination to detect early signs of cardiovascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Quantitative Research Career Development Award (K25)
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Special Emphasis Panel (ZHL1-CSR-X (O1))
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Carlson, Drew E
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University of Pennsylvania
Schools of Medicine
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Rodgers, Zachary B; Jain, Varsha; Englund, Erin K et al. (2013) High temporal resolution MRI quantification of global cerebral metabolic rate of oxygen consumption in response to apneic challenge. J Cereb Blood Flow Metab 33:1514-22
Langham, Michael C; Englund, Erin K; Mohler 3rd, Emile R et al. (2013) Quantitative CMR markers of impaired vascular reactivity associated with age and peripheral artery disease. J Cardiovasc Magn Reson 15:17