Imaging of pulmonary arterial hypertension with proton MRI

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PROJECT SUMMARY Goal/Significance. Pulmonary arterial hypertension (PAH) arises from progressive remodeling of the pulmonary circulation leading to the secondary effects of elevated pulmonary arterial pressure and resistance after 50% of vessels are affected. The leads to increased afterload, followed by right heart failure and death. Improvement in medical therapy in PAH is related to the development of new drugs and combination therapies rather than the identification of new pathways. This proposal meets a critical need for tools that will better identify those who respond to these new therapies. The goal of this proposal is to translate and refine biomarkers derived from proton magnetic resonance imaging (MRI), and evaluate their sensitivity to predict disease progression in patients with PAH. Scientific Premise. Functional proton MRI may provide increased sensitivity to disease progression because of the ability to detect local changes related to vascular remodeling that is obscured by regions of normal lung. Innovation/Hypothesis. Building on our previous work developing innovative proton MRI biomarkers that are markedly altered in patients with established PAH, we predict that the onset of PAH manifests as a progressive alteration in images of the pulmonary circulation as follows: 1. an increase in un-perfused lung regions as vessels succumb to remodeling 2. a resultant increase in the spatial heterogeneity of perfusion and 3. an increase in fluctuations in perfusion reflecting a failure of local pressure regulation. Our selected biomarkers reflect these processes. We hypothesize that these biomarkers are altered in patients with PAH, with disease progression, by physiological changes induced by therapy and are early predictors of outcome. Approach. Supported by our preliminary data we will: 1. Determine the sensitivity of proton MRI biomarkers for patients with established PAH receiving therapy, evaluate biomarkers as a measures of disease severity and compare these to clinical findings, and cardiac MRI (CMR) data. 2. optimize image acquisition protocol efficiency to facilitate translation. Evaluate reproducibility, and effects of noise and artifacts. 3. Evaluate proton MRI biomarkers as a means to monitor response to therapy by longitudinally monitoring newly diagnosed PAH patients and assess the ability of lung biomarkers to predict time to clinical worsening compared to CMR, and current standards. Impact. Successful completion of this work will lead to new monitoring tools for patients with PAH using noninvasive proton MRI, potentially providing prognostic information in patients with PAH. The techniques proposed here could be ultimately conducted on any 1.5 T clinical MRI scanner in less than 30 minutes, increasing utility for screening.