Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive thickening and obliteration of resistance-determining vessels of the pulmonary circulation. Despite current therapies, survival following the diagnosis of PAH remains approximately 50% at 5 years, with mortality a result of disease progression and right heart failure. Delayed diagnosis, the lack of more direct biomarkers of disease activity, and the lack of treatments that can arrest or reverse pulmonary vascular remodeling are all barriers to improved outcomes in PAH. A sensitive, non-invasive imaging test that directly monitors pulmonary vascular disease activity could help expedite diagnosis and identify effective interventions. This proposal will validate the utility of a novel positron emission tomography (PET) molecular imaging modality, using 89Zr-bevacizumab to detect pathologic VEGF activity in the vessels affected by PH. Preliminary data demonstrates that PET imaging using 89Zr- bevacizumab detects enhanced VEGF activity in the distal circulation of the pulmonary vasculature in experimental PAH, and has the potential to recognize active lesions of remodeling in human PAH. These studies will directly test whether or not PET 89Zr- bevacizumab imaging can detect early disease, prior to the development of significant vessel loss and hemodynamically significant PAH, predict the severity and progression of disease, and reflect the ability of approved vasodilator and novel therapeutic interventions to intercept angiogenic remodeling activity in the pulmonary circulation. Validation studies will be performed using living, explanted human lungs affected by PAH using an ex-vivo perfusion approach, to raise confidence in the translatability of these findings. The validation of this approach would constitute a breakthrough in our ability to assess ongoing remodeling in a vascular bed which is ordinarily inaccessible to clinicians, to allow objective stratification of disease severity and rik, tailor pharmacotherapy based on disease activity, and potentially identify therapies acting by entirely novel mechanisms to arrest or reverse disease progression.
Pulmonaryhypertensiondescribesadiversesetofdiseasescharacterizedbyelevatedpressuresand progressiveobstructionandlossofthelungvesselswithamediansurvivalofapproximately5years afterdiagnosisdespitecurrenttreatments.Thereisanurgentneedforsensitiveandnon-?invasivetests thatcanpermittheearlierdiagnosisofpulmonaryhypertension,tofacilitateearlyinterventionbefore irreversiblelossofvesselshasoccurred,andtohelpidentifymoreeffectivetherapiesthatcanarrestthe progressionofdisease.Thisproposalwilldevelopanovelscanningtechniquewhichcansensitively detecttheabnormalexpressionofgrowthfactorsinlungvessels,representingthefirsttestofitskindto detectactualdiseaseactivityinpulmonaryvessels,permittingearlierdiagnosis,andrapidassessments ofwhetherexistingornewmedicationscanarrestthediseaseactivityandtherebyimproveoutcomesin thisdisease.
