Pulmonary arterial hypertension (PAH) is a fatal disease in children and adults in which pro- gressive increases in load on the right ventricle (RV) ultimately lead to heart failure and death. Current clinical assessment of the disease involves invasive collection of main pulmonary artery pressure (mPAP) and cardiac output (CO), which are then used to determine pulmonary vascular resistance (PVR), the standard disease diagnostic. PVR is believed to represent RV afterload, and thus a primary determinant of heart failure. However, recent clinical studies of PAH by our group and others have sug- gested that including pulmonary vascular stiffness (PVS) as an additional component of RV afterload yields better prediction of PAH progression than standard PAH diagnostics. Our recent animal model studies have also established that proximal vascular stiffening increases as a consequence of vascular remodeling. Combining these findings, we propose that specific measurement of conduit proximal vas- cular stiffness (PVS) - and thus proximal remodeling - represents a new measure of disease progres- sion, and thus may offer beneficial diagnostic and prognostic information to the clinic. Dr Hunter's career goal is to contribute to cardiology at the nexus vascular mechanics and the clinical and basic science tools that diagnose and measure it. Although Dr Hunter has made significant progress in understanding the general issues of importance in clinical cardiology and for pulmonary ar- terial hypertension, his proposed career plan will address his lack of formal training in the quantitative analysis of MRI, mechanical measurements for the characterization of soft tissue, and the use and in- terpretation of animal models. Finally, it will provide protected time for the maturation of his research program. The research proposed above provides the core of a five-year career development plan;he will perform the research under the mentorship of five prominent investigators with specialties comple- mentary to the research and his training needs, while completing additional formal coursework. Through this additional training and with protected time, Dr Hunter will broaden the scope of his re- search and position himself as a noteworthy independent bioengineering investigator of pulmonary vascular disease. findings

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a fatal disease in children and adults in which pro- gressive increases in load on the right ventricle (RV) ultimately lead to heart failure and death. Current clinical assessment of the disease involves invasive collection of main pulmonary artery pressure (mPAP) and cardiac output (CO), which are then used to determine pulmonary vascular resistance (PVR), the standard disease diagnostic. PVR is believed to represent RV afterload, and thus a primary determinant of heart failure. However, recent clinical studies of PAH by our group and others have sug- gested that including pulmonary vascular stiffness (PVS) as an additional component of RV afterload yields better prediction of PAH progression than standard PAH diagnostics. Our recent animal model studies have also established that proximal vascular stiffening increases as a consequence of vascular remodeling. Combining these findings, we propose that specific measurement of conduit proximal vas- cular stiffness (PVS) - and thus proximal remodeling - represents a new measure of disease progres- sion, and thus may offer beneficial diagnostic and prognostic information to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25HL094749-04
Application #
8478166
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2010-08-10
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$140,769
Indirect Cost
$10,427
Name
University of Colorado Denver
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Di Maria, Michael V; Younoszai, Adel K; Mertens, Luc et al. (2014) RV stroke work in children with pulmonary arterial hypertension: estimation based on invasive haemodynamic assessment and correlation with outcomes. Heart 100:1342-7
Dodson, R Blair; Rozance, Paul J; Petrash, Carson C et al. (2014) Thoracic and abdominal aortas stiffen through unique extracellular matrix changes in intrauterine growth restricted fetal sheep. Am J Physiol Heart Circ Physiol 306:H429-37
Yunker, Bryan E; Dodd, Gerald D; Chen, S James et al. (2014) The design and fabrication of two portal vein flow phantoms by different methods. Med Phys 41:023701
Dodson, Reuben Blair; Rozance, Paul J; Fleenor, Bradley S et al. (2013) Increased arterial stiffness and extracellular matrix reorganization in intrauterine growth-restricted fetal sheep. Pediatr Res 73:147-54
Dodson, R Blair; Rozance, Paul J; Reina-Romo, Esther et al. (2013) Hyperelastic remodeling in the intrauterine growth restricted (IUGR) carotid artery in the near-term fetus. J Biomech 46:956-63
Dodson, R Blair; Martin, John T; Hunter, Kendall S et al. (2013) Determination of hyperelastic properties for umbilical artery in preeclampsia from uniaxial extension tests. Eur J Obstet Gynecol Reprod Biol 169:207-12
Mertens, Luc; Hunter, Kendall (2013) Imaging right ventricular shape and remodelling. Eur Heart J Cardiovasc Imaging 14:311-2
Tian, Lian; Lammers, Steven R; Kao, Philip H et al. (2011) Linked opening angle and histological and mechanical aspects of the proximal pulmonary arteries of healthy and pulmonary hypertensive rats and calves. Am J Physiol Heart Circ Physiol 301:H1810-8