Yanhang Zhang Department of Aerospace and Mechanical Engineering, Boston University, Boston, MA 02215 Martin L. Dunn Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, CO 80309 Kendall S. Hunter Craig Lanning D. Dunbar Ivy Lori Claussen Division of Cardiology, The Children’s Hospital of Denver, Denver, CO 80218 S. James Chen Department of Medicine, Division of Cardiology, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262 Robin Shandas Department of Mechanical Engineering, 427 UCB, University of Colorado, Boulder, CO 80309 and Division of Cardiology, The Children’s Hospital of Denver, Denver, CO 80218 e-mail: robin.shandas@colorado.edu Application of A Microstructural Constitutive Model of the Pulmonary Artery to Patient-Specific Studies: Validation and Effect of Orthotropy We applied a statistical mechanics based microstructural model of pulmonary artery mechanics, developed from our previous studies of rats with pulmonary arterial hyper- tension (PAH), to patient-specific clinical studies of children with PAH. Our previous animal studies provoked the hypothesis that increased cross-linking density of the mo- lecular chains may be one biological remodeling mechanism by which the PA stiffens in PAH. This study appears to further confirm this hypothesis since varying molecular cross-linking density in the model allows us to simulate the changes in the P-D loops between normotensive and hypertensive conditions reasonably well. The model was com- bined with patient-specific three-dimensional vascular anatomy to obtain detailed infor- mation on the topography of stresses and strains within the proximal branches of the pulmonary vasculature. The effect of orthotropy on stress/strain within the main and branch PAs obtained from a patient was explored. This initial study also puts forward important questions that need to be considered before combining the microstructural model with complex patient-specific vascular geometries. DOI: 10.1115/1.2485780 Keywords: pulmonary arterial hypertension, orthotropic hyperelasticity, color M-mode tissue Doppler imaging (CMM-TDI), biplane angiography, 3D pulmonary vasculature 1 Introduction Pulmonary arterial hypertension PAH is an important determi- nant of morbidity and mortality in children. Secondary PAH re- sults from a known cause whereas primary or idiopathic PAH is a diagnosis of exclusion, indicating absence of known cause. PAH may develop from a multitude of factors including increased pul- monary blood flow as in congenital heart lesions with a left-to- right shunt, left ventricular diastolic dysfunction, or intrinsic vas- cular changes as in primary PAH. Regardless of etiology, the effect is increased workload on the right ventricle RV. Children with PAH and/or increased pulmonary blood flow, also develop functional and structural alterations of the pulmonary vasculature 1–4. Progression of these vascular changes, referred to as pul- monary vascular disease PVD, largely determines the manage- ment and prognosis of these patients and can severely limit surgi- cal repair or long term survival. Pulmonary vascular remodeling, and thus PVD, starts from the onset of abnormal hemodynamics and eventually leads to remodeling of the artery wall. This remod- eling process occurs in the upstream arteries as well, leading to arterial wall thickening and extracellular matrix modulation, ulti- mately resulting in stiffening of the pulmonary arterial walls 5–8. For both primary and secondary PAH, it is important to accu- rately diagnose the severity of PAH and consequently the level of afterload imposed on the RV. Hemodynamic measurement of pul- monary vascular resistance PVR has been the clinical standard for evaluating pulmonary vascular function and, with the use of novel treatments such as low-dose inhaled nitric oxide and/or prostacyclin agents, evaluating reactivity of the pulmonary vascu- lar bed by measuring changes in PVR upon clinical challenge. Recent studies show that measuring PVR alone may not provide a sufficiently comprehensive metric to evaluate pulmonary vascular reactivity and function; instead, obtaining upstream compliance information either indirectly by measuring the full input imped- ance of the vascular system, or directly through novel ultrasound tissue Doppler techniques, is needed to more fully quantify RV Contributed by the Bioengineering Division of ASME for publication in the JOUR- NAL OF BIOMECHANICAL ENGINEERING. Manuscript received October 7, 2005; final manuscript received August 22, 2006. Review conducted by Yoram Lanir. Journal of Biomechanical Engineering APRIL 2007, Vol. 129 / 193 Copyright © 2007 by ASME