Kendall S. Hunter

Changes in the structure-function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves

Extracellular matrix remodeling has been proposed as one mechanism by which proximal pulmonary arteries stiffen during pulmonary arterial hypertension (PAH). Although some attention has been paid to the role of collagen and metallomatrix proteins in affecting vascular stiffness, much less work has been performed on changes in elastin structure-function relationships in PAH. Such work is warranted, given the importance of elastin as the structural protein primarily responsible for the passive elastic behavior of these conduit arteries. Here, we study structure-function relationships of fresh arterial tissue and purified arterial elastin from the main, left, and right pulmonary artery branches of normotensive and hypoxia-induced pulmonary hypertensive neonatal calves. PAH resulted in an average 81 and 72% increase in stiffness of fresh and digested tissue, respectively. Increase in stiffness appears most attributable to elevated elastic modulus, which increased 46 and 65%, respectively, for fresh and digested tissue. Comparison between fresh and digested tissues shows that, at 35% strain, a minimum of 48% of the arterial load is carried by elastin, and a minimum of 43% of the change in stiffness of arterial tissue is due to the change in elastin stiffness. Analysis of the stress-strain behavior revealed that PAH causes an increase in the strains associated with the physiological pressure range but had no effect on the strain of transition from elastin-dominant to collagen-dominant behavior. These results indicate that mechanobiological adaptations of the continuum and geometric properties of elastin, in response to PAH, significantly elevate the circumferential stiffness of proximal pulmonary arterial tissue.

An integrated wave-effects model for an underwater explosion bubble

A model for a moderately deep underwater explosion bubble is developed that integrates the shock wave and oscillation phases of the motion. A hyperacoustic relationship is formulated that relates bubble volume acceleration to far-field pressure profile during the shock-wave phase, thereby providing initial conditions for the subsequent oscillation phase. For the latter, equations for bubble-surface response are derived that include wave effects in both the external liquid and the internal gas. The equations are then specialized to the case of a spherical bubble, and bubble-surface displacement histories are calculated for dilational and translational motion. Agreement between these histories and experimental data is found to be substantially better than that produced by previous models.

Mechanics and Function of the Pulmonary Vasculature: Implications for Pulmonary Vascular Disease and Right Ventricular Function

he relationship between cardiac function and the afterload against which the heart muscle must work to circulate blood throughout the pulmonary circulation is defined by a complex interaction between many coupled system parameters. These parameters range broadly and incorporate system effects originating primarily from three distinct locations: input power from the heart, hydraulic impedance from the large conduit pulmonary arteries, and hydraulic resistance from the more distal microcirculation. These organ systems are not independent, but rather, form a coupled system in which a change to any individual parameter affects all other system parameters. The result is a highly nonlinear system which requires not only detailed study of each specific component and the effect of disease on their specific function, but also requires study of the interconnected relationship between the microcirculation, the conduit arteries, and the heart in response to age and disease. Here, we investigate systems-level changes associated with pulmonary hypertensive disease progression in an effort to better understand this coupled relationship.

Increased arterial stiffness and extracellular matrix reorganization in intrauterine growth–restricted fetal sheep

Background:Fetal intrauterine growth restriction (IUGR) results in increased placental resistance to blood flow, fetal hypertension, and increased pulsatility stresses shown to lead to vascular remodeling. We tested our hypothesis that IUGR causes decreased compliance in the carotid and umbilical arteries due to altered extracellular matrix (ECM) composition and structure.Methods:A sheep model of placental insufficiency–induced IUGR (PI-IUGR) was created by exposure of the pregnant ewe to elevated ambient temperatures. Umbilical and carotid arteries from near-term fetuses were tested with pressure–diameter measurements to compare passive compliance in control and PI-IUGR tissues. ECM composition was measured via biochemical assay, and the organization was determined by using histology and second-harmonic generation imaging.Results:We found that PI-IUGR increased arterial stiffness with increased collagen engagement, or transition stretch. PI-IUGR carotid arteries exhibited increased collagen and elastin quantity, and PI-IUGR umbilical arteries exhibited increased sulfated glycosaminoglycans. Histomorphology showed altered collagen-to-elastin ratios with altered cellular proliferation. Increased stiffness indicates altered collagen-to-elastin ratios with less elastin contribution leading to increased collagen engagement.Conclusion:Because vessel stiffness is a significant predictor in the development of hypertension, disrupted ECM deposition in IUGR provides a potential link between IUGR and adult hypertension.

Vascular stiffening in pulmonary hypertension: cause or consequence? (2013 Grover Conference series)

Recent studies have indicated that systemic arterial stiffening is a precursor to hypertension and that hypertension, in turn, can perpetuate arterial stiffening. Pulmonary artery (PA) stiffening is also well documented to occur in pulmonary hypertension (PH), and there is evidence that pulmonary vascular stiffness (PVS) may be a better predictor of outcome than pulmonary vascular resistance (PVR). We have hypothesized that the decreased flow-damping function of elastic PAs in PH likely initiates and/or perpetuates dysfunction of pulmonary microvasculature. Recent studies have shown that large-vessel stiffening increases flow pulsatility in the distal pulmonary vasculature, leading to endothelial dysfunction within a proinflammatory, vasoconstricting, and profibrogenic environment. The intricate role of stiffening-stimulated high pulsatile flow in endothelial cell dysfunction includes stepwise molecular events underlying PA hypertrophy, inflammation, endothelial-mesenchymal transition, and fibrosis. In addition to contributing to microenvironmental alterations of the distal vasculature, disordered proximal-distal PA coupling likely also plays a role in increasing ventricular afterload, ultimately causing right ventricle (RV) dysfunction and death. Current therapeutic treatments do not provide a realistic approach to destiffening arteries and, thus, to potentially abrogating the effects of high pulsatile flow on the distal pulmonary vasculature or the increased work imposed by stiffening on the RV. Scrutinizing the effect of PA stiffening on high pulsatile flow–induced cellular and molecular changes, and vice versa, might lead to important new therapeutic options that abrogate PA remodeling and PH development. With a clear understanding that PA stiffening may contribute to the progression of PH to an irreversible state by contributing to chronic microvascular damage in lungs, future studies should be aimed first at defining the underlying mechanisms leading to PA stiffening and then at improved treatment approaches based on these findings.

RV stroke work in children with pulmonary arterial hypertension: estimation based on invasive haemodynamic assessment and correlation with outcomes

Background RV performance is an important determinant of outcomes in children with pulmonary arterial hypertension (PAH). RV stroke work (RVSW), the product of mean pulmonary artery pressure and stroke volume, integrates contractility, afterload and ventricular-vascular coupling. RVSW has not been evaluated in children with PAH. We tested the hypothesis that RVSW would be a predictor of outcomes in children with PAH. Methods Patients in the Childrens Hospital Colorado PAH database were evaluated retrospectively, and those with idiopathic PAH and those with minor or repaired congenital heart disease were included. Haemodynamic data were obtained by catheterisation and echocardiography, performed within 3 months. RVSW was calculated: mean pulmonary arterial pressure × stroke volume, and indexed to body surface area. Statistics included Kruskal–Wallis, Wilcoxon rank sum, and Spearman correlation. Results Fifty patients were included. Median age of the cohort was 9.5 (6.0, 15.7) years, with a median indexed pulmonary vascular resistance (PVRi) of 6.5 (3.7, 11.6) WU m2. RVSW had a significant association with PVRi (r=0.6, p<0.0001), tricuspid annular systolic plane excursion (r=0.55, p=0.0001), and RV fractional area change (r=−0.4, p=0.005). Grouped by WHO class, there was a significant difference in RVSW (p=0.04). Need for atrial septostomy and death were associated with higher RVSW (p=0.04 and p=0.03, respectively). Conclusions RVSW can be estimated in children with PAH, and is significantly associated with abnormal WHO class, the need for septostomy, as well as mortality. Indices accounting for RV performance as well as ventricular-vascular coupling may be useful in the prognosis and, hence, management of children with PAH.

A Microstructurally-Driven Model for Pulmonary Artery Tissue

A new constitutive model for elastic, proximal pulmonary artery tissue is presented here, called the total crimped fiber model. This model is based on the material and microstructural properties of the two main, passive, load-bearing components of the artery wall, elastin, and collagen. Elastin matrix proteins are modeled with an orthotropic neo-Hookean material. High stretch behavior is governed by an orthotropic crimped fiber material modeled as a planar sinusoidal linear elastic beam, which represents collagen fiber deformations. Collagen-dependent artery orthotropy is defined by a structure tensor representing the effective orientation distribution of collagen fiber bundles. Therefore, every parameter of the total crimped fiber model is correlated with either a physiologic structure or geometry or is a mechanically measured material property of the composite tissue. Further, by incorporating elastin orthotropy, this model better represents the mechanics of arterial tissue deformation. These advancements result in a microstructural total crimped fiber model of pulmonary artery tissue mechanics, which demonstrates good quality of fit and flexibility for modeling varied mechanical behaviors encountered in disease states.

Stiffening-Induced High Pulsatility Flow Activates Endothelial Inflammation via a TLR2/NF-κB Pathway

Stiffening of large arteries is increasingly used as an independent predictor of risk and therapeutic outcome for small artery dysfunction in many diseases including pulmonary hypertension. The molecular mechanisms mediating downstream vascular cell responses to large artery stiffening remain unclear. We hypothesize that high pulsatility flow, induced by large artery stiffening, causes inflammatory responses in downstream pulmonary artery endothelial cells (PAECs) through toll-like receptor (TLR) pathways. To recapitulate the stiffening effect of large pulmonary arteries that occurs in pulmonary hypertension, ultrathin silicone tubes of variable mechanical stiffness were formulated and were placed in a flow circulatory system. These tubes modulated the simulated cardiac output into pulsatile flows with different pulsatility indices, 0.5 (normal) or 1.5 (high). PAECs placed downstream of the tubes were evaluated for their expression of proinflammatory molecules (ICAM-1, VCAM-1, E-selectin and MCP-1), TLR receptors and intracellular NF-κB following flow exposure. Results showed that compared to flow with normal pulsatility, high pulsatility flow induced proinflammatory responses in PAECs, enhanced TLR2 expression but not TLR4, and caused NF-κB activation. Pharmacologic (OxPAPC) and siRNA inhibition of TLR2 attenuated high pulsatility flow-induced pro-inflammatory responses and NF-κB activation in PAECs. We also observed that PAECs isolated from small pulmonary arteries of hypertensive animals exhibiting proximal vascular stiffening demonstrated a durable ex-vivo proinflammatory phenotype (increased TLR2, TLR4 and MCP-1 expression). Intralobar PAECs isolated from vessels of IPAH patients also showed increased TLR2. In conclusion, this study demonstrates for the first time that TLR2/NF-κB signaling mediates endothelial inflammation under high pulsatility flow caused by upstream stiffening, but the role of TLR4 in flow pulsatility-mediated endothelial mechanotransduction remains unclear.

Pulmonary Arterial Stiffness: Toward a New Paradigm in Pulmonary Arterial Hypertension Pathophysiology and Assessment

Stiffening of the pulmonary arterial bed with the subsequent increased load on the right ventricle is a paramount feature of pulmonary hypertension (PH). The pathophysiology of vascular stiffening is a complex and self-reinforcing function of extracellular matrix remodeling, driven by recruitment of circulating inflammatory cells and their interactions with resident vascular cells, and mechanotransduction of altered hemodynamic forces throughout the ventricular-vascular axis. New approaches to understanding the cell and molecular determinants of the pathophysiology combine novel biopolymer substrates, controlled flow conditions, and defined cell types to recapitulate the biomechanical environment in vitro. Simultaneously, advances are occurring to assess novel parameters of stiffness in vivo. In this comprehensive state-of-art review, we describe clinical hemodynamic markers, together with the newest translational echocardiographic and cardiac magnetic resonance imaging methods, to assess vascular stiffness and ventricular-vascular coupling. Finally, fluid-tissue interactions appear to offer a novel route of investigating the mechanotransduction processes and disease progression.

Pulmonary Vascular Stiffness: Measurement, Modeling, and Implications in Normal and Hypertensive Pulmonary Circulations

This article introduces the concept of pulmonary vascular stiffness, discusses its increasingly recognized importance as a diagnostic marker in the evaluation of pulmonary vascular disease, and describes methods to measure and model it clinically, experimentally, and computationally. It begins with a description of systems-level methods to evaluate pulmonary vascular compliance and recent clinical efforts in applying such techniques to better predict patient outcomes in pulmonary arterial hypertension. It then progresses from the systems-level to the local level, discusses proposed methods by which upstream pulmonary vessels increase in stiffness, introduces concepts around vascular mechanics, and concludes by describing recent work incorporating advanced numerical methods to more thoroughly evaluate changes in local mechanical properties of pulmonary arteries.