Stiffening of the Extrapulmonary Arteries From Rats in Chronic Hypoxic Pulmonary Hypertension.

Changes in the compliance properties of large blood vessels are critical determinants of ventricular afterload and ultimately dysfunction. Little is known of the mechanical properties of large vessels exhibiting pulmonary hypertension, particularly the trunk and right main artery. We initiated a study to investigate the influence of chronic hypoxic pulmonary hypertension on the mechanical properties of the extrapulmonary arteries of rats. One group of animals was housed at the equivalent of 5000 m elevation for three weeks and the other held at ambient conditions of ~1600 m. The two groups were matched in age and gender. The animals exposed to hypobaric hypoxia exhibited signs of pulmonary hypertension, as evidenced by an increase in the RV/(LV+S) heart weight ratio. The extrapulmonary arteries of the hypoxic animals were also thicker than those of the control population. Histological examination revealed increased thickness of the media and additional deposits of collagen in the adventitia. The mechanical properties of the trunk, and the right and left main pulmonary arteries were assessed; at a representative pressure (7 kPa), the two populations exhibited different quantities of stretch for each section. At higher pressures we noted less deformation among the arteries from hypoxic animals as compared with controls. A four-parameter constitutive model was employed to fit and analyze the data. We conclude that chronic hypoxic pulmonary hypertension is associated with a stiffening of all the extrapulmonary arteries.

Comparison of mechanical behavior among the extrapulmonary arteries from rats.

Results of comparative tests on pulmonary arteries from untreated Long-Evans rats are presented from three sections of the artery: the trunk, and the right and left main extrapulmonary arteries. Analyses were conducted looking for mechanical differences between the flow (longitudinal) and circumferential directions, between the right and left main arteries, and between each of the mains and the trunk. The mechanical properties of rat pulmonary arteries were obtained with a bubble inflation technique. A flat disk of rat pulmonary artery was constrained at the periphery and inflated, and the geometry of the resulting bubble of material recorded from six different angles. To analyze the data, the area under the stress-strain curve was calculated for each test and orientation. This area, related to the strain-energy density, was calculated at stress equal to 200kPa, for the purpose of statistical comparison. The mean values for the area show that the trunk is less compliant than the main arteries; this difference is supported by histological evidence. When comparing the circumferential and longitudinal properties of the arteries, differences are found for the trunk and left main arteries, but with opposite orientations being more compliant. The mean values for the two orientations for the right main artery are statistically identical. There was indication of significant difference in mechanical properties between the trunk and the main arteries. The left main artery in the circumferential orientation is highly compliant and appears to strongly influence the likelihood that significant differences will exist when included in a statistical population. These data show that each section of the extrapulmonary arterial system should not be expected to behave identically, and they provide the baseline mechanical behavior of the pulmonary artery from normotensive rats.

Bubble-test method for synthetic and bovine vascular material.

A measurement system has been designed and constructed at NIST for the study of the mechanical properties of synthetic and bovine vascular materials. The measurement technique was validated on latex, where good agreement was found with the Neo-Hookean model. Measurements were also made on expanded polytetrafluoroethylene, which is commonly used for vascular grafts. The measurements of this material were carried out over a pressure range greater than would be seen in vivo. However, the strains were still small enough to effectively apply the Neo-Hookean model to these data.

A microstructural hyperelastic model of pulmonary arteries under normo- and hypertensive conditions.

This work represents the first application of a statistical mechanics based microstructural orthotropic hyperelastic model to pulmonary artery mechanics under normotensive and hypertensive conditions. The model provides an analogy between the entangled network of long molecular chains and the structural protein framework seen in the medial layer, and relates the mechanical response at macro-level to the deformation (entropy change) of individual molecular chains at the micro-level. A finite element approach was adopted to implement the model. Material parameters were determined via comparing model output to measured pressure-stretch results from normotensive and hypertensive trunks and branches obtained from a rat model of pulmonary arterial hypertension. Results from this initial study show that this model appears reasonable for the study of hyperelastic and anisotropic pulmonary artery mechanics. Typical tangent modulus values ranged from 200 to 800 kPa for normotensive arteries-this increased to beyond 1 MPa for hypertensive vessels. Our study also provokes the hypothesis that increase of cross-linking density may be one mechanism by which the pulmonary artery stiffens in hypertension.

Comparison of strength properties of normotensive and hypertensive rat pulmonary arteries.

A series of tests were conducted to quantify the difference in the mechanical properties of normo- and hypertensive pulmonary arteries. A bubble-test design was employed to measure the biaxial properties of a segment of artery. The test results compare the properties at multiple orientations of the trunk, right, and left pulmonary arteries from normal (Control) and monocrotaline-treated male Long-Evans wild rats that ranged in age from 8 to 17 weeks old, along with some preliminary results from hypoxic Long-Evans knock-out rats. Data show little difference between the stress-strain relationship of the control pulmonary arteries and that of the monocrotaline-treated pulmonary arteries. However, the preliminary results from the hypoxic pulmonary arteries show that the arterial material strains less before the onset of strain-stiffening behavior. The longitudinal orientation exhibits strain stiffening at lower strains than does the circumferential orientation. The differences between the left and right main arteries are minor. The trunk consistently demonstrates less stiffening in the region of larger strains for all conditions.

An Experimental Method for Measuring Mechanical Properties of Rat Pulmonary Arteries Verified With Latex.

This paper describes a test method for measuring the mechanical properties of small, nonlinear membrane samples from a rat model for pulmonary hypertension. The size and nonlinearity of the pulmonary artery samples poses a challenge for developing a test method that will generate quality, reproducible data in the pressure range experienced by the hypertensive pulmonary artery. The experimental method described here has sufficient precision to yield a combined relative standard uncertainty of 4 %. The method is calibrated against 75 µm thick latex and the data agree well with the neo-Hookian model.