Comparison of Mechanical Properties of Human Ascending Aorta and Aortic Sinuses

Transcription

1 Comparison of Mechanical Properties of Human Ascending Aorta and Aortic Sinuses Ali N. Azadani, PhD, Sam Chitsaz, MD, Peter B. Matthews, MS, Nicolas Jaussaud, MD, James Leung, MS, Tonia Tsinman, BS, Liang Ge, PhD, and Elaine E. Tseng, MD Department of Surgery, University of California at San Francisco Medical Center and San Francisco Veterans Affairs Medical Center, San Francisco, California ADULT CARDIAC Background. Computational finite element models of the aortic root have previously used material properties of the ascending aorta to describe both aortic sinuses and ascending aorta. We have previously demonstrated significant material property differences between ascending aorta and sinuses in pigs. However, it is unknown whether these regional material property differences exist in humans. The main objective of this study was to investigate biomechanics of fresh human ascending aorta and aortic sinuses and compare nonlinear material properties of these regions. Methods. Fresh human aortic root specimens obtained from the California Transplant Donor Network (Oakland, CA) were subjected to displacement-controlled equibiaxial stretch testing within 24 hours of harvest. Stress-strain data recorded were used to derive strain energy functions for each region. Tissue behavior was quantified by tissue stiffness and a direct comparison was made between different regions of aortic root at physiologic stress levels. Results. All regions demonstrated a nonlinear response to strain during stretch testing in both circumferential and longitudinal directions. No significant difference in tissue stiffness was found between anterior and posterior regions of the ascending aorta or among the three sinuses in both directions. However, our results demonstrated that human ascending aorta is significantly more compliant than aortic sinuses in both circumferential and longitudinal directions within the physiologic stress range. Conclusions. Significant material and structural differences were observed between human ascending aorta and aortic sinuses. Regionally specific material properties should be employed in computational models used to assess treatments of structural aortic root disease. (Ann Thorac Surg 2012;93:87 94) 2012 by The Society of Thoracic Surgeons Accepted for publication Aug 2, Address correspondence to Dr Tseng, Division of Cardiothoracic Surgery, UCSF Medical Center, 500 Parnassus Ave, Ste 405W, Box 0118, San Francisco, CA ; elaine.tseng@ucsfmedctr.org. Valve-sparing aortic root replacement is an effective operation to save native aortic valves in patients with aneurysms involving the sinus of Valsalva. Two primary surgical techniques, remodeling and reimplantation, along with various iterations have been proposed for the valve sparing operation to restore aortic root anatomy and function [1, 2]. In general, restoring normal root geometry between native and synthetic aortic root components is essential for acceptable valvular function. Finite element modeling has been a powerful method to examine the impact of aortic root geometry and material properties on the stress/strain characteristics of the aortic valve [3, 4]. It is widely accepted that alterations in leaflet stress and strain may affect long-term durability of the native valve and its function after valve sparing operations [3 5]. As such, computational modeling has been used as predictive tools to quantify and better understand the complex interplay between the aortic root and aortic leaflets [6]. To date, mechanical properties of ascending aorta and aortic sinuses have been considered identical in computational models [3 5]. However, we have previously demonstrated that aortic sinuses were significantly stiffer than ascending aorta in pigs [7]. It is unknown whether these regional material property differences within the aortic root exist in humans. Furthermore, when mechanical properties from frozen human cadaver hearts were recently quantified and compared with fresh porcine aortic roots, mechanical differences between human and porcine aortic roots were significant in both circumferential and longitudinal directions [8]. Yet, there are limited data on mechanical properties of fresh and healthy human ascending aorta [9, 10] and almost none on the sinuses. Whether mechanical properties of fresh human ascending aorta are similar to that of aortic sinuses is currently unknown. The aim of this study was to investigate the regional variations in mechanical properties of fresh human aortic roots obtained from the California Transplant Donor Network (CTDN). Constitutive equations were generated for each region based on obtained experimental data that may be used in future computational modeling of human aortic root. Material and Methods This study was approved by the Committee on Human Research from University of California at San Francisco Medical Center, Institutional Review Board of the San Francisco VA Medical Center, and CTDN. Fresh healthy 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 ADULT CARDIAC 88 AZADANI ET AL Ann Thorac Surg HUMAN AORTIC ROOT MECHANICAL PROPERTIES 2012;93:87 94 human aortic root specimens (n 14, aged years) were obtained from CTDN (Oakland, CA) from unused donor hearts with noncardiac causes of death, consented for research and tested within 24 hours. Square specimens of anterior and posterior ascending aorta (AA) were excised from each heart approximately 1 cm distal to sinotubular junction. In addition, square aortic sinus samples were cut from left coronary (LC), right coronary (RC), and noncoronary (NC) sinuses. As sample orientation is crucial in determining mechanical properties with respect to anatomical orientation, care was taken to align specimen edges in circumferential and longitudinal directions. In the LC and RC sinuses, specimens were cut from the largest region aside or beneath the coronary ostia along the two orthogonal directions. Sample thicknesses were measured using Mitutoyo Digital waterproof caliper (Model ) by lightly sandwiching the tissue between two glass slides. Excised samples were stored in Dulbecco s phosphate-buffered saline solution without calcium and magnesium. All mechanical testing was completed within 24 hours after cross-clamp time. Planar Biaxial Testing System A custom-built planar biaxial stretching system was used to determine mechanical properties of ascending aorta and aortic sinuses (Fig 1). Details of biaxial tensile testing methods and analyses have been previously described [7]. Briefly, three 5-0 silk sutures were anchored to each edge of the specimen using small, barbless fishhooks. These sutures were attached to four linear arms of the stretcher, aligning circumferential and longitudinal edges with direction of deformation. Five black ceramic markers (MO-SCI Corp, Rolla, MO), 250 m to355 m, were placed on the tissue, creating a3mm 3 mm grid in the specimen center. Tissue was then floated in a saline bath at room temperature. Load cells (model 31/ ; Honeywell Sensotec, Columbus, OH), 1,000 g 0.1%, located on two orthogonal arms were zeroed and monitored while mounting the sample to ensure that measurement of zero force corresponded to resting tissue length. During extension, data from load cells were amplified and used to determine force on the sample during deformation. Real-time displacement of marker beads on tissue surface was obtained using a noncontacting CCD camera placed over the tissue (30 fps, model TM 9701; Pulnix, Sunnyvale, CA) 0.1 pixels/mm. Images of tissue surface during deformation were digitized in MATLAB, version 7.0 (The Mathworks, Natick, MA), and markers were located based on their contrast to the surrounding tissue. Coordinates of each marker were tracked through the loading cycle, and their relative movement was used to calculate Green strains in principal and shear directions. Samples were tested over a large strain range using equibiaxial displacement controlled protocols. First, 10 preconditioning cycles of 10% stretch, using a triangular waveform at 0.5 Hz, were applied. Subsequently, each specimen was repeatedly cycled up to 55% peak strain. The same protocol in the same order was repeated for each specimen. Constitutive Modeling Ascending aorta and aortic sinuses were assumed to be anisotropic, incompressible, nonlinear hyperelastic materials. Stress was defined as measure of the average force acting per unit area of a surface within a deformable body in the deformed configuration. Planar forces (f) measured by load cells during deformation were converted to Cauchy stresses (T) in the principal directions, given by T f tl L T LL L f L tl. (1a) (1b) where t is tissue thickness and l l 0 represents the ratio of deformed length (l) to resting tissue length after preconditioning (l 0 ). Indices and L represent circumferential and longitudinal directions, respectively. Components of Green strain (E) were calculated using the following equations E (2a) E LL 1 2 L 2 1 (2b) Material s response to stress can be described mathematically by a set of constitutive equations, derived from scalar strain energy function W. Mechanical data from the regions were fit to two-dimensional Fung strain energy function, given by Fig 1. Custom-built biaxial stretcher used in the experiments. W c 2 eq 1

3 Ann Thorac Surg AZADANI ET AL 2012;93:87 94 HUMAN AORTIC ROOT MECHANICAL PROPERTIES 2 2 Q c E 2c L E E LL c LL E LL where c and c, c L, c LL are coefficients to the Fung model. A nonlinear regression Levenberg-Marquardt leastsquares algorithm in MATLAB (version 7.0.1) was used to fit experimentally obtained stresses to corresponding theoretically calculated stresses for ascending aorta and aortic sinuses. Cauchy stresses based on the model (identified by the superscript S) were given by s T 2 ce Q c E c L E LL (3) s T LL 2 L ce Q c L E c LL E LL (4) Histological Analysis From three additional hearts obtained from CTDN, fibrous structure of human ascending aorta and aortic sinuses were examined. First, fresh human tissue samples were cut as described above and fixed in 10% formalin. Subsequently, samples were embedded in paraffin and sectioned for histology. Sections were stained with hematoxylin and eosin, sirius red for collagen, and for elastin. Digital images of each section were obtained by an upright microscope (model DM 2000; Leica Microsystems, Buffalo Grove, IL). A cardiovascular pathologist blinded to specimen regions qualitatively analyzed and compared relative content and orientation of collagen and elastin in each component. Data and Statistical Analysis Tissue stiffness defined as the first derivative of stressstrain response at a given point was quantified and compared among tissue samples. As a result, direct comparison was made between different regions of aortic root at each principal direction. Owing to high sensitivity of tissue initial strain to amount of force applied on the tissue before extension, tissue stiffness was obtained at physiologic stress of ascending aorta and aortic sinuses, 72.8 kpa and 120 kpa, respectively. Physiologic stress of ascending aorta was calculated in the circumferential direction based on the Laplace equation considering mean aortic pressure of 100 mm Hg and using average aortic wall thickness and diameter of aortic roots. Average diameter of ascending aorta ( mm) was obtained from mean circumference of ascending aorta measured before dissection. In addition, peak stress value of 120 kpa was obtained as the physiologic stress level of aortic sinuses from literature [11]. For statistical analysis, normal distribution of tissue stiffness at the two physiologic stresses was first verified for all regions using the Kolmogorov-Smirnov test. Consequently, individual paired t tests were utilized to compare tissue stiffness of different regions. A p value less than 0.05 was considered statistically significant. Reported values are quoted as mean SD. To further investigate mechanical changes of human aortic root tissue with respect to age, a computerfitted power trendline was generated based on tissue stiffness of ascending aorta and aortic sinuses at physiologic stress, 72 kpa and 120 kpa, respectively. Statistical analyses were performed using IBM SPSS Statistics 19 (SPSS, Chicago, IL). Results Square samples of consistent size were cut from ascending aorta and aortic sinuses. Average length and thickness of square samples obtained from each individual region are shown in Table 1. Mean thickness of anterior AA was not significantly different than posterior AA samples (p 0.17). Furthermore, there was no significant difference between thickness of LC, RC, and NC sinuses (p 0.13). However, thickness of both anterior and posterior AA samples was significantly greater than that of the three sinuses (p 0.001). Experimental raw data from equibiaxial testing are shown as Cauchy stress Green strain plots for AA in circumferential and longitudinal directions (Fig 2). Furthermore, raw stress-strain data obtained from the three aortic sinuses are shown (Fig 2). All regions presented nonlinear response to strain in the two directions during testing. Qualitatively, aortic sinuses rapidly stiffened, whereas AA had a more gradual increase in the stressstrain curve slope (Fig 3). Stress-strain data were fit to the Fung form constitutive equation and average coefficients obtained are shown (Table 2). Tissue stiffness was obtained at two different stress levels, 72.8 kpa and 120 kpa, corresponding to physiological stress of ascending aorta and aortic sinuses. At stress level of 72.8 kpa, there was no significant difference in stiffness of ascending aorta between circumferential and longitudinal directions ( kpa versus kpa, p 0.209). Similarly, our results showed no difference in stiffness between circumferential and longitudinal directions of aortic sinuses ( kpa versus kpa, p 0.522). Comparison between ascending aorta and sinuses revealed that overall, ascending aorta was significantly more compliant than aortic sinuses in both circumferential (p 0.026) and longitudinal (p 0.010) directions. Our results showed no difference in stiffness between anterior and posterior AA in circumferential (p 0.668) or longitudinal (p 0.573) axes. Furthermore, there was no significant difference among the three sinuses both in circumferential (p 0.809) and longitudinal (p 0.509) directions (Fig 4A). At stress level of 120 kpa, there was no significant difference in stiffness of ascending aorta between circumferential and longitudinal directions ( kpa versus kpa, p 0.229). Similarly, our results showed no difference in stiffness between circumferential and longitudinal directions of aortic sinuses ( kpa versus kpa, p Table 1. Thickness of Ascending Aorta and Aortic Sinuses Specimens Region Thickness (mm) Length (mm) Anterior ascending aorta Posterior ascending aorta Left coronary (LC) sinus Right coronary (RC) sinus Noncoronary (NC) sinus ADULT CARDIAC

4 ADULT CARDIAC 90 AZADANI ET AL Ann Thorac Surg HUMAN AORTIC ROOT MECHANICAL PROPERTIES 2012;93:87 94 no significant difference among the three sinuses in both circumferential (p 0.830) and longitudinal (p 0.613) directions (Fig 4B). The relationship between stiffness and age is presented in Figure 5: aortic sinuses were significantly stiffer than ascending aorta throughout the age range examined in this study (range, 31 to 67 years; median 51 years). Histologic analysis showed structural differences between human ascending aorta and aortic sinuses (Fig 6). Images were taken from ascending aorta and aortic sinuses through the tissue thickness in the longitudinal direction at an objective magnification of 10. Staining effectively rendered elastin fibers black, collagen fibers pink, and smooth muscle green. Ascending aorta had tight denser weave of elastin than aortic sinuses (Fig 6A and B). Furthermore, elastin directionality through the thickness in aortic sinuses was found to be more irregular than ascending aorta. In addition, collagen had a more regular distribution in ascending aorta than aortic sinuses. In both ascending aorta and aortic sinuses, collagen was distributed more on the lumen side and smooth cell muscles on the adventitia side (Fig 6C and D). Comment In this study, we examined mechanical properties of fresh human ascending aorta and aortic sinuses using biaxial stretching. Tissue behavior was quantified by Fig 2. Equibiaxial stretch data from the ascending aorta in the (A) circumferential direction and (B) longitudinal direction. Equibiaxial stretch data from the aortic sinus in the (C) circumferential direction and (D) longitudinal direction. Each geometric shape represents the experimental raw data obtained from a different human aortic root ). Comparison between ascending aorta and sinuses revealed that overall ascending aorta was significantly more compliant than aortic sinuses in both circumferential (p 0.039) and longitudinal (p 0.018) directions. Our results showed no difference in stiffness between anterior and posterior AA in circumferential (p 0.635) or longitudinal (p 0.554) axes. Furthermore, there was Fig 3. Composite curves for the ascending aorta (light gray line) and aortic sinus (dark gray line) in the (A) circumferential direction and (B) longitudinal direction. Each curve is constructed using the average value of coefficients to the strain energy function.

5 Ann Thorac Surg AZADANI ET AL 2012;93:87 94 HUMAN AORTIC ROOT MECHANICAL PROPERTIES Table 2. Coefficients to Fung Strain Energy Functions Used to Fit Ascending Aorta and Aortic Sinus Parameter Ascending Aorta Aortic Sinuses c c L c LL c tissue stiffness and direct comparison was made between different regions of aortic root at physiologic stress levels. Both ascending aorta and aortic sinuses demonstrated nonlinear material properties in circumferential and longitudinal directions. Our results indicated that biaxial response of both ascending aorta and aortic sinuses was isotropic, with no directional dependence. Furthermore, there was no significant difference between anterior and posterior regions of ascending aorta or among the three sinuses in the two directions. However, our results showed that ascending aorta was significantly more compliant than aortic sinuses both in circumferential and longitudinal directions within physiologic stress range. Our data suggest that fresh human ascending aorta and aortic sinus show no directional dependence under equibiaxial loading, consistent with reports published in the literature on directional dependency of biaxial biomechanical response of human aortic tissue. In a recent study, Haskett and colleagues [10] quantified both biomechanical and microstructural alterations of human aorta as a function of age and location. Specimens were harvested from 31 autopsy donor aortas (aged 3 days to 93 years) from five separate locations ascending thoracic, aortic arch, descending thoracic, suprarenal, and abdominal. Their results demonstrated that the aorta becomes more biomechanically and structurally anisotropic after age 60, correlating with the lack of anisotropy in our specimens whose average age was 47 years, with significant changes occurring preferentially in abdominal aorta. Ascending aorta, however, was least anisotropic for all ages, corresponding to findings of Choudhury and associates [9], Okamoto and colleagues [12], and Tremblay and coworkers [13]. In another study, Martin and coworkers [8] examined mechanical properties of aged ( years) human ascending aorta and aortic sinuses harvested from frozen human cadaver hearts. Human tissues exhibited different stress-strain responses in both directions with circumferential direction being stiffer in most specimens, again reflecting the tendency toward anisotropy with increased age. Given increasing 91 ADULT CARDIAC Fig 4. Comparisons of tissue stiffness for the ascending aorta and aortic sinus at (A) 72.8 kpa and (B) 120 kpa. (AA ascending aorta; LC left coronary; NC noncoronary; RC right coronary; Dark gray bars circumferential; light gray bars longitudinal.)

6 ADULT CARDIAC 92 AZADANI ET AL Ann Thorac Surg HUMAN AORTIC ROOT MECHANICAL PROPERTIES 2012;93:87 94 Fig 5. Age dependence of ascending aorta (dark gray solid line circumferential; light gray solid line longitudinal) and aortic sinuses (dark gray dashed line circumferential; light gray dashed line longitudinal) tissue stiffness at physiologic stress level, 72 kpa and 120 kpa, respectively. Power trendlines were fitted to the experimental data. stiffness of arterial tissues with advanced age (90 years or more), it is not surprising that, unlike our results, no statistically significant differences were found between mean stiffness at physiologic stress in either direction for ascending aorta and aortic sinuses. As presented in Figure 5, tissue stiffness of both ascending aorta and aortic sinuses increased with age; however, the rate of increase was relatively higher in aortic sinuses than ascending aorta. Although tissue anisotropy in the aortic root was not statistically significant, the difference between tissue stiffness in circumferential and longitudinal directions increased relatively with age, particularly in aortic sinuses and to some extent in ascending aorta. A larger sample size is required to increase statistical power and confirm these observations. We found that fresh human ascending aorta was significantly more compliant than aortic sinuses both in circumferential and longitudinal directions. Similarly, Gundiah and colleagues [7] have previously demonstrated that porcine ascending aorta was significantly more compliant than aortic sinuses in the two directions. Recently, Martin and associates [8] characterized and compared biomechanical properties of ascending aorta and aortic sinuses obtained from fresh porcine and frozen human cadaver hearts. They found that there was no statistically significant difference in stiffness of porcine ascending aorta and aortic sinuses Fig 6. Histologic sections of human ascending aorta and aortic sinuses: (A) elastin-stained ascending aorta, (B) elastin-stained sinus, (C) sirius red-stained ascending aorta, and (D) sirius red-stained aortic sinus. Elastin (black), collagen fibers (red/pink), and smooth muscle (green); adventitia on top. Scale bar 250 micrometers.

7 Ann Thorac Surg AZADANI ET AL 2012;93:87 94 HUMAN AORTIC ROOT MECHANICAL PROPERTIES in the circumferential direction. However, ascending aorta was significantly more compliant in the longitudinal direction than LC and RC sinus. No difference was found between the stiffness of AA and NC sinus in the longitudinal direction. In the human cadaver hearts, however, they found no significant differences in mean tissue stiffness among human sinuses or between sinuses and ascending aorta, aside from RC sinus being stiffer than AA in the circumferential direction. Differences in their results from ours are reflective of specimens of advanced age as well as lack of fresh tissue that has been previously frozen of long duration till time of testing. Structural differences between human ascending aorta and aortic sinuses may explain differences found in mechanical properties. The load-bearing functionality of human aortic tissue is primarily due to elastic lamina, collagen bundles, and smooth muscle cells. However, in passive mechanical responses, the contribution of smooth muscle cells is believed to be minimal [14, 15]. The majority of fiber angles in human aorta were preferentially oriented in the circumferential direction [10], and soft tissue mechanical response at low stress has been attributed mainly to elastin. However, as stress increases, collagen fibers dominate the mechanical response to bear tension [16]. Based on our histologic analysis, human ascending aorta contains a tighter and denser weave of elastin than aortic sinuses, and may contribute to the greater compliance of ascending aorta at physiologic stress. Furthermore, distribution of collagen and smooth cell muscles in human aortic tissue collagen mostly on the lumen side and muscle cells mostly on the adventitia side may explain the common formation of false lumen on the outer part of aortic media in aortic dissection [17]. Computational modeling of reimplantation and remodeling techniques have shown that aortic root geometry and material properties have significant impact on valve stress, strain, and coaptation [3, 5]. The major limitation of most computational simulations has been simplification of aortic root material properties as being isotropic and elastic. There is clearly a need to better understand the complex interplay of various components of aortic root and aortic leaflets. Future computational models may more realistically simulate valve dynamics and flow through the root by modeling the sinus separately to reflect non-linear loading and a reduced compliance. Ideally, the material used in the valve-sparing aortic root replacement techniques should replicate the stiffness of aortic root tissue. Results of the present study revealed that, overall, the aortic sinus was approximately 2.5 times stiffer circumferentially and longitudinally than the proximal AA. Thus, a reduced compliance of the sinus should be used as the standard for a normal aortic root when assessing aneurysm formation and repair with valve-sparing operations. Comparison of stiffness of specially designed Valsalva grafts versus tailored straight tube grafts in the sinus of reimplantation valvesparing roots is one possibility of future study, particularly in relation to remodeling roots which retain some portions of native aortic root. Study Limitations Results in this study are limited to the in vitro setting. Limitations associated with planar biaxial testing protocols have been described in detail elsewhere [18]. Ascending aorta and aortic sinuses are not flat tissue in their native state. Therefore, the curved geometry of specimens introduces error in applying appropriate stresses and strains in vitro using a planar biaxial stretching system. Another limitation of this study was that residual stress was not considered in the constitutive equations. The full mechanical state of the tissue is determined by considering the deformed state and residual stress state. Instead, equations proposed in this study considered the tissue to be in a zero-stress state. Experiments needed to assess residual strains in the sinuses are complicated and beyond the scope of this report. Lastly, a larger sample size over a greater age range would be ideal to confirm these observations and increase statistical power for clinical translation; however, acquiring fresh and healthy human hearts from the donor network is difficult and has required collection of tissue over the past 5 years. In conclusion, we report mechanical properties of fresh human ascending aorta and aortic sinuses using a planar biaxial stretching system. Substantial variations in material properties were found within components of the aortic root. Both ascending aorta and aortic sinuses demonstrated nonlinear material properties in the circumferential and longitudinal directions. Our results indicated that the biaxial response of both ascending aorta and aortic sinuses was isotropic with no directional dependence. There was no significant difference in tissue stiffness between anterior and posterior regions of ascending aorta or among the three sinuses in the two directions. However, our results demonstrated that ascending aorta is significantly more compliant than aortic sinuses both in circumferential and longitudinal directions at physiologic stress. Regionally specific material properties should be employed in computational models to assess more realistically the treatment of structural aortic root disease. We thank Dr Philip Ursell for his histologic characterization and the California Transplant Donor Network for the hearts. This work was supported by an American Heart Association Grantin-Aid, which was administered by the Northern California Institute for Research and Education with resources of the Veterans Affairs Medical Center, San Francisco, California. References 1. David TE, Feindel CM, Webb GD, Colman JM, Armstrong S, Maganti M. Long-term results of aortic valve-sparing operations for aortic root aneurysm. J Thorac Cardiovasc Surg 2006;132: Yacoub MH, Gehle P, Chandrasekaran V, Birks EJ, Child A, Radley-Smith R. Late results of a valve-preserving operation in patients with aneurysms of the ascending aorta and root. J Thorac Cardiovasc Surg 1998;115: Grande KJ, Cochran RP, Reinhall PG, Kunzelman KS. 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