Ajit P. Yoganathan

Experimental measurement of dynamic fluid shear stress on the aortic surface of the aortic valve leaflet

Aortic valve (AV) calcification is a highly prevalent disease with serious impact on mortality and morbidity. Although exact causes and mechanisms of AV calcification are unclear, previous studies suggest that mechanical forces play a role. Since calcium deposits occur almost exclusively on the aortic surfaces of AV leaflets, it has been hypothesized that adverse patterns of fluid shear stress on the aortic surface of AV leaflets promote calcification. The current study characterizes AV leaflet aortic surface fluid shear stresses using Laser Doppler velocimetry and an in vitro pulsatile flow loop. The valve model used was a native porcine valve mounted on a suturing ring and preserved using 0.15% glutaraldehyde solution. This valve model was inserted in a mounting chamber with sinus geometries, which is made of clear acrylic to provide optical access for measurements. To understand the effects of hemodynamics on fluid shear stress, shear stress was measured across a range of conditions: varying stroke volumes at the same heart rate and varying heart rates at the same stroke volume. Systolic shear stress magnitude was found to be much higher than diastolic shear stress magnitude due to the stronger flow in the sinuses during systole, reaching up to 20 dyn/cm2 at mid-systole. Upon increasing stroke volume, fluid shear stresses increased due to stronger sinus fluid motion. Upon increasing heart rate, fluid shear stresses decreased due to reduced systolic duration that restricted the formation of strong sinus flow. Significant changes in the shear stress waveform were observed at 90 beats/min, most likely due to altered leaflet dynamics at this higher heart rate. Overall, this study represents the most well-resolved shear stress measurements to date across a range of conditions on the aortic side of the AV. The data presented can be used for further investigation to understand AV biological response to shear stresses.

In Vitro Characterization of Bicuspid Aortic Valve Hemodynamics Using Particle Image Velocimetry

The congenital bicuspid aortic valve (BAV) is associated with increased leaflet calcification, ascending aortic dilatation, aortic stenosis (AS) and regurgitation (AR). Although underlying genetic factors have been primarily implicated for these complications, the altered mechanical environment of BAVs could potentially accelerate these pathologies. The objective of the current study is to characterize BAV hemodynamics in an in vitro system. Two BAV models of varying stenosis and jet eccentricity and a trileaflet AV (TAV) were constructed from excised porcine AVs. Particle Image Velocimetry (PIV) experiments were conducted at physiological flow and pressure conditions to characterize fluid velocity fields in the aorta and sinus regions, and ensemble averaged Reynolds shear stress and 2D turbulent kinetic energy were calculated for all models. The dynamics of the BAV and TAV models matched the characteristics of these valves which are observed clinically. The eccentric and stenotic BAV showed the strongest systolic jet (Vxa0=xa04.2xa0m/s), which impinged on the aortic wall on the non-fused leaflet side, causing a strong vortex in the non-fused leaflet sinus. The magnitudes of TKE and Reynolds stresses in both BAV models were almost twice as large as comparable values for TAV, and these maximum values were primarily concentrated around the central jet through the valve orifice. The in vitro model described here enables detailed characterization of BAV flow characteristics, which is currently challenging in clinical practice. This model can prove to be useful in studying the effects of altered BAV geometry on fluid dynamics in the valve and ascending aorta. These altered flows can be potentially linked to increased calcific responses from the valve endothelium in stenotic and eccentric BAVs, independent of concomitant genetic factors.

The Effects of a Three-Dimensional, Saddle-Shaped Annulus on Anterior and Posterior Leaflet Stretch and Regurgitation of the Tricuspid Valve

Tricuspid regurgitation (TR) is present in trace amounts or more in 82–86% of the population and is greater than mild in 14% of the population. In severe cases, it can contribute to right heart failure and adversely affect mitral valve repair durability. One major cause of TR is the dilation of the tricuspid annulus, which alters the geometry of the annulus from a saddle-shape to a more planar profile. Another cause of TR is the displacement of the papillary muscles (PMs), which results from right ventricular dilation. The objective of this study was to identify the effect of a saddle-shaped annulus on native tricuspid leaflet stretch mechanics and TR. In addition, the effects of geometric alterations, including annular dilatation and PM displacement, on leaflet stretch was investigated. Fresh porcine tricuspid valves (TVs) (nxa0=xa08) were excised and sutured to an adjustable three-dimensional annulus plate (allowing for dilatation and saddle-shape) and three PM attachment rods. The valve was then placed in the in vitro Georgia Tech right heart simulator. Dual-camera photogrammetry, was used to quantify the stretch ratio experienced by the valve leaflets at peak systole for the following conditions: physiologically normal, 100% annular dilatation, displaced PMs, and a combination of annular dilatation and PM displacement. In addition, a saddle and flat annulus were implemented for each of the four conditions. PM displacement was simulated by displacing all PMs by 10xa0mm in all directions (laterally, apically, posteriorly/anteriorly). The physiologically normal condition—normal annulus area, saddle-shaped annulus with PMs in a normal position, was used as a control. The results showed that the posterior leaflet exhibited significantly (pxa0≤xa00.05) higher major and areal stretch ratios as compared to the anterior leaflet at peak systole for all conditions tested. No significant difference was seen in stretch when a flat annulus was compared to saddle for the anterior or posterior leaflet for normal or disease conditions. Investigation of the impact of disease found a significant increase (pxa0≤xa00.10) in stretch in the posterior leaflet with a combination of annular dilatation and PM displacement (2.01xa0±xa00.68) as compared to the normal condition with a saddle annulus (1.43xa0±xa00.20). In addition displacement of the PMs resulted in a significant (pxa0≤xa00.01) reduction in TR, although the actual volume reduced was minimal (1.2xa0mL). Stretch values were measured for the anterior and posterior leaflet under both physiologic and pathologic conditions for the first time. Further, these results provide an understanding of the effects of geometric parameters on valve mechanics and function, which may lead to improved TV repairs.

Experimental Technique of Measuring Dynamic Fluid Shear Stress on the Aortic Surface of the Aortic Valve Leaflet

Aortic valve (AV) calcification is a highly prevalent disease with serious impact on mortality and morbidity. The exact cause and mechanism of the progression of AV calcification is unknown, although mechanical forces have been known to play a role. It is thus important to characterize the mechanical environment of the AV. In the current study, we establish a methodology of measuring shear stresses experienced by the aortic surface of the AV leaflets using an in vitro valve model and adapting the laser Doppler velocimetry (LDV) technique. The valve model was constructed from a fresh porcine aortic valve, which was trimmed and sutured onto a plastic stented ring, and inserted into an idealized three-lobed sinus acrylic chamber. Valve leaflet location was measured by obtaining the location of highest back-scattered LDV laser light intensity. The technique of performing LDV measurements near to biological surfaces as well as the leaflet locating technique was first validated in two phantom flow systems: (1) steady flow within a straight tube with AV leaflet adhered to the wall, and (2) steady flow within the actual valve model. Dynamic shear stresses were then obtained by applying the techniques on the valve model in a physiologic pulsatile flow loop. Results show that aortic surface shear stresses are low during early systole (<5 dyn/cm²) but elevated to its peak during mid to late systole at about 18-20 dyn/cm². Low magnitude shear stress (<5 dyn/cm²) was observed during early diastole and dissipated to zero over the diastolic duration. Systolic shear stress was observed to elevate only with the formation of sinus vortex flow. The presented technique can also be used on other in vitro valve models such as congenitally geometrically malformed valves, or to investigate effects of hemodynamics on valve shear stress. Shear stress data can be used for further experiments investigating effects of fluid shear stress on valve biology, for conditioning tissue engineered AV, and to validate numerical simulations.

Heart valve dynamics

During coronary underperfusion, there is downregulation of cytosolic 5nucleotidase (5NT), mediating AMP hydrolysis to adenosine. The present study tested whether 5NT remains downregulated during more extreme oxidative stress. Rabbit hearts were studied during two sequential periods of coronary underperfusion (90% flow reduction, 30 min.) separated by 20 min. of reperfusion. In the second period, the perfusate gas equilibrium was decreased from the normal 95% 02 to 30% O> In the second period, myocardial lactate production was increased by 20%, compared to the first period, creatine phosphate decreased further (73% vs. 49%), and calculated cytosolic AMP concentration increased to 2.7 gM. Despite the 40% higher AMP concentration, total coronary purine efflux (adenosine + inosine + hypoxanthine) was decreased by nearly 40%, indicating decreased activity of 5NT. In conclusion, even when oxidative stress is increased to extreme levels, coronary underperfusion still produces downregulation of 5NT. (Supported by NIH grants HL51152 and RR01243) 112 SHEAR STRESS MODULATES THE PROTEINASE ACTIVITY OF ENDOTHELIAL CELLS IN PORCINE CAROTID ARTERY H.C. Han, B. S. Conklin, G. Hamilton*, P. R. Girard*, D N. Ku

The congenital bicuspid aortic valve can experience high-frequency unsteady shear stresses on its leaflet surface

The bicuspid aortic valve (BAV) is a common congenital malformation of the aortic valve (AV) affecting 1% to 2% of the population. The BAV is predisposed to early degenerative calcification of valve leaflets, and BAV patients constitute 50% of AV stenosis patients. Although evidence shows that genetic defects can play a role in calcification of the BAV leaflets, we hypothesize that drastic changes in the mechanical environment of the BAV elicit pathological responses from the valve and might be concurrently responsible for early calcification. An in vitro model of the BAV was constructed by surgically manipulating a native trileaflet porcine AV. The BAV valve model and a trileaflet AV (TAV) model were tested in an in vitro pulsatile flow loop mimicking physiological hemodynamics. Laser Doppler velocimetry was used to make measurements of fluid shear stresses on the leaflet of the valve models using previously established methodologies. Furthermore, particle image velocimetry was used to visualize the flow fields downstream of the valves and in the sinuses. In the BAV model, flow near the leaflets and fluid shear stresses on the leaflets were much more unsteady than for the TAV model, most likely due to the moderate stenosis in the BAV and the skewed forward flow jet that collided with the aorta wall. This additional unsteadiness occurred during mid- to late-systole and was composed of cycle-to-cycle magnitude variability as well as high-frequency fluctuations about the mean shear stress. It has been demonstrated that the BAV geometry can lead to unsteady shear stresses under physiological flow and pressure conditions. Such altered shear stresses could play a role in accelerated calcification in BAVs.