Michael D. VanAuker

Potential Role of Mechanical Stress in the Etiology of Pediatric Heart Disease: Septal Shear Stress in Subaortic Stenosis

OBJECTIVES The objective of this study was to show elevations in septal shear stress in response to morphologic abnormalities that have been associated with discrete subaortic stenosis (SAS) in children. Combined with the published data, this critical connection supports a four-stage etiology of SAS that is advanced in this report. BACKGROUND Subaortic stenosis constitutes up to 20% of left ventricular outflow obstruction in children and frequently requires surgical removal, and the lesions may reappear unpredictably after the operation. The etiology of SAS is unknown. This study proposes a four-stage etiology for SAS that I) combines morphologic abnormalities, II) elevation of septal shear stress, III) genetic predisposition and IV) cellular proliferation in response to shear stress. METHODS Morphologic structures of a left ventricular outflow tract were modeled based on measurements in patients with and without SAS. Septal shear stress was studied in response to changes in aortoseptal angle (AoSA) (120 degrees to 150 degrees), outflow tract convergence angle (45 degrees, 22.5 degrees and 0 degree), presence/location of a ventricular septal defect (VSD) (3-mm VSD; 2 and 6 mm from annulus) and shunt velocity (3 and 5 m/s). RESULTS Variations in AoSA produced marked elevations in septal shear stress (from 103 dynes/cm2 for 150 degrees angle to 150 dynes/cm2 for 120 degrees angle for baseline conditions). This effect was not dependent on the convergence angle in the outflow tract (150 to 132 dynes/cm2 over full range of angles including extreme case of 0 degree). A VSD enhanced this effect (150 to 220 dynes/cm2 at steep angle of 120 degrees and 3 m/s shunt velocity), consistent with the high incidence of VSDs in patients with SAS. The position of the VSD was also important, with a reduction of the distance between the VSD and the aortic annulus causing further increases in septal shear stress (220 and 266 dynes/cm2 for distances of 6 and 2 mm from the annulus, respectively). CONCLUSIONS Small changes in AoSA produce important changes in septal shear stress. The levels of stress increase are consistent with cellular flow studies showing stimulation of growth factors and cellular proliferation. Steepened AoSA may be a risk factor for the development of SAS. Evidence exists for all four stages of the proposed etiology of SAS.

Effect of three-dimensional valve shape on the hemodynamics of aortic stenosis: Three-dimensional echocardiographic stereolithography and patient studies

OBJECTIVES This study tested the hypothesis that the impact of a stenotic aortic valve depends not only on the cross-sectional area of its limiting orifice but also on three-dimensional (3D) valve geometry. BACKGROUND Valve shape can potentially affect the hemodynamic impact of aortic stenosis by altering the ratio of effective to anatomic orifice area (the coefficient of orifice contraction [Cc]). For a given flow rate and anatomic area, a lower Cc increases velocity and pressure gradient. This effect has been recognized in mitral stenosis but assumed to be absent in aortic stenosis (constant Cc of 1 in the Gorlin equation). METHODS In order to study this effect with actual valve shapes in patients, 3D echocardiography was used to reconstruct a typical spectrum of stenotic aortic valve geometrics from doming to flat. Three different shapes were reproduced as actual models by stereolithography (computerized laser polymerization) with orifice areas of 0.5, 0.75, and 1.0 cm(2) (total of nine valves) and studied with physiologic flows. To determine whether valve shape actually influences hemodynamics in the clinical setting, we also related Cc (= continuity/planimeter areas) to stenotic aortic valve shape in 35 patients with high-quality echocardiograms. RESULTS In the patient-derived 3D models, Cc varied prominently with valve shape, and was largest for long, tapered domes that allow more gradual flow convergence compared with more steeply converging flat valves (0.85 to 0.90 vs. 0.71 to 0.76). These variations translated into differences of up to 40% in pressure drop for the same anatomic area and flow rate, with corresponding variations in Gorlin (effective) area relative to anatomic values. In patients, Cc was significantly lower for flat versus doming bicuspid valves (0.73 +/- 0.14 vs. 0.94 +/- 0.14, p < 0.0001) with 40 +/- 5% higher gradients (p < 0.0001). CONCLUSIONS Three-dimensional valve shape is an important determinant of pressure loss in patients with aortic stenosis, with smaller effective areas and higher pressure gradients for flatter valves. This effect can translate into clinically important differences between planimeter and effective valve areas (continuity or Gorlin). Therefore, valve shape provides additional information beyond the planimeter orifice area in determining the impact of valvular aortic stenosis on patient hemodynamics.

Abnormalities of the Left Ventricular Outflow Tract Associated With Discrete Subaortic Stenosis in Children: An Echocardiographic Study

OBJECTIVES The purpose of this study was to examine the echocardiographic abnormalities of the left ventricular outflow tract associated with subaortic stenosis in children. BACKGROUND Considerable evidence suggests that subaortic stenosis is an acquired and progressive lesion, but the etiology remains unknown. We have proposed a four-stage etiologic process for the development of subaortic stenosis. This report addresses the first stage by defining the morphologic abnormalities of the left ventricular outflow tract present in patients who develop subaortic stenosis. METHODS Two study groups were evaluated-33 patients with isolated subaortic stenosis and 12 patients with perimembranous ventricular septal defect and subaortic stenosis-and were compared with a size- and lesion-matched control group. Subjects ranged in age from 0.05 to 23 years, and body surface area ranged from 0.17 to 2.3 m2. Two independent observers measured aortoseptal angle, aortic annulus diameter and mitral-aortic separation from previously recorded echocardiographic studies. RESULTS The aortoseptal angle was steeper in patients with isolated subaortic stenosis than in control subjects (p < 0.001). This pattern was also true for patients with ventricular septal defect and subaortic stenosis compared with control subjects (p < 0.001). Neither age nor body surface area was correlated with aortoseptal angle. A trend toward smaller aortic annulus diameter indexed to patient size was seen between patients and control subjects but failed to achieve statistical significance (p = 0.08). There was an excellent interrater correlation in aortoseptal angle and aortic annulus measurement. The mitral-aortic separation measurement was unreliable. Our results, specifically relating steep aortoseptal angle to subaortic stenosis, confirm the results of other investigators. CONCLUSIONS This study demonstrates that subaortic stenosis is associated with a steepened aortoseptal angle, as defined by two-dimensional echocardiography, and this association holds in patients with and without a ventricular septal defect. A steepened aortoseptal angle may be a risk factor for the development of subaortic stenosis.

Turbulent/viscous interactions control doppler/catheter pressure discrepancies in aortic stenosis : The role of the Reynolds number

BACKGROUND Despite good correlation between Doppler and catheter pressure drops in numerous reports, it is well known that Doppler tends to apparently overestimate pressure drops obtained by cardiac catheterization. Neither (1) simplification of the Bernoulli equation nor (2) pressure recovery effects can explain this dilemma when taken alone. This study addressed the hypothesis that a Reynolds number-based approach, which characterizes (1) and (2), provides a first step toward better agreement of catheter and Doppler assessments of pressure drops. METHODS AND RESULTS Doppler and catheter pressure drops were studied in an in vitro model designed to isolate the proposed Reynolds number effect and in a sheep model with varying degrees of stenosis. Doppler pressure drops in vitro correlated with the directly measured pressure drop for individual valves (r = .935, .960, .985, .984, .989, and .975) but with markedly different slopes and intercepts. A Bland-Altman type plot showed no useful pattern of discrepancy. The Reynolds number was successful in collapsing the data into the profile proposed in the hypothesis. Parallel results were found in the animal model. CONCLUSIONS Apparent overestimation of net pressure drop by Doppler is due to pressure recovery effects, and these effects are countered by both viscous effects and inertial/turbulent effects. Only by reconciliation of discrepancies by use of a quantity such as Reynolds number that embodies the relative importance of competing factors can the noninvasive and invasive methods be connected. This study shows that a Reynolds number-based approach accomplishes this goal both in the idealized in vitro setting and in a biological system.

Development of a Noninvasive Marker of Wall Shear Stress Effects in Discrete Subaortic Stenosis

The precise etiology of discrete subaortic stenosis is unknown. It has been suggested that shear forces play a role in its initiation and progression. Because shear stress and its derivatives cannot be directly measured in vivo, we designed this study to define a clinical index of the wall shear stress and its spatial derivative using Doppler echocardiography. Using a computational model, we tested the hypothesis that a modification of the Dean number, a dimensionless index that describes shear rates in curved vessels, may yield a correlate of shear stresses in the region of interest. This would enable verification of our proposed etiology and may yield a noninvasive method to predict the development of subaortic stenosis. With the results from the computational model, we determined an index based on modifications to the Dean number that linearly correlates with the magnitude and the spatial derivative of shear stress.

Pulsatile Wall Shear Stress Gradient and Aortoseptal Angle: Implications for Subaortic Stenosis |[dagger]| 147

A better understanding of the etiology of discrete subaortic stenosis (SAS) would be useful in identifying patients at risk and in surgical decision making since the onset, progression, and recurrence of SAS are difficult to predict. Previous studies have shown that congenital defects and morphologic abnormalities associated with SAS (such as steepened aortoseptal angle [AoSA]) cause significant, localized elevations in peak wall shear stress and the wall shear stress gradient (WSSG). High WSSG has been associated with cellular changes in the endothelium. Since the magnitude of wall shear stress varies thoughout the cardiac cycle, we addressed the hypothesis that these morphologic abnormalities have similar effects on the time-averaged shear stress and WSSG. Methods: A finite element model of the left ventricular outflow tract was implemented on the Cray C90 at the Pittsburgh Supercomputing Center for typical pulsatile flow conditions. AoSA was varied between 120 and 150 degrees, maximum aortic velocities from 0.5 to 1 m/s, and aortic diameter from 1 to 1.5 cm. Shear stress and WSSG were directly calculated from the velocity field at discrete points in time. The time-averaged wall shear stress and WSSG at the location of the peak was determined. Results: At an aortic velocity of 1 m/s, the peak and time-averaged shear stress increased with steeper AoSA by 52% and 49.5% respectively. WSSG was more sensitive to changes in AoSA with the peak WSSG increasing by 217%, compared to the time-averaged WSSG which increased by 225%. Conclusions: Geometric variables had similar effects on both the peak and mean shear stress and WSSG. Although the progression and recurrence of SAS may be dependent on time-varying exposure to shear stress, this exposure may be quantified using either a peak or a mean value.

VENTRICULAR SEPTAL DEFECT MODULATES SEPTAL SHEAR STRESS CAUSED BY AORTO-SEPTAL ANGLE: IMPLICATIONS FOR SUBAORTIC STENOSIS. † 219

VENTRICULAR SEPTAL DEFECT MODULATES SEPTAL SHEAR STRESS CAUSED BY AORTO-SEPTAL ANGLE: IMPLICATIONS FOR SUBAORTIC STENOSIS. † 219