Abstract
Aims
While mechanical stress caused by blood flow, e.g. wall shear stress (WSS), and related parameters, e.g. oscillatory shear index (OSI), are increasingly being recognized as key moderators of various cardiovascular diseases, studies on valves have been limited because of a lack of appropriate imaging modalities. We investigated the influence of aortic root geometry on WSS and OSI on the aortic valve (AV) leaflet.
Methods and results
We applied our novel approach of intraoperative epi-aortic echocardiogram to measure the haemodynamic parameters of WSS and OSI on the AV leaflet. Thirty-six patients were included, which included those who underwent valve-sparing aortic root replacement (VSARR) with no significant aortic regurgitation (n = 17) and coronary artery bypass graft (CABG) with normal AV (n = 19). At baseline, those who underwent VSARR had a higher systolic WSS (0.52 ± 0.12 vs. 0.32 ± 0.08 Pa, respectively, P < 0.001) and a higher OSI (0.37 ± 0.06 vs. 0.29 ± 0.04, respectively, P < 0.001) on the aortic side of the AV leaflet than those who underwent CABG. Multivariate regression analysis revealed that the size of the sinus of Valsalva had a significant association with WSS and OSI. Following VSARR, WSS and OSI values decreased significantly compared with the baseline values (WSS: 0.29 ± 0.12 Pa, P < 0.001; OSI: 0.26 ± 0.09, P < 0.001), and became comparable to the values in those who underwent CABG (WSS, P = 0.42; OSI, P = 0.15).
Conclusions
Mechanical stress on the AV gets altered in correlation with the size of the aortic root. An aneurysmal aortic root may expose the leaflet to abnormal fluid dynamics. The VSARR procedure appeared to reduce these abnormalities.
Keywords: wall shear stress, aortic valve leaflet, oscillatory shear index, echocardiography, vector flow mapping
Introduction
The coexistence of aortic valve (AV) abnormalities and aneurysmal changes in the proximal aorta is observed frequently. Combinations of genetic, anatomical, and haemodynamic causes have been proposed as mechanisms for this association.1–3 Fluid dynamics influence progressive aortic dilation by modulating the spatiotemporal variability of the wall shear stress (WSS), affecting the endothelial function and promoting vascular remodelling. WSS, a central parameter of fluid dynamics, has been increasingly recognized as the key moderator of various cardiovascular diseases.4,5 Computational and experimental methods have suggested a possibly important role of WSS in AV diseases.6–8 Preliminary data suggest that a large aortic root aneurysm is a risk factor for the failure of a valve-sparing aortic root replacement (VSARR), highlighting the detrimental effects of a large aneurysm on the leaflet.9,10 We hypothesized that an aortic root aneurysm would alter the fluid dynamics around the AV, placing abnormal mechanical stress on the leaflets. Testing this hypothesis, however, has been hindered by the low temporal and spatial resolutions of the existing imaging modalities, precluding in vivo assessment of the fluid dynamics on the AV leaflets. To overcome this obstacle, we recently developed a novel methodology that quantifies the WSS and oscillatory shear index (OSI) on the AV leaflet using vector flow mapping (VFM).11 The present study aimed to (i) investigate the association between aneurysm-related changes in the anatomy of the aortic root and the mechanical stress on the AV leaflet, and (ii) examine the changes in these parameters following VSARR.
Methods
Design and study participants
This study was approved by the Columbia University Institutional Review Board, and the participants provided written informed consent.
WSS and its fluctuations in one cardiac cycle, represented by OSI, were measured separately on the aortic layer (fibrosa) and the ventricular layer (ventricularis) of the leaflet using VFM. To describe the aortic root anatomy, we chose the following anatomical measurements: diameters of the aortic annulus, the sinotubular junction, the sinuses of Valsalva (SOV)–the height of SOV, and the effective/geometric heights of the leaflet. Effective height is the height difference between the free margin of the leaflet and the aortoventricular junction in the diastole. Geometric height is measured from the nadir of the sinus to the centre of the free margin.12–14
The associations of these anatomical parameters with the WSS and OSI on the AV leaflet were assessed in varying root sizes. We prospectively enrolled patients who were scheduled to undergo VSARR for aortic root aneurysm between March 2018 and March 2020 (pre-VSARR). Postoperative changes in the WSS and OSI were also examined (post-VSARR). Patients who underwent coronary artery bypass graft (CABG) with no root aneurysm during the same period served as the controls. The exclusion criteria were as follows: abnormal appearance or AV function, defined as an increase in echogenicity and thickness of the aortic leaflets or restriction in mobility on intraoperative transoesophageal echocardiography (TOE); bicuspid AV or congenital heart disease; greater than moderate AV or other valvular heart diseases; non-sinus rhythm, bradycardia (heart rate < 50 beats/min), or tachycardia (heart rate > 100 beats/min); decreased left ventricular ejection fraction (<50%); a history of cardiac surgery; anaemia (men, haemoglobin < 13 g/dL; women, <12 g/dL); and end-stage renal disease on haemodialysis.
Echocardiography
Before the surgical procedure, baseline intraoperative TOE measurements were obtained under stable haemodynamic conditions after induction of general anaesthesia (Supplementary data online, Videos S1–S3). The left ventricular ejection fraction, end-diastolic dimensions, end-systolic dimensions, and the presence of valvular heart disease were assessed following the guidelines.15,16
The details of the epi-aortic echocardiogram have been previously reported11 (Figure 1). The geometric parameters in end-diastole were analysed in this view (Figure 1D). The systolic SOV area was defined as the area enclosed by non-coronary cusp leaflet and SOV in mid-systole (Figure 1B). The colour Doppler images were acquired at a frame rate of over 20 fps. The Nyquist limit for colour Doppler images was set sufficiently high to mitigate aliasing phenomena (Supplementary data online, Figure S1).
Figure 1.
Epi-aortic echocardiography images. (A) View of the aortic valve leaflets, left ventricular outflow tract, and ascending aorta using three-dimensional images in mid-systole. (B) Multi-planar reconstruction used to determine the centre of the non-coronary cusp and commissure between the left and right coronary cusps from (A). (C) View of the aortic valve leaflets, left ventricular outflow tract, and ascending aorta using three-dimensional images in end-diastole. (D) Multi-planar reconstruction is used to determine the centre of the non-coronary cusp and commissure between the left and right coronary cusps from (C). a, systolic SOV area; b, sinotubular junction diameter; c, SOV diameter; d, annulus diameter; e, height of SOV; f, effective height; g, geometric height. LA, left atrium; LCC, left coronary cusp; LVOT, left ventricular outflow tract; NCC, non-coronary cusp; RA, right atrium; RCC, right coronary cusp; SOV, sinuses of Valsalva.
All measurements were averaged using at least three different beats. The results were interpreted in an echocardiography laboratory by experienced attending physicians.
Image analysis of VFM
VFM is a method of processing colour Doppler information that demonstrates the vector of local blood flow velocity. This method is based on the integral of the continuity equation applied to both colour Doppler data, and wall-motion tracking data.5,17 Colour Doppler images were analysed using the commercially available VFM analysis software (Echo VFM®, Cardio Flow Design, Tokyo, Japan) to obtain the WSS and OSI. WSS was calculated using the following formula:
where μ is the coefficient of blood viscosity (4.0 × 10−3 N•s•m−2), ν is the velocity along the flow, and y is the orthogonal axis to the flow.5,11 OSI represents the temporal changes in WSS during a cardiac cycle, and was calculated according to the following formula:11
WSS on fibrosa and ventricularis of AV were separately measured for the entire cardiac cycle, except when the leaflet was rapidly opening or closing. The belly (the middle of the leaflet) of the non-coronary cusp was chosen as the representative WSS value. The systolic WSS and diastolic WSS were defined as the peak values during the systolic and diastolic phases according to a previously published method.11 The WSS and OSI values were averaged over at least three cardiac cycles.
VSARR procedure
The surgical indications for a VSARR procedure were determined according to the published guidelines.18 One surgeon (H.T.) performed all VSARRs using the David V technique with a Gelweave Valsalva graft (Vascutek Ltd., Renfrewshire, Scotland). A graft 3–5-mm larger than the aortic annular diameter was chosen (graft sizes used: 28 mm, 30 mm, and 32 mm in 4, 9, and 4 patients, respectively). Coronary buttons were created and the sinus tissue was excised, leaving a 5-mm rim. The skirt of the graft was secured at the level of the nadirs of the sinuses, using 6–12 pledgeted mattress sutures. When an additional arch replacement was needed, moderate hypothermic circulatory arrest with selective antegrade cerebral perfusion was used.
Statistical analysis
The normality of data was assessed using the D’Agostino–Pearson test. Results are presented as mean and standard deviation for continuous variables. Categorical variables are presented as frequencies (%). The data between the groups were compared using Student’s t-test or Mann–Whitney U test for continuous variables and chi-squared or Fisher’s exact tests for categorical variables. Paired t-test or Wilcoxon signed-rank test was used to detect any significant differences between the pre- and-post-VSARR observations regarding the haemodynamic and aortic root parameters; when appropriate, possible relationships between each geometric parameter of the aortic root and the WSS or OSI were examined using bivariate Pearson correlation coefficients. The geometric parameters associated with the WSS or OSI, with P-values < 0.1 on univariate analyses, were entered into a multivariate linear regression model to determine the independent importance of each of these parameters.
To assess the reproducibility of the WSS, OSI, and echocardiographic measurements, as described by absolute difference ± standard deviation and intraclass correlation, systolic WSS and OSI on the fibrosa and systolic SOV area of all patients were repeated by a second observer. One observer evaluated the same study at least 1 month after the initial measurement to assess intra-observer variability.
All tests were two-tailed, with significance defined as P-value < 0.05. All statistical analyses were performed using MedCalc v15.8 (MedCalc Software, Ostend, Belgium) and R v3.5.1 (The R Foundation, Vienna, Austria).
Results
Patient characteristics
Out of 36 patients, 19 underwent CABG and 17 underwent VSARR. The characteristics of these patients are summarized in Table 1. The prevalence of diabetes mellitus and dyslipidaemia was higher in those who underwent CABG. There were no significant differences in terms of age, sex, body surface area, left ventricular ejection fraction, and left ventricular size between the groups. Two patients underwent VSARR and CABG concomitantly.
Table 1.
Patients’ characteristics
| Characteristics | Controls (CABG) (n = 19) | VSARR (n = 17) | P-value |
|---|---|---|---|
| Age (years) | 65 ± 6 | 62 ± 10 | 0.17 |
| Sex (male/female) | 14/5 (74%) | 15/2 (88%) | 0.28 |
| BSA (m2) | 2.0 ± 0.3 | 2.0 ± 0.2 | 0.82 |
| Hypertension | 16 (84%) | 10 (59%) | 0.09 |
| eGFR < 60 mL/min/1.73 m2 | 3 (16%) | 3 (18%) | 0.88 |
| Diabetes mellitus | 11 (58%) | 0 (0%) | <0.001 |
| COPD | 1 (5%) | 0 (0%) | 0.34 |
| Dyslipidaemia | 17 (89%) | 4 (24%) | <0.001 |
| Concomitant CABG | 2 (11%) | ||
| Haematocrit (%) | 42 ± 4 | 40 ± 3 | 0.10 |
| TOE parameters | |||
| LVEF (%) | 59 ± 5 | 57 ± 4 | 0.23 |
| LVDd (mm) | 47 ± 5 | 46 ± 7 | 0.79 |
| LVDs (mm) | 31 ± 5 | 31 ± 6 | 0.84 |
| IVS (mm) | 11 ± 2 | 11 ± 1 | 0.56 |
| PW (mm) | 10 ± 2 | 11 ± 1 | 0.86 |
Values are presented as mean ± standard deviation or number (%).
BSA, body surface area; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; IVS, interventricular septum; LVDd, left ventricular diastolic dimension; LVDs, left ventricular systolic dimension; LVEF, left ventricular ejection fraction; PW, posterior wall; TOE, transoesophageal echocardiography; VSARR, valve-sparing aortic root replacement.
Aortic root geometry, WSS, and OSI
The haemodynamic data, geometric measurements of the aortic root, the WSS, and OSI are summarized in Table 2. Compared with the patients in the CABG group, those in the pre-VSARR group had a larger aortic root (aortic annulus diameter: 21 ± 2 vs. 26 ± 3 mm, respectively, P < 0.001; SOV diameter: 35 ± 3 vs. 47 ± 3 mm, respectively, P < 0.001; sinotubular junction diameter: 27 ± 3 vs. 37 ± 4 mm, respectively, P < 0.001; height of SOV: 23 ± 2 vs. 35 ± 6 mm, respectively, P < 0.001; systolic SOV area: 1.0 ± 0.2 vs. 2.9 ± 0.9 cm2, respectively, P < 0.001). Similarly, they had a higher effective height (10 ± 2 vs. 12 ± 1 mm, respectively, P = 0.02) and geometric height (19 ± 2 vs. 21 ± 1 mm, respectively, P < 0.001).
Table 2.
Parameters of aortic root geometry, WSS, and OSI
| Characteristics | Controls (CABG) (n = 19) | VSARR (n = 17) |
Pre-VSARR vs. post-VSARR | Controls vs. pre-VSARR | Controls vs. post-VSARR | |
|---|---|---|---|---|---|---|
| Pre-VSARR | Post-VSARR | P-value | P-value | P-value | ||
| Systolic BP (mmHg) | 110 ± 12 | 107 ± 11 | 108 ± 11 | 0.32 | 0.34 | 0.62 |
| Diastolic BP (mmHg) | 62 ± 12 | 64 ± 6 | 61 ± 5 | 0.12 | 0.42 | 0.45 |
| Heart rate (beats/min) | 67 ± 12 | 73 ± 11 | 74 ± 10 | 0.63 | 0.10 | 0.06 |
| Aortic peak velocity (m/s) | 1.0 ± 0.2 | 1.0 ± 0.2 | 1.2 ± 0.2 | <0.001 | 0.15 | 0.11 |
| Aortic regurgitation (mild/none) | 14/5 (74%) | 15/2 (88%) | 14/3 (82%) | 0.63 | 0.28 | 0.54 |
| Aortic root geometry | ||||||
| Aortic annulus diameter (mm) | 21 ± 2 | 26 ± 3 | 26 ± 2 | 0.23 | <0.001 | <0.001 |
| SOV diameter (mm) | 35 ± 3 | 47 ± 3 | 37 ± 2 | <0.001 | <0.001 | 0.01 |
| Sinotubular junction diameter (mm) | 27 ± 3 | 37 ± 4 | 28 ± 2 | <0.001 | <0.001 | 0.14 |
| Height of SOV (mm) | 23 ± 2 | 35 ± 6 | 29 ± 2 | <0.001 | <0.001 | <0.001 |
| Effective height (mm) | 10 ± 2 | 12 ± 1 | 11 ± 1 | 0.21 | 0.02 | 0.10 |
| Geometric height (mm) | 19 ± 2 | 21 ± 1 | 21 ± 1 | 0.46 | <0.001 | 0.003 |
| Systolic SOV area (cm2) | 1.0 ± 0.2 | 2.9 ± 0.9 | 1.1 ± 0.3 | <0.001 | <0.001 | 0.36 |
| WSS and OSI | ||||||
| Systolic WSS on the fibrosa (Pa) | 0.32 ± 0.08 | 0.52 ± 0.12 | 0.29 ± 0.12 | <0.001 | <0.001 | 0.42 |
| Diastolic WSS on the fibrosa (Pa) | 0.19 ± 0.07 | 0.21 ± 0.09 | 0.16 ± 0.08 | 0.10 | 0.51 | 0.17 |
| OSI on the fibrosa | 0.29 ± 0.04 | 0.37 ± 0.06 | 0.26 ± 0.09 | <0.001 | <0.001 | 0.15 |
| Systolic WSS on the ventricularis (Pa) | 2.37 ± 0.39 | 2.25 ± 0.51 | 2.14 ± 0.45 | 0.53 | 0.41 | 0.11 |
| Diastolic WSS on the ventricularis (Pa) | 0.19 ± 0.06 | 0.23 ± 0.10 | 0.24 ± 0.14 | 0.80 | 0.15 | 0.57 |
| OSI on the ventricularis | 0.05 ± 0.03 | 0.07 ± 0.05 | 0.07 ± 0.04 | 0.61 | 0.25 | 0.07 |
Values are presented as mean ± standard deviation.
BP, blood pressure; CABG, coronary artery bypass graft; OSI, oscillatory shear index; SOV, sinuses of Valsalva; VSARR, valve-sparing aortic root replacement; WSS, wall shear stress.
In terms of the fluid dynamics of the AV leaflet, those in the pre-VSARR group had a higher systolic WSS (0.52 ± 0.12 vs. 0.32 ± 0.08 Pa, respectively, P < 0.001) and higher OSI (0.37 ± 0.06 vs. 0.29 ± 0.04, respectively, P < 0.001) on the fibrosa, compared to the controls (Table 2, Figure 2, Supplementary data online, Figure S2). As presented in Figure 3 and Supplementary data online, Videos S4–S6, patients in the pre-VSARR group had a larger vortex in the aneurysmal aortic root than those without an aneurysmal aortic root. There were no significant differences in the diastolic WSS on the fibrosa or fluid dynamics in the ventricularis.
Figure 2.
Box plot of the systolic WSS and OSI on the fibrosa vs. controls (CABG), pre-VSARR, and post-VSARR. CABG, coronary artery bypass graft; OSI, oscillatory shear index; VSARR, valve-sparing aortic root replacement; WSS, wall shear stress.
Figure 3.
Epi-aortic echocardiography images of VFM during systole. (A) Small vortex in the aortic root of controls (CABG). (B) Large vortex in the aneurysmal aortic root of pre-VSARR. (C) Small vortex in the aortic root of post-VSARR. CABG, coronary artery bypass graft; LVOT, left ventricular outflow tract; NCC, non-coronary cusp; VFM, vector flow mapping; VSARR, valve-sparing aortic root replacement.
To further assess the relationship between aortic root geometry and systolic WSS or OSI on the fibrosa, the pre-VSARR and the CABG parameters were combined and analysed as continuous variables (Table 3 and Supplementary data online, Table S1). The systolic WSS on the fibrosa was strongly associated with the SOV diameter and systolic SOV area (correlation coefficient, r = 0.84, P < 0.001, and r = 0.90, P < 0.001, respectively) (Table 3 and Figure 4). Its association with the diameters at the aortic annulus and sinotubular junction was also significant, but weak (r = 0.51, P = 0.002 and r = 0.59, P < 0.001, respectively) (Table 3 and Figure 4). Multiple linear regression analysis revealed that the systolic SOV area was an independent determinant of systolic WSS on the fibrosa (Supplementary data online, Table S1).
Table 3.
Pearson correlation coefficients (r) between aortic geometry and WSS or OSI (n = 36)
| Variables | WSS |
OSI |
||||
|---|---|---|---|---|---|---|
| r | 95% CI | P-value | r | 95% CI | P-value | |
| Aortic annulus diameter (mm) | 0.51 | 0.21–0.72 | 0.002 | 0.42 | 0.10–0.66 | 0.01 |
| SOV diameter (mm) | 0.84 | 0.71–0.92 | <0.001 | 0.58 | 0.31–0.76 | <0.001 |
| Sinotubular junction diameter (mm) | 0.59 | 0.32–0.77 | <0.001 | 0.52 | 0.24–0.73 | 0.001 |
| Height of SOV (mm) | 0.78 | 0.61–0.88 | <0.001 | 0.63 | 0.38–0.80 | <0.001 |
| Effective height (mm) | 0.39 | 0.07–0.63 | 0.02 | 0.19 | −0.15–0.47 | 0.26 |
| Geometric height (mm) | 0.56 | 0.29–0.75 | <0.001 | 0.34 | 0.02–0.60 | 0.04 |
| SOV/sinotubular junction diameter | 0.25 | −0.08–0.54 | 0.14 | 0.04 | −0.29–0.36 | 0.82 |
| Systolic SOV area (cm2) | 0.90 | 0.81–0.95 | <0.001 | 0.60 | 0.34–0.77 | <0.001 |
| Aortic peak velocity (m/s) | −0.16 | −0.46–0.18 | 0.36 | −0.12 | −0.43–0.22 | 0.50 |
BP, blood pressure; CABG, coronary artery bypass graft; CI, confidence interval; OSI, oscillatory shear index, SOV, sinuses of Valsalva; VSARR, valve-sparing aortic root replacement; WSS, wall shear stress.
Figure 4.
Regression plots demonstrating correlations between systolic WSS on the fibrosa and systolic SOV area (A), SOV diameter (B), aortic annulus diameter (C), and sinotubular junction diameter (D). SOV, sinuses of Valsalva.
The OSI on the fibrosa also correlated with a number of geometric parameters, including the height of SOV (r = 0.63, P < 0.001), SOV diameter (r = 0.58, P < 0.001), aortic annulus diameter (r = 0.42, P = 0.01), and sinotubular junction diameter (r = 0.52, P = 0.001) (Table 3 and Figure 5). Multiple linear regression analysis revealed that the height of SOV was an independent determinant of OSI on the fibrosa (Supplementary data online, Table S1).
Figure 5.
Regression plots demonstrating correlations between OSI on the fibrosa and height of SOV (A), SOV diameter (B), aortic annulus diameter (C), and sinotubular junction diameter (D). SOV, sinuses of Valsalva.
Changes after VSARR
Compared with the control group, patients in the post-VSARR group had a larger aortic annulus diameter (21 ± 2 vs. 26 ± 2 mm, respectively, P < 0.001), SOV diameter (35 ± 3 vs. 37 ± 2 mm, respectively, P = 0.01), height of SOV (23 ± 2 vs. 29 ± 2 mm, respectively, P < 0.001), and geometric height (19 ± 2 vs. 21 ± 1, respectively, P = 0.003), whereas there were no significant differences in the sinotubular junction diameter, the effective height, and systolic SOV area. The post-VSARR aortic peak velocity was greater than the pre-VSARR velocity (1.2 ± 0.2 vs. 1.0 ± 0.2 m/s, respectively, P < 0.001); however, no patients exhibited greater than moderate aortic regurgitation (effective regurgitant orifice area ≥ 0.10 cm2) or mild aortic stenosis (aortic peak velocity ≥ 2.0 m/s). After the VSARR procedures, both systolic WSS and OSI values on the fibrosa had reduced significantly compared with the pre-VSARR values (WSS: 0.29 ± 0.12, P < 0.001; OSI: 0.26 ± 0.09, P < 0.001), and were comparable to those in the CABG group (WSS, P = 0.42 and OSI, P = 0.15, Figure 2). The larger vortex in the aneurysmal aortic root in the pre-VSARR group became similar to that of the CABG group after the VSARR procedure (Figure 3).
Reproducibility
The respective intra- and inter-observer variabilities, as assessed by intraclass correlations and absolute mean difference, were as follows: systolic WSS on the fibrosa (CABG), 0.96 and 0.02 ± 0.02 Pa, 0.98 and 0.01 ± 0.02 Pa; systolic WSS on the fibrosa (pre-VSARR), 0.97 and 0.02 ± 0.02 Pa, 0.96 and 0.03 ± 0.03 Pa; systolic WSS on the fibrosa (post-VSARR), 0.96 and 0.02 ± 0.03 Pa, 0.97 and 0.01 ± 0.02 Pa; OSI on the fibrosa (CABG), 0.87 and 0.01 ± 0.02, 0.91 and 0.01 ± 0.02; OSI on the fibrosa (pre-VSARR), 0.89 and 0.01 ± 0.02, 0.87 and 0.01 ± 0.02; OSI on the fibrosa (post-VSARR), 0.91 and 0.02 ± 0.03, 0.85 and 0.03 ± 0.03; systolic SOV area (CABG); 0.96 and 0.01 ± 0.07 cm2, 0.93 and 0.02 ± 0.08 cm2; systolic SOV area (pre-VSARR), 0.98 and 0.02 ± 0.18 cm2, 0.99 and 0.01 ± 0.16 cm2; systolic SOV area (post-VSARR), 0.96 and 0.02 ± 0.10 cm2, 0.98 and 0.01 ± 0.07 cm2.
Discussion
The available knowledge on this subject has been limited to the data obtained from simulation models. Computational fluid dynamics imports of computed tomography angiograms allow for the analyses of the anatomical information; however, they are severely limited because of the need for assumptions of unknown material properties of the AV owing to the control of large displacement mesh motion, especially, in AV disease.19 Experimental studies are limited because the in vitro environment for the valve leaflet is different from the in vivo environment.20 Based on the lack of an appropriate imaging modality to assess the valvular fluid dynamics, we developed an epi-aortic echocardiogram-guided VFM. We report the first in vivo fluid dynamic assessment of AV in relation to aortic root aneurysm.
Our novel observations have important clinical implications. WSS is related to the endothelial degeneration of the vessel wall in atherosclerotic diseases.4,5 The changes in the mechanical stress on AV leaflets in patients with aortic root aneurysms may predispose the leaflets to degeneration. As a matter of fact, elevated shear stress activates the valvular endothelium on the fibrosa of the AV via bone morphogenetic protein-4 and transforming growth factor-beta1-dependent pathways.20 A higher OSI on the fibrosa upregulates gene expression for the endothelial-to-mesenchymal cell transformation and inflammation, which results in AV degeneration.21,22 Interestingly, a larger root size has been demonstrated to be an independent risk factor of AV failure following VSARR.9,10 This clinical observation is in line with the present data.
AV consists of three cusps, the SOV, and the sinotubular junction, which are characterized by morphological features and functional properties. While we did not perform an in-depth quantitative analysis of the three-dimensional shape of the SOV, our data suggest an important role of SOV in the function of the AV leaflets. The patients in the pre-VSARR group had a larger vortex in the aneurysmal aortic root than did those without aneurysmal aortic root; therefore, the size of the vortex became comparable to that in the controls following VSARR. Furthermore, SOV diameter and systolic SOV area but not the aortic annulus or the sinotubular junction diameters, had the strongest correlation with the systolic WSS on the fibrosa. Leonardo da Vinci described that vortices in SOV promote valve closure.23 Recent studies have revealed the importance of SOV and vortex formation in SOV; they contribute by optimizing the valve opening and closure and minimizing leaflet stress as well as transvalvular pressure gradients.24,25 SOV may play a crucial role in maintaining the integrity of the AV leaflets. In our patients, the Valsalva graft facilitated reforming of SOV in addition to reducing its diameter, and both components might have contributed to the restoration of the mechanical stress to the aortic leaflet. However, the universal use of a Valsalva graft without using a straight tube graft prevented a comparative analysis in this regard. VSARR with a reimplantation technique using a straight tube graft was demonstrated to decrease the opening and closing of the AV and resulted in a shorter ejection time as compared with VSARR with the recreation of SOV.26 Experimental studies have demonstrated that SOV plays an important role in optimizing the haemodynamics around AV and minimizing energy losses.27 A larger aortic root dilation could lead to higher WSS and OSI, whereas the absence of SOV in a straight tube graft may be related to the altered valve function through deformed sinus vortices.28 Appropriate sizes of the SOV are required to optimize the mechanical stress around the leaflets and the AV function.
Despite acknowledging the importance of SOV in AV function, the debate continues regarding the clinical relevance of the shape of a root graft continues. In a previous study, there were no significant differences in clinical short- to mid-term outcomes between VSARR with and without recreation of SOV.29 The quest to improve valve durability and lower the risk of future aortic events is needed because VSARR is often performed in younger patients.
The SOV in the Gelweave Valsalva (Vascutek Ltd.) graft has a more spherical form, whereas the normal aortoventricular junction is cylindrical and the aortic sinuses bulge from this cylinder.30 The epi-aortic echocardiogram-guided assessment used in our study may help develop a graft and comparisons of the two major techniques—reimplantation by David and Feindel31 and remodelling by Sarsam and Yacoub.32
Our study has several limitations. First, it was a single-centre prospective study with a small sample size. Nonetheless, statistically significant differences between groups were identified. Second, while we included the patients who underwent CABG as controls, mechanical stress on the AV could be abnormal due to decreased coronary flow and co-existing atherosclerotic changes of the aorta or the AV leaflets.6 We mitigated these concerns by selecting the belly of the non-coronary cusp to minimize the effects of coronary flow and by excluding patients with any abnormal appearance of the aortic root and valve. Our methodology required the using an epi-aortic echocardiogram, so we selected a control cohort from the patients who were undergoing open-heart surgery. We decided that CABG patients fit the best since the procedure is performed commonly and the patients typically do not have an overt valvular or aortic abnormality. Third, there exists no evidence that this corrective restoration of the physiology of aortic root flow mitigates long-term degenerative changes in the AV leaflets. Long acquisition and post-processing times limit the application of epi-aortic echocardiogram in clinical studies. Since TOE would have far wider applicability than an epi-aortic echocardiogram, we first obtained data using TOE; however, this preliminary study of ours showed that the quality of such images acquired by these modalities was not sufficient enough to allow the analysis. This failure led us to investigate the use of an epi-aortic echocardiogram, which shows clear images with sufficient spatio-temporal resolution.
In conclusion, the systolic WSS and OSI on the fibrosa correlated with the geometry of the aortic root. The AV leaflet within the aneurysmal aortic root is exposed to abnormal fluid dynamics, and VSARR may help revert these changes.
Supplementary data
Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.
Funding
G.F. is supported by NIH R01s, HL122805, and HL143008. H.T. is supported by the Thoracic Surgery Foundation grant (https://thoracicsurgeryfoundation.org/2017awards/) and Rubin Foundation.
Data availability statement
Data cannot be shared for ethical/privacy reasons.
Conflict of interest: G.F. is supported by NIH R01s, HL122805, and HL143008. H.T. is supported by the Thoracic Surgery Foundation grant (https://thoracicsurgeryfoundation.org/2017awards/) and Rubin Foundation. K.I. is an endowed chair at the Kyoto Prefectural University of Medicine, financially supported by Medtronic Japan, and Founder and Technical Advisor of Cardio Flow Design Inc. P.C.C. is a recipient of a research grant from Abbott. He also serves as a consultant (with no honoraria) to the same company. Other authors declare no financial interests.
Supplementary Material
References
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Supplementary Materials
Data Availability Statement
Data cannot be shared for ethical/privacy reasons.
Conflict of interest: G.F. is supported by NIH R01s, HL122805, and HL143008. H.T. is supported by the Thoracic Surgery Foundation grant (https://thoracicsurgeryfoundation.org/2017awards/) and Rubin Foundation. K.I. is an endowed chair at the Kyoto Prefectural University of Medicine, financially supported by Medtronic Japan, and Founder and Technical Advisor of Cardio Flow Design Inc. P.C.C. is a recipient of a research grant from Abbott. He also serves as a consultant (with no honoraria) to the same company. Other authors declare no financial interests.