Abstract
Aims
To compare the progression of aortic stenosis (AS) in patients with bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV).
Methods and results
One hundred and forty-one patients with mild-to-moderate AS, recruited prospectively in the PROGRESSA study, were included in this sub-analysis. Baseline clinical, Doppler echocardiography and multidetector computed tomography characteristics were compared between BAV (n = 32) and TAV (n = 109) patients. The 2-year haemodynamic [i.e. peak aortic jet velocity (Vpeak) and mean transvalvular gradient (MG)] and anatomic [i.e. aortic valve calcification density (AVCd) and aortic valve calcification density ratio (AVCd ratio)] progression of AS were compared between the two valve phenotypes. The 2-year progression rate of Vpeak was: 16 (−0 to 40) vs. 17 (3–35) cm/s, P = 0.95; of MG was: 1.8 (−0.7 to 5.8) vs. 2.6 (0.4–4.8) mmHg, P = 0.56; of AVCd was 32 (2–109) vs. 52 (25–85) AU/cm2, P = 0.15; and of AVCd ratio was: 0.08 (0.01–0.23) vs. 0.12 (0.06–0.18), P = 0.16 in patients with BAV vs. TAV. In univariable analyses, BAV was not associated with AS progression (all, P ≥ 0.26). However, with further adjustment for age, AS baseline severity, and several risk factors (i.e. sex, history of hypertension, creatinine level, diabetes, metabolic syndrome), BAV was independently associated with faster haemodynamic (Vpeak: β = 0.31, P = 0.02) and anatomic (AVCd: β = 0.26, P = 0.03 and AVCd ratio: β = 0.26, P = 0.03) progression of AS.
Conclusion
In patients with mild-to-moderate AS, patients with BAV have faster haemodynamic and anatomic progression of AS when compared to TAV patients with similar age and risk profile. This study highlights the importance and necessity to closely monitor patients with BAV and to adequately control and treat their risk factors.
Clinical trial registration
https://clinicaltrials.gov Unique identifier: NCT01679431.
Keywords: aortic stenosis, bicuspid aortic valve, tricuspid aortic valve, haemodynamic progression, aortic valve calcification, anatomic progression
Introduction
Calcific aortic stenosis (AS) is the most common valvular heart disease and the third most common cardiovascular disease in high-income countries. AS is characterized by a progressive thickening and remodelling of the valvular leaflets and the development and accumulation of fibro-calcific deposits in the leaflets over time.1 In high-income countries, the main aetiologies of AS are calcific disease on a tricuspid aortic valve (TAV) and on congenital anomalies of the aortic valve, essentially bicuspid aortic valves (BAVs).2 BAV is the most frequent congenital heart disease, with a prevalence of 1–2% in the general population, and constitutes a strong risk factor for the development of aortic valve diseases, particularly AS.3–5 Subjects with BAV generally develop AS more frequently and earlier than subjects with TAV (10–20 years earlier),6,7 and are at higher risk for an aortic valve intervention during their lifetime, with nearly 50% of them requiring aortic valve replacement (AVR) because of development of severe AS.1
The progression rate of AS is highly variable from one patient to another, even if several risk factors have been found to be associated with faster progression of AS.1,8–14
The impact of the aortic valve phenotype (i.e. BAV vs. TAV) on progression of AS severity has not been systematically reported15–17 and has been examined in few studies.18–21 In the current study, we thus aimed to assess the anatomic and haemodynamic progression of AS in patients with BAV and patients with TAV.
Methods
Study population
The study population consisted of patients prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study (ClinicalTrials.gov #NCT01679431), a prospective longitudinal and observational cohort study aiming at determining the predictors of AS progression. Patients were included in the PROGRESSA study if they were at least 18 years old and had AS defined by a peak aortic jet velocity (Vpeak) >2 m/s. They were excluded if they had a left ventricular ejection fraction (LVEF) <50%, an aortic or mitral regurgitation >mild, a concomitant mitral stenosis, a previous intervention on the aortic or mitral valve, and if they were pregnant or lactating.
From April 2005 to October 2018, 343 patients with AS were recruited. Among those patients, 141 patients with mild to moderate AS and at least 2 years of follow-up were included in the present sub-analysis of the PROGRESSA study. These 141 patients underwent both a comprehensive Doppler echocardiography and multidetector computed tomography (MDCT) at baseline and at 2-year follow-up, to assess progression of both haemodynamic and anatomic severity of AS. Doppler echocardiography and MDCT exams were done within a period of 3 months from each other.
This study was approved by the institutional review board (ethics committee of the Quebec Heart and Lung Institute) and all participants signed a written informed consent at the time of inclusion.
Clinical data
Clinical data included age, sex, body surface area (BSA), systolic and diastolic blood pressures, heart rate, hypertension, dyslipidaemia, diabetes, coronary artery disease, history of smoking, metabolic syndrome,22 and creatinine level.
Doppler echocardiography data
All Doppler echocardiography exams were performed with a Philips iE33 or EPIQ 7 ultrasound system and analysed according to the current echocardiographic recommendations.2 Aortic valve phenotype was assessed in the parasternal short-axis view. Left ventricular outflow tract (LVOT) diameter was measured at the insertion of the leaflets in a zoom of the parasternal long-axis view and used to calculate the LVOT area. Stroke volume was obtained by multiplying the LVOT area by the velocity time integral measured by pulsed wave Doppler in the LVOT. Stroke volume was indexed to BSA to obtain stroke volume index. The transvalvular flow rate was calculated by dividing the stroke volume by the left ventricular ejection time. LVEF was calculated with Simpson’s biplane method. AS haemodynamic severity was assessed with the following haemodynamic parameters: Vpeak measured by continuous wave Doppler, mean transvalvular gradient (MG) calculated by the modified Bernoulli equation, and aortic valve area (AVA) calculated by the standard continuity equation. The dimensionless index was calculated as the ratio of the velocity time integral of the LVOT flow on the velocity time integral of the aortic valve flow.
MDCT data
Non-contrast MDCT exams were performed with a dual-source MDCT scanner (Siemens SOMATOM Definition or a Philips iCT) to assess the anatomic severity and progression of AS. All exams were acquired and analysed by trained technicians who were blinded to the clinical and Doppler echocardiography data of the patients. Acquisition and interpretation followed a protocol that was previously described.23 Briefly, a scan run consisted of a prospective acquisition of contiguous transverse slices, with a thickness of 3 mm and triggered at 60–80% of the electrocardiogram R-to-R wave interval. Image analyses were performed offline on dedicated workstations with validated software (Aquarius iNtuition, TeraRecon). Aortic valve calcification (AVC) was measured using the Agatston method24 and results were expressed in arbitrary units (AUs). For this measurement, particular attention was paid to exclude any calcification from the aorta wall, the mitral valve annulus or the coronary arteries, so that AVC only included calcification of the aortic valve leaflets. Calcification was defined as four adjacent pixels with density >130 Hounsfield units. AVC load was summated from all contiguous MDCT planes and was expressed as an absolute value or as AVC density [AVC indexed by the LVOT area obtained by Doppler echocardiography (AVCd)]. Previously validated sex-specific thresholds were used to define severe AVC (2065 AU in men and 1274 AU in women) and severe AVCd (476 AU/cm2 in men and 292 AU/cm2 in women).23 Furthermore, in order to standardize for sex differences in the assessment of anatomic progression, AVC ratio and AVCd ratio were also calculated as follows: for AVC ratio, AVC/2065 in men and AVC/1274 in women; and for AVCd ratio, AVCd/476 in men and AVCd/292 in women. Total radiation exposure related to this study was estimated to be <4 mSV.
Study endpoints
The primary endpoint was the 2-year haemodynamic (i.e. progression of the haemodynamic parameters: Vpeak, MG) and anatomic (i.e. progression of the anatomic parameters: AVC, AVCd, AVC ratio, and AVCd ratio) progression of AS which was assessed by subtracting the baseline measurement from the 2-year follow-up measurement. The secondary endpoint was the occurrence of the composite of AVR or all-cause mortality between baseline and last follow-up.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation or as median (25th–75th percentile) and categorical variables were expressed as n (%). Continuous variables were tested for normality of distribution with a Shapiro–Wilk test and comparisons between BAV and TAV patients were done with Student’s t tests for variables following a normal distribution and with Wilcoxon–Mann–Whitney tests for variables not following a normal distribution. Comparisons between BAV and TAV patients for the categorical variables were done with a χ2 test or a Fisher’s exact test as appropriate.
To determine if BAV was associated with a faster haemodynamic and/or anatomic progression of AS, univariable and multivariable linear regression analyses were used. Variables were included in the multivariable models if they were clinically relevant or reached a P < 0.10 in univariable analyses. In those univariable and multivariable analyses, AVC and AVCd were normalized with a square root transformation and creatinine level was normalized with a logarithmic transformation. The composite event endpoint was reported and compared between BAV and TAV patients using a log-rank test. A multivariable Cox proportional hazards model was performed to assess the independent association between BAV and the composite endpoint.
Statistical analyses were performed with IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, NY, USA) and a P value <0.05 was considered as statistically significant.
Results
Baseline characteristics of the study population
The baseline clinical, Doppler echocardiography, and MDCT data are presented in Table 1. Of the 141 patients, 32 (23%) had BAV and 109 (77%) had TAV, and 106 (75%) presented a mild AS, while the remaining 35 (25%) had a moderate AS. As expected, patients with BAV were much younger (49 ± 12 vs. 70 ± 7 years old, P < 0.0001) and had less risk factors and comorbidities (all, P ≤ 0.02) than patients with TAV. Furthermore, patients with BAV had a lower level of creatinine [75 (62–84) vs. 82 (73–97) μmol/L, P = 0.02], and had a trend towards lower prevalence of metabolic syndrome (22% vs. 39%, P = 0.07) than patients with TAV.
Table 1.
Baseline characteristics of the patients with a tricuspid aortic valve and bicuspid aortic valve
| TAV (N = 109, 77%) | BAV (N = 32, 23%) | P value | |
|---|---|---|---|
| Clinical data | |||
| Age (years) | 70 ± 7 | 49 ± 12 | <0.0001 |
| Male, n (%) | 88 (81) | 22 (69) | 0.15 |
| Body surface area (m2) | 1.91 ± 0.19 | 1.86 ± 0.20 | 0.16 |
| SBP (mmHg) | 141 ± 18 | 132 ± 19 | 0.02 |
| DBP (mmHg) | 76 ± 9 | 79 ± 8 | 0.04 |
| HR (bpm) | 63 ± 11 | 68 ± 13 | 0.08 |
| Hypertension, n (%) | 91 (84) | 8 (25) | <0.0001 |
| Dyslipidaemia, n (%) | 83 (76) | 8 (25) | <0.0001 |
| Diabetes, n (%) | 29 (27) | 2 (6) | 0.02 |
| Metabolic syndrome, n (%) | 43 (39) | 7 (22) | 0.07 |
| CAD, n (%) | 47 (43) | 0 (0) | <0.0001 |
| History of smoking, n (%) | 77 (71) | 20 (63) | 0.38 |
| Creatinine (μmol/L) | 82 (73–97) | 75 (62–84) | 0.02 |
| Doppler echocardiography data | |||
| LVOT diameter (mm) | 22.0 ± 1.7 | 23.0 ± 2.7 | 0.14 |
| Baseline Vpeak (cm/s) | 258 (235–286) | 268 (249–302) | 0.10 |
| Baseline MG (mmHg) | 14.4 (12.5–18.0) | 17.0 (14.7–21.8) | 0.006 |
| Baseline AVA, cm2 | 1.25 (1.10–1.43) | 1.23 (1.04–1.45) | 0.91 |
| Baseline AVAi, cm2/m2 | 0.65 (0.56–0.74) | 0.67 (0.59–0.74) | 0.41 |
| Baseline dimension less index | 0.33 ± 0.07 | 0.31 ± 0.06 | 0.08 |
| LVEF (%) | 64 ± 5 | 65 ± 4 | 0.90 |
| Stroke volume index (mL/m2) | 40.7 (36.5–44.4) | 43.0 (39.2–45.8) | 0.06 |
| Baseline Qmean (mL/s) | 228 (205–257) | 256 (204–292) | 0.02 |
| Baseline LVET (ms) | 338 ± 31 | 318 ± 27 | 0.002 |
| Baseline AS haemodynamic severity | 0.16 | ||
| Mild, n (%) | 85 (78) | 21 (66) | |
| Moderate, n (%) | 24 (22) | 11 (34) | |
| Multidetector computed tomography data | |||
| Baseline AVC (AU) | 571 (320–938) | 411 (95–1280) | 0.17 |
| Baseline AVCd (AU/cm2) | 151 (95–224) | 108 (26–323) | 0.09 |
| Baseline AVC ratio | 0.29 (0.18–0.46) | 0.24 (0.05–0.62) | 0.32 |
| Baseline AVCd ratio | 0.34 (0.21–0.50) | 0.26 (0.05–0.68) | 0.19 |
| Severe AVC at baseline, n (%) | 3 (3) | 4 (13) | 0.047 |
| Severe AVCd at baseline, n (%) | 5 (5) | 3 (9) | 0.38 |
Statistically significant P values are highlighted in bold.
AVA, aortic valve area; AVAi, aortic valve area indexed by body surface area; AVC, aortic valve calcification; AVCd, aortic valve calcification indexed by LVOT area; BAV, bicuspid aortic valve; CAD, coronary artery disease; DBP, diastolic blood pressure; HR, heart rate; LVEF, left ventricular ejection fraction; LVET, left ventricular ejection time; LVOT, left ventricular outflow tract; MG, mean transvalvular gradient; Qmean, transvalvular flow rate; SBP, systolic blood pressure; TAV, tricuspid aortic valve; Vpeak, peak aortic jet velocity.
At baseline, patients with BAV had a higher MG [17.0 (14.7–21.8) vs. 14.4 (12.5–18.0) mmHg, P = 0.006] and a higher transvalvular flow rate [256 (204–292) vs. 228 (205–257) mL/s, P = 0.02] than patients with TAV. However, the AVA, indexed AVA, and thus AS severity grade were similar in both groups (Table 1).
There were no statistically significant differences between patients with BAV and TAV regarding the baseline anatomic severity of AS (baseline AVC, AVCd, AVC ratio, and AVCd ratio, all P ≥ 0.09). Patients with BAV had a higher proportion of severe AVC score (13% vs. 3%, P = 0.047), but when AVC was indexed to LVOT area (AVCd), the proportion of patients with a severe AVCd was similar in both groups (9% vs. 5% for BAV and TAV, respectively, P = 0.38).
Haemodynamic and anatomic progression of AS severity in BAV vs. TAV
Progression of haemodynamic and anatomic parameters of AS severity are presented in Table 2.
Table 2.
Haemodynamic and anatomic progression data in patients with tricuspid aortic valve and bicuspid aortic valve over a 2-year follow-up
| TAV N = 109 (77%) | BAV N = 32 (23%) | P value | |
|---|---|---|---|
| Doppler echocardiography data | |||
| 2-year Vpeak progression (cm/s) | 17 (3 to 35) | 16 (−0 to 40) | 0.95 |
| 2-year MG progression (mmHg) | 2.6 (0.4 to 4.8) | 1.8 (−0.7 to 5.8) | 0.56 |
| 2-year AVA progression (cm2) | −0.10 (−0.19 to 0.00) | −0.08 (−0.19 to 0.01) | 0.46 |
| 2-year AVAi progression (cm2/m2) | −0.05 (−0.10 to 0.01) | −0.06 (−0.09 to 0.02) | 0.66 |
| 2-year change in stroke volume index (mL/m2) | −0.1 (−2.9 to 2.8) | −1.0 (−2.9 to 3.5) | 0.93 |
| 2-year change in dimension less index | −0.03 ± 0.04 | −0.03 ± 0.04 | 0.91 |
| 2-year change in Qmean (mL/s) | 1.3 (−17.8 to 14.8) | −1.4 (−15.4 to 18.6) | 0.97 |
| Multidetector computed tomography data | |||
| 2-year AVC progression (AU) | 187 (79 to 326) | 128 (9 to 457) | 0.30 |
| 2-year AVCd progression (AU/cm2) | 52 (25 to 85) | 32 (2 to 109) | 0.15 |
| 2-year AVC ratio progression | 0.10 (0.05 to 0.18) | 0.08 (0.01 to 0.26) | 0.37 |
| 2-year AVCd ratio progression | 0.12 (0.06 to 0.18)) | 0.08 (0.01 to 0.23) | 0.16 |
| Severe AVC at follow-up, n (%) | 6 (6) | 7 (22) | 0.005 |
| Severe AVCd at follow-up, n (%) | 11 (10) | 6 (19) | 0.19 |
Statistically significant P values are highlighted in bold.
AVA, aortic valve area; AVAi, aortic valve area indexed by body surface area; AVC, aortic valve calcification; AVCd, aortic valve calcification indexed by LVOT area; BAV, bicuspid aortic valve; LVET, left ventricular ejection time; MG, mean transvalvular gradient; Qmean, transvalvular flow rate; TAV, tricuspid aortic valve; Vpeak, peak aortic jet velocity.
Progression of haemodynamic severity
The 2-year progression rates of haemodynamic parameters of AS severity were similar between patients with BAV and TAV, whether Vpeak, MG, AVA, or AVAi was used as a haemodynamic parameter (all, P ≥ 0.46). The 2-year progression of Vpeak was 16 (−0 to 40) vs. 17 (3 to 35) cm/s for patients with BAV and TAV, respectively (P = 0.95, Figure 1A) and the 2-year progression for MG was 1.8 (−0.7 to 5.8) vs. 2.6 (0.4–4.8) mmHg for patients with BAV and TAV, respectively (P = 0.56, Figure 1B).
Figure 1.
Two-year haemodynamic progression of aortic stenosis in patients with tricuspid aortic valve and bicuspid aortic valve. (A) Two-year peak aortic jet velocity (Vpeak) progression. (B) Two-year MG progression. The box shows 25th and 75th percentiles, the median line shows the median value, error bars the 10th and 90th percentiles; circles are outliers. The numbers at the top of the graph are median (25th–75th percentiles).
At 2-year follow-up, 75 (53%) patients remained with a mild AS, while 56 (40%) progressed to a moderate AS and 10 (7%) to a severe AS (Figure 2A). There was a trend for higher proportion of patients who progressed to higher class of severity in BAV vs. TAV (41% vs. 26%; P = 0.10) (Figure 2B) and for higher proportion of moderate or greater AS severity at 2-year follow-up (66% vs. 41%; P = 0.052) (Figure 2A).
Figure 2.
Proportion and distribution of patients with a mild, moderate or severe aortic stenosis at baseline and 2-year follow-up according to haemodynamic severity (A) and proportion of patients progressing in aortic stenosis severity grade (from mild to moderate, mild to severe, or moderate to severe) from baseline to follow-up (B). The numbers in the boxes are number of patients in each group.
Progression of anatomic severity
The 2-year progression of anatomic severity of AS was also similar between the two valve phenotypes: AVCd progression: 32 (2–109) vs. 52 (25–85) AU/cm2; P = 0.15 for patients with BAV and TAV, respectively (Figure 3A); AVCd ratio progression: 0.08 (0.01–0.23) vs. 0.12 (0.06–0.18); P = 0.16 (Figure 3B). The proportion of patients reaching a severe AVC score at 2-year follow-up was higher in the BAV group compared to the TAV group (22% vs. 6%, P = 0.005); but using AVCd, this proportion was not significantly different (19% vs. 10%, P = 0.19) (Figure 4A). The proportion of patients who progressed to a severe AVCd in BAV vs. TAV was also not significantly different (9% vs. 6%, P = 0.42) (Figure 4B).
Figure 3.
Two-year anatomic progression of aortic stenosis in patients with tricuspid aortic valve and bicuspid aortic valve. (A) Two-year AVCd progression. (B) Two-year AVCd ratio progression. The box shows 25th and 75th percentiles, the median line shows the median value, error bars the 10th and 90th percentiles; circles are outliers. The numbers at the top of the graph are median (25th–75th percentiles).
Figure 4.
Proportion and distribution of patients with a non-severe or severe aortic stenosis at baseline and 2-year follow-up according to anatomic severity (A) and proportion of patients progressing from non-severe to severe aortic stenosis (from non-severe AVCd to severe AVCd) from baseline to follow-up (B). The numbers in the boxes are number of patients in each group.
Among the 32 patients with BAV, 24 (75%) had a raphe and 8 (25%) had no raphe. The haemodynamic and anatomic progression of AS was similar between both subgroups [2-year Vpeak progression: 16 (5–40) vs 9 (−6 to 42) cm/s, P = 0.59; 2-year MG progression: 1.7 (−0.4 to 5.8) vs 1.8 (−1.3 to 5.2) mmHg, P = 0.59; 2-year AVCd progression: 33 (3–109) vs. 40 (0–162) AU/cm2, P = 0.91; and 2-year AVCd ratio progression was of: 0.08 (0.01–0.23) vs. 0.10 (0.00–0.34), P = 0.90 in raphe vs. no raphe BAV subgroups].
Association of BAV with progression of AS after adjustment for age and risk factors
In univariable analyses, BAV was not associated with the progression of neither haemodynamic (i.e. Vpeak and MG progression, all P ≥ 0.60) nor anatomic parameters (i.e. AVC, AVC ratio, AVCd, and AVCd ratio progression, all P ≥ 0.26) of AS severity (Table 3). When adjusted for age, BAV became significantly associated with the progression of Vpeak (standardized β = 0.28, P = 0.02), AVC (standardized β = 0.40, P = 0.001), AVC ratio (standardized β = 0.42, P = 0.0004), AVCd (standardized β = 0.29, P = 0.01), and AVCd ratio (standardized β = 0.32, P = 0.006) (Model 1) (Table 3). After further adjustment for baseline AS severity, male sex, hypertension, creatinine level, diabetes, and metabolic syndrome, BAV remained significantly associated with the progression of Vpeak (standardized β = 0.31, P = 0.02), the progression of AVC (standardized β = 0.36, P = 0.002), the progression of AVC ratio (standardized β = 0.35, P = 0.003), the progression of AVCd (standardized β = 0.26, P = 0.03), and the progression of AVCd ratio (standardized β = 0.26, P = 0.03) (Table 3).
Table 3.
Univariable and multivariable analyses of the association between BAV and haemodynamic and/or anatomic progression of aortic stenosis
| Univariable |
Model 1a |
Model 2b |
||||
|---|---|---|---|---|---|---|
| Standardized beta | P value | Standardized beta | P value | Standardized beta | P value | |
| Haemodynamic progression of aortic stenosis | ||||||
| 2-year Vpeak progression (cm/s) | ||||||
| BAV | 0.04 | 0.60 | 0.28 | 0.02 | 0.31 | 0.02 |
| 2-year MG progression (mmHg) | ||||||
| BAV | 0.02 | 0.82 | 0.23 | 0.06 | 0.18 | 0.16 |
| Anatomic progression of aortic stenosis | ||||||
| 2-year AVC progression (AU) | ||||||
| BAV | 0.09 | 0.27 | 0.40 | 0.001 | 0.36 | 0.002 |
| 2-year AVC ratio progression | ||||||
| BAV | 0.10 | 0.26 | 0.42 | 0.0004 | 0.35 | 0.003 |
| 2-year AVCd progression (AU/cm2) | ||||||
| BAV | −0.02 | 0.78 | 0.29 | 0.01 | 0.26 | 0.03 |
| 2-year AVCd ratio progression | ||||||
| BAV | −0.02 | 0.80 | 0.32 | 0.006 | 0.26 | 0.03 |
Statistically significant P values are highlighted in bold.
Adjusted for age.
Adjusted for age, baseline severity (Vpeak or MG or AVC or AVC ratio or AVCd or AVCd ratio, as appropriate), male sex, history of hypertension, creatinine level, diabetes, and metabolic syndrome.
Association of BAV with aortic valve replacement or all-cause mortality
The mean follow-up duration was similar in BAV vs. TAV (3.2 ± 1.9 vs. 3.2 ± 2.0 years, P = 0.89). During this period, there were 64 events [AVR (n = 55) or all-cause mortality (n = 9)]: 16 (50%) in patients with BAV and 48 (44%) in patients with TAV. In univariable analyses, there were no differences in terms of occurrence of events between the two groups of patients (log-rank test P = 0.62) (Figure 5A). However, in a Cox proportional hazards model adjusted for age, sex, hypertension, diabetes, and creatinine level, BAV was associated with a higher incidence of the composite of AVR and death (hazard ratio: 2.88, 95% confidence interval: 1.12–7.41, P = 0.03) (Figure 5B).
Figure 5.
Unadjusted (A) and adjusted (B) Kaplan–Meier curves censored at time of AVR or all-cause death according to aortic valve phenotype (BAV vs. TAV). aHR obtained by Cox multivariable analysis and adjusted for age, sex, hypertension, diabetes, and creatinine level.
Discussion
The main findings of the current study are that: (i) patients with BAV and mild-to-moderate AS had similar 2-year progression rates of anatomic and haemodynamic severity of AS, compared to TAV patients; (ii) however, after adjusting for age and cardiovascular risk factors, BAV phenotype was independently associated with faster progression of AS severity and higher occurrence of AS-related clinical events, i.e. AVR or death.
Several studies reported that BAV phenotype is associated with higher risk of incident aortic sclerosis and AS in the population, and development at an earlier age.4,6 The effect of aortic valve phenotype, BAV vs. TAV, on the progression of AS disease once established is uncertain. Most of previous studies that analysed the factors associated with AS progression did not examine the effect of valve phenotype. The few studies that assessed the impact of valve phenotype on AS progression generally found no association between BAV and haemodynamic or anatomic AS progression rates.19,21 However, these previous studies did not adjust for the important differences that exist between patients with BAV vs. those with TAV. As illustrated in the present study, patients with BAV are generally much younger and have less cardiovascular risk factors and comorbidities compared to those with TAV. One study in series of patients from South Korea reported an association between BAV and haemodynamic progression of AS severity.20
The present study is the first to report and compare the progression of both haemodynamic and anatomic AS severity in BAV vs. TAV patients during the same follow-up time and to adjust for the differences in the baseline characteristics between BAV vs. TAV, and in particular for age. Similar to previous studies,19,21 AS progression rates were similar in BAV vs. TAV in univariable analyses. However, after adjusting for age and comorbidities, BAV was independently associated with faster AS progression and higher risk of AVR or death.
There are several potential mechanisms that may explain the association between BAV and faster AS progression. Mutations of the NOTCH1 gene that causes an early developmental defect leading to the BAV phenotype are also associated with loss of repression of the calcifying processes of the aortic valve later in life.25 The abnormal morphology of the valve leaflets and orifice in the BAV may increase the mechanical stress on the leaflets and disturb the flow patterns through and downstream to the valve; therefore, altering the flow shear stress at the surface of the valve endothelium, particularly on the aortic side.5,26–28 This may contribute to endothelial dysfunction and activation of inflammation and fibro-calcifying processes within the aortic valve.29 In subjects with TAV, these factors are not present, at least initially, and the initiation and progression of AS are more related to ageing processes and/or to inflammation, fibrosis, and calcification induced by lipids, insulin resistance, and/or activation of the renin–angiotensin system. Several studies reported an independent association between cardiometabolic risk factors, including older age, hypertension, metabolic syndrome, diabetes, elevated lipoprotein(a), and elevated low-density lipoprotein, and faster AS progression.1,8,10,11 In age-matched cohorts of patients with severe AS undergoing AVR, Huntley et al.30 reported that patients with TAV and severe AS have greater prevalence of cardiovascular risk factors compared to BAV patients. Hence, in subjects with TAV, early initiation and progression of AS appear to be mainly driven by cardiometabolic risk factors, whereas in BAV subjects, the genetic predispositions and abnormal valve morphology appear to have an independent contribution to AS development and progression.
Study limitations
The BAV group included 32 patients, which limits the statistical power for the multivariable analyses of AS progression and for the analyses of the clinical events. In this study, we focused on patients with mild to moderate AS (due to the design of the PROGRESSA study) and the results can thus not be directly transposed to patients with severe AS. Another limitation is that even if the aortic valve phenotype was carefully assessed, there might be misclassification of the aortic valve phenotype in some patients as it was assessed by transthoracic echocardiography. MDCT exams were performed but without contrast and it was thus not possible to assess the valve phenotype with this imaging modality. Also, in this study, we only perform non-contrast MDCT, which does not allow us to measure LVOT area and calculate AVC density from MDCT only. Finally, given the small number of patients with BAV, further studies with larger number of patients will be necessary to analyse the effect of the different subtypes of BAV on AS progression.
Conclusion
In patients with mild to moderate AS, patients with BAV have faster haemodynamic and anatomic progression of AS and higher risk of AVR or death, when compared with TAV patients with similar age and risk profile. This study therefore supports the need for closer monitoring of patients with BAV AS and for optimal management of their cardiovascular risk factors.
Acknowledgements
The authors would like to thank Isabelle Fortin, Jocelyn Beauchemin, Céline Boutin, Louise Marois, Virginie Bergeron, Danielle Tardif, Martine Poulin, Caroline Dionne, Martine Fleury, and Martine Parent for their help in data collection and management.
Funding
This work was supported by grants MOP-114997, MOP-2455048, and FDN-143225 from Canadian Institutes of Health Research (CIHR), Ottawa, Ontario, Canada and a grant from the Foundation of the Quebec Heart and Lung Institute. M.S. is supported by a PhD grant from the Fonds de Recherche Québec—Santé (FRQS), Montréal, Québec, Canada. L.T. is supported by a PhD grant from the Fonds de Recherche Québec—Santé (FRQS), Montréal, Québec, Canada. R.C. is supported by a ‘Connect Talent’ research chair from Region Pays de la Loire and Nantes Metropole. M.A. is a research scholar from the Fonds de Recherche Québec—Santé (FRQS), Montreal, Québec, Canada. P.P. holds the Canada Research Chair in Valvular Heart Diseases from CIHR, Ottawa, Ontario, Canada.
Conflict of interest: none declared.
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