Abstract
Background
Previous research on congenital aortic stenosis (AS) mainly focused on children, while data on long-term outcomes in adults is scarce. Therefore, this study aims to evaluate outcomes in adult patients with congenital AS and identify prognostic markers for aortic valve replacement (AVR).
Methods
In this multicentre study, patients aged 18–55 years with congenital AS (peak velocity ≥2.5 m/s) registered in the Dutch CONCOR (Congential Cor Vitia) registry from expert centres for congenital heart disease between 2001 and 2019 were included. Exclusion criteria were severe aortic regurgitation (AR) or prior AVR. Associations with the composite endpoint of all-cause mortality and AVR were assessed with multivariable Cox regression.
Results
Of the 427 included patients (median age 26 years, 62.5% male) median aortic peak velocity was 3.1 (IQR 2.7–3.6) m/s, 35% had moderate AR and 29% showed signs of left ventricular (LV) remodelling. During a median follow-up period of 7.9 (IQR 4.1–12.6) years, 7 patients died (1.6%) and 177 patients underwent AVR (41.5%). LV systolic dysfunction was the primary indication for AVR in three patients (1.7%). Peak velocity at baseline (HR 3.17, 95% CI 2.29 to 4.39), non-sinus rhythm (HR 3.12, 95% CI 1.62 to 6.02) and concentric LV geometry (HR 1.64, 95% CI 1.04 to 2.58) were associated with the primary endpoint beside age. Significant male–female differences were observed in prognostic factors for the primary endpoint.
Conclusion
AVR was often indicated in adult patients with congenital AS, even if the stenosis at baseline was mild. Moreover, monitoring LV remodelling alongside severity of AS is more important than focusing on systolic LV dysfunction.
Keywords: Echocardiography; Congenital Abnormalities; Outcome Assessment, Health Care; Aortic Valve Stenosis
WHAT IS ALREADY KNOWN ON THIS TOPIC
Congenital aortic stenosis (AS) is a heterogenous disease. As a result, the clinical course of disease can vary greatly. Data on the clinical course of disease in young adults with a congenital AS is limited.
WHAT THIS STUDY ADDS
In this study, we focused on clinical outcome in young adult patients with a native aortic valve. Aortic valve replacement (AVR) was often performed at a relatively young age (median of 42 years), even when the stenosis at baseline was mild. Although mortality was low, morbidity was high. After 10 years of follow-up, half of the patients had experienced a cardiac event, highlighting the burden of disease. Besides the severity of stenosis, presence of left ventricular (LV) remodelling held important prognostic information, while LV systolic dysfunction was rarely observed as indication for AVR.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Current guidelines recommend AVR in symptomatic patients or in asymptomatic patients with LV systolic dysfunction. However, the latter showed to be only seldom the indication for AVR in our study, indicating it is a suboptimal criterion in this young adult population. Possibly, monitoring parameters indicating LV remodelling hold more prognostic information.
Introduction
Congenital valvular aortic stenosis (AS) accounts for 4–8% of all congenital heart disease (CHD) diagnoses and is often caused by a bicuspid aortic valve (BAV).1 2 The clinical course of disease can vary greatly. In some patients disease progression is slow, while others develop severe AS early in life due to gradual deterioration of the valve.3 Once valve dysfunction progresses and patients become symptomatic, aortic valve replacement (AVR) is indicated.4 However, determining the optimal timing for AVR in asymptomatic patients remains challenging, and the search for proper risk factors is ongoing. Current guidelines recommend AVR in asymptomatic patients with a left ventricular (LV) ejection fraction (LVEF) <50%.4 5 Hence, in the absence of symptoms, the decision to intervene is ultimately driven by the condition of the myocardium. This underlines the importance of monitoring not only the valve, but also LV characteristics in the risk prediction for AVR. Moreover, sex differences in both the progression to valve dysfunction and the need for intervention have been described in patients with BAV.6 Therefore, attention to male–female differences is essential when investigating disease course and clinical outcome in patients with congenital AS.
It is known that even before AVR is indicated, patients with congenital AS are at risk of developing complications such as arrhythmias, heart failure and endocarditis.7,10 In addition, 20–40% of patients with congenital AS develop thoracic aortic dilatation and there is an increased risk for dissection.3 11 Previous research describing the clinical course of disease in congenital AS is mainly focused on children, while data in adulthood is limited. As these complications do imply an important health problem, insight into event rates of both cardiac and aortic events before AVR in adult patients with congenital AS is warranted.
Therefore, the aim of this study is to (1) investigate disease course and indications for AVR in adult patients with congenital AS and (2) describe the event rates of cardiac and aortic events and (3) identify prognostic factors for clinical outcome with focus on both valvular and LV characteristics and special attention for male–female differences.
Methods
Study design and population
For this observational multicentre cohort study, patients with congenital AS prospectively registered in the CONCOR registry (Congenital Cor Vitia; Dutch registry for adult patients with CHD) by one of the six expert centres between 2001 and 2019 were included. Inclusion criteria for the study were: age 18–55 years and aortic valve peak velocity ≥2.5 m/s on the echocardiogram. If patients were pregnant at the time of inclusion, the first follow-up visit after delivery was taken as baseline visit. Exclusion criteria were: concomitant subvalvular or supravalvular AS, severe aortic regurgitation (AR), severe mitral valve dysfunction or complex CHD as defined by the European Society of Cardiology (ESC) guidelines.5 Moreover, patients with prior AVR or indication for AVR at inclusion were excluded. There was no patient or public involvement in the design or conduct of this study.
Data collection
Demographic and clinical characteristics were obtained from chart abstraction at the time of inclusion in the study. AS was classified into mild/moderate/severe according to peak velocity. For chamber quantification, recommendations by the American Society of Echocardiography and the European Association of Cardiovascular Imaging were followed.12 Echocardiographic data was used to determine the presence of LV remodelling. LV concentric geometry was defined as a relative wall thickness >0.42. The ascending aorta was classified as dilated if the diameter was >40 mm on any imaging modality.13
Indications for AVR were classified as: symptomatic valve disease, asymptomatic severe valve disease with presence of risk factor (such as very severe valve disease, fast progression ≥0.3 m/s, abnormal biomarker levels), thoracic aortic dilatation, endocarditis and other indications. If AVR was indicated because of a positive exercise test (symptoms during test, inadequate blood pressure response or clear decline in exercise tolerance), this was classified as symptomatic disease.
Study endpoints
The primary study endpoint was a composite endpoint of AVR and all-cause mortality, to assess the risk for major cardiac adverse events in patients with a native aortic valve. For the secondary endpoint, occurrence of the following events was evaluated: arrhythmias (ventricular and supraventricular), heart failure (requiring start or change in diuretics or requiring hospitalisation), endocarditis of the aortic valve, surgical or percutaneous aortic valve intervention (balloon valvuloplasty or surgical valvulotomy without replacement of the valve) and aortic events (aortic dissection or ascending aorta surgery). Arrhythmic events were included when symptomatic, recorded and treatment was indicated. Arrhythmias that occurred only during hospitalisation after cardiac intervention were not taken into consideration. Premature ventricular and atrial complexes were not considered arrhythmias. Patients who did not reach the primary endpoint were censored at 1 March 2023.
Statistical analysis
Continuous variables were presented as mean±SD or median (IQR) according to their distribution and compared using a Student’s t-test or Mann-Whitney U test respectively. Categorical data was presented as frequencies and percentages and compared using a χ² test or Fisher’s exact test as appropriate. Yearly risk of events was calculated as patients with an event divided by total of person-years and displayed as percentage. Intervention and event-free survival were assessed using the Kaplan-Meier estimator. Kaplan-Meier curves were stratified for sex, AS severity and LV remodelling pattern and compared using a Log-rank test or Peto and Peto Gehan Wilcoxon test when appropriate. Associations between baseline characteristics and the primary endpoint were assessed by Cox-proportional hazard modelling, corrected for clustered data within the study centres. Difference in associations between baseline characteristics and the primary endpoint per sex was evaluated using interaction terms consisting of the interaction and main effects. For the multivariable Cox regression analysis, multiple imputation was used to handle missing data using five imputed data sets with 25 iterations. Independent variables with up to 30% rate of missing values were imputed. Variables with a p value <0.1 in univariable analysis were entered into the multivariable model. The multivariable model was constructed with backward selection and variables with p value <0.1 were kept in the model. Multicollinearity was assessed using correlation plots. Sensitivity analysis was performed with only AVR as endpoint to assess influence of combining AVR and all-cause mortality in the primary endpoint. Two-sided p value <0.05 was considered to be statistically significant. For statistical analysis, SPSS (IBM. Released 2021. IBM SPSS Statistics for Windows, V.28.0. Armonk, New York, USA: IBM) and R V.4.3.2 (R Foundation for Statistical Computing, Vienna, Austria) were used.
Results
Baseline characteristics
A total of 427 patients were included in this study. Baseline characteristics are described in table 1. Median age at inclusion was 26 (19–41) years and 62.5% of patients were male. Associated CHD was present in 52 patients (12.2%), of which atrial septal defect (9 patients; 2.1%), ventricular septal defect (23 patients, 5.4%) and patent ductus arteriosus (14 patients, 3.3%) were most common. Moreover, a history of aortic coarctation was present in 90 patients (21.1%). Median aortic peak velocity was 3.1 (2.7–3.6) m/s and 148 patients (34.9%) had moderate AR. Moreover, 104 patients (29.0%) showed signs of LV concentric geometry at baseline. Presence of concentric geometry was weakly correlated with peak velocity at baseline (rs=0.24, p<0.001) and age (rs=0.17, p<0.001), but not with LV systolic function or systolic/diastolic blood pressure.
Table 1. Baseline characteristics.
| Valid cases | All patients N=427 |
Males n=267 |
Females n=160 |
P value | |
|---|---|---|---|---|---|
| Patient characteristics | |||||
| Age, years | 427 (100) | 26 (19–41) | 24 (19–39) | 29 (20–43) | 0.04 |
| Body surface area, m2 | 348 (81.5) | 1.9±0.2 | 2.0±0.2 | 1.8±0.2 | <0.001 |
| Systolic blood pressure, mm Hg | 397 (93.0) | 124 (115–136) | 125 (117–140) | 120 (110–131) | 0.007 |
| Diastolic blood pressure, mm Hg | 397 (93.0) | 76 (70–83) | 76 (70–81) | 75 (70–85) | 0.85 |
| Smoking, n (%) | 340 (79.6) | 0.59 | |||
| Current | 57 (16.8) | 37 (17.5) | 20 (15.6) | ||
| Past | 55 (16.2) | 31 (14.6) | 24 (18.8) | ||
| NYHA class ≥2, n (%) | 398 (93.2) | 23 (5.8) | 8 (3.2) | 15 (10.3) | 0.006 |
| Cardiac medication use*, n (%) | 418 (97.9) | 80 (19.1) | 41 (15.6) | 39 (25.0) | 0.02 |
| Hypertension, n (%) | 427 (100) | 84 (19.7) | 45 (16.9) | 39 (24.4) | 0.06 |
| Turner syndrome, n (%) | 427 (100) | 10 (2.3) | 0 (0) | 10 (6.3) | <0.001 |
| Bicuspid aortic valve, n (%) | 422 (98.8) | 394 (93.4) | 246 (92.8) | 148 (94.3) | 0.57 |
| Other CHD, n (%) | 427 (100) | 52 (12.2) | 29 (10.9) | 23 (14.4) | 0.28 |
| Aortic coarctation, n (%) | 427 (100) | 90 (21.1) | 52 (19.5) | 38 (23.8) | 0.30 |
| Treated, n (%) | 90 (100) | 80 (88.9) | 46 (88.5) | 34 (89.5) | 0.88 |
| Ascending aortic aneurysm, n (%) | 427 (100) | 96 (22.5) | 61 (22.8) | 35 (21.9) | 0.82 |
| Treated, n (%) | 96 (100) | 9 (9.4) | 7 (11.5) | 2 (5.7) | 0.48 |
| Ascending aortic dissection, n (%) | 427 (100) | 1 (0.2) | 0 (0) | 1 (0.6) | 0.38 |
| Prior AV intervention, n (%) | 427 (100) | 100 (23.4) | 70 (26.2) | 30 (18.8) | 0.08 |
| Balloon valvuloplasty | 44 (10.3) | 30 (11.2) | 14 (8.8) | ||
| Surgical valvulotomy | 33 (7.7) | 24 (9.0) | 9 (5.6) | ||
| >1 prior intervention | 23 (5.4) | 16 (6.0) | 7 (4.4) | ||
| Echocardiography | |||||
| Impaired LV systolic function | 414 (97.0) | 14 (3.4) | 7 (2.7) | 7 (4.5) | 0.40 |
| LV end-diastolic dimension, mm | 369 (86.4) | 51±6 | 53±6 | 48±5 | <0.001 |
| LV end-systolic dimension, mm | 346 (81.0) | 31±5 | 32±6 | 30±5 | <0.001 |
| Interventricular septum, mm | 369 (86.4) | 9.9 (8.3–11.0) | 10.0 (9.0–12.0) | 9.0 (8.0–10.0) | <0.001 |
| LV posterior wall, mm | 363 (85.0) | 9.9 (8.1–11.0) | 10.0 (9.0–11.2) | 9.0 (8.0–10.0) | <0.001 |
| LV mass index, g/m2 | 295 (69.1) | 92 (78–111) | 99 (84–119) | 81 (67–97) | <0.001 |
| LV concentric geometry, n (%) | 359 (84.1) | 104 (29.0) | 73 (32.4) | 31 (23.1) | 0.04 |
| E/A ratio | 223 (52.2) | 1.5 (1.2–1.9) | 1.6 [1.3–2.1) | 1.5 (1.2–1.8) | 0.10 |
| AV peak velocity, m/s | 427 (100) | 3.1 (2.7–3.6) | 3.1 [2.7–3.7) | 3.0 (2.7–3.5) | 0.48 |
| Aortic regurgitation, n (%) | 424 (99.3) | 0.28 | |||
| None–mild | 276 (65.1) | 168 (63.2) | 108 (68.4) | ||
| Moderate | 148 (34.9) | 98 (36.8) | 50 (31.6) | ||
| Ascending aortic diameter, mm | 284 (66.5) | 36±7 | 37±7 | 35±7 | 0.04 |
| Electrocardiography | |||||
| Sinus rhythm, n (%) | 414 (97.0) | 407 (98.3) | 255 (98.8) | 152 (97.4) | 0.43 |
| Heart rate, bpm | 413 (96.7) | 69±13 | 67±13 | 71±13 | <0.001 |
| QRS duration, ms | 405 (94.8) | 98 (90–106) | 100 (94–110) | 92 (85–100) | <0.001 |
| PR-interval, ms | 391 (91.6) | 149 (136–166) | 152 (137–168) | 147 (132–162) | 0.07 |
Medication included: beta-blocker, ACE inhibitor, diuretics, antiarrhythmic, angiotensin II receptor blocker, calcium channel blocker, alpha blocker.
AV, aortic valve; CHD, congenital heart disease; LV, left ventricle; NYHA, New York Heart Association.
Clinical outcome
During a median follow-up period of 7.9 (4.1–12.6) years, 184 patients experienced a primary event: 177 patients underwent AVR (41.5%) and 7 patients died (1.6%). Causes of death are displayed in online supplemental table S1. A total of 78 patients underwent ascending aortic surgery (18.3%), which was performed simultaneous with AVR in 92.3%. Moreover, 28 patients developed an arrhythmia (6.6%), 6 patients developed heart failure (1.4%), 11 patients had endocarditis of the native aortic valve (2.6%) and aortic valve intervention (balloon valvuloplasty or valvulotomy) was performed in 16 patients (3.7%). None of the patients experienced an aortic dissection. The yearly occurrence of events is displayed in figure 1. No significant differences were observed between males and females. A detailed overview of events can be found in online supplemental table S2.
Figure 1. Average yearly risk of events stratified by sex. AVR, aortic valve replacement.
Kaplan-Meier estimates for the primary endpoint of all-cause mortality and AVR (intervention-free survival) and the secondary endpoint of all-cause mortality, AVR, arrhythmia, heart failure, endocarditis, ascending aortic dissection, ascending aortic surgery and aortic valve intervention (event-free survival) are displayed in figure 2. Intervention-free survival probability at 5 and 10 years of follow-up was 81.2% (95% CI 77.4% to 85.1%) and 60.0% (95% CI 55.0% to 65.4%), respectively. Probabilities for event-free survival after 5 and 10 years of follow-up were 76.5% (95% CI 72.4% to 80.8%) and 54.4% (95% CI 49.4% to 59.9%). Intervention-free survival was significantly lower for patients with severe AS (p<0.001) and concentric LV geometry (p<0.001). In patients with a mild stenosis at baseline, intervention-free survival at 10 years was 74.2% (95% CI 66.9% to 82.4%). No significant male–female differences were observed in intervention-free survival (p=0.38) (figure 3).
Figure 2. Kaplan-Meier estimates for (A) intervention-free survival, composite endpoint of all-cause mortality and AVR and (B) event-free survival, composite endpoint of all-cause mortality, AVR, arrhythmia, heart failure, endocarditis, aortic valve intervention and ascending aortic surgery. AVR, aortic valve replacement.
Figure 3. Kaplan-Meier estimates for primary composite endpoint of aortic valve replacement and all-cause mortality stratified for (A) aortic stenosis severity group, (B) sex and (C) left ventricular concentric geometry. AS, aortic stenosis.
Indications for AVR
Indications for all patients undergoing AVR are displayed in figure 4. Median age at AVR was 42 (29–52) years. The most common indication for AVR was the development of symptoms (62.1%). 22 patients (12.4%) patients were classified as symptomatic because of a positive exercise test. Development of LV systolic dysfunction (LVEF <50%) during follow-up was the primary indication for AVR in three patients (1.7%). Thoracic aortic dilatation was the primary indication for AVR in 15 patients (8.4%).
Figure 4. Indications for aortic valve replacement. *Other indications were: active pregnancy wish (n=3), reduced left ventricular ejection fraction (n=3), indication for coronary artery bypass grafting with concomitant valve replacement (n=2), mobile structure on aortic valve (n=1).
Prognostic factors
Table 2 displays the associations between baseline characteristics and the primary endpoint of all-cause mortality and AVR. In univariable analysis, higher age, history of hypertension, higher diastolic blood pressure, New York Heart Association class ≥2 and non-sinus rhythm were significantly associated with the primary endpoint. Echocardiographic characteristics associated with the primary endpoint were higher peak velocity (HR 2.88, 95% CI 2.21 to 3.76), LV end-diastolic diameter (HR 0.96, 95% CI 0.94 to 0.99), LV end-systolic diameter (HR 0.98, 95% CI 0.96 to 1.00) and concentric LV geometry (HR 2.75, 95% CI 1.91 to 3.96). Sensitivity analysis with only AVR as primary endpoint showed no additional significant associations (online supplemental table S3). In multivariable analysis, older age, higher AV peak velocity, non-sinus rhythm and presence of LV concentric geometry remained significantly associated with the primary endpoint.
Table 2. Univariable and multivariable Cox regression analysis for the composite endpoint of all-cause mortality and aortic valve replacement.
| Univariable analysis | Multivariable analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P value | HR (95% CI) | P value |
| Age, per 5 years* | 1.22 (1.15 to 1.30) | <0.001 | 1.26 (1.18 to 1.34) | <0.001 |
| Sex, female | 1.19 (0.96 to 1.48) | 0.12 | ||
| Turner syndrome | 1.04 (0.56 to 1.95) | 0.90 | ||
| History of hypertension* | 2.01 (1.59 to 2.54) | <0.001 | ||
| History of coarctation | 1.07 (0.77 to 1.50) | 0.68 | ||
| NYHA≥2* | 2.09 (1.19 to 3.68) | 0.01 | ||
| Prior AV intervention* | 0.78 (0.68 to 0.90) | <0.001 | ||
| SBP, per 5 mm Hg | 1.02 (0.97 to 1.07) | 0.36 | ||
| DBP, per 5 mm Hg* | 1.09 (1.01 to 1.17) | 0.03 | ||
| AV peak velocity, m/s* | 2.88 (2.21 to 3.76) | <0.001 | 3.17 (2.29 to 4.39) | <0.001 |
| AR, moderate | 0.89 (0.60 to 1.33) | 0.56 | ||
| Impaired LV systolic function | 1.43 (0.84 to 2.44) | 0.19 | ||
| LVEDD, mm* | 0.96 (0.94 to 0.99) | 0.006 | ||
| LVESD, mm | 0.98 (0.96 to 1.00) | 0.047 | ||
| LV concentric geometry* | 2.75 (1.91 to 3.96) | <0.001 | 1.64 (1.04 to 2.58) | 0.03 |
| Non-sinus rhythm* | 2.15 (1.27 to 3.67) | 0.005 | 3.12 (1.62 to 6.02) | 0.002 |
| Heart rate, bpm | 1.01 (1.00 to 1.02) | 0.19 | ||
| PR-interval, ms * | 1.01 (1.00 to 1.02) | 0.01 | 1.00 (1.00 to 1.01) | 0.07 |
| QRS duration, ms | 1.00 (1.00 to 1.01) | 0.32 | ||
Included in full model for backward selection in multivariable analysis.
AV, aortic valve; AR, aortic regurgitation; DBP, diastolic blood pressure; LV, left ventricle; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; NYHA, New York Heart Association; SBP, systolic blood pressure.
Significant differences were observed between males and females in prognostic factors (online supplemental table S3). History of hypertension (HR 2.54, 95% CI 1.84 to 3.49 vs HR 1.40, 95% CI 1.00 to 1.97) and diastolic blood pressure (HR 1.15, 95% CI 1.03 to 1.27 vs HR 1.00, 95% CI 0.88 to 1.12) were stronger associated with the primary endpoint in males compared with females, while peak velocity was a stronger prognostic factor in females (HR 2.54, 95% CI 1.91 to 3.36 vs HR 3.40, 95% CI 2.70 to 4.29; Online supplemental table S4).
Discussion
This multicentre study evaluated disease course of congenital AS in a large adult population. Overall mortality in this study cohort was low. However, morbidity was high as 42% of patients required AVR at the age of 42 (29–52) years. The most common indication for AVR was presence of symptoms, while systolic dysfunction as an indication was rare. Markers associated with primary outcome were higher peak velocity, non-sinus rhythm and the presence of concentric LV geometry. No significant male–female differences were observed in outcome, but prognostic factors did significantly differ between male and female patients.
Survival
In our study population of adults with congenital AS, all-cause mortality was low. Previous studies that described mortality in patients with BAV in a similar age group reported good survival with 10-year survival rates around 95–96%.7 8 14 However, these studies included patients with BAV with and without aortic valve dysfunction and did not focus solely on congenital AS. It is therefore reassuring that our study including patients with more severe valve dysfunction also showed a good life expectancy. Although sudden cardiac death (SCD) occurred in one patient with an asymptomatic severe valve disease only, such cases remain worrisome.
Aortic valve replacement
Balancing the risks and determining the optimal timing for AVR remains challenging. AVR was often performed in our population, with a yearly risk of 5%. Even in patients with a mild stenosis at baseline, AVR was performed in 26% of patients at 10 years. The most common indication for AVR was the presence of symptoms. This indicates that regular monitoring and awareness of potential symptoms is crucial, even when the stenosis is mild. In asymptomatic patients, exercise testing is recommended to unmask symptoms and to provide valuable insights into cardiac function. Moreover, the ESC guidelines on valvular heart diseases and adult CHD recommend AVR in asymptomatic patients with LVEF <50%.4 5 Our study demonstrated, however, that LV systolic impairment is seldom the indication for AVR. It can therefore be debated whether this criterion of a decline in LVEF below 50% is suitable, even more so in young patients with congenital AS who do not often show signs of systolic dysfunction.15
In the past years, the focus has shifted from monitoring not only the valve but also the myocardium. AS causes pressure overload in the LV. As a result, LV remodelling can occur to reduce wall stress and maintain adequate cardiac output.16 Although this adaptation is a physiological response, it can become maladaptive over time. The presence of LV hypertrophy has been associated with higher morbidity and mortality in patients with AS.17,20 In our study cohort, the presence of concentric LV geometry was an important prognostic marker. Moreover, smaller LV end-diastolic dimension was significantly associated with a worse clinical outcome in univariable analysis. This may be caused by a relatively smaller LV cavity in patients with signs of concentric LV remodelling, which can negatively affect diastolic function and contribute to adverse prognosis. This is in line with prior research that also found worse intervention-free survival for concentric remodelling and hypertrophy in patients with BAV21 and patients with moderate–severe AS.22 The presence of concentric geometry might be an earlier marker for LV dysfunction and therefore a more suitable criterion for AVR. However, further research is needed to investigate the precise role of LV geometry in the decision process for AVR alongside other echocardiographic markers such as global longitudinal strain (GLS), blood biomarkers and tissue characterization with MRI.
Cardiac events
The most common cardiac events besides AVR were arrhythmias, with a burden of 6.6%. This is in accordance with previous studies that described occurrence rates of 5–10% in patients with BAV.7 8 23 The majority of arrhythmias observed in our study were supraventricular. However, two patients experienced an episode of ventricular fibrillation (VF) which resulted in an out-of-hospital cardiac arrest. In these cases, resuscitation was successful and aortic valve intervention was planned soon after the cardiac arrest. Although prevalence is low, these cases of VF and the one SCD in our study population demonstrate the risk for serious life-threatening complications in the congenital AS population.
A recent meta-analysis studied the incidence of endocarditis in patients with BAV and described a risk of 48 per 10 000 patient-years,24 which is similar to our findings in congenital AS. Endocarditis of the aortic valve occurred in 11 patients in our study cohort, corresponding with a yearly risk of 0.3%. Although this yearly risk is low, endocarditis can have significant consequences and was the indication for AVR in 10 of 11 cases. Antibiotic prophylaxis is no longer indicated for patients with BAV. However, general preventive measures such as good oral hygiene and strict cutaneous hygiene remain important and should be communicated with patients to prevent endocarditis.25
Aortic events
Although the incidence of aortic dissection is low with reported rates from 0.4 to 0.6 in patients with BAV11 26 and a rate of 0.06 per patient-year of follow-up in congenital AS,1 it is a feared complication of aortic dilatation. In our study, no aortic dissection was observed. Whether this is due to a lower risk of aortic dissection than previously described, or proves that current cut-offs for prophylactic aortic surgery adequately prevent dissection, is fuel for discussion. In our study population, aortic surgery was performed simultaneously with AVR in the majority of cases (>90%), which might suggest that the latter of the two is the case.
Male–female differences
No significant sex differences were observed in event rates and intervention-free survival. However, both previous work from our research group and Michelena et al, did describe a higher percentage of valve interventions and arrhythmias in male patients with BAV.23 27 A possible explanation for this difference is the focus of our study on AS and exclusion of patients with severe AR, as AR is more common in men and consequently more often the indication for valve intervention in male patients.6 9 28
We did find significant sex differences in prognostic factors for intervention-free survival. In male patients, hypertension and diastolic blood pressure seemed to hold more prognostic information, whereas peak velocity was a more pronounced marker in female patients. It has been stated that AS is a more common indication for AVR in female patients with BAV.29 Moreover, the response to pressure overload and hypertension in women and men may differ.30 Myocardial fibrosis in patients with AS seems to be less common in women than men.31 32 This different remodelling of the myocardium in response to pressure overload could be based on differences in mitochondrial function between males and females and might be affected by estrogen.33 However, further research is warranted to investigate these differences in prognostic factors between male and female patients.
Limitations
There are a few limitations to this report. First, the congenital AS population is a heterogeneous population with varying degrees of AS and AR, and presence of comorbidities. This makes it difficult to generalise study findings to the overall congenital AS population. To create a more homogenous population, we excluded patients with prior AVR and patients with severe AR. Second, because inclusion in the CONCOR registry started in 2001, not all echocardiographic or blood biomarkers that are of interest nowadays such as NT-proBNP, left atrial volume index and GLS were available at baseline in all our patients. Therefore, associations of these parameters with the primary endpoint could not be assessed in this study. Moreover, due to the limited mortality events, risk factor analysis for mortality alone was not possible. Lastly, all included patients in our study were treated in tertiary care centres that are specialised in CHD care, providing a possible bias in the included study population.
Conclusion
Although mortality is low, adults with congenital AS show a high intervention rate at a young age. Even in patients with mild AS at baseline, AVR is often warranted. No aortic dissections were observed in our study. Impaired LV systolic function is rarely an indication for AVR and might not be a suitable criterion in congenital AS. Monitoring LV remodelling seems to be more important, with focus on the presence of concentric geometry.
Supplementary material
Footnotes
Funding: We acknowledge the support from the Netherlands Cardiovascular Research lnitiative: an initiative with support of the Dutch Heart Foundation and Hartekind, CVON2019-002 OUTREACH.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: The study was approved by the Medical Ethical Committee and performed according to the declaration of Helsinki (MEC 2021–0169). All patients signed informed consent for inclusion in CONCOR and agreed their data could be used for research. For the current analysis, further informed consent was waived.
Data availability statement
Data are available upon reasonable request.
References
- 1.van der Linde D, Konings EEM, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58:2241–7. doi: 10.1016/j.jacc.2011.08.025. [DOI] [PubMed] [Google Scholar]
- 2.Hoffman JI, Christianson R. Congenital heart disease in a cohort of 19,502 births with long-term follow-up. Am J Cardiol. 1978;42:641–7. doi: 10.1016/0002-9149(78)90635-5. [DOI] [PubMed] [Google Scholar]
- 3.van der Linde D, Andrinopoulou E-R, Oechslin EN, et al. Congenital valvular aortic stenosis in young adults: predictors for rate of progression of stenosis and aortic dilatation. Int J Cardiol. 2013;168:863–70. doi: 10.1016/j.ijcard.2012.10.027. [DOI] [PubMed] [Google Scholar]
- 4.Vahanian A, et al. ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2021;43:561–632. doi: 10.1093/eurheartj/ehab395. [DOI] [PubMed] [Google Scholar]
- 5.Baumgartner H, De Backer J. The ESC Clinical Practice Guidelines for the Management of Adult Congenital Heart Disease 2020. Eur Heart J. 2020;41:4153–4. doi: 10.1093/eurheartj/ehaa701. [DOI] [PubMed] [Google Scholar]
- 6.Kong WKF, Bax JJ, Michelena HI, et al. Sex differences in bicuspid aortic valve disease. Prog Cardiovasc Dis. 2020;63:452–6. doi: 10.1016/j.pcad.2020.06.004. [DOI] [PubMed] [Google Scholar]
- 7.Rodrigues I, Agapito AF, de Sousa L, et al. Bicuspid aortic valve outcomes. Cardiol Young. 2017;27:518–29. doi: 10.1017/S1047951116002560. [DOI] [PubMed] [Google Scholar]
- 8.Tzemos N, Therrien J, Yip J, et al. Outcomes in adults with bicuspid aortic valves. JAMA. 2008;300:1317–25. doi: 10.1001/jama.300.11.1317. [DOI] [PubMed] [Google Scholar]
- 9.Yang L-T, Ye Z, Wajih Ullah M, et al. Bicuspid aortic valve: long-term morbidity and mortality. Eur Heart J. 2023;44:4549–62. doi: 10.1093/eurheartj/ehad477. [DOI] [PubMed] [Google Scholar]
- 10.van Melle JP, Roos-Hesselink JW, Bansal M, et al. Infective endocarditis in adult patients with congenital heart disease. Int J Cardiol. 2023;370:178–85. doi: 10.1016/j.ijcard.2022.10.136. [DOI] [PubMed] [Google Scholar]
- 11.Masri A, Svensson LG, Griffin BP, et al. Contemporary natural history of bicuspid aortic valve disease: a systematic review. Heart. 2017;103:1323–30. doi: 10.1136/heartjnl-2016-309916. [DOI] [PubMed] [Google Scholar]
- 12.Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16:233–70. doi: 10.1093/ehjci/jev014. [DOI] [PubMed] [Google Scholar]
- 13.Erbel R, et al. ESC Guidelines on the diagnosis and treatment of aortic diseases] Wytyczne ESC dotyczace rozpoznawania i leczenia chorob aorty w 2014 roku. Kardiol Pol. 2014;72:1169–252. doi: 10.5603/KP.2014.0225. [DOI] [PubMed] [Google Scholar]
- 14.Aschauer J, Zilberszac R, Gleiss A, et al. Long-term outcome of bicuspid aortic valve disease. Eur Heart J Cardiovasc Imaging. 2024;25:425–35. doi: 10.1093/ehjci/jead312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Hecht S, Butcher SC, Pio SM, et al. Impact of Left Ventricular Ejection Fraction on Clinical Outcomes in Bicuspid Aortic Valve Disease. J Am Coll Cardiol. 2022;80:1071–84. doi: 10.1016/j.jacc.2022.06.032. [DOI] [PubMed] [Google Scholar]
- 16.Rader F, Sachdev E, Arsanjani R, et al. Left ventricular hypertrophy in valvular aortic stenosis: mechanisms and clinical implications. Am J Med. 2015;128:344–52. doi: 10.1016/j.amjmed.2014.10.054. [DOI] [PubMed] [Google Scholar]
- 17.Cioffi G, Faggiano P, Vizzardi E, et al. Prognostic effect of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis. Heart. 2011;97:301–7. doi: 10.1136/hrt.2010.192997. [DOI] [PubMed] [Google Scholar]
- 18.Gerdts E, Rossebø AB, Pedersen TR, et al. Relation of Left Ventricular Mass to Prognosis in Initially Asymptomatic Mild to Moderate Aortic Valve Stenosis. Circ Cardiovasc Imaging. 2015;8:e003644. doi: 10.1161/CIRCIMAGING.115.003644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Park K, Park T-H, Jo Y-S, et al. Prognostic effect of increased left ventricular wall thickness in severe aortic stenosis. Cardiovasc Ultrasound. 2021;19:5. doi: 10.1186/s12947-020-00234-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Stassen J, Ewe SH, Hirasawa K, et al. Left ventricular remodelling patterns in patients with moderate aortic stenosis. Eur Heart J Cardiovasc Imaging. 2022;23:1326–35. doi: 10.1093/ehjci/jeac018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Butcher SC, Pio SM, Kong WKF, et al. Left ventricular remodelling in bicuspid aortic valve disease. Eur Heart J Cardiovasc Imaging. 2022;23:1669–79. doi: 10.1093/ehjci/jeab284. [DOI] [PubMed] [Google Scholar]
- 22.Debry N, Maréchaux S, Rusinaru D, et al. Prognostic significance of left ventricular concentric remodelling in patients with aortic stenosis. Arch Cardiovasc Dis. 2017;110:26–34. doi: 10.1016/j.acvd.2016.05.010. [DOI] [PubMed] [Google Scholar]
- 23.Keuning ZA, Hendriks PM, Duijnhouwer AL, et al. Blood and Imaging Biomarkers in the Long-term Follow-up of Bicuspid Aortic Valve Patients. CJC Open . 2024;6:1–10. doi: 10.1016/j.cjco.2023.09.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Pereira SC, Abrantes AL, António PS, et al. Infective endocarditis risk in patients with bicuspid aortic valve: Systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2023;47:101249. doi: 10.1016/j.ijcha.2023.101249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Habib G, et al. ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM) Eur Heart J. 2015;36:3075–128. doi: 10.1093/eurheartj/ehv319. [DOI] [PubMed] [Google Scholar]
- 26.Wilson-Smith AR, Eranki A, Muston B, et al. Incidence of bicuspid valve related aortic dissection: a systematic review and meta-analysis. Ann Cardiothorac Surg. 2022;11:363–8. doi: 10.21037/acs-2022-bav-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Michelena HI, Suri RM, Katan O, et al. Sex Differences and Survival in Adults With Bicuspid Aortic Valves: Verification in 3 Contemporary Echocardiographic Cohorts. J Am Heart Assoc. 2016;5:10.:e004211. doi: 10.1161/JAHA.116.004211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Li Y, Chen X, Qi Y, et al. Gender differences in bicuspid aortic valve Sievers types, valvulopathy, aortopathy, and outcome of aortic valve replacement. Echocardiography. 2022;39:1064–73. doi: 10.1111/echo.15405. [DOI] [PubMed] [Google Scholar]
- 29.Andrei A-C, Yadlapati A, Malaisrie SC, et al. Comparison of outcomes and presentation in men-versus-women with bicuspid aortic valves undergoing aortic valve replacement. Am J Cardiol. 2015;116:250–5. doi: 10.1016/j.amjcard.2015.04.017. [DOI] [PubMed] [Google Scholar]
- 30.Regitz-Zagrosek V, Kararigas G. Mechanistic Pathways of Sex Differences in Cardiovascular Disease. Physiol Rev. 2017;97:1–37. doi: 10.1152/physrev.00021.2015. [DOI] [PubMed] [Google Scholar]
- 31.Petrov G, Dworatzek E, Schulze TM, et al. Maladaptive remodeling is associated with impaired survival in women but not in men after aortic valve replacement. JACC Cardiovasc Imaging. 2014;7:1073–80. doi: 10.1016/j.jcmg.2014.06.017. [DOI] [PubMed] [Google Scholar]
- 32.Treibel TA, Kozor R, Fontana M, et al. Sex Dimorphism in the Myocardial Response to Aortic Stenosis. JACC Cardiovasc Imaging. 2018;11:962–73. doi: 10.1016/j.jcmg.2017.08.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Fliegner D, Ellieva A, Angelov A, et al. Sex differences and estrogen effects in cardiac mitochondria in human aortic stenosis and in the mouse heart. Front Endocrinol (Lausanne) 2023;14:1181044. doi: 10.3389/fendo.2023.1181044. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available upon reasonable request.