Bicuspid Aortic Valve Disease with Early-Onset Complications: Characteristics and Aortic Outcomes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Bicuspid aortic valve is the most prevalent congenital cardiac disease in the general population. The present study aims to emphasize the importance of characterizing a specific cohort of affected patients who present complications at an earlier age (early onset BAV, EBAV) in contrast to most BAV-affected population from selected published articles. The authors propose that the EBAV cohort may exhibit distinct anatomic and clinical characteristics that differentiate them from late onset patients due to an enrichment of highly penetrant genetic triggers. Finally, the authors emphasize the necessity of improving diagnosis and follow-up of EBAV patients in order to reduce the associated health burdens.

General comments

This reviewer finds the conclusions of this study to be of interest. The authors have compared own valuable previous data from EBAV patients with data from other BAV patient populations provided by already published articles to characterize the EBAV cohort. This reviewer suggests that the manuscript would be improved if the authors select one of the following strategies: to make the comparison between EBAV and published studies the objective of the manuscript, showing it in the results section (strategy 1); or to limit the results to EBAV characterization and compare them with other BAV patient populations from literature in the discussion section (strategy 2). The manuscript is currently a combination of both. Since now there is comparative purpose, the strategy followed to select papers from literature and patient cohorts should be explained in the Methods section (only inclusion criteria for EBAV patients are indicated). Table 1 in the Results section shows the demographic data comparison between EBAV cohort and patients from two published studies (Refs 3 and 4). However, the comparative strategy does not include the analysis of clinical interventions which is key to the article’s conclusions (specific genetic characteristics in the EBAV cohort entail higher health burdens than other BAV patients). Regarding the Discussion section, some results discussed are not included in the Results section.

Specific comments

Introduction

- References are missing in the whole section.

Materials and Methods

- The strategy to select previous studies is missing.

- A comparison analysis strategy among EBAV cohort and patients from the literature is missing.

- L69. The study protocol was previously published [1].

The aim of the referenced paper was different. This reviewer assume that authors used the same EBAV patient cohort. If that is the case, it should be indicated in this sentence.

- L73-74. Unpaired t-test and chi-squared tests were used to compare subgroups.

It is unclear whether the statistical method employed in this study was applied for comparison with patients from the literature. P-values are missing.

Results

- L76-89. The mean age at diagnosis was 18 years. Two-thirds were male and almost 30% had other congenital heart malformations, most frequently aortic coarctation, ventricular septal defects, atrial septal defects, patent ductus arteriosus, or mitral valve abnormalities. Half of participants had their first surgery in childhood (mean age 7), and 25% had their first surgery as adults (mean age 33). One-third of adult surgeries were second operations after a childhood surgery. Aortic valve repair or replacement (44%) was the single most common indication for intervention. One-quarter underwent isolated repair of the ascending aorta and 21% had combined valve and aortic operations (Bentall or David). Fifteen probands (22%) required at least one additional intervention after their index operation. Eight of the initial interventions occurred in childhood and required reinterventions before age 25. The most frequent indications for reintervention were aortic aneurysm repair and aortic valve replacement. The median time between the first and second interventions was 14 years. Half of those who underwent aortic surgery required intervention within 30 months of diagnosis.

If the authors choose strategy 1 (comparative study as main objective), this data should be compared here with other BAV patient populations from literature. In contrast, if the authors decide to implement strategy 2 (characterization of EBAV cohort only), the aforementioned paragraph is accurate including demographic data description.

These results could be better shown in a table or graph.

- L90-95. We compared the demographics of the EBAV cohort to a previously published meta-analysis of 4379 adult cases and a retrospective cohort study of Olmsted County residents with BAV[2,3,4]. The authors of the Olmstead County study defined a complex valvulo-aortopathy phenotype that is similar to the EBAV phenotype, except for the inclusion of syndromic and complex congenital cases that were excluded from the EBAV cohort (18% of complex cases).

In this case, this paragraph is in accordance with strategy 1 and the selection strategy of these published studies should be specified in the Methods section. If the authors choose strategy 2, the comparison should be done in the discussion section.

- L107-108. Right-non-coronary cusp fusion was more prevalent in EBAV probands (32%) than in community-living adults with BAV (14%)[5].

The authors do not specify how many BAV types exist in the EBAV cohort and their proportions. This information should be included in paragraph L76-89, where the EBAV cohort is described.

- L108-110. In individuals with TAAs, the location of the maximum aortic diameter was evenly divided between the root (16) and the proximal ascending aorta (18).

The authors do not describe the proportion of EBAV patients with TAA. This information should be included in paragraph L76-89, where the EBAV cohort is described. It seems that (16) and (18) are references missing in the reference list. This reviewer does not understand why they are necessary.

-L110-112. The proportion of EBAV probands who had at least one relative with BAV (32%) was significantly higher than previous estimates for community-living adults with BAV (5-10%)[7,8].

The percentage of relatives with BAV from the EBAV cohort (32%%) is not compared with the meta-analysis study (6.4%) shown in Table 1. It is compared with data from two additional studies with vaguely described patient populations (community-living adults with BAV). A better explanation of these studies is recommended.

- Table 1. Categorical variables are described by number and percentage (%). Continuous variables are described by mean and standard deviation. n: number of EBAV participants with available data; Meta: meta-analysis of 4379 adult BAV cases[3]; EBAV: bicuspid aortic valve with early onset complications requiring intervention prior to age 30; Complex: bicuspid aortic valve with complex valvulo-aortopathy phenotype, as defined by Yang et al.[4].

Not all the results shown in Table 1 are exposed in the body text (i.e., LV ejection fraction, maximum aortic Z-score). Ref. 3 included around 9,500 BAV patients. How did the authors select the 4,379 used in this study? The number of patients provided by Ref. 4 is missing.

Discussion

-L116-117. In contrast, the mean age at presentation of adult BAV patients from 15 prospective studies was 52 years[3].

This result is not described in the Results section.

- L125-127. The proportions of females (33%) and family members with a BAV (32%) were substantially higher than previously reported estimates.

Which are the previously reported estimates?

- L127-130. We also observed that the ‘root phenotype’ of BAV aortopathy, which predisposes to aortic regurgitation and was identified as a potential biomarker of genetically triggered or early onset disease, appears to be enriched in EBAV cases.

The root phenotype of BAV aortopathy should be defined. A reference for this sentence is missing.

- L130-131. Aortic regurgitation tends to be more pronounced in individuals with unusual BAV morphologies, who were also overrepresented in the EBAV cohort[6].

These results are not described in the Results section. What are the unusual BAV morphologies identified in the EBAV cohort?

- L133-136. Even with these potentially aggravating factors, we only observed one aortic dissection (Type 134 A) in the EBAV cohort in a 36 year old man without syndromic features or a family history or aortic dissection.

These results are not described in the Results section.

- L145-149. Our observations highlight stark contrasts between the prognosis of the EBAV cohort and typical later-onset BAV disease that becomes clinically apparent after age 50, highlighting the need for prompt recognition, regular surveillance, and targeted interventions to address the significant health burdens related to the EBAV phenotype.

The conclusion reached would be more meaningful if a comparison were made between surgical interventions for EBAV and late-onset BAV patients.

-L149-150. This study also demonstrates the potential value of familial screening or genetic testing to identify relatives who may be at risk for BAV-related complications.

This conclusion makes more sense if it is discussed together with the result of higher incidence of family members with BAV (L125-127).

Author Response

Response to Reviewer 1

1. Introduction: References are missing in the whole section.

Response: We added references to the Introduction as requested.

2. Materials and Methods: the strategy to select previous studies is missing.

Response: In lines 85-88, we added: “For comparisons with study-level data from the BAV meta-analysis, we removed 17 of 32 studies (5062 of 9441 patients) that excluded subgroups systematically or had incomplete data (Supplemental Data).” The supplemental data file shows the studies from the meta-analysis that we included for comparison with the EBAV cohort.

3. Materials and Methods: a comparison analysis strategy among EBAV cohort and patients from the literature is missing.

Response: In lines 83-85, we added: “T-tests or chi-squared tests were used for comparisons between EBAV subgroups or between the EBAV cohort and published cohorts as appropriate.”

4. ‘The study protocol was previously published.’ The aim of the referenced paper was different. This reviewer assume that authors used the same EBAV patient cohort. If that is the case, it should be indicated in this sentence.
   

Response: We changed this sentence to read: “Details of the study protocol were previously published for a different analysis of the same EBAV cohort.”

5. ‘Unpaired t-test and chi-squared tests were used to compare subgroups.’ It is unclear whether the statistical method employed in this study was applied for comparison with patients from the literature. P-values are missing.

Response: In lines 83-85, we added: “T-tests or chi-squared tests were used for comparisons between EBAV subgroups or between the EBAV cohort and published cohorts as appropriate.” We added P-values to Table 1 as requested.

6. If the authors choose strategy 1 (comparative study as main objective), this data should be compared here with other BAV patient populations from literature. In contrast, if the authors decide to implement strategy 2 (characterization of EBAV cohort only), the aforementioned paragraph is accurate including demographic data description.

Response: We selected a hybrid strategy (1 and 2) because demographics were available from the comparison cohorts but comparable interventional and outcomes data were not available from the comparison cohorts. We rearranged the order of the Results section to reflect this approach. The first two paragraphs detail demographic characteristics and comparisons with the published cohorts. The last paragraph includes intervention and outcomes data for the EBAV cohort. In lines 137-138, we added: “Comparable data on reintervention rates were not available for the meta-analysis or complex valvulo-aortopathy cohorts.” We added a comparison of reintervention rates after valve operations in separate BAV surgical cohorts to the Discussion.

7. In this case, this paragraph (on demographics) is in accordance with strategy 1 and the selection strategy of these published studies should be specified in the Methods section.

Response: We included a description of the selection strategy for meta-analysis studies in the Methods section as requested in lines 85-88: “For comparisons with study-level data from the BAV meta-analysis, we removed 17 of 32 studies (5062 of 9441 patients) that excluded subgroups systematically or had incomplete data (Supplemental Data).”

8. The authors do not specify how many BAV types exist in the EBAV cohort and their proportions. This information should be included in paragraph L76-89, where the EBAV cohort is described.

Response: We added this information to lines 146-150 as requested. There were no BAV types other than R-L and R-N in the study cohort: “While most EBAV probands had left-right cusp fusion (68%), right-non-coronary cusp fusion was more prevalent in the EBAV cohort (32%) than in an outpatient cohort of adults with BAV who were followed for more than twenty years in community settings (14%).”

9. The authors do not describe the proportion of EBAV patients with TAA. This information should be included in paragraph L76-89, where the EBAV cohort is described. It seems that (16) and (18) are references missing in the reference list. This reviewer does not understand why they are necessary.

Response: We added this information to lines 152-153: “More than one-third of EBAV probands (35%) were diagnosed with TAAs.” The (16) and (18) are not references but refer to the number of EBAV probands. We edited the sentence in lines 152-155 to make this clearer: “In the subgroup of these individuals who had available images, the location of the maximum aortic diameter was evenly divided between the root (16 cases) and the proximal ascending aorta (18 cases).”

10. The percentage of relatives with BAV from the EBAV cohort (32%) is not compared with the meta-analysis study (6.4%) shown in Table 1. It is compared with data from two additional studies with vaguely described patient populations (community-living adults with BAV). A better explanation of these studies is recommended. 

Response: In lines 148-149, we expanded the description of this cohort from ‘community-living adults’ to “an outpatient cohort of adults with BAV who were followed for more than twenty years in community settings.” We removed the comparison with the two other studies and now only compare the prevalence of familial BAV to the meta-analysis study.

11. Not all the results shown in Table 1 are exposed in the body text (i.e., LV ejection fraction, maximum aortic Z-score). Ref. 3 included around 9,500 BAV patients. How did the authors select the 4,379 used in this study?

Response: We added this information to lines 85-88: “For comparisons with study-level data from the BAV meta-analysis, we removed 17 of 32 studies (5062 of 9441 patients) that excluded subgroups systematically or had incomplete data (Supplemental Data).” The list of patients and studies that were included in comparisons is in the Supplemental Data.

12. ‘In contrast, the mean age at presentation of adult BAV patients from 15 prospective studies was 52 years[3].’ This result is not described in the Results section. 

Response: We added this information to the Results section in lines 112-114: “The results highlight the relative youth of the EBAV and complex cohorts with a mean age of 14-18 years at diagnosis compared to the meta-analysis of adult BAV cohorts with a mean age of 52 years at diagnosis (Table 1).”

13. The number of patients [for the complex valvulo-aortopathy phenotype] is missing.

Response: We added the number of patients with the complex valvulo-aortopathy phenotype to the legend to Table 1 and also added the total number of patients in the community BAV study (652) to line 208.

14. ‘The proportions of females (33%) and family members with a BAV (32%) were substantially higher than previously reported estimates.’ Which are the previously reported estimates?

Response: We revised this sentence in lines 171-173 to read: “The proportions of women (33% vs. 28%) and family members with a BAV (32% vs. 6.5%) were both substantially higher than estimates for adults with typical BAV disease[9,10,11].”

15. ‘We also observed that the ‘root phenotype’ of BAV aortopathy, which predisposes to aortic regurgitation and was identified as a potential biomarker of genetically triggered or early onset disease, appears to be enriched in EBAV cases.’ The root phenotype of BAV aortopathy should be defined. A reference for this sentence is missing.

Response: We changed this sentence in lines 175-178 to define the root phenotype and included a reference: “We also observed that the ‘root phenotype’ of BAV aortopathy (root > ascending aortic diameter), which predisposes to aortic regurgitation and was identified as a potential biomarker of genetically triggered or early onset disease, appears to be enriched in EBAV probands[1].”

16. ‘Aortic regurgitation tends to be more pronounced in individuals with unusual BAV morphologies, who were also overrepresented in the EBAV cohort.’ These results are not described in the Results section. What are the unusual BAV morphologies identified in the EBAV cohort? 

Response: We changed this sentence in lines 178-180 to clarify: “Aortic regurgitation tends to be more pronounced in individuals with less common BAV morphologies such as R-N cusp fusion, who were also overrepresented in the EBAV cohort.” We added a description of this data to the Results section in lines 146-148.

17. ‘Even with these potentially aggravating factors, we only observed one aortic dissection (Type A) in the EBAV cohort in a 36 year old man without syndromic features or a family history or aortic dissection.’ These results are not described in the Results section. 

Response: We added this description to the Results section in lines 135-137: “There was only one reported aortic dissection (Type A) in a 36-year-old EBAV proband without syndromic features or a family history of aortic dissection.”

18. ‘Our observations highlight stark contrasts between the prognosis of the EBAV cohort and typical later-onset BAV disease that becomes clinically apparent after age 50, highlighting the need for prompt recognition, regular surveillance, and targeted interventions to address the significant health burdens related to the EBAV phenotype.’ The conclusion reached would be more meaningful if a comparison were made between surgical interventions for EBAV and late-onset BAV patients.

Response: We amended one sentence in the Discussion at line 193 to include two comparisons between surgical interventions and reinterventions in EBAV and late-onset BAV patients: “We confirmed that EBAV participants required surgical interventions at a higher rate (50% vs. 27% over 20 years), underwent second interventions more frequently within 15 years of their index procedures (22% vs 4-10% in a recent meta-analysis of surgical outcomes), and had twice as many concomitant congenital heart malformations than older BAV patients that comprise the majority of longitudinal BAV study cohorts.”

19. ‘This study also demonstrates the potential value of familial screening or genetic testing to identify relatives who may be at risk for BAV-related complications.’ This conclusion makes more sense if it is discussed together with the result of higher incidence of family members with BAV.

Response: We moved this sentence to the end of the paragraph where we discuss the higher rates of BAV in family members of EBAV probands (lines 225-227).

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very interesting study on bicuspid aortopathy in which the authors hypothesize that people with early onset complications of BAV may have anatomic, clinical, or genetic predictors that distinguish them from the majority of individuals with BAV who progresses along a more benign clinical course. The necessity of repeated surgical interventions in such a young population has significant implications for life expectancy and quality of life. Therefore, closer follow-up is necessary in these patients.  

A genetic study would have been of interest in these patients, in whom there is also a higher familial incidence than in other series. 

In any case, it is a relevant study that reveals another aspect of bicuspid valve disease, the most common congenital heart disease in our environment and of great relevance.

It would be of interest to suggest the creation of international registries in this specific subgroup and genetic studies of candidate variants that could help with earlier diagnosis .

Author Response

Reviewer 2

A genetic study would have been of interest in these patients, in whom there is also a higher familial incidence than in other series.

It would be of interest to suggest the creation of international registries in this specific subgroup and genetic studies of candidate variants that could help with earlier diagnosis .

Response: We added this sentence to the Conclusion in lines 227-229: “Genetic biomarkers derived from larger cohort studies may eventually prove useful to predict complications and promote personalized treatment algorithms for BAV disease.”

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Congratulation for this paper. The subject is interesting and highlights the few cases of bicuspid aortic valve (BAV) detected at a young age. It is a well described cohort of patients from multiple center. You demonstrate that those patients are not the same patient diagnosed with BAV at an older age. 

The strength of the paper may be reinforced with a better description of the different surgical technique offered to the patients. For exemple the rate of valve repair at the time of valve surgery as well as the replacement rate and the type of substitute used (mechanical and biological prosthesis, Ross procedure, Ozaki...). Only a brief description with a flow chart as an example would be a valuable add. 

Another point is about genetics. Rate of genetics marker detection and eventual results would be other informations interesting in the fiel of BAV research. 

Author Response

Reviewer 3

Congratulation for this paper. The subject is interesting and highlights the few cases of bicuspid aortic valve (BAV) detected at a young age. It is a well described cohort of patients from multiple center. You demonstrate that those patients are not the same patient diagnosed with BAV at an older age. 

1. The strength of the paper may be reinforced with a better description of the different surgical technique offered to the patients. For example, the rate of valve repair at the time of valve surgery as well as the replacement rate and the type of substitute used (mechanical and biological prosthesis, Ross procedure, Ozaki...). Only a brief description with a flow chart as an example would be a valuable add.

Response: We amended the sentence in lines 126-128 with the replacement rate and type of substitute used: “Aortic valve repair or replacement with mechanical prostheses (17), bioprostheses (8), or homografts (2) was the single most common indication for intervention (44%).” Unfortunately, we do not have specific data on the valve repair rate.

2. Another point is about genetics. Rate of genetics marker detection and eventual results would be other informations interesting in the field of BAV research. 

Response: We added this sentence to the Conclusion in lines 227-229: “Genetic biomarkers derived from larger cohort studies may eventually prove useful to predict complications and promote personalized treatment algorithms for BAV disease.”

Author Response File: Author Response.docx