Sofya Latrache

Chloe Melchior

Charlotte Desprez

Sabrina Sidali

Julien Recton

Olivier Touchais

Elise Van Der Eecken

Fabien Wuestenberghs

Cloe Charpentier

Anne Marie Leroi

Pr Guillaume Gourcerol

Is it necessary to perform a morphological assessment for an esophageal motility disorder? A retrospective descriptive study

Keywords: Esophageal motility disorders, Achalasia, Tomography, Endosonography, Manometry, Etiology

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Is it necessary to perform a morphological assessment for an esophageal motility disorder? A retrospective descriptive study

Sofya LATRACHE 1 , Chloe MELCHIOR 1 , Charlotte DESPREZ 1 ,Sabrina SIDALI 1 , Julien RECTON 1 , Olivier TOUCHAIS 1 , Elise VAN DER EECKEN 1 ,Fabien WUESTENBERGHS 1 , Cloe CHARPENTIER 1 , Anne Marie LEROI 1 , Guillaume GOURCEROL 1

Introduction

Esophageal motility disorders (EMD) are a rare pathology resulting from complex mechanisms, involving motor or sensory abnormalities of peripheral or central origin [START_REF] Galmiche | Functional Esophageal Disorders[END_REF].

EMD are classified as primary (e.g., achalasia) or secondary (e.g., pseudoachalasia).. Achalasia is the most prominent entity, with an overall incidence of 0.18 to 8.7 per 100.000 person-years [START_REF] Marlais | Rawat DJ UK incidence of achalasia: an 11-year national epidemiological study[END_REF]. It is typically revealed by dysphagia and/or symptoms of reflux, or retrosternal pain that may eventually lead to a deterioration of nutritional status [START_REF] Vakil | Dysphagia in patients with erosive esophagitis: Prevalence, severity, and response to proton pump inhibitor treatment[END_REF].

High-resolution manometry (HRM) is considered the gold standard for diagnosing EMD [START_REF] Rohof | Chicago Classification of Esophageal Motility Disorders: Lessons Learned[END_REF].

Based on this method, the Chicago classification v3.0 of 2015 developed an updated analysis scheme for clinical esophageal HRM recordings [START_REF] Kahrilas | The Chicago Classification of esophageal motility disorders, v3.0[END_REF]. The particularity of this method consists in its capacity to distinguish non-specific from specific EMD, i.e. achalasia, esophagogastric junction (EGJ) outflow obstruction, distal esophageal spasm, jackhammer esophagus and absent contractility [START_REF] Rohof | Chicago Classification of Esophageal Motility Disorders: Lessons Learned[END_REF][START_REF] Ivashkin | High resolution manometry and new classification of esophageal motility disorders[END_REF].

The common form is primary EMD. Secondary forms are less common and have been little studied [START_REF] Park | An Unusual Case of Submucosal Invasion of Esophageal Squamous Cell Carcinoma Mistaken as Primary Achalasia[END_REF][START_REF] Segal | Achalasia leading to diagnosis of adenocarcinoma of the oesophagus[END_REF]. At yet, pseudoachalasia or "secondary achalasia" is the most studied secondary EMD. It is characterized by achalasia-like symptoms caused by secondary etiologies, malignancy in 70% cases. [START_REF] Abubakar | Pseudoachalasia: A review[END_REF] Conventional diagnoses using manometry and barium esophagogram cannot distinguish between primary and secondary achalasia [START_REF] Abubakar | Pseudoachalasia: A review[END_REF][START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF].

Endoscopic ultrasound (EUS) and computed tomography are relevant imaging investigations that proved their usefulness in differentiating primary and secondary achalasia [START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF][START_REF] Dancygier | Endoscopic ultrasonography in esophageal diseases[END_REF][START_REF] Ziegler | Endosonographic appearance of the esophagus in achalasia[END_REF][START_REF] Licurse | Utility of chest CT for differentiating primary and secondary achalasia[END_REF].

Dancygier et al. [START_REF] Dancygier | Endoscopic ultrasonography in esophageal diseases[END_REF]were the first to conclude that EUS should be applied early in the work-up of patients with dysphagia to identify small intra-and extramural esophageal lesions and carcinoma. Krishnan et al. [START_REF] Krishnan | Endoscopic ultrasound as an adjunctive evaluation in patients with esophageal motor disorders subtyped by high-resolution manometry[END_REF] identified clinically significant lesions using EUS in 9/62 patients (15%) with dysphagia and altered the management of their disease. In two of these patients, submucosal carcinoma was identified as a cause of pseudoachalasia. In complicated cases with achalasia, computed tomography(CT-scan) may be invaluable in confirming the diagnosis or in detecting atypical features such as benign or malignant processes [START_REF] Licurse | Utility of chest CT for differentiating primary and secondary achalasia[END_REF][START_REF] Rabushka | CT Evaluation of Achalasia[END_REF]. In their retrospective series of 333 patients with achalasia, Ponds et al. diagnosed 18 patients (5.4%) with malignant pseudoachalasia, and identified a certain number of risk factors [START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF].To date, studies are limited only in patients with confirmed achalasia, but no study adressed the frequency of secondary EMD in a cohort of patients with HRM-confirmed EMD.

The purpose of this study was therefore to investigate the usefulness of morphological assessments, computed tomography (CT-scan) and EUS, in all patients suffering from EMD, and to identify demographic, clinical or manometric risk factors of secondary EMD.

Patients and Methods

Patients

In French hospital settings, patients are informed that their data can be used for research purposes if they have no objection. The data used in this study are derived from de-identified files, and thus, this study was exempt from Ethics Committee approval. This retrospective study was conducted in the Physiology department of Rouen University Hospital. All adult patients (≥18-year-old) (including esophageal biopsies), who underwent an esophageal HRM between the first January2011 and the 20 th September 2016 for suspected EMD, were eligible. All patients underwent an upper gastro-intestinal endoscopy before HRM that showed no structural explanation for symptoms. Patients with diagnosis of EMD suspected to originate from a secondary cause, i.e. achalasia, esophagogastric junction (EGJ) outflow obstruction, distal esophageal spasm, and Jackhammer esophagus made by HRM were considered for final analysis. Patients with absent contractility, rolling hiatus hernia that may simulate extrinsic compression on HRM, history of esophageal surgery, history of esophageal dilation, eosinophilic esophagitis, incomplete manometric exploration not allowing to use the Chicago classification, and aged< 18 years were not analyzed.

Data collection

Medical records of eligible patients were reviewed. The following data were collected retrospectively: HRM indication, i.e. dysphagia, regurgitation, gastroesophageal reflux, retrosternal pain, deterioration of the health status, preoperative check-up; patient history, specifically smoking, chronic alcoholism, diabetes, cervicothoracic radiotherapy and cancer; findings of EUS and CT-scan carried out in the 3 months preceding or the year following the esophageal HRM.

As there no standard criteria, including timing, nature of the lesion or HRM pattern, to specifically address the imputability of structural lesion to HRM findings, a panel of 5 gastroenterology experts, being expert either in EMD and/or in EUS, assessed whether the manometric anomaly could be due to scan or EUS abnormalities. This assessment was carried out independently and blindly by each expert and an agreement by at least 3 experts was necessary to take a result into account.

Patients were then classified into three groups: those with morphological abnormalities on EUS and/or CT-scan probably causing the manometric anomaly were classified "Positive";patients without morphological abnormalities on EUS and/or CT-scan, or whose detected abnormality was assessed independent of the EMD were classified "Negative";patients without CT-scan and/or EUS were classified "Unexplored". Only "Positive" and "Negative" groups were compared to identify predictive factors of secondary EMD.

High-resolution manometry (HRM) system

HRM (Medical Measurement System, Enschede, The Netherlands) was performed in patients after 6 fasting hours. An electronic catheter probe (Unisensor, Attinkon, Switzerland) was placed transnasally to record pressures from the hypopharynx to the stomach with 1 cm intervals over 36 cm. For patients with a history of esophageal diverticulum, the probe was placed under videoscopic control.

Data collection was carried out over approximately 20 min. Patients were in supine position and swallowed 10 water boluses of 5 ml with an interval of 30 s (water manometry). This was followed by 10 chicken solid swallows:

Basal lower esophageal sphincter (LES) pressure, LES relaxation pressure, the mean integrated relaxation pressure (IRP) over 4 seconds, the mean distal contraction integral (DCI) and the mean distal latency (LD) were collected for water and perprandial manometries.

Standard analysis of the motor pattern was performed for liquid and solid swallows using the of Chicago classification version 3.0 (CC v3.0) [START_REF] Kahrilas | The Chicago Classification of esophageal motility disorders, v3.0[END_REF].Distal, as well as compartmentalized pressurizations revealed by the manometric plot were also analyzed [START_REF] Kahrilas | The Chicago Classification of esophageal motility disorders, v3.0[END_REF]. Because of the lack of validated international standards for solid swallows, we performed a separated analysis for liquid et solid swallows using Chicago classification version 3.0 metrics.

Statistical analysis

Quantitative data were described by mean and standard error of the mean (SEM) and compared between groups by a Student t-test. Qualitative variables were described as absolute numbers and percentage and compared between groups usingChi² tests. A P value <0.05 was considered statistically significant.

Results

Study population

From January 2011 to September 2016, 2138 patients underwent an HRM. From this cohort, 1636 patients (76.5%) were excluded mainly for having normal HRM (993 patients) or nonspecific EMD/absent contractility (288 patients) (Figure 1). The remaining 502 patients (23.5%) were diagnosed with specific EMD and considered as being potentially secondary to structural disease; from them, 182 patients (36.2%) had a morphological assessment by CTscan and/or EUS. The 320 patients without morphological assessment were included in the "Unexplored" group.

According to the expert panel, in 16 of the 182 explored patients (8.8%) there was a correlation between the manometric diagnosis, and the morphological abnormality revealed by the CT-scan and/or the EUS. They were considered to have secondary EMD and were included in the "Positive" group. The remaining 166 patients (normal CT-scan and/or EUS for 132 patients and lack of correlation between morphological abnormalities and manometric diagnosis for 34 patients) were considered to have primary EMD and were included in the "Negative" group (Figure 1).

Characteristics of population with suspected secondary EMD

Suspected secondary EMD population included 502 patients with a mean age of 61.2 ± 0.7 years and 61.2% were women. HRM was indicated for dysphagia, gastroesophageal reflux, retrosternal pain, regurgitation, deterioration of the health status and preoperative check-up (Table 1).

Secondary origins of the EMD

According to the expert panel, CT-scan and EUS allowed to identify 16 patients (8.8% of the explored patients) with secondary EMD ("Positive" group). Eight patients (50%) were diagnosed with a malignant secondary origin proven histologically, five (31.2%) were diagnosed with benign secondary origin and three (18.7%) with doubtful secondary origin(no histological proof of malignancy) (Table 2).

Malignant origins were adenocarcinoma of the cardia (n=3), esophageal squamous-cell carcinoma (n=2), gastric signet ring cell carcinoma (n=1), gastric adenocarcinoma (n = 1) and pancreatic adenocarcinoma with metastatic cardial lymphnodes (n=1). Leiomyoma (n=3) and lymphadenopathy (n=2) were the most benign and doubtful causes of secondary EMD, respectively.

Most of the patients with a secondary origin were diagnosed with EGJ outflow obstruction (n=7), followed by jackhammer disorder (n=4), achalasia (n=3) and localized pressurization (n=2).

Seven abnormalities with a malignant or doubtful origin were discarded by the experts: 1 pancreas head cancer, 4 mediastinal lymphadenopathies including one melanoma metastasis, and 2 pleural mesotheliomas.

Water and solid swallows efficiently in diagnosis of malignancy associated EMD

Among the 8 patients with malignant secondary origin, 5 (62.5%) were successfully diagnosed using HMR with water swallows: one patient (with gastric signet ring cell carcinoma) diagnosed with achalasia type II and 4 patients (2 with adenocarcinoma of the cardia, 2 with esophageal squamous-cell carcinoma) were diagnosed with EGJ outflow obstruction confirmed by HRM with solid swallows. The remaining 3 patients (37.5%), had a normal exam using HRM with water swallows. The disorder was successfully diagnosed only when they underwent HRM with solid swallows: 2 patients with jackhammer disorder (gastric adenocarcinoma, pancreatic adenocarcinoma) and 1 patient with EGJ outflow obstruction in (adenocarcinoma of the cardia). Noteworthy, all patients had a normal endoscopy at the time of the HRM, the diagnosis of malignancy being confirmed on CT and/or EUS or even on subsequent endoscopies.

Risk factors associated with secondary EMD: Comparison of the "Positive" and "Negative" groups

As shown in Table 3, there was no significant difference in gender, mean age, alcohol history, diabetes, radiotherapy, or a history of other cancers between the "Positive" and "Negative" groups. The two factors that appeared significantly different between "Positive" and "Negative" groups were the rate of smokers (P = 0.03) and the rate of patients at least 58year-old (93.8% vs 65.7%, P = 0.02). There was no significant difference in the symptoms leading to a manometric indication between the two groups.

Of note, characteristics of explored patients were not different from unexplored patients, except for dysphagia that was more prevalent in the explored group.

As shown in Table 4, there was no significant difference between the two groups for the LES relaxation pressure, the IRP or the DCI recorded by HRM either with water or solid swallows. However, 100% of patients in the "Positive" group had an IRP greater than 10 mmHg for water swallows, whereas they were only 58.4% in the "Negative" group (P = 0.0006). This last criteria remains significant once achalasia patients have been excluded (P = 0.0002).There was no significant difference in HRM diagnosis between the two groups.

Discussion

The present study highlighted the advantages of carrying out a morphological assessment during the diagnosis of suspected secondary EMD with esophageal HRM. In our series, a conventional diagnosis with HRM was not enough to detect an organic origin of the motility disorder, hence the interest of additional imaging investigations such as EUS or CT-scan. We also found that smoking, an age ≥ 58-years and IRP for water swallows higher than 10mmHg are risk factors for a potential suspected secondary EMD.

After an EMD diagnosis using HRM, 182 out of 502 patients with suspected secondary EMD underwent EUS and/or CT-scan to identify a possible secondary origin of their EMD.

Characteristics of patients were not different between the explored and non explored groups, except for dysphagia that was more prevalent in the explored group. This is however unlikely to explain by itself why patients where explored or not as the difference, although significant, is only 10% between the two groups.

According to the analysis performed by the panel expert, 16 patients (8.8%) were considered to have specific motility disorders with secondary origin. These findings are in contrast with recent findings suggesting that EUS have limited contribution in achalasia or other EMD diagnosis [START_REF] Oumrani | Do we need endoscopic ultrasonography for the workup of patients with esophageal motility disorder?[END_REF]. However, our findings are consistent with the majority of imaging investigations used to identify a secondary origin of achalasia [START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF][START_REF] Dancygier | Endoscopic ultrasonography in esophageal diseases[END_REF][START_REF] Ziegler | Endosonographic appearance of the esophagus in achalasia[END_REF][START_REF] Licurse | Utility of chest CT for differentiating primary and secondary achalasia[END_REF][START_REF] Krishnan | Endoscopic ultrasound as an adjunctive evaluation in patients with esophageal motor disorders subtyped by high-resolution manometry[END_REF][START_REF] Vaezi | ACG Clinical Guideline: Diagnosis and Management of Achalasia[END_REF].EUS was useful to rule out a pseudoachalasia in doubtful cases; when a thickened circular muscle layer is observed, infiltrating tumor is rejected , therefore providing supportive evidence of achalasia [START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF][START_REF] Ziegler | Endosonographic appearance of the esophagus in achalasia[END_REF]. For these reason, the American College of Gastroenterology advises an endoscopic assessment of the EGJ and gastric cardia if pseudoachalasia is suspected [START_REF] Vaezi | ACG Clinical Guideline: Diagnosis and Management of Achalasia[END_REF].However in patients with negative EUS but suspected pseudoachalasia, CT or other cross-sectional imaging is necessary. CT-scan is useful in differentiating primary and secondary achalasia [START_REF] Licurse | Utility of chest CT for differentiating primary and secondary achalasia[END_REF].

Among the 16/182 (8.8%) patients with secondary motility disorders, eight patients (4.4%)

were diagnosed with secondary malignant origin. These proportion are comparable with previous studies reported rates of pseudoachalasia between 4% and 12.5% [START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF][START_REF] Ziegler | Endosonographic appearance of the esophagus in achalasia[END_REF][START_REF] Campo | Pseudoachalasia: A peculiar case report and review of the literature[END_REF][START_REF] Barthet | Relationships between endosonographic appearance and clinical or manometric features in patients with achalasia[END_REF].

However, these studies were performed only with patients with secondary achalasia and did not include other motility disorders. In our study, we identified only 3 cases with secondary achalasia; among them only one case had malignant secondary origin (gastric signet ring cell carcinoma) and the two other patients had benign secondary origin (lipoma and leiomyoma).

Most of motility disorders in patients with secondary EMD were EGJ outflow obstruction (n = 7), and jackhammer disorder (n = 4). Beyond specific EMD, we also found 2 patients diagnosed with localized pressurization secondary to benign and doubtful mediastinal lymphadenopathy origin. These findings highlight the importance of the morphological assessment of all EMD phenotypes. Surprisingly, EGD negative (including systematic biopsies) preceding the HRM were all negative in the two patients further diagnosed with cardia adenocarcinoma. Whether the strategy to perform a second endoscopy instead of a combined second endoscopy associated with an EUS remains to be evaluated in a larger population study.

In order to avoid anesthesia risks and to reduce the examinations costs, it seemed important to target the population for which a morphological assessment is most relevant. We found that 100% of our "Positive" group patients had an IPR higher than 10mmHg for water swallows, 93.5% were aged of 58 years or older (one patient was 29-year-old and had a cardiac adenocarcinoma) and half of them had a smoking history. Our findings are consistent with 8 reports studying 28 cases of pseudoachalasia. After exclusion of 9 cases with unavailable detailed information, 84% of patients were ≥ 60-year-old at the time of diagnosis [START_REF] Hassan | Aetiologic mechanisms of dysphagia in lung cancer: A case series[END_REF][START_REF] Can | Achalasia secondary to lung adenocarcinoma[END_REF][START_REF] Lee | Paraneoplastic gastrointestinal motor dysfunction: clinical and laboratory characteristics[END_REF][START_REF] Anaizi | Large cell neuroendocrine carcinoma of the lung presenting as pseudoachalasia: a case report[END_REF][START_REF] Rozman | Features distinguishing secondary achalasia from primary achalasia[END_REF][START_REF] Liu | The pathogenesis of pseudoachalasia: a clinicopathologic study of 13 cases of a rare entity[END_REF][START_REF] Hirano | Two cases of pseudoachalasia with lung cancer: Case report and short literature review[END_REF][START_REF] Katzka | Achalasia secondary to neoplasia: a disease with a changing differential diagnosis[END_REF].

Ponds et al. [START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF] suggested that an age≥55 year-old was a the factor for potential malignancy associated pseudoachalasia. In another series including five patients with pseudoachalasia, four (80%) were 54-year-old or older (only one patient was 28-year-old had a leiomyomatosis of the gastric cardia) and four (80%) had a IRP higher than 13 mmHg (one patient had non available data) [START_REF] Gockel | Pseudoachalasia: a case series and analysis of the literature[END_REF]. Comparably, Our study suggest that smoking, age of 58-year-old or older and an IRP higher than 10mmHg for water swallows are risk factors that indicate potential secondary EMD.

Use of HRM has improved the accuracy and diagnostic yield of clinical investigation in patients with suspected EMD [START_REF] Ivashkin | High resolution manometry and new classification of esophageal motility disorders[END_REF].However, our results showed that HRM findings based on water swallows alone failed to detect motility disorders in 4 out of 16 (25%) cases with secondary origin (3 of them had malignant secondary origin). Their disorders were diagnosed only when HRM with solid swallows was performed. This is in favor of additional examination. The performance of a esophageal HRM is generally carried out on 10 water swallows, but this approach may not be clinically relevant for the diagnosis of disorders with symptoms occurring only during the ingestion of solid foods. HRM measurements with solid swallows are more sensitive to clinically relevant dysfunction, to identify the cause of symptoms and guide effective management [START_REF] Sweis | Assessment of esophageal dysfunction and symptoms during and after a standardized test meal: development and clinical validation of a new methodology utilizing high-resolution manometry[END_REF][START_REF] Ang | Diagnostic yield of high-resolution manometry with a solid test meal for clinically relevant, symptomatic oesophageal motility disorders: serial diagnostic study[END_REF].In the present study, multiple rapid swallows or rapid drink challenge tests data are unfortunately lacking although recent studies suggest these may be of use in such patients [START_REF] Carlson | Esophageal provocation tests: Are they useful to improve diagnostic yield of high resolution manometry[END_REF]. Further studies are warranted to evaluate if these parameters may also be predictive of secondary EMD.

In our study, there was a lack of distinction between EUS and Computed Tomography. The EUS allows precise information of the esophageal wall but has a low sensitivity in the detection of off-site injuries whereas the CT-scan allows a good analysis of injuries far from the esophagus but is not very sensitive in the detection of esophageal wall intrinsic anomalies. This is in favor of the complementarities of these two exams.

Our study presents some limitations. First, it is a retrospective study where available data, especially clinical, are collected from medical files of patients, which can lead to an information bias. Second, a majority of patients in our cohort were not explored. This did not mean however, that these patients had no secondary EMD. Our study provides even clues to speculate they may have similar rates of secondary EMD. Indeed, patients of explored and non explored group were comparable in term of age, gender, symptoms, and HRM metrics.

We can therefore speculate that these parameters did not guided clinicians to perform additional exploration. However, weight loss or co-morbidities were note systematically recorded in our cohort due to the retrospective nature of the study. These parameters may nevertheless have participated in clinician's choice. Other aspects may have also taken part in clinician's choice. These include the anticipation of a low detection rate, which was however unknown until our study was conducted. In addition, the unavailability of the exploration, in particular EUS, at different center may have also influence the performance of additional tests. The different rate of additional exploration in our study varied from 13.6% to 62.5% across centers, which may reflect limited access in a region (Normandy) where inequity in the access to healthcare providers has already been pointed out [START_REF] Dejardin | Access to care, socioeconomic deprivation and colon cancer survival[END_REF].

Lastly, the size of the present cohort may be viewed as small. However, when compared with the existing literature, the number of patients analyzed is comparable and even superior to the majority of studies on secondary esophageal motor disorders. Indeed, they reciprocally included 62 [START_REF] Carlson | Esophageal provocation tests: Are they useful to improve diagnostic yield of high resolution manometry[END_REF], 333 [START_REF] Ponds | Diagnostic features of malignancy-associated pseudoachalasia[END_REF], 28 [START_REF] Licurse | Utility of chest CT for differentiating primary and secondary achalasia[END_REF], and 69 patients [START_REF] Oumrani | Do we need endoscopic ultrasonography for the workup of patients with esophageal motility disorder?[END_REF].The small number of secondary EMD of our series limits the statistical interpretation and the possibility of highlighting differences between "positive" and "negative" patterns. The causal link between the morphological abnormalities and MHR data was validated by a committee of independent experts who discardedseven abnormalities of malignant or doubtful origin. However, several reports presented cases of pseudoachalasia secondary to pleural mesothelioma [START_REF] Branchi | A Case of Pseudoachalasia Hiding a Malignant Pleural Mesothelioma[END_REF]- [START_REF] Seki | Malignant Pleural Mesothelioma Presenting as Achalasia[END_REF],

pancreatic [START_REF] Kim | Extragastroesophageal Malignancy-Associated Secondary Achalasia: A Rare Association of Pancreatic Cancer Rendering Alarm Manifestation[END_REF] or hepatobiliary [START_REF] Choi | Cardiac magnetic resonance in myocarditis from adult onset Still's disease successfully treated with anakinra[END_REF][START_REF] García-Alonso | Hepatobiliary and Pancreatic: Pseudoachalasia from pancreatic cancer: Education and Imaging[END_REF], pulmonary [START_REF] Can | Achalasia secondary to lung adenocarcinoma[END_REF][START_REF] Anaizi | Large cell neuroendocrine carcinoma of the lung presenting as pseudoachalasia: a case report[END_REF][START_REF] Hirano | Two cases of pseudoachalasia with lung cancer: Case report and short literature review[END_REF][START_REF] Jian | Case report of achalasia secondary to a lung carcinoma of the mediastinal type: Achalasia secondary to lung carcinoma[END_REF], or lymphnode metastases [START_REF] Lahbabi | Pseudoachalasia secondary to metastatic breast carcinoma mimicking radiation stenosis[END_REF]. Furthermore, other 23 morphological abnormalities with no malignant origin were not retained by the panel of experts. This shows the difficulties encountered to judge the accountability between morphological abnormalities and manometric diagnosis.

In order to limit these biases, prospective multicenter studies should be performed to confirm these results and to determine more precisely the incidence of secondary esophageal motility disorders in the French population.

Figure 1 :

 1 Figure 1: Patient flow chart

Table 3 .

 3 Clinical features in the three groups: Positive, Negative and Unexplored groups

	Groups	« Positive » N= 16	« Negative» N=166	« Unexplored» N=320	P value Positive vs Negative	P value Explored vs Non explored
	Age (years) [Mean±SD] Age ≥ 58 years old n (%)	66.9 ±13.3 15 (93.8%)	62.3 ± 15,8 109 (65.7%)	60.2 ±16,7 196 (61,3%)	0.21 0.02	0,09 0,77
	Gender
	Male n (%) Female n (%)	10 (62.5%) 6 (37.5%)	68 (41.0%) 98 (59.0%)	117 (36.6%) 203 (63.4%)	0.12	0,18
	History n (%)
	Tobacco	8 (50.0%)	39 (23.5%)	MD	0.03
	Alcohol	2 (12.5%)	11 (6.6%)	MD	0.32
	Diabetes	1 (6.3%)	13 (7.8%)	MD	1.00
	Radiotherapy	0 (0.0%)	7 (4.2%)	MD	1.00
	Other cancer	2 (12.5%)	14 (8.4%)	MD	0.64
	Symptoms n (%)
	Dysphagia	13 (81.3%)	135(81.3%)	233 (72.6%)	1.00	0,04
	Vomiting/regurgitation	1 (6.3%)	14 (8.4%)	27 (8.4%)	1.00	1,00
	Pain	0 (0.0%)	20 (12.0%)	29 (9.0%)	0.22	0,53
	AHS	0 (0.0%)	13 (7.8%)	20 (6.2%)	0.25	0,71
	GERD	1 (6.3%)	15 (9.0%)	36 (11.3%)	0.24	0,44

SD: Standard deviation. AHS: Alteration in Health Status. GERD:gastroesophageal reflux disease MD : missing data

Table 4 .

 4 HRM characteristics in the three groups: Positive, Negative and Unexplored groups Standard deviation, IRP: integrated relaxation pressure, LES :lower esophageal sphincter, DCI : Distal contractile integral, EGJ:esophagogastric junction, HLES : Hypertonia of lower esophageal sphincter.

		« Positive »	« Negative »	« Unexplored »	P-value
		N= 16	N=166	N=320	Positive vs Negative
	Manometry: Mean [mmHg ±SD]
	LES relaxation pressures Water IRP Solid IRP	39.8 ±27,2 24.8 ±22,6 17.8 ±13,8	34.9 ±17,6 14.6 ±10,4 16.1±10,0	34.8 ± 17,9 14.6 ±11,1 16.8 ±11,5	0.76 0.12 0.78
	Water IRP> 10mmHg Water DCI Solid DCI	16 (100%) 2010.6 ±2058 4272.9 ±4146	97 (58.4%) 2587.2±4403 6376.1±8606	198 (61,9%) 2311.5±3489 4706.9±6042	0.0006 0.68 0.28
	Water manometry: diagnosis : n (%)
	Normal	4 (25.0%)	36 (21.7%)	54 (16.9%)	0.75
	EGJ obstruction	6 (31.5%)	34 (20.5%)	82 (25.6%)	0.34
	Achalasia type I	0 (0.0%)	4 (2.4%)	8 (2.5%)	1.00
	Achalasia type II	1 (6.2%)	25 (15.1%)	59 (18.4%)	0.48
	Achalasia type III	2 (12.5%)	11 (6.6%)	11 (3.4%)	0.32
	Spasm	0 (0.0%)	12 (7.2%)	13 (4.0%)	0.60
	Jackhammer	1 (6.2%)	11 (6.6%)	16 (5.0%)	1.00
	HLES alone	0 (0.0%)	21 (12.7%)	54 (16.9%)	0.22
	Localized pressurization	2 (12.5%)	10 (6.0%)	22 (6.9%)	0.28
	Perprandial manometry: diagnosisn (%)
	Normal	0 (0.0%)	2 (1.2%)	2 (0.6%)	1.00
	EGJ Obstruction	5 (31.3%)	41 (24.7%)	80 (25.0%)	0.50
	Achalasia type I	0 (0.0%)	2 (1.2%)	5 (1.7%)	1.00
	Achalasia type II	0 (0.0%)	18 (10 .8%)	44 (13.8%)	0.30
	Achalasia type III	1 (6.3%)	12 (7.3%)	13 (4.0%)	1.00
	Spasm	1 (6.3%)	14 (8.4%)	18 (11.3%)	1.00
	Jackhammer	5 (25.0%)	26 (15.7%)	39 (12.2%)	0.10
	HLES alone	0 (0.0%)	8 (4.8%)	20 (6.3%)	1.00
	Localized pressurization	1 (6.2%)	14 (8.4%)	27 (8.4%)	1.00

SD:

Acknowledgements, funding and disclosures

This work was supported solely by the University Hospital of Rouen -France. Medicalwriting assistance was provided by ImenAissa of MediAxe (funded by the University hospital of Rouen). The paper is dedicated to the memory of Philippe Ducrotté, who was part of the HRM expert panel mentioned above, and who unfortunately passed away before the drafting of the manuscript.

Conflict of Interest Statement:

The authors have no conflict of interest to declare. Table 1: Clinical features of patients with suspected secondary esophageal motility disorder.

Tables

Patients (n=502)

Age (years) [Mean±SD]

61.


MD Charles Cheng

MD Yohann Bohbot

MD Hector I Michelena

MD, PhD Dan Rusinaru

MD Floriane Fay

MD Frederic Elmkies

MD Maurice Enriquez Sarano

Professor Christophe Tribouilloy
email: tribouilloy.christophe@chu-amiens.fr

Clinical Outcomes of Adults With Bicuspid Aortic Valve: A European Perspective

Keywords: bicuspid aortic valve, outcome, survival, surgery, aorta, AVA: aortic valve area BAV: bicuspid aortic valve IE: infective endocarditis LV : left ventricular LVEF : left ventricular ejection fraction VS: Valsalva sinuses

Objective: To describe the clinical history of patients with a wide age range diagnosed with bicuspid aortic valve (BAV) and no surgical indication and to evaluate the long-term outcome of BAV patients referred for elective surgery.

Patients and methods

: Between 2005 and 2017, 350 consecutive patients with no surgical indication (surveillance group, mean age 53±16, 71% men) and 191 with a surgical indication (surgical group, mean age 59±13, 71% men) were prospectively included. Median follow-up was 80[32-115] months.

Results: In the surveillance group, the 5-year and 10-year survival rates were 93±1% and 89±2%, respectively, with a relative survival of BAV patients compared to an age-and-sexmatched control population of 98.7%. During follow-up, the cumulative 10-year incidence of aortic valve/aorta surgery was high, of 35±4%, the incidence of native valve IE of 0.2% per patient-year and no cases of aortic dissection were observed. In the surgical group, the 5-year and 10-year survival rates were 97±1% and 89±3%, respectively, with a relative survival of 99.4% compared to the general population. The incidence of IE was 0.4% per patient-year and no cases of aortic dissection were observed.

Conclusions: This regional cohort, shows that the 10-year survival rates of BAV patients with a wide age range but mostly middle-aged adults, were similar to those of the general population with a very low rate of complications. Adherence to prophylactic surgical indications and younger age might have contributed to this lack of difference.

INTRODUCTION

Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality(1) that has been touted to cause a cardiovascular morbidity burden higher than all other congenital heart diseases [START_REF] Ward | Clinical significance of the bicuspid aortic valve[END_REF]. Nevertheless, the BAV condition remains poorly understood from several perspectives. On one hand, the high morbidity burden(2), the progression of aortic dilatation similar to Marfan's disease [START_REF] Detaint | Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy[END_REF] and calls for indicating aortic surgery at an early stage of aortic dilatation based on a high risk of aortic dissection (AD)(4) have suggested a high potential for ominous prognosis. Conversely, a US and a Canadian longitudinal series, suggested [START_REF] Tzemos | Outcomes in adults with bicuspid aortic valves[END_REF][START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF] that BAV could be associated with normal life expectancy and very low rate of AD at the cost of high rates of aortic valve/ aorta surgery [START_REF] Michelena | Incidence of aortic complications in patients with bicuspid aortic valves[END_REF][START_REF] Iung | Recommendations on the management of the asymptomatic patient with valvular heart disease[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease. The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012) The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)[END_REF]. However, these studies do not resolve fully the concern for the potential complications due to BAV.. Indeed, the 2 North American series [START_REF] Tzemos | Outcomes in adults with bicuspid aortic valves[END_REF][START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF] enrolled overwhelmingly very young carriers of BAV and the good outcome may have more to do with the youth of the patients than the BAV itself. The Olmsted County study [START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF] included also patients that were quite young at diagnosis and was conducted in the community where care is provided by the Mayo Clinic, a high-volume center of excellence. Therefore, it is unclear whether it is the care provided or the natural history of BAV that explain the good outcomes observed, or both. It is important to know whether such results can be generalized and if the good long-term clinical outcome of BAV can be achieved in the circumstances of a regional medical center. Indeed, to our knowledge, no data are available regarding the natural history and outcome of European BAV patients with a broad age range, as the 2 largest studies were conducted on young adults in North America [START_REF] Tzemos | Outcomes in adults with bicuspid aortic valves[END_REF][START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF].

Therefore, our objectives were to gather a large cohort of adults with BAV, dwelling in the Somme French department to (i)describe the clinical history of adults diagnosed with BAV under those auspices and to (ii)evaluate the long-term outcome of BAV patients referred for elective surgery. We aimed at determining the rates of cardiovascular events, and assessing the long-term survival relative to that of the general population receiving a standard medical care.

METHODS

Study population

Between January 2005 and December 2017, consecutive patients≥18 years of age diagnosed with BAV at our echocardiographic laboratory were prospectively identified and included in an electronic database. The present analysis was based on 541 consecutive patients with BAV:350 without an indication for surgery at inclusion (surveillance group) and 191 with an indication for aortic valve and/or ascending aorta surgery, operated within 6 months following inclusion (surgical group). The study was approved by an independent ethics committee and was conducted in accordance with institutional policies, national legal requirements, and the revised Declaration of Helsinki.

Echocardiography

All patients underwent a comprehensive Doppler-echocardiographic assessment using commercially available ultrasound systems. BAV was diagnosed in the short axis view based on Sievers and Schmidtke classification and was confirmed by another imaging technique when there was a doubt about the diagnosis. Aortic flow was systematically recorded using continuous wave Doppler on several views. Aortic valve area(AVA) was calculated using the continuity equation. AS was defined by AVA<2 cm² and aortic regurgitation(AR) was classified as mild, moderate or severe using an integrated approach [START_REF] Lancellotti | Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging[END_REF]. AR was considered significant when it was greater than mild. Measurements of aortic Valsalva sinuses(VS) and proximal ascending aorta(AA) dimensions were performed at end-diastole in a strictly perpendicular plane to that of the long axis of the aorta using the leading-edge method.

Dilatation of VS and/or AA was defined by dimensions ≥40 mm [START_REF] Lang | Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF].

Follow-up

Median [interquartile range] follow-up was 80[32-115] months. Most patients were followed annually by clinical consultations and echocardiography. Follow-up was closer for patients approaching surgical thresholds (twice a year) but less frequent for those with nondilated aorta and normal/ minimally dysfunctional valves (every 2 to 3 years). Some patients were followed in public hospitals or private practices by referring cardiologists working in collaboration with our center. Information on follow-up was obtained yearly over the same period for the entire cohort. Follow-up was complete up until death or the end of the study (2017) for 97% of patients. Clinical decisions regarding surveillance and referral for surgery were taken by the heart team with the approval of the patient's cardiologist in accordance with practice guidelines in place at the time of the inclusion [START_REF] Iung | Recommendations on the management of the asymptomatic patient with valvular heart disease[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease. The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012) The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)[END_REF]. Causes of deaths were ascertained by hospital records, death certificates and autopsy records, or by contacting the patient's physician. Patients of the surveillance group operated-on during follow-up remained in this group. Survival encompassed all modalities of surveillance and surgical management.

Statistical analysis

Data were analyzed using SPSS 25.0 (SPSS Inc. Chicago, IL). Continuous variables are expressed as mean±standard deviation or median [interquartile range], and categorical variables are expressed as numbers and percentages. Patients were retrospectively divided into 3 groups according to valve function (normal or minimally dysfunctional aortic valve, AS and AR). The relationship between baseline continuous variables and the various groups was explored using one-way ANOVA tests. Pearson's chi-square statistic or Fisher's exact test was used to examine the association between the various groups and baseline categorical variables. The significance between the reference group and the other groups was examined when a significant difference across categories was observed. Individual differences were compared with Mann-Whitney U tests and Tukey tests for normally distributed data. Event rates±standard errors were estimated using the Kaplan-Meier method and compared by twosided log-rank tests. Each patient with BAV was matched for the average survival (per year) of all patients of the same age and same gender from our region (Somme, department of 555,551 inhabitants, north of France). Control data were obtained from Somme life tables established on the basis of the 1999 population census carried out by the French Institute of National Statistics and represent the survival of the entire Somme general population [START_REF] Tribouilloy | Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based study[END_REF].

Survival rates of BAV patients were compared with the expected survival of persons of the same age and gender in the Somme department. Relative survival was computed as the ratio of observed-to-expected survival (observed number of deaths in the BAV population/expected number of deaths in the general population). Factors associated with surgery performance were identified by a multivariate logistic regression model including all significant variables in univariate analysis with p <0.1. The limit of statistical significance was p<.05 and all tests were two-tailed.

RESULTS

Surveillance group

BAV was mostly discovered incidentally during a systematic echocardiogram (n=168;48%).

Baseline clinical characteristics of the 350 patients without a surgical indication at inclusion (71.1% of men, mean age 53±16) are displayed in Tables 1 and2. Most patients were in NYHA class I or II (95.1%), 164(46.8%) had hypertension, 48(13.7%) were diabetics and CAD was diagnosed in 31(8.8%) patients. Patients with AS (n=142,40.5%) were older (P<.001), more often diabetics with more comorbidity (both P<.05) and more often had a history of atrial fibrillation (P<.001) than patients with normal or minimally dysfunctional aortic valve (n=128,36.6%; reference group) (Table 2). Eighty patients (22.9%) had moderate-to-severe AR. Patients with moderate-to-severe AR had greater aortic (LV outflow tract [P<.001], VS and AA [both P<.05]) and LV diameters (P<.001) and larger left atrium area (P<.05) compared to the reference group (Table 2). One hundred and sixty seven(48%) had an enlarged aorta During follow-up, 34 deaths (9.7%) occurred, 10 of which (29%) were cardiovascular-related.

The 5-year and 10-year survival rates were 93±1% and 89±2%, respectively. The 10-year relative survival of BAV patients compared to the age-and-sex-matched population was 98.7% (Figure 1A). During follow-up, 9 patients (2.6%) were diagnosed with IE: 5 with native aortic valve IE and 4 with prosthetic IE (incidence of 0.4% per patient-year [0.2% per patient-year for native valve IE]): 5 patients required urgent surgery and 4 patients were treated medically. No AD occurred during follow-up. The 5-year and 10-year event-free survivals (cardiovascular death, IE or AD) were 96±1% and 91±2%, respectively.

During follow-up, 102 patients(29%) underwent aortic valve and/or ascending aorta surgery (Table 3)(98% in our center) and the diagnosis of BAV was confirmed by the surgeon and/or the pathologist for all patients. On Kaplan-Meier analysis, the 2-year, 6-year and 10-year cumulative surgery rates were 3±1%, 11±2%, and 35±4%, respectively(Figure 2 2). One hundred and fourteen patients(60%) had an enlarged aorta.

During follow-up, 12 deaths(6.3%) occurred, 5 of which(2.6%) were cardiovascular-related.

Perioperative mortality was 0.5%(n=1). The 5-year and 10-year survival rates were 97±1% and 89±3%, respectively. The 10-year relative survival of BAV patients compared to the ageand sex-matched population was 99.4%(Figure 1B). The 5-year and 10-year event-free survivals (cardiovascular death, IE, AD and reoperation) were 98±1% and 87±4%, respectively. During follow-up, 5 patients were diagnosed with prosthetic IE(incidence of 0.4% per patient-year) and no AD or valve thrombosis occurred. Only 5 patients were operated during follow-up: 2 for bioprosthetic degeneration(at 7 and 10 years respectively, estimated rate of 5±3% at 15 years) and 3 for IE.

DISCUSSION

To the best of our knowledge, this long-term follow-up study of 541 consecutive patients is the first large-scale European series providing important information about the clinical history and outcomes of BAV in adults of a wide range age but mostly middle-aged. The present cohort gathered in a regional medical center in Europe, shows that under surveillance, 10-year mortality is low, not different from expected, provided that the guidelines for indication of surgery are followed. Complication rates are relatively low and are generally manageable.

Patients often require cardiac surgery during follow-up but outcomes after surgery are generally excellent with in our study, post-operative survival at 10-years comparable to that of the general population. In adults carriers of BAV, the 10-years outcomes observed in Europe are very coherent with observed in North-America, without variance related to the medical care system, the type those of institution managing the patients or the age at diagnosis, and emphasizing a generally good survival at the cost of a high rate of cardiac or prophylactic aortic surgery warranting careful monitoring of the progression of the aortic valve and ascending aortic alterations.

Natural history of BAV patients

Two larges cohorts from North-America have focused on the natural history of BAV in young adults with no surgical indication at baseline [START_REF] Tzemos | Outcomes in adults with bicuspid aortic valves[END_REF][START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF], providing crucial information but leaving important doubts related to either youth of the population or the nature of the care received by these patients. Indeed, a Canadian cohort of 642 asymptomatic young adults (mean age 35 years, mean follow-up 9 years) with BAV and a spectrum of valve function, showed a 10-year survival of 96±1%(3). The population-based cohort of Olmsted County, involved asymptomatic young adults with BAV(mean age 32, mean follow-up 15 years) and no significant valve dysfunction at baseline, also demonstrated an excellent survival of 90±3% [START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF]. However, due to the specific circumstances of each cohort, it is not possible to ascertain whether these good outcomes truly represent the "natural" history of adults with BAV. In our population diagnosed at an older age(mean age 53±16 years), the 10-year survival was comparable to that of the general French population. Hence our series from a regional center in Europe enrolling patients diagnosed mostly in their middle-age demonstrates that indeed BAV "good" outcomes can now be attributed without a doubt to the BAV itself and not to the patients' age, or recruitment in high-ranking referral centers, so that we can affirm that such results are truly generalizable to the adult population.

The main event observed during follow-up in BAV patients was aortic valve and/or ascending aorta surgery. In the study by Michelena et al, 29% of patients underwent surgery (mean follow-up:15 years) [START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF] and 22% in the study by Tzemos et al (mean follow-up:9 years)(5).

The 10-year surgery rate was higher(35±4%) in our study, probably because of the more advanced age of our population. Moreover, the risk of AVR after 25 years could reach more than 50% [START_REF] Michelena | Incidence of aortic complications in patients with bicuspid aortic valves[END_REF].

The most dreaded complication of BAV is AD, which is associated with high mortality. The incidence of AD has been estimated for BAV patients to be eightfold higher than in the general population, but still remains exceedingly low from 0.015 to 0.03% per year, if the guidelines in terms of follow-up and indications for prophylactic aortic surgery are followed [START_REF] Michelena | Incidence of aortic complications in patients with bicuspid aortic valves[END_REF][START_REF] Michelena | Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon)[END_REF]. In the Toronto series(5), during 9 years of follow-up, only 2 AD out of 642 patients occurred and, in the Olmsted County study, no AD occurred during follow-up [START_REF] Michelena | Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community[END_REF].

Similarly, in our study, following the guidelines for prophylactic aortic surgery(50mm before 2012 and 55mm since) no case of AD was observed during follow-up.

IE is a severe complication of BAV and warrants prompt diagnosis and treatment.

Furthermore, BAV patients with IE incurs higher severity of complications as compared to tricuspid aortic valves with high risk of abscess formation and often require early surgery [START_REF] Tribouilloy | Clinical characteristics and outcome of infective endocarditis in adults with bicuspid aortic valves: a multicenter observational study[END_REF].

Older series have estimated the prevalence of IE to be between 10% and 30% in the presence of BAV [START_REF] Ward | Clinical significance of the bicuspid aortic valve[END_REF]. However, those studies presented numerous biases and more recent estimates of the incidence of IE are lower, at about 0.14% per patient-year(0.10% per patient-year for native valve IE) [START_REF] Michelena | Incidence of Infective Endocarditis in Patients With Bicuspid Aortic Valves in the Community[END_REF]. Accordingly, in our study, the IE incidence was 0.4% per patient-year(0.2% per patient-year for native valve IE).

Prognosis of BAV patients after surgery

The most common complication of BAV in adults is valve dysfunction requiring surgery, and the development of severe AS is the main indication for AVR [START_REF] Borger | The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve-related aortopathy[END_REF], while AR is observed in only 10% to 15% of cases [START_REF] Borger | The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve-related aortopathy[END_REF][START_REF] Sabet | Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases[END_REF]. Accordingly, in our surgical group, the indications for aortic valve surgery were severe AS in 65.5% of cases and severe AR in 13.5% of cases.

McKellar et al [START_REF] Mckellar | Long-term risk of aortic events following aortic valve replacement in patients with bicuspid aortic valves[END_REF] and Sievers et al [START_REF] Sievers | Toward individualized management of the ascending aorta in bicuspid aortic valve surgery: The role of valve phenotype in 1362 patients[END_REF] reported that after AVR, the 5 and 10-years survival of patients with BAV was not different from the general population. Similarly, in our study, the 10-year survival of the surgical group was good (89±3%) and comparable to that of the general population(relative survival of 99.4%). Only 5 patients were reoperated for the aortic valve during follow-up.

BAV patients have larger aortic dimensions than adults with tricuspid aortic valves [START_REF] Siu | Bicuspid aortic valve disease[END_REF][START_REF] Nkomo | Bicuspid aortic valve associated with aortic dilatation: a community-based study[END_REF][START_REF] Cecconi | Aortic dimensions in patients with bicuspid aortic valve without significant valve dysfunction[END_REF] with a risk of aortic aneurysm 80-fold higher than in the general population [START_REF] Michelena | Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon)[END_REF]. In our study, about 40% of patients of the surgical group underwent ascending aorta surgery and only 6% of them had had an associated replacement of the aortic arch. McKellar et al [START_REF] Mckellar | Long-term risk of aortic events following aortic valve replacement in patients with bicuspid aortic valves[END_REF] reported a 15-year freedom from AD, aortic enlargement, or replacement rate of 93% in patients with normal aortic dimensions at the time of AVR, but of only 85% in patients with aortic enlargement. In a population of 201 BAV patients with an aorta<5cm undergoing isolated AVR, 10 years after surgery, 22 patients(11%) had long-term complications related to the ascending aorta [START_REF] Borger | Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease?[END_REF]. Based on these data, guidelines, when aortic valve surgery is scheduled for severe AS and/or severe AR, consider associated prophylactic ascending aorta surgery in patients with maximum aortic diameter>45mm [START_REF] Iung | Recommendations on the management of the asymptomatic patient with valvular heart disease[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease. The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology[END_REF][START_REF] Vahanian | Guidelines on the management of valvular heart disease (version 2012) The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)[END_REF][START_REF] Nishimura | AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[END_REF]. In our study, when complying with the guidelines for prophylactic aortic surgery(8-10), no AD occurred and no patient required reoperation for the aorta during follow-up despite few preventive aortic arch replacement, in accordance with the study by Greason et al(25).

According to current guidelines(26,27), BAV Patients can be reviewed on a yearly basis and echocardiography performed every 2 years in case of mild to moderate AR and every year if asymptomatic severe AR without LV dysfunction. If the ascending aorta is dilated(>40mm) a computed tomography or magnetic resonance imaging is recommended at baseline, which should be repeated for increases>3 mm or when the patient is close to surgical thresholds. In other cases, aortic dimensions can be monitored by annual echocardiography, especially if exceeding 45 mm. In case of nondilated aorta and normal/minimally dysfunctional valve a longer interval between imaging studies seems appropriate [START_REF] Nishimura | AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[END_REF]26,27).

Limitations

Significant improvements were made to Doppler echocardiographic techniques during the study period. However, we believe that the quality of imaging throughout this period was sufficient to diagnose BAV. When cusp numbers were not unequivocally determined by echocardiography, we confirmed the diagnosis by another imaging technique or the patients concerned were excluded. These results can only be interpreted at 10 years and some cases of AD could be observed with longer follow-up and a larger number of patients(28).

Furthermore, it has been shown that BAV patients who present at later points in their clinical history when they are older (time of referral to a tertiary care facility and time of surgery), have higher mortality likely related to the accumulation of morbidity(28). Similar to the study of Tzemos et al [START_REF] Tzemos | Outcomes in adults with bicuspid aortic valves[END_REF], this was not a community-based study. However, our center is a tertiary center but also a regional center which takes care of the Somme region. We report for the first time, the follow-up of a large European cohort showing overall good survival despite being tertiary-referral-based.

CONCLUSION

In adults carriers of BAV, over the western world and diagnosed at any age, the 10-years outcomes observed in Europe are very coherent with observed in North-America, without variance related to the medical care system, the type of institution managing the patients or the age at diagnosis, and emphasizing a generally good survival at the cost of a high rate of cardiac or prophylactic aortic surgery warranting careful monitoring of the progression of the aortic valve and ascending aortic alterations.

Acknowledgments

Figure 1 :A.

 1 Figure 1:

Figure 2 :

 2 Figure 2:

Table 2 .

 2 In multivariate logistic regression analysis, NYHA stage (Adjusted OR:3.99[2.04-7.82] per class;P<.001), Doppler peak aortic velocity (Adjusted OR:1.95[1.51-2.52] per m/s;P<.001) and ascending aorta diameter(Adjusted OR:1.06[1.01-1.12] per mm;P=.04) were independently associated with surgery performance(Supplemental table 1). Indications for surgery and surgical procedures (98.5% performed in our center) are reported in

	Surgical group
	Baseline characteristics of the surgical group (191 patients operated within 6 months
	following inclusion) are displayed in Table 1 and supplemental

).

Table 3 .

 3 The diagnosis of BAV was confirmed for all patients during surgery. Patients with severe AS were older(P<.001), had more comorbidity(P<.05) and smaller aortic dimensions(P<.001) compared to patients with normal or minimally dysfunctional aortic valve (reference group) (Supplemental table2). Patients with severe AR were younger (P<.001), had greater LV diameters(P<.001) and lower LVEF(P<.001) compared to the reference group (Supplemental

	table

:

  None ascending aorta replacement for aortopathy during initial bicuspid aortic valve replacement. [published online September 25, 2019]. J Thorac Cardiovasc Surg. Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).

		doi: 10.1016/j.jtcvs.2019.09.028
	26.	Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the
		management of valvular heart disease. Eur Heart J. 2017;38(36):2739-91.
	27.	Erbel R, Aboyans V, Boileau C et al. 2014 ESC Guidelines on the diagnosis and
		treatment of aortic diseases: Eur Heart J. 2014;35(41):2873-926.
	28.	Michelena HI, Suri RM, Katan O, et al. Sex Differences and Survival in Adults
		With Bicuspid Aortic Valves: Verification in 3 Contemporary Echocardiographic
		Cohorts. [published online September 29, 2016]. J Am Heart Assoc. doi:
		10.1161/JAHA.116.004211

Table 1 :

 1 Baseline characteristics of the study population.

	Surveillance group	Surgical group
	(n=350)	(n=191)

Table 2 :

 2 Clinical and echocardiographic characteristics according to the valvular function in the surveillance group. Continuous variables are expressed as mean±standard deviation (SD) and categorical variables as number and percentage. NYHA New York heart association class; AVA: aortic valve area; LVOT: left ventricular outflow tract a: p<.05 each group versus normal or minimally dysfunctional aortic valve group b: p<.001 each group versus normal or minimally dysfunctional aortic valve group.

		Normal or
	Variable	minimally dysfunctional aortic valve	Aortic stenosis (n=142)	(n=80) Aortic regurgitation	p
		(n=128)
	Clinical and demographic characteristics
	Age(y)	48±15	59±15 b	50±16	<.001
	Male Sex(n,%)	85(66.4%)	99(69.7%)	65(81.2%) a	.03
	Body mass index(m²)	1.97±0.2	1.98±0.3	1.99±0.19	.83
	NYHA(n,%)
	1-2 3-4	126(98.4%) 2(1.6%)	131(92.2%) 11(7.8%) a	76(95%) 4(5%)	.10
	Angina(n,%)	6(4.7%)	17(11.9%)	6(7.5%)	.06
	Creatinine(µmol/l)	79±23	76±21	78±20	.22
	Risk factor
	Hypertension(n,%)	45(35.2%)	85(59.9%) a	34(42.5%)	.001
	Diabetes mellitus(n,%)	12(9.4%)	32(22.5%) a	4(5.0%)	.001
	Coronary artery disease(n,%)	10(7.8%)	15(10.6%)	6(7.5%)	.70
	Atrial fibrillation(n,%)	3(2.3%)	12(8.5%) b	6(7.5%) a	<.001
	Charlson score	0.95±1.6	1.5±1.9	0.51±0.9	<.001
	Logistic Euroscore(%)	2.6±2.2	5±8.9a	2.8±2	.03
	Echocardiographic parameters
	Aortic valve and ascending aorta
	Sievers and Schmidtke classification				.029
	Type 0	41 (32.0%)	27 (19.0%)	24 (30.0%)
	Type 1	86 (67.2%)	115 (81.0%)	54 (67.5%)
	Type 2	1 (0.8%)	0 (0.0%)	2 (2.5%)
	LVOT diameter(mm)	23±2.6	23±2.6	26±3 b	<.001
	Aortic valve area(cm²)	2.7±0.6	1.1±0.4 b	2.7±1	<.001
	Indexed aortic valve area(cm²/m²)	1.5±0.3	0.6±0.3 b	1.6±0.7	<.001
	Aortic jet velocity(m/s)	1.7±0.5	3.5±1 b	2.2±1	<.001
	Mean gradient(mmHg)	8±5	33±19 b	13±14	<.001
	Aortic Valsalva sinuses(mm)	37±6	37±6	41±6 a	<.001
	Proximal ascending aortic(mm)	37±7	38±7	41±7 a	<.001
	Left ventricular function
	Left ventricular end-diastolic diameter(mm)	51±6	52±7	60±7 b	<.001
	Left ventricular end-systolic diameter(mm)	32±6	33±8	39±7 b	<.001
	Left ventricular ejection fraction(%)	64±6	63±11	59±9 b	.006
	Left atrium area(cm²)	18±5	22±6 b	21±6 a	.04

Table 3 :

 3 Surgical indications and surgical procedures of the study population according to initial management.

	Surveillance	Surgical group
	group	(n=191)
	(n=102)