Etude de biomarqueurs de dysfonction atriale. - Theses.fr

THESE DE DOCTORAT DE L’ETABLISSEMENT UNIVERSITE BOURGOGNE FRANCHE-COMTE

PREPAREE A L’UNITE DE RECHERCHE EA3920 ET L’UFR SCIENCES MEDICALES ET PHARMACEUTIQUES

École doctorale Environnements-Santé (ED ES n°554)

Doctorat de Sciences agronomiques et écologiques

Biologie, médecine et santé

Par

Marc BADOZ

Né le 01/06/1986 à Pontarlier

Etude de biomarqueurs de dysfonction atriale.

Thèse présentée et soutenue à Besançon, le 22/10/2021

Composition du Jury :

Me Laurence JESEL-MOREL, professeur de cardiologie, Université de Strasbourg Rapporteur Mr Damien LOGEART, professeur de cardiologie, Université de Paris VII Rapporteur Me Marie-France SERONDE, professeur de cardiologie, Université de Franche-Comté Examinatrice Mr Christian DE CHILLOU, professeur de cardiologie, Université de Lorraine Examinateur Mr Gabriel LAURENT, professeur de cardiologie, Université de Bourgogne Examinateur Mr Nicolas MENEVEAU, professeur de cardiologie, Université de Franche-Comté Directeur de thèse

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Remerciements

Madame le Professeur Laurence JESEL-MOREL

Vous me faites l’honneur de juger ce travail et d’en être rapporteur. Veuillez trouver l’expression de ma profonde gratitude.

Madame le Professeur Marie-France SERONDE

Votre intérêt pour les biomarqueurs en cardiologie et vos précédents travaux sur ce sujet ont été initiateurs de cette thèse. Soyez assurée de ma profonde reconnaissance.

Monsieur le Professeur Christian DE CHILLOU

Vous m’avez fait l’honneur de suivre l’évolution de mes travaux, d’y participer et de m’aider dans la finalisation de ceux-ci. C’est une grande fierté de vous compter dans les membres de ce jury.

Monsieur le Professeur Gabriel LAURENT

Vous avez accepté de participer à ce travail de thèse, votre aide et vos conseils ont été précieux. Je vous en suis profondément reconnaissant.

Monsieur le Professeur Damien LOGEART

Votre expertise dans le domaine des biomarqueurs est précieuse pour juger ce travail. Vous avez accepté d’en être rapporteur. Veuillez trouver l’expression de ma sincère reconnaissance.

Monsieur le Professeur Nicolas MENEVEAU

Vous m’avez apporté votre soutien pour chacun des travaux de cette thèse, votre œil expert et critique pour la méthodologie et la rédaction a permis d’aboutir aux différentes publications. Pour tout cela je vous remercie infiniment.

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Publications en relation avec la thèse d’université :

Acutely decompensated heart failure with preserved and reduced ejection fraction present with

comparable haemodynamic congestion.

Lucas N.L. Van Aelst, Mattia Arrigo, Rui Placido, Eiichi Akiyama, Nicolas Girerd, Faiez Zannad,

Philippe Manivet, Patrick Rossignol, Marc Badoz, Malha Sadoune, Jean-Marie Launay, Etienne Gayat,

Carolyn S.P. Lam, Alain Cohen-Solal, Alexandre Mebazaa and Marie-France Seronde.

European Journal of Heart Failure (2018) 20, 738–747.

Role of cardiovascular biomarkers for the assessment of mitral stenosis and its complications.

Marc Badoz, Mattia Arrigo, Bernard Iung, Gullu Amioglu, Mehmet Birhan Yilmaz, Nicolas Meneveau,

Malha Sadoune, Agnes Brunette, Alexandre Mebazaa, Marie-France Seronde.

European Journal of Internal Medicine 34 (2016) 58–62.

Assessment of successful percutaneous mitral commissurotomy by MRproANP and sCD146.

Marc Badoz, Mattia Arrigo, Anne-Claire Mogenet, Malha Sadoune, Nicolas Meneveau, Alexandre

Mebazaa and Marie-France Seronde.

BMC Cardiovascular Disorders (2020) 20:157.

Impact of Midregional N-Terminal Pro–Atrial Natriuretic Peptide and Soluble Suppression of

Tumorigenicity 2 Levels on Heart Rhythm in Patients Treated With Catheter Ablation for Atrial

Fibrillation: The Biorhythm Study.

Marc Badoz, Guillaume Serzian, Baptiste Favoulet, Jean-Marc Sellal , Christian De Chillou, Néfissa

Hammache, Gabriel Laurent, Alexandre Mebazaa, Fiona Ecarnot, Karine Bardonnet, Marie-France

Seronde, François Schiele, Nicolas Meneveau.

Journal of the American Heart Association 2021;10:e020917. DOI: 10.1161/JAHA.121.020917.

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Table des matières

Résumé

Abstract

I. Introduction

II. Rationnel

II.1. Biomarqueurs d’intérêt potentiel dans les pathologies atriales

II.1.1. Mid-Regional pro Atrial Natriuretic Peptide (MRproANP)

II.1.2. Soluble Cluster of Differentiation 146 (sCD146)

II.1.3. Soluble Suppression of Tumorigenicity 2 (sST2)

II.2. Situations cliniques pouvant justifier l’utilisation de ces biomarqueurs

II.2.1. Impact de l’insuffisance cardiaque au niveau atrial

II.2.2. Sténose mitrale et commissurotomie mitrale par voie percutanée

II.2.3. Fibrillation atriale et ablation endocavitaire

II.3. Synthèse

III. Corrélation entre Mid-Regional pro Atrial Natriuretic Peptide, Soluble Cluster of

Differentiation 146 et surfaces atriales droite et gauche

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IV. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide et du Soluble Cluster of

Differentiation 146 dans l’évaluation de la sévérité et du traitement percutané de la sténose mitrale

IV.1. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide et du Soluble Cluster of

Differentiation 146 dans l’évaluation de la sévérité de la sténose mitrale

IV.2. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide et du Soluble Cluster of

Differentiation 146 dans l’évaluation du traitement percutané de la sténose mitrale

V. Evaluation du risque de récidive de fibrillation atriale à distance d’une procédure

d’ablation par le Mid-Regional pro Atrial Natriuretic Peptide et le Soluble Suppression of Tumorigenicity 2

VI. Synthèse et perspectives

VI.1. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide chez des patients atteints

de sténose mitrale

VI.2. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide chez des patients atteints

de fibrillation atriale

VI.3. Lien entre modifications structurelles de l’oreillette et Mid-Regional pro Atrial

Natriuretic Peptide

VI.4. Mid-Regional pro Atrial Natriuretic Peptide, synthèse et perspectives de recherche

VI.5. Intérêt du Soluble Cluster of Differentiation 146 chez des patients atteints de

sténose mitrale.

VI.6. Place du Soluble Cluster of Differentiation 146 dans l’insuffisance cardiaque

VI.7. Perspectives actuelles de recherche pour le Soluble Cluster of Differentiation 146

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VI.8. Place du Soluble Suppression of Tumorigenicity 2 chez des patients traités par

ablation de fibrillation atriale

VI.9. Soluble Suppression of Tumorigenicity 2 et insuffisance cardiaque

VI.10. Synthèse et perspectives de recherche concernant le Soluble Suppression of

Tumorigenicity 2

VII. Conclusion

VIII. Références bibliographiques

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Résumé

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La pratique de la cardiologie fait appel de façon quotidienne à l’utilisation de biomarqueurs.

Cependant dans les pathologies à atteinte atriale prédominante, la performance diagnostique et

pronostique des biomarqueurs classiquement utilisés est peu démontrée. Nous nous sommes

donc intéressés à l’intérêt potentiel de trois biomarqueurs dans des pathologies affectant en

premier lieu l’oreillette : la fibrillation atriale (FA) et la sténose mitrale. Les biomarqueurs

concernés sont le MRproANP un peptide d’origine atriale, le sCD146 un marqueur d’origine

endothéliale et le sST2 un marqueur de fibrose. L’objectif de ce travail était l’évaluation de

leurs capacités diagnostiques et pronostiques chez des patients atteints de FA et de sténose

mitrale.

Dans la première publication (1) il était mis en évidence que le MRproANP, le sCD146

et le sST2 permettaient de discriminer une origine cardiaque congestive chez des patients

consultant pour dyspnée. Seuls les taux de MRproANP et sCD146 étaient liés à la dilatation

atriale, suggérant l’intérêt potentiel de ces biomarqueurs dans des pathologies avec atteinte

atriale.

Nous avons évalué dans une seconde publication (2) les concentrations plasmatiques de

MRproANP et de sCD146 chez des patients porteurs de sténoses mitrales serrées et

moyennement serrées. Les concentrations de ces deux biomarqueurs étaient toutes deux plus

élevées chez les patients porteurs de sténoses mitrales serrées en comparaison à ceux ayant des

sténoses moyennement serrées.

La troisième publication (3) fait suite à cette seconde étude. Elle a évalué les

concentrations de MRproANP, sCD146, BNP et NTproBNP, en pré et post commissurotomie

mitrale percutanée (CMP). Les taux initiaux de BNP, MRproANP, et sCD146 étaient

significativement abaissés en post CMP. Il n’existait pas de baisse significative de ces

biomarqueurs si les critères de succès de la CMP n’étaient pas remplis. Cette baisse semble

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donc refléter l’amélioration hémodynamique induite par une procédure réalisée avec succès,

conférant au MRproANP et au sCD146 le rôle de marqueurs de succès d’une CMP.

L’ensemble de ces résultats concernant le sCD146 s’explique par sa libération au niveau

de l’endothélium de la circulation pulmonaire en réponse à la congestion induite par le

rétrécissement mitral. Les résultats concernant le MRproANP sont expliqués par une libération

conditionnée par la pression intra atriale gauche chez les patients porteurs de sténose mitrale.

A l’issu de ces 3 premières études, nous pouvons conclure que les taux de MRproANP

et de sCD146 sont des marqueurs de sévérité de la sténose mitrale et du résultat de son

traitement percutané.

Nous nous sommes enfin focalisés sur l’étude de ces biomarqueurs chez les patients en

FA (4). L’ablation de FA est au cœur de la prise en charge de cette pathologie. L’identification

des patients à risque de récidive post ablation est primordiale. Nous nous sommes ainsi

intéressés à l’impact des niveaux plasmatiques de MRproANP et de sST2 avant une ablation

sur le taux de récidive à un an. Le MRproANP était un prédicteur indépendant de récidive de

fibrillation atriale dans notre étude, le sST2 ne l’était pas. Un MRproANP au-delà d’un seuil de

107.9pmol/L était lié à un risque de récidive de FA multiplié par 25. Inversement en dessous

de ce seuil le risque de récidive à un an était de 4,2% avec une valeur prédictive négative très

élevée de 95.7%.

Dans cette même étude les concentrations pré-ablation de MRproANP étaient plus

élevées chez les patients en fibrillation qu’en rythme sinusal, et plus élevées dans les oreillettes

que dans le sang veineux périphérique. Ces données sont en faveur d’une sécrétion atriale du

MRproANP chez les patients en fibrillation.

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Nous avons par ce travail pu montrer l’intérêt du MRproANP, du sCD146 et du sST2

pour le pronostic, le diagnostic de sévérité et le suivi des patients atteints de sténose mitrale ou

de FA.

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Abstract

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The assessment of biomarkers has become an integral part of the daily practice of

cardiology. However, in diseases affecting primarily the atria, the diagnostic and prognostic

role of widely used biomarkers is less well documented. Thus, we investigated the potential

utility of 3 biomarkers in diseases affecting primarily the atrium, namely atrial fibrillation (AF)

and mitral stenosis. The biomarkers investigated were MRproANP, a natriuretic peptide of

atrial origin; sCD146, a biomarker of endothelial origin; and sST2, a marker of fibrosis. The

aim of this work was to evaluate the diagnostic and prognostic capacities of these biomarkers

in patients with AF or mitral stenosis.

The first publication (1) investigated the performance of several biomarkers in patients

consulting for dyspnea. In this context, MRproANP, sCD146 and sST2 made it possible to

identify the cardiac origin of the dyspnea. In this study, only MRproANP and sCD146 levels

were found to be associated with right and left atrial dilation. This suggested the potential

interest of these biomarkers in pathologies affecting the atria.

In a second publication (2), we assessed plasma concentrations of MRproANP and

sCD146 in patients with moderate to severe mitral stenosis. Both biomarkers were significantly

higher in patients with severe mitral stenosis compared to those with moderate mitral stenosis.

The third publication (3) followed up on this theme by investigation the concentrations

of MRproANP, sCD146, BNP and NTproBNP before and after percutaneous mitral

commissurotomy (PMC). MR-proANP and plasma sCD146 were shown to decrease

significantly immediately after PMC. Of note, in this study, the significant changes in

biomarker levels were observed mainly in patients in whom the PMC procedure was judged

successful. The decrease in these biomarkers therefore seems to reflect the improvement in

hemodynamics induced by the successful procedure, making MRproANP and sCD146

adequate markers of procedural success after PMC.

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Taken together, the results observed with sCD146 can be explained by the fact that it is

released by the endothelium in the pulmonary circulation in response to congestion caused by

mitral stenosis. A possible explanation for our findings regarding MRproANP is that its release

is conditioned by left intra-atrial pressure in patients with mitral stenosis.

After these three studies, we can conclude that MRproANP and sCD146 are markers of

the severity of mitral stenosis, and of the success of PMC.

Subsequently, we went on to investigate the utility of these biomarkers in patients with

AF (4). Catheter ablation is currently the cornerstone of AF therapy. The main limitation of

catheter ablation of AF is the success rate of the procedure, which ranges between 50 and 80%.

There is a strong need to identify patients at risk of recurrence after catheter ablation. To this

end, we investigated the impact of pre-procedural plasma levels of MRproANP and sST2 on

the rate of AF recurrence at 1 year after catheter ablation. We found that MRproANP was an

independent predictor of recurrence in our study, whereas sST2 was not. An MRproANP levels

above a threshold of 107.9pmol/L was found to be associated with a 25-fold increase in the risk

of AF recurrence. Conversely, patients with values below the threshold had a recurrence rate of

4.2%, with a high negative predictive value, at 95.7%.

In this study, we also observed that pre-procedural rates of MRproANP were highest in

patients in AF, compared to those in sinus rhythm. Concentrations did not significantly differ

between the right and left atria, but intra-atrial concentrations were significantly higher than

those observed in the peripheral blood. These data plead in favour of the atrial release of

MRproANP in patients in AF.

We demonstrated the utility of MRproANP, sCD146 and sST2for prognosis, diagnosis

of severity, and follow-up of patients with mitral stenosis or AF.

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I. Introduction

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La pratique de la cardiologie fait appel de façon quotidienne à l’utilisation de

biomarqueurs. Qu’il s’agisse des syndromes coronaires aigus, de la maladie thromboembolique

veineuse ou de l’insuffisance cardiaque, ils sont au cœur de la prise en charge par l’aide qu’ils

apportent dans le diagnostic, le pronostic et la stratification du risque, guidant ainsi le

traitement. La performance des biomarqueurs les plus utilisés, à savoir le BNP ou le NTproBNP

et la troponine, en termes de diagnostic et de pronostic dans ces pathologies est démontrée (5-

8). Cependant dans les pathologies à atteinte atriale prédominante, n’impliquant ni nécrose ni

atteinte ventriculaire, la performance diagnostique et pronostique de ces biomarqueurs

classiquement utilisés est moins bonne. C’est le cas par exemple de la sténose mitrale où la

survenue d’une HTAP et d’une dysfonction ventriculaire droite n’apparait qu’à un stade évolué

de la maladie alors que l’atteinte de l’oreillette gauche est au premier plan. Les données

échographiques permettent d’évaluer la sévérité de la sténose mitrale et ses complications mais

il n’existe que très peu de données concernant des biomarqueurs adaptés spécifiquement à cette

pathologie.

De manière plus générale il n’existe que peu de données concernant des biomarqueurs

plus spécifiquement atriaux qui puissent également s’appliquer aux pathologies rythmiques

atriales, en particulier à la fibrillation atriale. On s’appuie dans la fibrillation atriale sur des

données cliniques et échographiques permettant d’évaluer le niveau d’évolution et le pronostic

de cette pathologie. Il n’existe en revanche pas de biomarqueur fiable notamment pour prédire

l’évolution ou la récidive de la fibrillation atriale après une cardioversion électrique ou une

ablation endocavitaire. Pourtant leur utilisation en routine dans ces pathologies aurait une utilité

certaine dans le diagnostic de gravité de la pathologie, le suivi et également le pronostic à long

terme.

Le Mid-Regional pro Atrial Natriuretic Peptide (MRproANP) est la portion mid-

regional du NTproANP, il est un peptide plus spécifiquement atrial. Le Suppression of

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Tumorigenicity 2 (sST est un marqueur de fibrose et le Soluble cluster of differentiation 146

(sCD146) est un marqueur d’origine endothéliale. Ces biomarqueurs ne sont pas utilisés dans

la pratique clinique actuelle.

Nous avons dans un premier travail collaboratif évalué le lien entre les concentrations

plasmatiques de ces trois biomarqueurs et la dilatation atriale ainsi que la capacité de ces

biomarqueurs à discriminer une origine cardiaque chez des patients dyspnéiques. Nous avons

ensuite choisi de nous intéresser au MRproANP et au sCD146 chez des patients porteurs de

sténoses mitrales, et notamment à leur capacité à évaluer la sévérité du rétrécissement et le

succès du traitement percutané de la sténose mitrale. Enfin chez des patients atteints de

fibrillation atriale, nous avons choisi d’évaluer la capacité du MRproANP et du sST2 à prédire

un succès ou une récidive de FA à distance d’une ablation endocavitaire.

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II. Rationnel

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II.1. Biomarqueurs d’intérêt potentiel dans les pathologies atriales

Trois biomarqueurs ont donc retenu notre attention pour être étudiés dans des

pathologies avec atteinte atriale : le MRproANP, un peptide natriurétique plus spécifiquement

atrial, portion mid-regional du NTproANP, le sCD146 un marqueur d’origine endothéliale et

enfin le sST2 un marqueur de fibrose notamment myocardique. Nous allons détailler dans ce

chapitre les données connues sur la sécrétion et la physiologie de ces biomarqueurs.

II.1.1. Mid-Regional pro Atrial Natriuretic Peptide (MRproANP)

L’ANP est un peptide natriurétique. Sa synthèse se fait sous la forme initiale d’une pro

hormone : le proANP. Chez l’homme, il existe une synthèse extracardiaque de ce peptide mais

le cardiomyocyte atrial est le principal site de synthèse. L’expression génique du proANP dans

les cardiomyocytes atriaux est en effet 30 à 50 fois plus élevée que dans les tissus extra atriaux

(9-11). Le proANP est libéré par les cardiomyocytes atriaux en réponse à la tension pariétale.

Il est clivé en ANP mature et en sa portion N Terminal le NTproANP. Il est plus stable et sa

demi-vie est beaucoup plus longue que l’ANP mature rendant son dosage plus intéressant (12,

13). Un dosage du NTproANP a été élaboré grâce à une méthode immunologique avec fixation

de deux anticorps en sandwich sur la portion mid-regional du NTproANP, région appelée

MRproANP (figure 1). Le dosage du MRproANP est donc possible et fiable par cette méthode

réalisée à l’aide du système KRYPTOR (BRAHMS, AG, Henningsdorf/Berlin, Germany) (13).

Les concentrations plasmatiques moyennes de MRproANP chez un sujet sain entre 56 et 65 ans

sont de 64,8pmol/L chez l’homme et 68.6pmol/L chez la femme (13). En situation clinique

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stable, sa variabilité est faible, elle ne varie pas significativement d’une année à l’autre chez un

même patient sans changement significatif de son poids (14). Son intérêt a été démontré dans

le diagnostic et le pronostic de l’insuffisance cardiaque (15-18). Il semble être un bon marqueur

de congestion et de rétention hydrosodée (19). Néanmoins il existe peu de données sur l’intérêt

de peptides plus spécifiquement atriaux dans des pathologies impliquant l’oreillette en premier

lieu.

Figure 1 : Fixation de 2 anticorps en sandwich sur la portion mid-regional du NTproANP pour

en permettre le dosage (MRproANP).

II.1.2. Soluble cluster of differentiation 146 (sCD146)

Le CD146 est une molécule d’adhésion exprimée par les cellules endothéliales

vasculaires. Elle est un composant de la jonction endothéliale (20, 21). Elle est impliquée dans

l’intégrité du vaisseau et dans la cohésion intercellulaire de l’endothélium (21, 22). Il a été

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démontré sur modèle animal qu’elle était particulièrement présente dans l’intima des gros

vaisseaux (23). CD146 de surface joue un rôle central dans la régulation de la perméabilité

vasculaire. Sa forme soluble le sCD146 est libérée par l’endothélium suite à la perte du CD146

de surface (figure 2). Les taux circulants de sCD146 semblent associés aux manifestations

d’insuffisance cardiaque et à la dysfonction ventriculaire gauche (23, 24). Il a également été

démontré que le sCD146 était libéré du système vasculaire périphérique en réponse à l'étirement

veineux et reflète une congestion systémique (25). La physiologie de la libération de CD146

n’est néanmoins pas complétement connue, l’implication potentielle des cavités cardiaques,

notamment atriales, n’a par exemple pas été étudiée. L’intérêt de ce biomarqueur dans des

pathologies touchant en premier lieu l’oreillette reste inconnu.

Figure 2 : CD146 de surface libéré sous la forme CD146 soluble (sCD146) suite à un signal

(stress mécanique) au sein de la cellule endothéliale.

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II.1.3. Soluble Suppression of Tumorigenicity 2 (sST2)

Suppression of tumorigenicity 2 (ST2) est une famille de récepteur à l’interleukine 1.

Le ST2 soluble (sST2) est la forme actuellement dosable biologiquement. Il est lié à la réaction

inflammatoire, libéré en réponse à un signal de danger (nécrose, lésions cellulaires,

traumatismes, stimulus inflammatoire, stress mécanique….) (figure 3), il n’est donc pas

spécifiquement cardiaque et s’élève dans de nombreuses pathologies (26). Cependant il semble

entre autre être un biomarqueur de fibrose et de contrainte biomécanique cardiaque (27, 28).

sST2 est un important marqueur pronostique dans l’insuffisance cardiaque (29-33) mais a peu

été étudié dans des pathologies touchant en premier lieu l’oreillette.

Figure 3 : Libération de ST2 soluble (sST2) suite à un signal de danger intracellulaire (nécrose,

lésions cellulaires, traumatismes, stimulus inflammatoire, stress mécanique).

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II.2. Situations cliniques pouvant justifier l’utilisation de ces biomarqueurs

La sténose mitrale et la fibrillation atriale sont deux pathologies où l’atteinte est

prédominante sur l’oreillette gauche. Les trois biomarqueurs étudiés pourraient montrer un

intérêt pour le diagnostic et l’évaluation de la gravité de ces pathologies. Ils pourraient

également avoir un intérêt dans la prise en charge thérapeutique en tant que marqueur

pronostique ou de succès des interventions percutanées concernant l’oreillette gauche comme

la commissurotomie mitrale percutanée ou l’ablation de fibrillation atriale.

II.2.1. Impact de l’insuffisance cardiaque au niveau atrial

Dans l’insuffisance cardiaque, qu’elle soit à fraction d’éjection préservée ou altérée, la

pression télédiastolique ventriculaire ou précharge s'élève. Il s'en suit une élévation des

pressions en amont, notamment dans l’oreillette gauche puis dans les veines pulmonaires. Ce

phénomène est par la suite responsable de l’œdème pulmonaire. L’augmentation de pression

intra atriale entraine une dysfonction et une éventuelle dilatation atriale (34). L’insuffisance

cardiaque semble un modèle possible pour l’étude des biomarqueurs de dysfonction atriale.

II.2.2. Sténose mitrale et commissurotomie mitrale par voie percutanée

La sténose mitrale ou rétrécissement mitral s’observe préférentiellement chez les

femmes. Elle est secondaire à un rhumatisme articulaire aigu dans la grande majorité des cas.

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Les autres causes possibles sont rares, qu’elles soient toxiques, congénitales ou post radiques.

Les lésions anatomiques caractéristiques du rétrécissement mitral associent :

- une fusion ou symphyse des commissures ;

- un épaississement des feuillets valvulaires qui peuvent, chez certains patients être calcifiés ;

- un remaniement de l’appareil sous-valvulaire associant, à des divers degrés, fusion des

cordages, raccourcissements et rétractions.

Le diagnostic et l’évaluation de la sévérité repose sur l’échographie cardiaque. La

surface mitrale et le gradient trans-mitral sont les paramètres pris en compte dans l’évaluation

de la sévérité. On parle de sténose mitrale pour un gradient dépassant 5 mmHg, la sténose

devient probablement serrée au-delà de 10 mmHg. Le gradient trans-mitral n’est pas le

paramètre de référence, celui-ci ne dépend en effet pas uniquement de la surface mitrale mais

également de la fréquence cardiaque, du débit cardiaque, du rythme cardiaque, des conditions

de charge et de l’existence d’une fuite associée. La surface mitrale mesurée en planimétrie est

la méthode de référence pour l’évaluation de la sévérité du rétrécissement mitral. La sténose

mitrale est considérée serrée pour une surface ≤ 1.5cm2 (35) ou 0.9-1cm2/m2. La mesure se

fait en coupe petit axe (figure 4). Les mesures réalisées ainsi sont les plus fiables, elles sont en

effet les mieux corrélées aux mesures directes per opératoires de l’orifice mitrale (36).

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Une fois le diagnostic de sévérité posé, l’échographie cardiaque doit guider le

traitement : chirurgie mitrale ou valvuloplastie mitrale par voie percutanée. Pour identifier les

candidats à une valvuloplastie mitrale par voie percutanée, les classifications de Wilkins et/ou

de Cormier sont utilisées (35, 37). Elles prennent en compte la mobilité des valves, l’aspect de

l’appareil sous-valvulaire, l’épaississement et les calcifications valvulaires. En cas de forme

favorable une valvuloplastie mitrale percutanée (VMP) est réalisée (38). Il est à noter que plus

l’atteinte de l’appareil valvulaire et sous valvulaire est importante, moins la forme est favorable

à une VMP.

La procédure de VMP se fait par abord veineux fémoral avec ponction transseptale après

avoir vérifié la vacuité de l’auricule. La valve mitrale est ensuite dilatée par un ballon d’Inoué,

avec plusieurs inflations (39-41) (figure 5).

Figure 4 : Echocardiographie

coupe petit axe, planimétrie

d’une sténose mitrale serrée (1.34cm2).

25

L’objectif de la procédure de la VMP est d’obtenir une ouverture commissurale, une

diminution du gradient trans-mitral et une augmentation de la surface, sans entrainer de fuite

mitrale significative (42). En cas de contre-indication ou de forme non favorable à la

commissurotomie mitrale percutanée, un traitement chirurgical est réalisé. Chez les patients

asymptomatiques sans possibilité de valvuloplastie percutanée, un traitement médical associé à

une surveillance clinique et échographique est recommandé (35). En l’absence de traitement la

sténose mitrale a un retentissement sur la circulation d’amont, en premier lieu sur l’oreillette

gauche. L’augmentation de pression au sein de cette dernière entraine sa dilatation, un risque

Figure 5a : Vue antéropostérieure.

Ballon d’Inoué dégonflé dans le VG (voie transseptale), avant inflation

dans la valve mitrale.

Figure 5b : Vue antéropostérieure.

Ballon d’Inoué gonflé durant une inflation dans la valve mitrale.

Encoches visibles sur le ballon liées à

la valve mitrale sténosée.

26

accru de fibrillation atriale et de formation de thrombus intra-atrial gauche. Cette pathologie est

ainsi un bon modèle d’étude de biomarqueurs de dysfonction atriale gauche. Son évolution et

le succès ou l’échec de son traitement devraient en effet avoir un retentissement sur les niveaux

de ces biomarqueurs. Elle évolue ensuite vers une hypertension artérielle pulmonaire d’abord

post capillaire puis fixée. Le retentissement se fait par la suite naturellement sur les cavités

cardiaques droites avec une dilatation et une dysfonction ventriculaire droite. A un stade évolué

la sténose se manifeste essentiellement par des signes d’insuffisance cardiaque droite.

II.2.3. Fibrillation atriale et ablation endocavitaire

La fibrillation atriale (FA) est le trouble du rythme cardiaque de l’adulte le plus fréquent.

Il est particulièrement fréquent en Europe et en Amérique du Nord avec une prévalence au-delà

de 600 pour 100000 habitants. Sa prévalence est en augmentation constante. Les facteurs

connus favorisant la survenue de FA sont multiples, entre autres : la présence de cardiopathies

en particulier valvulaires ou ischémiques, l’insuffisance cardiaque, l’hypertension artérielle, le

diabète, l’obésité, le syndrome d’apnée du sommeil, la consommation excessive d’alcool,

l’excès ou le manque d’activité physique (43-47). La FA est identifiée sur un

électrocardiogramme par une absence d’activité atriale organisée, et une irrégularité des espaces

RR. Initialement la FA évolue sur un mode paroxystique défini par des passages en arythmie

de moins de 7 jours avec ou sans intervention médical (46). Elle est alors liée à des foyers

ectopiques situés dans plus de 90% des cas au niveau des veines pulmonaires (figure 6),

responsables des passages en FA (48).

27

Figure 6 : Situation de 69 foyers ectopiques focaux “triggers’’ des passages en FA chez 45

patients. Adapté de : Haïssaguerre M et al. Spontaneous initiation of atrial fibrillation by

ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339(10):659-66.

Sans traitement la FA devient ensuite persistante avec des passages de plus de 7 jours

puis “long-standing persistent’’ définie par plus d’un an de FA sans retour en rythme sinusal.

Enfin la FA est dite permanente lorsque médecin et patient s’accordent sur le fait de respecter

l’arythmie, de contrôler la fréquence cardiaque et les symptômes sans chercher à restaurer le

rythme sinusal (46). Cette évolution vers la FA persistante et éventuellement permanente est

liée à un remodelage électrique qui modifie l'expression et / ou la fonction des canaux ioniques

(49-54) (figure 7). Le remodelage électrique stabilise les réentrées et pérennise la fibrillation

atriale, il induit une récidive rapide après une cardioversion et également une résistance aux

anti-arythmiques (49). Le remodelage structurel, en particulier la fibrose (55-59), fait suite au

remodelage électrique (49, 50, 52, 53, 60, 61) (figure 7). La fibrose interstitielle sépare les

faisceaux musculaires, la fibrose réparatrice remplace quant à elle les cardiomyocytes. La

28

présence de fibroblastes ralenti ensuite localement la conduction. Il produit des zones de

conduction lente et des blocs de conduction. De cette manière le remodelage des oreillettes est

responsable d’activités électriques focales ou rotationnelles anormales de plus en plus

nombreuses (57). L’anatomie macroscopique de l’oreillette gauche se modifie alors également,

avec une dilatation de celle-ci (55, 56, 58).

Figure 7 : Les mécanismes de la fibrillation atriale (FA). A : Foyers ectopiques “triggers’’, B :

Circuit de réentrée unique ou peu nombreux et simples, C : Multiples réentrées complexes, D :

correspondance avec les formes cliniques : dans la FA paroxystique, l’action de foyers

29

ectopiques “gâchettes’’ prédomine, particulièrement dans les veines pulmonaires, la FA

devient ensuite persistante et éventuellement permanente, il s’installe alors des circuits de

réentrées de plus en plus nombreux qui prédominent. Ces circuits ont d’abord un substrat

fonctionnel et secondairement un substrat structurel.

VCS : veine cave supérieure, VCI : veine cave inférieure, OD : oreillette droite, OG : oreillette

gauche, VPs : veines pulmonaires.

Adapté de Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology:

implications for management. Circulation. 2011.

Les principales manifestations cliniques de la fibrillation atriale sont les palpitations, la

dyspnée. Elle se complique essentiellement d’insuffisance cardiaque avec ou sans dysfonction

ventriculaire gauche ainsi que d’événements cardio-emboliques. La prévention des événements

cardio-emboliques repose sur la prescription d’anticoagulants oraux à doses curatives en cas de

score de risque embolique CHA2DS2 VASC ≥ 1 chez l’homme et ≥ 2 chez la femme (46, 62-

65).

En ce qui concerne la gestion rythmique il est décidé soit un contrôle de fréquence

cardiaque avec utilisation de traitements bradycardisants en cas de besoin, soit un contrôle de

rythme c’est-à-dire le maintien du rythme sinusal. Le maintien du rythme sinusal a fait la preuve

de sa supériorité dans la prise en charge de FA de découverte récente, sur la survenue

d’événements cardiovasculaires (66). L’ablation de fibrillation atriale est actuellement au centre

de la stratégie de contrôle du rythme cardiaque (46, 62, 67). Elle consiste en l’isolation des

veines pulmonaires où sont localisés les foyers ectopiques “triggers’’ de la FA (48). La

supériorité de l’ablation de fibrillation atriale, en comparaison au traitement anti-arythmique,

pour le maintien du rythme sinusal ainsi qu’en termes de morbi-mortalité chez les patients

30

insuffisants cardiaques a été démontrée (68-73). Plusieurs techniques sont disponibles pour

isoler les veines pulmonaires : la radiofréquence (figure 8), la cryoablation (74) (figure 9) ou le

laser (75, 76).

Figure 8 : Reconstruction anatomique tridimensionnelle de l’oreillette gauche en vue

postérieure (CARTO System, Biosense Webster Inc. Diamond, CA, USA). Veines pulmonaires

droites en vert, gauches en bleu. Isolation des veines pulmonaires, 2 à 2, par radiofréquence

(points d’ablation matérialisés en rose).

31

En cas de fibrillation persistante la radiofréquence est utilisée préférentiellement,

d’autres lésions peuvent alors être réalisées mais aucune n’a clairement démontré sa supériorité

(77) (figure 10).

Figure 9 : Ablation de fibrillation

atriale par cryothérapie. Vue

antéropostérieure. Opacification

d’une veine pulmonaire supérieure

gauche avec le cryoballon (Artic

Front Advance, Medtronic,

Minneapolis, MN, USA) en vue de

l’isolation.

32

Figure 10a : Ablation de fibrillation atriale persistante avec isolation des veines pulmonaires.

Adapté de Verma A et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med. 2015;372(19):1812-22.

Figure 10b : Ablation de fibrillation atriale persistante avec isolation des veines pulmonaires et lignes mitrale et du toit.


Figure 10c : Ablation de fibrillation atriale persistante avec isolation des veines pulmonaires et ablation des potentiels fragmentés.


33

L’alcoolisation de la veine de Marschall est une technique récente largement étudiée

actuellement et potentiellement prometteuse dans l’ablation de la fibrillation atriale persistante

(78-81) (figure 11). Elle induit une nécrose de l’isthme mitrale, zone privilégiée de réentrées.

Figure 11 : Cathétérisation du sinus coronaire et opacification de la veine de Marschall en vue

de son alcoolisation. Vue OAG 30°.

Opacification de la

veine de Marschall

occluse au ballon

2.25*8mm.

Cathéter

d’angioplastie dans le sinus coronaire

Opacification de la veine de

Marschall après cathétérisation

du sinus coronaire avec une

gaine orientable et un cathéter

d’angioplastie coronaire.

Cathéter de cartographie et

d’ablation dans l’oreillette gauche, par voie transseptale,

en vue de l’ablation.

34

II.3. Synthèse

Dans un premier temps nous avons choisi d’évaluer ces 3 biomarqueurs en tant que

marqueurs de congestion chez des patients dyspnéiques et plus précisément, le lien entre

dilatation atriale et concentrations plasmatiques de MRproANP et sCD146 a été recherché.

Au vu de l’ensemble ces données, nous avons également décidé d’étudier le lien entre

les niveaux de MRproANP, sCD146 et la sévérité des sténoses mitrales, la présence de

complications de ces sténoses, ainsi que la capacité des biomarqueurs à identifier un succès de

commissurotomie mitrale percutanée.

Dans la fibrillation atriale nous avons choisi d’évaluer la capacité du MRproANP et du

sST2 à prédire un succès ou une récidive de FA à 1 an d’une ablation.

35

III. Corrélation entre Mid-Regional

pro Atrial Natriuretic Peptide,

Soluble Cluster of Differentiation 146

et surfaces atriales droite et gauche

36

Acutely decompensated heart failure with preserved and reduced ejection fraction

present with comparable haemodynamic congestion.

Lucas N.L. Van Aelst, Mattia Arrigo, Rui Placido, Eiichi Akiyama, Nicolas Girerd, Faiez

Zannad, Philippe Manivet, Patrick Rossignol, Marc Badoz, Malha Sadoune, Jean-Marie

Launay, Etienne Gayat, Carolyn S.P. Lam, Alain Cohen-Solal, Alexandre Mebazaa and

Marie-France Seronde.

European Journal of Heart Failure (2018) 20, 738–747.

AVANT PROPOS

L’insuffisance cardiaque gauche entraine une congestion veineuse pulmonaire liée à une

anomalie cardiaque structurelle ou fonctionnelle. Cette congestion est responsable de la

dyspnée ressentie par les patients insuffisants cardiaques, en particulier au moment des épisodes

de décompensation cardiaque. Chez un patient dyspnéique, le diagnostic étiologique vise à

discriminer une cause cardiaque liée à la congestion, d’une cause extra cardiaque.

La pathologie évolue naturellement vers l’hypertension pulmonaire et la dysfonction

ventriculaire droite (8, 82). L’insuffisance cardiaque, y compris à fraction d’éjection préservée,

est associé à une dysfonction et dilatation atriale (34).

L’article suivant s’intéresse à l’aide que pourraient apporter différents biomarqueurs,

notamment le MRproANP, le sCD146 et le sST2 dans l’évaluation de la congestion et dans le

bilan étiologique d’une dyspnée (cardiaque ou extra cardiaque). Il s’intéresse également au lien

entre dilatation atriale et niveau de sCD146 et de MRproANP.

European Journal of Heart Failure (2018) 20, 738–747 RESEARCH ARTICLEdoi:10.1002/ejhf.1050

Acutely decompensated heart failure with

preserved and reduced ejection fraction

present with comparable haemodynamic

congestionLucas N.L. Van Aelst1,2,3†, Mattia Arrigo3,4,5†, Rui Placido3,6†, Eiichi Akiyama3,7,

Nicolas Girerd8, Faiez Zannad8, Philippe Manivet3,9,10, Patrick Rossignol8,

Marc Badoz11, Malha Sadoune3, Jean-Marie Launay3,9,10, Etienne Gayat3,5,12,

Carolyn S.P. Lam13, Alain Cohen-Solal2,3,12, Alexandre Mebazaa3,5,12*†,

and Marie-France Seronde3,11†

1Department of Cardiovascular Sciences KU Leuven, Campus Gasthuisberg O&N1, Leuven, Belgium; 2Department of Cardiology, Hôpital Lariboisière, Paris, France; 3U942

INSERM, Assistance Publique – Hôpitaux de Paris, Paris, France; 4Division of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland; 5Department

of Anesthesia and Critical Care, Hôpitaux Universitaires Saint Louis-Lariboisière, Paris, France; 6Hospital Santa Maria, Serv Cardiologia I, Lisbon Academic Medical Centre,

CCUL, Lisbon, Portugal; 7Division of Cardiology, Yokohama City University Medical Center, Minamiku, Yokohama, Japan; 8INSERM, Centre d’Investigations Cliniques

Plurithématique, CHRU de Nancy, Université de Lorraine, CHRU de Nancy, and F-CRIN INI-CRCT, Nancy, France; 9Department of Medical Biochemistry and Molecular Biology,

Hôpital Lariboisière, Paris, France; 10Biossip Analytical Platform, Center for Biological Resources, Lariboisière Hospital, Paris, France; 11Department of Cardiology, University

Hospital Jean Minjoz, Besançon, France; 12University Paris Diderot, Sorbonne Paris Cité, Paris, France; and 13National Heart Centre Singapore and Duke-National University of

Singapore, Singapore

Received 14 July 2017; revised 18 September 2017; accepted 26 September 2017 ; online publish-ahead-of-print 18 December 2017

Aims Congestion is a central feature of acute heart failure (HF) and its assessment is important for clinical decisions (e.g.

tailoring decongestive treatments). It remains uncertain whether patients with acute HF with preserved ejection

fraction (HFpEF) are comparably congested as in acute HF with reduced EF (HFrEF). This study assessed congestion,

right ventricular (RV) and renal dysfunction in acute HFpEF, HFrEF and non-cardiac dyspnoea.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methods

and results

We compared echocardiographic and circulating biomarkers of congestion in 146 patients from the MEDIA-DHF

study: 101 with acute HF (38 HFpEF, 41 HFrEF, 22 HF with mid-range ejection fraction) and 45 with non-cardiac

dyspnoea. Compared with non-cardiac dyspnoea, patients with acute HF had larger left and right atria, higher E/e’,

pulmonary artery systolic pressure and inferior vena cava (IVC) diameter at rest, and lower IVC variability (all

P< 0.05). Mid-regional pro-atrial natriuretic peptide (MR-proANP) and soluble CD146 (sCD146), but not B-type

natriuretic peptide (BNP), correlated with echocardiographic markers of venous congestion. Despite a lower BNP

level, patients with HFpEF had similar evidence of venous congestion (enlarged IVC, left and right atria), RV dysfunction

(tricuspid annular plane systolic excursion), elevated MR-proANP and sCD146, and renal impairment (estimated

glomerular filtration rate; all P> 0.05) compared with HFrEF.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusion In acute conditions, HFpEF and HFrEF presented in a comparable state of venous congestion, with similarly altered

RV and kidney function, despite higher BNP in HFrEF.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Keywords Heart failure • Biomarkers • Echocardiography • Diagnosis • Prognosis

*Corresponding author. Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint Louis-Lariboisière, 2 Rue Ambroise-Paré, 75010 Paris, France. Tel: +33 01

49958071, Fax: +33 01 49956954, Email: [email protected]†These authors contributed equally to this manuscript.

© 2017 The AuthorsEuropean Journal of Heart Failure © 2017 European Society of Cardiology

Acutely decompensated HFpEF and HFrEF 739

Introduction

Heart failure (HF) is a clinical syndrome resulting from an abnor-

mal cardiac structure or function which impairs the heart’s ability

to meet the oxygen and nutrient requirements of metabolizing

tissues, and leads to pulmonary venous congestion.1,2 ‘Backward’

failure may further lead to pulmonary venous hypertension, right

ventricular (RV) dysfunction, renal venous hypertension and renal

dysfunction. Bedside assessment of venous congestion is important

for the classification of acutely decompensated patients into ‘wet’

vs. ‘dry’ phenotypes, which then guides clinical management, e.g.

aggressive diuresis in ‘wet’ patients. Conversely, under-recognition

of the extent of venous congestion can lead to inadequate diure-

sis and higher rehospitalization rates. The assessment of venous

congestion is particularly challenging in patients with HF and pre-

served ejection fraction (HFpEF), who are frequently obese with

age-related non-cardiac co-morbidities.

We aimed to compare the extent of venous congestion, RV and

renal dysfunction at acute presentation in patients with HFpEF

vs. HF with reduced ejection fraction (HFrEF) and non-cardiac

dyspnoea using echocardiographic and circulating biomarkers.

Methods

Patient population

We analysed the data of patients included in MEDIA-DHF (The

Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure

study; NCT02446327). MEDIA-DHF enrolled patients with acute dys-

pnoea of non-cardiac origin, acutely decompensated heart failure

(ADHF) and chronic HF. For this specific substudy, a database was

constructed between February 2011 and April 2014, including eligible

patients admitted for acute dyspnoea of cardiac or non-cardiac ori-

gin as the main symptom at the emergency departments of Hôpital

Lariboisière (Paris) and Hôpital Universitaire Jean Minjoz (Besançon),

both in France. The aim of this study was to characterize acute HFpEF,

HFrEF and acute dyspnoea of non-cardiac origin, with special empha-

sis on congestion, RV and kidney dysfunction at admission. Inclusion

criteria were age>18 years and acute dyspnoea. Exclusion criteria

were acute coronary syndromes, inotropic support within the last 2 h

before inclusion, systolic blood pressure persistently below 90mmHg,

severe aortic or mitral valvulopathy, pneumothorax, recent surgery or

trauma (< 3months), severe or end-stage renal impairment (clearance

<30mL/min or dialysis), chronic liver disease, chronic infectious (bac-

terial of viral) disease, cerebrovascular disease or stroke in the last

3months, any malignant concomitant diseases or a malignant disease

in the last 5 years, systemic inflammatory diseases, such as autoim-

mune diseases, connective tissue diseases or collagenoses, pregnancy.

The adjudicated final diagnosis (ADHF or non-cardiac dyspnoea) was

performed independently by two cardiologists not in charge of the

patients, yet with unlimited access to clinical, biochemical and imaging

materials obtained in the emergency departments, intensive or cardiac

care units and during the remainder of the hospitalization. When the

two experts disagreed regarding the final diagnosis, a third physician

adjudicated the final diagnosis.3

The study protocol complied with the Declaration of Helsinki and

was approved by the ethics committee of the participating institutions

[Commission Nationale de l’Informatique et des Libertés (CNIL)

910198; Comité d’Evaluation de l’Ethique des projets de Recherche ........................................................................................................................................................................ Biomedicale (CEERB) 10–017]. All patients provided written informed

consent.

Echocardiography

Echocardiographic measurements of chamber and vessel dimensions

and cardiac systolic and diastolic functions were obtained according

to the guidelines by cardiologists experienced in echocardiographic

measurements (R.P. and M.F.S.) within 4 h of presentation for dysp-

noea in the emergency department, using standard acoustic windows

on a Philips CX50 or iE33 ultrasound system.4 We aimed for a com-

prehensive assessment of echocardiographic parameters of congestion,

systolic and diastolic ventricular function in every patient. When clin-

ical presentation interfered with appropriate cardiac imaging, assess-

ment of systolic function was prioritized over diastolic function and

left ventricular filling pressures, which were preferred over additional

echocardiographic parameters of congestion. Ventriculo–arterial cou-

pling was calculated as the quotient of end-systolic volume and stroke

volume.5 Investigators involved in image acquisition were blinded to

obtained natriuretic peptide levels and were not involved in further

statistical analysis of the data. ADHF patients were divided into three

subgroups based on their left ventricular ejection fraction (LVEF) on

admission: reduced LVEF <40% (HFrEF); mid-range LVEF between 40

and 49% (HFmrEF); preserved LVEF >50% (HFpEF).1

Biomarkers

During initial presentation in the emergency department and at dis-

charge, blood samples were collected in plastic tubes containing

ethylenediaminetetra-acetic acid. Aliquots of plasma samples were

stored at −80 ∘C for further analysis. Apart from routinely used mark-

ers of kidney and liver function, several plasma biomarkers reflect-

ing different pathophysiological pathways in HF were assessed: brain

natriuretic peptide (BNP; Abbott), mid-regional pro-atrial natriuretic

peptide (MR-proANP; BRAHMS AG - ThermoFisher), high sensitive

troponin I (hsTnI; Roche Diagnostics), cluster of differentiation 62E

and 146 (CD62E, soluble CD146 or sCD146; Biocytex), mid-regional

pro-adrenomedullin (MR-proADM; ThermoFisher Diagnostics), solu-

ble ST2 (Critical Diagnostics), galectin 3 (Abbott), C-reactive protein

(CRP; Siemens), procalcitonin (BRAHMS AG - ThermoFisher), inter-

cellular adhesion molecule 3 (ICAM3; Abcam), cystatine C (Abbott),

neutrophil gelatinase associated lipocalin (NGAL; Abbott).

Follow-up and outcome

After discharge, patient outcome was followed for 1 year, with struc-

tured telephone calls at 3, 6 and 12months after admission. An

adverse event was defined as death or cardiovascular rehospital-

ization, whichever came first. Death occurring on the first day of

(re)hospitalization was defined as death rather than (re)hospitalization.

Statistical analysis

Continuous variables are expressed as means with standard deviations

(SD) when normally distributed or as medians with interquar-

tile ranges (IQR) when not normally distributed. Normality was

assessed by the Shapiro–Wilk test. Categorical variables are pre-

sented as numbers and percentages. Groups were compared using

one-way analysis of variance (ANOVA) or non-parametric alter-

natives as appropriate. Subsequent pairwise comparisons were


740 L.N.L. Van Aelst et al.

Table 1 Clinical characteristics at admission

Acute dyspnoea ADHF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ADHF Non-cardiac P-value HFpEF HFrEF P-value. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Number of patients (% of total cohort) 101 (69) 45 (31) 38 (26) 41 (28)

Age (years) 76 [62–84] 72 [53–85] 0.108 79 [70–87] 63 [56–77] 0.003

Male/female (%) 55/46 (54/46) 16/29 (36/64) 0.048 13/25 (34/66) 32/9 (78/22) <0.001

Weight (kg) 76±19 77±17 0.572 77± 20 76±18 1.000

Body surface area (kg/m2) 1.84± 0.23 1.84± 0.23 0.935 1.83± 0.25 1.88± 0.22 1.000

Clinical

Dyspnoea duration (days) 2 [1–7] 3 [1–7] 0.481 2 [1–8] 3 [2–7] 0.517

NYHA functional class I/II/III/IV (%) 0/2/24/74 3/22/22/53 0.001 0/3/24/73 0/3/32/65 0.796

Respiratory rate (r.p.m.) 28 [22–32] 26 [24–34] 0.866 28 [22–32] 26 [20–32] 1.000

SpO2 (%) 93± 6 95± 4 0.098 91± 6 95± 4 0.006

Heart rate (b.p.m.) 87 [71–103] 92 [76–105] 0.337 75 [69–95] 95 [80–108] 0.026

Systolic blood pressure (mmHg) 148± 32 144± 25 0.665 154± 35 139± 31 0.124

Diastolic blood pressure (mmHg) 83 [71–98] 82 [75–88] 0.562 80 [69–100] 83 [72–97] 0.639

Jugular distension, n (%) 36 (36) 4 (9) 0.001 13 (34) 16 (39) 0.816

Peripheral oedema, n (%) 55 (54) 9 (20) <0.001 23 (61) 19 (46) 0.261

Hepatomegaly, n (%) 9 (9) 1 (2) 0.168 4 (11) 3 (9) 1.000

Pulmonary rales <0.001 0.804

None (%) 16 60 13 19

Single base (%) 5 2 3 8

Single base and >1/3 up lung fields (%) 3 2 3 5

Bi-basilar (%) 41 22 43 38

Bi-basilar and >1/3 up lung fields (%) 35 14 38 30

Medical history

Obesity, n (%) 21 (21) 3 (7) 0.032 10 (26) 5 (12) 0.150

Diabetes mellitus, n (%) 35 (35) 11 (24) 0.251 14 (37) 14 (34) 0.818

Arterial hypertension, n (%) 75 (74) 25 (56) 0.034 30 (79) 27 (66) 0.219

Dyslipidaemia, n (%) 42 (42) 8 (18) 0.005 17 (45) 14 (34) 0.365

Never smoked, n (%) 66 (65) 30 (67) 0.700 27 (71) 25 (61) 0.393

Previous myocardial infarction, n (%) 21 (21) 0 (0) 0.001 6 (16) 7 (17) 1.000

Coronary artery disease, n (%) 31 (31) 6 (13) 0.038 11 (29) 11 (27) 1.000

Previous CABG/PCI, n (%) 22 (22) 4 (9) 0.065 8 (21) 8 (20) 1.000

Known heart failure, n (%) 37 (37) 5 (11) 0.001 10 (26) 19 (46) 0.102

Previous stroke, n (%) 7 (7) 5 (11) 0.518 4 (11) 2 (5) 0.419

Atrial fibrillation/atrial flutter, n (%) 22 (22) 4 (9) 0.018 12 (32) 3 (7) 0.001

Peripheral artery disease, n (%)

COPD, n (%)

8 (8)

8 (8)

3 (7)

7 (16)

1.000

0.236

5 (13)

3 (8)

1 (2)

1 (2)

0.100

0.347

Asthma, n (%)

Chronic kidney disease, n (%)

4 (4)

8 (8)

13 (29)

2 (4)

0.001

0.489

2 (5)

3 (8)

1 (2)

2 (5)

0.606

0.640

Chronic treatment

Beta blockers, n (%) 60 (59) 9 (20) 0.001 23 (61) 24 (59) 1.000

ACE inhibitors or ARBs, n (%)

Aldosterone receptor antagonists, n (%)

65 (64)

10 (10)

12 (27)

4 (9)

0.001

1.000

23 (61)

2 (5)

25 (61)

8 (20)

1.000

0.089

Diuretics, n (%) 72 (71) 11 (24) 0.001 26 (68) 28 (68) 1.000

Digoxin, n (%) 10 (10) 0 (0) 0.032 5 (13) 3 (7) 0.471

Nitrates, n (%) 7 (7) 0 (0) 0.049 1 (3) 2 (5) 1.000

Vitamin K antagonists, n (%) 31 (31) 4 (9) 0.006 14 (37) 9 (22) 0.215

Inhaled beta-agonists, n (%) 5 (5) 7 (16) 0.110 2 (5) 1 (2) 0.569

First adverse event

Death or rehospitalization 53 (52) 7 (16) 0.001 18 (47) 21 (51) 0.227

Death, n (%) 9 (9) 2 (4) 0.149 4 (11) 2 (5) 0.145

Rehospitalization, n (%) 44 (44) 5 (11) 0.001 14 (37) 19 (46) 0.498

ACE, angiotensin converting enzyme; ADHF, acutely decompensated heart failure; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; COPD, chronic

obstructive pulmonary disease; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NYHA, New York Heart Association;

PCI, percutaneous coronary intervention.



Table 2 Echocardiographic parameters at admission

Acute dyspnoea ADHF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Ventricular function

Ejection fraction (%) 40 [30–55] 60 [54–65] 0.001 60 [52–64] 29 [20–33] <0.001

LVEDD (mm) 56±11 46± 7 0.001 50± 9 64± 9 <0.001

LVESD (mm) 43 [33–51] 29 [25–32] 0.001 32 [25–37] 54 [48–60] <0.001

Posterior wall thickness (mm) 11 [9–13] 10 [8–13] 0.130 12 [11–15] 10 [9–13] 0.015

Relative wall thickness (mm) 0.39 [0.31–0.50] 0.43 [0.37–0.59] 0.077 0.48 [0.39–0.60] 0.31 [0.27–0.38] <0.001

Left ventricular mass (g) 261 [201–317] 164 [132–215] 0.001 245 [191–291] 304 [232–334] 0.042

Ventriculo–arterial coupling 1.22 [0.66–2.46] 0.40 [0.31–0.55] 0.001 0.53 [0.24–0.79] 2.93 [2.21–3.72] <0.001

MAPSE (mm) 10 [9–14] 16 [13–19] 0.006 11 [9–14] 10 [9–10] 0.439

TAPSE (mm) 17 [14–20] 24 [20–28] 0.001 17 [15–22] 17 [15–21] 1.000

TAPSE/syst PAP (mm/mmHg)

E wave (cm/s)

0.43± 0.18

100± 32

0.71± 0.20

73± 22

0.001

0.001

0.41± 0.18

105± 33

0.46± 0.19

91± 32

1.000

0.206

E wave deceleration time (ms) 138 [114–178] 175 [152–249] 0.001 152 [131–187] 131 [107–158] 0.093

A wave (cm/s) 55 [29–87] 87 [70–108] 0.001 75 [39–103] 35 [25–68] 0.015

E/A 1.5 [0.9–2.8] 0.8 [0.7–1.0] 0.001 1.2 [0.7–1.7] 2.5 [1.3–3.1] 0.012

Parameters of congestion

Left atrial area (cm2)

E/e’ average

26± 8

17 [12–23]

18± 6

9 [8–12]

0.001

0.001

25± 8

17 [12–26]

29± 8

18 [13–21]

0.169

1.000

Systolic PAP (mmHg) 46±14 32± 8 0.014 47±14 43±16 1.000

Right atrial area (cm2) 19± 6 14± 4 0.025 17± 6 21± 6 0.424

IVC diameter (mm) 21± 6 15± 6 0.001 21± 5 20± 7 1.000

Variability of IVC diameter (%) 33 [9–50] 52 [33–67] 0.004 30 [10–44] 32 [9–50] 1.000

ADHF, acutely decompensated heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IVC, inferior vena cava;

LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; MAPSE, mitral annular peak systolic excursion; PAP, pulmonary artery pressure;

TAPSE, tricuspid annular plane systolic excursion.

performed using Bonferroni correction for multiple comparisons.

A P-value of <0.05 was considered statistically significant.

Statistical analyses were performed using STATA 14.1 (Stata-

Corp, College Station, TX, USA) and GraphPad Prism 6.0 h (GraphPad

Software, La Jolla, CA, USA).

Results

Patient characteristics at admission

In total, 146 patients were prospectively included in the MEDIA

cohort. Table 1 presents baseline characteristics of groups sep-

arated according to the aetiology of acute dyspnoea: ADHF vs.

non-cardiac dyspnoea, and within ADHF: HFpEF (LVEF >50%,

n= 38) vs. HFrEF (LVEF <40%, n= 41).

Among ADHF patients, HFpEF patients were nearly two decades

older [79 years (70–87)] than HFrEF patients [63 years (56–77);

P= 0.003). Most HFpEF patients were women (66%), whereas 78%

of HFrEF patients were men (P< 0.001). Whereas most clinical

signs of congestion (jugular vein distension, peripheral oedema,

pulmonary rales) were significantly different between ADHF and

non-cardiac dyspnoea, the clinical presentation of HFpEF and

HFrEF was comparable. Yet, at admission, oxygen saturation

(SaO2) and heart rate were lower in HFpEF patients compared

with HFrEF patients [SaO2: 91± 6% vs. 95± 4%, P= 0.006; heart

rate: 75 b.p.m. (69–95) vs. 95 b.p.m. (80–108), P= 0.026]. ............................................................................ After 1 year of follow-up, death or rehospitalization occurred

in 16% of patients with dyspnoea of non-cardiac origin while

markedly higher (52%; P= 0.001) in patients admitted for

ADHF, including 47% (18 out of 38 patients) for HFpEF and

51% (21 out of 41 patients) for HFrEF (P= 0.227; Table 1 and

supplementary material online, Figure S1).

When comparing HFpEF with HFmrEF (LVEF 40–49%, n= 22),1

there was no difference in clinical characteristics nor in the rate of

death or rehospitalization (data not shown).

Echocardiographic parametersat admission (Table 2 and Figure 1)

Left and right ventricular function

In our MEDIA-DHF cohort, parameters of left and right ven-

tricular function were both altered in ADHF patients compared

to non-cardiac dyspnoea patients (Figure 1A). Notably, tricuspid

annular plane systolic excursion (TAPSE) was on average 17mm

in ADHF (IQR: 14–20mm) and 24mm (IQR: 20–28mm) in

non-cardiac dyspnoea patients (P= 0.001).

Concerning ADHF patients, HFpEF manifested higher LVEF

(P< 0.001) and left ventricular mass (P= 0.042), yet lower left

ventricular end-diastolic diameter (P< 0.001) and left ventricular

end-systolic diameter (P< 0.001) compared with HFrEF. However,

RV function was similarly altered in HFpEF and HFrEF, with a



Table 3 Circulating biological markers at admission

Acute dyspnoea ADHF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Inflammation and fibrosis

Soluble ST2 (ng/mL) 78.6 [56.5–131.0] 53.3 [34.5–78.8] 0.001 74.4 [50.8–117.0] 84.6 [59.3–138.2] 0.692

CRP (mg/L) 11 [4–41] 19 [6–67] 0.228 12 [5–29] 8 [3–25] 1.000

ICAM3 (ng/mL) 208 [93–443] 287 [178–623] 0.042 219 [104–497] 166 [74–375] 0.467

Galectin 3 (ng/mL) 21.7 [18.7–26.9] 23.1 [15.7–30.9] 0.703 21.9 [19.3–24.8] 19.5 [15.7–27.3] 0.656

Procalcitonin (ng/mL) 0.10 [0.07–0.14] 0.08 [0.04–0.24] 0.392 0.11 [0.08–0.14] 0.08 [0.07–0.16] 0.492

CD62E (ng/mL) 30 [16–60] 25 [5–59] 0.323 29 [16–57] 34 [14–60] 1.000

Cardiovascular stress and

congestion

BNP (pg/mL) 928 [401–1588] 128 [28–237] 0.001 443 [321–981] 1083 [807–2692] <0.001

MR-proANP (pmol/L) 396 [272–580] 87 [47–176] 0.001 330 [267–464] 474 [293–660] 0.176

sCD146 (ng/mL) 526 [388–654] 266 [193–411] 0.001 518 [388–615] 524 [396–660] 1.000

hsTnI (pg/mL)

MR-proADM (nmol/L)

27 [15–77]

1.85± 0.82

7 [3–32]

1.20± 0.38

0.001

0.112

24 [12–75]

1.58± 0.85

42 [18–89]

1.95±1.05

0.356

1.000

Distant organ dysfunction

Creatinine (mg/dL) 1.13 [0.87–1.47] 0.83 [0.70–1.03] 0.001 1.10 [0.87–1.41] 1.18 [0.98–1.48] 0.567

eGFR MDRD (mL/min) 62 [47–84] 85 [77–101] 0.001 60 [45–74] 63 [53–86] 0.358

Cystatin C (mg/L) 1.4 [1.1–2.0] 1.2 [0.9–1.6] 0.016 1.5 [1.2–2.4] 1.3 [1.1–1.6] 0.358

NGAL (ng/mL) 114 [84–191] 89 [67–165] 0.048 114 [82–277] 103 [85–145] 0.491

ADHF, acutely decompensated heart failure; BNP, brain natriuretic peptide; CD62E, cluster of differentiation 62E; sCD146, soluble cluster of differentiation 146; CRP, C-reactive

protein; eGFR, estimated glomerular filtration rate; ICAM3, intercellular adhesion molecule 3; MDRD, Modification of Diet in Renal Disease; HFpEF, heart failure with preserved

ejection fraction; HFrEF, heart failure with reduced ejection fraction; hsTnI, high sensitive troponin I; ICAM3, intercellular adhesion molecule 3; MR-proADM, mid-regional

pro-adrenomedullin; MR-proANP, mid-regional pro-atrial natriuretic peptide; NGAL, neutrophil gelatinase associated lipocalin.

comparable percentage of HFpEF and HFrEF patients having

reduced (TAPSE <15mm in 20% and 18% of patients, respectively;

P=1.000) or severely reduced RV longitudinal function (TAPSE

<10mm in 10% and 4% of patients, respectively; P= 0.563).

Echocardiographic parameters of haemodynamic

congestion

At admission, ADHF showed higher left and right atrial areas,

E/e’, pulmonary artery systolic pressure, IVC diameter at rest and

lower IVC variability compared to non-cardiac dyspnoea patients

(Figure 1B).

Among ADHF patients, HFpEF and HFrEF had compara-

ble echocardiographic signs of haemodynamic congestion (all

P> 0.05).

Circulating biological markersat admission (Table 3)

Markers of inflammation and fibrosis

ADHF patients had increased levels of markers of inflammation

and fibrosis, as evidenced by increased soluble ST2 and ICAM3

compared to non-cardiac dyspnoea patients (P= 0.001 and 0.042,

respectively). However, levels of CRP, galectin 3, procalcitonin and

CD62E were similar in ADHF and non-cardiac dyspnoea groups.

No difference in any of these biomarkers could be seen between

HFpEF and HFrEF. .................................................................................. Markers of cardiovascular stress and congestion

BNP, MR-proANP, hsTnI and sCD146 all discriminated well

between our ADHF and non-cardiac dyspnoea groups (P= 0.001

for all comparisons; Table 3). Table 3 further shows that BNP

was higher in HFrEF than HFpEF patients (P< 0.001) while

MR-proANP, hsTnI and sCD146 appeared similarly elevated in

HFpEF and HFrEF patients (all P> 0.05).

Correlation between echocardiographicand biochemical markers of congestion

Comparison of echocardiographic parameters of cardiac (right

and left atrial) or peripheral (IVC) congestion and BNP, hsTnI or

MR-proADM, showed no correlation. In contrast, circulating levels

of MR-proANP and sCD146 were tightly associated with left and

right atrial areas, IVC diameter at end expiration (Figure 2a), IVC

variability, E/e’ and pulmonary artery systolic pressure (see supple-

mentary material online, Table S1). Figure 2b shows that the combi-

nation of elevated MR-proANP and sCD146 at admission for acute

dyspnoea was associated with cardiac and peripheral congestion.

Acutely decompensated heartfailure-induced kidney dysfunction

Several markers of kidney function (creatinine, cystatin C and

NGAL) and estimated glomerular filtration rate (eGFR) were dete-

riorated in ADHF compared with non-cardiac dyspnoea patients.



HFpEF HFrEF

0

15

30

HFpEF HFrEF

0

20

40

Non

Cardiac

Non

Cardiac

Non

Cardiac

HFpEF HFrEF

0

15

30

right atrial area (cm2)

0

20

40

0

15

30

0

40

80

E/e’

left atrial area (cm2)IVC diameter (mm)

*

†

LVEF (%)

†

† †

TAPSE (mm)

†

‡

‡‡

A

B

‡

Figure 1 Comparison of left ventricular ejection fraction (LVEF), E/e’, tricuspid annular plane systolic excursion (TAPSE), inferior vena cava

(IVC) diameter at end expiration, left atrial area and right atrial area between patients with non-cardiac dyspnoea, heart failure with preserved

(HFpEF) and reduced ejection fraction (HFrEF). *P< 0.05 in HFpEF vs. HFrEF; †P< 0.05 in non-cardiac vs. HFrEF; ‡P< 0.05 in non-cardiac vs.

HFpEF.

However, these markers were similarly altered in HFpEF and HFrEF

patients.

In all ADHF patients combined, Figure 3 shows that eGFR was

not correlated with cardiac index (r= 0.096 and P= 0.5939), nor

right atrial area (r=−0.332 and P= 0.0734) yet with IVC diameter

(r=−0.291 and P= 0.0241).

The supplementary material online, Figure S2 shows that in

both HFpEF and HFrEF, eGFR did not correlate with cardiac

index nor TAPSE. In contrast, right atrial area and IVC diam-

eter at rest associated with eGFR in HFrEF, yet not in HFpEF

patients.

Discussion

The MEDIA-DHF study showed that acute HFpEF and HFrEF

present with comparable echocardiographic and biomarker

(MR-proANP, sCD146) signs of venous congestion, RV and renal

dysfunction, in spite of differences in left ventricular wall stress

(BNP). This suggests that patients with acute HFpEF may benefit

from aggressive decongestion with diuretics as much as patients ............................................................. with acute HFrEF, and that these therapeutic efforts should not be

guided by presenting BNP levels.

Consistent with prior studies,6–11 our study confirmed that

acute HFpEF predominantly affects old hypertensive women

who present with acute dyspnoea and hypoxaemia. We further

showed, using imaging and circulating biomarkers, that acute

HFpEF and acute HFrEF shared similar features: (i) increased

natriuretic peptides, (ii) increased pulmonary pressure, (iii) altered

RV function, (iv) enlarged IVC, (v) altered renal function, and

(vi) poor outcomes. Altogether, those data demonstrated that

acute HFpEF represents bona fide ADHF as much as acute HFrEF.

Our data are in line with findings in the chronic setting, in which

haemodynamic congestion and RV dysfunction have been similarly

reported in chronic HFpEF and HFrEF, and associated with worse

outcomes.12–14

Filling pressures are frequently assessed by echocardiography

to substantiate an equivocal clinical diagnosis of congestion and

to guide titration of diuretic therapy.15,16 In our study population,

non-cardiac dyspnoea patients had significantly lower E/e’ values

compared with ADHF patients. In contrast, filling pressures could



0 10 20 30 400

5

10

0 10 20 30 400

5

10

15

0

15

30

20

40

0 10 20 30 400

5

10

0 20 40 600

5

10

0 10 20 30 400

5

10

15

0 20 40 600

5

10

15

MR-proANP

A

B

(x100 pmol/L)

MR-proANP

(x100 pmol/L)

MR-proANP

(x100 pmol/L)

sCD146

(x100 ng/mL)

sCD146

(x100 ng/mL)

sCD146

(x100 ng/mL)

surface left atrium (cm2) surface right atrium (cm2) IVC diameter (mm)

r = 0.25

P = 0.0076

r = 0.54

P = 0.0004

r = 0.30

P = 0.0031

r = 0.50

P = < 0.0001

r = 0.47

P = 0.0023

r = 0.38

P = 0.0002

-

-

0

MR-proANP

sCD146

+

+

-

-

+

+

*

surface left atrium (cm2) IVC diameter (mm)

*

Figure 2 Correlation of mid-regional pro-atrial natriuretic peptide (MR-proANP) and soluble CD146 (sCD146) with echocardiographic

indices of haemodynamic congestion. Discriminatory potential of MR-proANP and sCD146 to detect dilated left atrium and inferior vena cava

(IVC). Event free survival of studied cohorts. (A) Correlation of MR-proANP (top panels) and sCD146 (bottom panels) with left atrial area,

pulmonary artery systolic pressure, IVC diameter at end expiration. (B) Elevated levels of the biomarkers MR-proANP and sCD146 allow to

distinguish congested from non-congested patients. *P < 0.05.

not differentiate between acute HFrEF and HFpEF. Importantly, this

straightforward measurement becomes unreliable with incorrect

sample volume placement and rather common clinical scenarios

such as sinus tachycardia, atrial fibrillation, mitral annular calcifi-

cation, severe mitral regurgitation, ventricular dyssynchrony and

regional wall motion abnormalities.17 We hypothesize that in an

all-comer, real world situation, the discriminatory potential of

filling pressures between cardiac and non-cardiac dyspnoea is

likely worse than reported in our study, given our non-inclusion ........................... of patients with acute coronary syndromes and severe aortic

or mitral valvuloplasty, as well as our reliance on experienced

cardiologists for imaging.

Our study confirmed that all circulating biomarkers of conges-

tion were similarly high in both acute HFpEF and HFrEF, with the

exception of a much lower level of BNP in acute HFpEF compared

to HFrEF.6,18 A higher BNP may be expected in acute HFrEF vs.

HFpEF given the greater left ventricular wall stress, the stimulus

for BNP release, in an eccentrically remodeled heart in HFrEF.



0 10 20 30 400

40

80

120

0 10 20 30 400

40

80

120

0 1 2 3 4 5 60

40

80

120

eGFR

(ml/min)

eGFR A B C(ml/min)

eGFR

(ml/min)r = 0.096

P = 0.5939

r = -0.332

P = 0.0734

r = -0.291

P = 0.0241

right atrial area (cm2)cardiac index (l/m2) inferior vena cava diameter (mm)

Figure 3 Correlation of estimated glomerular filtration rate (eGFR) with selected indices of ventricular function and haemodynamic

congestion in acutely decompensated heart failure: cardiac index (A), right atrial area (B) and inferior vena cava diameter at rest (C).

Importantly, BNP levels (marker of left ventricular wall stress)

did not correlate with echocardiographic markers of venous con-

gestion, whereas MR-proANP (marker of cardiac congestion) and

sCD146 (marker of venous congestion) did. MR-proANP is the

stable prohormone fragment of proANP, mainly released by the

atrial myocardium in response to increased filling pressures.1,19,20

Soluble CD146 is expressed on the endothelial cell surface and

is released in the bloodstream in response to venous stretch or

stress in acute HF patients21 and in chronic HF patients.22 Our

study showed a relationship between MR-proANP and sCD146

and echocardiographic signs of venous congestion in acute dys-

pnoeic patients. Based on these results, we hypothesize that in

ADHF, BNP, while a good marker of HF vs. non-cardiac dyspnoea,

may not accurately reflect the degree of venous congestion and

may therefore not be the ideal marker to guide decongestion ther-

apy. In contrast, MR-proANP and sCD146 could hold potential to

be used as markers in ADHF for venous congestion, a hypothesis

worthy of testing in future prospective studies. Admittedly, another

mechanism at play in acute HF, not necessarily pertaining to venous

congestion, might account for our observed associations.

MEDIA-DHF also showed that kidney dysfunction was associ-

ated with echocardiographic parameters of right-sided congestion

rather than RV and LV systolic performance in ADHF patients.

Importantly, further subdivision of ADHF in HFpEF and HFrEF

revealed a divergent impact of haemodynamic congestion on kidney

dysfunction. Whereas the latter and right-sided congestion cor-

related in HFrEF, this relationship was not present in HFpEF. We

hypothesize that this finding indicates that different pathophysio-

logic mechanisms may being responsible for kidney dysfunction in

acute HFpEF and HFrEF.Whereas haemodynamic congestion might

be the main determinant of kidney dysfunction in acute HFrEF,

endothelial dysfunction could be the main driver of kidney dys-

function in acute HFpEF.23

Our study has several clinical implications. Similarities in the level

of haemodynamic congestion between acute HFpEF and HFrEF

may suggest the use of similar decongestive therapies in the ini-

tial phase, especially with regard to diuretics and vasodilators.

Our study further showed that haemodynamic congestion could .................................................................................................................... be assessed by the combination of elevated MR-proANP and

sCD146. In the future, those biomarkers might help to adjust ini-

tial decongestive therapies, in case echocardiography is not imme-

diately available. Our study also showed that kidney dysfunction

may have different mechanisms in HFrEF and HFpEF. This find-

ing may support the combined use of decongestive and reno-

protective therapies as optimal standard therapy in all ADHF

patients.

Our study has its limitations. First, included patients were

derived from two tertiary care facilities only. Whereas the advan-

tages of this approach certainly were uniform sample handling, anal-

yses and data management, this approach might have introduced

bias, in particular deviation of the studied sample from the gen-

eral population. However, the clinical characteristics at admission

of HFpEF, HFrEF and non-cardiac dyspnoea patients are reminis-

cent of clinical practice and earlier studies,24,25 making us confident

about the generalizability and reliability of our results. Secondly,

we included 146 patients in our cohort; yet, we felt this pro-

vided enough power to detect statistical significance and clinical

relevance between (sub)group differences, while avoiding statisti-

cally significant, although clinically irrelevant, findings. Nonetheless,

future research should validate our findings in a medium-sized or

large-sized independent set of patients in a multicentre study.

In conclusion, under acute conditions, HFpEF and HFrEF present

in a comparable state of venous congestion, with similarly altered

RV and kidney function, despite lower BNP in HFpEF. These findings

carry implications for decongestive therapy in ADHF regardless

of EF.

Supplementary Information

Additional Supporting Information may be found in the online

version of this article:

Figure S1. Event free survival in non-cardiac dyspnoea, HFpEF and

HFrEF patients.

Figure S2. Correlation of estimated glomerular filtration rate

(eGFR) with selected indices of ventricular function and cardio-

vascular congestion in HFpEF and HFrEF: cardiac index (A), surface



of the right atrium (B) and inferior vena cava (IVC) diameter at

rest (C).

Table S1. Correlation of selected biomarkers with echocardio-

graphic parameters of haemodynamic congestion.

Funding

L.N.L.V.A. is supported by a training grant from the European Soci-

ety of Cardiology (2015; Sophia Antipolis, France) and a travelling

award from the International Society for Heart and Lung Trans-

plantation (August 2015 and 2016; Addison, TX, USA). L.N.L.V.A.

gratefully acknowledges the financial support from the Belgian Fund

for Cardiac Surgery through the Jacqueline Bernheim prize 2015

(Brussels, Belgium). M.A. is recipient of a fellowship of the Collège

de Médecine des Hôpitaux de Paris (Paris, France). M.F.S. received

a grant from the Ligue Française contre la Cardiomyopathie (Mont-

boissier, France). E.A. is supported by a research fellowship from

the Japan Heart Foundation (Tokyo, Japan). This study is supported

by a grant from the European Union (FP7-HEALTH-2010-MEDIA;

Luxembourg) to F.Z., P.R., A.M.

Conflict of interests: L.N.L.V.A., M.A., R.P., E.A., N.G., F.Z.,

P.M., M.B., M.S., J.M.L., E.G. and M.F.S. report no conflict of

interests. P.R. received lecture fees from CVRx and consult-

ing fees from Novartis, Relypsa, AstraZeneca, Stealth Peptides,

Fresenius, Vifor Fresenius Medical Care Renal Pharma, CTMA.

P.R. is cofounder of CardioRenal. A.C.S. received honoraria or

grants from Novartis, Servier, Roche Diagnostics, Alere, Bayer,

Vifor. A.M. received fees as member of advisory board and/or

Steering Committee from Cardiorentis, Adrenomed, MyCartis,

Neurotronik, ZS Pharma and Critical Diagnostics. C.S.P.L. has

received research support from Boston Scientific, Bayer, Ther-

moFisher, Medtronic and Vifor Pharma; and has consulted for

Bayer, Novartis, Takeda, Merck, Astra Zeneca, Janssen Research

& Development, LLC, Menarini, Boehringer Ingelheim and Abbott

Diagnostics.

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47

IV. Intérêt du Mid-Regional pro

Atrial Natriuretic Peptide et du

Soluble Cluster of Differentiation 146

dans l’évaluation de la sévérité et du

traitement percutané de la sténose

mitrale

48

IV.1. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide et du Soluble Cluster

of Differentiation 146 dans l’évaluation de la sévérité de la sténose mitrale

Role of cardiovascular biomarkers for the assessment of mitral stenosis and its

complications.

Marc Badoz, Mattia Arrigo, Bernard Iung, Gullu Amioglu, Mehmet Birhan Yilmaz,

Nicolas Meneveau, Malha Sadoune, Agnes Brunette, Alexandre Mebazaa, Marie-France

Seronde.

European Journal of Internal Medicine 34 (2016) 58–62.

AVANT PROPOS

La sténose mitrale est essentiellement d’origine rhumatismale. Même si la prévalence

du rhumatisme articulaire aigu a considérablement diminué, la sténose mitrale représente

encore 10% des valvulopathies (83). Les autres étiologies de sténose mitrale sont dégénératives,

et exceptionnellement post-radiques, congénitales ou toxiques.

La sténose mitrale provoque une augmentation de pression dans la circulation d’amont

à savoir dans l’oreillette gauche, la circulation pulmonaire et enfin les cavités droites. Elle

entraine donc : dilatation de l’oreillette gauche, fibrillation atriale, hypertension artérielle

pulmonaire post capillaire, et enfin à un stade évolué dilatation des cavités droites et

dysfonction ventriculaire droite.

49

L’utilisation de biomarqueurs liés à la sévérité de la sténose et donc au degré d’atteinte

de l’oreillette gauche aurait un intérêt majeur dans cette pathologie. En effet l’évaluation de la

sténose mitrale et de ses complications est classiquement réalisée en échographie cardiaque.

Cette évaluation est nécessaire pour le suivi et en cas d’apparition ou d’aggravation de la

dyspnée chez un porteur de sténose mitrale. L’échographie cardiaque peut poser problème en

termes notamment de disponibilité dans certains centres ou certaines zones peu médicalisées,

elle est opérateur dépendant, subjective et sa qualité dépend de l’échogénicité du patient. Les

formes très évoluées de sténoses mitrales, avec atteinte majeure de l’appareil sous valvulaire,

sont de plus en plus fréquentes, leur évaluation échographique est d’autant plus complexe. Dans

ces conditions l’utilisation d’un biomarqueur lié à la sévérité de la sténose et à ses complications

permettrait de s’affranchir des limites de l’échographie cardiaque. Nous nous sommes donc

intéressés aux performances d’un biomarqueur classique, le BNP, ainsi qu’au MRproANP et

au sCD146 dans ce cadre.

Original Article

Role of cardiovascular biomarkers for the assessment of mitral stenosisand its complications

Marc Badoz a,1, Mattia Arrigo b,c,d,e,1, Bernard Iung f, Gullu Amioglu g, Mehmet Birhan Yilmaz g,Nicolas Meneveau a, Malha Sadoune b, Agnes Brunette a, Alexandre Mebazaa b,c,⁎,2, Marie-France Seronde a,2

a Besancon University Hospital, Besancon, Franceb INSERM UMR-S 942, Paris, Francec Department of Anesthesiology and Critical Care Medicine, AP-HP, Saint Louis Lariboisière University Hospitals, Paris, Franced Department of Cardiology, AP-HP, Saint Louis Lariboisière University Hospitals, Paris, Francee Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerlandf Department of Cardiology, AP-HP, Bichat University Hospitals, Paris, Franceg Sivas Numune Hospital, Sivas, Turkey

a b s t r a c ta r t i c l e i n f o

Article history:

Received 1 February 2016

Received in revised form 21 March 2016

Accepted 11 May 2016

Available online 25 May 2016

Background: Mitral stenosis (MS) may cause progressive dyspnea on exertion, pulmonary hypertension (PH),

atrial fibrillation and right ventricular (RV) failure. Patients with MS presenting with change in dyspnea severity

often require a complete cardiologic assessment, but the use of biomarkers may be an alternative for the initial

assessment of MS and its complications. The aim of this study was to evaluate the role of several cardiovascular

biomarkers for this purpose.

Methods: Clinically stable patientswithmoderate or severeMSwere included in this prospectivemulticenter ob-

servational study. ECG, transthoracic echocardiography and biomarker measurement (BNP, MR-proANP and

sCD146) were performed at inclusion. One cohort of patients with pre-capillary PH (PAH)was included for com-

parison of biomarker levels in different etiologies of PH.

Results: A total of 117 MS (70% severe, 30% moderate stenosis) were included. Plasma levels of all three bio-

markers were higher in severe MS compared to moderate MS. PH was associated with higher levels of BNP

and MR-proANP. The presence of atrial fibrillation increased plasma levels of BNP and sCD146, whereas MR-

proANPwas not affected by atrial fibrillation. PAH patients had higher levels of sCD146 compared toMS patients

with PH. RV dysfunction was associated with higher levels of sCD146.

Conclusion: MS and its complications affect plasma levels of cardiovascular biomarkers. The use of MR-proANP

may be helpful for the assessment of severe stenosis and the presence of PH in the early phase. sCD146 might

help identifying patients with more advanced PH and RV-dysfunction.

© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Keywords:

Mitral stenosis

Pulmonary hypertension

Biomarker

BNP

MR-proANP

sCD146

1. Introduction

Mitral stenosis (MS) is often a sequel of rheumatic fever and,although rheumatic fever has greatly decreased in industrialized coun-tries, MS still causes significant morbidity and mortality worldwide.MS may not cause symptoms for years and then present with progres-sive dyspnea on exertion, pulmonary hypertension (PH), atrial fibrilla-tion, right ventricular (RV) failure.

Patients with MS presenting with change in dyspnea severity oftenrequire a complete cardiologic assessment including ECG and echocar-diography to exclude disease progression or complications. Indeed,echocardiography allows a comprehensive assessment of valve mor-phology, severity of stenosis and associated conditions. However, asdyspnea is a frequent cause of consultation of emergency departmentsand echocardiography is not always immediately available, especiallyin countries where MS is particularly frequent, the use of biomarkersmay be an interesting alternative for the initial assessment of MS andits complications.

The aims of this studywere to evaluate the role of several cardiovas-cular biomarkers (BNP, MR-proANP, sCD146) in the assessment of MSseverity and its complications, in particular atrialfibrillation, pulmonaryhypertension and RV dysfunction. Natriuretic peptides (e.g. BNP, NT-proBNP and MR-proANP) have been shown to accurately identify

European Journal of Internal Medicine 34 (2016) 58–62

⁎ Corresponding author at: Saint Louis LariboisièreUniversity Hospitals, 2, rueAmbroise

Paré, 75010 Paris, France. Tel.: +33 1 49 95 80 71.

E-mail address: [email protected] (A. Mebazaa).1 Equally contributing first authors.2 Equally contributing senior authors.

http://dx.doi.org/10.1016/j.ejim.2016.05.008

0953-6205/© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Contents lists available at ScienceDirect

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j ourna l homepage: www.e lsev ie r .com/ locate /e j im

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mailto:[email protected]


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cardiac origin of dyspnea [1–3]. Very recently, the novel endothelial bio-marker sCD146, a marker of peripheral congestion, has been shown tohave similar diagnostic properties to detect cardiac origin of acutedyspnea [4].

Aim of the study was a more complete understanding of cardiovas-cular biomarker behavior in presence ofMS.We hypothesized that BNP,MR-proANP and sCD146 might be useful for the assessment of MSseverity and its complications, in particular pulmonary hypertension.

2. Methods

2.1. Study population

Consecutive, clinically stable patients withmoderate (valve area be-tween 1.5 and 2 cm2) or severe (valve area b 1.5 cm2)MSwere includedin the study between January 1st, 2011 andMarch 31st, 2015. This pro-spective multicenter observational study was performed at the Univer-sity Hospital of Besancon (France), Bichat University Hospital in Paris(France), and Cumhuriyet University Hospital of Sivas (Turkey). Exclu-sion criteria were: age b 18 years; left ventricular ejection fractionb40%; recent acute coronary syndrome or documented coronary dis-ease; combination of MS with severe aortic valve disease or more thanmild mitral regurgitation; recent (b1 month) cardiac decompensation.Patients with high heart rate (N110 beats perminute), uncontrolled hy-pertension (systolic blood pressure N 180 mm Hg), severe anemia(hemoglobin b 9 g/dL) or pregnancy were excluded as well.

One small cohort (n = 16) of patients with pre-capillary PH (PAH)examined at University Hospital of Besancon was included forcomparison of biomarker levels in different etiologies of pulmonaryhypertension.

2.2. Echocardiographic study

All patients underwent transthoracic echocardiography at inclusion,and measurements were made in accordance with the recommenda-tions of the European Association for Echocardiography [5]. Severity ofmitral valve stenosis (MS) was assessed by planimetric evaluation inthe parasternal short axis view. MS was considered severe if the valvearea was ≤1.5 cm2 and moderate if the valve area was between 1.5and 2 cm2. Extent of mitral regurgitation was estimated by color Dopp-ler according to an integrative approach [6] Left ventricular (LV) systolicfunction was evaluated by measurement of the LV ejection fraction bythe Simpson's biplane method. The left atrial size was assessed bymea-suring its area from the apical four chamber view or its volume in boththe four and two chamber views. The left atrium (LA)was considered tobedilated if areawas N20 cm2, or volume N 60mL, or diameter N 40mm.Pulmonary pressures were calculated from maximal tricuspid regurgi-tation velocity on continuous Doppler in the apical four chamberview, taking into account the size and compliance of the inferior venacava. A diagnosis of PH was retained for a tricuspid regurgitationvelocity N 2.8 m/s, corresponding to systolic pulmonary artery pressure(PAP) N30 mm Hg. Right ventricular (RV) function was assessed bymeasuring RV fractional area change (RV fac), tricuspid annular planesystolic excursion (TAPSE) and systolicmyocardial velocity at the lateraltricuspid annulus (TAPSE S′). RV dysfunction was defined as thealteration of any one of these three criteria (i.e. RV fac b 40%,TAPSE b 18 mm; TAPSE S′ b 12 cm/s).

2.3. Biomarker testing

Samples of venous bloodwere drawn on the same day as echocardi-ography was performed. Samples were centrifuged within 10 min in arefrigerated centrifuge, and stored at−80 °C.

BNP was measured using the ARCHITECT i2000 system (AbbottLaboratories, Chicago, IL, USA). MR-proANP was measured usingimmunoluminometric assay (B.R.A.H.M.S. AG, Hennigsdorf, Germany)

and sCD146 using the CY-QUANT ELISA sCD146 kit (Biocytex, Asnieres,France).

2.4. Statistical analysis

Continuous variables are expressed as median (interquartile range),nominal variables as frequency (percentages). Group characteristicswere compared with non-parametric tests: Fisher's exact test or theMann–Whitney U-test for two groups, as appropriate; Chi-square orthe Kruskal–Wallis H-test for three groups, as appropriate. For statisti-cally significant differences between the groups, subsequent pairwisecomparisons were performed using Dunn's procedure with Bonferronicorrection of the p-value for multiple comparisons. Corrected p-valuesare reported. Correlation analysis was performed using Spearman's cor-relation coefficient. The diagnostic performance of all three biomarkerswas assessed by receiver operating characteristic (ROC) analysis andexpressed as area under the curve (AUC). The null hypothesis wasrejected with an adjusted two-sided p-value b 0.05. All analyses wereperformed with the use of IBM SPSS Statistics, Version 21.0. (IBMCorp, Armonk NY, USA).

2.5. Ethical considerations

The study was conducted in accordance with the principles of theDeclaration of Helsinki and local national laws and was approved bythe local Ethical Committee. All patients provided written informedconsent. The study is registered with ClinicalTrials.gov under thenumber NCT01374880.

3. Results

3.1. Study population

A total of 117 patients, predominantly women (n = 96, 72%) withmitral stenosis were included (France n=51; Turkey n=66). In 82 pa-tients (70%) the stenosis was classified as severe and moderate in theother 35 patients (30%). The median planimetric area was 1.34 cm2

(IQR 1.1–1.58 cm2) and left atria were dilated in themajority of patients(n = 104, 89%) with a median diameter of 49 mm (42–54 mm) and avolume of 101 ml (75–135 ml). Pulmonary hypertension (n = 83,71%) and atrial fibrillation (n= 49, 42%) were common among MS pa-tients. Supplementary Fig. 1 illustrates the prevalence of severe stenosis,atrial fibrillation, pulmonary hypertension and their combinations inthe MS population. Table 1 summarizes the baseline characteristics ofthe MS patients. Baseline characteristics of patients with severe MS ac-cording to geographic region of enrollment are summarized in Supple-mentary Table 1.

3.2. Impact of severity ofMS, pulmonary hypertension and atrial fibrillation

on biomarkers.

Patients with severe MS were older (58 years (IQR 49–69 years) vs.47 years (IQR 40–59 years), p = 0.001) and reported more severesymptoms (NYHA classes III–IV: 39% vs. 3%, p b 0.001) compared to pa-tients withmoderateMS.Meanwhile, half of patients were in functionalclass NYHA II (39 patients (48%) with severe stenosis and 19 patients(54%) with moderate stenosis).

As shown in Fig. 1A, plasma levels of BNP (p = 0.029), MR-proANP(p = 0.027) and sCD146 (p = 0.011) were higher in patients with se-vere MS compared to moderate MS. The area under the curve (AUC)after ROC analysis to discriminate between severe and moderate MSwas between 0.63 and 0.65 for all three biomarkers (SupplementaryTable 2). Fig. 1B illustrates that MS patients with systolic pulmonarypressure above 30 mm Hg had higher levels of BNP (p = 0.025) andMR-proANP (p = 0.034) but no change of sCD146 levels compared topatients without PH. Systolic pulmonary artery pressure (sPAP)

59M. Badoz et al. / European Journal of Internal Medicine 34 (2016) 58–62

http://ClinicalTrials.gov

modestly correlated with BNP (ρ = 0.185, p = 0.044), MR-proANP(ρ = 0.338, p b 0.001), sCD146 (ρ = 0.341, p b 0.001), as shown inthe Supplementary Fig. 2. The area under the curve (AUC) after ROCanalysis to discriminate between sPAP ≤30mmHg and sPAP N30mmHgmmHg was between 0.60 and 0.64 for all three biomarkers (Supple-mentary Table).

As shown in Fig. 1C, plasma levels of BNP (p = 0.002), and sCD146(p b 0.001) were higher in MS patients with atrial fibrillation comparedto patients in sinus rhythm. However, the presence or not of atrial fibril-lation did not influence plasma MR-proANP (p = 0.69).

3.3. Biomarkers in pulmonary hypertension

Among patientswith elevated pulmonary artery pressures (n=99),the median systolic pulmonary artery pressure was 45 mm Hg (35–50 mm Hg) in MS patients with PH (n = 83) and 68 mm Hg (46–

80 mm Hg) in patients with pre-capillary PAH (p b 0.001). Baselinecharacteristics of the cohort of patients with PAH (n= 16) are summa-rized in Table 1.

Fig. 2 illustrates plasma levels of all three biomarkers in MS patientswith PH compared to levels in patients with PAH: PAH patients hadhigher levels of sCD146 compared to MS patients with PH (p =0.007), whereas no differences in BNP and MR-proANP were observed.Furthermore, among patients with elevated pulmonary artery pres-sures, RV dysfunction was present in 5 cases (5%) and associated withhigher median levels of sCD146 (612 vs. 344 ng/ml, p = 0.013)

Table 1

Baseline characteristics of the studied patients.

Mitral stenosis

(n = 117)

PAH

(n = 16)

p-Value

Demographics

Age |years] 55 (46–67) 64 (53–71) 0.10

Male gender 21 (18%) 8 (50%) 0.008

Weight [kg] 73 (60–82) 61 (49–89) 0.31

Height [cm] 160 (155–166) 168 (158–173) 0.052

BMI [kg/m2] 27.8 (23.5–31.3) 23.6 (19.1–28.2) 0.01

Hypertension 37 (32%) 6 (38%) 0.78

NYHA class

I 26 (22%) 3 (19%)

II 58 (50%) 5 (31%)

III 32 (27%) 2 (12%)

IV 1 (1%) 6 (38%)

Treatment

Betablockers 61 (52%) 2 (13%) 0.003

ACE-inhibitors or ARBs 15 (29%) 4 (25%) 1.00

Aldosterone antagonist 34 (29%) 4 (25%) 1.00

Diuretics 57 (49%) 13 (81%) 0.017

Digoxin 14 (28%) 0 (0%) 0.016

Vital signs

Systolic blood pressure [mm Hg] 120 (108–130) 123 (118–132) 0.41

Diastolic blood pressure [mm

Hg]

71 (65–81) 70 (69–78) 0.76

Heart rate [bpm] 75 (69–86) 78 (66–95) 0.62

Atrial fibrillation 49 (42%) 2 (13%) 0.028

Laboratory values

Hemoglobin [g/dl] 13.7 (12.6–14.5) 14 (12.5–15) 0.54

eGFR [ml/min] 75 (59–90) 65 (57–97) 0.52

BNP [pg/ml] 121 (77–205) 103 (56–165) 0.35

MR-proANP [pmol/l] 96 (39–188) 174 (103–225) 0.054

sCD146 [ng/ml] 320 (263–440) 562 (322–620) 0.003

Echocardiography

Left ventricle

Septal wall thickness [mm] 9 (8–10) 11 (9–13) 0.016

Posterior wall thickness [mm] 9 (8–10) 10 (9–11) 0.032

LV-EDD [mm] 47 (43–51) 45 (40–50) 0.11

LV-ESD [mm] 32 (29–35) 26 (19–33) 0.002

LV-EF [%] 60 (57–68) 65 (60–70) 0.11

Right ventricle

RV dilation 29 (25%) 14 (87%) b0.001

RV dysfunction 0 (0%) 5 (31%) b0.001

Systolic PAP [mm Hg] 37 (30–45) 68 (46–80) b0.001

Mitral valve

Area [cm2] 1.34 (1.1–1.58) 2.05 (2–2.1) b0.001

Left atrium

LA diameter [mm] 49 (42–54) 39 (32–43) b0.001

LA area |cm2] 33 (28–38) 18 (16–20) b0.001

ACE— angiotensin converting enzyme, ARBs— angiotensin receptor blockers, BMI— body

mass index, eGFR— estimated glomerularfiltration rate, LA— left atrial, LV-EDD— left-ven-

tricular end-diastolic diameter, LV-ESD — left-ventricular end-systolic diameter, LV-EF —

left-ventricular ejection fraction, NYHA— New York Heart Association, PAP— pulmonary

artery pressure, RV — right ventricular.

Fig. 1. Plasma biomarker levels according to severity of mitral stenosis, pulmonary

hypertension and atrial fibrillation. Legend: Panel A illustrates plasma levels of BNP

[pg/ml], MR-proANP [pmol/l] and sCD146 [ng/ml] in patients with moderate or severe

stenosis. Panel B shows plasma levels of the 3 biomarkers in MS patients with or

without pulmonary hypertension. Panel C resumes biomarker levels in presence or

absence of atrial fibrillation.

60 M. Badoz et al. / European Journal of Internal Medicine 34 (2016) 58–62

compared to patients with normal RV function, whereas no differencesin BNP and MR-proANP levels were observed.

4. Discussion

This study aimed at understanding the behavior of cardiovascularbiomarkers in presence of MS and testing their value in the assessmentof MS severity and its complications. This study, performed in a largeprospective cohort of MS patients, demonstrated that plasma levels ofBNP, MR-proANP and sCD146 were higher in patients with severe MScompared to patients with moderate MS. Atrial fibrillation affected allbiomarkers butMR-proANP, and pulmonary hypertensionwas associat-ed with higher levels of BNP and MR-proANP. Finally, PAH and RV dys-function were associated with elevated levels of sCD146.

The usefulness of measurement of natriuretic peptides, especiallyNT-proBNP to assess MS severity was previously described in severalanalyses of small cohorts [7–11]. Our study confirmed the associationbetween levels of BNP and severity of MS and extended the concept totwo other cardiovascular biomarkers, MR-proANP and sCD146. Further-more, atrial fibrillationwas shown to be associatedwith higher levels ofBNP and sCD146 in MS patients. Similar findings were previously de-scribed by Arat-Ozkan and coworkers [7], whereas subsequent studiescould not confirm an effect of atrial fibrillation on BNP or NT-proBNPlevels in MS [12,13]. As BNP and sCD146 levels are affected by the pres-ence of atrial fibrillation, intermittent arrhythmic episodes may impairthe ability of BNP or sCD146 in detecting changes in MS severity duringfollow-up. In contrast, our study showed that levels MR-proANP werenot affected by atrialfibrillation. This characteristicmakes this biomark-er particularly interesting for the evaluation of disease progression inMS patients, as changes in plasma levels might more accurately reflectchanges in MS severity, but needs to be confirmed in further studies.

Previous studies showed the association between pulmonary pres-sure and increased levels of BNP or NT-proBNP in MS [7,9,11,12]. Ourstudy confirmed that MS patients with PH, had higher levels BNP com-pared to MS patients without PH. Similar findings were shown for MR-proANP, whereas no difference in sCD146 levels was found.

On the other hand, among patients with pulmonary hypertension,higher levels of sCD146 were observed in patients with pre-capillaryPAH and in those with RV-dysfunction. The cause for this difference insCD146 levels is unknown.We hypothesize that elevated sCD146 levelsmight represent a more severe stage of pulmonary hypertension. In-deed, PAH patients had significantly higher levels of systolic pulmonarypressure compared toMS patients with PH. However, different underly-ing pathophysiologicalmechanisms between pre- and post-capillary PH(e.g. endothelial dysfunction) may also influence levels of sCD146 [14].

4.1. Limitations

This study also aimed at testing the behavior of cardiac biomarkersin more advanced PH with severe RV pressure overload and ventriculardysfunction. Severe PH and RV dysfunction are serious and, fortunately,rare complications of MS. In addition to including a quite large numberofMS patients through amulti-centric study design, a cohort of PAH pa-tients was included to explore biomarker behavior in advanced PH.However, since the number of patients with RV dysfunction remainedsmall and notable pathophysiological differences between PH second-ary to MS and PAH exist, our observations should be interpreted withcaution.

Given the observational design of the present study, the robustnessof these biomarkers for diagnostic and prognostic purposes and theircost-effectiveness in the follow-up evaluation of MS patients shouldbe prospectively validated in large multi-centric studies.

5. Conclusions

Mitral stenosis and its complications affect plasma levels ofcardiovascular biomarkers. The use of MR-proANP may be useful forthe assessment of severe stenosis and the presence of pulmonaryhypertension in the early phase,whereas sCD146might help identifyingpatients with more advanced pulmonary hypertension and RV-dysfunction.

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.ejim.2016.05.008.

Disclosures

This project was supported by the European Commission's SeventhFramework program under grant agreement N° 305507 (HOMAGE).MA is a recipient of a fellowship of the Collège de Médecine desHôpitaux de Paris. AM received speaker's honoraria from Abbott,Novartis, Orion, Roche et Servier. AM received fee as a member of advi-sory board and/or Steering Committee from Cardiorentis, Adrenomed,MyCartis, ZS Pharma and Critical Diagnostics.

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sCD146 [ng/ml] in patients with pulmonary hypertension secondary to mitral stenosis

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55

Supplementary Table 1: Baseline characteristics of patients with severe mitral stenosis according to geographic region of enrollment.

France

(n=50)

Turkey

(n=32)

p-value

Demographics

Age |years] 64 (54 - 74) 51 (45 - 59) <0.001

Male gender 10 (20% ) 7 (22% ) 1.00

Weight [kg] 65 (55 - 80) 75 (65 - 80) 0.62

Height [cm] 161 (156 - 169) 160 (158 - 168) 0.89

BMI [kg/m2] 24.6 (22.5 - 29.3) 28.9 (24.8 - 31.3) 0.017

Hypertension 13 (26% ) 10 (31% ) 0.62

NYHA class III-IV 28 (56%) 6 (19%) 0.001

Vital signs

Systolic blood pressure [mmHg] 124 (110 - 143) 118 (107 - 128) 0.08

Diastolic blood pressure [mmHg] 72 (65 - 85) 74 (68 - 80) 0.82

Heart rate [bpm] 73 (62 - 89) 78 (71 - 86) 0.33

Atrial fibrillation 25 (50% ) 16 (50% ) 1.00

Laboratory values

Hemoglobin [g/dl] 13.4 (12.5 - 14.2) 13.8 (12.9 - 15) 0.07

eGFR [ml/min] 62 (49 - 77) 82 (69 - 90) <0.001

BNP [pg/ml] 128 (80 - 194) 152 (105 - 216) 0.34

MR-proANP [pmol/l] 197 (146 - 304) 38 (23 - 90) <0.001

sCD146 [ng/ml] 372 (313 - 459) 317 (251 - 439) 0.048

Echocardiography

Septal wall thickness [mm] 9 (8 - 11) 9 (7 - 10) 0.03

Posterior wall thickness [mm] 9 (8 - 10) 9 (8 - 10) 0.56

LV-EDD [mm] 47 (45 - 52) 45 (42 - 49) 0.06

LV-ESD [mm] 30 (28 - 34) 34 (30 - 36) 0.021

LV-EF [%] 65 (58 - 70) 61 (57 - 67) 0.14

Systolic PAP [mmHg] 45 (39 - 50) 31 (28 - 36) <0.001

Mitral valve area [cm2] 1.17 (1.00 - 1.30) 1.34 (1.14 - 1.43) 0.002

LA diameter [mm] 47 (40 - 54) 49 (45 - 56) 0.42

LA volume [ml] 138 (103 - 167) 103 (73 - 135) 0.033

Legend: BMI body mass index – eGFR estimated glomerular filtration rate – LA left atrial – LV-EDD left-ventricular end-diastolic diameter – LV-ESD left-ventricular end-systolic diameter – LV-EF left-ventricular ejection fraction – NYHA New York Heart Association – PAP pulmonary artery pressure

56

Supplementary Table 2: Receiver operating characteristics curves of different biomarkers for the assessment of complications of mitral stenosis

Area under the curve (95% confidence interval)

Severe stenosis Pulmonary hypertension

Biomarkers

BNP [pg/ml] 0.633 (0.512 – 0.754) 0.636 (0.521 – 0.752)

MR-proANP [pmol/l] 0.635 (0.525 – 0.744) 0.629 (0.516 – 0.741)

sCD146 [ng/ml] 0.653 (0.532 – 0.775) 0.604 (0.490 – 0.717=

57

Supplementary Fig. 1. Prevalence of severe stenosis, atrial fibrillation and pulmonary hypertension and their combination in MS patients.

58

Supplementary Fig. 2. Correlation of biomarker values to systolic pulmonary artery pressure.

59

IV.2. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide et du Soluble Cluster

of Differentiation 146 dans l’évaluation du traitement percutané de la sténose

mitrale

Assessment of successful percutaneous mitral commissurotomy by MRproANP and

sCD146.

Marc Badoz, Mattia Arrigo, Anne-Claire Mogenet, Malha Sadoune, Nicolas Meneveau,

Alexandre Mebazaa and Marie-France Seronde.

BMC Cardiovascular Disorders (2020) 20:157.

AVANT PROPOS

La précédente publication a montré la pertinence du sCD146 pour évaluer la sévérité

d’une sténose mitrale ainsi que la présence de complications qu’elles soient rythmiques pour le

passage en FA, ou hémodynamiques avec la présence d’hypertension pulmonaire. Au vu des

connaissances actuelles (20-24) ceci pourrait s’expliquer par la répercussion quasi immédiate

qu’a la sténose mitrale sur la circulation pulmonaire. Nous pourrions émettre en effet

l’hypothèse que celui-ci est sécrété par l’endothélium pulmonaire en réponse à l’élévation de

pression.

Le MRproANP était lui aussi lié à la sévérité de la sténose mitrale, et à la présence de

complications en raison du retentissement directe qu’a la sténose mitrale sur le myocarde

60

atriale. L’élévation de sa concentration plasmatique n’était en revanche pas liée au passage en

FA dans cette pathologie.

Le traitement de la sténose mitrale serrée repose sur une levée de cet obstacle à la

vidange de l’oreillette gauche dans le ventricule. Si la forme anatomique le permet, une

valvuloplastie mitrale est réalisée par voie percutanée (VMP). Ce geste entraine une ouverture

de la valve mitrale, et de ce fait une baisse de pression intra atriale gauche. L’amélioration

hémodynamique et le succès de cette procédure pourraient être monitorés grâce au MRproANP

et au sCD146 étudiés dans la précédente publication. L’objectif étant de nouveau de s’affranchir

des limites de l’échographie cardiaque. Ce monitorage du succès procédural est possible si les

biomarqueurs en question sont liés au niveau de sévérité de la sténose, à la surface mitrale, et

aux modifications hémodynamiques qu’entraine la procédure en termes de baisse de gradient

OG/VG et de baisse des pressions artérielles pulmonaires. Le monitorage du succès immédiat

de la procédure est possible à condition également que la cinétique de libération des

biomarqueurs soit suffisamment réactive et soit telle qu’un succès procédural entraine une

diminution rapide des niveaux plasmatiques des biomarqueurs

La VMP se fait par abord veineux fémoral puis ponction transseptale. La valve mitrale

est alors dilatée grâce à un ballon d’Inoué, cette dilatation permet l’ouverture des commissures

mitrales particulièrement fusionnées dans les formes rhumatismales, la diminution du gradient

de pression entre oreillette gauche et ventricule et donc la limitation des répercussions

hémodynamiques d’amont.

Nous nous sommes donc intéressés aux niveaux de MRproANP et sCD146 avant et

après une procédure de VMP et leur capacité à évaluer le succès de la procédure.

RESEARCH ARTICLE Open Access

Assessment of successful percutaneousmitral commissurotomy by MRproANP andsCD146Marc Badoz1*, Mattia Arrigo2,3,4,5, Anne-Claire Mogenet1, Malha Sadoune2, Nicolas Meneveau1,

Alexandre Mebazaa2,3 and Marie-France Seronde1

Abstract

Background: We studied the course of plasma concentrations of 4 cardiovascular biomarkers: natriuretic peptides

(BNP, NT-proBNP; mid-regional (MR) pro-atrial NP); and soluble endothelial CD146 (sCD146), in patients with severe

mitral valve stenosis undergoing percutaneous mitral commissurotomy (PMC) to identify potential markers of

procedural success.

Methods: Biomarkers were tested in 40 patients the day before and the day after PMC. Success was defined as

mitral valve area ≥ 1.5 cm2; or an increase of ≥0.5 cm2 in mitral valve area associated with echocardiographic mitral

regurgitation <grade 3–4 post-PMC.

Results: Average age was 63.5 ± 12.7 years; 32(80%) were female. Before PMC, mean valve area was 1.1 ± 0.2 cm2,

mean gradient 9.1 ± 3.5 mmHg. PMC was successful in 30 (75%) and unsuccessful in 10 (25%). PMC yielded a significant

reduction in MR-proANP and sCD146, driven by a significant reduction in these biomarkers in patients with successful

procedure, whereas no reduction was observed in patients with unsuccessful procedure. A significant correlation was

found between changes in plasma sCD146 and the relative change in mitral valve area. Elevated pre-procedural sPAP

correlated with high sCD146, and accordingly, a significant correlation between the decrease in sPAP and sCD146 after

PMC was shown.

Conclusions: MR-proANP and plasma sCD146 decreased significantly immediately after successful PMC. They appear

to be markers of immediate success of PMC and of the hemodynamic improvement achieved by this procedure in

patients with MS.

Trial registration: This study is part of the cohorts registered with ClinicalTrials.gov on June 16, 2011 under the

number NCT01374880.

Keywords: Mitral stenosis, Biomarker, Brain natriuretic peptide, MRproANP

© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

* Correspondence: [email protected] University Hospital, and EA3920, University of Burgundy

Franche-Comté, Besancon, France

Full list of author information is available at the end of the article

Badoz et al. BMC Cardiovascular Disorders (2020) 20:157

https://doi.org/10.1186/s12872-020-01435-y

http://crossmark.crossref.org/dialog/?doi=10.1186/s12872-020-01435-y&domain=pdf

https://clinicaltrials.gov/ct2/show/NCT01374880?term=NCT01374880&draw=2&rank=1

http://creativecommons.org/licenses/by/4.0/

http://creativecommons.org/publicdomain/zero/1.0/


Background

The use of natriuretic peptides has become widespread in

cardiology, with brain natriuretic peptide (BNP) and N-

terminal pro-B-type natriuretic peptide (NT-proBNP)

used daily as markers of heart failure [1–3]. However,

these two biomarkers remain imperfect for the diagnosis

of pulmonary and systemic congestion [4–6]. Therefore,

combining BNP/NT-proBNP with other biomarkers could

help to improve their diagnostic value. In this regard,

other natriuretic peptides such as mid-regional pro-atrial

natriuretic peptide (MR-proANP) are emerging as bio-

markers that are more strongly associated with venous

congestion of cardiac origin [7, 8].

Furthermore, the soluble form of CD146 (sCD146) - an

adhesion molecule expressed by vascular endothelial cells

and implicated in vessel integrity - is released by the endo-

thelium [9] and circulating sCD146 levels are related to pul-

monary congestion in heart failure [10, 11]. However, the

physiology of sCD146 release remains poorly described.

Some authors have shown that sCD146 is released from

the peripheral veins in response to stretch [12], but the in-

volvement of the heart cavities, notably the left ventricle,

and pulmonary circulation in the release of sCD146 during

congestion is unknown.

Mitral stenosis (MS) is a clinical condition that induces

left atrial and pulmonary congestion, with preservation of

the left ventricle. Successful percutaneous mitral commis-

surotomy (PMC) reduces left atrial and pulmonary pres-

sures. In this context, the objectives of the present study

were 1) to describe the behaviour of circulating natriuretic

peptides, namely BNP, NT-proBNP, MR-proANP, and

sCD146 before and after PMC for severe MS, and 2) to in-

vestigate a potential role of these cardiovascular bio-

markers to assess procedural success of PMC.

Methods

Prospective study performed in two university hospitals

(University Hospital Jean Minjoz, Besancon, and Univer-

sity Hospital Bichat, Paris, France). Biomarker measure-

ments were performed in the UMR-S942 Inserm, Paris,

France. The study was approved by the Institutional Re-

view Board of Paris North Hospitals, Paris 7 University,

AP-HP, Paris, France (Comité d’Evaluation de l’Ethique

des Projets de Recherche Biomédicale (CEERB) du GHU

Nord, IRB N°00006477) under the number 10–017. All

patients provided written informed consent.

Study population

Patients with symptomatic severe rheumatic MS with an

indication for PMC were included.

Echocardiographic evaluation

All patients underwent transthoracic (TTE) and trans-

oesophageal echocardiography (TOE) by trained operators

on the day before PMC. Echocardiographic control by

TTE was performed 24 h after the procedure to evaluate

procedural success.

Echocardiography was performed to assess left ven-

tricular ejection fraction (LVEF), measured using Simp-

son’s biplane method, severity of MS as assessed by the

mean transmitral gradient on continuous transmitral

Doppler, and mitral valve area as assessed by planimetry

in the parasternal short axis view in accordance with

current guidelines (14). MS was considered severe if the

valve area was ≤1.5 cm2 by planimetry. Further, the anat-

omy of the mitral valve was classified according to the

Wilkins score [13], which takes into account leaflet mo-

bility, leaflet thickening, subvalvular thickening, and cal-

cification. A Wilkins’ score > 8 is associated with

advanced leaflet deformity and unfavorable anatomy,

while a score ≤ 8 corresponds to a valve anatomy more

amenable to PMC. Mitral regurgitation grade was evalu-

ated semi-quantitatively by color flow Doppler imaging

[14]. Left atrial diameter was measured in the paraster-

nal long axis view; left atrial area and volume were eval-

uated in the 2-chamber and 4-chamber apical views.

The left atrium was considered to be dilated if diam-

eter > 40 mm or area > 20 cm2, or volume > 60 mL. Sys-

tolic pulmonary artery pressure was calculated according

to usual techniques and a diagnosis of pulmonary arter-

ial hypertension was retained if peak tricuspid regurgi-

tant velocity > 2.8 m/sec [15]. Significant (moderate or

severe) aortic stenosis was defined as a mean transaortic

gradient > 20mmHg by transthoracic echocardiography.

Definition of procedural success of PMC

Successful PMC was defined as a mitral valve area ≥ 1.5

cm2; or as an increase of ≥0.5 cm2 in mitral valve area

associated with mitral regurgitation less than grade 3–4

post-PMC as measured by echocardiography. Unsuc-

cessful procedural outcome was defined as a post-PMC

mitral valve area < 1.5 cm2; or an increase of < 0.5 cm2 in

mitral valve area or appearance of mitral regurgitation ≥

grade 3–4 [16].

PMC procedure

All procedures were performed in the cardiac

catheterization laboratory under local anesthetic by

trained, experienced operators using the femoral ap-

proach. The Inoue balloon (Toray Medical Co. Ltd.,

Tokyo, Japan) was used in all procedures. The balloon was

inflated gradually with echocardiographic guidance after

each inflation to check for appearance or aggravation of

mitral regurgitation and opening of the two commissures.

Commissural splitting was defined as either an increased

apparent opening angle of either commissure or increased

leaflet separation associated with an increased transverse

diameter of the orifice, or both [17, 18].

Badoz et al. BMC Cardiovascular Disorders (2020) 20:157 Page 2 of 9

Data recorded

We recorded demographic and clinical characteristics

for all patients. Venous blood samples were drawn on

the day before, and on the day of PMC using EDTA

tubes that were centrifuged and stored at − 80 °C for

later analysis. Analysis of BNP levels was performed

using the ARCHITEXT i2000 system (Abbott Architect

System, Abbott Laboratories, Abbott Park, IL, USA);

NT-proBNP using the COBAS e601 analyzer (Roche

Diagnostics, Indianapolis, IN, USA); MR-proANP was

analyzed by immunoluminometric assays (B.R.A.H.M.S.

AG, Hennigsdorf, Germany). Finally, sCD146 was mea-

sured using the CY-QUANT ELISA sCD146 kit (Biocy-

tex, Marseille, France).

Statistical analysis

Quantitative data are expressed as mean ± standard devi-

ation when normally distributed, and median [interquar-

tile range] when non-normally distributed. Qualitative

data are expressed as number (percentage). Independent

variables were compared using the Mann-Whitney U-

test, the chi square or Fisher’s exact tests, as appropriate.

Paired variables were compared with the paired-samples

t-test. Correlations between the relative change in each

biomarker, and the relative change in mitral valve area

were evaluated using Spearman’s correlation coefficient.

A p-value < 0.05 was considered statistically significant.

All analyses were performed using MedCalc software

(MedCalc, Mariakerke, Belgium).

Results

Forty-eight patients with severe symptomatic MS were

identified and screened for inclusion in the study from

January 2011 to January 2012. Eight patients (16.6%) had

an anatomical form that was incompatible with PMC

and were thus excluded. The remaining 40 patients (32

women, 8 men) underwent PMC and constitute the

population of this study, and their characteristics are de-

scribed in Table 1. Thirty patients (75%) had a successful

PMC procedure as defined by echocardiographic criteria,

Table 1 Characteristics of the 40 patients submitted to percutaneous mitral commissurotomy, in the overall population and

according to procedural success

Whole population (N = 40) Successful PMC (n = 30) Unsuccessful PMC (n = 10) p value

Age, years 63.5 ± 12.7 60.2 ± 12.8 68.2 ± 10.2 0.08

Female sex 32 (80) 22 (73) 10 (100) 0.6

NYHA class 3–4 23 (57.5) 18 (60) 5 (50) 0.17

Atrial fibrillation 18 (45) 12 (40) 6 (60) 0.46

Previous mitral surgery or PMC 7 (17.5) 4 (13) 7 (70) 0.002

Significant aortic stenosis 6 (15) 5 (17) 1 (10) 0.95

Hypertension 9 (22.5) 5 (17) 4 (40) 0.95

Renal failure (CrCl ≤60 ml/min) 18 (45) 12 (40) 6 (60) 0.46

Obesity 9 (22.5) 7 (23) 2 (20) 0.81

ACEI or ARB 10 (25) 7 (23) 3 (30) 0.98

Beta blockers 20 (50) 13 (43) 7 (70) 0.26

Diuretics 25 (62.5) 17 (57) 8 (80) 0.35

Aldosterone antagonist 8 (20) 4 (13) 4 (40) 0.16

Left atrial diameter, mm 48 ± 7.1 46 ± 7.8 49 ± 6.9 0.28

Left atrial area, cm2 32 ± 7.1 32 ± 37 47 ± 6.9 < 0.0001

Left atrial volume, mm3 129 ± 42 62 ± 20.5 185 ± 37 < 0.0001

Mitral valve gradient, mmHg 9.1 ± 3.5 9.2 ± 3.5 8.7 ± 3.4 0.7

Mitral valve area, cm2 1.1 ± 0.2 1.1 ± 0.2 1.1 ± 0.2 1

LV end-diastolic diameter, mm 49 ± 7.7 49 ± 7.9 46 ± 6.3 0.28

LV end-systolic diameter, mm 31 ± 4.6 31 ± 4.5 30 ± 5 0.55

LVEF % 64 ± 7.9 64 ± 8.1 64 ± 6.9 1

sPAP, mmHg 44 ± 14± 46 ± 15 42 ± 7 0.42

Mitral regurgitation ≥2 8 (20) 6 (20) 2 (20) 0.65

Wilkins score > 8 14 (35) 9 (30) 5 (50) 0.44

PMC percutaneous mitral commissurotomy, NYHA New York Heart Association, CrCl creatinine clearance, ACEI angiotension-converting enzyme inhibitor, ARB

angiotensin-receptor blocker, LVEF left ventricular ejection fraction, sPAP systolic pulmonary artery pressure


and 10 (25%) were considered to have unsuccessful

outcome.

Average age was 63.5 ± 12.7 years; the majority were

female (n = 32, 80%). Half of the patients were in atrial

fibrillation, and almost 60% had New York Heart Associ-

ation (NYHA) grade 3 or 4 dyspnea.

The echocardiographic findings in the study popula-

tion are detailed in Table 2. The mean valve area was

1.1 ± 0.2 cm2, while mean gradient was 9.0 ± 3.5 mmHg.

Median left atrial volume was 129 mm3, median left

atrial area was 32 cm2 and mean systolic pulmonary ar-

terial pressure was 44 ± 14 mmHg. Left ventricular ejec-

tion fraction was preserved in all patients. Unfavorable

valve anatomy was present in 14 patients (35%) with a

Wilkins score > 8; 8 patients (20%) had mitral regurgita-

tion ≥2, and 7 (17.5%) patients had a history of previous

PMC or surgical commissurotomy.

PMC yielded an average increase of 0.6 cm2 in plani-

metric mitral valve area (0.7 cm2 in those with successful

procedure (n = 30) vs. 0.2 cm2 in those with unsuccessful

procedure (n = 10)) and an average reduction of 3.9

mmHg in mitral gradient (4.5 mmHg in those with suc-

cessful procedure vs. 2.6 mmHg in those with unsuccess-

ful procedure, respectively). Systolic pulmonary artery

pressure was significantly reduced after PMC (− 8

mmHg, p = 0.0003) (Table 2).

Patients with unsuccessful procedure were on average

slightly older, with significantly more frequent history of

PMC or mitral surgery and larger left atria despite

similar grade of MS than those in whom the procedure

was successful (Table 1), perhaps indicating a longer his-

tory of disease.

Circulating cardiovascular biomarkers before and after

PMC are shown in Table 3 and Fig. 1. Before PMC, MR-

proANP and sCD146 were markedly elevated in the

large majority of patients with severe MS. In the overall

population, PMC yielded a significant reduction in

plasma MR-proANP and sCD146. Significant reductions

in these two biomarkers were seen in patients with suc-

cessful procedural outcome, whereas no significant re-

duction was observed in MR-proANP and sCD146 in

patients who had an unsuccessful procedure (Table 3).

There was no significant difference between pre-and post-

PMC levels of NT proBNP. Conversely, BNP, MR

proANP and sCD146 were all significantly lower after

PMC, compared to pre-PMC levels. Notably, a significant

correlation was found between changes in plasma sCD146

and the relative change in mitral valve area (Fig. 2).

Elevated pre-procedural sPAP correlated with high

sCD146 (Fig. 3), but not MR-proANP. Accordingly, a

significant correlation between the decrease in sPAP and

sCD146 after PMC was shown (Fig. 4), whereas no cor-

relation between changes in sPAP and MR-proANP was

shown.

Discussion

Our study describes the behaviour of cardiovascular bio-

markers before and after PMC in patients with severe

Table 2 Echocardiographic findings before and after PMC in the overall study population (n = 40), and according to procedural

success

Whole population (N = 40) Successful PMC (n = 30) Unsuccessful PMC (n = 10)

Pre-PMC Post-PMC p value Pre-PMC Post-PMC p value Pre-PMC Post-PMC p value

Mitral gradient, mmHg 9.0 ± 3.5 5.1 ± 1.6 < 0.0001 9.3 ± 3.5 4.8 ± 1.5 < 0.0001 8.7 ± 3.6 6.1 ± 1.6 0.06

Mitral valve area, cm2 1.1 ± 0.2 1.7 ± 0.3 < 0.0001 1.1 ± 0.2 1.8 ± 0.3 < 0.0001 1.1 ± 0.3 1.3 ± 0.1 0.06

LVEF, % 63 ± 7.9 62 ± 14.7 0.8 64 ± 8.1 66 ± 11.2 0.43 64 ± 7.3 53 ± 18.2 0.09

sPAP, mmHg 44 ± 14 36 ± 8 0.0003 46 ± 15 36 ± 9 0.003 42 ± 7 34 ± 6 0.01

PMC percutaneous mitral commissurotomy, LVEF left ventricular ejection fraction, sPAP systolic pulmonary artery pressure

P-values are for the comparison before vs after by paired Student t test

Table 3 Plasma levels of the 4 cardiovascular biomarkers under study before and after PMC, in the overall population and according

to procedural success

Whole population (N = 40) Successful PMC (n = 30) Unsuccessful PMC (n = 10)

Pre-PMC Post-PMC p value Pre-PMC Post-PMC p value Pre-PMC Post-PMC p value

BNP, pg/mL 182 [80–194] 132 [56–125] 0.028 184 [63–194] 122 [53–123] 0.03 176 [87–193] 161 [60–344] 0.62

NT-proBNP,pg/mL

1050[232–1171] 739 [219–909] 0.08 1067 [200–1171] 654 [141–706] 0.08 999 [311–1128] 994 [375–1951] 0.97

MR-proANP,nmol/mL

220 [142–273] 187 [130–224] 0.0025 219 [142–257] 179 [123–219] 0.0012 223 [139–284] 210 [133–347] 0.6

sCD146, ng/mL 379 [308–441] 343[277–416] 0.0081 370 [298–427] 327 [268–378] 0.002 406 [323–483] 389 [283–555] 0.7

PMC percutaneous mitral commissurotomy. P-values are for the comparison before vs after by paired Student t test

Reference values for middle-aged women: BNP < 100 pg/ml, NT-proBNP< 300 pg/mL, MR-proANP< 85 nmol/mL, sCD146 still under investigation, likely < 320 ng/mL


Fig. 1 Individual data for the plasma cardiovascular biomarkers under study, before (pre) and after (post) percutaneous mitral commissurotomy

for each patient (top panels) and overall (bottom panels)


MS and investigated the potential role of those cardio-

vascular biomarkers to assess procedural success of

PMC. We showed a significant decrease in plasma levels

of MR-proANP and sCD146 after successful PMC,

whereas no such decrease in these biomarkers is ob-

served in patients in whom the procedure is not

successful.

ANP is a natriuretic peptide specific to the atria, and a

sandwich immunoassay has been developed specifically

for the assessment of MR-proANP [19], which is more

stable and a more reliable analyte for measurement than

mature ANP and its C- and N-terminal segments [20, 21].

The link between MR-proANP and congestion has previ-

ously been established [7], but to date, there has been little

research into the utility of MR-proANP in pathologies

specifically affecting the left atrium. In this regard, our

study provides further evidence that patients with elevated

LA pressure due to MS and preserved LVEF have elevated

MR-proANP levels, which decline after successful PMC,

without any significant relation with the variation in pul-

monary arterial pressure. We can therefore hypothesize

that the elevated left atrial pressure induces wall stretch,

Fig. 2 Correlation between relative change in sCD146 and relative change in mitral valve area

Fig. 3 Correlation between sPAP pre-PMC and sCD146 pre-PMC


leading to release of MR-proANP and resulting in elevated

plasma concentrations. Successful PMC leads to an im-

provement in hemodynamics, with a drop in left atrial

pressure, and thus, a corresponding drop in plasma levels

of MR-proANP. Our findings are coherent with earlier

publications showing a reduction in ANP after PMC, and

a correlation between changes in plasma ANP and those

in left atrial pressure [22]. Furthermore, MR-proANP has

been shown to be a predictor of adverse cardiac events

after percutaneous repair of severe mitral valve regurgita-

tion [8]. Therefore, it would seem that MR-proANP is a

marker of left atrial disease.

Previous publications have reported that sCD146 was

useful for identifying signs of left heart failure, and the

cardiac origin of dyspnea [10, 11]. However, the patho-

physiology of sCD146 release is not well understood in

the context of pulmonary congestion without left-

ventricular failure. In our study, all patients had pre-

served LVEF, and there was no evidence of increased left

ventricular pressure. Therefore, the elevated pre-proced-

ural sCD146 concentrations are unlikely to be related to

left ventricular release. Our results plead more in favour

of the hypothesis that sCD146 is released at least par-

tially by the pulmonary vasculature. MS leads to pul-

monary congestion, which is reduced by successful

PMC, providing a potential explanation for the reduc-

tion in sCD146 after successful procedure (PMC), and

for the link between pulmonary artery pressure and

sCD146. This hypothesis is in line with previously pub-

lished data showing that sCD146 is markedly elevated in

patients with pulmonary hypertension, and that it is par-

ticularly elevated in patients with MS when their

pulmonary artery pressure exceeds 30 mmHg [23].

sCD146 has also been shown to reflect systemic conges-

tion [12]. Unsuccessful PMC only yields a small reduc-

tion in systolic PAP that has little or no effect on right

ventricular hemodynamics. Consequently, no improve-

ment in systemic congestion ensues, thus explaining

why there is no significant reduction in sCD146 after

unsuccessful PMC.

It is established that sCD146 is at least partially released

by the endothelium, and this fits with our hypothesis [9].

Taken together, these data indicate that sCD146 could be

a relevant marker of PMC success by reflecting the

hemodynamic improvement achieved by the successful

procedure (i.e. reduction in pulmonary and systemic con-

gestion). They also suggest that sCD146 could be a marker

of pulmonary congestion, released in the presence of in-

creased pulmonary pressure, or a marker of systemic con-

gestion, in line with previous publications [10–12].

The success of PMC is usually evaluated by transtho-

racic echocardiography (TTE). However, this technique

suffers from several limitations, including the echogeni-

city of the patient, intra-operator variability, operator ex-

perience, and variability linked to changes in the loading

conditions in a same patient. In this context, assessment

of biomarkers that reflect immediate hemodynamic im-

provement seems to be a good indicator of PMC suc-

cess, and less subject to variability than TTE. Data are

controversial regarding the utility of more widely used

biomarkers, such as BNP and NT-proBNP, to assess the

success of PMC, precluding their use as a reliable indica-

tor in this context [22, 24–26]. Our results suggest that

the drop in sCD146 and MR-proANP could indicate

Fig. 4 Correlation between reduction in sPAP and reduction in sCD146. Negative values mean increase of sCD146 or sPAP between pre

and post-PMC


immediate procedural success after PMC, reflecting the

hemodynamic improvement achieved by the proced-

ure, especially since the magnitude of the drop in

sCD146 is related to the benefit yielded by the PMC.

To the best of our knowledge, this is the first study

to report the utility of assessing sCD146 and MR-

proANP in the context of PMC.

Our study nonetheless has some limitations that deserve

to be underlined. Firstly, the sample size is relatively small,

although comparable to that of other studies in the field.

Clearly, the sample size is too small to allow identification

of a threshold for procedural success for these two bio-

markers, and consequently, also too low to allow calcula-

tion of their sensitivity and specificity. Furthermore, we

also lack additional hemodynamic parameters, notably in-

vasively measured left atrial pressure measurements. Fi-

nally, our data are from the immediate post-procedural

period, and no follow-up data regarding clinical, echo-

graphic or biological parameters were available in the

medium to long term. Therefore, further studies are war-

ranted to elucidate the pathophysiological mechanisms

underpinning the changes in these biomarkers and to

identify their exact relevance in this indication.

Conclusion

MR-proANP decreased significantly after PMC, likely

due to a reduction in atrial stretch achieved by the suc-

cessful procedure. Plasma sCD146 decreased signifi-

cantly immediately after successful PMC, likely due to

reduced endothelial release secondary to a reduction in

pulmonary pressure. MR-proANP and sCD146 appear

to be markers of immediate success of PMC and of the

hemodynamic improvement achieved by this procedure

in patients with MS.

Abbreviations

ANP: Atrial natriuretic peptide; BNP: Brain natriuretic peptide; LA: Left atrium/

atrial; LVEF: Left ventricular ejection fraction; MRproANP: Mid-regional pro-

atrial natriuretic peptide; MS: Mitral stenosis; NTproBNP: N-terminal pro-B-

type natriuretic peptide; PMC: Percutaneous mitral commissurotomy;

sCD146: Soluble CD146; sPAP: Systolic pulmonary artery pressure; TOE: Trans-

oesophageal echocardiography; TTE: Transthoracic echocardiography

Acknowledgements

None.

Authors’ contributions

NM, AM, MFS designed the study; MB, MA, ACM, MS, NM, AM, MFS acquired

the data; MA, MS, AM, MFS performed the assays and analysed the results;

MB, ACM, NM, AM, MFS interpreted the results; MB, ACM, NM, MFS drafted

the first version of the manuscript; MB, MA, ACM, MS, NM, AM, MFS read and

critically reviewed the final version of the manuscript; MB, MA, ACM, MS, NM,

AM, MFS approved the final version for publication.

Funding

This study received no extramural funding.

Availability of data and materials

The datasets used and/or analysed during the current study are available

from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of Paris North

Hospitals, Paris 7 University, AP-HP, Paris, France (Comité d’Evaluation de

l’Ethique des Projets de Recherche Biomédicale (CEERB) du GHU Nord, IRB

N°00006477) under the number 10-017. All patients provided written in-

formed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details1Besancon University Hospital, and EA3920, University of Burgundy

Franche-Comté, Besancon, France. 2INSERM UMR-S 942, Paris, France.3Department of Anesthesiology and Critical Care Medicine, AP-HP, Saint

Louis Lariboisière University Hospitals, Paris, France. 4Department of

Cardiology, AP-HP, Saint Louis Lariboisière University Hospitals, Paris, France.5Department of Cardiology, University Heart Center, University Hospital

Zurich, Zurich, Switzerland.

Received: 25 November 2019 Accepted: 13 March 2020

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70

V. Evaluation du risque de récidive

de fibrillation atriale à distance d’une

procédure d’ablation par le Mid-

Regional pro Atrial Natriuretic

Peptide et le Soluble Suppression of

Tumorigenicity 2.

71

Impact of Midregional N-Terminal Pro–Atrial Natriuretic Peptide and Soluble

Suppression of Tumorigenicity 2 Levels on Heart Rhythm in Patients Treated With

Catheter Ablation for Atrial Fibrillation: The Biorhythm Study.

Marc Badoz, Guillaume Serzian, Baptiste Favoulet, Jean-Marc Sellal , Christian De

Chillou, Néfissa Hammache, Gabriel Laurent, Alexandre Mebazaa, Fiona Ecarnot,

Karine Bardonnet, Marie-France Seronde, François Schiele, Nicolas Meneveau.

Journal of the American Heart Association 2021;10:e020917. DOI:

10.1161/JAHA.121.020917.

AVANT PROPOS

La fibrillation atriale est le trouble du rythme cardiaque le plus fréquent (46, 67). Elle

est initialement liée à des foyers ectopiques localisés au niveau de l’ostium des veines

pulmonaires initiateurs des passages en fibrillation atriale (48), elle se manifeste alors de

manière paroxystique. L’évolution naturelle de la pathologie se fait vers la persistance de celle-

ci, il s’y associe alors dilatation et fibrose de l’oreillette gauche (55, 56, 58, 59). L’ablation de

la fibrillation atriale est actuellement au centre de la prise en charge de cette pathologie, elle

consiste en l’isolation électrique des veines pulmonaires par abord transseptal (46, 48, 62, 67),

et en la réalisation éventuelle de lésions complémentaires (77). Les techniques les plus

couramment utilisées sont la radiofréquence et la cryoablation (74). La principale limite de la

technique est le pourcentage de récidive non négligeable (74, 76, 77, 84, 85), d’où l’importance

de stratifier le risque de récidive post procédure et d’identifier les potentiels bons répondeurs à

l’ablation. Cette évaluation du risque de récidive permet notamment de guider le suivi et le

traitement post procédure, par exemple en termes d’anti arythmiques.

72

Il n’existe pas de données solides concernant un biomarqueur prédicteur de récidives

dans les suites d’une ablation de fibrillation atriale. Le MRproANP est un peptide plus

spécifiquement atriale. Les deux publications précédentes (2, 3) ont montré son intérêt dans la

sténose mitrale, une pathologie affectant directement l’oreillette gauche. Il est marqueur de

sévérité du rétrécissement mitral et marqueur de succès d’une commissurotomie mitrale

percutanée. Il a peu été étudié dans l’ablation de fibrillation atriale.

Le sST2 est un marqueur de fibrose (27) et pronostique important dans l’insuffisance

cardiaque (29-33). Il n’existe que très peu de données sur le sST2 en tant que marqueur

pronostique dans l’ablation de fibrillation atriale.

L’article suivant s’intéresse donc à l’impact des niveaux de MRproANP et de sST2

plasmatiques pré procédure sur le taux de récidive à un an d’une ablation de fibrillation atriale.

Journal of the American Heart Association

J Am Heart Assoc. 2021;10:e020917. DOI: 10.1161/JAHA.121.020917 1

ORIGINAL RESEARCH

Impact of Midregional N- Terminal Pro– Atrial Natriuretic Peptide and Soluble Suppression of Tumorigenicity 2 Levels on Heart Rhythm in Patients Treated With Catheter Ablation for Atrial Fibrillation: The Biorhythm StudyMarc Badoz, MD; Guillaume Serzian, MD; Baptiste Favoulet, MD; Jean- Marc Sellal , MD;

Christian De Chillou , MD, PhD; Néfissa Hammache , MD; Gabriel Laurent, MD, PhD;

Alexandre Mebazaa, MD, PhD; Fiona Ecarnot, PhD; Karine Bardonnet, MD; Marie- France Seronde, MD, PhD;

François Schiele , MD, PhD; Nicolas Meneveau , MD, PhD

BACKGROUND: We assessed the impact of preprocedural plasma levels of MRproANP (midregional N- terminal pro– atrial natriu-

retic peptide) and sST2 (soluble suppression of tumorigenicity 2) on recurrence of atrial fibrillation (AF) at 1 year after catheter

ablation of AF.

METHODS AND RESULTS: This was a prospective, multicenter, observational study including patients undergoing catheter abla-

tion of AF. MRproANP and sST2 were measured in a peripheral venous blood preprocedure, and MRproANP was assessed

in the right and left atrial blood during ablation. The primary end point was recurrent AF between 3 and 12 months postab-

lation, defined as a documented (>30 seconds) episode of AF, flutter, or atrial tachycardia. We included 106 patients from

December 2017 to March 2019; 105 had complete follow- up, and the mean age was 63 years with 74.2% males. Overall, 34

patients (32.1%) had recurrent AF. In peripheral venous blood, MRproANP was significantly higher in patients with recurrent AF

(median, 192.2; [quartile 1– quartile 3, 155.9– 263.9] versus 97.1 [60.9– 150.7] pmol/L; P<0.0001), as was sST2 (median, 30.3

[quartile 1– quartile 3, 23.3– 39.3] versus 23.4 [95% CI, 17.4– 33.0] ng/mL; P=0.0033). In the atria, MRproANP was significantly

higher than in peripheral blood and was higher during AF than during sinus rhythm. Receiver operating characteristic curve

analysis identified a threshold of MRproANP>107.9 pmol/L to predict AF recurrence at 1 year and a threshold of >26.7 ng/mL

for sST2. By multivariate analysis, MRproANP>107.9 pmol/L was the only independent predictor of recurrent AF (OR, 24.27;

95% CI, 4.23– 139.18). MRproANP<107.9 pmol/L identified subjects at very low risk of recurrence (negative predictive value

>95%).

CONCLUSIONS: Elevated MRproANP level independently predicts recurrent AF, whereas sST2 levels do not appear to have any

prognostic value in assessing the risk of recurrence of AF up to 1 year after catheter ablation.

REGISTRATION: URL: https://www.clini caltr ials.gov; Unique identifier: NCT03351816.

Key Words: atrial fibrillation ■ biomarkers ■ catheter ablation ■ MRproANP ■ sST2

Correspondence to: Nicolas Meneveau, MD, PhD, Department of Cardiology, University Hospital Jean Minjoz, Boulevard Fleming, 25000 Besançon,

France.E- mail: [email protected]

Supplementary Material for this article is available at https://www.ahajo urnals.org/doi/suppl/ 10.1161/JAHA.121.020917.

For Sources of Funding and Disclosures, see page 10.

© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creat ive

Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and

is not used for commercial purposes.

JAHA is available at: www.ahajournals.org/journal/jaha

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Badoz et al MRproANP and Recurrent AF After Catheter Ablation

Catheter ablation is the cornerstone of therapy for

atrial fibrillation (AF).1,2 The main limitation of this

procedure is the success rate, which varies be-

tween 50% and 75%.3– 8 It may also lead to potentially

serious complications,3– 9 and therefore the careful se-

lection of patients is warranted to identify those likely to

yield the greatest benefit, in particular among patients

with preserved left ventricular function in whom no re-

duction in mortality has been reported after catheter

ablation of AF.10

Several clinical factors have previously been

identified as predictors of AF recurrence after cath-

eter ablation, including left atrium (LA) dilation,

type of AF (persistent versus paroxysmal), obe-

sity, diabetes mellitus, hypertension, sleep apnea,

or CHA2DS2VASC score.11– 23 Although biomarkers

are widely used in cardiac disease,24– 26 there is a

paucity of data concerning the prognostic impact

of biomarkers on the course of AF after catheter

ablation. Indeed, in a recent report from a National

Heart, Lung, and Blood Institute Virtual Workshop

describing research needs and priorities for cathe-

ter ablation of atrial fibrillation, Al- Khatib et al called

for the development of biomarkers “with the goal of

stratifying individuals for risks of complications and

benefit from AF ablation.”27

MRproANP (midregional N- terminal pro– atrial na-

triuretic peptide) is a stable peptide that results from

the cleavage of proANP (pro– atrial natriuretic pep-

tide) and is elevated in numerous pathologies spe-

cifically affecting the LA, such as mitral stenosis.28,29

Charitakis et al previously suggested that recurrent

AF postablation is more frequent in patients with ele-

vated MRproANP.30

Fibrosis is frequent in AF, and the degree of fibrosis

may be associated with AF recurrence after catheter

ablation.31 ST2 (suppression of tumorigenicity 2) from

the family of interleukin- 1 receptors, is a biomarker of

fibrosis and cardiac biomechanical constraint.32,33 Its

soluble form, sST2, can be detected using commer-

cially available assays. sST2 has been shown to be of

prognostic importance in heart failure,34– 38 but its utility

has not been widely investigated in the setting of AF.

In this context, the aim of the present study was to

assess the impact of plasma levels of MRproANP and

sST2 measured before catheter ablation for AF on the

rate of recurrence of AF at 1 year after ablation.

Secondary objectives were to (1) compare MRproANP

concentrations in the LA, right atrium (RA), and periph-

eral venous blood; (2) compare MRproANP concen-

trations in the LA and RA in sinus rhythm and during

AF; and (3) investigate the existence of a link between

plasma levels of MRproANP and sST2 and the LA area.

METHODS

The data that support the findings of this study are

available from the corresponding author upon reason-

able request.

We performed a prospective, multicenter, observa-

tional study in 3 university teaching hospitals in Eastern

France (Besançon, Nancy, and Dijon) from December

2017 to March 2019. The study protocol was approved

by the Ethics Committee Comité de Protection des

Personnes (CPP) Ile- de- France VI (CPP Ile- de- France

VI, No. 34– 17, approval number: 2017- A00731- 52, ap-

proved on June 9, 2017). The study was registered with

ClinicalTrials.gov under the number NCT03351816.

All patients provided written informed consent for

participation.

Study PopulationInclusion criteria were patients aged >18 years with

symptomatic paroxysmal or persistent AF2 with pre-

served left ventricular ejection fraction (≥45%) and in

whom a first catheter ablation of AF was to be per-

formed. The decision to perform catheter ablation was

made in accordance with the European Society of

Cardiology (ESC) guidelines.2,39

Exclusion criteria were patients aged <18 years

or >80 years; patients with significant valvular heart

CLINICAL PERSPECTIVE

What Is New?• We show for the first time that MRproANP

(midregional N- terminal pro– atrial natriuretic peptide) is an independent predictor of recurrent atrial fibrillation at 1 year after catheter ablation, whereby patients with preprocedural plasma MRproANP values exceeding 107.9 pmol/L have a 24- fold increase in risk.

What Are the Clinical Implications?• Patients with elevated MRproANP before cath-

eter ablation of atrial fibrillation warrant closer monitoring up to 1 year after the procedure and an adaptation of medical therapy, notably anti-arrhythmics, to take account of the increased risk of recurrence.

Nonstandard Abbreviations and Acronyms

MRproANP midregional N- terminal pro– atrial

natriuretic peptide

RA right atrium

sST2 soluble suppression of tumorigenicity 2

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disease, defined as symptomatic aortic regurgitation,

severe aortic or mitral stenosis, or mitral or tricuspid

insufficiency grade 3/4 or 4/4; presence of pulmonary

hypertension on echocardiography (>45 mm Hg);

chronic respiratory disease; chronic obstructive pul-

monary disease stages 2, 3, or 4; left ventricular ejec-

tion fraction <45%; recent (<1 month) decompensation

of heart failure; recent (<1 month) acute coronary syn-

drome; or anemia (hemoglobin <10 g/dL). We also ex-

cluded pregnant women, people under judicial or legal

protection, people with poor anticipated compliance,

people with no social security coverage, and individu-

als within the exclusion period of a prior clinical trial as

per the national register of research volunteers.

Ablation ProcedureTransthoracic and transoesophageal echocardiog-

raphy were performed by a trained operator before

the procedure to ensure the absence of intracardiac

thrombus and to record the following data as per cur-

rent guidelines40: left ventricular ejection fraction, LA

area in the 4- cavity view, and maximum thickness of

the interventricular septum. A maximum thickness

>13 mm was considered as left ventricular hypertro-

phy. Usual curative anticoagulant therapy was not

interrupted before the procedure. The aim of the pro-

cedure was pulmonary vein isolation. Additional lesions

were made at the discretion of the operator. A total of 2

types of procedures could be performed, namely, radi-

ofrequency ablation with an irrigated tip ablation cath-

eter with electrophysiological and anatomical mapping

of the LA or cryoablation.5 The choice of technique

(cryoablation or radiofrequency ablation) and the sys-

tem used for electroanatomical navigation in case of

radiofrequency ablation were at the discretion of the

operator. Procedures were performed by qualified and

experienced operators having a volume of activity of

at least 50 procedures each per year. Transthoracic

echocardiography was performed at the end of the

procedure to ensure an absence of pericardial effu-

sion. Treatment was administered after the procedure

in accordance with guidelines in force at the time of

the inclusions.1,39 Usual anticoagulant therapy was

then pursued for 8 weeks postprocedure in patients

with CHA2DS2VASC scores of 0 or indefinitely for pa-

tients with CHA2DS2VASC scores ≥1.1,2 Antiarrhythmic

agents could be continued at the operator’s discre-

tion. It was recommended that every effort be made to

maintain sinus rhythm.

MRproANP and sST2 MeasurementsMRproANP and sST2 were measured in peripheral

venous blood drawn within 24 hours before the cath-

eter ablation procedure. MRproANP was also meas-

ured in a sample of blood from the RA at the start of

the procedure and in a sample of blood from the LA

drawn immediately after transseptal puncture. Tubes

were centrifuged and stored at −20°C for later cen-

tralized analysis in the Biochemistry Department of

the University Hospital of Besancon. MRproANP was

measured using BRAHMS Kryptor Compact Plus

(Thermo Fisher Diagnostics SAS, Dardilly, France).

sST2 was also centrally analyzed in the Biochemistry

Department of the University Hospital of Besancon

using the Aspect Plus kit from Eurobio Ingen (Les Ulis,

France).

Study End PointsThe primary end point was recurrence of AF, defined as

occurrence between 3 and 12 months after the proce-

dure of a documented episode (documented by ECG,

Holter monitoring, ECG event recorder, or telemetry) of

AF, atrial tachycardia, or atrial flutter lasting >30 sec-

onds. All patients were followed up with 24- hour Holter

ECG monitoring and a clinical consultation at 3 months

(the end of a blanking period) and 12 months after the

procedure. Between the end of the blanking period

and the 12- month follow- up, patients were followed by

their treating cardiologist and/or general practitioner

who were informed of the patient’s participation in this

study and were requested to inform the coordinating

center of any intercurrent events. In case of symptoms

suggestive of recurrent arrhythmia, patients were seen

in consultation and had an ECG with the possibility of

additional Holter ECG monitoring, ECG event recorder,

or hospitalization with continuous ECG to identify

recurrence.

Statistical AnalysisQuantitative data are described as mean±SD or me-

dian (25th percentile [quartile 1]– 75th percentile [quar-

tile 3]) and were compared with the Student t test for

normally distributed variables or the Mann– Whitney

test for nonnormally distributed variables. Paired

tests were used as appropriate. Qualitative data are

expressed as number (percentage) and were com-

pared using the chi- square or Fisher exact test as

appropriate. Multivariate analysis was performed

using multivariable logistic regression. Variables with

a P value <0.20 by univariate analysis were included

in the model, and the results are expressed as odds

ratios (OR) and 95% CI. Receiver operating charac-

teristic (ROC) curves were constructed to identify the

threshold of sST2 and MRproANP that best predict

recurrence. Survival curves were generated using the

Kaplan– Meier method and compared with the log-

rank test. Correlations between quantitative variables

were examined using the Spearman correlation coef-

ficient. All tests were 2 sided, and a P value <0.05 was

considered statistically significant. All analyses were

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performed using SAS version 9.4 (SAS Institute Inc.,

Cary, NC).

RESULTS

A total of 106 patients were included from December

2017 to March 2019. One patient withdrew con-

sent, and thus, 105 patients were followed up to

1 year.

Characteristics of Study PopulationThe baseline characteristics of the study population

are displayed in Table 1. Median age was 63 (56– 96)

years, and 20.1% had diabetes mellitus. The median

time since onset of AF was 18 (6.75– 48) months; 61

patients (58.1%) had paroxysmal AF, and 44 patients

(41.9%) had persistent AF.

Catheter Ablation ProceduresA total of 68 patients (64.7%) were in sinus rhythm at

the beginning of the ablation procedure. Overall, 38

(36.2%) underwent cryoablation, and 67 (63.8%) had

radiofrequency ablation. Of the 105 patients included,

all pulmonary veins were successfully isolated in 104

patients (99%). A total of 14 patients (13.3%) had com-

plex fractionated atrial electrogram ablation in addition

to pulmonary vein isolation, 11 patients (10.6%) had a

linear ablation across the roof of the LA, 10 patients

(9.5%) had cavotricuspid isthmus ablation, and 3 (2.8%)

had a mitral line (Table S1).

Table 1. Baseline Characteristics of the Study Population

Total, N=105 No Recurrence, n=71 Recurrence, n=34 P Value

Patient characteristics

Age, y, median (Q1– Q3) 63 (56– 69) 63 (54– 68) 65 (58– 69) 0.25*

Male sex, n (%) 78 (74.2) 55 (77.5) 23 (67.6) 0.28†

BMI, kg/m², mean±SD 28.7±5.2 28.7±5.1 28.8±5.3 0.96*

Medical history, n (%)

Hypertension 56 (53.3) 33 (46.5) 23 (67.6) 0.04†

Diabetes mellitus 22 (20.1) 11 (15.5) 11 (32.4) 0.05†

LVH 8 (7.6) 3 (4.2) 5 (14.7) 0.06†

Sleep apnea 12 (11.4) 8 (11.3) 4 (11.8) 0.94†

Coronary artery disease 12 (11.4) 3 (4.2) 9 (26.5) <0.01†

LVEF, %, median (Q1– Q3) 60 (55– 65) 60 (55– 65) 60 (50– 65) 0.19*

Prior stroke or TIA 7 (6.7) 4 (5.6) 3 (8.8) 0.54†

CHA2DS2VASC, median (Q1– Q3) 2 (0– 3) 1 (0– 3) 3 (1– 4) <0.01*

0, n (%) 30 (28.6) 26 (36.6) 4 (11.8) <0.01‡

1, n (%) 18 (17.1) 13 (18.3) 5 (14.7) 0.65‡

2, n (%) 15 (14.3) 9 (12.7) 6 (17.6) 0.50†

3, n (%) 21 (20.0) 16 (22.5) 5 (14.7) 0.35‡

4, n (%) 17 (16.2) 6 (8.5) 11 (32.4) <0.01†

≥5, n (%) 4 (3.8) 1 (1.4) 3 (3.8) 0.06‡

Arrhythmia history

Median time since onset, months, median (Q1– Q3) 18 (6.75– 48) 16 (6.25– 48) 24 (7– 48) 0.53*

Type of AF at inclusion, n (%) 0.17†

Paroxysmal 61 (58.1) 45 (63.4) 16 (47.1) 0.11†

Persistent 44 (41.9) 26 (36.6) 18 (52.9) 0.57†

Prior electrical cardioversion 37 (35.2) 23 (32.4) 14 (42.1) 0.38†

Prior ablation for atrial flutter 11 (10.5) 9 (12.7) 2 (5.9) 0.29‡

Rhythm control therapy at inclusion 74 (71.2) 53 (75.7) 21 (61.8) 0.14†

LA size

LA area, cm2, median§ (Q1– Q3) 22 (18– 26) 21 (17– 23.75) 24.5 (19– 29) <0.01*

AF indicates atrial fibrillation; BMI, body mass index; LA, left atrium; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; Q1, quartile 1;

Q3, quartile 3; and TIA, transient ischemic attack.

*Mann– Whitney test.†Chi- square test.‡Fisher exact test.§LA area measured by transthoracic echocardiography in the 4- chamber view.

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Regarding complications, 2 patients had transient

ischemic attack or ischemic stroke, there was no car-

diac tamponade, one patient had persistent phrenic

paralysis at discharge after cryoablation; 1 patient had

an access point hematoma, 1 patient had postproce-

dural pulmonary edema, and 1 patient had perforation

of the mitral valve with significant mitral insufficiency

(Table S1).

In total, 62 patients (59.0%) received rhythm- control

therapy at discharge (Table S1).

Primary OutcomeOverall, 34 patients (32.3%) had recurrent AF at 1 year

(recurrence group). There were significantly more pa-

tients with hypertension (67.6% versus 46.5%; P=0.04)

and ischemic heart disease (26.5% versus 4.2%;

P<0.01) in the recurrence group. In this group, there

was also a higher CHA2DS2VASC score (median, 3

[quartile 1– quartile 3, 1– 4] versus 1 [0– 3]; P<0.01) and

more dilation of the LA in terms of the area measured

by transthoracic echocardiography (median, 21 [quar-

tile 1– quartile 3, 17– 23.75] versus 24.5 [19– 29] cm2;

P=0.02).

There was no difference in the rate of antiarrhyth-

mics use at 1 year after the procedure between groups

(47.1% versus 35.2%, recurrence versus no recurrence,

respectively; P=0.25; Table S1).

Biomarker Levels and AF RecurrenceMRproANP measured in peripheral venous blood

drawn preprocedure was significantly higher in pa-

tients with recurrence versus those without recurrence

(median, 192.2 [quartile 1– quartile 3, 155.9– 263.9] ver-

sus 97.1 [60.9– 150.7] pmol/L; P<0.01). MRproANP lev-

els measured in blood drawn from the LA and RA were

also significantly higher in patients in the recurrence

group (Table 2). Similarly, sST2 levels were significantly

higher in the recurrence group (median30.3 [quartile

1– quartile 3, 23.3– 39.3] versus 23.4 [17.4– 33.0] ng/mL;

P<0.01).

ROC curve analysis of plasma MRproANP mea-

sured in peripheral venous blood identified a threshold

value of >107.9 pmol/L as having the best predictive

value for recurrent AF at 1 year after ablation, with

a sensitivity of 94.1%, a specificity of 63.4%, and an

area under the ROC curve of 0.838 (P<0.01; Figure 1).

The associated positive predictive value and negative

predictive value (NPV) were, respectively, 55.2% and

95.7% (Table 3). For sST2, the threshold identified by

ROC curve analysis was >26.7 ng/mL, with a sensi-

tivity and a specificity of 73.5% and 64.8%, respec-

tively. The area under the ROC curve for sST2 was

0.678 and was significantly lower than the area under

the ROC curve for MRproANP (P<0.01; Figure 1). The

associated positive predictive value and NPV were,

respectively, 49.0% and 83.3% (Table 3). The propor-

tion of recurrence and nonrecurrence per quartiles of

MRproANP and sST2 are presented in Figure 2. There

was a significant difference in AF recurrence be-

tween groups when classified according to whether

MRproANP measured in peripheral venous blood

was above or below the threshold of 107.9 pmol/L

(Figure 3).

MRproANP levels were significantly higher in blood

drawn from the LA and RA than in peripheral venous

blood (median, 143.5 [quartile 1– quartile 3, 89.8–

208.3] versus 131.5 [73.5– 200.6] pmol/L [P<0.01]; and

median, 142.2 [quartile 1– quartile 3, 90.3– 210.3] ver-

sus 131.5 [73.5– 200.6] pmol/L [P<0.01]; respectively).

There was a significant correlation between MRproANP

levels in the atria (left and right) and peripheral venous

blood (P<0.01; Figure S1). There was no significant dif-

ference in MRproANP levels between the LA and RA

(Figure S2). MRproANP levels were higher in the LA

and RA when patients were in AF at the time of the

blood draw compared with blood samples performed

in sinus rhythm (median, 187.9 [quartile 1– quartile 3,

135.1– 288.4] versus 115.2 [81.9– 168.6] [P<0.01]; and

median, 191.0 [quartile 1– quartile 3, 127.0– 276.9] ver-

sus 109.4 [82.3– 169.8] pmol/L [P<0.01]; respectively;

Figure S3). The predictive value of MRproANP was the

same, regardless of the site of blood draw, as illus-

trated by the lack of difference between ROC curves

(Figure 4) and the sensitivity, specificity, positive pre-

dictive value, and NPV (using the best predictive value

Table 2. Results of MRproANP and sST2 Assessments

Total, N=105 No Recurrence, n=71 Recurrence, n=34 P Value*

MRproANP PV, pmol/L 131.3 (73.5– 200.6) 97.1 (60.9– 150.7) 192.2 (155.9– 263.9) <0.01

MRproANP LA, pmol/L 143.5 (89.8– 208.3) 110.7 (79.3– 172.1) 234.3 (163.4– 334.2) <0.01

MRproANP RA, pmol/L 142.2 (90.3– 210.3) 108.8 (81.8– 168.1) 207.8 (159.1– 347.2) <0.01

sST2 PV, ng/mL 26.4 (19.5– 36.4) 23.4 (17.4– 33.0) 30.3 (23.3– 39.8) <0.01

Values are provided as median (quartile 1– quartile 3). MRproANP indicates midregional N- terminal pro– atrial natriuretic peptide; MRproANP LA, level of

midregional N- terminal pro– atrial natriuretic peptide measured in blood drawn from the left atrium; MRproANP PV, midregional N- terminal pro– atrial natriuretic

peptide measured in peripheral venous blood; MRproANP RA, level of midregional N- terminal pro– atrial natriuretic peptide measured in blood drawn from the

right atrium; sST2, level of soluble suppression of tumorigenicity 2; and sST2 PV, soluble suppression of tumorigenicity 2 measured in peripheral venous blood.

*P values from Mann– Whitney tests.

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of MRproANP as identified by ROC curve analysis)

measured in the LA and RA as well as in peripheral

venous blood (Table 3).

There was a significant correlation between both

MRproANP (r=0.465; P<0.01) and sST2 (r=0.256;

P<0.01) levels and LA area (Figure S4).

Figure 1. Receiver operating characteristic curves showing the levels of MRproANP and sST2

measured before the procedure in peripheral venous blood that best predict the recurrence of

atrial fibrillation up to 1 year after catheter ablation.

AUC indicates area under the curve; MRproANP, midregional N- terminal pro– atrial natriuretic peptide;

and sST2, soluble suppression of tumorigenicity 2.

Table 3. Sensitivity, Specificity, and Positive and Negative Predictive Values of MRproANP and sST2 for the Prediction of

Recurrent Atrial Fibrillation After Catheter Ablation

Sensitivity, % Specificity,% PPV, % NPV, %

MRproANP PV>107.9 pmol/L 94.1 63.4 55.2 95.7

MRproANP LA>143.5 pmol/L 88.2 69.0 57.7 92.5

MRproANP RA>122.1 pmol/L 84.1 59.2 52.5 95.5

sST2 PV>26.7 ng/mL 73.5 64.8 49.0 83.3

MRproANP indicates midregional N- terminal pro– atrial natriuretic peptide; MRproANP LA, level of midregional N- terminal pro– atrial natriuretic peptide

measured in blood drawn from the left atrium; MRproANP PV, midregional N- terminal pro– atrial natriuretic peptide measured in peripheral venous blood;

MRproANP RA, level of midregional N- terminal pro– atrial natriuretic peptide measured in blood drawn from the right atrium; NPV, negative predictive value; PPV,

positive predictive value; sST2, level of soluble suppression of tumorigenicity 2; and sST2 PV, soluble suppression of tumorigenicity 2 measured in peripheral

venous blood.

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By multivariate analysis, MRproANP measured

in peripheral venous blood was the only factor in-

dependently associated with recurrent AF at 1 year

postablation (OR, 1.01; 95% CI, 1.01– 1.02; Table 4).

When including MRproANP as a binary variable (using

the ROC- identified threshold of 107.9 pmol/L), an

Figure 2. Distribution of atrial fibrillation recurrence per quartile (Q1– Q4) of MRproANP and sST2 concentration as

measured in peripheral venous blood before the catheter ablation procedure.

MRproANP indicates midregional N- terminal pro– atrial natriuretic peptide; Q1, quartile 1; Q4, quartile 4; and sST2, soluble suppression

of tumorigenicity 2.

Figure 3. Kaplan– Meier curves of AF recurrence- free survival according to whether MRproANP level was above or below

the threshold of 107.9 pmol/L.

AF indicates atrial fibrillation; and MRproANP, midregional N- terminal pro– atrial natriuretic peptide.

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elevated MRproANP value (>107.9 pmol/L) was as-

sociated with an OR of 24.27 for recurrence of AF at

1 year (95% CI, 4.23– 139.18), after adjustment for hy-

pertension, ischemic heart disease, CHA2DS2VASC≥2,

sST2>26.7 ng/mL, LA area>22 cm2, diabetes mellitus,

left ventricular hypertrophy, type of AF and rhythm

control therapy at inclusion, and left ventricular ejec-

tion fraction.

DISCUSSION

To the best of our knowledge, this is the first prospec-

tive, multicenter study to investigate the impact of

plasma levels of MRproANP and sST2 before catheter

ablation of AF on the risk of recurrence of AF at 1 year

after the procedure. Preprocedural levels of MRproANP

and sST2 were higher in patients with recurrent AF at

1 year. By multivariate analysis, plasma MRproANP

measured preprocedure was found to be a signifi-

cant independent predictor of recurrent AF postabla-

tion. We observed a strong linear relation between the

level of MRproANP before the procedure and recur-

rence of AF up to 1 year after ablation. In patients with

preserved left ventricular ejection fraction, our results

show that MRproANP >107.9 pmol/L before the proce-

dure is indicative of a significant, 24- fold increase in the

risk of AF recurrence at 1 year. Conversely, MRproANP

levels <107.9 pmol/L can identify individuals who will

almost certainly not experience recurrence, with a NPV

of >95%. sST2 was not found to be an independent

predictor of AF recurrence after catheter ablation in our

study.

There is a compelling need for simple and objec-

tive criteria that can identify patients likely to respond

well to catheter ablation of AF, to facilitate selection

Figure 4. Receiver operating characteristic curves showing the levels of MRproANP measured

before the procedure in PV blood, the LA blood, and RA blood predicting the recurrence of atrial

fibrillation up to 1 year after catheter ablation.

LA indicates left atrium; MRproANP, midregional N- terminal pro– atrial natriuretic peptide; PV, peripheral

venous; and RA, right atrium.

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of candidates for ablation, and to guide postabla-

tion management. Certain clinical variables, such as

LA dilation, type of AF (persistent versus paroxys-

mal), obesity, diabetes mellitus, hypertension, sleep

apnea, or CHA2DS2VASC score have been shown

to predict recurrent AF postablation.11– 23 However,

to date no reliable biological parameter has been

identified that can identify patients at risk of AF re-

currence after catheter ablation. In a previous single-

center study, recurrent AF was found to be more

frequent in patients with an MRproANP value in the

fourth quartile compared with the first quartile.30 This

is line with our findings, as in our study no recurrence

was observed in the first quartile of MRproANP ver-

sus a recurrence rate of >60% in the fourth quar-

tile. In terms of quantitative thresholds, this means

that patients with MRproANP<73.5 pmol/L prepro-

cedure have no recurrence, whereas among those

with values >200 pmol/L, >60% experienced recur-

rent AF. Furthermore, our results also illustrate the

linear nature of the relation between preprocedural

MRproANP levels and postablation recurrence rates

and identified MRproANP as an independent predic-

tor of the risk of recurrence, which is a novel find-

ing. Regardless of the site from which the blood was

drawn (peripheral blood, LA, or RA), the predictive ca-

pacity of MRproANP for recurrent AF was the same.

Thus, it would seem that assessing MRproANP from

peripheral venous blood is sufficient to identify pa-

tients who will respond well or those who may be at

increased risk of AF recurrence after the procedure.

proANP is stored and released by atrial cardio-

myocytes and is cleaved into mature ANP, and its N-

terminal fragment, NTproANP.41 Within this fragment is

the midregional section, MRproANP, which has a lon-

ger half- life than mature ANP (atrial natriuretic peptide),

making its assessment more reliable.42,43 In stable

clinical conditions, which was the case of the patients

included in our study, the variability of MRproANP is

low.44 It was previously shown that MRproANP is in-

creased in patients with AF, independently of he-

modynamic conditions, and also that there is a link

between AF burden and MRproANP levels.45,46 Other

studies have also reported that catheter ablation for

AF significantly reduced plasma concentrations of

ANP and MRproANP in the long term.47,48 In our study,

MRproANP levels were higher in the RA and LA than

in peripheral venous blood, with a strong correlation

between the levels observed in the atria and those in

the peripheral circulation, and the levels in the atria

were higher during AF than in sinus rhythm. These

data complement previous knowledge and suggest

that there is an increased release of ANPs by the my-

ocytes of the LA and RA during AF. Taken together,

these findings suggest that MRproANP may be a good

marker of AF progression and prognosis. We purport

that MRproANP could be preferred over BNP (B- type

natriuretic peptide) in the context of AF, especially be-

cause it is established that ANP and BNP levels are

discordant in patients with AF.49

sST2 is a marker of fibrosis, particularly cardiac

fibrosis.32 The clinical course of AF is marked by the

development of atrial fibrosis.31,50– 53 In clinical prac-

tice, sST2 is an important prognostic marker in several

domains, such as heart failure and renal insufficien-

cy.34– 38,54,55 A previous study investigating sST2 found

that it was an independent predictor of AF recurrence.56

However, this was a single- center study performed

in patients with nonvalvular paroxysmal AF undergo-

ing cryoablation of AF.56 In our study, we did not find

sST2 to be an independent predictor of AF recurrence

after catheter ablation. It would seem that sST2 is less

determinant than MRproANP in light of our multivar-

iate analysis and the comparison of the ROC curves

comparing the predictive capacity of each marker.

However, we did observe a correlation between sST2

and LA dilation, corroborating the findings of Okar et

al.56 Taken together, the data regarding sST2 suggest

that it is an important biomarker for the prognosis and

overall follow- up of cardiac disease and progression

toward heart failure, but not specifically useful in the

setting of AF.

Our study has some limitations. First, it was an ob-

servational study with a relatively small sample size

(N=105), and certain known predictors of recurrence

(body mass index, sleep apnea) were not found to

be significant in our study, likely because of a lack of

statistical power. Second, the methods of assessing

AF recurrence may have led to an underestimation of

actual recurrence rates. Indeed, patients did not have

Table 4. Independent Predictors of Recurrent AF After

Catheter Ablation by Multivariate Logistic Regression

OR 95% CI

MRproANP*, per unit 1.01 1.01– 1.02

sST2, per unit 1.01 0.98– 1.05

Hypertension 1.78 0.47– 6.71

Coronary artery disease 5.40 0.76– 38.17

CHA2DS2VASC≥2 0.98 0.21– 4.45

LA area>22 cm2 2.69 0.71– 10.14

Diabetes mellitus 1.28 0.28– 5.92

LVH 0.35 0.02– 6.70

Type of AF at inclusion 2.00 0.93– 4.26

Rhythm control therapy at

inclusion

0.45 0.14– 1.46

LVEF, per unit 1.03 0.96– 1.11

AF indicates atrial fibrillation; LA, left atrium; LVEF, left ventricular ejection

fraction; LVH, left ventricular hypertrophy; MRproANP, midregional N-

terminal pro– atrial natriuretic peptide; OR, odds ratio; and sST2, soluble

suppression of tumorigenicity 2.

*Measured in peripheral venous blood.

Dow




implanted Holter devices (implantable cardiac moni-

tors), and the duration of systematic ECG Holter mon-

itoring was only 24 hours, without the performance

of longer duration monitoring. Nevertheless, the like-

lihood of underestimation of AF recurrence is low given

than the recurrence rate at 1 year observed in our

study was similar to, if not higher than that reported in

other prospective studies.5,10,57 This may be explained

by the fact that all patients were symptomatic, mak-

ing the detection of recurrence easier. Indeed, patients

were instructed to consult the cardiologist or general

practitioner immediately in case of symptoms. In addi-

tion, if underestimation occurred, it likely affected both

groups equivalently. We therefore believe that the mon-

itoring modalities likely had little effect on the results.

In addition, multiple factors affect the success rate of

AF ablation and may confound the predictive role of

the markers. Nevertheless, MRproANP was found to

be an independent predictor even after adjustment

for potential confounders in multivariate analysis, thus

supporting the robustness of our findings. Finally, our

data deserve confirmation in a larger population to

confirm the prognostic value of MRproANP to identify

patients at high risk of AF recurrence up to 1 year after

catheter ablation of AF on top of previously identified

predictors.11– 13,18– 23

CONCLUSIONS

An elevated MRproANP level is an independent

predictor of recurrent AF at 1 year after catheter

ablation, whereas sST2 levels do not appear to

have any prognostic value in assessing the risk

of recurrence of AF up to 1 year. An MRproANP

level >107.9 pmol/L before the procedure is asso-

ciated with a 24- fold increase in the risk of recur-

rent AF within 1 year. Conversely, an MRproANP

value <107.9 pmol/L identif ies patients unlikely

to experience recurrent AF, with a high NPV.

Larger prospective studies are warranted to

confirm the utility of assessing MRproANP in this

setting.

ARTICLE INFORMATION

Received February 12, 2021; accepted May 13, 2021.

AffiliationsDepartment of Cardiology (M.B., G.S., B.F., F.E., M.S., F.S., N.M.); and

Department of Biochemistry (K.B.), University Hospital Besançon, Besançon,

France; EA3920, University of Burgundy Franche- Comté, Besançon, France

(M.B., F.E., M.S., F.S., N.M.); Department of Cardiology, Centre Hospitalier

Régional Universitaire de Nancy, Université de Lorraine, Nancy, France

(J.S., C.D.C., N.H.); IADI, INSERM U1254, Université de Lorraine, Nancy,

France (J.S., N.H.); Department of Cardiology, University Hospital François

Mitterand, Dijon, France (G.L.); INSERM UMR- S 942, Paris, France (A.M.);

and Department of Anesthesiology and Critical Care Medicine, Assistance

Publique - Hôpitaux de Paris, Saint Louis Lariboisière University Hospitals,

Paris, France (A.M.).

Sources of Funding

This study was partially funded by an unrestricted

grant from Abbott Medical France.

DisclosuresDr de Chillou reports personal fees from Biosense Webster, Medtronic,

Stereotaxis, and Mylan and nonfinancial support from Abbott and

Microport outside the submitted work. Dr Sellal reports personal fees

from Microport, Bayer, Mylan, Pfizer, and Boeringher outside the submit-

ted work. Dr Meneveau reports personal fees from Abbott, Bayer, Boston

Scientific, Bristol Myers Squibb, Edwards Lifesciences, and Terumo outside

the submitted work. Dr Seronde reports personal fees from Astra Zeneca,

Boehringer Ingelheim, Bayer, Bristol Myers Squibb, Novartis, and Servier

outside the submitted work. Dr Mebazaa reports personal fees from Orion,

Servier, Otsuka, Philips, Sanofi, Epygon, and Fire 1; grants and personal

fees from Roche, Adrenomed, and 4TEEN4; personal fees from grants from

Abbott; and grants and personal fees from Sphyngotec outside the submit-

ted work. Dr Schiele reports grants and personal fees from Bayer, Sanofi

Aventis, MSD, and Amgen; grants from St Jude Medical and Daiichi Sankyo;

and personal fees from Boehringer Ingelheim, Pfizer, Astra Zeneca, Mylan,

and Servier outside the submitted work. The remaining authors have no dis-

closures to report.

Supplementary MaterialTable S1

Figures S1- S4

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failure in dogs. Circulation. 2002;105:2672– 2678. DOI: 10.1161/01.

CIR.00000 16826.62813.F5.

54. O’Meara E, Prescott MF, Claggett B, Rouleau JL, Chiang LM, Solomon

SD, Packer M, McMurray JJV, Zile MR. Independent prognostic value

of serum soluble ST2 measurements in patients with heart failure and

a reduced ejection fraction in the PARADIGM- HF Trial (Prospective

Comparison of ARNI With ACEI to Determine Impact on Global Mortality

and Morbidity in Heart Failure). Circ Heart Fail. 2018;11:e004446. DOI:

10.1161/CIRCH EARTF AILURE.117.004446.

55. Tuegel C, Katz R, Alam M, Bhat Z, Bellovich K, de Boer I, Brosius F,

Gadegbeku C, Gipson D, Hawkins J, et al. GDF- 15, galectin 3, sol-

uble ST2, and risk of mortality and cardiovascular events in CKD.

Am J Kidney Dis. 2018;72:519– 528. DOI: 10.1053/j.ajkd.2018.

03.025.

56. Okar S, Kaypakli O, Şahin DY, Koç M. Fibrosis marker soluble ST2 pre-

dicts atrial fibrillation recurrence after cryoballoon catheter ablation of

nonvalvular paroxysmal atrial fibrillation. Korean Circ J. 2018;48:920–

929. DOI: 10.4070/kcj.2018.0047.

57. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma

L, Jordaens L, Merkely B, Pokushalov E, Sanders P, Proff J, et al.

Catheter ablation for atrial fibrillation with heart failure. N Engl J Med.

2018;378:417– 427. DOI: 10.1056/NEJMo a1707855.

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https://doi.org/10.1007/s00392-018-1332-1

https://doi.org/10.1111/pace.12919

https://doi.org/10.1093/eurheartj/ehm577





https://doi.org/10.1093/eurheartj/ehv514

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https://doi.org/10.1161/01.CIR.0000016826.62813.F5


https://doi.org/10.1053/j.ajkd.2018.03.025

https://doi.org/10.1053/j.ajkd.2018.03.025

https://doi.org/10.4070/kcj.2018.0047


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Table S1. Procedural data and complications in patients with and without recurrence of

atrial fibrillation after catheter ablation.

Total (N=105) No recurrence

(n=71)

Recurrence

(n=34)

P value

Sinus rhythm at start of procedure 68 (64.7) 48 (67.6) 20 ( 58.8) 0.39*

Catheter ablation techniques

Cryoballoon ablation 38 (36.2) 24 (22.9) 14 (13.3) 0.46*

Radiofrequency ablation 67 (63.8) 47 (66.2) 20 (58.8) 0.46*

Pulmonary-vein isolation 104 (99.0) 71 (100) 33 (97.1) 0.14*

Ablation of CFAEs 14 (13.3) 8 (11.3) 6 (17.6) 0.37*

Linear ablation across the roof 11 (10.6) 2 (2.9) 9 (26.5) <0.01*

Linear ablation in mitral valve

isthmus 3 (2.9) 1 (2.8) 2 (2.9) 0.97*

Linear ablation in IVC-tricuspid

annulus isthmus 10 (9.5) 6 (8.5) 4 (12.9) 0.59*

Total procedure duration

(minutes), median [Q1-Q3] 115 [90-150] 105 [90-143.75] 120 [90-150] 0.32†

Procedural adverse events

Groin site complication 1 (0.9) 0 (0) 1 (2.9) 0.32‡

Cardiac tamponnade 0 (0) 0 (0) 0 (0)

TIA or stroke 2 (1.9) 1 (1.4) 1 (2.9) 0.60‡

Phrenic nerve injury 1 (0.9) 1 (1.4) 0 (0) 0.49‡

Other complications 2 (1.9) 0 (0) 2 (5.9) 0.04‡

Rhythm control therapy at discharge

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Antiarrhythmic drugs (all) 62 (59.0) 42 (59.2) 20 (58.8) 0.97*

Sotalol 10 (9.5) 7 (9.9) 3 (8.8) 0.87‡

Amiodarone 19 (18.1) 11 (15.5) 8 (23.5) 0.32‡

Flecainide 15 (14.3) 12 (16.9) 3 (8.8) 0.27‡

Beta blockers 42 (0.40) 26 (36.6) 16 (47.1) 0.31*

Rhythm control therapy at follow-up

Antiarrhythmic drugs (all) 41 (39.0) 25 (35.2) 16 (47.1) 0.25*

Sotalol 7 (6.7) 4 (5.6) 3(8.8) 0.87‡

Amiodarone 9 (8.6) 5 (7.0) 4 (11.8) 0.81‡

Flecainide 5 (4.8) 3 (4.2) 2 (5.9) 0.93‡

Beta blockers 30 (28.6) 18 (25.4) 12 (35.3) 0.56*

CFAEs: Complex Fractionated Atrial Electrograms; min: Minutes; TIA: Transient Ischemic

Attack.

Other complications: 1 mitral valve perforation, 1 pulmonary oedema

[Q1-Q3]: quartiles [25th and 75th percentiles]

*Chi square test

† Mann Whitney test

‡ Fisher’s exact test

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Figure S1. Correlation between MRproANP levels in the left and right atria, and in

peripheral venous blood.

0

100

200

300

400

500

600

0 100 200 300 400 500 600MRproANP LA blood

MR

proA

NP

PV b

lood

0

100

200

300

400

500

600

0 100 200 300 400 500 600MRproANP RA blood

MR

proA

NP

PV b

lood

rho = 0.94 p < 0.01

rho = 0.94 p < 0.01

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Figure S2. Correlation between MRproANP (pmol/L) concentration in peripheral

venous blood, and in the left atrium (LA blood) and right atrium (RA blood) prior to

the catheter ablation procedure.

0

100

200

300

400

500

600

MR

proA

NP

(pm

ol/L

)

Peripheral_venous_blood LA_blood RA_blood

p<0.01 p=0.14

p<0.01

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Figure S3. MRproANP (pmol/L) concentration in the left atrium (LA blood) and right

atrium (RA blood) prior to the catheter ablation procedure in patients in atrial

fibrillation and in patients in sinus rhythm at the time of the blood draw.

D

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Figure S4. Correlation between MRproANP and sST2 levels measured prior to the

procedure in peripheral venous blood, and left atrial area.

10

15

20

25

30

35

40

45

0 20 40 60 80 100 120 140sST2 ng/mL

Left

atria

l sur

face

(cm

2)

10

15

20

25

30

35

40

45

0 100 200 300 400 500 600MRproANP (pmol/L)

Left

atria

l sur

face

(cm

2)

rho = 0.47 p < 0.01

rho = 0.26 p = 0.01

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92

VI. Synthèse et

perspectives

93

Ce travail de thèse s’est intéressé, par la publication de 4 articles, à l’utilisation de

biomarqueurs potentiellement liés à la dysfonction atriale dans des pathologies affectant en

premier lieu l’oreillette.

Le MRproANP et le sCD146 étaient liés à la congestion et à la dilatation des oreillettes

droite et gauche chez des patients consultant pour dyspnée.

Dans la sténose mitrale le MRproANP et le sCD146 étaient liés à la fois à la sévérité de

la sténose, aux complications de la sténose et au succès d’une procédure de commissurotomie

percutanée.

Le MRproANP semblait avoir un intérêt pronostic important dans la fibrillation atriale,

alors que le sST2 n’était pas un prédicteur indépendant de récidive post ablation.

VI.1. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide chez des patients

atteints de sténose mitrale

Dans nos résultats nous avons montré que le MRproANP était significativement plus

élevé chez les patients lorsque la sténose mitrale était serrée en comparaison aux sténoses

mitrales moyennement serrées (2). Le MRproANP est secrété du fait de la contrainte pariétale

exercée sur les myocytes de l’oreillette gauche notamment. Ainsi plus la sténose mitrale devient

serrée, plus la pression atriale gauche augmente, plus la sécrétion s’élève.

Par ailleurs, chez les patients porteurs de sténose mitrale, le MRproANP était

significativement plus élevé en présence d’une hypertension artérielle pulmonaire (HTP)

compliquant la sténose mitrale. L’élévation du MRproANP était également présente chez des

patients atteints d’hypertension artérielle pulmonaire pré-capillaire, avec des niveaux proches

94

de ceux des patients porteurs de sténoses mitrales compliquées d’HTP (p=0.20). Par définition

l’oreillette gauche est épargnée dans l’hypertension artérielle pulmonaire pré-capillaire, la

répercussion de la pathologie se fait sur les cavités droites. Il existe probablement pour ces

patients une sécrétion de MRproANP provenant de l’oreillette droite. Cette hypothèse est

vraisemblable d’autant que les données de l’étude BIORHYTHM (4) plaidaient pour une

sécrétion du MRproANP par les oreillettes gauche et droite avec des concentrations de

MRproANP équivalentes entre oreillettes gauche et droite, plus élevées que dans le sang

veineux périphérique.

Lors d’une valvuloplastie mitrale percutanée (VMP), l’ouverture même partielle de

l’obstacle que constitue la sténose mitrale entraîne immédiatement une diminution de la

pression atriale gauche (86, 87), et ainsi une diminution significative du MRproANP que nous

avons mis en évidence (3). La diminution des pressions pulmonaires après VMP contribue

également à la diminution des concentrations de MRproANP par la diminution de la contrainte

pariétale exercée sur l’oreillette droite. La diminution significative du MRproANP dans les 24

heures en cas de succès d’une VMP est possible en raison d’une cinétique de sécrétion et de

décroissance adaptée et réactive, permettant à ce biomarqueur d’être un marqueur de succès

immédiat de la procédure. En cas d’échec de la VMP, la pression intra atriale gauche et les

pressions pulmonaires ne diminuent pas suffisamment pour entrainer une diminution

significative du MRproANP. Ces données confirment et actualisent, sur un plus grand nombre

de patients, de précédentes publications qui avaient mis en évidence une décroissance de l’ANP

après commissurotomie mitrale percutanée et un lien significatif entre diminution de la pression

atriale gauche et décroissance de l’ANP (86, 87).

Le MRproANP, d’après les articles publiés dans cette thèse, semble être un marqueur

fiable pour évaluer la sévérité d’une sténose mitrale et le succès de son traitement (2, 3). Il

n’existe pas de données plus récentes sur ce sujet.

95

VI.2. Intérêt du Mid-Regional pro Atrial Natriuretic Peptide chez des patients

atteints de fibrillation atriale

Il n’a pas été mis en évidence de différence significative de MRproANP entre les

patients atteints de sténose mitrale avec fibrillation atriale et ceux sans fibrillation atriale (2).

Cette absence de différence significative (p=0.69) est possiblement lié à un manque de

puissance lié au faible effectif de notre étude. Nous avons en effet montré sur un plus grand

effectif que les concentrations veineuses périphériques et intra-atriales de MRproANP étaient

plus élevées en fibrillation atriale qu’en rythme sinusal (4).

Dans le domaine de l’ablation de fibrillation atriale, nous avons identifié un seuil de

107.9pmol/L au-delà duquel le risque de récidive de FA à 1 an de l’ablation est multiplié par

presque 25. Inversement, en dessous de ce seuil les patients sont très peu sujets à la récidive

(4.2%) avec une valeur prédictive négative très élevée de 95.7% (4). Il existait une relation

linéaire entre les niveaux de MRproANP pré procédure et le risque de récidive à un an de

l’ablation de fibrillation atriale.

Dans cette même étude les concentrations intra atriales de MRproANP étaient plus

élevées chez les patients en fibrillation qu’en rythme sinusal, que ce soit dans l’oreillette droite

ou gauche. Les concentrations intra atriales droite et gauche ne différaient pas significativement

entre elles, en revanche, elles étaient plus élevées que dans le sang veineux périphérique. Ces

résultats vont dans le sens d’une sécrétion du MRproANP par les oreillettes droite et gauche

chez les patients en fibrillation atriale.

96

A notre connaissance, il n’existe pas d’autre étude prospective s’intéressant au lien entre

MRproANP pré procédure et récidive de FA à long terme après une ablation. Sacher et al.

avaient démontré que le maintien du rythme sinusal après une ablation de fibrillation atriale

persistante entrainait une diminution importante du MRproANP à 3 mois (88). Charitakis et al.

suggéraient que le pourcentage de récidive de fibrillation atriale post ablation était plus élevé

pour des patients ayant des concentrations de MRproANP dans le quatrième quartile en

comparaison au premier quartile (89). Nos données confirment, de façon plus robuste, celles

publiées précédemment, en allant plus loin dans le lien récidive de FA et concentrations

plasmatiques de MRproANP.

VI.3. Lien entre modification structurelles de l’oreillette et Mid-Regional pro

Atrial Natriuretic Peptide

En ce qui concerne les modifications structurelles de l’oreillette liées à l’évolution des

différentes pathologies, il existait une corrélation significative entre la surface de l’oreillette

gauche mesurée en échographie cardiaque transthoracique et les concentrations plasmatiques

de MRproANP (4). Le lien entre dilatation des oreillettes droite et gauche et MRproANP a été

mis en évidence également dans une 2ème publication chez des patients présentant une dyspnée

aigue en lien ou non avec des manifestations d’insuffisance cardiaque (1). Des données

précédemment publiées avaient identifié ce lien dans d’autres populations, par exemple chez

des patients après un syndrome coronaire aigu (90). Le lien entre ces deux variables semble

donc réel.

Le MRproANP était un marqueur de congestion fiable dans les données que nous avons

publiées. Il était en effet significativement plus élevé chez des patients dont la dyspnée était liée

97

à des manifestations d’insuffisance cardiaque en comparaison à une dyspnée d’origine

extracardiaque. En revanche il ne permet pas de discriminer l’insuffisance cardiaque à fraction

d’éjection préservée de celle secondaire à une dysfonction ventriculaire gauche systolique (1).

VI.4. Mid-Regional pro Atrial Natriuretic Peptide, synthèse et perspectives de

recherche

Au vu de l’ensemble de ces données, nous pouvons conclure que le MRproANP est un

biomarqueur de dysfonction et d’atteinte atriale pouvant présenter un intérêt en pratique

clinique notamment pour l’évaluation de la sévérité des sténoses mitrales, du succès de leur

traitement et pour le pronostic des pathologies rythmiques atriales en premier lieu dans la

fibrillation atriale. Il ne semble pas être un bon marqueur de dysfonction systolique

ventriculaire.

En ce qui concerne la capacité pronostique du MRproANP dans le domaine de

fibrillation atriale, de récentes publications vont dans le même sens que nos données. Le

MRproANP prélevé en pré opératoire semble notamment prédicteur de survenue de fibrillation

atriale en post opératoire de chirurgie cardiaque (91). L’intérêt pronostique suscité par le

MRproANP touche d’autres domaines, y compris les plus récents. Il est prédicteur indépendant

de mortalité en cas de COVID-19 (92). Des données récentes confirment également le fait que

le MRproANP est un marqueur de dysfonction atriale gauche et de remodelage de l’oreillette

gauche (93).

Nous poursuivons nos travaux de recherche concernant ce biomarqueur. En particulier,

nous nous intéressons à l’impact pronostique du MRproANP en termes de récidives de

98

fibrillation atriale chez les patients de BIORHYTHM soumis à une cardioversion électrique.

L’objectif est bien sûr d’identifier si les taux plasmatiques de MRproANP peuvent prédire le

risque de récidive, mais aussi de savoir si les résultats publiés dans BIORHYTHM à partir des

patients ayant fait l’objet d’une ablation, peuvent être étendus à d’autres situations et à d’autres

types de populations, plus âgées dans ce cas, avec beaucoup plus de comorbidités.

Nous avons également débuté un travail prospectif cherchant à documenter à l’aide d’un

holter implantable, l’incidence de la fibrillation atriale chez des patients traités par fermeture

percutanée de foramen ovale perméable après un accident vasculaire cérébral ischémique :

l’étude PFO-AF (Prevalence of atrial Fibrillation in cryptogenic stroke with patent foramen

Ovale closure: PFO-AF study). Dans cette étude la concentration de MRproANP plasmatique

est dosée sur un prélèvement veineux périphérique pré procédural. Nous évaluerons le lien entre

la concentration de MRproANP et la survenue de fibrillation atriale à distance de la fermeture

de foramen ovale perméable.

VI.5. Intérêt du Soluble Cluster of Differentiation 146 chez des patients atteints

de sténose mitrale.

La seconde publication présentée (2) a montré que le sCD146 était plus élevé chez les

patients porteurs de sténoses mitrales serrées en comparaison à des sténoses mitrales non

serrées. Le sCD146 peut donc être utilisé comme marqueur de la sévérité de la sténose mitrale

comme le MRproANP. Il semble être également un marqueur de survenue de complications de

la sténose mitrale, telles que le passage en fibrillation atriale et l’apparition d’hypertension

artérielle pulmonaire. Il est à noter que les concentrations de sCD146 étaient plus élevées chez

les patients atteints d’hypertension artérielle pré-capillaire (HTAP) que chez ceux atteints de

99

sténose mitrale. Cette différence était toujours significative en comparant cette fois les sténoses

mitrales compliquées d’hypertension pulmonaire aux patients atteints d’HTAP, avec des

niveaux de sCD146 plus élevés chez les patients HTAP.

Le sCD146 est un marqueur d’origine endothéliale, avec notamment une sécrétion par

les gros vaisseaux de la circulation pulmonaire (20-22). Le sCD146 est de ce fait un marqueur

indirect de souffrance de l’oreillette gauche. En devenant serrée la sténose mitrale augmente les

pressions pulmonaires, avec apparition également d’autres complications telles que la FA. Cette

hypertension pulmonaire post capillaire provoque la libération du sCD146, expliquant nos

résultats. Nous expliquons ainsi également l’élévation majeure du sCD146 chez les patients

atteints d’hypertension artérielle pré-capillaire, les chiffres de pressions artérielles pulmonaires

étant plus élevés que ceux des patients avec rétrécissement mitral.

Après une valvuloplastie mitrale percutanée (VMP) réalisée avec succès, on notait une

décroissance du sCD146 alors que si la valvuloplastie est un échec il ne décroit pas

significativement (3). La concentration de sCD146 est corrélée à l’élévation des pressions

artérielles pulmonaires systoliques (PAPs) avant une VMP. La diminution de la concentration

plasmatique du sCD146 est corrélée à l’augmentation de la surface mitrale et à la réduction des

PAPs. Après un succès de valvuloplastie mitrale percutanée, la levée de l’obstacle mitral

entraîne une diminution de la congestion pulmonaire, des PAPs et ainsi une diminution des

niveaux de sCD146, ce qui en fait un marqueur fiable de succès procédural. Il est à noter

également que la diminution significative du sCD146 dans les 24 heures en cas de succès d’une

VMP est possible en raison d’une cinétique de sécrétion et de décroissance adaptée et réactive,

permettant à ce biomarqueur d’être un marqueur de succès immédiat de la procédure.

Nous expliquons ainsi le comportement du sCD146 chez les patients porteurs de sténose

mitrale. Il est un marqueur indirect de dysfonction atriale gauche dans ce contexte, en

représentant l’impact qu’a la cardiopathie sur la circulation pulmonaire en amont de l’oreillette

100

gauche. Il est dans ce cadre un marqueur fiable de sévérité, de complications et de succès du

traitement du rétrécissement mitral.

VI.6. Place du Soluble Cluster of Differentiation 146 dans l’insuffisance

cardiaque

En ce qui concerne l’insuffisance cardiaque, le sCD146 est un marqueur de congestion

pulmonaire et périphérique. Il était en effet significativement plus élevé lorsque la dyspnée

présentée par un patient était liée à des manifestations d’insuffisance cardiaque (1). Il était,

dans la même publication, lié à la dilatation des oreillettes droite et gauche. En revanche il est

à noter que le sCD146 ne permettait pas de discriminer insuffisance cardiaque à fraction

d’éjection préservée ou altérée (1), il est donc purement dans ce cadre un marqueur de

congestion libéré par les gros vaisseaux pulmonaires et périphériques sans lien avec la fonction

ventriculaire gauche.

VI.7. Perspectives actuelles de recherche pour le Soluble Cluster of

Differentiation 146

Le sCD146 a essentiellement été étudié dans le domaine de l’insuffisance cardiaque (1,

23-25), il a montré son intérêt en tant que marqueur de congestion pulmonaire et périphérique.

A notre connaissance il n’existe pas d’autres publications s’intéressant au sCD146 dans le cadre

du rétrécissement mitral.

101

La recherche concernant le sCD146 se poursuit dans divers domaines extra

cardiologiques. Il semblerait par exemple que le sCD146 soit un marqueur d’inflammation au

niveau neurologique central et marqueur de dysfonctionnement de la barrière hémato-

encéphalique (94). Il aurait également une utilité en cancérologie (95) et un intérêt pronostique

dans les néphropathies diabétiques (96).

VI.8. Place du Soluble Suppression of Tumorigenicity 2 chez des patients traités

par ablation de fibrillation atriale

Le sST2 est un marqueur de fibrose (27, 28). L’évolution de la fibrillation atriale est

marquée au niveau structurel par une fibrose atriale (55, 58). Nous nous sommes donc intéressés

à la capacité qu’a ce biomarqueur à prédire les récidives de fibrillation atriale à un an d’une

procédure d’ablation (4). Le sST2 est en effet plus élevé chez patients présentant une récidive

de fibrillation atriale. Une valeur de seuil de 26.7ng/mL prédit une récidive de FA avec valeur

prédictive négative de 83.3% et valeur prédictive positive de 49%. Cependant le sST2 n’était

pas un prédicteur indépendant de récidive de fibrillation atriale dans nos résultats. Deux travaux

publiés récemment semblent aller à l’encontre de nos conclusions (97, 98). En effet dans ces

deux publications le sST2 était un prédicteur de récidive de FA chez des patients traités par

ablation avec des seuils identiques ou très proches de celui que nous avons identifié sur notre

courbe ROC : 26.7ng/mL (4) vs 26,9ng/mL (97) et 26,65ng/mL (98). Ce phénomène est lié à

notre modèle multivarié qui a inclu, à la différence des deux autres publications, une variable

particulièrement robuste dans la prédiction de la récidive : le niveau de MRproANP

plasmatique pré-procédural. Il s’agissait du seul prédicteur de récidive de FA dans notre

modèle. En utilisant, avec nos données, un autre modèle multivarié excluant cette variable, le

102

niveau de sST2 avant ablation est également prédicteur indépendant de récidive. Nos données

sont donc au final en accord avec les publications précédentes (97, 98). Nos résultats montrent

cependant que, même si le sST2 semble être un prédicteur de récidive de fibrillation atriale post

ablation, le MRproANP est plus performant dans ce cadre.

Le sST2 était par ailleurs lié à la dilatation de l’oreillette gauche dans nos données (4)

ainsi que dans différentes publications (97-99). Celui-ci semble également être lié à la présence

ou à l’apparition de zones atriales gauches pathologiques électriquement (zones de bas voltage)

chez des patients traités par ablation de FA (97, 98). Le sST2 est donc un marqueur de

modifications structurelles de l’oreillette gauche, que ce soit par la dilatation, la fibrose, ou la

présence de zones de bas de voltages identifiées en électrophysiologie.

VI.9. Soluble Suppression of Tumorigenicity 2 et insuffisance cardiaque

Dans nos données, sST2 était significativement plus élevé lorsqu’un patient présentait

une dyspnée d’origine cardiaque que lorsque la cause était extracardiaque (1). Il semble être lui

aussi un bon marqueur de congestion. Et, tout comme le MRproANP et le sCD146, il ne semble

pas être un marqueur de dysfonction systolique ventriculaire gauche puisque qu’il n’existait pas

de différence significative de sST2 entre les patients présentant une insuffisance cardiaque à

fraction d’éjection préservée et ceux en insuffisance cardiaque secondaire à une altération de la

fraction d’éjection ventriculaire gauche.

103

VI.10. Synthèse et perspectives de recherche concernant le Soluble Suppression

of Tumorigenicity 2

Le sST2 est connu comme marqueur pronostic dans l’insuffisance cardiaque (29-33,

100). Dans nos résultats il semble donc lié aux manifestations congestives et aux modifications

structurelles de l’oreillette gauche. Il semble lié à la récidive de FA post ablation mais

l’utilisation du MRproANP doit être préférée dans cette indication.

Dans la seconde partie de l’étude BIORHYTHM, nous nous intéresserons une nouvelle

fois à la capacité qu’a le sST2 (et le MRproANP) à prédire la récidive de fibrillation atriale à 1

an, mais cette fois après cardioversion électrique. Le sST2 ne semblait en effet pas le meilleur

biomarqueur pour prédire la récidive de FA dans une population traitée par ablation. La

population traitée par cardioversion électrique est différente, plus âgée, avec plus de

comorbidités et peut-être davantage de fibrose et de dilatation atriale. Nous évaluerons donc de

nouveau le sST2 dans une population différente.

Le sST2 suscite de l’intérêt actuellement dans le domaine de la fibrillation atriale, il est

lié à la présence de zones de bas voltages chez des patients traités par ablation (97-99), il est

associé chez les insuffisants rénaux au risque de survenue de FA (101). Le sST2 est étudié dans

d’autres domaines également, il semble par exemple être un bon marqueur de réponse

inflammatoire et de sévérité du COVID-19 (102).

104

VII. Conclusion

105

Les biomarqueurs étudiés (MRproANP, sCD146, sST2) sont encore peu ou pas utilisés

en pratique clinique quotidienne. Ils pourraient trouver leur place en complément des

biomarqueurs communément utilisés comme le BNP, le NTproBNP et la troponine dans des

pathologies affectant principalement l’oreillette. Nous avons, par ce travail, mis en évidence

leur capacité à identifier les répercussions hémodynamiques et structurelles, au niveau atrial,

de certaines pathologies cardiaques. Nous avons pu montrer leur intérêt pour le pronostic, le

diagnostic de sévérité et le suivi des patients atteints de sténose mitrale ou de fibrillation atriale.

Le MRproANP est un peptide natriurétique plus spécifiquement atrial. D’après les

articles publiés dans cette thèse, il semble être un marqueur fiable pour évaluer la sévérité d’une

sténose mitrale et le succès immédiat de son traitement par voie percutanée. Il est par ailleurs

un excellent prédicteur de récidive de fibrillation atriale à 1 an d’une ablation avec un seuil

identifié de 107.9pmol/L en pré procédure au-delà duquel le risque de récidive est multiplié par

presque 25. En dessous de ce seuil les patients sont très peu sujets à la récidive avec une valeur

prédictive négative très élevée de 95.7%

Le sCD146 est un marqueur indirect de dysfonction et de souffrance atriale gauche chez

les patients porteurs de sténose mitrale en représentant l’impact qu’a la cardiopathie sur la

circulation pulmonaire en amont de l’oreillette gauche. Il est dans ce cadre un marqueur fiable

de sévérité, de complication du rétrécissement mitral. Il s’élève en effet significativement

lorsque le rétrécissement devient serré ou qu’apparaissent fibrillation atriale ou hypertension

pulmonaire. Il est enfin un marqueur de succès immédiat du traitement du rétrécissement mitral

par commissurotomie percutanée, il décroit significativement en cas de succès procédural.

Le sST2 est lié à la récidive de fibrillation atriale post ablation, mais le MRproANP plus

performant dans cette indication doit lui être préféré.

Ces trois biomarqueurs sont liés significativement à la dilatation de l’oreillette gauche.

106

L’utilisation de ces trois biomarqueurs demande à être validée sur de plus grandes

populations notamment dans la fibrillation atriale, la sténose mitrale ou d’autres pathologies

affectant en premier lieu l’oreillette.

107

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Titre : Etude de biomarqueurs de dysfonction atriale.

Mots clés : biomarqueurs, dysfonction atriale, fibrillation atriale, sténose mitrale, MRproANP, sCD146

Résumé : La pratique de la cardiologie fait appel de façon quotidienne à l’utilisation de biomarqueurs. Cependant dans les pathologies à atteinte atriale prédominante, la performance diagnostique et pronostique des biomarqueurs classiquement utilisés est peu démontrée. Nous nous sommes donc intéressés à l’intérêt potentiel de trois biomarqueurs dans des pathologies affectant en premier lieu l’oreillette : la fibrillation atriale (FA) et la sténose mitrale. Les biomarqueurs concernés sont le MRproANP un peptide d’origine atriale, le sCD146 un marqueur d’origine endothéliale et le sST2 un marqueur de fibrose. L’objectif de ce travail était l’évaluation de leurs capacités diagnostiques et pronostiques chez des patients atteints de FA et de sténose mitrale. Dans la première publication (1) il était mis en évidence que le MRproANP, le sCD146 et le sST2 permettaient de discriminer une origine cardiaque congestive chez des patients consultant pour dyspnée. Seuls les taux de MRproANP et sCD146 étaient liés à la dilatation atriale, suggérant l’intérêt potentiel de ces biomarqueurs dans des pathologies avec atteinte atriale. Nous avons évalué dans une seconde publication (2) les concentrations plasmatiques de MRproANP et de sCD146 chez des patients porteurs de sténoses mitrales serrées et moyennement serrées. Les concentrations de ces deux biomarqueurs étaient toutes deux plus élevées chez les patients porteurs de sténoses mitrales serrées en comparaison à ceux ayant des sténoses moyennement serrées. La troisième publication (3) fait suite à cette seconde étude. Elle a évalué les concentrations de MRproANP, sCD146, BNP et NTproBNP, en pré et post commissurotomie mitrale percutanée (CMP). Les taux initiaux de BNP, MRproANP, et sCD146 étaient significativement abaissés en post CMP. Il n’existait pas de baisse significative de ces biomarqueurs si les critères de succès de la CMP n’étaient pas remplis. Cette baisse semble donc refléter l’amélioration hémodynamique induite par une procédure réalisée

avec succès, conférant au MRproANP et au sCD146 le rôle de marqueurs de succès d’une CMP. L’ensemble de ces résultats concernant le sCD146 s’explique par sa libération au niveau de l’endothélium de la circulation pulmonaire en réponse à la congestion induite par le rétrécissement mitral. Les résultats concernant le MRproANP sont expliqués par une libération conditionnée par la pression intra atriale gauche chez les patients porteurs de sténose mitrale. A l’issu de ces 3 premières études, nous pouvons conclure que les taux de MRproANP et de sCD146 sont des marqueurs de sévérité de la sténose mitrale et du résultat de son traitement percutané. Nous nous sommes enfin focalisés sur l’étude de ces biomarqueurs chez les patients en FA (4). L’ablation de FA est au cœur de la prise en charge de cette pathologie. L’identification des patients à risque de récidive post ablation est primordiale. Nous nous sommes ainsi intéressés à l’impact des niveaux plasmatiques de MRproANP et de sST2 avant une ablation sur le taux de récidive à un an. Le MRproANP était un prédicteur indépendant de récidive de fibrillation atriale dans notre étude, le sST2 ne l’était pas. Un MRproANP au-delà d’un seuil de 107.9pmol/L était lié à un risque de récidive de FA multiplié par 25. Inversement en dessous de ce seuil le risque de récidive à un an était de 4,2% avec une valeur prédictive négative très élevée de 95.7%. Dans cette même étude les concentrations pré-ablation de MRproANP étaient plus élevées chez les patients en fibrillation qu’en rythme sinusal, et plus élevées dans les oreillettes que dans le sang veineux périphérique. Ces données sont en faveur d’une sécrétion atriale du MRproANP chez les patients en fibrillation. Nous avons par ce travail pu montrer l’intérêt du MRproANP, du sCD146 et du sST2 pour le pronostic, le diagnostic de sévérité et le suivi des patients atteints de sténose mitrale ou de FA.

Title : Atrial dysfunction biomarkers.

Keywords : biomarkers, atrial dysfonction, atrial fibrillation, mitral stenosis, MRproANP, sCD146

Abstract : The assessment of biomarkers has become an integral part of the daily practice of cardiology. However, in diseases affecting primarily the atria, the diagnostic and prognostic role of widely used biomarkers is less well documented. Thus, we investigated the potential utility of 3 biomarkers in diseases affecting primarily the atrium, namely atrial fibrillation (AF) and mitral stenosis. The biomarkers investigated were MRproANP, a natriuretic peptide of atrial origin; sCD146, a biomarker of endothelial origin; and sST2, a marker of fibrosis. The aim of this work was to evaluate the diagnostic and prognostic capacities of these biomarkers in patients with AF or mitral stenosis. The first publication (1) investigated the performance of several biomarkers in patients consulting for dyspnea. In this context, MRproANP, sCD146 and sST2 made it possible to identify the cardiac origin of the dyspnea. In this study, only MRproANP and sCD146 levels were found to be associated with right and left atrial dilation. This suggested the potential interest of these biomarkers in pathologies affecting the atria. In a second publication (2), we assessed plasma concentrations of MRproANP and sCD146 in patients with moderate to severe mitral stenosis. Both biomarkers were significantly higher in patients with severe mitral stenosis compared to those with moderate mitral stenosis. The third publication (3) followed up on this theme by investigation the concentrations of MRproANP, sCD146, BNP and NTproBNP before and after percutaneous mitral commissurotomy (PMC). MR-proANP and plasma sCD146 were shown to decrease significantly immediately after PMC. Of note, in this study, the significant changes in biomarker levels were observed mainly in patients in whom the PMC procedure was judged successful. The decrease in these biomarkers therefore seems to reflect the improvement in hemodynamics induced by the successful procedure, making MRproANP and sCD146 adequate markers of procedural success after PMC.

Taken together, the results observed with sCD146 can be explained by the fact that it is released by the endothelium in the pulmonary circulation in response to congestion caused by mitral stenosis. A possible explanation for our findings regarding MRproANP is that its release is conditioned by left intra-atrial pressure in patients with mitral stenosis. After these three studies, we can conclude that MRproANP and sCD146 are markers of the severity of mitral stenosis, and of the success of PMC. Subsequently, we went on to investigate the utility of these biomarkers in patients with AF (4). Catheter ablation is currently the cornerstone of AF therapy. The main limitation of catheter ablation of AF is the success rate of the procedure, which ranges between 50 and 80%. There is a strong need to identify patients at risk of recurrence after catheter ablation. To this end, we investigated the impact of pre-procedural plasma levels of MRproANP and sST2 on the rate of AF recurrence at 1 year after catheter ablation. We found that MRproANP was an independent predictor of recurrence in our study, whereas sST2 was not. An MRproANP levels above a threshold of 107.9pmol/L was found to be associated with a 25-fold increase in the risk of AF recurrence. Conversely, patients with values below the threshold had a recurrence rate of 4.2%, with a high negative predictive value, at 95.7%. In this study, we also observed that pre-procedural rates of MRproANP were highest in patients in AF, compared to those in sinus rhythm. Concentrations did not significantly differ between the right and left atria, but intra-atrial concentrations were significantly higher than those observed in the peripheral blood. These data plead in favour of the atrial release of MRproANP in patients in AF. We demonstrated the utility of MRproANP, sCD146 and sST2for prognosis, diagnosis of severity, and follow-up of patients with mitral stenosis or AF.

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Etude de biomarqueurs de dysfonction atriale. - Theses.fr

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