caractérisation physiopathologique et pharmacologique d'un … · 2021. 2. 18. · ludwig van...

HAL Id: tel-01124196https://tel.archives-ouvertes.fr/tel-01124196

Submitted on 6 Mar 2015

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Caractérisation physiopathologique et pharmacologiqued’un modèle porcin de dysfonction diastolique avec

éjection préservée.Mario Rienzo

To cite this version:Mario Rienzo. Caractérisation physiopathologique et pharmacologique d’un modèle porcin de dys-fonction diastolique avec éjection préservée.. Médecine humaine et pathologie. Université Paris-Est,2013. Français. �NNT : 2012PEST0072�. �tel-01124196�

https://tel.archives-ouvertes.fr/tel-01124196

https://hal.archives-ouvertes.fr

UNIVERSITE PARIS-EST

ECOLE DOCTORALE : SCIENCES DE LA VIE ET DE LA SANT�

PïLE : PHARMACOLOGIE et BIOTH�RAPIES

ANN�E : 2013 SERIE DOCTORAT N¡

THéSE

Pr�sent�e

Ë LÕUNIT� DE FORMATION ET DE RECHERCHE

FACULTE DE MEDECINE PARIS-EST

pour lÕobtention du grade de

DOCTEUR DE LÕUNIVERSIT� PARIS-EST

par

Monsieur Mario RIENZO

CARACTERISATIONS PHYSIOPATHOLOGIQUE ET

PHARMACOLOGIQUE DÕUN MODELE PORCIN DE DYSFONCTION

DIASTOLIQUE AVEC EJECTION PRESERVEE

soutenue le 26 novembre 2013

JURY:

Mr. le Pr A. BERDEAUX Pr�sident du jury

Mme. le Dr Jane-Lise SAMUEL Rapporteur

Mr. le Pr Xavier MONNET Rapporteur

Mr. le Pr Jean Jacques MERCADIER Examinateur

Mr. le Pr Bernard CHOLLEY Examinateur

Mr. le Pr Bijan GHALEH-MARZBAN Directeur de th�se

Ë mes grands-parents Maddalena et Salvatore, Maria Luigia et Giuseppe

Ë mes parents Angela et Antonio

Ë ma sÏur Marilisa

Ë mon neveu Andrea

Mon amour et mon affection, ma reconnaissance et ma d�votion, mes pri�res et mes pens�es.

Time is a necessary representation on which all intuitions depend. We cannot take away time

from phenomena in general, though we can well take away phenomena out of time. Time

therefore is given a priori. In time alone is reality of phenomena possible.

Immanuel Kant

The true discovery trip is not to search for new land, but to see with new eyesight.

Fran�ois-Marie Arouet (Voltaire)

DonÕt only practice your art, but force your way into its secrets,

for it and knowledge can rise men to the Divine

Ludwig van Beethoven

"Staying young requires the unceasing cultivation

of the ability to unlearn old falsehoods."

Robert Anson Heinlein

The mind is like a parachute;

it only functions when it's open.

(Anonymous)

JÕadresse tous mes remerciements,

A Monsieur le Professeur Alain Berdeaux,

pour mÕavoir ouvert les portes de son laboratoire dans un moment pas tr�s facile de ma vie

professionnelle,

pour la gentillesse quÕil a manifest�e � mon �gard tout au long de mon parcours de th�sard,

pour la confiance quÕil mÕa accord�e au d�marrage de ce projet,

quÕil re�oive ici lÕexpression de ma profonde gratitude.

A Madame le Docteur Jean-Lise Samuel,

qui mÕa d�j� questionn� sur Ç mon È sujet dans le cadre des journ�es de la Soci�t� Fran�aise

dÕHypertension et qui aujourdÕhui a bien voulu accept� dÕ�tre rapporteur de ce travail de th�se,

quÕelle trouve ici lÕexpression de ma reconnaissance et de ma sinc�re gratitude.

A Monsieur le Professeur Xavier Monnet,

pour avoir accept�, sans me connaitre, ma collaboration de jeune interne lors de mon arriv�e en

France,

pour avoir manifest� envers moi son estime personnelle et professionnelle au fil du temps,

pour avoir accept� dÕ�tre rapporteur de ce travail

quÕil trouve ici lÕexpression de ma sinc�re et amicale gratitude.

A Monsieur le Professeur Jean Jacques Mercadier

qui a suivi mon parcours scientifique d�s le d�but, �tant responsable p�dagogique du Master 2,

pour avoir accept� de faire partie de ce jury,

qu'il trouve ici l'expression de ma reconnaissance et de ma sinc�re gratitude.

A Monsieur le Professeur Bernard Cholley,

pour avoir accept� de me rencontrer et me permettant ainsi dÕ�crire une Ç autre page È de ma vie

professionnelle,

pour avoir accept� de faire partie de ce jury,

qu'il trouve ici l'expression de ma reconnaissance et de ma sinc�re gratitude.

A Monsieur le Professeur Bijan Ghaleh-Marzban,

pour avoir men� le bateau dans des Ç eaux p�rilleuses È et accept� ouvertement la confrontation avec

moi, pas toujours d�tendue,

pour les nombreuses discussions, non seulement scientifiques, qui ont caract�ris� les s�ances

dÕ�criture des papiers et du pr�sent manuscrit,

pour le lien dÕamiti� qui sÕest progressivement install� entre nous,

je souhaite lui exprimer ma profonde reconnaissance et mon attachement.

A mes amis de Ç lÕ�quipe porc È Alain Biz�, Lucien Sambin, Jonathan Melka, Dyonissis Pongas et

Hon Lai Chan : sans leur collaboration et soutien rien de tout cela aurait �t� possible.

A mes amis de Ç lÕ�quipe lapin È Fanny Lidouren, Mourad Chenoune, Nicolas Couvreur, Lys Darbera,

Mathias Kohlhauer, Renaud Tissier pour leur soutien et ouverture dÕesprit.

A tous les autres membres de lÕEquipe 03 Sandrine Pons, St�phanie Michineau, Roland Zini, JinBo

Su, Hubert Dabire, Camille Bouissou-Schrtz, Alexandra dÕAnglemont de Tassigny, Bela�d Bouhemad,

Mathieu Jozwiak, Saadia Karim, Sandrine Bonizec, St�phanie Paradis, Val�rie Martin, Rana Assaly,

Lolita Portal, Romain Long, Didier Morin, Sophie Nunez, Corinne Deschenes, Lydie Laure, Luca

Zilberstein, Valerie Chetboul, Vassiliki Gouni, Roberto Motterlini, Roberta Foresti, Philippe

Lecorvoisier, Luc Hittinger pour leur gentillesse et accueil chaleureux.

En ce tournant de ma vie je tiens tout particuli�rement � exprimer ma profonde affection et ma

reconnaissance � ceux que je consid�re mon tr�sor humain:

mes amis dÕenfance avec qui jÕai grandi et muri ;

mes amis et coll�gues avec qui jÕai eu lÕhonneur et le plaisir de partager ma vie : merci pour mÕavoir

appuy� et soutenu quand les nuages ont occup� lÕhorizon ;

les figures socratiques qui ont pointill� ma vie et ont fa�onn� par leur d�marche mon esprit;

Sylvie, Claude, Antoine, Armelle, Charlotte, C�line et Charlotte qui mÕont accueilli.

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LB!1!B>A:>!3>!B95B=I=:;5A!;A:9=@>A:9;8GH=;9>!! !

6

LISTE DES FIGURES ET DES TABLEAUX

Figure 1 : Diff�rentes subdivisions et phases du cycle cardiaque 13

Figure 2 : Mod�le exp�rimental dÕErnest Starling 17

Figure 3 : Graphiques input-output de la performance cardiaque globale et plus particuli�re-

ment du ventricule gauche 18

Figure 4 : La fonction cardiaque repr�sent�e par les courbes pression-volume 19

Figure 5 : Courbes pression-volume et �lastance 20

Figure 6 : Exp�riences de Ôtwitch contractionÕ sur un muscle papillaire de chat : relations

longueur-temps (l/lmax) et force-temps (mN) 22

Figure 7 : Graphiques illustrant les effets dÕun clampage total de lÕaorte � diff�rents phases de

lÕ�jection (pr�coce, interm�diaire, tardive) 24

Figure 8 : Division du cycle cardiaque en tant que pompe musculaire et courbe pression-

volume correspondante 27

Figure 9 : Relation entre la pression et le volume ventriculaires gauche 32

Figure 10 : Crit�res �chocardiographiques Doppler pour la classification de la dysfonction

diastolique 35

Figure 11 : Pr�valence de lÕinsuffisance cardiaque en fonction de lÕorigine g�ographique 46

Figure 12 : Droites dÕ�lastance t�l�-systolique (Ees) 59

Figure 13 : Couplage des rigidit�s ventriculaire et art�rielle 59

Figure 14 : Paradigme temporel de la progression de lÕinsuffisance cardiaque chronique

64

Figure 15 : Instrumentation des animaux 84

Figure 16 : Sch�ma illustrant le principe de la mesure de la contractilit� r�gionale par la

technique de la sonomicrom�trie 86

Figure 17 : Courbe dose-r�ponse � lÕangiotensine II 91

Figure 18 : Protocole exp�rimental 92

Figure 19 : Evolution de la pression art�rielle moyenne chez les animaux trait�s par

angiotensine II 93

Figure 20 : Hypertrophie myocardique chez les animaux trait�s par angiotensine II 95

7

Figure 21 : Relation entre temps de relaxation isovolumique et fr�quence cardiaque 99

Figure 22 : LÕ�jection chez les animaux trait�s par angiotensine-II 99

Figure 23 : Relation entre temps de contraction isovolumique et fr�quence cardiaque 101

Figure 24 : Relation entre le temps de contraction isovolumique et le triple produit [(Pression

VG)*FC*dP/dtmax] en r�ponse � la perfusion de dobutamine 102

Figure 25 : Relation entre temps de contraction et relaxation isovolumiques 103

Figure 26 : Evaluation des temps dÕ�jection, de remplissage, de contraction isovolumique et

de relaxation isovolumique � J0 et � J28 109


de relaxation isovolumique � J0 sans ivabradine et � J28 avec ivabradine 110


de relaxation isovolumique pendant lÕadministration de dobutamine � J0 sans ivabradine et �

J28 avec ivabradine 110

Tableau 1 : Valeurs normales des indices �valuant la fonction diastolique par Doppler 34

Tableau 2 : Pr�valence des sympt�mes et des signes dÕinsuffisance cardiaque dans lÕIC-FEr

(systolic HF) et dans lÕIC-FEp (diastolic HF) 42

Tableau 3 : Param�tres h�modynamiques des porcs perfus�s par ATII 94

Tableau 4 : Param�tres h�modynamiques des porcs perfus�s par s�rum physiologique 94

Tableau 5 : Intervalles de temps chez les porcs trait�s par angiotensine-II 98

! X!

INTRODUCTION!

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! !

! "Y!

PARTIE

BIBLIOGRAPHIQUE

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CHAPITRE I : PHYSIOLOGIE DU CYCLE

CARDIAQUE

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'[!/)!0m0/)!0&(2'&nl)!

A. Historique

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:=93!3=AC!H\oG@9>!De Motu Cordis!^"g*X_]!;H!3489;@;:!H=!85A:9=8:;5A!3G!8oG9!>A!C7C:5H>!>:!H\4S>8:;5A!

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GA>!9>H=6=:;5A!EGC8GH=;9>]!GA!9>EBH;CC=I>!9=B;3>]!H=!3;=C:=C>!>:!H=!85A:9=8:;5A!=G9;8GH=;9>!^p;II>9C!

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B. Les diff�rentes phases du cycle cardiaque

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Figure 1. Diff�rentes subdivisions et phases du cycle cardiaque. En A, la subdivision en systole et diastole selon Henderson,

en B selon Wiggers, en C selon la d�finition utilis�e en clinique humaine et en D selon la subdivision modifi�e de Wiggers. La

petite ligne verticale sur le trac� de la pression ventriculaire avant la fermeture de la valve aortique indique le d�but de

lÕintervalle interm�diaire selon la subdivision de Wiggers. En E, le cÏur est consid�r� comme un syst�me muscle-pompe

int�gr�, o� la contraction et la relaxation constituent deux phases de la systole. Les traits verticaux au milieu de lÕ�jection

indiquent que la transition de la contraction � la relaxation ne peut �tre facilement identifi�e. Ainsi, la relaxation iso-

volumique et la succion font partie de la phase de relaxation de la pompe musculaire. (dÕapr�s Brutsaert, 1989)

!

!

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8H;A;MG>! >:! HR=BB958J>! BJ7C;5H5I;MG>! MG;! >6BH;MG>! >A! B=9:;>! H>C! 3;PP;8GH:4C! 85A8>B:G>HH>C! 3=AC! H=!

34P;A;:;5A!3>!H=!37CP5A8:;5A!3;=C:5H;MG>[!0\>C:!B5G9MG5;!A5GC!3489;95AC!H>C!3;PP49>A:C!:>EBC!3G!878H>!

8=93;=MG>! GA;MG>E>A:! B=9! 9=BB59:! =G! BJ4A5EFA>! BJ7C;5H5I;MG>! MG;! H>! 8=9=8:49;C>]! >:! 8>8;!

;A34B>A3=EE>A:!3>!:5G:>!A5:;5A!3>!C7C:5H>!5G!3>!3;=C:5H>[!

1- La contraction isovolumique

/=! 85A:9=8:;5A! ;C5@5HGE;MG>! 34TG:>! =@>8! H=! P>9E>:G9>! 3>! H=! @=H@>!E;:9=H>! >:! C\=8JF@>! =@>8!

H\5G@>9:G9>! 3>! H=! @=H@>! =59:;MG>]! H>! @5HGE>! >C:! =H59C! 85AC:=A:[!&;AC;! :5G:>C! H>C! P598>C! 85A:9=8:;H>C!

8>A:9;BF:>C! =BBH;MG4>C! B=9! H>! E758=93>! =T5G:;CC>A:! Q! GA>! 4H4@=:;5A! 9=B;3>! 3>! H=! B9>CC;5A!

@>A:9;8GH=;9>!I=G8J>[!

2- L'�jection ventriculaire

2FC!MG>!H=!B9>CC;5A!@>A:9;8GH=;9>!I=G8J>!34B=CC>!H=!B9>CC;5A!=59:;MG>]!H\;A@>9C;5A!3G!I9=3;>A:!

3>! B9>CC;5A! 5G@9>! H=! @=H@>! =59:;MG>[! 0>HH><8;!E=9MG>! H=! P;A! 3>! H=! 85A:9=8:;5A! ;C5@5HGE;MG>! >:! H>!

34TG:! 3>! H\4S>8:;5A[! /=! 85A:9=8:;5A! 3G!E758=93>! >C:!E=;A:>A=A:! =G65:5A;MG>]! H>C! 8=93;5E7587:>C!

8J=AI>=A:! H>G9! H5AIG>G9! >:! H=! P598>!34@>H5BB4>!c! H=! B=95;!E758=93;MG>! C\4B=;CC;:! >:! C>! 9=885G98;:[!

0>C! E5G@>E>A:C! 943G;C>A:! H>! @5HGE>! 3>! H=! 8=@;:4! @>A:9;8GH=;9>! I=G8J>! >:! 4S>8:>A:! H>! C=AI! @>9C!

H\=59:>!>:!H=!8;98GH=:;5A!B49;BJ49;MG>[!/>!I9=3;>A:!3>!B9>CC;5A!3>!B=9:!>:!3\=G:9>!3>!H=!@=H@>!=;AC;!MG>!

H\4H=C:;8;:4!3>!H\=59:>!>:!3>C!=9:F9>C!B49;BJ49;MG>C!34:>9E;A>A:!H=!@;:>CC>!3\4S>8:;5A!3G!C=AI[!

3- Le ralentissement de l'�jection et le d�but de la relaxation

&B9FC! =@5;9! =::>;A:! GA>! @=H>G9!E=6;E=H>! H59C! 3>! H\4S>8:;5A! 9=B;3>]! H=! B9>CC;5A! @>A:9;8GH=;9>!

34895Z:[!/>!8=H8;GE!87:5C5H;MG>!>C:!B95I9>CC;@>E>A:!B5EB4!B=9!H>!94:;8GHGE!C=985BH=CE;MG>!>:!H>C!

E75P;T9;HH>C! >A:9>A:! >A! 9>H=6=:;5A[! /=! @;:>CC>! 3\4B=;CC;CC>E>A:! 3G! E758=93>! 3;E;AG>[! ?=9!

85AC4MG>A:]! H=! @;:>CC>! 3\4S>8:;5A! 3;E;AG>! E=;C! H\4S>8:;5A! >C:! E=;A:>AG>! >A! B=9:;>! I9v8>! Q! H=!

3;C:>AC;T;H;:4!3>!H\=59:>]!E48=A;CE>!Q!H=!T=C>!3>!H\>PP>:!p;A3w>CC>H!^W>HU!"jj-_[!2FC!MG>!H=!B9>CC;5A!

@>A:9;8GH=;9>!34895Z:!=G<3>CC5GC!3>!H=!B9>CC;5A!=59:;MG>]!H\;A@>9C;5A!3G!I9=3;>A:!3>!B9>CC;5A!P>9E>!H=!

@=H@>!=59:;MG>]!I4A49=A:!H>!B9>E;>9!85EB5C=A:!&*!3G!3>G6;FE>!T9G;:!3G!8oG9!^W*_[!

! !

!

!

"-!

4- La relaxation isovolumique

&B9FC!H=!P>9E>:G9>!3>!H=!@=H@>!=59:;MG>]!>:!B>A3=A:!H>!85G9:!;AC:=A:!MG;!B948F3>!H\5G@>9:G9>!3>!

H=!@=H@>!E;:9=H>]!H>!@>A:9;8GH>!C>!9>H=6>!C=AC!8J=AI>9!3>!@5HGE>!1!8\>C:!H=!9>H=6=:;5A!;C5@5HGE;MG>[!

2FC! MG>! H=! B9>CC;5A! @>A:9;8GH=;9>! 3>C8>A3! =G<3>CC5GC! 3>! H=! B9>CC;5A! =G9;8GH=;9>! I=G8J>]! H=! @=H@>!

E;:9=H>!C\5G@9>!>:!H>!9>EBH;CC=I>!@>A:9;8GH=;9>!34TG:>[!

5- Le remplissage pr�coce (succion)

/=!BJ=C>!3>!9>EBH;CC=I>!CG9@>A=A:! SGC:>!=B9FC! H\5G@>9:G9>!3>! H=!@=H@>!E;:9=H>!=CCG9>! H=!BHGC!

I9=A3>! B=9:;>! 3G! 9>EBH;CC=I>!c! >HH>! >C:! B=9:;8GH;F9>E>A:! >PP;8=8>! I9v8>! Q! H=! 9>H=6=:;5A! =8:;@>! 3G!

@>A:9;8GH>! MG;! B95@5MG>! GA>! `CG88;5A! @>A:9;8GH=;9>`[! /=! B9>CC;5A! @>A:9;8GH=;9>! I=G8J>! 9>3>C8>A3!

T9GCMG>E>A:!>A!3>CC5GC!3>! H=!B9>CC;5A!=G9;8GH=;9>!I=G8J>!>:! H>!C=AI!B4AF:9>!T9GCMG>E>A:!3=AC! H>!

@>A:9;8GH>[!/=!85ET;A=;C5A!3>! H=! 9>H=6=:;5A!=8:;@>!3G!E758=93>!>:! H=!B9>CC;5A!3>! H\=PPHG6!C=AIG;A!

3;C:>A3>A:! H>C!B=95;C!3G!@>A:9;8GH>! 1! H>!E758=93>! C\=E;A8;:]! C\4H=9I;:! >:! C\=HH5AI>[!/>! 9>EBH;CC=I>!

@>A:9;8GH=;9>! 9=B;3>! B>G:! =H59C! r:9>! Q! H\59;I;A>! 3\GA! :95;C;FE>! T9G;:! 3G! 8oG9! W+]! BHGC!

B=9:;8GH;F9>E>A:!=G3;TH>!Q!H\>6>98;8>!5G!H59C!3\GA>!:=8J78=93;>!C;AGC=H>[!

6- La diastase

&!H\;CCG>!3>! H=!BJ=C>! 9=B;3>!3G! 9>EBH;CC=I>]! H>C!B9>CC;5AC!@>A:9;8GH=;9>C!>:!=G9;8GH=;9>C! C5A:!

MG=C;E>A:! 4I=H>C[! />! @>A:9;8GH>! A>! C>! 9>EBH;:! MG=C;E>A:! BHGC! >:! H=! @=H@>! E;:9=H>! C>! P>9E>!

B=9:;>HH>E>A:[!/>!@5HGE>!3>!H=!8=@;:4!@>A:9;8GH=;9>!A>!8J=AI>!BHGC[!0>::>!BJ=C>!3>!9>EBH;CC=I>!H>A:!

@5;9>!AGH!>C:!34A5EE4>!3;=C:=C>[!

7- La contraction atriale

&!H\;CCG>!3>!H=!3;=C:=C>]!=H59C!MG>!H>!9>EBH;CC=I>!@>A:9;8GH=;9>!>C:!MG=C;E>A:!:>9E;A4]!CG9@;>A:!

H=!85A:9=8:;5A!=:9;=H>[!)HH>!B95@5MG>!GA>!=GIE>A:=:;5A!3>!H=!B9>CC;5A!=:9;=H>]!9>C:=G9=A:!GA!I9=3;>A:!

3>!B9>CC;5A!>A:9>!H\=:9;GE!>:!H>!@>A:9;8GH>[!/=!@=H@>!E;:9=H>!C\5G@9>!>:!H>!9>EBH;CC=I>!9>B9>A3[!&!8>!

E5E>A:]!H=!@;:>CC>!3G!PHG6!C=AIG;A!Q!:9=@>9C!H=!@=H@>!E;:9=H>!=GIE>A:>[

''[!/&!O$V0K'$V!2)!?$%?)!!

2>BG;C! H>C! B9>E;F9>C! 3>C89;B:;5AC! 3>! N=9@>7]! H>! 8oG9! >:! H>! C7C:FE>! @=C8GH=;9>! 5A:! 4:4!

=CC;E;H4C!Q!GA!8;98G;:!J739=GH;MG>!P>9E4!=@>8!GA>!B5EB>!=G!E;H;>G!3>C:;A4>!Q!>AI>A39>9!GA!I9=3;>A:!

3>!B9>CC;5A!>A:9>!H>!C>8:>G9!3\=E5A:!>:!8>HG;!>A!=@=H[!2R4A59E>C!>PP59:C!85A8>B:G>HC!5A:!4:4!B953G;:C!

B5G9! P59EGH>9!3>C!E53FH>C!E=:J4E=:;MG>C!8=B=TH>C!3>! 9>B953G;9>! H>C!8=9=8:49;C:;MG>C!3G! C7C:FE>!

8=93;5@=C8GH=;9>[!

!

!

"g!

lA>!B5EB>!8599>CB5A3!Q!GA!E48=A;CE>!8=B=TH>!3>!:9=ACP49>9!GA!PHG;3>!3\GA!B5;A:!Q!GA!=G:9>!

3>! H\>CB=8>[! 0>! :9=ACP>9:! B>G:! C\=885EB=IA>9! 3\GA>! =GIE>A:=:;5A! 3>! B9>CC;5A! =G! B5;A:! P;A=H! 3>!

34BH=8>E>A:]!3\GA>!4H4@=:;5A!I9=@;E4:9;MG>!3>!H=!E=CC>!34BH=84>!5G!3\GA!E5G@>E>A:!@>9C!GA!C;:>!Q!

3;C:=A8>! 85AC;349=TH>! B=9! 9=BB59:! =G! B5;A:! ;A;:;=H[! />! 34BH=8>E>A:! 3\GA! PHG;3>! 85A:9>! H=! I9=@;:4!

;EB5C>!Q! H=!B5EB>!3>! :9=ACP49>9!3>! H\4A>9I;>!@>9C! H=!E=CC>!>A!E5G@>E>A:[!#=AC!8>::>!4A>9I;>]! H=!

E=CC>!3>! H;MG;3>!A>!B5G99=!=::>;A39>! H>!A5G@>=G!A;@>=G!I9=@;E4:9;MG>[!2>!ErE>]! H>!34BH=8>E>A:!

3\GA! PHG;3>! =G! :9=@>9C! 3\GA! :G7=G! 3>E=A3>! 3>! H\4A>9I;>! B5G9! @=;A89>! H>C! 94C;C:=A8>C! 3G>C! Q! H=!

P9;8:;5A!>A:9>!H>!H;MG;3>!>:!H>C!B=95;C!3G!:G7=G[!

/>!E53>!3>!:9=ACP>9:!3>!H\4A>9I;>!B9;C!>A!85EB:>!B>9E>:!3>!3;C:;AIG>9!H>C!`B5EB>C!8;A4:;MG>C`!

>:!H>C!`B5EB>C!Q!34BH=8>E>A:!B5C;:;P`!1!3=AC!H>!B9>E;>9!8=C]!>HH>C!:9=ACPF9>A:!H\4A>9I;>!3>!E=A;F9>!

85A:;AG>]!3=AC!H>!3>G6;FE>!3>!P=q5A!B49;53;MG>[!/>C!B5EB>C!Q!34BH=8>E>A:!B5C;:;P!=BBH;MG>A:!GA>!

P598>!Q!H=!CG9P=8>!3\GA!@5HGE>!3>!PHG;3>!P>9E4]!34:>9E;A=A:!GA>!=GIE>A:=:;5A!3>!B9>CC;5A!BG;C!GA!

E5G@>E>A:!@;=!3>C!@=H@>C!5G!3>C!B59:>C[!0>C!C5A:!8>C!B5EB>C!Q!34BH=8>E>A:!B5C;:;P!MG;!3489;@>A:!

H>!E;>G6!H>!8oG9!3>C!E=EE;PF9>C[!

!

A. Le cÏur comme pompe hydraulique

&! H=! P;A! 3G! u'uFE>! C;F8H>]! 4B5MG>! 85AA=;CC=A:! GA! >CC59! ;EB59:=A:! 3>! H=! BJ7C;MG>! >:! 3>C!

E=:J4E=:;MG>C]! GA! 3>C! 5TS>8:;PC! B9;A8;B=G6! 3>C! BJ7C;5H5I;C:>C! 8=93;5@=C8GH=;9>C! 4:=;:! 3\>6BH59>9!

H\=BBH;8=T;H;:4!3>C! H5;C!BJ7C;MG>C!85EE>!8>HH>C!3>!?5;C>G;HH>]!3>!W>9A5GHH;!5G!3>!O;8w!=G!C7C:FE>!

8=93;5@=C8GH=;9>[! )A! G:;H;C=A:! H>! 8oG9! >A:;>9! ;C5H4! >:! 9=885934! Q! GA! 8;98G;:! C>E;<P>9E4! Ô;I[! *=_]!

)9A>C:! #:=9H;AI! ^?=::>9C5A! "j",_! 85A8>@=;:! H\=A=H7C>! >:! H=! MG=A:;P;8=:;5A! 3>! H=! B>9P59E=A8>!

8=93;=MG>! 3=AC! H>! 8=39>! 3RGA! C7C:FE>! J739=GH;MG>!1! H=! `B5EB>`! 9>q5;:! GA>! 8>9:=;A>! MG=A:;:4! 3>!

H;MG;3>!MG\>HH>!35;:!B5GCC>9!3=AC!GA!C>8:>G9!Q!J=G:>!B9>CC;5A! c! H\>A:94>!3>! H=!B5EB>!^`B948J=9I>`_!

85A3;:;5AA>]!3=AC!8>9:=;A>C!H;E;:>C]!C=!C59:;>!^34T;:_!Ô;I[!*T_[!

nG>HMG>C!348>AA;>C!BHGC! :=93]!&9:JG9!.G7:5A! =! :9=ACB5C4! 8>C! 85A8>B:C! =G! 8oG9! in situ! >:! =!

4H=T594! H>C!I9=BJ;MG>C!>A:94><C59:;>!3489;@=A:! H=!B>9P59E=A8>!8=93;=MG>!>A!85A3;:;5AC!A59E=H>C!>:!

B=:J5H5I;MG>C!Ô;I[!+=_! ^.G7:5A!"j--_[! 'H!=!E;C!>A!9>H=:;5A! H=!B9>CC;5A!Q! H\>A:94>!3>! H=!B5EB>!^H=!

B9>CC;5A! =:9;=H>! 395;:>_! =@>8! H>! 34T;:! Q! C=! C59:;>! ^B953G;:! 3G!@5HGE>!3\4S>8:;5A! >:! 3>! H=! P94MG>A8>!

8=93;=MG>_[!2>!E=A;F9>! C;E;H=;9>]! #=9A5PP! >:!%;:8J>HH! ^#=9A5PP! =A3!%;:8J>HH! "jg"_! 5A:! 85994H4! H=!

B9>CC;5A!=:9;=H>!I=G8J>!=@>8!H>!34T;:!5G!H>!:9=@=;H!@>A:9;8GH=;9>!I=G8J>!Ô;I[!+T_[!!

!

!

!

"d!

!

!

! !

Figure 2. Mod�le exp�rimental dÕErnest Starling.

a) la partie gauche illustre le dispositif exp�rimental, la partie droite montre une transposition moderne du concept de pompe

hydraulique avec le r�servoir (bleu), la pompe (jaune) et la post-charge (rouge).

b) la partie gauche reproduit les trac�s originaux de lÕexp�rience de Starling: les dimensions ventriculaires (C), la pression

art�rielle (BP) et la pression du r�servoir atrial (VP). Avec la mont�e de VP, les dimensions ventriculaires C et la pression

art�rielle augmentent. La partie droite illustre la relation entre augmentation de la pression atriale droite et le d�bit cardiaque

aortique (dÕapr�s Patterson, 1914).

a

b

Pre

ssio

n a

tria

le d

roit

e (m

mH

2O

)

D�bit cardiaque (ml / 10 sec)

!

!

"X!

!

/\5G:;H!MG;!=!B>9E;C!H=!:9=ACB5C;:;5A!8H;A;MG>!3>!8>!:7B>!3\=BB958J>C!>A!8H;A;MG>!JGE=;A>!>C:!

H>!8=:J4:>9!3>!#f=AA<.=AU!1!H=!B9>CC;5A!=:9;=H>!395;:>!^>A:94>!3G!8oG9_]!H>!34T;:!@>A:9;8GH=;9>!395;:!>:!

H=! B9>CC;5A! BGHE5A=;9>! 3\588HGC;5A! ^>C:;E=:;5A! 3>! H=! B9>CC;5A! =:9;=H>! I=G8J>_! C5A:! >A9>I;C:94C! >:!

>6B9;E4C! CG9! GA! I9=BJ;MG>! B948J=9I><34T;:[! />C! 35AA4>C! 8H=CC;MG>E>A:! 5T:>AG>C! C5A:! H>! 34T;:!

8=93;=MG>! ^395;:_]! H>C!B9>CC;5AC!=9:49;>HH>C!BGHE5A=;9>!>:! C7C:4E;MG>]! H=!B9>CC;5A!=:9;=H>!I=G8J>]! H=!

B9>CC;5A! BGHE5A=;9>! 3\588HGC;5A]! H>C! 94C;C:=A8>C! B49;BJ49;MG>C]! H>! :9=@=;H! C7C:5H;MG>! >:! HR4H=C:=A8>!

=9:49;>HH>[!

! !

a

b

Fig3. Graphiques input-output de la performance cardiaque globale (a) et plus particuli�rement du ventricule gauche (b).

En (a) partie haute � gauche, la relation entre pression atriale droite et d�bit cardiaque, en conditions normale, dÕactivation

adr�nergique et pathologique. En (a) partie haute � droite, la relation entre pression atriale droite et retour veineux pour

diff�rents niveaux de pression moyenne syst�mique (qui sert de moteur pour le retour veineux). En (a) partie gauche en bas,

lÕint�gration des deux graphiques (dÕapr�s Guyton, 1955). En b, la relation entre pression atriale gauche et travail ventriculaire gauche en sortie de la pompe (travail n�cessaire pour

lÕ�jection ventriculaire) (dÕapr�s Sarnoff, 1961).

!

!

"j!

B. Le cÏur comme pompe h�modynamique

2>!ErE>!MG>!B5G9!:5G:>!B5EB>!J739=GH;MG>!>:!=G<3>HQ!3>C!E>CG9>C!3>!B9>CC;5A!>:!3>!34T;:]!

H>C! 8=9=8:49;C:;MG>C! 3>! H=! B5EB>! 8=93;=MG>! B>G@>A:! r:9>! =A=H7C4>C! >A! B9>A=A:! 4I=H>E>A:! >A!

85AC;349=:;5A! H>C!E53;P;8=:;5AC!878H;MG>C!3\GA!=G:9>!B=9=EF:9>!MGR>C:! H>!@5HGE>!@>A:9;8GH=;9>[!$A!

B>G:! =;AC;! >6B9;E>9! H=! P5A8:;5A! 8=93;=MG>! >A! :>9E>C! 3>! 9>H=:;5A! B9>CC;5A<@5HGE>[!$A! 35;:! Q!$::5!

O9=Aw!!H\4H=T59=:;5A!3>C!B9>E;F9>C!85G9T>C!B9>CC;5A<@5HGE>!B5G9!H>!@>A:9;8GH>!I=G8J>!3>!I9>A5G;HH>!

BG;C! 3>! E=EE;PF9>C! Ô;I[! ,_! Ô9=Aw! "Xj-_[! 0>8;! =! B>9E;C! HR4E>9I>A8>! 3RGA! 85A8>B:! >CC>A:;>H! 1!

H\=GIE>A:=:;5A!3G!@5HGE>!:4H4<3;=C:5H;MG>!;A3G;:!H>!34@>H5BB>E>A:!3\GA>!P598>!BHGC!;EB59:=A:>!B=9!

H>!@>A:9;8GH>[!

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/\=T5G:;CC>E>A:! 3>! 8>::>! @;C;5A! >C:! 9>B94C>A:4! B=9! H>! 85A8>B:! 3G! 8oG9! 85EE>! B5EB>! Q!

4H=C:=A8>! @=9;=TH>! P59EGH4! B=9! #GI=! >:! #=I=f=! ^#GI=! =A3! #=I=f=! "jd,_! Ô;I[! -_! 1! H=! B=95;!

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C=AI! CGT;:! 3>C! @=9;=:;5AC! 3>! B9>CC;5AC! ;EB59:=A:>C! =G! 85G9C! 3>C! BJ=C>C! ;C5<@5HGE;MG>C! 3G! 878H>!

8=93;=MG>[! />C! 4H=C:=A8>C! =::>;A:>C! Q! H=! P;A! 3>! H\4S>8:;5A! @>A:9;8GH=;9>! 3>! BHGC;>G9C! T=::>E>A:C!

85AC48G:;PC! >:! Q! 3;PP49>A:C! @5HGE>C! :4H4<3;=C:5H;MG>C]! CG;@>A:! GA>! 395;:>! 35A:! H=! B>A:>! 3;:>! )E=6!

Figure 4. La fonction cardiaque repr�sent�e par les courbes pression-volume.!x!I=G8J>!H\>6B49;>A8>!3>!O9=Aw!!CG9!GA! 8oG9! 3>! I9>A5G;HH>! 8H=EB4! =G! A;@>=G! 3>! H\=59:>! =H59C! MG>! H>! 9>EBH;CC=I>! @>A:9;8GH=;9>! >C:! H;T9>! 1! H>C! 878H>C!

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^9=BB59:! 3>! H=! B9>CC;5A! >:! 3G! @5HGE>! :4H4<3;=C:5H;MG>C! @>A:9;8GH=;9>C_]! H=! P9=8:;5A! 3\4S>8:;5A]! H=!

9>H=:;5A! a!:9=@=;H! C7C:5H;MG>! z! @5HGE>! @>A:9;8GH=;9>! :4H4<3;=C:5H;MG>!b! ^preload recruitable stroke

work_!>:!H=!9>H=:;5A!a!B9>CC;5A!=9:49;>HH>!C7C:5H;MG>!z!3;=EF:9>!:4H4<C7C:5H;MG>!3G!L.!b[!

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C. Limites des mod�les de pompes hydraulique et h�modynamique

?HGC;>G9C!85AC;349=:;5AC!85A8>B:G>HH>C!35;@>A:!r:9>!P59EGH4>C!MG=A3!5A!4@=HG>!H=!@=H;3;:4!3>C!

E53FH>C!B94C>A:4C!B94843>EE>A:[

1- Cadre temporel

/=!A5:;5A!3>!:>EBC!A\>C:!B=C!B9;C>!>A!85EB:>!3=AC!H>C!=BB958J>C!3489;:>C!^O;I[,_!1!34@>H5BB>9!

GA>!B9>CC;5A!35AA4>!BHGC!5G!E5;AC!9=B;3>E>A:!B>G:!r:9>!GA!C;IA>!3\>PP;8;>A8>!3>!H=!B5EB>!c!;H!>A!@=!

3>!ErE>!B5G9! H>! :9=@=;H!B953G;:!B=9! H=!8J=ET9>!@>A:9;8GH=;9>!=;AC;!MG>!B5G9! H>C!E53;P;8=:;5AC!3>C!

3;E>AC;5AC! 3G! @>A:9;8GH>! I=G8J>[! )A! >PP>:]! 8\>C:! 3=AC! H>! 85A:;AGGE! 3>! H\>CB=8><:>EBC! MG>! H>C!

E5G@>E>A:C! 8=93;=MG>C! C\;AC89;@>A:! >:! 35A8! H>! :>EBC! 3>@9=;:! P=;9>! B=9:;>! 3>! :5G:>! =A=H7C>! 3>! H=!

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Figure 5. Courbes pression-

volume et �lastance.! (>H=:;5AC!B9>CC;5A<@5HGE>! 5T:>AG>C! CG9! GA!@>A:9;8GH>! ;C5H4!4S>8:=A:! 85A:9>!GA!C7C:FE>! 3>! 8J=9I>! J739=GH;MG>!C>9@5<85A:9kH4! ^3\=B9FC! #GI=<#=I=f=]!"jd,_[!

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2- Concepts issus des �tudes men�es sur les fibres musculaires

/>C! :9=@=G6! CG9! H>C! P;T9>C!EGC8GH=;9>C! 8=93;=MG>C! ;C5H4>C!5A:!E5A:94!MG>! H>C! 9>H=:;5AC! >A:9>!

85A:9=8:;5A!>:!9>H=6=:;5A!C5A:!BHGC!4:95;:>C!3>!8>!MG\5A!B5G@=;:!;E=I;A>9!1!3\GA>!B=9:]!H>C!@=9;=:;5AC!

3>C! 85A3;:;5AC! 3>! 8J=9I>! B>A3=A:! H=! BJ=C>! 3>! 85A:9=8:;5A! ;APHG>A8>A:! H>! 3495GH>E>A:! 3>! H=!

9>H=6=:;5A!c!3\=G:9>!B=9:]!H>!BJ4A5EFA>!3\=8:;@=:;5A!85A:9=8:;H>!^8=B=8;:4!3>!B953G8:;5A!3>!H=!P598>_!

;A;:;>! H=! C7C:5H>]! BG;C! C\=::>AG>! B95I9>CC;@>E>A:]! 4@5HG=A:! @>9C! H\;A=8:;@=:;5A! 3=AC! GA! 85A:;AGGE!

4H>8:95E48=A;MG>! Ê5G@>E>A:C! 3>! 8=H8;GE! >:! 9>878H=I>! 4A>9I4:;MG>_[! /\>6BH59=:;5A! 3>! 8>C!

BJ4A5EFA>C!=!4:4!9>A3G>!B5CC;TH>!B=9!H\;A:953G8:;5A!3>!B=9=EF:9>C!3>!E>CG9>!=BBH;MG4C!=GB=9=@=A:!

Q! H=! 85A:9=8:;5A! :4:=A;MG>! 3G! EGC8H>! CMG>H>::;MG>! 1! H>C! 9>H=:;5AC! H5AIG>G9<:>AC;5A]! P598><@;:>CC>]!

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a) Modulation de la relaxation par la charge.

&G! 85G9C! 3>C! 85A:9=8:;5AC! ;C5:5A;MG>C! CG9! 3>C! P;T9>C! EGC8GH=;9>C! 8=93;=MG>C! ;C5H4>C! 3>!

E=EE;PF9>C!^W9G:C=>9:]!3>!0H>98w!>:!=H[!"jdX_]!H\=GIE>A:=:;5A!I9=3G>HH>!3>!H=!B5C:<8J=9I>!>AI>A39>!

GA>! 943G8:;5A! 3>! H=! @;:>CC>! 3>! 9=885G98;CC>E>A:! >:! GA! 9>:=93! 3G! 34TG:! 3>! H=! 9>H=6=:;5A! c! 3>! BHGC]!

H\=HH5AI>E>A:!;C5:5A;MG>!=G!85G9C!3>!H=!9>H=6=:;5A]!ErE>!=G6!8J=9I>C!BHGC!P=;TH>C]!>C:!85AC:=EE>A:!

CG;@;!B=9!GA>!8JG:>!=T9GB:>!3>!H=!P598>!;C5E4:9;MG>!^P;I[!g=_[!!

/\=8895;CC>E>A:! 3>! H=! 8J=9I>! 3G9=A:! H=! 85A:9=8:;5A! ;C5:5A;MG>! E53;P;>! H>! 3485G9C! 3>! H=!

85A:9=8:;5A!ErE>!>:!3>!H=!9>H=6=:;5A!MG;!C\>A!CG;:!1!C;!8>::>!8J=9I>!>C:!;EB5C4>!B>A3=A:!H=!B9>E;F9>!

E5;:;4! 3>! H=! BJ=C>! 3>! 9=885G98;CC>E>A:]! H=! BJ=C>! 3>! 9>H=6=:;5A! ;C5:5A;MG>! >C:! :9FC! H4IF9>E>A:!

E53;P;4>!c! C;! >HH>! >C:! ;EB5C4>! B>A3=A:! H=! 3>G6;FE>! B=9:;>! >:! CG9:5G:! H>! :;>9C! P;A=H! 3>! H=! BJ=C>! 3>!

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H>A:>! Ô;I[! gT_[! &! 85A:9=9;5]! H=! C5GC:9=8:;5A! 3>! H=! 8J=9I>! Q! 8>!E5E>A:!E53;P;>! H>! 3485G9C! 3>! H=!

85A:9=8:;5A! >:! 3>! H=! 9>H=6=:;5A!3=AC! H>! C>AC! ;A@>9C>! Ô;I[! g8_[!)AP;A]! H\=8895;CC>E>A:!3>! H=! 8J=9I>!

B>A3=A:!H=!BJ=C>!3\=HH5AI>E>A:!;C5:5A;MG>!3>!H=!9>H=6=:;5A!H\=T9FI>!3>!P=q5A!;EB59:=A:>!^W9G:C=>9:]!

(=3>E=w>9C!>:!=H[!"jX,_[!!

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;A;:;=G6!3>!H=!85A:9=8:;5A!;C5:5A;MG>!C5A:!5BB5C4C!Q!8>G6!;A3G;:C!3=AC!H>C!ErE>C!85A3;:;5AC!3G9=A:!

H\=HH5AI>E>A:! ;C5:5A;MG>[! />! B=CC=I>! >A:9>! 8>C! 3>G6! BJ=C>C! C>! C;:G>! =G!E5E>A:! 3>! H=! :9=AC;:;5A!

>A:9>! H=! 85A:9=8:;5A! >:! H=! 9>H=6=:;5A! ^W9G:C=>9:]!(=3>E=w>9C! >:! =H[! "jX,_!1! 8>::>! U5A>! S5G>! GA! 9kH>!

E=S>G9!3=AC!H>!85A:9kH>!3>!H=!B>9P59E=A8>!C7C:5H;MG>!3G!8oG9!>A:;>9[!

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b) Modulation de la relaxation par lÕactivation-inactivation

/>C!85EB59:>E>A:C!3>!H=!P;T9>!EGC8GH=;9>!>:!C>C!94B5AC>C!Q!H=!C4MG>A8>!3>!8J=9I>!C5A:!4:95;:>E>A:!

H;4C!=G6!E5G@>E>A:C!8=H8;MG>C[!0>8;!C\5TS>8:;@>!A5:=EE>A:!H59CMG>!3>C!8>HHGH>C!E758=93;MG>C!C5A:!

B94:9=;:4>C! B=9! H>! 34:>9I>A:! W9;S<-X! MG;! 34:9G;:! H>! 94:;8GHGE! C=985BH=CE;MG>! >:! 87:5BH=CE;MG>!

^W9G:C=>9:]!3>!0H>98w!>:!=H[!"jdX_!5G!>A!8=C!3\J7B56;>!^0JG8w]!.5>:J=HC!>:!=H[!"jX"_[!2=AC!8>C!8=C]!

H=! 9>H=6=:;5A! C>ETH>! r:9>! I5G@>9A4>! B=9! H>! B958>CCGC! 3\;A=8:;@=:;5A]! Q! C=@5;9]! H=! 3;CC58;=:;5A! 3>C!

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D. Le cÏur comme pompe musculaire

/\>AC>ETH>! 3>C! 35AA4>C! B94C>A:4>C! B94843>EE>A:! 94CGH:>! 3>! H\=T5G:;CC>E>A:! 3>C! 85A8>B:C!

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H>C! BJ4A5EFA>C! 3\=8:;@=:;5A<;A=8:;@=:;5A[! 2>! BHGC]! H=! 85EBH>6;:4! 3>! H=! C:9G8:G9>! 3>! H=! B=95;!

@>A:9;8GH=;9>! >:! H=! 3;C:9;TG:;5A! CB=:;5<:>EB59>HH>! 3>! H=! 34B5H=9;C=:;5A<94B5H=9;C=:;5A! 4H>8:9;MG>!

;EB5C>A:! 3>! :>A;9! 85EB:>! 3>! H=! A5A<GA;P59E;:4! @>A:9;8GH=;9>! 85EE>! =G:9>! 34:>9E;A=A:! 3>! H=!

85A:9=8:;5A<9>H=6=:;5A[!

1-Modulation par la charge.

/>C!B9;A8;B=G6!34:>9E;A=A:C!3>!H=!8J=9I>!3=AC!H>!8oG9!;A:=8:!C5A:!1! H=!34P59E=:;5A!3G9=A:!H=!

85A:9=8:;5A]! H>C! =H:49=:;5AC! 3>! H\;EB43=A8>! =9:49;>HH>! B>A3=A:! H=! BJ=C>! :=93;@>! 3>! H\4S>8:;5A]! H>!

9>EBH;CC=I>!3G! 94C>9@5;9! 8595A=;9>!B>A3=A:! H=! 9>H=6=:;5A! ;C5<@5HGE;MG>]! H>C! @=9;=:;5AC!3>!@5HGE>!

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05EE>! B5G9! H>C! P;T9>C! EGC8GH=;9>C! ;C5H4>C]! GA>! =GIE>A:=:;5A! 3>! H=! 8J=9I>! B>A3=A:! H>C!

B9>E;>9C!3>G6<:;>9C!3>!H=!85A:9=8:;5A!9>:=93>!H>!34TG:!3>!H=!9>H=6=:;5A!>:!=884HF9>!H=!@;:>CC>!3>!8JG:>!

3>!H=!B9>CC;5A!;A:9=<@>A:9;8GH=;9>!^?=9EH>7!=A3!#5AA>ATH;8w!"jgj_[!#;!H\;EB5C;:;5A!3>!H=!8J=9I>!>C:!

;EB59:=A:>!5G!C;!>HH>!CG9@;>A:!B>A3=A:!H=!BJ=C>!:=93;@>!3>!H\4S>8:;5A]!;H!7!=G9=!GA!34TG:!B94E=:G94!>:!

GA! 9=H>A:;CC>E>A:! 3>! H=! T=;CC>! 3>! B9>CC;5A! ;A:9=<@>A:9;8GH=;9>! ^%G9I5]! p>C:>9J5P! >:! =H[! "jXYc!

.;HH>T>9:! =A3! />f! "jj"c! />;:><%59>;9=! =A3! .;HH>T>9:! "jj,c! />;:><%59>;9=]! 0599>;=<?;A:5! >:! =H[!

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=@>8! H>! C7C:FE>!=9:49;>H! >:! 8>8;!B>G:!E53GH>9! H=!B>9P59E=A8>!E48=A;MG>!3G!@>A:9;8GH>!B>A3=A:! H=!

9>H=6=:;5A!^W9G:C=>9:]!(=3>E=w>9C!>:!=H[!"jX,_[!

2-Modulation par lÕactivation-inactivation

2=AC! H>! 8oG9! >A:;>9]! 85EE>! B5G9! H=! P;T9>! EGC8GH=;9>! ;C5H4>]! H\=8:;@=:;5A! 3>! H\=BB=9>;H!

85A:9=8:;H>! C>! 3;CC;B>! B95I9>CC;@>E>A:! I9v8>! Q! BHGC;>G9C! B958>CCGC! MG;! 85AC5EE>A:! 3>! H\4A>9I;>[!

/59CMG>!H>!B958>CCGC!3\=8:;@=:;5A!>C:!85AC:=A:]!H=!9>H=6=:;5A!>C:!E53GH4>!BHG:k:!B=9!H>C!@=9;=:;5AC!3>!

8J=9I>C[!&!85A:9=9;5]!>A!B94C>A8>!3>!85A3;:;5AC!3>!8J=9I>!C:=TH>C]!H=!9>H=6=:;5A!>C:!E53GH4>!BHG:k:!

B=9! H>C! @=9;=:;5AC! 3>C! BJ4A5EFA>C! 3\=8:;@=:;5A<;A=8:;@=:;5A[! />C! 85A3;:;5AC! ;A:>9E43;=;9>C! C5A:!

4@;3>EE>A:!GA!E4H=AI>!3>C!3>G6!E48=A;CE>C[!

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85A3;:;5AC!E4:=T5H;MG>C!85EE>!H=!C;:G=:;5A!;C8J4E;MG>!MG;!>C:!Q!H\59;I;A>!3\GA!9=H>A:;CC>E>A:!3>!H=!

9>H=6=:;5A!^N>9E=A!=A3!.59H;A!"jgjc!K7T>9I]!?=9EH>7!>:!=H[!"jgjc!.95CCE=A!=A3!%8/=G9;A!"jdgc!

#:! y5JA! #G::5A]! O97>! >:! =H[! "jdX_]! =G! 85A:9kH>! A>G95<J59E5A=H! >:! =G6! 4@>A:G>HH>C! E53GH=:;5AC!

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3-Modulation par la non-uniformit�

)A! 9=;C5A! 3>! H=! 85EBH>6;:4! 3G! 8oG9! ;A:=8:]! H=! 3;C:9;TG:;5A! A5A! GA;P59E>! 3>! H=! 8J=9I>! >:! 3>!

H\=8:;@=:;5A<;A=8:;@=:;5A!3=AC!H\>CB=8>!>:!H>!:>EBC!85AC:;:G>!GA!:95;C;FE>!E48=A;CE>!3>!85A:9kH>!3>C!

BJ4A5EFA>C!3>!85A:9=8:;5A!>:!3>!9>H=6=:;5A!^W9G:C=>9:]!(=3>E=w>9C!>:!=H[!"jX,_[!#G;:>!Q!H=!B9>E;F9>!

3>C89;B:;5A!>A!"j"-!3>!H=!B95B=I=:;5A!3G!B5:>A:;>H!3\=8:;5A!@;=!H>C!P;T9>C!3>!?G9w;AS>]!H\;34>!3\GA>!

=8:;@=:;5A!4:=I4>!3G!E758=93>!=!P=;:!C5A!=BB=9;:;5A!^/>f;C!"j"-_[!/\4H=T59=:;5A!B95I9>CC;@>!3>!8>!

!

!

*-!

85A8>B:!Q!=T5G:;!Q!H\J7B5:JFC>!C>H5A!H=MG>HH>!H>!E5G@>E>A:!E48=A;MG>!3G!8oG9!94CGH:>!3>!B=98>HH>C!

3>! 85A:9=8:;5A! >:! 3>! 9>H=6=:;5A! T;>A! 4MG;H;T94>C! >:! 3;C:9;TG4>C! 3>! E=A;F9>! J5E5IFA>! ^p;II>9C!

"j*d_[!O=G:>!3>! :>8JA;MG>C!=BB95B9;4>C!B5G9!34:>8:>9!8>!BJ4A5EFA>]! ;H! =! P=HHG!=::>A39>! SGCMG\=G6!

=AA4>C!"jXY!B5G9!H>!3489;9>!in vivo!^W9G:C=>9:!"jXd_[!

/=!A5A<GA;P59E;:4!3>!H=!85A:9=8:;5A<9>H=6=:;5A!3G!8oG9!;A:=8:!349;@>!3\GA>!B=9:!3>C!@=9;=:;5AC!

94I;5A=H>C!3>!H\;A;:;=:;5A!>:!3>!H=!@;:>CC>!3\=8:;@=:;5A<;A=8:;@=:;5A]!>:!3\=G:9>!B=9:!3>!H=!3;C:9;TG:;5A!

94I;5A=H>!3>!H=!P598>!3=AC!C=!BJ=C>!3>!E5A:4>!>:!3>!8JG:>[!0>C!BJ4A5EFA>C!C5A:!>A!9>H=:;5A!=@>8!H>C!

3;PP49>A:C!A;@>=G6!3>!C:9>CC!>:!3>!34P59E=:;5A!^m;A!"jX"_!MG;!34B>A3>A:!3>!H=!I45E4:9;>!8=@;:=;9>]!

3>!H\59;>A:=:;5A!3>C!P;T9>C!E758=93;MG>C!>:!3>C!3;PP49>A:C!B95P;HC!3>!9>EBH;CC=I>!8595A=;9>[!/=!A5A<

GA;P59E;:4!>C:!BJ7C;5H5I;MG>!>:!85A:9;TG>!Q!E=;A:>A;9!H=!B>9P59E=A8>!@>A:9;8GH=;9>!:5G:!=G!H5AI!3G!

878H>!8=93;=MG>[!#5A!=GIE>A:=:;5A!;A=BB95B9;4>]!B94C>A:>!=G!85G9C!3>C!B=:J5H5I;>C!8=93;=MG>C]!A>!

P>9=! MG\=HH5AI>9! H=! 3G94>! 3>C! BJ4A5EFA>C! 3>! 85A:9=8:;5A<9>H=6=:;5A! >A! 943G;C=A:! H\>PP;8;>A8>!

E48=A;MG>!3>!H=!B5EB>!EGC8GH=;9>!8=93;=MG>[!

'H! 3485GH>! 3>! 8>::>! @;C;5A! MG>! H>C! B=9=EF:9>C! 8H=CC;MG>C! 3489;@=A:! H=! P5A8:;5A! 8=93;=MG>]!

85EE>!H=!P9=8:;5A!3\4S>8:;5A]!A>!:;>AA>A:!B=C!85EB:>!3>!H=!3;E>AC;5A!:>EB59>HH>!1!H=!8;A4:;MG>!3>!H=!

85A:9=8:;5A!>:!3>!H=!9>H=6=:;5A!35;@>A:!r:9>!85AC;3494>C!^W9G:C=>9:!=A3!#7C!"jjdc!/=P;::>]!W593=8J=9!

>:! =H[! *YYg_! =P;A! 3>! 3489;9>! >:! 3\;A:>9B94:>9! =@>8! >6=8:;:G3>! H>! P5A8:;5AA>E>A:! 3>! H=! B5EB>!

8=93;=MG>[!/=!37CP5A8:;5A!3>!H=!B5EB>!EGC8GH=;9>!8=93;=MG>!B>G:!=GS5G93\JG;!r:9>!5TS>8:;@4>!:9FC!

B948;C4E>A:!B=9! H>!25BBH>9! :;CCGH=;9>!E758=93;MG>!>:! H\;E=I>9;>!3>!34P59E=:;5A!B=9! H\48J5I9=BJ;>!

>A!a speckle tracking b !=;AC;!MG>!B=9!H=!94C5A=A8>!E=IA4:;MG>!AG8H4=;9>[!

F. Implications physiologiques et physiopathologiques du concept de pompe musculaire

/=! B9;A8;B=H>! 85AC4MG>A8>! 3G! 85A8>B:! 3>! B5EB>! EGC8GH=;9>! >C:! H=! 9>34P;A;:;5A! 3>! H=!

CGT3;@;C;5A! 3G! 878H>! 8=93;=MG>! ^O;I[! "_!1! H=! 85A:9=8:;5A! >:! H=! 9>H=6=:;5A! 3G! @>A:9;8GH>! C5A:! =;AC;!

85AC;3494>C!85EE>!3>G6!BJ=C>C!3>! H=!C7C:5H>]! H=! :9=AC;:;5A!3>! H=!85A:9=8:;5A!@>9C! H=! 9>H=6=:;5A!A>!

B5G@=A:! B=C! r:9>! P=8;H>E>A:! 34P;A;>[! /=! 9>H=6=:;5A! ;C5<@5HGE;MG>! >:! H=! CG88;5A! ^9>EBH;CC=I>!

@>A:9;8GH=;9>! 9=B;3>_! P5A:! B=9:;>! ;A:4I9=A:>! 3>! H=! 9>H=6=:;5A! 3>! H=! B5EB>!EGC8GH=;9>[! /=! 3;=C:5H>!

85EB9>A3! GA;MG>E>A:! H=! 3;=C:=C>! >:! H=! 85A:9=8:;5A! =:9;=H>!c! >HH>! C4B=9>! 3>G6! 878H>C! =8:;PC! 3>!

85A:9=8:;5A<9>H=6=:;5A!^W9G:C=>9:!=A3!#7C!"jXj_[!

! !

!

!

*g!

CHAPITRE II : LA DYSFONCTION

DIASTOLIQUE

!

!

*d!

'[!/&!2m#O$V0K'$V!2'&#K$/'nl)!1!?()&%Wl/)!

05EE>!A5GC!HR=@5AC!@G!B94843>EE>A:]!H\4@=HG=:;5A!3>!H=!P5A8:;5A!8=93;=MG>!B>G:!85AC;349>9!

H>!8oG9!85EE>!GA>!B5EB>!EGC8GH=;9>[!/=!85AC4MG>A8>!H=!BHGC!;EB59:=A:>!3>!8>::>!@;C;5A!>C:!MG>!H=!

943G8:;5A!3>! H=!B9>CC;5A!;A:9=@>A:9;8GH=;9>!=G!85G9C!3>! H=!9>H=6=:;5A!;C5<@5HGE;MG>!3>! H=!B5EB>!>:!

H\=GIE>A:=:;5A! 3G! @5HGE>! @>A:9;8GH=;9>! =G! 85G9C! 3G! 9>EBH;CC=I>! 9=B;3>! P5A:! B=9:;>! 3G! 878H>!

85A:9=8:;5A<9>H=6=:;5A! 3>! H=! C7C:5H>! EGC8GH=;9>! 8=93;=MG>! 1! H=! `@9=;>`! 3;=C:5H>! 3>! H=! B5EB>!

EGC8GH=;9>!85EB9>A3!H=!3;=C:=C>!>:!H=!BJ=C>!3>!85A:9=8:;5A!=:9;=H>!^W9G:C=>9:!=A3!#7C!"jXj_[!

&G6! P94MG>A8>C! 8=93;=MG>C! A59E=H>C! 3>! 9>B5C]! H=! 3;=C:5H>! 3G9>! =BB956;E=:;@>E>A:! -Ye!3G!

878H>!8=93;=MG>!=H59C!MG\>HH>!A>!9>B94C>A:>!MG>!-!Q!"-e!H59CMG>!HR5A!85AC;3F9>!H>C!85G9T>C!B9>CC;5A<

@5HGE>!^O;I[X_[!)A!>PP>:]!8\>C:!H>!34BH=8>E>A:!@>9C!H>!J=G:!3>!H=!B=9:;>!:>9E;A=H>!3>!8>::>!85G9T>!MG;!

34P;A;:!H=!37CP5A8:;5A!3;=C:5H;MG>!BG;CMG>!H=!B9>CC;5A!3>!9>EBH;CC=I>!3G!@>A:9;8GH>!I=G8J>!=GIE>A:>!

B95B59:;5AA>HH>E>A:!BHGC!MG>!C5A!@5HGE>[!/>C!8=GC>C!B9;A8;B=H>C!3>!8>!34BH=8>E>A:!3>! H=!85G9T>!

B9>CC;5A<@5HGE>!>AIH5T>A:!A5:=EE>A:!GA>!943G8:;5A!3>!H=!85EBH;=A8>!@>A:9;8GH=;9>!3;=C:5H;MG>!>:!

GA>!=H:49=:;5A!3>!H=!9>H=6=:;5A!@>A:9;8GH=;9>!I=G8J>[!

!

! !

P

V

F

Ic ejection

Contraction

S D

IR Diasstasis AtrialContr

Compliance

1

1

2

2

34

4

t

3

PPump

D

V

4

32

1

Inappropriate rise

in diastolic P-V

Diastolic dysfunction

diastolic failure

Relaxation

RFP

Figure 8. Division du cycle cardiaque en tant que pompe musculaire et courbe pression-volume correspondante.

IC: contraction isovolumique; IR: relaxation isovolumique; S: systole; D: diastole.

1: fermeture de la valve aortique; 2: ouverture de la valve mitrale; 3: fin de la succion; 4: fermeture de la valve mitrale.

Diastasis

!

!

*X!

''[!/&!2m#O$V0K'$V!2'&#K$/'nl)!)V!0/'V'nl)!Nl%&'V)!

A. Manifestation

/=!B94C>A8>!3\=H:49=:;5AC!3;=C:5H;MG>C!3G!@>A:9;8GH>!I=G8J>!C>!9>:95G@>!3=AC!GA!H=9I>!4@>A:=;H!

3>!B=:J5H5I;>C!=G!85G9C!3>CMG>HH>C!8>C!=A5E=H;>C!B>G@>A:!9>B94C>A:>9!H=!B9>E;F9>!>:!B=9P5;C!HRGA;MG>!

E=A;P>C:=:;5A! 3>! HR=::>;A:>! 8=93;=MG>[! /R4H4E>A:! B9;A8;B=H! 3>! 8>::>! 37CP5A8:;5A! 3;=C:5H;MG>! >C:! H=!

943G8:;5A!3>!H=!8=B=8;:4!3G!@>A:9;8GH>!Q!C>!9>EBH;9[!05EE>!A5GC!H>!@>995AC!GH:49;>G9>E>A:!3=AC!H>!

8J=B;:9>! 85A8>9A=A:! HR'0<O)B]! HR4@5HG:;5A! 3>! 8>C! =H:49=:;5AC! B>G:! =T5G:;9! Q! GA>! =::>;A:>! 3=AC! H>!

E=;A:;>A! 3>! H\4S>8:;5A! >:! 35A8! 3G! 34T;:! 8=93;=MG>[! lA! :>H! B958>CCGC! B>G:! =GCC;! >AI>A39>9! GA>!

=GIE>A:=:;5A! 3>C! B9>CC;5AC! >A! =E5A:! 3G! @>A:9;8GH>! I=G8J>[! 0>! BJ4A5EFA>! C>! :9=3G;:! B=9! GA>!

37CBA4>!3R>PP59:!3=AC!GA!B9>E;>9!:>EBC!SGCMGRQ!GA!o3FE>!=;IG!3G!B5GE5A!3=AC!H>C!C:=3>C!H>C!BHGC!

=@=A84C[

/>! 8=9=8:F9>! =CB48;P;MG>! 3>! H=! 37CP5A8:;5A! 3;=C:5H;MG>! =;AC;! MG>! C=! B94C>A8>! `MG=C;<

=A>835:;MG>`! 3=AC! 3>! A5ET9>GC>C! B=:J5H5I;>C! 9>A85A:94>C! >A! E43>8;A>! ;A:>9A>! 3RGA>! B=9:]! >:!

H\4H=T59=:;5A!:=93;@>!3>!89;:F9>C!B948;C!B5G9!C=!34P;A;:;5A!=G!85G9C!3>!HR'0<O)B!3R=G:9>!B=9:!^O=;HG9>`!

"jjX_! SGC:;P;>A:! H>! 9>:=93! 3>! HR>6BH59=:;5A! 3>! HR;A8;3>A8>! 3>! 8>C! =H:49=:;5AC! 3=AC! H=! B5BGH=:;5A!

I4A49=H>]! ;A34B>A3=EE>A:! 3>! H=! B94C>A8>! 3>! C7EB:kE>C! 3\;ACGPP;C=A8>! 8=93;=MG>[! 2>! BHGC]!

HR4@=HG=:;5A!3>!H=!37CP5A8:;5A!3;=C:5H;MG>!>A!8H;A;MG>!JGE=;A>!C>!J>G9:>!Q!C=!34:>8:;5A[!&!8>!:;:9>]!H=!

3;PPGC;5A!Q!I9=A3>!48J>HH>!3>!H\48J58=93;5I9=BJ;>!=@>8!H>C!E>CG9>C!25BBH>9!3G!PHG6!:9=AC<E;:9=H!=!

5G@>9:!H=!@5;>!Q!HR>6BH59=:;5A!A5A!;A@=C;@>!>:!>6:>AC;@>!3RGA!BHGC!I9=A3!A5ET9>!3>!CGS>:C!^V;CJ;EG9=!

=A3!K=S;w!"jjd_[!

B. Etiologies

1- Impact de lÕ�ge

0J>U!3>C!CGS>:C!S>GA>C]!GA>!4:G3>!A59@4I;>AA>!^#8J;9E>9]!/GA3>!>:!=H[!*YYY_!=!E5A:94!GA!B;8!

4H>@4!3>!HR5A3>!)!=CC58;4!Q!GA!B;8!T=C!3>!HR5A3>!&!H59C!3R>6=E>AC!48J58=93;5I9=BJ;MG>C[!&@>8!H\vI>]!

H>! B;8! 3>! HR5A3>! )! C>! 943G;:! =H59C! MG>! 8>HG;! 3>! HR5A3>!&! CR4HF@>[! 0>! 8J=AI>E>A:! 3G! 9=BB59:! )D&!

:4E5;IA>! 3G! B=CC=I>! 3RGA! B95P;H! 3;=C:5H;MG>! 3;:! A59E=H! Q! 8>HG;! 8=9=8:49;C4! B=9! GA>! 9>H=6=:;5A!

@>A:9;8GH=;9>!I=G8J>!=A59E=H>[!'H!>C:!Q!A5:>9!MG>!8>::>!:9=AC;:;5A!>C:!;A34B>A3=A:>!3>!H=!B94C>A8>!3>!

B=:J5H5I;>C!8=93;5@=C8GH=;9>C]!3RGA>!J7B>9:95BJ;>!@>A:9;8GH=;9>!I=G8J>]!3RGA>!J7B>9:>AC;5A!=9:49;>HH>!

5G! 3RGA>! 5T4C;:4[! )G! 4I=93! Q! H=! P94MG>A8>! =@>8! H=MG>HH>! C5A:! 9>:95G@4>C! H>C!E53;P;8=:;5AC! 3>! 8>C!

;A3;8>C!25BBH>9]!H>G9!B94C>A8>!8J>U!GA!;A3;@;3G!35AA4!AR>C:!B=C!P5984E>A:!C7A5A7E>!3>!B=:J5H5I;>[!

)A!>PP>:]!H>C!C>G;HC!G:;H;C4C!B5G9!34P;A;9!H=!37CP5A8:;5A!3;=C:5H;MG>!^9>85EE=A3=:;5AC!"jjX!3>!HR)#0!

B5G9! H>! 3;=IA5C:;8! 3>! HR'0<O)B_! AR=BB=9=;CC>A:! B=C! =3=B:4C! Q! H=! B5BGH=:;5A! I4A49=H>! ErE>! CR;HC!

!

!

*j!

9>C:>A:! G:;H>C! 3=AC! H>C! 8=C! 3R;ACGPP;C=A8>! 8=93;=MG>[! 0>C! 35AA4>C! 5A:! 4:4! 85AP;9E4>C! B=9! 3R=G:9>C!

4:G3>C!^(>3P;>H3]!y=85TC>A!>:!=H[!*YY+c!&TJ=7=9=:A=]!%=9f;8w!>:!=H[!*YYgc!iGUA>:C5@=]!N>9T5:C!>:!

=H[! *YYj_[! nG5;MGR;H! >A! C5;:]! ;H! P=G:! C5GH;IA>9! MG>! H>C! 89;:F9>C! G:;H;C4C! B5G9! 3;=IA5C:;MG>9! H=!

37CP5A8:;5A! 3;=C:5H;MG>! per se! A>! C5A:! B=C! =3=B:4C! >:! A>! :;>AA>A:! B=C! 85EB:>! 3>! HRvI>]! 8>! MG;!

;EBH;MG>!GA>!E4C>C:;E=:;5A!3>!H=!B94@=H>A8>!3>!8>::>!37CP5A8:;5A!Q!GA!C:=3>!;AP9=<8H;A;MG>[!

2- Le sexe

lA>!4:G3>! =GC:9=H;>AA>! ^&TJ=7=9=:A=]!%=9f;8w! >:! =H[! *YYg_! =! 9>:95G@4!3=AC!GA>!B5BGH=:;5A!

I4A49=H>!vI4>!3>!BHGC!3>!gY!=AC!MG>!H=!37CP5A8:;5A!3;=C:5H;MG>!4:=;:!B94C>A:>!8J>U!H>C!J5EE>C!>:!H>C!

P>EE>C!3=AC!H>C!ErE>C!B95B59:;5AC[!

3- Le diab�te

0>::>!B=:J5H5I;>!>C:!94IGH;F9>E>A:!=CC58;4>!Q! H=!37CP5A8:;5A!3;=C:5H;MG>[!'H!=!4:4!E5A:94!MG>!

3>C!B=:;>A:C!3;=T4:;MG>C!A>!B94C>A:=A:!=G8GA>!8595A=95B=:J;>!5G!J7B>9:>AC;5A!=9:49;>HH>!B>G@>A:!@5;9!

H>G9!B9>CC;5A!@>A:9;8GH=;9>!:4H43;=C:5H;MG>!=GIE>A:>9!^(>I=A]!/75AC!>:!=H[!"jddc!2>@>9>G6]!(5E=A!

>:!=H[!*YYYc!W57>9]!KJ=A;I=9=S!>:!=H[!*YY,c!%=9f;8w!*YY,_!>:!8>]! ;A34B>A3=EE>A:!3>! H\vI>]!3>! H=!

P5A8:;5A!C7C:5H;MG>!>:!3>!H=!E=CC>!@>A:9;8GH=;9>!^/;G]!?=HE;>9;!>:!=H[!*YY"_[!0>C!=H:49=:;5AC!5A:!4:4!

;EBG:4>C!Q!H=!E;895<=AI;5B=:J;>!>:!=G!C:9>CC!5673=A:!MG;!>A!3485GH>]!Q!HR>PP>:!3>!H\J7B>9IH784E;>!CG9!

H>C! P;T9>C! E758=93;MG>C! >:! =G6! =H:49=:;5AC! 3>! H=! E=:9;8>! >6:9=8>HHGH=;9>! C>85A3=;9>C! Q! H=!

IH785C7H=:;5A! 3>! C>C! 85EB5C=A:>C! ^&@>A3=A5]!&I=9f=H! >:! =H[! "jjjc!W>9I]! #A59I==93! >:! =H[! "jjjc!

W95fAH>>! *YY"c! .5AU=H>U<L;H8J>U]! &7G>H=! >:! =H[! *YY-_[! &! 85A:9=9;5]! H>! 85A:9kH>! C:9;8:! 3>! H=!

IH784E;>!B>9E>:!GA>!94I9>CC;5A!3>!H=!37CP5A8:;5A!3;=C:5H;MG>!^O>;A]!%=HJ5:9=!>:!=H[!"jX,c!?5HH=8w]!

%=HJ5:9=!>:!=H[!"jXgc!N=GC359P]!(;>I>9!>:!=H[!"jXXc!2>@>9>G6]!(5E=A!>:!=H[!*YYY_[!

4- L'hypertension art�rielle

/RJ7B>9:>AC;5A! =9:49;>HH>! >C:! H\GA! 3>C! P=8:>G9C! H>C! BHGC! 4:95;:>E>A:! H;4C! Q! H=! 37CP5A8:;5A!

3;=C:5H;MG>!^O;C8J>9]!W=>CCH>9!>:!=H[!*YY+c!(>3P;>H3]!y=85TC>A!>:!=H[!*YY+c!&TJ=7=9=:A=]!%=9f;8w!>:!

=H[!*YYgc!iGUA>:C5@=]!N>9T5:C!>:!=H[!*YYj_!@;=!BHGC;>G9C!E48=A;CE>C[!/>C!=H:49=:;5AC!3>!H=!C:9G8:G9>!

3>!H=!E=:9;8>!>6:9=8>HHGH=;9>!S5G>A:!GA!9kH>!;EB59:=A:[!)HH>C!C>ETH>A:!r:9>!85AC48G:;@>C!=G!34Bk:!3>!

85HH=IFA>! 3>! :7B>! '! ;A3G;:! B=9! H>! C:9>CC!E48=A;MG>! >:! HR=8:;@=:;5A!3G! C7C:FE>! 94A;A><=AI;5:>AC;A>[!

0>8;! >C:! A5:=EE>A:! 4:=74! B=9! HR>PP>:! T4A4P;MG>! 3>C! ;AJ;T;:>G9C! 3>! HR>AU7E>! 3>! 85A@>9C;5A! 3>!

HR=AI;5:>AC;A>!>:!B=9!H\4H4@=:;5A!3>C!:=G6!3>!B95<85HH=IFA>!3>!:7B>!'''!8J>U!H>C!B=:;>A:C!J7B>9:>A3GC!

^K=w=:CGS;]!%;w=E;!>:!=H[!"jjgc!%=:CGT=9=]!%=:CGT=9=!>:!=H[!*YYYc!#B;A=H>]!.GA=C;AIJ>!>:!=H[!*YY*c!

?5GHC>A]!&A3>9C>A! >:! =H[! *YY-_[!lA>! =8:;@=:;5A! 3>C! P;T95TH=C:>C! >C:! Q! HR59;I;A>! 3>! 8>! BJ4A5EFA>[!

0>::>! =8:;@=:;5A! 3>C! P;T95TH=C:>C! =@=;:! 4:4! 34SQ! 3489;:>! 3=AC! H>! 9>E53>H=I>! =B9FC! GA! ;AP=98:GC! 3G!

!

!

+Y!

E758=93>! ^09>>E>9C]! 0H>G:S>AC! >:! =H[! *YY"_[! $A! C=;:! 34C59E=;C! MG>! H>! C:9>CC! 5673=A:! >:! H>C!

E43;=:>G9C! 3>! HR;APH=EE=:;5A! B>G@>A:! E53;P;>9! HR>6B9>CC;5A! I4A;MG>! 3>C! P;T95TH=C:>C! >:! E53GH>9!

=;AC;!H=!C4894:;5A!3>!E4:=HH5B95:4=C>C!^#B;A=H>!*YY*c!KCG9G3=]!W5>99;I:>9!>:!=H[!*YY*_!>:!3>!K.O<!!

^(>=B>!=A3!.955:!"jjjc!iGf=J=9=]!i=;!>:!=H[!*YY*c!iGf=J=9=]!i=;!>:!=H[!*YY+c!iGf=J=9=]!i=;!>:!

=H[!*YY,_[!

5- La cardiopathie isch�mique

2=AC! H>C! P59E>C! =;IG{! >:! 8J95A;MG>! 3>! H=! 8=93;5B=:J;>! ;C8J4E;MG>]! 5A! B>G:! 5TC>9@>9!

HR;AC:=HH=:;5A! 3\=H:49=:;5AC! 3>! H=! P5A8:;5A! 3;=C:5H;MG>! H;4>C! Q! 3>C! E53;P;8=:;5AC! 3>! HRJ5E45C:=C;>!

8=H8;MG>! >:! =G! 9>E53>H=I>! @>A:9;8GH=;9>! B5C:! ;C8J4E;MG>[! />C! ;A3;8>C! 4@=HG=A:! H=! 37CP5A8:;5A!

3;=C:5H;MG>!5A:!GA!8>9:=;A!B5G@5;9!B943;8:;P! CG9! H=!E59T;<E59:=H;:4!8J>U!3>C!B=:;>A:C!@;8:;E>C!3RGA!

;AP=98:GC! ^?;B;H;C]! %>7>9! >:! =H[! "jj*c! />H>]! KJ5EC5A! >:! =H[! "jj-c! V;SH=A3]! i=EB! >:! =H[! "jjdc!

0>9;C=A5]!W5H5IA>C>!>:!=H[!*YY"c!%5HH>9]!?5GHC>A!>:!=H[!*YY+_[!

6- La cardiomyopathie hypertrophique

0>9:=;A>C!E=H=3;>C!J4943;:=;9>C!H;4>C!Q!3>C!EG:=:;5AC!3>C!IFA>C!853=A:!B5G9!H>C!B95:4;A>C!3G!

C=985EF9>!C5A:!8=9=8:49;C4>C!B=9!GA>!P;T95C>!;A:>9C:;:;>HH>]!GA>!E;895=AI;5B=:J;>!>:!GA>!J7B>9:95BJ;>!

=C7E4:9;MG>! 3G! @>A:9;8GH>! I=G8J>]! 8>:! >AC>ETH>! 85A85G9=A:! Q! HR=BB=9;:;5A! 3>! H=! 37CP5A8:;5A!

3;=C:5H;MG>[! /=! P;T95C>! >C:! GA! 4H4E>A:! 8H>P! 3=AC! 8>C! B958>CCGC[! /=! 943G8:;5A! 3>! H=! 85EBH;=A8>!

@>A:9;8GH=;9>!MG;!>A!3485GH>!B=9:;8;B>!Q!HR;A8=B=8;:4!3>!E=;A:>A;9!H>!34T;:!8=93;=MG>!B>A3=A:!HR>PP59:!

^/>H>]! KJ5EC5A! >:! =H[! "jj-c!V;CJ;EG9=]!&BBH>:5A! >:! =H[! "jjg_[! ?=9! =;HH>G9C]! H=! B94C>A8>! 3>! 8>::>!

37CP5A8:;5A! 3;=C:5H;MG>! E53;P;>! H>! B95A5C:;8! 3>C! B=:;>A:C! =::>;A:C! B=9! H=! E=H=3;>! ^V;CJ;EG9=]!

&BBH>:5A!>:!=H[!"jjg_[!

7- Les maladies auto-immunes syst�miques

/>C!E=H=3;>C! =G:5<;EEGA>C! C7C:4E;MG>C! B>G@>A:! r:9>! 9>CB5AC=TH>C! 3RGA>! =::>;A:>! 8=93;=MG>!

MG;! C>! E=A;P>C:>! C5G@>A:! C5GC! H=! P59E>! 3R=A5E=H;>C! 3;=C:5H;MG>C[! 2=AC! H>! C7A395E>! =A:;<

BJ5CBJ5H;B;3>C]! GA>! 85994H=:;5A! =! 4:4! 34E5A:94>! >A:9>! H>C! B=9=EF:9>C! 3;=C:5H;MG>C! >:! H>C! :=G6!

3R=A:;859BC! 8;98GH=A:C! ^K>w:5A;35G]! '5=AA;3;C! >:! =H[! *YY"_[! 2=AC! H>! 8=C! 3G! HGBGC]! 5A! 5TC>9@>! GA>!

37CP5A8:;5A! 3;=C:5H;MG>! ;C5H4>! ^/>GAI]! p5AI! >:! =H[! "jjY_[! /R;APH=EE=:;5A! E;895@=C8GH=;9>!

=885EB=IA4>! 3>! 34Bk:C! 3>! P;T9;A>! >:! 3RGA>! B95H;P49=:;5A! 3>C! P;T95TH=C:>C! B5G99=;:! >6BH;MG>9! H>C!

=H:49=:;5AC! 3;=C:5H;MG>C! =G! 85G9C! 3>! H=! E=H=3;>! 3>! W>J8>:! ^W=9;C]! $w=A! >:! =H[! *YYg_[! )AP;A]! H=!

B953G8:;5A!3494IH4>!3>!85HH=IFA>!>C:!E;C>!>A!8=GC>!3=AC!H=!B=:J5I4A;>!3>C!=A5E=H;>C!3;=C:5H;MG>C!

MG;!=885EB=IA>A:!H=!C8H4953>9E;>!^%=;5A>]!L=H>A:;A;!>:!=H[!"jj"_[!

!

!

+"!

8- Les maladies endocriniennes

0>9:=;A>C! B=:J5H5I;>C! >A3589;A;>AA>C! 5A:! GA! 9>:>A:;CC>E>A:! CG9! H=! P5A8:;5A! 8=93;=MG>[! />!

C7A395E>!3>!CG9B953G8:;5A!3>!HRJ59E5A>!3>!895;CC=A8>!>AI>A39>!GA>!=B5B:5C>!3>C!8=93;5E7587:>C!

Q! H\59;I;A>! 3\GA>! =88GEGH=:;5A! 3>! 85HH=IFA>! 3=AC! H>! E758=93>! >:! GA>! ;AP;H:9=:;5A! H7EBJ5<

E5A587:=;9>[! 0>::>! E53;P;8=:;5A! 3>! HR=98J;:>8:G9>! E758=93;MG>! >C:! 9>CB5AC=TH>! 3\=A5E=H;>C!

3;=C:5H;MG>C!9>CB5AC=TH>C!3RGA>!943G8:;5A!3>!H=!:5H49=A8>!Q!HR>PP59:!^#B;A>HH;]!?>:9>::=!>:!=H[!*YY+_[!&G!

85G9C!3>!H=!E=H=3;>!3>!0GCJ;AI]!H>C!:=G6!4H>@4C!3>!859:;C5H!P=@59;C>A:!H>!9>E53>H=I>!3G!@>A:9;8GH>!

I=G8J>! ^pJ;:f59:J]!%=AI5C! >:! =H[! *YYYc!%G;>C=A]!/GB;=! >:! =H[! *YY+_! >:! 8>! ;A34B>A3=EE>A:! 3>C!

@=H>G9C!3>!B9>CC;5A!=9:49;>HH>!^O=HH5]!WG3=A5!>:!=H[!"jj,_[!

9- Association dysfonction diastolique Ð insuffisance cardiaque

/>C! 35AA4>C! 349;@4>C! 3G! 9>I;C:9>! 85A8>9A=A:! H>C! J=T;:=A:C! 3>! HR$HEC:>3! 05GA:7! ^(>3P;>H3]!

y=85TC>A! >:! =H[! *YY+_! 5A:! E5A:94! MG>! H=! 37CP5A8:;5A! 3;=C:5H;MG>! ;C5H4>! 4:=;:! P94MG>A:>! 3=AC! H=!

B5BGH=:;5A! I4A49=H>! >:! MGR>HH>! A\4:=;:! B=C! A48>CC=;9>E>A:! =CC58;4>! Q! GA>! ;ACGPP;C=A8>! 8=93;=MG>!

8H;A;MG>[! 'H! >C:! Q! A5:>9! MGRGA>! 37CP5A8:;5A! 3;=C:5H;MG>! SGI4>! C4@F9>! CG9! H=! T=C>! 3>! 89;:F9>C!

48J58=93;5I9=BJ;MG>C! B>G:! 9>C:>9! 85EBHF:>E>A:! =C7EB:5E=:;MG>[! /=! B95T=T;H;:4! 3>! H=! B94C>A8>!

C;EGH:=A4>! 3RGA>! 37CP5A8:;5A! 3;=C:5H;MG>! >:! 3>! C;IA>C! 3R;ACGPP;C=A8>! 8=93;=MG>! 85AI>C:;@>!

=GIE>A:=;:! =@>8! H=! C4@49;:4! 3>! H=! B9>E;F9>[! 2>! ErE>]! 3=AC! GA>! B5BGH=:;5A! =GC:9=H;>AA>! 3\vI>!

CGB49;>G9!Q!gY!=AC!^&TJ=7=9=:A=]!%=9f;8w!>:!=H[!*YYg_]!H>C!C:=3>C!C4@F9>C!3>!37CP5A8:;5A!3;=C:5H;MG>!

A\4:=;>A:!B=C!:5GS5G9C!=CC58;4C!Q!3>C!C7EB:kE>C!3R;ACGPP;C=A8>!8=93;=MG>[!

'''[!)L&/l&K'$V!0/'V'nl)!2)!/&!O$V0K'$V!2'&#K$/'nl)!

A. Evaluation invasive

/=! 94P49>A8>! B5G9! H\4@=HG=:;5A! 3>! H=! P5A8:;5A! @>A:9;8GH=;9>! 3;=C:5H;MG>! >C:! H>! 8=:J4:49;CE>!

8=93;=MG>[! 0>! :7B>! 3\4@=HG=:;5A! 9>B5C>! CG9! 3>G6! B;H;>9C!1! H\4:G3>! 3>! H=! 8;A4:;MG>! 3>! H=! 9>H=6=:;5A!

@>A:9;8GH=;9>! >:! 8>HH>! 3>! H=! 3;C:>AC;T;H;:4! 3;=C:5H;MG>! 3G! @>A:9;8GH>! I=G8J>[! 2\GA! B5;A:! 3>! @G>!

:>8JA;MG>]! >HH>! C\=BBG;>! CG9! HRG:;H;C=:;5A! 3>! 8=:J4:>9C! 35:4C! 3>! E;895<E=A5EF:9>C! B>9E>::=A:! H=!

E>CG9>! B948;C>! ^J=G:>! P94MG>A8>! 3>! 94B5AC>_! 3>! H=! B9>CC;5A! @>A:9;8GH=;9>! >:! CG9! 3>C! 8=:J4:>9C! Q!

85A3G8:=A8>]!5G!3>C!=AI;5I9=EE>C]!B5G9!H=!E>CG9>!3G!@5HGE>!1!H>C!>A9>I;C:9>E>A:C!3>C!E>CG9>C!3>!

@5HGE>! >:! B9>CC;5A! @>A:9;8GH=;9>C! C5A:! C;EGH:=A4C[! 0>C! >6BH59=:;5AC! C5A:! Q! HR59;I;A>! 3>! H=!

34:>9E;A=:;5A! 3R;A3;8>C! 3489;@=A:! H=! 9>H=6=:;5A! @>A:9;8GH=;9>! ;C5@5HGE;MG>! >:! H=! 85EBH;=A8>!

@>A:9;8GH=;9>[!05A:9=;9>E>A:!=G!85A8>B:!3>!B5EB>!EGC8GH=;9>]! H=!34P;A;:;5A!8H;A;MG>!3>!H=!3;=C:5H>!

>AIH5T>!H=!BJ=C>!3>!H=!9>H=6=:;5A!;C5@5HGE;MG>!>:!8R>C:!B5G9MG5;!A5GC!HR;A:4I9>95AC!3=AC!8>:!>6B5C4[!

!

!

+*!

1- La cin�tique de la relaxation ventriculaire (remplissage pr�coce)

)HH>!B>G:!r:9>!3489;:>!Q!HR=;3>!3>C!3>G6!B=9=EF:9>C!CG;@=A:C!1!

dP/dtmin 1! H=! @=H>G9! E;A;E=H>! 3>! H=! 349;@4>! B9>E;F9>! B=9! 9=BB59:! =G! :>EBC! 3>! H=! B9>CC;5A!

@>A:9;8GH=;9>!I=G8J>!>C:!B=9P5;C!G:;H;C4>!B5G9!3489;9>!H=!@;:>CC>!3>!H=!9>H=6=:;5A!;C5@5HGE;MG>!E=;C!8>!

A\>C:!B=C!GA!T5A!;A3;8>!>:!;H!>C:!:9FC!H;4!=G6!85A3;:;5AC!3>!8J=9I>!>:!Q!H=!P94MG>A8>!8=93;=MG>[!

La constante de relaxation isovolumique!!!1!H=!B49;53>!3>!9>H=6=:;5A!;C5<@5HGE;MG>!8=9=8:49;C>!

H=! BJ=C>! 3>! 34895;CC=A8>! 3>! H=! B9>CC;5A! @>A:9;8GH=;9>! B>A3=A:! H=MG>HH>! H>! @5HGE>! 3>! H=! 8=@;:4! A>!

@=9;>!B=C[!)HH>!>C:!34P;A;>!B=9!H\;A:>9@=HH>!3>!:>EBC!85EB9;C!>A:9>!H>!B;8!A4I=:;P!3>!3?D3:!^=CC;E;H4!Q!

H=!P>9E>:G9>!3>!H=!@=H@>!=59:;MG>_!>:!H=!@=H>G9!3>!H=!B9>CC;5A!@>A:9;8GH=;9>!I=G8J>!8599>CB5A3=A:!Q!H=!

B9>CC;5A!:4H4<3;=C:5H;MG>!3G!T=::>E>A:!CG;@=A:!Q!H=MG>HH>!*!5G!-!EENI!C5A:!=S5G:4C[!/=!85G9T>!3>!

34895;CC=A8>! 3>! H=! B9>CC;5A! @>A:9;8GH=;9>! I=G8J>! B>G:! r:9>!E534H;C4>! Q! H\=;3>! 3>!E53FH>C!E5A5<

>6B5A>A:;>HC!MG;!B>G@>A:! r:9>! =C7EB:5:;MG>C!5G!A5A!=C7EB:5:;MG>C[!/>!E53FH>!3>!p>;CC! ^p>;CC]!

O9>3>9;wC>A! >:! =H[! "jdg_! CGBB5C>! GA>! =C7EB:5:>! AGHH>! >:! MG>! H=! B9>CC;5A! 4@5HG>! C>H5A! H\4MG=:;5A!

CG;@=A:>!1!?|?Y!><:D!]!=@>8!?Y!4:=A:!H=!@=H>G9!3>!B9>CC;5A!=G!B;8!A4I=:;P!3>!3?D3:]!:!4:=A:!H>!:>EBC!>:!!!

H=!85AC:=A:>!3>!9>H=6=:;5A! ;C5@5HGE;MG>[!/>C!=G:9>C!E53>C!3>!8=H8GH!3>! H=!85AC:=A:>!3>!9>H=6=:;5A!

;C5@5HGE;MG>!G:;H;C>A:!3>C!E53FH>C!Q!=C7EB:5:>!A5A!AGHH>!1!?|^?Y<?W_!><:D!}!?W]!5~!?W!>C:!8=9=8:49;C4!

B=9! 3>C! @=H>G9C! A5A! BJ7C;5H5I;MG>C! BG;CMG\>HH>C! C5A:! A4I=:;@>C[! 2=AC! 8>::>! E4:J53>! E5A5<

>6B5A>A:;>HH>]! GA>! 9>H=:;5A! H;A4=;9>! >A:9>! H=! B9>CC;5A! >:! C=! 349;@4>!B9>E;F9>! >C:! 4:=TH;>! B>A3=A:! H=!

B49;53>! 3>! 9>H=6=:;5A! ;C5@5HGE;MG>! C>H5A! H\4MG=:;5A! CG;@=A:>!1! 3?D3:! |! <^"D!_^?Y_! 5~! 3?D3:! |! <

^"D!_^?<?W_[!'H!>C:!B958434!>A!CG;:>!Q!GA>!94I9>CC;5A!A5A!H;A4=;9>!C>H5A!H\=HI59;:JE>!3>!/>@>AT>9I<

%=9MG=93:! >A! G:;H;C=A:! H>C! B=9=EF:9>C! 5T:>AGC! =@>8! H=! 94I9>CC;5A! H;A4=;9>! B5G9! ;A;:;>9! H\;:49=:;5A[!

2=AC! H\=H:>9A=:;@>]! 5A! B>G:! 34:>9E;A>9! GA>! 85AC:=A:>! 3>! :>EBC! 3>! 9>H=6=:;5A! B=9! GA! E53FH>!

H5I;C:;MG>! ^%=:CGT=9=]! K=w=w;! >:! =H[! "jj-c! #>AU=w;! =A3!i=CC! *Y"Y_[! lA>! @=H>G9! CGB49;>G9>! Q! ,X!

EC>8!34P;A;:!H=!B94C>A8>!3RGA>!37CP5A8:;5A!^L=C=A!=A3!/>@7!*YYY_[!!

2- Distensibilit� diastolique du ventricule gauche (diastase et remplissage

tardif)

?>A3=A:! H>C! BJ=C>C! 3>! 3;=C:=C>! >:! 3>! C7C:5H>! =G9;8GH=;9>]! H>C! B>9P59E=A8>C! @>A:9;8GH=;9>C! A>!

C5A:! ;APHG>A84>C! MG>! B=9! H>C! 8=9=8:49;C:;MG>C! B=CC;@>C! ;A:9;ACFMG>C! 5G! >6:9;ACFMG>C! 3G! @>A:9;8GH>!

I=G8J>!^.95CCE=A!=A3!%8/=G9;A!"jdg_[!

La contrainte pari�tale 1! BHGC! I9=A3! >C:! H\4:;9>E>A:! 3\GA! EGC8H>]! BHGC! ;EB59:=A:>! >C:! H=!

85A:9=;A:>! MG;! HG;! 94C;C:>[! />! 8=H8GH! 3>! 8>::>! 85A:9=;A:>!"! 349;@>! 3>! H=! H5;! 3>! /=BH=8>! >:! >HH>! >C:!

!

!

++!

>6B9;E4>!C5;:!B=9! H=!85A:9=;A:>!8;985AP49>A:;>HH>]! C5;:!B=9! H=!E49;3;>AA>[!)A!B9=:;MG>]! H=!85A:9=;A:>!

E49;3;>AA>!>C:!8=H8GH4>!C>H5A! H=! P59EGH>!1!"!|!?9! D!*>!^"!}!>D9_]!5~!?!>C:! H=!B9>CC;5A!@>A:9;8GH=;9>!

;AC:=A:=A4>!^EENI_]!>!>C:!H\4B=;CC>G9!3>!H=!B=95;!E758=93;MG>!>A!EE]!9!H>!9=75A!>A!EE[!

La rigidit� volumique 1!>HH>!>C:!=A=H7C4>!B=9!H>C!85G9T>C!B9>CC;5A<@5HGE>!^.==C8J]!W=::H>!>:!=H[!

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8\>C:!H=!B5C;:;5A!3>!H=!85G9T>!B9>CC;5A<@5HGE>!MG;!>C:!34:>9E;A=A:>!B5G9!HR=BB948;=:;5A!3>C!8=B=8;:4C!

3>!9>EBH;CC=I>!3G!@>A:9;8GH>!I=G8J>!^.H=A:U!=A3!?=9EH>7!"jdX_[!

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HR=AI;5I9=BJ;>!B=9!9=3;5<;C5:5B>C[!)HH>!B>9E>:!H>!8=H8GH!3G!normalized filling peak rate!MG;!E>:!>A!

9>H=:;5A! H\4@5HG:;5A! 3G! @5HGE>! @>A:9;8GH=;9>! I=G8J>! =@>8! H>! :>EBC! >:! MG;! B>9E>:! H\4:G3>! 3G!

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B. Evaluation non-invasive

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Figure 9. Relation entre la pression et le

volume ventriculaires gauches.!!/=!P5A8:;5A!3;=C:5H;MG>!Q! H\4:=:!A59E=H!>:!>A! C;:G=:;5AC! B=:J5H5I;MG>C[! ^3\=B9FC!.H=A:U]!"jdX_[!

!

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1- L'�chocardiographie

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!

Mesure des v�locit�s transmitrales

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Measurement Age group (y)

16–20 21–40 41–60 .60

IVRT (ms) 50+9(32–68) 67+8(51–83) 74+7(60–88) 87+7(73–101)E/A ratio 1.88+0.45(0.98–2.78) 1.53+0.40(0.73–2.33) 1.28+0.25(0.78–1.78) 0.96+0.18(0.6–1.32)

DT (ms) 142+19(104–180) 166+14(138–194) 181+19(143–219) 200+29(142–258)A duration (ms) 113+17(79–147) 127+13(101–153) 133+13(107–159) 138+19(100–176)PV S/D ratio 0.82+0.18(0.46–1.18) 0.98+0.32(0.34–1.62) 1.21+0.2(0.81–1.61) 1.39+0.47(0.45–2.33)

PV Ar (cm/s) 16+10(1–36) 21+8(5–37) 23+3(17–29) 25+9(11–39)PV Ar duration (ms) 66+39(1–144) 96+33(30–162) 112+15(82–142) 113+30(53–173)

Septal e (cm/s) 14.9+2.4(10.1–19.7) 15.5+2.7(10.1–20.9) 12.2+2.3(7.6–16.8) 10.4+2.1(6.2–14.6)Septal e/a ratio 2.4* 1.6+0.5(0.6–2.6) 1.1+0.3(0.5–1.7) 0.85+0.2(0.45–1.25)Lateral e (cm/s) 20.6+3.8(13–28.2) 19.8+2.9(14–25.6) 16.1+2.3(11.5–20.7) 12.9+3.5(5.9–19.9)

Lateral e/a ratio 3.1* 1.9+0.6(0.7–3.1) 1.5+0.5(0.5–2.5) 0.9+0.4(0.1–1.7)

Tableau 1. Valeurs normales des indices �valuant la fonction diastolique par Doppler. Les donn�es sont exprim�es en

moyennes ± SD (95% de lÕintervalle de confiance) (IVRT : temps de relaxation iso-volumique; DT : temps de

d�c�l�ration de lÕonde E mitrale; PV S/D ratio : rapport onde systolique/diastolique du flux des veines pulmonaires; PV

Ar : onde de r�gurgitation de la contraction atriale dans les veines pulmonaires; � = EÕ, � = AÕ).

!

!

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Figure 10. Crit�res �chocardiographiques Doppler pour la classification de la dysfonction diastolique

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Surface et volume de l'oreillette gauche

C>!B=9=EF:9>!>C:!P=8;H>E>A:!5T:>AG!CG9!3>C!85GB>C!*<!5G!,<8=@;:4C[!)A!8H;A;MG>]!;H!>6;C:>!GA>!

9>H=:;5A!>A:9>!H>!9>E53>H=I>!3>!H\59>;HH>::>!I=G8J>!>:!3\=G:9>C!;A3;8>C!3>!P5A8:;5A!3;=C:5H;MG>!^KC=AI]!

W=9A>C! >:! =H[! *YY*_[! 0>B>A3=A:]! H>! @5HGE>! 3>! H\59>;HH>::>! I=G8J>! 9>PHF:>! GA;MG>E>A:! H>C! >PP>:C!

8GEGH4C!3>C!B9>CC;5AC!3>!9>EBH;CC=I>!3=AC!H>!:>EBC[!lA!@5HGE>!CGB49;>G9!5G!4I=H!Q!+,!EHDE*!>C:!

GA! P=8:>G9! B943;8:;P! ;A34B>A3=A:! 3R;ACGPP;C=A8>! 8=93;=MG>]! 3>! P;T9;HH=:;5A! =:9;=H>! >:! 3R=88;3>A:!

@=C8GH=;9>!8494T9=H!^&TJ=7=9=:A=]!#>f=93!>:!=H[!*YYg_[!'H!P=G:!:5G:!3>!ErE>!I=93>9!Q!H\>CB9;:!MGRGA>!

3;H=:=:;5A!3>!H\59>;HH>::>!C=AC!37CP5A8:;5A!3;=C:5H;MG>!B>G:!C>!9>:95G@>9!8J>U!H>C!B=:;>A:C!B94C>A:=A:!

GA>! T9=378=93;>]! GA>! =A4E;>]! 3>C! B=:J5H5I;>C! Q! J=G:! 34T;:! 8=93;=MG>]! GA! PHG::>9]! GA>! P;T9;HH=:;5A!

=:9;=H>! 5G! 3>C! B=:J5H5I;>C! ;EB59:=A:>C! 3>! H=! @=H@>! E;:9=H>[! /\59>;HH>::>! E53GH>! H>! 9>EBH;CC=I>!

@>A:9;8GH=;9>!>A!8GEGH=A:!H>!C=AI!B>A3=A:!H=!P>9E>:G9>!3>!H=!@=H@>!E;:9=H>!>:!>A!HR>6BGHC=A:!3=AC!H>!

@>A:9;8GH>! I=G8J>! =@>8! C=! 85A:9=8:;5A[! &@>8! H=! B95I9>CC;5A! 3>! H=! 37CP5A8:;5A! 3;=C:5H;MG>]! H=!

85A:9;TG:;5A!=G9;8GH=;9>!P=;TH;:!>A!9=;C5A!3\GA>!943G8:;5A!3>!C=!P598>!85A:9=8:;H>!>:!3>!H\=GIE>A:=:;5A!

3>!H=!B9>CC;5A!:4H4<3;=C:5H;MG>!3G!L.[!

Pressions systolique et diastolique de l'art�re pulmonaire

/>C! B=:;>A:C! C7EB:5E=:;MG>C! =@>8! GA>! 37CP5A8:;5A! 3;=C:5H;MG>! B94C>A:>A:! C5G@>A:! 3>C!

B9>CC;5AC!4H>@4>C!3=AC!H\=9:F9>!BGHE5A=;9>[!)A!H\=TC>A8>!3>!B=:J5H5I;>C!BGHE5A=;9>C]!GA>!4H4@=:;5A!

3>! H=! B9>CC;5A! =9:49;>HH>! BGHE5A=;9>! ^8=H8GH4>! >A! G:;H;C=A:! H>C! PHG6! 3>! 94IG9I;:=:;5A! :9;8GCB;3>! 5G!

!

!

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BGHE5A=;9>_! B>G:! r:9>! GA! C;IA>! ;A3;9>8:! 3>! B9>CC;5AC! 3>! 9>EBH;CC=I>! @>A:9;8GH=;9>C! I=G8J>C!

=GIE>A:4>C!^W5G8J=93]!&G9;I>EE=!>:!=H[!*YYX_[!

La manÏuvre de Valsalva

0>::>!E=AoG@9>!>C:!>648G:4>!>A!94=H;C=A:!GA>!>6B;9=:;5A!P5984>!^>A@;95A!,Y!EENI_!85A:9>!GA!

A>U!>:!GA>!T5G8J>! P>9E4C[!0>8;!B>9E>:! H>!3;=IA5C:;8!3;PP49>A:;>H! >A:9>!GA! PHG6!A59E=H! >:!BC>G35<

A59E=H! >A! 943G;C=A:! H=! B948J=9I>! 3G! 8oG9! I=G8J>[! )A! 8=C! 3>! PHG6! :9=ACE;:9=H! BC>G35<A59E=H]! H=!

E=AoG@9>!>C:!8=B=TH>!3>!34E=CMG>9!GA>!=H:49=:;5A!3>!H=!9>H=6=:;5A!1!H\5A3>!)!C>!943G;:!>:!H>!:>EBC!

3>! 3;=C:5H>! C\=HH5AI>! =H59C! MG>! H\5A3>!&! 9>C:>! C:=TH>! ^943G8:;5A!)D&_[!)A! 8=C! 3>! PHG6! A59E=H]! H>C!

3>G6!5A3>C!)!>:!&!34895;CC>A:!B95B59:;5AA>HH>E>A:!^NG99>HH]!V;CJ;EG9=!>:!=H[!"jjd_[!

Flux veineux pulmonaire

/>!PHG6!@>;A>G6!BGHE5A=;9>!>C:!4@=HG4!>A!85GB>!,<8=@;:4C!B=9!25BBH>9!BGHC4!=@>8!GA>!94I;5A!

3\48J=A:;HH5AA=I>! BH=84>! =G! A;@>=G! 3>! H=! @>;A>! BGHE5A=;9>[!/=! @;:>CC>! 3G! PHG6! @>;A>G6! 9>PHF:>! H=!

B9>CC;5A! =:9;=H>! I=G8J>[! />! PHG6! A59E=H! 85EB9>A3! GA>! 85EB5C=A:>! =A:495I9=3>! C7C:5H;MG>! T;<

BJ=C;MG>!^3G>!Q!H=!9>H=6=:;5A!=:9;=H>!>:!Q!H\=GIE>A:=:;5A!3>!H=!B9>CC;5A!BGHE5A=;9>_]!GA>!3>G6;FE>!

85EB5C=A:>! =A:495I9=3>! 3;=C:5H;MG>! ?L3! ^3G>! Q! H\5G@>9:G9>! 3>! H=! @=H@>! E;:9=H>_! >:! GA>! 5A3>!

94:95I9=3>!H;4>!Q!H=!85A:9=8:;5A!=:9;=H>!?L=[!0J>U!H>C!CGS>:C!A59E=G6]!H>!PHG6!C7C:5H;MG>!>C:!CGB49;>G9!

5G! 4I=H! =G! PHG6! 3;=C:5H;MG>! c! >A! 8=C! 3\=H:49=:;5A! 3>! H=! 9>H=6=:;5A]! H=! E=S>G9>! B=9:;>! 3G! PHG6!

=A:495I9=3>! >C:! 85AC:;:G4>! B=9! H=! 85EB5C=A:>! 3;=C:5H;MG>! ^?L3!�! ?LC_[!&@>8! H\=GIE>A:=:;5A! 3>C!

B9>CC;5AC! 3>! 9>EBH;CC=I>! 3G! @>A:9;8GH>! I=G8J>]! H>! B;8! 3>! ?L3! =GIE>A:>[! lA>! 3G94>! 3>! ?L=!

CGB49;>G9>! Q! 8>HH>! 3>! H\5A3>! &! E;:9=H>! CGIIF9>! GA>! 4H4@=:;5A! 3>! H=! B9>CC;5A! :4H43;=C:5H;MG>! 3G!

@>A:9;8GH>!I=G8J>!^&BBH>:5A!"jjdc!i;AA=;93]!KJ5EBC5A!>:!=H[!*YY"_[!

Mesures de la d�formation cardiaque!!

K5G:! =G! H5AI! 3G! 878H>! 8=93;=MG>]! H>! E758=93>! CGT;:! 3>C! 34P59E=:;5AC! :9;3;E>AC;5AA>HH>C!

85EBH>6>C! MG;! B953G;C>A:! 3>C! P598>C! 3>! 8;C=;HH>E>A:[!/>!25BBH>9! :;CCGH=;9>! B>9E>:! H=!E>CG9>! 3>C!

@;:>CC>C! ;A:9=<E758=93;MG>C! =G! A;@>=G! 3>! 3;PP49>A:C! C>IE>A:C! 3G! 8oG9]! >A! C7C:5H>! >:! >A! 3;=C:5H>]!

3=AC!3;PP49>A:>C!3;9>8:;5AC!^9=3;=H>]!H5AI;:G3;A=H>]!8;985AP49>A:;>HH>_!^2>9GE>=G6]!$@;U>!>:!=H[!"jjXc!

N=:H>! =A3! #G:J>9H=A3! *YYYc! .9>>AT>9I]! O;9C:>AT>9I! >:! =H[! *YY*c! #>99;]! (>=A:! >:! =H[! *YYgc! ?>9w]!

KGA;8w!>:!=H[!*YYd_[!0>B>A3=A:]!8>C!@;:>CC>C!C5A:!H>!9>PH>:!3>C!@;:>CC>C!3>!34BH=8>E>A:!E758=93;MG>!

>A!9=BB59:!A5A!C>GH>E>A:!=@>8! H=!85A:9=8:;5A!5G! H=! 9>H=6=:;5A]!E=;C!=GCC;!=@>8! H>!34BH=8>E>A:!3G!

8oG9! Q! H\;A:49;>G9! 3G! :J59=6[! />C! I9=3;>A:C! 3>! @4H58;:4! 9=BB59:4C! Q! H=! 3;C:=A8>! >A:9>! 3>G6! B5;A:C!

;A:9=E758=93;MG>C!^strain rate_!B>9E>::>A:!3>!P=;9>!=TC:9=8:;5A!3>!8>!C>85A3!B=9=EF:9>]!>A!E>CG9=A:!

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H=!3;PP49>A8>!3>!@;:>CC>!>A:9>!8>C!3>G6!B5;A:C!9=BB59:4>!Q!H=!3;C:=A8>!C4B=9=A:!8>C!3>G6!B5;A:C!^/Y_[!

/\;A:4I9=H>!3>!8>::>!@=H>G9!B>9E>:!3>!E>CG9>9!H=!34P59E=:;5A!3G!E758=93>!=G!A;@>=G!3>C!3;PP49>A:C!

C>IE>A:C! ^strain_[! 2>! A5ET9>G6! :9=@=G6! 5A:! @=H;34! 8>C! =BB958J>C! :=A:! 8J>U! H\=A;E=H! MG>! 8J>U!

H\J5EE>[! V4=AE5;AC]! GA>! 3>C! H;E;:>C! 3>! H\4@=HG=:;5A! 3G! strain rate! >:! 3G! strain! B=9! H>! 25BBH>9!

:;CCGH=;9>!>C:!H;4>!=G!P=;:!MG>!8>::>!E>CG9>!A>!B>G:!r:9>!P=;:>!MG>!3=AC!H\=6>!3>C!GH:9=C5AC[!

lA>! A5G@>HH>! :>8JA;MG>! B>9E>:! GA>! E>CG9>! 3G! strain! C=AC! H\=;3>! 3G! 25BBH>9]! >A! ;E=I>9;>!

T;3;E>AC;5AA>HH>!A5;9!>:!TH=A8! ^*2 strain_! ^#>99;]!(>=A:!>:! =H[!*YYgc!?>9w]!KGA;8w!>:! =H[!*YYd_!1! ;H!

C\=I;:! 3G! speckle-tracking! 35A:! H>! B9;A8;B>! 85AC;C:>! Q! CG;@9>! H>!E5G@>E>A:! 3\GA!B>:;:! 4H4E>A:! 3>!

E758=93>!3>!*Y!Q!,Y!B;6>HC]!;E=I>!B=9!;E=I>[!0>::>!:>8JA;MG>!948>A:>!=!P=;:!34SQ!H\5TS>:!3>!BHGC;>G9C!

4:G3>C!3>!@=H;3=:;5A!9>:95G@=A:!GA>!T5AA>!9>B953G8:;T;H;:4! ;A:9=<!>:! ;A:>9<5TC>9@=:>G9]!=;AC;!MG\GA>!

T5AA>!85994H=:;5A!=@>8!H>C!E4:J53>C!3>!C5A5E;895E4:9;>!>:!H>C!E4:J53>C!3>!tagging!>A!'(%!35A:!

>HH>C!C5A:!349;@4>C! ^&EGA3C>A]!N>HH><L=HH>!>:!=H[!*YYg_[!/>!B5G98>A:=I>!3>!C>IE>A:C!=A=H7C=TH>C!

=::>;A:!XYe!Q!BHGC!3>!jYe!>A!P5A8:;5A!3>C!B=:J5H5I;>C!4:G3;4>C[!/>!*2!strain!B>9E>:!3\=@5;9!=88FC!Q!

H=! 85A:9=8:;5A! 9=3;=H>]! H5AI;:G3;A=H>! >:! 4I=H>E>A:! Q! H=! :59C;5A! 3G! @>A:9;8GH>! I=G8J>! ^E5G@>E>A:!

=A:;J59=;9>! 3>! H\=B>6! B=9! 9=BB59:! Q! H=! T=C>! 3G! 8oG9_! C=AC! H=! H;E;:>! 3G! 25BBH>9! 3=AC! H\=6>! 3>C!

GH:9=C5AC[!

x!85:4!3>!H\=A=H7C>!MG=A:;:=:;@>!3>!H=!P5A8:;5A!8=93;=MG>]!H\=A=H7C>!:>EB59>HH>!3>C!4@FA>E>A:C!

>C:! 3>@>AG>! >6:9rE>E>A:! ;EB59:=A:>! 8=9! H\5A! C=;:! =GS5G93\JG;! MG>! H\=TC>A8>! 3>! C7A8J95A;C=:;5A!

3=AC! H=! 85A:9=8:;5A! 5G! H=! 9>H=6=:;5A! >A:9>! H>C! 3;PP49>A:>C! 94I;5AC! 3G! 8oG9! 5TF9>! H>! T5A!

P5A8:;5AA>E>A:!3>!H=!B5EB>!8=93;=MG>!>:!B>G:!=II9=@>9!GA>!;ACGPP;C=A8>!8=93;=MG>[!/>C!:>8JA;MG>C!

B94843>A:>C!B>9E>::>A:!GA>!=A=H7C>!P;A>!3>!H=!85A:9=8:;5A!>:!C5A:!35A8!B=9:;8GH;F9>E>A:!Q!ErE>!3>!

34B;C:>9!8>C!BJ4A5EFA>C!3>!34C7A8J95A;C=:;5A[!

2- L'imagerie par r�sonance magn�tique

/\=E4H;59=:;5A! 3>C! :>8JA;MG>C! 3\=8MG;C;:;5A! >:! 3>! 9>85AC:9G8:;5A! 3>C! ;E=I>C! =CC58;4>! Q! H=!

B5CC;T;H;:4!3>!C7A8J95A;C>9!H>C!;E=I>C!Q!H\4H>8:958=93;5I9=EE>!=!B>9E;C!3\4:>A39>!H\G:;H;C=:;5A!3>!H=!

94C5A=A8>! E=IA4:;MG>! =G! 8oG9[! 0>::>! :>8JA;MG>! =! H\=@=A:=I>! 3\5PP9;9! GA>! 34P;A;:;5A! B948;C>! 3>C!

85A:5G9C!E758=93;MG>C!MG;!B>G@>A:!r:9>!E>CG94C!3=AC!H>C!:95;C!3;E>AC;5AC!3>!H\>CB=8>[!/=!E>CG9>!

3>C!@5HGE>C!=:9;=H!>:!@>A:9;8GH=;9>!B>G:!=;AC;!C\>PP>8:G>9!C=AC!H=!A48>CC;:4!3>!P59EGH>9!GA>!J7B5:JFC>!

I45E4:9;MG>[! /=! ErE>! B948;C;5A! >C:! B5CC;TH>! B5G9! H=! 34P;A;:;5A! 3>C! PHG6! C=AIG;AC! Q! :9=@>9C! H>C!

@=H@>C!E;:9=H>!>:!:9;8GCB;3>[!?=9!9=BB59:!=G6!B=9=EF:9>C!48J5I9=BJ;MG>C]!5A!B=9H>9=!3>!@5HGE>!B=9!

C>85A3>! ^EHDC>8_! BHG:k:! MG>! 3>! @;:>CC>C! ^8EDC>8_[! />C! PHG6! 3>C! @>;A>C! BGHE5A=;9>C]! >A! I4A49=H!

3;PP;8;H>E>A:!4@=HG=TH>C!B=9!48J5I9=BJ;>]!C5A:!B=9:;8GH;F9>E>A:!=88>CC;TH>C[!

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B948;C;5A!3>!34P;A;:;5A!3>C!85A:5G9C!E758=93;MG>C!B=9!'(%[!/=!:>8JA;MG>!3G!tagging!E758=93;MG>!

B>9E>:! GA>! =A=H7C>! MG=A:;:=:;@>! 3>! H=! 34P59E=:;5A! E758=93;MG>! ^strain_! 3=AC! :5GC! H>C! BH=AC! 3>!

H\>CB=8>! 3G9=A:! H>! 878H>! 8=93;=MG>! ^)AA;C]! )BC:>;A! >:! =H[! *YY+_[! )HH>! 9>B5C>! CG9! H>! E=9MG=I>! 3G!

E758=93>!B=9!3>C!;EBGHC;5AC!3>!9=3;5P94MG>A8>!C4B=94>C!B=9!3>C!I9=3;>A:C!E=IA4:;MG>C[!/>C!H;IA>C!

MG;! =BB=9=;CC>A:! CG9! H>C! 85GB>C! E758=93;MG>C! 3=AC! H>C! 3;PP49>A:C! BH=AC! 3>! H\>CB=8>! H59C! 3>!

H\=8MG;C;:;5A!>A!94C5A=A8>!E=IA4:;MG>!C>!34P59E>A:!=G!85G9C!3>! H=!85A:9=8:;5A!>:!3>! H=! 9>H=6=:;5A!

8=93;=MG>[!/\=A=H7C>!MG=A:;:=:;@>!3>!8>C!34P59E=:;5AC!B>9E>:!3>!34:>9E;A>9!3;PP49>A:C! ;A3;8>C!3>C!

P5A8:;5AC! C7C:5H;MG>! >:! 3;=C:5H;MG>!E758=93;MG>! G:;H>C! B5G9! MG=A:;P;>9! H=! 85A:9=8:;H;:4! C>IE>A:=;9>!

^&U>@>35]! &E=35! >:! =H[! *YY,_[! />C! strains! 3>! 8;C=;HH>E>A:]! 7! 85EB9;C! H=! :59C;5A]! B>G@>A:! r:9>!

E>CG94C! 3>! 8>::>! P=q5A[!/=! :59C;5A! >C:! GA! 4H4E>A:!E48=A;MG>! ;EB59:=A:! 3>! H=! I45E4:9;>! 5@=H;C4>!

^/59>AU]!?=C:59>w!>:! =H[! *YYY_!3G!@>A:9;8GH>!I=G8J>!>:!B>9E>:!GA>! P9=8:;5A!3\4S>8:;5A!4H>@4>! ^g-<

dYe_!B=9!GA!9=885G98;CC>E>A:!H;E;:4!3>C!P;T9>C!EGC8GH=;9>C!^"-e_[!/=!:59C;5A!5G!a!untwisting!b!>C:!

GA>! 8=9=8:49;C:;MG>! 8H>P! 3>! H=! B>9P59E=A8>! 3;=C:5H;MG>! ^(=3>E=w>9C]! WG8J=H:>9! >:! =H[! "jj*c!

WG8J=H:>9]! (=3>E=w>9C! >:! =H[! "jj,_! >:! C>! B953G;:! >A! T5AA>! B=9:;>! =@=A:! H>! 9>EBH;CC=I>! ^(5C>A]!

.>9T>9!>:!=H[!*YY,_[!&;AC;!8>!BJ4A5EFA>!>C:!>CC>A:;>H!B5G9! H=! CG88;5A! ^V=I>H]!#:GT>9!>:!=H[!*YYYc!

OG8JC]!%�HH>9!>:!=H[!*YY,_!

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CHAPITRE III : L'INSUFFISANCE

CARDIAQUE A FRACTION D'EJECTION

PRESERVEE

!

!

,*!

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/>C! E=A;P>C:=:;5AC! 8H=CC;MG>C! 3>! HR;ACGPP;C=A8>! 8=93;=MG>! C5A:! H=! 85AI>C:;5A! BGHE5A=;9>!

85AC4MG>A8>! 3>C! B9>CC;5AC! @>;A>GC>C! 4H>@4>C! MG;! 9>PHF:>A:! GA>! ;ACGPP;C=A8>! 3;=C:5H;MG>[! /=!

3;C:;A8:;5A! >A:9>! H>C! ;ACGPP;C=A8>C! C7C:5H;MG>! >:! 3;=C:5H;MG>! A>! B>G:! B=C! C>! T=C>9! C>GH>E>A:! CG9!

HRJ;C:5;9>! 8H;A;MG>]! HR>6=E>A! BJ7C;MG>]! H\4H>8:958=93;5I9=EE>! 5G! H=! 9=3;5I9=BJ;>! BGHE5A=;9>[! )A!

>PP>:]! H>C!ErE>C!=A5E=H;>C!C>! 9>:95G@>A:!=G!85G9C!3>! H\'0<O)B!>:!3>! H\'0<O)9!^�;H>!=A3!W9G:C=>9:!

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A. Signes dÕinsuffisance cardiaque

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SYSTOLIC HF DIASTOLIC

(EF <50%) HF (EF ≥50%)

SymptomsOrthopnea 73 60Paroxysmal nocturnal dyspnea 50 55Dyspnea on exertion 96 85

Physical examinationJugular venous distention 46 35Edema 40 30Hepatomegaly 16 15Displaced apical impulse 60 50

S3 65 45 S4 65 45Rales 70 72

Chest radiographyPulmonary venous hypertension 80 75Cardiomegaly 96 90

Tableau 2. Pr�valence des sympt�mes et des signes dÕinsuffisance cardiaque

dans lÕIC-FEr (systolic HF) et dans lÕIC-FEp (diastolic HF).

!

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B. Une fraction dÕ�jection pr�serv�e

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C. La dysfonction diastolique du ventricule gauche

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1- Approche de lÕAmerican Heart Association

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2- Approche de lÕEuropean Society of Cardiology

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A. G�n�ralit�s

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Figure 11. Pr�valence de lÕinsuffisance cardiaque en fonction de lÕorigine g�ographique. Les parties noires des

histogrammes indiquent la pr�valence de lÕinsuffisance cardiaque, les parties blanches indiquent la proportion de cas

avec une fraction dÕ�jection conserv�e. (dÕapr�s Hogg, 2004)

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H>C!B=:;>A:C!=7=A:!GA!vI>!CGB49;>G9!Q!g-!=AC[!2=AC!H\4:G3>!3\$f=A!>:!=H[!^$f=A]!N53I>!>:!=H[!*YYg_]!

H=!P9=8:;5A!3\4S>8:;5A!4:=;:!A59E=H>!8J>U!,Ye!3>C!B=:;>A:C!vI4C!3>!E5;AC!3>!-Y!=AC!>:!8J>U!,je!3>!

8>G6!MG;!=@=;>A:!GA!vI>!CGB49;>G9!Q!g-!=AC!3=AC!GA>!B5BGH=:;5A!3>!gYdg!B=:;>A:C!=3E;C!Q!H\JkB;:=H!

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C. Impact de sexe

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3>! V>f! m59w]! >A@;95A! :95;C<MG=9:C! 3>C! B=:;>A:C! J5CB;:=H;C4C! B5G9! GA>! '0<O)B! C5A:! 3>C! P>EE>C!

B94C>A:=A:! GA>!E=CC>! @>A:9;8GH=;9>! =GIE>A:4>! >:! GA>! J;C:5;9>! 3\J7B>9:>AC;5A! =9:49;>HH>! îH=BJ5HU]!

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85J59:>!O9=E;AIJ=E!^L=C=A]!/=9C5A!>:!=H[!"jjj_!>:! H\4:G3>!3>! H=!B5BGH=:;5A!3G!85E:4!3\$HEC:>3!

^#>AA;]!K9;T5G;HH57!>:!=H[!"jjXc!$f=A]!N53I>!>:!=H[!*YYg_[!)A!)G95B>]!H>C!B=:;>A:C!=@>8!GA>!'0<O)B!

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D. Impact des comorbidit�s

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P59EGH>9! 3>C! J7B5:JFC>C! BJ7C;5B=:J5H5I;MG>C! C5H;3>C! ^^&:J>9]! 0J=A! >:! =H[! *Y"*_]! ^%5J=EE>3]!

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1- LÕhypertension art�rielle

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J7B>9:>AC;5A<'0<O)B[! 0>B>A3=A:]! ;H! C>ETH>9=;:! MG>! H=! B94@=H>A8>! 3>! HRJ7B>9:>AC;5A! C5;:! H=!ErE>!

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2- Les pathologies coronaires et valvulaires

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H>C! J5EE>C[! /R=A=H7C>!EGH:;@=9;4>! >PP>8:G4>! CG9! H>C! 35AA4>C! ;CCG>C! 3>!Medicare! =! 85AP;9E4! 8>C!

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3- Le diab�te et lÕob�sit�

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B=:;>A:C! =@>8! GA>! '0<O)B[! 2=AC! H>! 9>I;C:9>! A>f<759w=;C]! H=! B94@=H>A8>! 3>! 8J=8GA>! 3>C! 3>G6!

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9>H=:;5A!>A!�l\!1!H=!E59:=H;:4!=GIE>A:>!B5G9!GA!'%0!�*+!5G!�+*[!

4- La fibrillation atriale

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;ACGPP;C=A8>!8=93;=MG>!C7EB:5E=:;MG>]!;A34B>A3=EE>A:!3>!H=!P9=8:;5A!3R4S>8:;5A!3>!34B=9:[!

5- La Broncho-Pneumopathie Chronico-Obstructive (BPCO)

/=!B94@=H>A8>!3>!H=!W?0$!8J>U!H>C!B=:;>A:C!=@>8!;ACGPP;C=A8>!8=93;=MG>!>C:!=G:5G9!3>!*Y<,Ye!

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8=93;=MG>[!/=!W?0$!>C:!Q! H=! P5;C!GA! ;3>A:;P;8=:>G9!3>!'0<O)B!^W;CJG]!N=E3=A;!>:!=H[!*Y""_!>:!GA!

P=8:>G9! P=@59;C=A:! H=!E59:=H;:4! ^&:J>9]! 0J=A! >:! =H[! *Y"*_[!2=AC! GA>! 4:G3>! 948>A:>!E>A4>! CG9! "X,!

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6- LÕan�mie

2=AC!H=!85J59:>!3>!H\>:G3>!#)V'$(#!^@5A!N=>JH;AI]!@=A!L>H3JG;C>A!>:!=H[!*Y""_!>:!3=AC!8>HH>!

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85EBH;=A8>!:4H4<3;=C:5H;MG>C!BHGC!;EB59:=A:C!>:!GA!B95A5C:;8!BHGC!C5ET9>!^%5J=EE>3]!W59H=GI!>:!

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7- Les maladies renales chroniques

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8- Commentaires

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CHAPITRE IV : DYSFONCTION

DIASTOLIQUE ET INSUFFISANCE

CARDIAQUE A FRACTION D'EJECTION

PRESERVEE : MECANISMES

PHYSIOPATHOLOGIQUES ET

TRAITEMENTS

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A. Alt�rations structurelles : la rigidit� ventriculaire gauche

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H=!85EB5C;:;5A!3>!H=!E=:9;8>!>6:9=8>HHGH=;9>!>:!B=9!8>9:=;A>C!8=9=8:49;C:;MG>C!3>C!8=93;5E7587:>C[!

1- Composition de la matrice extracellulaire

/=! E=:9;8>! >6:9=8>HHGH=;9>! =! :95;C! B9;A8;B=H>C! 85EB5C=A:>C! 1! ^"_! H>C! B95:4;A>C! P;T9;HH=;9>C!

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2- Modification du sarcom�re

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B. Alt�rations fonctionnelles: la relaxation ventriculaire

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1- Alt�rations de l'hom�ostasie calcique

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2- Augmetation de la rigidit� du sarcom�re

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3- Alt�ration par la charge

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C. Anomalie du couplage ventriculo-art�riel

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Figure 12. Droites dÕ�lastance t�l�-

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Figure 13. Couplage des rigidit�s

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D. Influence de la non-uniformit� du myocarde

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E. Dysfonction systolique

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O)9! ^05HG88;]! (;T>;95! >:! =H[! "jXj_]! 8>8;! >C:! B95T=TH>E>A:! H;4! Q! GA! 34P;8;:! 3>! H=! C;IA=H;C=:;5A! #<

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G. Tachycardie

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H. Une ou des insuffisances cardiaques ?

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!

100

P

t50

A

B

Pump perform

ance

Adaptive Maladaptive

Adverse remodelingHypertrophyI II III

Time (yrs)

Pump perform

ance

Time (yrs)

systolic activation systolic dysfunctionsystolic dysfunction

%

%

100

Diastolic

heart failure

NYHA-class

NYHA-class

NYHA-class I

I II III

II III

IV

IV

IV

I II III

patient C

patient B

patient A

EF

>55–60%

EF

>50%EF <40–45%

Global pump failure

Systolic dysfunction of muscular pump

Failure of hemodynamic pump

EF < 35%

Failure of CV system

Figure 14. Paradigme temporel de la progression de lÕinsuffisance cardiaque chronique. Continuum

physiopathologique (A) et clinique (B) de lÕhistoire naturelle de lÕinsuffisance cardiaque.

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1. Inhibition du syst�me r�nine-angiotensine-aldost�rone

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2. Les !-bloquants

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3. Les inhibiteurs calciques

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4. Diur�tiques, antagonistes de l'aldost�rone

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5. Contr�le m�tabolique

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B=:;>A:C!=@>8!'0<O)9[!/\>CC=;!y<2NO!^m=E=E5:5]!$9;I=C=!>:!=H[!*Y"*_!@;>A:!3>!E5A:9>9!3>C!94CGH:=:C!

A4I=:;PC!3=AC!GA>!B5BGH=:;5A!S=B5A=;C>!:9=;:4>!B=9!GA>!35C>!P=;TH>!^>A@;95A!d[-!EIDwI_!3>!8=9@43;H5H!

E=;C! H=;CC>! >A:9><=B>98>@5;9! MG\Q! GA>! BHGC! P59:>! 35C>! ^*Y! EIDwI_! H>C! >PP>:C! B5G99=;>A:! r:9>!

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lA! =G:9>! #<TH5MG=A:! =! 4I=H>E>A:! P=;:! H\5TS>:! 3\;A@>C:;I=:;5AC]! H>! A4T;@5H5H! MG;! B94C>A:>! H=!

B=9:;8GH=9;:4!3>!P=@59;C>9!H=!H;T49=:;5A!3>!V$!^05A9==3C]!%>:9=!>:!=H[!*Y"*_[!/\4:G3>!#)V'$(#!=!4:4!

94=H;C4>!>A!)G95B>!>:!=!;A8HGC!*"+-!B=:;>A:C!vI4C!3>!BHGC!3>!dY!=AC]!J5CB;:=H;C4C!B5G9!;ACGPP;C=A8>!

8=93;=MG>! ;A34B>A3=EE>A:! 3>! H>G9! P9=8:;5A!3\4S>8:;5A! ^OH=:J>9]! #J;T=:=! >:! =H[! *YY-_[!/>C!B=:;>A:C!

5A:! 4:4! 9=A35E;C4C! B5G9! 9>8>@5;9! >A! 35GTH>! =@>GIH>! H>! A4T;@5H5H! ^35C>! 8;TH>! "Y!EIDS5G9_! 5G! GA!

BH=8>T5[! &G! :>9E>! 3>! :95;C! =AC! 3>! CG;@;]! H>! 89;:F9>! B9;E=;9>! ^E59:=H;:4! :5G:>! 8=GC>! 85AP5A3G>! >:!

=3E;CC;5A!B5G9!4@FA>E>A:C!8=93;5<@=C8GH=;9>C_!=!4:4!943G;:!3>!",e!=@>8!GA!T4A4P;8>!3FC!H>!C;6;FE>!

E5;C[! K5G:>P5;C]! H>! T4A4P;8>! 3G! A4T;@5H5H! A\=! B=C! 4:4! 9>:95G@4! 8J>U! H>C! B=:;>A:C! MG;! =@=;>A:! GA>!

P9=8:;5A! 3\4S>8:;5A! C7C:5H;MG>! CGB49;>G9>! Q! ,Ye[! 2=AC! H\4:G3>! )/&V22! 948>EE>A:! BGTH;4>!

^05A9==3C]! %>:9=! >:! =H[! *Y"*_]! H>! A4T;@5H5H! A\=! B=C! =E4H;594! H=! 8=B=8;:4! 3\>6>98;8>! 5G! H>C!

C7EB:kE>C]!85EB=94!=G!BH=8>T5[!

2>! E=A;F9>! BHGC! I4A49=H>]! H>! 9>I;C:9>! $?K'%'�)<NO! =! >A9kH4! ,"-+! B=:;>A:C! =@>8! NOB)O!

S=E=;C! :9=;:4C! B=9! #<TH5MG=A:C! H59C! 3>! H>G9! B9>E;F9>! J5CB;:=H;C=:;5A! B5G9! 37CP5A8:;5A! 8=93;=MG>!

^N>9A=A3>U]! N=EE;HH! >:! =H[! *YYj_[! &! H=! C59:;>]! +je! 3>! 8>C! B=:;>A:C! 9>8>@=;>A:! GA! :9=;:>E>A:!#<

TH5MG=A:!1!8>!:9=;:>E>A:!A\=!B=C!E53;P;4!3>!P=q5A!C;IA;P;8=:;@>!H=!E59:=H;:4]!H=!94<J5CB;:=H;C=:;5A!5G!

3\=G:9>C! B=9=EF:9>C! 85ET;A4C! 3>! SGI>E>A:[! lA! =G:9>! >CC=;! 8H;A;MG>! 3>! I9=A3>! =EBH>G9! ^"*YY!

B=:;>A:C_!>C:!>A!85G9C!^H\>CC=;!#<?()#)(L)!^�J5G]!#J;!>:!=H[!*Y"Y__[!

3- Les antagonistes calciques

#>GH>C! 3>C! 4:G3>C!E>A4>C! Q! GA>! B>:;:>! 48J>HH>! 5A:! :>C:4! H>C! >PP>:C! 3\=A:=I5A;C:>C! 8=H8;MG>C!

85EE>!H>!@49=B=E;H[!2=AC!GA!>CC=;!;A8HG=A:!*Y!B=:;>A:C!B5G9!GA>!3G94>!3>!-!C>E=;A>C!^#>:=95]!�=9>:!

>:!=H[!"jjY_]!H>!@49=B=E;H!=!=GIE>A:4!H=!8=B=8;:4!Q!H\>6>98;8>!3>!++e!>:!H>!9>EBH;CC=I>!3;=C:5H;MG>!

3>! +Ye[! 2=AC! GA! =G:9>! >CC=;! E>A4! CG9! "-! B=:;>A:C! vI4C! >A! 8H=CC>! ''<'''! 3>! H=!New Y ork Heart

Association!>:!B94C>A:=A:!GA>!P9=8:;5A!3\4S>8:;5A!A59E=H>]!^NGAI]!0J>9AI!>:!=H[!*YY*_]!=B9FC!+!E5;C!

3>! :9=;:>E>A:]! H>! @49=B=E;H! =! C;IA;P;8=:;@>E>A:! =E4H;594! H>! C859>! 3>! H\;ACGPP;C=A8>! 8=93;=MG>]! H=!

3G94>!3\>6>98;8>!>:!H>C!B=9=EF:9>C!3>!H=!P5A8:;5A!3;=C:5H;MG>[!/=!A;P43;B;A>]!GA!TH5MG>G9!3>C!8=A=G6!

8=H8;MG>C!3>!:7B>!/!>C:!=8:G>HH>E>A:!>A!85G9C!3\>CC=;!^V0KY""-d,X"_[!

4- Les digitaliques

/>C!3;I;:=H;MG>C!B5G99=;>A:!:J459;MG>E>A:!B94C>A:>9!GA!T4A4P;8>!>A!9=;C5A!3>!H=!943G8:;5A!3>!

H=! P94MG>A8>! 8=93;=MG>! >:! 3\GA>! =8:;@=:;5A! 3>C! P5A8:;5AC! 3>C! T=958>B:>G9C[! /\>CC=;! 8H;A;MG>! 2'.!

^&JE>3]!(;8J! >:! =H[! *YYg_! =! 9=A35E;C4! jXX! B=:;>A:C! =@>8! '0<O)B! 9>8>@=A:! 3>! H=! 3;I56;A>! 5G! GA!

BH=8>T5[! &G8GA! T4A4P;8>! A\=! 4:4! 85AC:=:4! >A! :>9E>C! 3\J5CB;:=H;C=:;5A! 5G! 3>! E59:=H;:4! H;4>C! Q!

H\;ACGPP;C=A8>!8=93;=MG>!>HH><ErE>[!

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5- Les diur�tiques

/>C! 3;G94:;MG>C! C5A:! ;A3;CB>AC=TH>C! B5G9! H>! 85A:9kH>! 3>C! C7EB:kE>C! 85AI>C:;PC! 8J>U! H>C!

B=:;>A:C! =@>8! '0<O)B! :5G:! 85EE>! B5G9! H\'0<O)9[! ?=9! H=! 943G8:;5A! 3>! H=! 85AI>C:;5A! 8>A:9=H>]! H>!

@>A:9;8GH>!B>G:!5B49>9!3=AC!GA>!U5A>!BHGC!85EBH;=A:>!3>!H=!85G9T>!B9>CC;5A<@5HGE>[!/>C!3;G94:;MG>C!

C5A:!E5;AC!G:;H>C!8J>U!H>C!B=:;>A:C!C=AC!4@;3>A8>!8H;A;MG>!3>!CG98J=9I>]!>:!>A!9=;C5A!3>!H=!B948J=9I><

34B>A3=A8>!BHGC!;EB59:=A:>!=G!85G9C!3>!H\NOB)O]!H>G9!G:;H;C=:;5A!B5G99=;:!r:9>!3=AI>9>GC>!^W59H=GI!

=A3!i=CC!*YYX_[!2=AC!H\4:G3>!&//N&K!^2=@;C]!i5C:;C!>:!=H[!*YYX_]!H=!8JH59:=H;35A>]!GA!3;G94:;MG>!

:J;=U;3;MG>]! 943G;C=;:! H\;A8;3>A8>! 3>! H\'0<O)B]!2>!ErE>]! GA>! =G:9>! 4:G3>! =! 85A8HG! Q! GA! T4A4P;8>!

3=AC! H\=E4H;59=:;5A! 3>C! C7EB:kE>C! B=9! H>C! 3;G94:;MG>C! =G! 85G9C! 3>! H\'0<O)B! ^m;B]!p=AI! >:! =H[!

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6- Les d�riv�s nitr�s

L;=!GA!E48=A;CE>!.%?8<34B>A3=A:!>:!?i.<34B>A3=A:]!H>C!349;@4C!A;:94C!B>G@>A:!943G;9>!H=!

B948J=9I>]!B>9E>::=A:! =;AC;! =G!@>A:9;8GH>!3>! :9=@=;HH>9! Q!3>C!A;@>=G6!3>! 8J=9I>!BHGC!T=C! ^W59H=GI!

=A3!i=CC!*YYg_[!%=HI94!H=!EGH:;:G3>!3\>PP>:C!B5:>A:;>HH>E>A:!T4A4P;MG>C!^KC=;!=A3!i=CC!*YYj_]!H>C!

35AA4>C!8H;A;MG>C!C5A:! 9=9>C!1! H>G9!G:;H;C=:;5A!CG9!3>C!85G9:>C!5G! H5AIG>C!3G94>C!B5G99=;:!r:9>!G:;H>!

3=AC!H>!:9=;:>E>A:!3>!H=!37CBA4>!8J>U!H>C!B=:;>A:C!=@>8!'0<O)B]!CG9:5G:!8>G6!MG;!C5A:!>G@5H4E;MG>C!

>:!8J>U!H>CMG>HC!H>C!3;G94:;MG>C!A>!C5A:!B=C!;A3;MG4C[!/=!85ET;A=;C5A!3>!3;A;:9=:>!3\;C5C59T;3>!>:!3>!

H\J739=H=U;A>!B5G99=;:!=@5;9!GA!>PP>:! P=@59=TH>!=G!85G9C!3>! H\'0<O)B!c!>HH>!>C:! :>C:4>!3=AC!GA!>CC=;!

8H;A;MG>!=8:G>HH>E>A:!>A!85G9C!^VK0Y"-"g+,g_[!

)AP;A]! =G! 85G9C! 3>! H\;ACGPP;C=A8>! 8=93;=MG>]! H>! C:9>CC! 5673=A:! P=@59;C>! H>! 3485GBH=I>! 3>! H=!

V$#[!2>!8>!P=;:]!;H!B5G99=;:!>6=8>9T>9!H=!37CP5A8:;5A!3;=C:5H;MG>[!/=!:>:9=J7395T;5B:49;A>!^WN,_]!GA!

85P=8:>G9! >CC>A:;>H! 3>! H=! V$#! >A35:J4H;=H>]! >C:! 8=B=TH>! 3\=::4AG>9! H>! 9>E53>H=I>! >:! =E4H;59>9! H>!

85GBH=I>!3>!H=!V$#!3=AC!GA!E53FH>!=A;E=H!3>!CG98J=9I>!@5HGE;MG>!^%5>AC]!K=w;E5:5!>:!=H[!*YYX_[!

'H!A\7!=!B=C!3>!35AA4>C!8H;A;MG>C!3;CB5A;TH>C!Q!8>!S5G9[!

C. Les nouvelles approches pharmacologiques

1- Les inhibiteurs des 5-phosphodiest�rases

lA>! =G:9>! @5;>! =H:>9A=:;@>! >C:! 9>B94C>A:4>! B=9! H\G:;H;C=:;5A! 3\;AJ;T;:>G9C! 3>! H=!

BJ5CBJ53;>C:49=C><-[! 'HC!B>G@>A:!=::4AG>9! H=!C:;EGH=:;5A!=394A>9I;MG>!^W59H=GI]!%>H>A5@Cw7!>:!=H[!

*YY-_]! 943G;9>! H=! 9;I;3;:4! @>A:9;8GH5<@=C8GH=;9>! ^LH=8J5B5GH5C]!N;9=:=! >:! =H[! *YY+_]! H>! 9>E53>H=I>!

@>A:9;8GH=;9>!^K=w;E5:5]!0J=EB;5A!>:!=H[!*YY-_]!=E4H;59>9!H=!P5A8:;5A!>A35:J4H;=H>!^i=:U]!W=H;3>E=S!

>:! =H[! *YYY_! >:! 943G;9>! H>C! 94C;C:=A8>C! 3G! C7C:FE>!@=C8GH=;9>! BGHE5A=;9>! ^/>f;C]!/=8JE=AA! >:! =H[!

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B=:;>A:C! =@>8! '0<O)B! >:! GA>! J7B>9:>AC;5A! =9:49;>HH>! ^.G=UU;]! L;8>AU;! >:! =H[! *Y""_! 5G! GA! 3;=TF:>!

^.;=AA>::=]! 'C;359;! >:! =H[! *Y"*_]! 8>::>! E5H48GH>! =E4H;59=;:! H=! P5A8:;5A! @>A:9;8GH=;9>! I=G8J>[! />C!

>CC=;C!3>!BHGC!I9=A3>! :=;HH>!5A:! 9>P95;3;! H>C!=::>A:>C!1!8J>U! H>C!B=:;>A:C!=@>8!GA! ;AP=98:GC! 948>A:!3G!

E758=93>!^4:G3>!#'2&%'!^&A3>9C>A]!)9CT5HH!>:!=H[!*Y"+__!5G!GA>!'0<O)B!^>CC=;!()/&u!^(>3P;>H3]!

W59H=GI!>:!=H[!*Y"*__]!5A!A>!9>:95G@>!B=C]!9>CB>8:;@>E>A:]!3>!943G8:;5A!3>C!B9>CC;5AC!3>!9>EBH;CC=I>!

>:! 3>! 37A=E;MG>! 3G! @>A:9;8GH>! 395;:]! 5G! GA! >PP>:! B5C;:;P! CG9! H=! 8=B=8;:4! Q! H\>6>98;8>! =;AC;! MG>! H=!

P5A8:;5A!>:!H=!E59BJ5H5I;>!3G!@>A:9;8GH>!I=G8J>[!'H!=!4:4!=9IGE>A:4!MG>!H=!B5BGH=:;5A!9>89G:4>!3=AC!

8>C! >CC=;C! =@=;:! 3>C! 85E59T;3;:4C! BHGC! B95A5A84>C! ^85EE>! 3;=TF:>! >:! ;ACGPP;C=A8>! 94A=H>!

8J95A;MG>_!c! =;AC;]! HRG34A=P;H]! ;AJ;T;:>G9! Q! 34E;<@;>! BHGC! H5AIG>]! >C:! =8:G>HH>E>A:! :>C:4! CG9! 3>C!

B=:;>A:C!=@>8!B>G!3>!85E59T;3;:4C!^V0KY"-jj""d_[!

2- Modulation s�lective de la fr�quence cardiaque

'H!P=G:!4I=H>E>A:!C5GH;IA>9!H=!B5CC;T;H;:4!3\GA>!E53GH=:;5A!C4H>8:;@>!3>!H=!P94MG>A8>!8=93;=MG>!

3=AC!H>!:9=;:>E>A:!3>!H\'0<O)B[!)A!9=;C5A!3>!H\;ACGPP;C=A8>!8J95A5:95B>]!^W9GT=w>9]!y55!>:!=H[!*YYgc!

?J=A]! &T5UIG;=! >:! =H[! *YYj_]! H\>CC=;! ()#)K! C>! B95B5C>! 3\>6=E;A>9! H>C! >PP>:C! 3>! H\>A:9=;A>E>A:!

4H>8:95C7C:5H;MG>!!CG9!H=!8=B=8;:4!3\>6>98;8>!8J>U!H>C!B=:;>A:C!=@>8!GA>!'0<O)B!^i=CC]!i;:UE=A!>:!=H[!

*Y"Y_[!&!H\;A@>9C>]!8>9:=;AC!B9485A;C>A:!GA>!943G8:;5A!3>!H=!P94MG>A8>!8=93;=MG>[!&;AC;!H\G:;H;C=:;5A!

3\GA! ;AJ;T;:>G9! 3>C! 8=A=G6! 'f! 85EE>! H\;@=T9=3;A>]! B>9E>::9=;:! 3>! 943G;9>! H=! P94MG>A8>! 8=93;=MG>[!

2>C!4:G3>C!B948H;AMG>C!>:! 8H;A;MG>C!5A:!8H=;9>E>A:!E;C!>A!4@;3>A8>! C>C!>PP>:C!=A:;<;C8J4E;MG>C!>:!

T4A4P;MG>C!CG9!H=!P5A8:;5A!@>A:9;8GH=;9>!I=G8J>!^%5AA>:]!/G8=:C!>:!=H[!*YYd_!^/G8=:C]!.J=H>J!>:!=H[!

*YYd_!E=;C!C5A!>PP;8=8;:4!=G!85G9C!3>!H=!37CP5A8:;5A!3;=C:5H;MG>!>:!H\'0<O)B!A\>C:!B=C!85AAG>[!

3- Modulation du Ç turn-over È de la matrice extracellulaire

/=!E=:9;8>!>6:9=8>HHGH=;9>!=!4I=H>E>A:!4:4!B95B5C4>!85EE>!8;TH>!BJ=9E=85H5I;MG>[!)A!>PP>:]!

H>C! E53;P;8=:;5AC! MG=A:;:=:;@>C! >:! MG=H;:=:;@>C! 3>! H=! E=:9;8>! >6:9=8>HHGH=;9>! 85A:9;TG>A:! =G6!

8J=AI>E>A:C!3>!85EBH;=A8>!@>A:9;8GH=;9>! ^�;H>! =A3!W9G:C=>9:!*YY*_[!?=9! =;HH>G9C]! H=!IH785C7H=:;5A!

>C:!GA!BJ4A5EFA>!MG;!C\;A:>AC;P;>!=@>8!H\vI>!>:!MG;!943G;:!H=!85EBH;=A8>!:;CCGH=;9>[!&;AC;!H>!8JH59G9>!

3\=H=I4T9;GE!^&/K<d""_!>C:!8=B=TH>!3>!95EB9>!H>C!B5A:C!3>!IHG85C>!>:!3\=E4H;59>9!H=!85EBH;=A8>!

=9:49;>HH>!>:!@>A:9;8GH=;9>!8J>U!H>C!=A;E=G6!^L=;:w>@;8;GC]!/=A>!>:!=H[!*YY"_]!=;AC;!MG>!3>!943G;9>!H=!

B9>CC;5A!=9:49;>HH>!>:!H=!9;I;3;:4!@=C8GH=;9>!^i=CC]!#J=B;95!>:!=H[!*YY"_[!/\&/K<d""!=!4:4!:>C:4!CG9!*+!

B=:;>A:C!=@>8!GA>!'0<O)B!>:!=!B>9E;C!3>!943G;9>!H=!E=CC>!@>A:9;8GH=;9>!>:!3\=E4H;59>9!H>C!B=9=EF:9>C!

3>! 9>EBH;CC=I>! 3;=C:5H;MG>! =;AC;! MG>! H=! MG=H;:4! 3>! @;>! ^/;::H>]!�;H>! >:! =H[! *YY-_[!K5GS5G9C! 3=AC! 8>!

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37CP5A8:;5A!3;=C:5H;MG>!îGf=J=9=]!i=;!>:!=H[!*YY*_[!

4- Modulation du m�tabolisme �nerg�tique

?G;CMG>!H>C!94B5AC>C!@>A:9;8GH=;9>C!C7C:5H;MG>!>:!3;=C:5H;MG>!Q!H\>PP59:!C5A:!=H:494>C!=G!85G9C!3>!

H\;ACGPP;C=A8>!8=93;=MG>]!;H!>C:!9=;C5AA=TH>!3\;E=I;A>9!MG\>HH>C!B5G99=;>A:!94CGH:>9!3\GA>!G:;H;C=:;5A!

5G! 3>! 3;CB5A;T;H;:4! =A59E=H>C! 3>C! CGTC:9=:C! 4A>9I4:;MG>C! ^#E;:J]! W5::5EH>7! >:! =H[! *YYgc! ?J=A]!

&T5UIG;=!>:!=H[!*YYj_[!lA!=BB59:!3>!/<8=9A;:;A>!3=AC!GA!E53FH>!=A;E=H!^9=:_!3\'0<O)B!=T5G:;:!Q!GA>!

3;E;AG:;5A! 3>! H=! P;T95C>! @;=! GA>! =GIE>A:=:;5A! 3>! H=! B953G8:;5A! 3>! B95C:=878H;A>! B=9! H=! @5;>! 3>!

H\=8;3>! =9=8J;35A;MG>! ^$E59;]! $J:=A;! >:! =H[! *Y"*_[! ?=9! =;HH>G9C]! ;H! =! 4:4! 9=BB59:4! GA>! 943G8:;5A!

E=9MG4>!3>!H\5673=:;5A!8=93;=MG>!3G!IHG85C>!>:!3G!H=8:=:>]!C=AC!E53;P;8=:;5A!3>!H=!IH785H7C>!5G!3>!

H\5673=:;5A! 3>C! =8;3>C! I9=C[! 0>::>! 34B9>CC;5A! C>9=;:! H;4>! Q! GA>! =GIE>A:=:;5A! 3\>6B9>CC;5A! 3>! H=!

B79G@=:><34CJ7395I4A=C><w;A=C><,[! 2=AC! 8>! 85A:>6:>]! H>C! =A:;3;=T4:;MG>C! 59=G6! 3>! H=! P=E;HH>! 3>C!

:J;=U5H;3;A43;5A>C! ^95C;IH;:=U5A>! >:! B;5IH;:=U5A>_! C5A:! 3>C! BG;CC=A:C! =I5A;C:>C! 3G! peroxisome

proliferator-activated receptor-gamma]!948>B:>G9!AG8H4=;9>!3>!H=!:9=AC89;B:;5A!3>C!IrA>C!94B5A3=A:!Q!

H\;ACGH;A>[!2=AC!H\>CC=;!?'(&%'2]!3>C!3;=T4:;MG>C!C=AC!=::>;A:>!8=93;=MG>!9>8>@=A:!H=!B;5IH;:=U5A>!Q!

H=!BH=8>!3>! H=!E>:P59E;A>!E5A:9=;>A:!GA>!E>;HH>G9>!G:;H;C=:;5A!3G!IHG85C>!=G!A;@>=G!E758=93;MG>!

^@=A!3>9!%>>9]!(;SU>f;Sw!>:!=H[!*YYj_[!'H!>6;C:>]!B=9!85A:9>]!GA>!85A:9><;A3;8=:;5A!Q!H\G:;H;C=:;5A!3>!

8>C!E5H48GH>C!8J>U!H>C!B=:;>A:C!>A!8H=CC>!VmN&!8H=CC>!'''!>:!'L[!/=!C:;EGH=:;5A!3>C!948>B:>G9C!B5G9!

H=!./?<"!^B95:4;A>!C>ETH=TH>!=G!IHG8=I5A_!=8:;@>!H\G:;H;C=:;5A!3G!IHG85C>!=G!A;@>=G!E758=93;MG>[!

/>C!=A=H5IG>C!3G!./?<"!^>64A=:;3>_!5G!H>C!;AJ;T;:>G9C!3>!C=!34I9=3=:;5A!^C;:=IH;B:;A>_!C5A:!>A!85G9C!

3\4@=HG=:;5A!8H;A;MG>!C5GC!H\4I;3>!3G!V'N[!

5- Modulation du calcium intracellulaire

KJ459;MG>E>A:]! >EBr8J>9! H>C! PG;:>C! 8=H8;MG>C! 3G! 94:;8GHGE! C=985BH=CE=:;MG>! >:! H\>A:94>! 3>!

8=H8;GE! @;=! H\48J=AI>G9! C53;MG>! 3=AC! H>! 87:5BH=CE>! B>A3=A:! H=! 3;=C:5H>! 3>@9=;:! =E>H;59>9! H=!

9>H=6=:;5A!3G!E758=93>[!/>!i*Y"]!GA!C:=T;H;C=:>G9!3G!(7(*]!=!E5A:94!GA!>PP>:!;A5:95B>!>:!HGC;:95B>!

B5C;:;P!CG9!H>C!8oG9C!;C5H4C!3>!H=B;A]!ErE>!3=AC!3>C!85A3;:;5AC!3>!CG98J=9I>!8=H8;MG>!î>HH7]!)HH;5::!

>:!=H[!*Y"*_[!2=AC!GA!E53FH>!EG9;A!J7B>9:>A3G!=@>8!'0<O)B]!H>!#)&Y,YY]!GA!;AJ;T;:>G9!3G!V0u!

=::>AG>!H=!P;T95C>!E758=93;MG>!;A3G;:>!B=9!H\5G=T=�A>!î=E;EG9=]!$J:=A;!>:!=H[!*Y"*_[!

6- Modulation du courant sodique lent

/=! 9=A5H=U;A>]! ;AJ;T;:9;8>!3G!85G9=A:!>A:9=A:! C53;MG>! H>A:]! =!4:4!B95B5C4>!85EE>! :9=;:>E>A:!

B5:>A:;>H! 3>! H\'0<O)B! 1! >HH>! B5G99=;:! 85A:9;TG>9! =;AC;! Q! 943G;9>! H=! 85A8>A:9=:;5A! ;A:9=8>HHGH=;9>! 3>!

0=*}! >:! B95T=TH>E>A:! =E4H;59>9! H=! 9>H=6=:;5A! >:D5G! H=! 9;I;3;:4!3;=C:5H;MG>! ^#5CC=HH=]!p=IA>9! >:! =H[!

!

!

dd!

*YYX_[! (48>EE>A:]! GA! >CC=;! 8H;A;MG>! =! 34TG:4! B5G9! >6BH59>9! 8J>U! H\J5EE>! 8>::>! 5B:;5A!

:J49=B>G:;MG>! ^y=85TCJ=I>A]! W>H=93;A>HH;! >:! =H[! *Y""_! 1! ;H! C>ETH>9=;:]! 3\=B9FC! H>C! 94CGH:=:C!

B94H;E;A=;9>C]! MG>!E=HI94!GA>! 943G8:;5A!3>C!B9>CC;5AC! =9:49;>HH>! BGHE5A=;9>! >:! :4H4<3;=C:5H;MG>!3G!

@>A:9;8GH>!I=G8J>]!H=!8;A4:;MG>!3>!H=!9>H=6=:;5A!9>C:>!;A8J=AI4>[!

7- modulation du syndrome inflammatoire

/R'/<++! >C:! GA>! 87:5w;A>! E>ET9>! 3>! H=! P=E;HH>! '/<"1! 8>C! C5A:! 3>C! E5H48GH>C! B95<

;APH=EE=:5;9>C! ;EBH;MG4>C! ! 3=AC! H>! 9>E53>H=I>! @>A:9;8GH=;9>! ^WGS=w! =A3! O9=AI5I;=AA;C! *YYj_[!

/R=A=w;A9=]!GA!=A:=I5A;C:>!3G!948>B:>G9!B5G9!HR'/<"]!G:;H;C4!3=AC!HR=9:J9;:>!9JGE=:5;3>]!>C:!>A!85G9C!

3R4@=HG=:;5A!^V0KY"-,*-Y*_[

8- Inhibition des rho-kinases

/>C!;AJ;T;:>G9C!3>C!9J5<w;A=C>C!85EE>!H>!PGC;3;H!>:!H>!m<*dg+*!5A:!E5A:94!H>G9!>PP;8=8;:4!3=AC!

H>! 9=H>A:;CC>E>A:!3>! H\J7B>9:95BJ;>!3>C! 8=93;5E7587:>C! >:! 3G! 9>E53>H=I>! 8=93;=MG>!3=AC! 8>9:=;AC!

E53FH>C!=A;E=G6!3\;ACGPP;C=A8>!8=93;=MG>!^/=;!=A3!O9;CJE=A!*YY-_[!!

9- Les statines

V\=7=A:! B=C! 34E5A:94! 3\>PP>:C! T4A4P;MG>C! =G! 85G9C! 3>! H\'0<O)9]! H>C! C:=:;A>C! A\5A:! B=C! 4:4!

:>C:4>C!=G!85G9C!3>!H\'0<O)B[!!

D. Commentaires

/>C! 4:G3>C! 8H;A;MG>C! 94=H;C4>C! SGCMG\Q! B94C>A:! A\5A:! B=C! 94GCC;! Q! P=;9>! 4E>9I>9! 3\5B:;5A!

:J49=B>G:;MG>! ;A3;C8G:=TH>!B5G9! H=! 943G8:;5A!3>C! :=G6!3\J5CB;:=H;C=:;5A!5G!3>! H=!E59:=H;:4!3>! H\'0<

O)B[!0>8;! B>G:! r:9>! H;4! Q! 3;PP49>A:>C! 9=;C5AC[! /=! MG=H;:4!E4:J535H5I;MG>! 3>C! 3;PP49>A:C! >CC=;C! >C:!

@=9;=TH>!>:!H=!MG>C:;5A!3G!A;@>=G!3>!P9=8:;5A!3\4S>8:;5A!3>C!B=:;>A:C!;A8HGC!3=AC!H>C!>CC=;C!C>!B5C>[!

lA>!9>@G>!=A=H7C=A:!*"!>CC=;C!8H;A;MG>C!CG9!H\'0<O)B!=!C5GH;IA4!H>!E=AMG>!3>!89;:F9>C!3;=IA5C:;MG>C!

85EEGAC!^?=GHGC!=A3!@=A!W=HH>I5;S!*Y"Y_]!34:>9E;A=A:!=;AC;!GA!>68FC!3\;A8HGC;5A!3>!B=:;>A:C!=@>8!

GA!9>E53>H=I>!>68>A:9;MG>!3G!@>A:9;8GH>!I=G8J>!>:!H=!B94C>A8>!3\GA>!B=:J5H5I;>!8595A=;9>!=CC58;4>[!

'H! >C:! 35A8! B95T=TH>! MG\GA>! B=9:;>! 3>C! B=:;>A:C! A\4:=;:! B=C! >A! @49;:=TH>! C;:G=:;5A! 3\;ACGPP;C=A8>!

8=93;=MG>!=G!E5E>A:!3>!H\;A8HGC;5A!3=AC!H>C!>CC=;C!>:!H=!B94C>A8>!3>!B=:J5H5I;>C!=CC58;4>C!B5G99=;:!

85AC:;:G>9! GA! P=8:>G9! 85AP5A3=A:! ^mGCGP]! ?P>PP>9! >:! =H[! *YY+_[! ?=9! =;HH>G9C]! ;H! >6;C:>! 3>! I9=A3>C!

@=9;=T;H;:4C!34E5I9=BJ;MG>C!3=AC!H>C!:9=;:>E>A:C!5G!H>C!3G94>C!3\J5CB;:=H;C=:;5A!H59CMG\5A!4:G3;>!H>C!

3;PP49>A8>C!I45I9=BJ;MG>C!3>C!B=:;>A:C!=::>;A:C!3\'0<O)B!^p>C:]!/;=AI!>:!=H[!*Y""_[!0>8;!C\5TC>9@>!

A5:=EE>A:! H59CMG\5A!85EB=9>! H>C!35AA4>C!3>C!9>I;C:9>C!&2N)()<l#!>:!&2N)()<'A:>9A=:;5A=H[!

&;AC;]! H>C!J=T;:G3>C! :J49=B>G:;MG>C]! H>C! :9=;:>E>A:C!=CC58;4C!=;AC;!MG>! H>C!3;PP;8GH:4C!3>!3;=IA5C:;8!

!

!

dX!

>6BH;MG>A:! B95T=TH>E>A:! GA>! B=9:;>! 3>C! 94CGH:=:C! 3;@>9I>A:C! 5G! B>G! 85A8HG=A:C! 3>C! >CC=;C!

:J49=B>G:;MG>C!94=H;C4C!SGCMG\Q!B94C>A:[!

! !

!

!

dj!

PARTIE EXPERIMENTALE

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!

XY!

!!!!!!!!!!!!!!!!!!!

CHAPITRE V : OBJECTIFS DU TRAVAIL

!

!

X"!

05EE>!A5GC!H\=@5AC!4@5MG4!=G!85G9C!3>!H=!B=9:;>!T;TH;5I9=BJ;MG>!3>!8>!E=AGC89;:]!BHGC;>G9C!

3;PP;8GH:4C!85A8>B:G>HH>C!5A:!SGCMGRQ!B94C>A:!85EBH;MG4!H=!85EB94J>AC;5A!3>!H=!BJ7C;5B=:J5H5I;>!3>!

H\'0<O)B!1! H=! 34P;A;:;5A! >:! H=! 94B=9:;:;5A! 3>C! 3;PP49>A:>C! BJ=C>C! 3G! 878H>! 8=93;=MG>]! H=! @;C;5A!

E48=A;MG>!3G! 8oG9! 85EE>!GA>!B5EB>!J4E537A=E;MG>!5G!EGC8GH=;9>]! H=! 3;CB5A;T;H;:4! Q! I9=A3>!

48J>HH>! 3>!E4:J53>C! 3\4@=HG=:;5A! 3>C! B=9=EF:9>C! 3489;@=A:! H=! P5A8:;5A! 3>! B5EB>!EGC8GH=;9>! 3G!

8oG9]! H\=TC>A8>!3\4:G3>C!3=AC!H=!B5BGH=:;5A!I4A49=H>!48H=;98;CC=A:! H>C!9=BB59:C!>:! H>C!B5;3C!9>H=:;PC!

>A!:>9E>C!3>!B94@=H>A8>!>:!;A8;3>A8>!3>!H=!37CP5A8:;5A!3;=C:5H;MG>!>:!3>!H\'0<O)B[!

2=AC! 8>! 85A:>6:>]! notre premier objectif! =! 4:4! 3>! mettre au point un mod�le de

dysfonction diastolique reproduisant les caract�ristiques de la pathologie humaine 1! B5G9! 8>!

P=;9>]!H>!B598!=!4:4!9>:>AG!85EE>!>CBF8>!3\>6B49;E>A:=:;5A!>:!H=!B>9PGC;5A!85A:;AG>!3\=AI;5:>AC;A>!

''!=!4:4!G:;H;C4>!B5G9!;A3G;9>!GA>!J7B>9:>AC;5A!=9:49;>HH>!B953G;C=A:!3>C!=H:49=:;5AC!8=93;=MG>C[!!

&!H\=;3>!3>!8>!3;CB5C;:;P!>6B49;E>A:=H]!notre deuxi�me objectif!=!4:4!3\=BBH;MG>9!H>!85A8>B:!

3>!B5EB>!EGC8GH=;9>!=P;A!3\interpr�ter les modifications fonctionnelles du ventricule gauche au

cours de lÕhypertension art�rielle chronique[!

&G!85G9C!3G!34@>H5BB>E>A:!>:!3>!H\>6BH59=:;5A!3G!E53FH>!=A;E=H]!A5GC!A5GC!C5EE>C!=B>9qGC!

3\GA>!;A=34MG=:;5A!>A:9>!H>C!@=9;=:;5AC!3>!P94MG>A8>!8=93;=MG>!>:!H>C!E53;P;8=:;5AC!3>C!3;PP49>A:>C!

BJ=C>C! 3G! 878H>[!0\>C:! B5G9MG5;]! ;H! A5GC! =! B=9G! ;A:49>CC=A:! 3\4@=HG>9! H>C! >PP>:C! 3>! H=!E53GH=:;5A!

BJ=9E=85H5I;MG>! 3>! H=! P94MG>A8>! 8=93;=MG>! CG9! H>! 85GBH=I>! 85A:9=8:;5A<9>H=6=:;5A[! &;AC;! notre

troisi�me objectif! =!4:4!3\�valuer les effets de la r�duction pharmacologique de la fr�quence

cardiaque par lÕivabradine, un inhibiteur des canaux If, sur les �quilibres entre les diff�rentes

phases du cycle[!

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X*!

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!

!

CHAPITRE VI : MATERIEL ET METHODES

!

!

X+!

'[!2'#?$#'K'O!)u?)('%)VK&/!1!?$(0#!)L)'//)#!0N($V'nl)%)VK!'V#K(l%)VK)#!

A. Cadre r�glementaire

/>C! >6B49;>A8>C! 5A:! 4:4! E>A4>C! =G! C>;A! 3>C! H58=G6! 3>! H\4MG;B>! Y+! 3>! H\'V#)(%! l! j--!

H58=H;C4C! =G! C>;A! 3>! H\)85H>! V=:;5A=H>! L4:49;A=;9>! 3\&HP59:[! />C! >6B49;>A8>C! 5A:! 4:4! 94=H;C4>C! >A!

=88593! =@>8! H=! H4I;CH=:;5A! P9=Aq=;C>! 9>H=:;@>! Q! H\>6B49;E>A:=:;5A! =A;E=H>! ^=G:59;C=:;5AC!

3\4:=TH;CC>E>A:!>:!;A3;@;3G>HH>C]!=@;C!3G!85E;:4!3\4:J;MG>_[!

B. Animaux

0>C!:9=@=G6!5A:!4:4!E>A4C!CG9!3>C!B598C!P>9E;>9C!P>E>HH>C!B>C=A:!>A:9>!*Y!Q!+Y!wI!B95@>A=A:!

3\GA!4H>@=I>!348H=94!3=AC!H=!B953G8:;5A!3>!B598C!Q!@;C4>!>6B49;E>A:=H>[!!

C. Instrumentation des animaux

/=!B=9:;8GH=9;:4! 3>! 8>! 3;CB5C;:;P! >6B49;E>A:=H! 94C;3>! 3=AC! H=! 94=H;C=:;5A!3>C!E>CG9>C! Q! H\4:=:!

4@>;HH4! >A! H\=TC>A8>! 3>! :5G:! =I>A:! =A>C:J4C;MG>! CGC8>B:;TH>! 3>! E53;P;>9! H>C! 85A3;:;5AC!

>6B49;E>A:=H>C! H59C! 3>C! >6B49;>A8>C[! ?5G9! 8>! P=;9>]! H>C! =A;E=G6! 5A:! 4:4! 8J95A;MG>E>A:!

;AC:9GE>A:4C!1! 3=AC! GA! B9>E;>9! :>EBC]! H\>AC>ETH>! 3>C! 3;CB5C;:;PC! A48>CC=;9>C! =G6! E>CG9>C!

J4E537A=E;MG>C! =! 4:4! E;C! >A! BH=8>! =G! 85G9C! 3\GA>! 8J;9G9I;>! ;A;:;=H>!c! =B9FC! GA>! B49;53>! 3>!

948GB49=:;5A! B5C:<8J;9G9I;8=H>! 3>! 3>G6! Q! :95;C! C>E=;A>C]! H>C! =A;E=G6! 5A:! 4:4! ;A8HGC! 3=AC! H>C!

B95:585H>C!>6B49;E>A:=G6[!

/>C! =A;E=G6! 5A:! CGT;! GA>! ;A:>9@>A:;5A! 8J;9G9I;8=H>! 3=AC! H>! 9>CB>8:! 3>C! 9FIH>C! C:9;8:>C!

3R=C>BC;>[! &B9FC! GA>! B94E43;8=:;5A! C43=:;@>! =@>8! H\=U=B495A>! ^X! EIDwI]! '%_]! H>C! B598C! 5A:! 4:4!

=A>C:J4C;4C!=@>8!3G!B95B5P5H!^*!EIDwI]!'L_]!BG;C! ;A:GT4C!>:!@>A:;H4C!=@>8!GA!@5HGE>!85G9=A:!3>!X!

EHDwI! >:! Q! P94MG>A8>! 9>CB;9=:5;9>! =3=B:4>! B5G9! =::>;A39>! GA>! 85A8>A:9=:;5A! 3>! 0$*! >A! P;A!

3\>6B;9=:;5A! 85EB9;C>! >A:9>! +Y! >:! +,! EENI! ^9>CB;9=:>G9! &HBJ=@>:]! %;A>9@>]! )C:>9A=7]! O9=A8>_[!

&B9FC!8G9=9;C=:;5A!^T95EG9>!3>!B=A859GA;GE!1!,!EI]!'L_]!H>C!=A;E=G6!5A:!CGT;!GA>!:J59=85:5E;>!=G!

A;@>=G!3G!8;AMG;FE>!>CB=8>! ;A:>985C:=H[!/=!948H;A=;C5A!3>C! H5T>C!BGHE5A=;9>C!I=G8J>C!=!=CCG94! H=!

@;CG=H;C=:;5A! 3>! HR=59:>! :J59=8;MG>! 3>C8>A3=A:>! CG9! H=MG>HH>! =! 4:4! ;A:953G;:! GA! 8=:J4:>9! 9;I;3>! >A!

K7I5A!^3;=EF:9>!;A:>9A>!3>!"!EE]!W;5TH58w]!'HHw9;8J]!O9=A8>_[!/>!B49;8=93>!=!>ACG;:>!4:4!;A8;C4[!lA!

8=:J4:>9!C5GBH>!>A!#;H=C:;8!^3;=EF:9>!;A:>9A>!"!EE]!#>3=:]!'9;IA7]!O9=A8>_!=!4:4!;AC494!3=AC!H\=9:F9>!

BGHE5A=;9>!>:!GA!C>85A3!8=:J4:>9!9;I;3>!3=AC!HR59>;HH>::>!I=G8J>[!lA!8=B:>G9!3>!B9>CC;5A!E;A;=:G9;C4!

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Figure 15. Instrumentation des animaux.

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D. Param�tre mesur�s

1. Mesure des pressions aortique, atriale et ventriculaire

/>C! B9>CC;5AC! =59:;MG>! >:! =:9;=H>! 5A:! 4:4! E>CG94>C! Q! HR=;3>! 3RGA! 8=B:>G9! 3>! B9>CC;5A! .5GH3!

#:=:J=E!?*+'2!^#:=:J=E!'AC:9GE>A:C]!$6A=93]!0&]!l#&_!85AA>8:4!Q!GA!=EBH;P;8=:>G9!^#7C:FE>!g]!

E53GH>! *Y,]! #=A!2;>I5]! 0&]! l#&_[! /=! B9>CC;5A! @>A:9;8GH=;9>! I=G8J>! =! 4:4!E>CG94>! Q! B=9:;9! 3G!

E=A5EF:9>!;EBH=A:=TH>!^i�A;ICT>9I!?+&_[!/=!8=H;T9=:;5A!3G!E=A5EF:9>!;EBH=A:=TH>!=!4:4!P=;:>!in

vivo!Q!H\=;3>!3>C!B9>CC;5AC!=G9;8GH=;9>!>:!=59:;MG>[!

2. Mesure du d�bit cardiaque

/>!34T;:!8=93;=MG>!=!4:4!E>CG94!Q!HR=;3>!3>!H=!T=IG>!3>!34T;:!;EBH=A:4>!=G:5G9!3>!HR=59:>!9>H;4>!

Q!GA!E53GH>!3>!E>CG9>!K9=AC5A;8!K*Yg!^K9=AC5A;8!#7C:>E!'A8[]!':J=8=]!Vm]!l#&_[!

3. Mesure de lÕ�paisseur pari�tale et du diam�tre ventriculaire

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Figure 16. Sch�ma illustrant le principe de la mesure de la contractilit� r�gionale par la technique de

la sonomicrom�trie.

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Dur�e de transit

Distance = dur�e de transit x vitesse de propagation (vitesse de propagation = 1,58 mm/!s)

Signal obtenu au cours d!un cycle cardiaque

dP/dt (mmHg/s)

12000

-8000

0

Epaisseur Pari�tale

(mm)

12

0

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Xd!

4. Mesure des conditions de charge

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B5G9!8>H=!:9=8>9!H=!85G9T>!3>!C:9>CC!B=9;4:=H!3>!E=A;F9>!85A:;AG>!CG9!GA!878H>!>:!34:>9E;A>9!C=!@=H>G9!

E=6;E=H>_! >:! GA! C:9>CC! :4H4C7C:5H;MG>[!/=!B5C:<8J=9I>! =! 4:4! 34P;A;>! 85EE>! H=! @=H>G9!E57>AA>!3G!

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E5E>A:C!3\5G@>9:G9>!>:!3>!P>9E>:G9>!3>!H=!@=H@>!=59:;MG>[!!

5. Mesure des intervalles de temps du cycle cardiaque

/=!:4H43;=C:5H>!=!4:4!34P;A;>!85EE>!4:=A:!H>!34TG:!3>!H=!E5A:4>!3>!H=!B9>CC;5A!@>A:9;8GH=;9>!I=G8J>!

SGC:>! =B9FC! H=! 85A:9=8:;5A! =:9;=H>! >:! 8599>CB5A3=A:! Q! H\=GIE>A:=:;5A! ;A;:;=H>! 3G! C;IA=H! 3>! 3?D3:[!

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B9>CC;5AC! =59:;MG>! >:! @>A:9;8GH=;9>[! 0>C! 34:>9E;A=:;5AC! 5A:! 4:4! 85AP;9E4>C! B=9! H>G9! CGB>9B5C;:;5A!

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! !

!

!

XX!

6. Evaluation de la relaxation isovolumique

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8=93;=MG>[!

/=! B49;53>! 3>! 9>H=6=:;5A! ;C5@5HGE;MG>! 8=9=8:49;C>! H=! BJ=C>! 3>! 34895;CC=A8>! 3>! H=! B9>CC;5A!

@>A:9;8GH=;9>!B>A3=A:!H=MG>HH>!H>!@5HGE>!3>!H=!8=@;:4!A>!@=9;>!B=C[!)HH>!>C:!34P;A;>!B=9!H\;A:>9@=HH>!3>!

:>EBC!85EB9;C!>A:9>!H>!B;8!A4I=:;P!3>!3?D3:!^8599>CB5A3=A:!Q!H=!P>9E>:G9>!3>!H=!@=H@>!=59:;MG>_!>:!H=!

@=H>G9!3>!H=!B9>CC;5A!@>A:9;8GH=;9>!I=G8J>!8599>CB5A3=A:!Q!H=!B9>CC;5A!:4H43;=C:5H;MG>!3G!T=::>E>A:!

CG;@=A:! Q! H=MG>HH>! -!EENI! C5A:! =S5G:4C[! /=! 85G9T>! 3>! 34895;CC=A8>! 3>! H=! B9>CC;5A! @>A:9;8GH=;9>!

I=G8J>!B>G:!r:9>!E534H;C4>!Q!H\=;3>!3>!E53FH>C!E5A5<>6B5A>A:;>HC!MG;!B>G@>A:!r:9>!=C7EB:5:;MG>C!

5G!A5A!=C7EB:5:;MG>C[!/>!E53FH>!3>!p>;CC!CGBB5C>!MG>!H\=C7EB:5:>!>C:!4I=H>!Q!Y!>:!MG>!H=!B9>CC;5A!

4@5HG>!C>H5A!H\4MG=:;5A!CG;@=A:>!1!?!|!?Y!><:D"!=@>8!?Y!4:=A:!H=!@=H>G9!3>!B9>CC;5A!=G!B;8!A4I=:;P!3>!

3?D3:! ^:|Y_]! :! 4:=A:! H>! :>EBC! >:! "! H=! 85AC:=A:>! 3>! :>EBC! 3>! H=! 9>H=6=:;5A! ;C5@5HGE;MG>! ^p>;CC]!

O9>3>9;wC>A!>:!=H[!"jdg_[!/>C!=G:9>C!E53>C!3>!8=H8GHC!3>!H=!85AC:=A:>!3>!:>EBC!3>!9>H=6=:;5A!G:;H;C>A:!

3>C!E53FH>C!Q!=C7EB:5:>!A5A!AGHH>!1!?!|!^?Y<?W_!><:D"!}!?W]!5~!?W!>C:!H=!@=H>G9!3>!H\=C7EB:5:>!^(=PP!

=A3!.H=A:U!"jX"_[!V5GC!=@5AC!8J5;C;C!H=!E4:J53>!3489;:>!B=9!%=:CGT=9=!^%=:CGT=9=]!K=w=w;!>:!=H[!

"jj-_! >:! @=H;34>! B=9! #>AC=w;! ^#>AU=w;! =A3! i=CC! *Y"Y_! 85AC;C:=A:! Q! G:;H;C>9! GA>! 94I9>CC;5A!

H5I;C:;MG>!1!?!|!?&D^"!}!><:D"_!}!?W!5~!?&!>C:!GA>!85AC:=A:>!3\=EBH;:G3>[!&P;A!3\=E4H;59>9!H>!8=H8GH]!;H!

>C:!B5CC;TH>!3\>PP>8:G>9!GA>!94I9>CC;5A!A5A!H;A4=;9>!C>H5A!H\=HI59;:JE>!3>!/>@>AT>9I<%=9MG=93:[!

7. Recueil des donn�es

/R>AC>ETH>! 3>C! C;IA=G6! E>CG94C! =! 4:4! C;EGH:=A4E>A:! >A9>I;C:94! >A! 85A:;AG! ^P94MG>A8>!

3R=8MG;C;:;5A! 1! "YYY!NU_! >:! AGE49;C4! Q! HR=;3>! 3RGA! H5I;8;>H! 3R=8MG;C;:;5A]! H>C! 3;PP49>A:C! B=9=EF:9>C!

4:G3;4C!4:=A:!8=H8GH4C!>:!=A=H7C4C!CG9!:=TH>G9[!K5G:!8>8;!=!4:4!94=H;C4!Q!HR=;3>!3G!H5I;8;>H!3R=8MG;C;:;5A!

>:!3R=A=H7C>!N)%!@,[-!^V5:58593!#7C:>E]!095;CC7!CG9!#>;A>]!O9=A8>_[!

E. Analyses histologiques

&B9FC!C=89;P;8>!3>C!=A;E=G6]! H>!8oG9!=!4:4!B94H>@4!>:!3>C!85GB>C!3G!@>A:9;8GH>!I=G8J>!5A:!4:4!

P;64>C!3=AC!3G!P59E5H!,e!>:!;A8HGC>C!3=AC!H=!B=9=PP;A>[!2>C!C>8:;5AC!3\GA>!4B=;CC>G9!3>!-!&E!5A:!

!

!

Xj!

4:4!85H594>C!B=9!H>!95GI>!#;9;GC!=P;A!3>!@;CG=H;C>9!H>C!P;T9>C!3>!85HH=IFA>[!/=!P;T95C>!;A:>9C:;:;>HH>!=!

4:4! MG=A:;P;4>! >:! >6B9;E4>! >A! B5G98>A:=I>! 3>C! 8J=EBC! 5TC>9@4C! ^"Y! 8J=EBC! =A=H7C4C! Q! GA!

=I9=A3;CC>E>A:!u!"Y_[!

F. Substances utilis�es

/>C! CGTC:=A8>C! G:;H;C4>C! 3=AC! 8>! :9=@=;H! 5A:! 4:4! H\=AI;5:>AC;A>! ''! ^&AI;5:>AC;A! '']! NGE=A]!

0=HT;58J>E%]/=! y5HH=]! ):=:C<lA;C_]! H\=U=B495A>! ^#:9>CA;H%]! y=ACC>A! #=A:4! &A;E=H>]! 'CC7<H>C<

%5GH;A>G6]! O9=A8>_]! H>! B95B5P5H! ^(=B;A5@>:%]! #8J>9;AI<?H5GIJ! L4:49;A=;9>]! />@=HH5;C<?>99>:]!

O9=A8>_]! H\;C5PHG9=A>! ^'C5PHG9=A>! W>H=E5A:%]! V;8J5H=C! W>H=E5A:]! /5A35A]! (57=GE><lA;C_]! H=!

TGB94A59BJ;A>! ^K>EI>C;8%]! #8J>9;AI<?H5GIJ]! />@=HH5;C<?>99>:]! O9=A8>_]! H\=E56;8;HH;A>!

^0H=E567H%]! ?P;U>9! #=A:4!&A;E=H>]! W59I5! #=A!%;8J>HH>]! ':=H;>_]! H>! 3;=U>B=E! ^L=H;GE%]! (58J>]!

V>G;HH7<#G9<#>;A>]! O9=A8>_]! H>! B>A:5T=9T;:=H! C53;MG>! ^?>A:5T=9T;:=H! #53;MG>%]! 0>@=! #=A:4!

&A;E=H>]!/;T5G9A>]!O9=A8>_]!H=!35TG:=E;A>!^?=ABJ=9E=]!O5GI>9>C]!O9=A8>_]!>:!H\J4B=9;A>!^N4B=9;A>!

0J5=7%]!#=A5P;!&@>A:;C]!?=9;C]!O9=A8>_[!

G. Analyses statistiques

/>C! 94CGH:=:C! 5A:! 4:4! >6B9;E4C! C5GC! P59E>! 3>! E57>AA>! �! #)%! 3>C! @=H>G9C! ;A3;@;3G>HH>C!

5T:>AG>C!8J>U!8J=MG>!=A;E=H[!/=!85EB=9=;C5A!3>C!3;PP49>A:C!B=9=EF:9>C!E>CG94C!3>!y"!Q!y*X!=!4:4!

>PP>8:G4>!Q! HR=;3>!3RGA>!=A=H7C>!3>!@=9;=A8>!Q!3>G6! P=8:>G9C!=@>8!E>CG9>C! 94B4:4>C!Q! H=! 9>8J>98J>!

3\GA!>PP>:!a!:>EBC!b]!3\GA!>PP>:!a!CGTC:=A8>!4:G3;4>!b!5G!3\;A:>9=8:;5A!>A:9>!8>C!3>G6!P=8:>G9C[!/>!

C>G;H! 3>! C;IA;P;8=:;@;:4! =! 4:4! P;64! Q! B�Y]Y-[! #;! T>C5;A]! 3>C! 85EB=9=;C5AC! ;A3;@;3G>HH>C! 5A:! 4:4!

4@=HG4>C!Q!H\=;3>!3\GA!:>C:!t!3>!#:G3>A:!=@>8!GA>!8599>8:;5A!3>!W5AP>995A;[!/>C!=A=H7C>C!C:=:;C:;MG>C!

5A:!4:4!94=H;C4>C!Q!HR=;3>!3G!H5I;8;>H!#:=:L;>f!-[Y!^&T=8GC]!W>9wH>7]!0&]!):=:C<lA;C_[!

H. Justification du dispositif exp�rimental

/\>6BH59=:;5A! 3>! H=! 37CP5A8:;5A! 3;=C:5H;MG>! >:! 3>! H\'0<O)B! A48>CC;:>! H>! 34@>H5BB>E>A:! 3>!

E53FH>C! >6B49;E>A:=G6! B>9E>::=A:! H\=8MG;C;:;5A! 3>! 35AA4>C! >6:9=B5H=TH>C! Q! H=! 8H;A;MG>! JGE=;A>[!

lA>! 3>C! 9=;C5AC! B9;A8;B=H>C! 3>C! 3;PP;8GH:4C! 3=AC! H=! 85EB94J>AC;5A! 3>C! E48=A;CE>C!

BJ7C;5B=:J5H5I;MG>C!3>! HR'0<O)B!>:! HR4@=HG=:;5A!3>! C:9=:4I;>C!BJ=9E=85H5I;MG>C! >C:! H>!E=AMG>!3>!

E53FH>C! =A;E=G6!B>9:;A>A:C[!/R4@=HG=:;5A!3>! H=! 9>H=6=:;5A! ;C5@5HGE;MG>! >:! 3G! 9>EBH;CC=I>! >C:! GA!

B94<9>MG;C! ;A85A:5G9A=TH>! B5G9! H=! B>9:;A>A8>! 3>! :5G:! E53FH>! >6B49;E>A:=H! B95B5C4[! #;! H=! C5G9;C]!

E53FH>! =A;E=H! H>!BHGC! 94B=A3G!=8:G>HH>E>A:]!B>9E>:!3R=BB94J>A3>9!3>C!E48=A;CE>C!8>HHGH=;9>C! >:!

E5H48GH=;9>C! 3>! 8>::>! B=:J5H5I;>]! H>C! 35AA4>C! J4E537A=E;MG>C! MG;! H=! 8=9=8:49;C>A:! 9>C:>A:!

>A:=8J4>C! 3>! H;E;:>C! ;EB59:=A:>C! MG;! 9>A3>A:! 3;PP;8;H>C! H>G9! >6:9=B5H=:;5A! Q! HRN5EE>[!)A! B9>E;>9!

!

!

jY!

H;>G]! H=! P94MG>A8>! 8=93;=MG>! :9FC! 4H>@4>! 3>! 8>::>! >CBF8>! >C:! C=AC! =G8GA>! 85EB=9=;C5A! =@>8! 8>HH>!

E>CG94>!8J>U! HRN5EE>!^gYY!T=::DE;A!@C!dY!T=::DE;A!Q! HR4:=:!4@>;HH4_[!$A!5TC>9@>!B=9!=;HH>G9C!GA>!

J5E45C:=C;>!8=H8;MG>!=;AC;!MG>!3>C!3;C:9;TG:;5AC!3=AC!H>C!;C5P59E>C!3>!B95:4;A>C!3G!C=985EF9>!>:!3>!

H=!E>ET9=A>!3;PP49>A:>C! 3>! 8>HH>C! 9>A85A:94>C! 8J>U! HRN5EE>[!/=! 8=9=8:49;C=:;5A! J4E537A=E;MG>!

8J>U!H=!C5G9;C!AR>C:!B=C!=;C4>!ErE>!C;!H>C!=BB958J>C!48J58=93;5I9=BJ;MG>C!C>!C5A:!85AC;349=TH>E>A:!

=PP;A4>C! 8>C! 3>9A;F9>C! =AA4>C[! 2>! BHGC]! 5A! B>G:! 5TS>8:>9! MG>! 8>::>! =BB958J>! 9>C:>! 4E;A>EE>A:!

5B49=:>G9<34B>A3=A:>! >:! 3RGA>! 9>B953G8:;T;H;:4! B>9P>8:;TH>[! 2=AC! 8>! 85A:>6:>]! C>GHC! H>C! E53FH>C!

=A;E=G6!94=H;C4C!8J>U!H>!I95C!=A;E=H!B>9E>::>A:!3R=BB94J>A3>9!3>!E=A;F9>!=BB95P5A3;>!H=!P5A8:;5A!

@>A:9;8GH=;9>! I=G8J>[! ?=9! =;HH>G9C]! H>! E53FH>! =A;E=H! MG>! A5GC! =@5AC! G:;H;C4! >C:! GA! 3;CB5C;:;P! 3;:!

`4@>;HH4!8J95A;MG>E>A:!;AC:9GE>A:4`[!2=AC!8>C!85A3;:;5AC!H>C!=A;E=G6!C5A:!4:G3;4C!Q!3;C:=A8>!3RGA>!

8J;9G9I;>! =G! 85G9C! 3>! H=MG>HH>! H>C! 3;CB5C;:;PC! 3>C:;A4C! Q! HR4@=HG=:;5A! 3>! H=! P5A8:;5A! C7C:5H;MG>! >:!

3;=C:5H;MG>!C5A:!;EBH=A:4C!34P;A;:;@>E>A:!in situ[!/>C!=A;E=G6!C5A:!4:G3;4C!Q!3;C:=A8>!>A!HR=TC>A8>!

3>!:5G:>!C43=:;5A!5G!=A>C:J4C;>!35A:!5A!C=;:!MGR>HH>C!E53;P;>A:!H=!P5A8:;5A!@>A:9;8GH=;9>!^L=:A>9!=A3!

W9=GAf=H3!"jd-_[!0R>C:!HQ!>A859>!GA!=@=A:=I>!;A34A;=TH>!CG9!H>C!E53FH>C!EG9;AC!MG;!A48>CC;:>A:!GA>!

C43=:;5A!5G!GA>!=A>C:J4C;>!=@=A:!HR4@=HG=:;5A!48J58=93;5I9=BJ;MG>[!

''[!%$2)/)!)u?)('%)VK&/!2\Nm?)(K)V#'$V!&(K)(')//)!0N($V'nl)!

A. Pr�ambule

&P;A!3>! C\=BB958J>9!3\GA>! C;:G=:;5A!8H;A;MG>!Q! H\59;I;A>!3\GA>!37CP5A8:;5A!3;=C:5H;MG>!>:!3>!

H\'0<O)B]!A5GC!=@5AC!8J5;C;!3\;A3G;9>!GA>!J7B>9:>AC;5A!=9:49;>HH>!8J95A;MG>!Q!H\=;3>!3\GA>!B>9PGC;5A!

3\=AI;5:>AC;A>! ''[! )A! >PP>:]! H\J7B>9:>AC;5A! =9:49;>HH>! >C:! H\GA! 3>C! P=8:>G9C! 4:;5H5I;MG>C! H>! BHGC!

P94MG>EE>A:! 9>A85A:94! 8J>U! H>C!B=:;>A:C!34@>H5BB=A:!GA>! '0<O)?[!2=AC! 8>! 8=39>]! H\=8:;@=:;5A!3G!

C7C:FE>! 94A;A>! =AI;5:>AC;A>! >C:! GA! 4H4E>A:! 8>A:9=H! 3=AC! H\4H4@=:;5A! 3>C! @=H>G9C! 3>! B9>CC;5A!

=9:49;>HH>! >:! 3=AC! H>! 9>E53>H=I>! @>A:9;8GH=;9>[! 0>9:=;AC! =G:>G9C! 5A:! =;AC;! B94843>EE>A:! B95B5C4!

3\=3E;A;C:9>9!3>!E=A;F9>!8J95A;MG>!3>!H\=AI;5:>AC;A>!''!5G!3\G:;H;C>9!H>!E53FH>!3>!85AC:9;8:;5A!94A=H!

^%GA=I=H=]!N=9:!>:!=H[!*YY-_[!0>B>A3=A:!H>!34@>H5BB>E>A:!3>!8>C!J7B>9:>AC;5AC!>C:!;994@>9C;TH>!>:!

H\;APHG>A8>!3>!H\=GIE>A:=:;5A!3>C!85A3;:;5AC!3>!8J=9I>!A>!B>G:!B=C!r:9>!3;C:;AIG4>!3>C!E53;P;8=:;5AC!

;A:9;ACFMG>C!3G!@>A:9;8GH>!I=G8J>[!V5GC!=@5AC!8J5;C;!3\=35B:>9!H=!ErE>!C:9=:4I;>!>A!H=!E53;P;=A:!>:!

9>EBH=q=A:! H\G:;H;C=:;5A! 3>! B5EB>C! 5CE5:;MG>C! ;EBH=A:4>C! B=9! 8>HH>! 3>! B>9PGC>G9C! E;A;=:G9>C!

>6:>9A>C[!0>8;!B>9E>:]!Q!H=!3;PP49>A8>!3>C!B5EB>C!5CE5:;MG>C]!H\=99r:!3>!H=!B>9PGC;5A!>:!H>!9>:5G9!3>C!

@=H>G9C!3>!B9>CC;5A!=9:49;>HH>!^>:!3>!85A3;:;5AC!3>!8J=9I>_!Q!3>C!A;@>=G6!C;E;H=;9>C!=G6!85A3;:;5AC!3>!

T=C>[!&;AC;]! A5GC! B5G@5AC! 4@=HG>9! H=! P5A8:;5A! @>A:9;8GH=;9>! I=G8J>! ;A:9;ACFMG>]! ;A34B>A3=EE>A:!

3>C!@=9;=:;5AC!3>C!85A3;:;5AC!3>!8J=9I>!MG;!C5A:!GA!P=8:>G9!85AP5A3=A:[!

!

!

j"!

B. Courbe dose-r�ponse

2=AC!GA!B9>E;>9! :>EBC!>:!=P;A!3>!34:>9E;A>9! H=!35C>!=34MG=:>!3\=AI;5:>AC;A>! ''!Q!B>9PGC>9]!

A5GC! =@5AC! 4:=TH;! H=! 85G9T>! 35C><94B5AC>! J7B>9:>AC;@>! Q! H\=3E;A;C:9=:;5A! 3>! 35C>C! 895;CC=A:>C!

3R=AI;5:>AC;A>! ''! ^P;IG9>!"d_[!V5GC!=@5AC! 9>:>AG! H=!35C>!3>!+Y!AIDwIDE;A!MG;! 9>B94C>A:=;:! H=!35C>!

C5GC<E=6;E=H>! >:! MG;! B>9E>::=;:! 3\;A3G;9>! GA>! =GIE>A:=:;5A! =;I�>! 3\>A@;95A! +Y! EENI! 3>C!

B9>CC;5AC!=9:49;>HH>C!C7C:5H;MG>]!3;=C:5H;MG>!>:!E57>AA>[!

!

C. Protocole hypertensif

2=AC!GA!B9>E;>9!:>EBC]!3>C!>A9>I;C:9>E>A:C!5A:!4:4!94=H;C4C!B5G9!5T:>A;9!3>C!E>CG9>C!Q!HR4:=:!

3>! T=C>! ^yY_! >:! >A! 94B5AC>! Q! HR=3E;A;C:9=:;5A! 3>! 35TG:=E;A>! ^"Y! !IDwIDE;A]! -! E;A_! ^O;I[! "X_[!

)ACG;:>]! GA>! B>9PGC;5A! 85A:;AG>! 3R=AI;5:>AC;A>! ''! ^+Y! AIDwIDE;A]! 'L_! =! 4:4! ;AC:=G94>! B5G9! GA>!

B49;53>!3>!,!C>E=;A>C[!0>HH><8;!=!4:4!>PP>8:G4>!Q!HR=;3>!3RGA>!B5EB>!E;A;=:G9;C4>!P;64>!CG9!35C!3>!

H\=A;E=H!^%'0($y)0K]!#59>AC5A!%>3;8=H]!O9=A8>_[!/>!T5A!P5A8:;5AA>E>A:!3>!8>::>!B5EB>!=!4:4!

@49;P;4!3>!E=A;F9>!MG5:;3;>AA>[!/RJ4E537A=E;MG>!C7C:4E;MG>!>:!8=93;=MG>!=!4:4!>A9>I;C:94>!Q!HR4:=:!

4@>;HH4! Q! y+]! yd]! y",]! y*"! >:! y*X[! &! 8J=MG>! >A9>I;C:9>E>A:]! H>C! 3;PP49>A:C! B=9=EF:9>C!

J4E537A=E;MG>C!5A:!4:4!9>8G>;HH;C!3=AC!GA!B9>E;>9! :>EBC!>A!B94C>A8>!3R=AI;5:>AC;A>!''[!2=AC!GA!

Figure 17. Courbe dose-r�ponse � l!angiotensine II. PAS : pression art�rielle systolique ; PAM : pression

art�rielle moyenne ; PAD : pression art�rielle diastolique (n=6).

60

80

100

120

140

160

180

0 10 20 30 40 50 60 70 80 90 100

Angiotensine II (ng/kg/min)

Pre

ssio

n a

rt�r

iell

e (m

mH

g)

PAS

PAM

PAD

!

!

j*!

C>85A3!:>EBC]!H=!B>9PGC;5A!=!4:4!=99r:4>!gY!E;A!=P;A!3>!B>9E>::9>!GA!9>:5G9!3>!H=!B9>CC;5A!=9:49;>HH>!

=G6! 85A3;:;5AC! 5TC>9@4>C! Q! yY[! 0>::>! 35GTH>! 4@=HG=:;5A! =@=;:! B5G9! 5TS>8:;P! 3R4@=HG>9! H>C!

B>9P59E=A8>C!@>A:9;8GH=;9>C!I=G8J>C!;A:9;ACFMG>C]!i.e.]!>A!E;A;E;C=A:!H=!E53;P;8=:;5A!3>C!85A3;:;5AC!

3>! 8J=9I>[! &! y*X]! =H59C! MG>! H=! B>9PGC;5A! 3R=AI;5:>AC;A>! ''! 4:=;:! =99r:4>]! A5GC! =@5AC! 4@=HG4! H>C!

94B5AC>C! J4E537A=E;MG>C! Q! HR=3E;A;C:9=:;5A! 3>! 35TG:=E;A>[! &G! :>9E>! 3>C! >6B49;>A8>C]! H>C!

=A;E=G6!5A:!4:4!C=89;P;4C!Q!HR=;3>!3RGA>!;AS>8:;5A!3>!B>A:5T=9T;:=H!^gY!EIDwI_[!/>!8oG9!=!4:4!>68;C4!

>:!B>C4[!/=!B5C;:;5A!3>C!89;C:=G6!B;4U54H>8:9;MG>C!=!4:4!@49;P;4>[!lA!3>G6;FE>!I95GB>!3\=A;E=G6!=!

4:4!4:G3;4!3>!E=A;F9>!C;E;H=;9>!E=;C!H\=AI;5:>AC;A>!''!=!4:4!9>EBH=84>!B=9!H\=3E;A;C:9=:;5A!3>!C49GE!

BJ7C;5H5I;MG>[!

!

D. Caract�ristiques du mod�le exp�rimental

1- H�modynamique g�n�rale

05EE>! H\;HHGC:9>! H=!O;IG9>!"j]! H\=3E;A;C:9=:;5A!8J95A;MG>!3\=AI;5:>AC;A>! ''! =!B95@5MG4!GA>!

=GIE>A:=:;5A!3>C!B9>CC;5AC!=9:49;>HH>C!C7C:5H;MG>]!3;=C:5H;MG>!>:!E57>AA>[!?5G9!>6>EBH>!>:!CG9!GA!

H5:!3>!X!=A;E=G6]!A5GC!=@5AC!5TC>9@4!3>C!=GIE>A:=:;5AC!9>CB>8:;@>C!3>!g"!�!+]!-Y!�!+!>:!-,!�!+!

EENI! CG9! H=! B49;53>! ,! C>E=;A>C[! &! y*X]! H>C! B9>CC;5AC! =9:49;>HH>C! C7C:5H;MG>C]! 3;=C:5H;MG>C! >:!

E57>AA>A:!5A:!=::>;A:C!9>CB>8:;@>E>A:!H>C!@=H>G9C!3>!"X,!�!-]!"+,!�!+!>:!"-X!�!-!EENI[!!

2>!E=A;F9>!85A85E;:=A:>]!H=!P94MG>A8>!8=93;=MG>!E>CG94>!Q!y*X!=!=GIE>A:4>!B=9!9=BB59:!Q!yY!

^9>CB>8:;@>E>A:!=@>8!>:!C=AC!=AI;5:>AC;A>!''!vs!yY]!j+!�!,!>:!"Yd!�!X!vs!XY!�!*!T=::DE;A_!^K=TH>=G!

+_[!'H!>C:!;EB59:=A:!3>!C5GH;IA>9!MG>!H=!B9>CC;5A!:4H43;=C:5H;MG>!3G!@>A:9;8GH>!I=G8J>!>C:!3>E>G94>!

Figure 18. Protocole exp�rimental. Figure 18. Protocole exp�rimental.

¡ Au cours de la perfusion d!AT II

¡ 1 heure apr�s l!arr�t de la perfusion

Angiotensine II (30 ng/kg/min)

J0 J3 J7 J14 J28 J21

Dobutamine

(10 !g/kg/min)

Evaluation h�modynamique Dobutamine

(10 !g/kg/min)

Figure 18. Protocole exp�rimental.

!

!

j+!

;A8J=AI4>]!E5A:9=A:! =;AC;! H\=TC>A8>! 3>! :5G:>! 3485EB>AC=:;5A[! ?=9! =;HH>G9C]! A5GC! A\=@5AC! 5TC>9@4!

=G8GA!C;IA>!85AI>C:;P!Q!8>!C:=3>[!

!

/>!8=H8GH!3G!C:9>CC!B=9;4:=H!4S>8:;5AA>H!E57>A!=!B>9E;C!3>!85AP;9E>9!MG>!H\=99r:!:>EB59=;9>!3>!

H=!B>9PGC;5A!B>9E>::=;:!GA!9>:5G9!=G6!@=H>G9C!3>!T=C>!^yY_!3>C!85A3;:;5AC!3>!8J=9I>!^*,d!�!*+!Q!yY!vs!

*dY!�!+j!ID8E*!Q!y*X_[!

2- Hypertrophie ventriculaire gauche

/=! B>9PGC;5A! 8J95A;MG>! 3\=AI;5:>AC;A>! ''! =! ;A3G;:! GA>! =GIE>A:=:;5A! B95I9>CC;@>! >:!

C;IA;P;8=:;@>! 3>! H\4B=;CC>G9! B=9;4:=H>! :4H43;=C:5H;MG>! 3G! @>A:9;8GH>! I=G8J>! ^O;I[! *Y]! K=T[! +_[! />!

I95GB>!3\=A;E=G6!9>8>@=A:!H>!C49GE!BJ7C;5H5I;MG>!A\=!B=C!E5A:94!8>C!E53;P;8=:;5AC!^K=T[!,_[!

?=9! =;HH>G9C]! H>! 9=BB59:! 3>! H=! E=CC>! 3G! @>A:9;8GH>! I=G8J>! vs! H=! E=CC>! 859B59>HH>! 4:=;:!

C;IA;P;8=:;@>E>A:!=GIE>A:4]!34E5A:9=A:!H>!34@>H5BB>E>A:!3\GA>!J7B>9:95BJ;>!@>A:9;8GH=;9>!I=G8J>[!

! !

mm

Hg

60

100

140

180

0 3 7 14 21 28

Jours

Pression art�rielle moyenne

Ang II +

Ang II -

A

Jour 0 Jour 28

Ang II Ð

Ang II +

PAS

mm

Hg

mm

Hg

0

50

100

150

200

0

50

100

150

200

PAS

*

PAD

PAD

*

PAM

PAM

*

B

C

Figure 19. Evolution de la pression art�rielle moyenne chez les animaux

trait�s par angiotensine II. A) La pression art�rielle moyenne mesur�e � J0, 3,

7, 14, 21, 28 du protocole, en pr�sence (cercle ouvert) et absence (cercle plein)

dÕangiotensine II. B) la pression art�rielle systolique (PAS), diastolique (PAD)

et moyenne (PAM) mesur�e � J0 (histogramme ouvert) et � J28 (histogramme

gris) en pr�sence dÕangiotensine II. C) la pression art�rielle systolique (PAS),

diastolique (PAD) et moyenne (PAM) mesur�e � J0 (histogramme ouvert) et �

J28 (histogramme gris) en lÕabsence dÕangiotensine II. p<0,05 pour un effet

temps sur les 4 semaines de traitement (ANOVA). *p<0,05 vs J0 (n = 8).

!

!

j,!

!

!

!

n Jour 28

Ang - Ang +

Fr�quence cardiaque (batt/min) 8 80 ± 2 107 ± 8* 93 ± 4*

Pression art�rielle moyenne (mmHg) 8 101 ± 3 105 ± 3 158 ± 5*

Pression VG (mmHg) 8 120 ± 3 130 ± 5 186 ± 4*

Pression t�l�-diastolique du VG (mmHg) 8 11 ± 3 9 ± 2 14 ± 2

Epaisseur pari�tale t�l�diastolique du VG (mm) 7 9,4 ± 0,7 12,4 ± 0.5* 11,8 ± 0.7*

Epaisseur pari�tale t�l�systolique du VG (mm) 7 11,9 ± 0,8 15,9 ± 1.1* 14,4 ± 0.8*

Epaissisement pari�tale du VG(mm) 7 2,5 ± 0,2 2,6 ± 0,3 2,6 ± 0,2

Diam�tre interne t�l�diastolique du VG (mm) 6 40 ± 2 42 ± 1 44 ± 1*

Diam�tre interne t�l�systolique du VG (mm) 6 33 ± 1 35 ± 1 37 ± 1*

Fraction de raccourcissement (%) 6 18 ± 1 16 ± 1 17 ± 2

LV dP/dt max (mmHg/s) 8 2305 ± 140 3277 ± 316* 3537 ± 169*

Values are mean ± s.e.m.

* p<0.05 vs Day 0

Jour 0

Table 3. Param�tres h�modynamiques des porcs trait�s par ATII

n Day 28

Saline - Saline +

Fr�quence cardiaque (batt/min) 6 84 ± 1 84 ± 3 81 ± 2

Pression art�rielle moyenne (mmHg) 6 107 ± 2 111 ± 2 113 ± 3

Pression VG (mmHg) 6 132 ± 3 135 ± 3 132 ± 3

Pression t�l�-diastolique du VG (mmHg) 6 12 ± 2 13 ± 3 12 ± 4

Epaisseur pari�tale t�l�diastolique du VG (mm) 4 9,2 ± 0,2 10,1 ± 0,4 10,2 ± 0,4

Epaisseur pari�tale t�l�systolique du VG (mm) 4 11,7 ± 0,7 12,3 ± 0,9 12,3 ± 0,8

Epaissisement pari�tale du VG(mm) 4 2,5 ± 0,7 2,1 ± 0,5 2,2 ± 0,5

Diam�tre interne t�l�diastolique du VG (mm) 5 42 ± 2 45 ± 1* 44 ± 1

Diam�tre interne t�l�systolique du VG (mm) 5 35 ± 2 40 ± 2* 40 ± 2*

Fraction de raccourcissement (%) 5 18 ± 2 18 ± 3 18 ± 2

LV dP/dt max (mmHg/s) 6 2352 ± 41 2318 ± 179 2276 ± 42

Values are mean ± s.e.m.

* p<0.05 vs Day 0

Day 0

Table 4. Param�tres h�modynamiques des porcs perfus�s par s�rum physiologique

!

!

j-!

0>::>! J7B>9:95BJ;>! C\>C:! =885EB=IA4>! 3\GA>! =GIE>A:=:;5A! 3>! H=! P;T95C>! ;A:>9C:;:;>HH>! ^g]*!�!

Y]d!@C!"Y]*!�!"]*!e!8J>U!H>C!=A;E=G6!B>9PGC4C!=@>8!H\=AI;5:>AC;A>!''!vs.! H>!C49GE!BJ7C;5H5I;MG>_!

^O;I[!*Y_[!

! !

Epaisseur pari�tale t�l�diastolique du VG

mm

0 3 7 14 21 28

Jours

7

9

11

13

Controles Ang II

Rapport poids du cÏur/

poids du corps

0

1

2

3

*

A

g/k

g

B 4

Contr�les Ang II C

Figure 20. Hypertrophie myocardique chez les animaux trait�s par angiotensine II. A) LÕ�paisseur pari�tale t�l�diastolique mesur�e aux

jours 0, 3, 7, 14, 21 et 28 du protocole, apr�s arr�t de la perfusion dÕangiotensine II. B) Rapport poids du cÏur / corps chez les contr�les

(histogramme ouvert, n=6) et les trait�s (histogramme gris, n=8). C) Coloration par rouge Sirius des fibres de collag�ne chez les contr�les et les

trait�s. p<0,05 pour un effet temps sur les 4 semaines de traitement (ANOVA). *p<0,05 vs J0 (n = 8).

!

!

jg!

CHAPITRE VII : ETUDE DU COUPLAGE

CONTRACTION-RELAXATION

0>::>!4:G3>!=!P=;:!H\5TS>:!3\GA>!BGTH;8=:;5A!1!!Impaired left ventricular function in presence of preserved ejection in chronic

hypertensive conscious pigs.

!B=9! (;>AU5! %]! W;U4! &]! ?5AI=C! 2]! %;8J;A>=G! #]! %>Hw=! y]! 0J=A! N/]! #=ET;A! /]! #G! yW]!2GT5;C<(=A34!y/]!N;::;AI>9!/]!W>93>=G6!&]!.J=H>J!W[!!W=C;8!(>C!0=93;5H!^*Y"*_]!"Yd!1!*jX[!

ORIGINAL CONTRIBUTION

Impaired left ventricular function in the presence of preservedejection in chronic hypertensive conscious pigs

Mario Rienzo • Alain Bize • Dionyssis Pongas • Stephanie Michineau •

Jonathan Melka • Hon Lai Chan • Lucien Sambin • Jin Bo Su • Jean-Luc Dubois-Rande •

Luc Hittinger • Alain Berdeaux • Bijan Ghaleh

Received: 16 May 2012 / Revised: 23 July 2012 / Accepted: 24 August 2012

! Springer-Verlag 2012

Abstract Systolic function is often evaluated by mea-

suring ejection fraction and its preservation is often

assimilated with the lack of impairment of systolic left

ventricular (LV) function. Considering the left ventricle as

a muscular pump, we explored LV function during chronic

hypertension independently of increased afterload condi-

tions. Fourteen conscious and chronically instrumented

pigs received continuous infusion of either angiotensin II

(n = 8) or saline (n = 6) during 28 days. Hemodynamic

recordings were regularly performed in the presence and

1 h after stopping angiotensin II infusion to evaluate

intrinsic LV function. Throughout the protocol, the mean

arterial pressure steadily increased by 55 ± 4 mmHg in

angiotensin II-treated animals. There were no significant

changes in stroke volume, LV fractional shortening or LV

wall thickening, indicating the lack of alterations in LV

ejection. In contrast, we observed maladaptive changes

with (1) the lack of reduction in isovolumic contraction and

relaxation durations with heart rate increases, (2) abnor-

mally blunted isovolumic contraction and relaxation

responses to dobutamine and (3) a linear correlation

between isovolumic contraction and relaxation durations.

None of these changes were observed in saline-infused

animals. In conclusion, we provide evidence of impaired

LV function with concomitant isovolumic contraction and

relaxation abnormalities during chronic hypertension while

ejection remains preserved and no sign of heart failure is

present. The evaluation under unloaded conditions shows

intrinsic LV abnormalities.

Keywords Isovolumic contraction ! Isovolumic

relaxation ! Hypertension ! Left ventricular function

Introduction

Systolic function is often evaluated by measuring ejection

fraction, and its preservation is often interpreted as an

absence of impairment of systolic left ventricular (LV)

function [15]. Usual description of LV function distin-

guishes systolic from diastolic alterations based on a

classic hemodynamic model of the heart [36]. However, it

has to be emphasized that the classical so-called diastole

and systole are tightly coupled [14, 21], and it is well

known that concomitant alterations of systolic and diastolic

ventricular function occur during ischemic heart disease

[22, 26]. Moreover, several human studies have reported

some alterations in parameters describing systolic function,

e.g., mitral annular DTI velocity [2] or long axis systolic

DTI velocity [33, 37] when ejection fraction was

M. Rienzo ! A. Bize ! D. Pongas ! S. Michineau ! J. Melka !H. L. Chan ! L. Sambin ! J. B. Su ! J.-L. Dubois-Rande !L. Hittinger ! A. Berdeaux ! B. Ghaleh (&)

Faculte de Medecine, INSERM Unite U955 Equipe 03,

8 rue du General Sarrail, 94000 Creteil, France

e-mail: [email protected]

M. Rienzo ! A. Bize ! D. Pongas ! S. Michineau ! J. Melka !H. L. Chan ! L. Sambin ! J. B. Su ! J.-L. Dubois-Rande !L. Hittinger ! A. Berdeaux ! B. GhalehFaculte de Medecine, Universite Paris-Est,

UMR-S U955, 94000 Creteil, France

M. Rienzo ! A. Bize ! D. Pongas ! S. Michineau ! J. Melka !H. L. Chan ! L. Sambin ! J. B. Su ! J.-L. Dubois-Rande !L. Hittinger ! A. Berdeaux ! B. GhalehEcole Nationale Veterinaire d’Alfort,

Universite Paris-Est, 94000 Maisons-Alfort, France

D. Pongas ! J.-L. Dubois-Rande ! L. Hittinger ! A. BerdeauxAP-HP, Groupe Hospitalier Henri Mondor,

Federation de Cardiologie, 94000 Creteil, France

123

Basic Res Cardiol (2012) 107:298

DOI 10.1007/s00395-012-0298-9

preserved. Most of these studies analyzed LV function as a

hydraulic input–output system as opposed to a muscular

pump perspective [7, 23, 38].

In this setting and considering the heart as a muscular

pump, we aimed at investigating LV function during

chronic hypertension in a large mammal. Previous large

animal hypertensive models used renal wrapping [13, 27]

or angiotensin II delivered through implanted osmotic

pumps [29, 30]. This hypertension was irreversible and the

influence of increased afterload per se could not be easily

distinguished from intrinsic LV alterations. Moreover,

there is generally missing information about early phases

of LV dysfunction development. Alternatively, we focused

on the development of LV dysfunction during chronic

hypertension in the absence of any signs of heart failure

and investigated LV contraction, relaxation and filling

independently of increased afterload condition. In the

present study, hypertension was induced by continuously

infusing angiotensin II during 4 weeks with external peri-

staltic pumps in chronically instrumented conscious pigs.

During the protocol, hemodynamic status was regularly

investigated and, at each scheduled recording, infusion of

angiotensin II was stopped for an hour in order to allow

arterial blood pressure to return to pre-treatment values.

This novel approach allowed both the characterization of

LV function during hypertension and the evaluation of the

intrinsic LV properties under unloaded conditions, i.e., in

the absence of angiotensin II infusion.

Methods

The experiments were conducted in accordance with the

regulations concerning the use of animals in research.

Surgical instrumentation

Under anesthesia, 14 female pigs (20–30 kg) underwent

left thoracotomy. Fluid-filled Tygon catheters were

implanted in the proximal descending thoracic aorta, in the

left atrium and in the pulmonary artery for the measure-

ment of arterial blood pressure and angiotensin II infusion.

A solid-state pressure transducer (P5A, Konigsberg

Instruments, Pasadena, CA, USA) was introduced into LV.

A flow probe (Transonic Systems Inc., Ithaca, NY, USA)

was implanted around the aortic root. Piezoelectric crystals

were implanted (1) on opposing LV anterior and posterior

endocardial surfaces to measure LV internal diameter, and

(2) on opposing LV endocardial and epicardial anterior free

wall surfaces to measure wall thickness. All catheters and

wires were exteriorized between the scapulae. Animals

were sedated with diazepam (0.2–0.4 mg/kg iv) for post-

operative care. Enrofloxacin (2 mg/kg/day, im) and long

acting amoxicillin (15 mg/kg every 2 days, im) were

administered for 10 days after surgery. Buprenorphine

(0.3 mg sc) was administered for 5 days after surgery. The

position of all catheters and crystals was confirmed at

autopsy.

Hemodynamic measurements

All hemodynamic data were recorded (1 kHz), digitized

and analyzed using HEM v4.2 software (Notocord Sys-

tems, Croissy sur Seine, France). Aortic and left atrial

pressures were measured with P23XL pressure transducers

(Becton–Dickinson, Franklin Lakes, NJ, USA). Cardiac

output was measured using a T206 blood flow meter

(Transonic Systems Inc., Ithaca, NY, USA). Left ventric-

ular pressure was cross calibrated with the left atrial and

aortic pressures. The change in LV pressure over time

(dP/dt) was computed from the LV pressure signal. Per-

centage of wall thickening was defined as end-systolic

minus end-diastolic thicknesses divided by end-diastolic

thickness 9 100. The signal of LV wall thickness and LV

internal diameter were suitable in 11 of the 14 instrumented

pigs.

LV end-diastole was defined as the initiation of the

upstroke of LV pressure tracing after atrial contraction and

indicated by the initial increase in LV dP/dt. Aortic valve

opening and closure were identified by crossing LV and

aortic pressure waveforms. Furthermore, these determina-

tions were confirmed by matching the waveforms with the

aortic flow signal. The isovolumic contraction time was

defined as the time interval between end diastole and aortic

valve opening. The ejection time was defined as the time

interval between aortic valve opening and closure. Mitral

valve opening was identified by crossing LV and atrial

pressure waveforms. The isovolumic relaxation period was

defined as the period elapsed from aortic valve closure and

mitral valve opening. The filling period was computed

from the end of isovolumic relaxation to end diastole.

Mean ejection LV wall stress

Cylindrical wall stress was calculated as: stress = 1.36

[(LVP 9 ID)/2 h], where LVP is LV pressure, ID is

internal diameter (short axis) and h is wall thickness. The

integral of the systolic wall stress over time, so-called

mean ejection wall stress, was calculated during the ejec-

tion period.

Isovolumic relaxation time constant

The time constant of isovolumic LV pressure (LVP) decay

s was calculated using pressure data points during the

Page 2 of 10 Basic Res Cardiol (2012) 107:298

123

isovolumic relaxation period and was computed using the

logistic method [25, 31]:

LVP ¼ PA=ð1þ et=sÞ þ PB

where PA is an amplitude constant and PB is the pressure

asymptote. The non-linear least squares problem was

solved utilizing the Levenberg–Marquardt algorithm.

Protocol

The experiments were conducted 2–3 weeks after surgery

when pigs were healthy and apyretic. All animals were

studied in the conscious state staying in a sling and care

was taken that at least two respiratory cycles were included

in each recording. The first set of recordings was performed

to obtain measurements at Day 0. Then, responses

to dobutamine (10 lg/kg/min, 5 min) were evaluated.

Thereafter, eight pigs received a continuous angiotensin II

infusion (30 ng/kg/min) for 4 weeks using external peri-

staltic portable pumps. This dose was chosen on the basis

of dose–response curves established in preliminary exper-

iments (angiotensin II, 10–100 ng/kg/min iv).

Hemodynamic data were regularly recorded at Days 3,

7, 14, 21 and 28. Each recording was performed in the

presence and 1 h after stopping the angiotensin II infu-

sion in order to minimize the impact of changes on

loading conditions, i.e., to evaluate the intrinsic LV

contractile properties. Dobutamine infusions were repe-

ated at Day 28 in the absence of angiotensin II. Each

animal served as its own control. In addition, six other

pigs received saline infusion and served as matched

controls.

Histology

Slices from the left ventricle were fixed in 4 % formalin

and embedded in paraffin for histology. Thick paraffin-

embedded sections of 5 lm were stained with Sirius red for

the visualization of collagen fibers. Sections were mounted

in Eukitt and examined under a bright-field microscope.

Interstitial fibrosis was quantified and expressed as a per-

centage of the field area (10 fields analyzed at 109

magnification).

Statistical analysis

All results are mean ± SEM. Statistical analysis was per-

formed using one-way analyses of variance for repeated

measures. When overall differences were detected, indi-

vidual comparisons were performed by Student’s t test for

paired observations with Bonferroni’s correction. A value

of p\ 0.05 was considered statistically significant.

Results

Hemodynamic

Hemodynamic parameters in angiotensin II- and saline-

treated pigs are shown in Tables 1 and 2, respectively. The

angiotensin II-treated animals did not develop any clinical

signs of heart failure such as dyspnea, edema or ascitis.

In angiotensin II-treated animals, arterial blood pressure

significantly increased during 4 weeks of angiotensin II

infusion and this effect remained stable (Fig. 1a), con-

firming the constant effectiveness of angiotensin II infu-

sion. The rises in systolic, diastolic and mean blood

pressures averaged 61 ± 3, 50 ± 3 and 54 ± 3 mmHg

over 4 weeks, respectively. At Day 28, systolic, diastolic

and mean arterial blood pressures reached 184 ± 5,

134 ± 3 and 158 ± 5 mmHg, respectively (Fig. 1b).

In order to evaluate the intrinsic LV function indepen-

dently of an increase in arterial blood pressure, angiotensin

II infusion was stopped for 1 h during each recording.

Values of systolic, diastolic and mean arterial pressure

returned to Day 0 levels (122 ± 3 vs. 120 ± 3, 85 ± 4 vs.

82 ± 3 and 105 ± 3 vs. 101 ± 3 mmHg, respectively)

(Fig. 1c). Calculation of mean ejection wall stress con-

firmed that the loading conditions were matched between

Day 0 and Day 28 when the infusion of angiotensin II was

stopped (247 ± 23 vs. 270 ± 39 g/cm2, respectively,

p = NS).

Heart rate values measured at Day 28 either with or

without angiotensin II were significantly increased versus

Day 0 (93 ± 4 and 107 ± 8 vs. 80 ± 2 beats/min,

respectively). None of these effects were observed in saline

treated pigs.

Development of LV hypertrophy

Chronic infusion of angiotensin II induced a progressive

and significant increase in LV end-diastolic wall thickness

(Fig. 2a). As compared to age and weight-matched control

pigs (n = 6), LV to body weight ratio was significantly

increased in angiotensin II-treated animals (Fig. 2b), indi-

cating LV hypertrophy. Histological analysis also showed a

clear increase in interstitial fibrosis (Fig. 2c). Collagen

content evaluated with Sirius red was increased from

6.2 ± 0.7 to 10.2 ± 1.2 % in saline- versus angiotensin II-

treated animals (p\ 0.05).

Isovolumic relaxation alterations

We observed abnormal evolution of isovolumic relaxation

over 4 weeks of angiotensin II infusion (Table 3). Along

with the increase in heart rate at Day 28, total cycle was

significantly reduced by 22 % in the absence of angiotensin

Basic Res Cardiol (2012) 107:298 Page 3 of 10

123

II. However, isovolumic relaxation time remained para-

doxically unchanged between Day 0 and Day 28, i.e., the

ratio of isovolumic relaxation to total systolic time was

significantly increased by 21 %. That is, the time devoted

to isovolumic relaxation during each minute increased by

36 % (8.0 ± 0.3 vs. 5.9 ± 0.1 s/min at Day 28 vs. Day 0,

respectively). Similar alterations were observed in the

presence of angiotensin II at Day 28 as compared to Day 0.

Thus, regardless of the presence or absence of angiotensin

II, the relative time of isovolumic relaxation was abnor-

mally prolonged at Day 28. These changes were not

observed in control pigs (Table 4).

We further analyzed the isovolumic relaxation period by

calculating the isovolumic time constant s. Paradoxically, s

remained unchanged at Day 28 both in the presence and

absence of angiotensin II as compared to Day 0 (17 ± 1

and 18 ± 1 vs. 17 ± 1 ms), i.e., isovolumic relaxation

failed to accelerate with the increase in heart rate.

Importantly, as increasing heart rate differently influ-

ences the various phases of the cardiac cycle, we further

analyzed the hemodynamic recordings at different levels of

heart rate measured at Day 0 before any angiotensin II

infusion. As shown in Fig. 3a, the physiological increase in

heart rate in these pigs (before starting angiotensin II

infusion, n = 8) induced significant decreases in isovolu-

mic relaxation time, as opposed to the lack of decrease

after 4 weeks of angiotensin II infusion.

Concerning dobutamine infusion, at Day 0, isovolumic

relaxation time decreased by 18 % with the normal

increase in triple product of heart rate, LV dP/dtmax and

maximal LV pressure. Interestingly, this response was

significantly blunted after 4 weeks of angiotensin II

Table 1 Hemodynamic

parameters in angiotensin II-

treated pigs

Values are mean ± SEM

* p\ 0.05 versus Day 0

n Day 0 Day 28

Ang- Ang?

Heart rate (beats/min) 8 80 ± 2 107 ± 8* 93 ± 4*

Mean arterial pressure (mmHg) 8 101 ± 3 105 ± 3 158 ± 5*

LV pressure (mmHg) 8 120 ± 3 130 ± 5 186 ± 4*

LV end-diastolic pressure (mmHg) 8 11 ± 3 9 ± 2 14 ± 2

LV end-diastolic wall thickness (mm) 7 9.4 ± 0.7 12.4 ± 0.5* 11.8 ± 0.7*

LV end-systolic wall thickness (mm) 7 11.9 ± 0.8 15.9 ± 1.1* 14.4 ± 0.8*

LV wall thickening (mm) 7 2.5 ± 0.2 2.6 ± 0.3 2.6 ± 0.2

LV end-diastolic internal diameter (mm) 6 40 ± 2 42 ± 1 44 ± 1*

LV end-systolic internal diameter (mm) 6 33 ± 1 35 ± 1 37 ± 1*

LV fractional shortening (%) 6 18 ± 1 16 ± 1 17 ± 2

LV dP/dtmax (mmHg/s) 8 2,305 ± 140 3,277 ± 316* 3,537 ± 169*

LV dP/dtmin (mmHg/s) 8 -2,182 ± 97 -2,277 ± 150 -3,411 ± 105*

Table 2 Hemodynamic

parameters in saline-treated

control pigs

Values are mean ± SEM


n Day 0 Day 28

Saline- Saline?

Heart rate (beats/min) 6 84 ± 1 84 ± 3 81 ± 2

Mean arterial pressure (mmHg) 6 107 ± 2 111 ± 2 113 ± 3

LV pressure (mmHg) 6 132 ± 3 135 ± 3 132 ± 3

LV end-diastolic pressure (mmHg) 6 12 ± 2 13 ± 3 12 ± 4

LV end-diastolic wall thickness (mm) 4 9.2 ± 0.2 10.1 ± 0.4 10.2 ± 0.4

LV end-systolic wall thickness (mm) 4 11.7 ± 07 12.3 ± 0.9 12.3 ± 0.8

LV wall thickening (mm) 4 2.5 ± 0.7 2.1 ± 0.5 2.2 ± 0.5

LV end-diastolic internal diameter (mm) 5 42 ± 2 45 ± 1* 44 ± 1

LV end-systolic internal diameter (mm) 5 35 ± 2 40 ± 2* 40 ± 2*

LV fractional shortening (%) 5 18 ± 2 18 ± 3 18 ± 2

LV dP/dtmax (mmHg/s) 6 2,352 ± 41 2,318 ± 179 2,276 ± 42

LV dP/dtmin (mmHg/s) 6 -2,560 ± 78 -2,442 ± 101 -2,473 ± 68


123

infusion (-11 %) (Fig. 3b). Saline-treated animals exhib-

ited similar response between Day 0 and Day 28 (-16 and

-17 %, respectively).

Preserved ejection

During 4 weeks of chronic angiotensin II infusion, stroke

volume, LV fractional shortening and LV wall thickening

were similar both in the presence and absence of angio-

tensin II as compared to Day 0 (Fig. 4). Concomitantly and

due to the rise in heart rate, cardiac output increased at Day

28 as compared to Day 0 (3.5 ± 0.4 and 3.3 ± 0.5 L/min

with or without angiotensin II at Day 28, respectively, vs.

2.7 ± 0.3 L/min at Day 0, p\ 0.05).

Altered isovolumic contraction

We next analyzed isovolumic contraction to determine

whether it was altered along with isovolumic relaxation.

We first focused on time intervals (Table 3). Despite sig-

nificant decrease in cycle time, absolute values of isovol-

umic contraction time remained paradoxically unchanged

mm

Hg †

60

100

140

180

0 3 7 14 21 28

Days

Mean arterial pressure

Ang II +

Ang II -

A

Day 0 Day 28

Ang II–

Ang II +

SAP

mm

Hg

mm

Hg

0

50

100

150

200

0

50

100

150

200

SAP

*

DAP

DAP

*

MAP

MAP

*

B

C

Fig. 1 Arterial blood pressure

in angiotensin II-treated

animals. a Mean arterial

pressure measured at Days 0, 3,

7, 14, 21 and 28 of the protocol,

in the presence (open circle) and

absence (filled circle) of

angiotensin II; b systolic (SAP),

diastolic (DAP) and mean

(MAP) arterial blood pressures

measured at Day 0 (open bars)

and Day 28 (gray bars) in the

presence of angiotensin II;

c systolic (SAP), diastolic

(DAP) and mean (MAP) arterial

blood pressures measured in the

absence of angiotensin II, at

Day 0 (open bars) and Day 28

(gray bars). !p\ 0.05, time

effect over 4 weeks of the

protocol (ANOVA). *p\ 0.05

versus Day 0 (n = 8)

End diastolic wall thickness

mm

0 3 7 14 21 28

Days

7

9

11

13

Saline Ang II

LV/Body weight ratio

0

1

2

3

*

†

A

g/k

g

B 4

Saline Ang IIC

Fig. 2 Myocardial hypertrophy

in angiotensin II-treated

animals. a End diastolic-wall

thickness measured at Days 0, 3,

7, 14, 21 and 28 of the protocol,

in the absence of angiotensin II;

b LV to body weight ratio in

saline (open bar, n = 6) and in

angiotensin II-treated (gray bar,

n = 8) animals.

c Representative staining of

collagen (Sirius red staining)

fiber network in the left

ventricle of saline- and

angiotensin II-treated pigs.

Scale bars 100 lm. !p\ 0.05,

time effect over 4 weeks of the

protocol (ANOVA). *p\ 0.05

versus Day 0 (n = 8)


123

at Day 28 in the absence of angiotensin II as compared to

Day 0, i.e., it was significantly increased by 30 % when

related to cycle time. Thus, the time devoted to isovolumic

contraction during each minute was significantly increased

by 38 % (5.9 ± 0.3 vs. 4.3 ± 0.2 s/min at Day 28 and Day

0, respectively). These changes were not observed in

control pigs (Table 4).

At Day 0 (before starting angiotensin II infusion), these

parameters were also analyzed at different levels of heart

rate. Isovolumic contraction time decreased when heart

rate was rising (Fig. 5a). This parameter (expressed as % of

cycle) remained unchanged (8 ± 1, 8 ± 1 and 8 ± 1 % of

cycle for heart rates at 80 ± 2, 93 ± 1 and 102 ± 1 beats/

min, respectively). This contrasts with the changes of these

parameters observed after 4 weeks of angiotensin II

infusion.

Table 3 Diastolic time intervals in angiotensin II-treated pigs

Day 0 Day 28

Ang- Ang?

Total cycle time (ms) 754 ± 19 587 ± 42* 654 ± 29*

Isovolumic contraction time

(ms)

54 ± 2 56 ± 3 61 ± 3

Ejection time (ms) 251 ± 6 196 ± 7* 210 ± 5*

Isovolumic relaxation time

(ms)

74 ± 2 78 ± 5 78 ± 4

Total systolic time (ms) 378 ± 8 330 ± 12* 349 ± 8

Total diastolic filling time

(ms)

376 ± 16 258 ± 32* 305 ± 23*

Systolic time to total cycle

time (%)

50 ± 1 57 ± 2* 54 ± 2

Diastolic filling time to total

cycle time (%)

50 ± 1 43 ± 2* 46 ± 2

Isovolumic contraction time

to total systolic time (%)

14 ± 1 17 ± 1* 17 ± 1*

Ejection time to total systolic

time (%)

66 ± 1 59 ± 1* 60 ± 1*

Isovolumic relaxation time to

total systolic time (%)

19 ± 1 23 ± 1* 22 ± 1*

Values are mean ± SEM, n = 8


Table 4 Time intervals in saline-treated pigs

Day 0 Day 28

Saline- Saline?

Total cycle time (ms) 723 ± 8 752 ± 19 719 ± 23

Isovolumic contraction

time (ms)

51 ± 3 54 ± 3 53 ± 2

Ejection time (ms) 250 ± 6 251 ± 8 244 ± 6

Isovolumic relaxation time (ms) 65 ± 2 70 ± 3 68 ± 3

Total systolic time (ms) 366 ± 6 376 ± 13 365 ± 10

Total diastolic filling time (ms) 357 ± 10 377 ± 9 354 ± 18

Systolic time to total cycle

time (%)

51 ± 1 50 ± 1 51 ± 1

Diastolic filling time to total

cycle time (%)

49 ± 1 49 ± 1 50 ± 1

Isovolumic contraction time to


14 ± 1 14 ± 1 15 ± 1

Ejection time to total systolic

time (%)

68 ± 1 67 ± 1 67 ± 1

Isovolumic relaxation time to


18 ± 1 19 ± 1 19 ± 1

Values are mean ± SEM, n = 6

No statistical differences were detected

A

B

70 80 90 100 110

Heart rate (beats/min)

Iso

vo

lum

ic r

elax

atio

n t

ime

(ms)

*

55

65

75

85

*

Triple product (x 107)

Iso

vo

lum

ic r

elax

atio

n t

ime Baseline

Dobutamine

0 3 6 9 12 15

Day 0

Day 28

Saline Ang II

50

60

70

80

90

Fig. 3 Isovolumic relaxation in saline- and angiotensin-II treated

animals. a Relationship between heart rate and isovolumic relaxation

time measured at Day 0 before starting angiotensin II infusion

(n = 8); *p\ 0.05 by ANOVA; b relationship between isovolumic

relaxation time and the triple product (heart rate 9 LV dP/

dtmax 9 LV pressure) in response to dobutamine (10 lg/kg/min,

n = 6) evaluated at Day 0 (open circles and open squares for

angiotensin II- and saline-treated animals, respectively) and Day 28

(filled circles and filled squares for angiotensin II- and saline-treated

animals, respectively). Measurements were performed in the absence

of infusion. Asterisks indicate that change in isovolumic relaxation

time was significantly reduced for angiotensin II-treated animals at

Day 28 versus Day 0 (p\ 0.05), while absolute variations in triple

product were similar


123

Finally, we investigated isovolumic contraction using

dobutamine infusion. At Day 0 (Fig. 5b), isovolumic con-

traction time decreased by 45 %, while the triple product of

heart rate, LV dP/dtmax and maximal LV pressure

increased. After 4 weeks of angiotensin II infusion (in the

absence of angiotensin II), this response was significantly

blunted (-27 %). This shows a maladaptive response to

inotropic stimulation with a lack of reduction in isovolumic

contraction time. Saline-treated animals exhibited similar

response between Day 0 and Day 28 (-42 % and -44 %,

respectively).

Diastolic filling alterations

In parallel to the maladaptive response of isovolumic

contraction and relaxation, the absolute diastolic filling

time was significantly reduced (Table 3). Saline-treated

pigs showed similar values between Day 0 and Day 28

(Table 4).

Relationship between isovolumic contraction

and relaxation

As illustrated in Fig. 6a, there was a linear relationship

between the isovolumic relaxation time values (% of

cycle time) and corresponding times of isovolumic

contraction (% of cycle time) either in the presence or

the absence of angiotensin II. Values were measured at

Days 0, 3, 7, 14, 21 and 28. This indicates that the

development of alterations in isovolumic relaxation

mirrored those of isovolumic contraction (Fig. 6b). The

timing of alterations did not differ between contraction

and relaxation. For example, both isovolumic contrac-

tion time and isovolumic relaxation time (expressed as

% of cycle) increased up to 8.9 ± 0.6 and 12.7 ± 0.4 %

at Day 14 from 7.2 ± 0.3 and 9.8 ± 0.1 % at Day 0,

respectively.

Day 0 Day 28, Ang II - Day 28, Ang II +

Stroke volume

0

10

20

30

40

50

Wall thickening

0

1.0

2.0

3.0

mm

mL

Cardiac output

0

1.0

2.0

3.0

4.0

5.0

Fractional shortening

0

5

10

15

20

25

%

L/m

in

* *

Fig. 4 Ejection in angiotensin II-treated animals. Parameters were

evaluated at Days 0 (open bars) and 28 (gray bars). a Stroke volume

(mL); b left ventricular fractional shortening (%), c cardiac output

(L/min), d wall thickening (mm). Values were measured in the

presence and the absence of angiotensin II (Ang II). *p\ 0.05 versus

Day 0 (n = 8)

A

70 80 90 100 110

Heart rate (beats/min)

Isovolu

mic

contr

acti

on t

ime

(ms)

*

35

45

55

65

*

Triple product (x 107)

Isovolu

mic

contr

acti

on t

ime

Baseline

Dobutamine

B

20

40

60

80

0 3 6 9 12 15

Day 0

Day 28

Saline Ang II

Fig. 5 Isovolumic contraction in saline- and angiotensin II-treated

animals. a Relationship between heart rate and isovolumic contraction

time measured at Day 0 before starting angiotensin II infusion

(n = 8); *p\ 0.05 by ANOVA; b relationship between isovolumic

contraction time and the triple product (heart rate 9 LV dP/dtmax 9

LV pressure) in response to dobutamine (10 lg/kg/min, n = 6)

evaluated at Day 0 (open circles and open squares for angiotensin

II- and saline-treated animals, respectively) and Day 28 (filled circles

and filled squares for angiotensin II- and saline-treated animals,

respectively). Measurements were performed in the absence of

infusion. Asterisks indicate that change in isovolumic contraction

time was significantly reduced for angiotensin II-treated animals at

Day 28 versus Day 0 (p\ 0.05), while absolute variations in triple

product were similar


123

Discussion

The present study demonstrates impaired left ventricular

function in the presence of a preserved ejection in chronic

hypertensive pigs as demonstrated by maladaptive changes

in isovolumic contraction and relaxation, regardless of

changes in loading conditions. These two periods were

tightly coupled and simultaneously altered. Indeed, we

observed (1) a paradoxical increase in relative durations of

isovolumic contraction and relaxation concomitant with the

increase in heart rate over 4 weeks of angiotensin II infu-

sion, (2) both abnormal isovolumic contraction and relax-

ation responses to dobutamine and (3) a linear correlation

between isovolumic contraction and relaxation durations.

The link between contraction and relaxation has been

previously described in intact animal and human studies

investigating the effects of acute load changes, ischemic

heart disease, pulmonary hypertension or systemic chronic

hypertension [5, 6, 8, 18–21, 37]. However, they did not

distinguish between load influences and intrinsic LV

changes nor analyze the consequences of stress conditions

such as dobutamine.

In this study, we investigated our animals during chronic

hypertension and did not observe any of the usual signs of

heart failure. As previously described [9, 11, 17], LV

hypertrophy correlates with the impaired LV isovolumic

relaxation and delayed mitral valve opening. In this pig

model, isovolumic relaxation time remained unchanged

despite the increase in heart rate observed over 4 weeks of

angiotensin II infusion. This was accompanied by a

reduced diastolic filling time. We also evaluated LV

pressure decay during isovolumic relaxation by a mathe-

matical model based on a logistic equation, yielding a

constant s which shows a stable estimate of relaxation [25,

31]. At Day 28, despite the increase in heart rate, s was

abnormally unchanged as compared to Day 0. This con-

trasts with the normal heart which accelerates LV relaxa-

tion at higher rates as shown by our results obtained at Day

0 at various levels of heart rate and by previous reports [4].

We further investigated isovolumic relaxation during

dobutamine infusion and demonstrated again the inability

of the heart to adequately adapt to stress.

We next focused on stroke volume, fractional shortening

and LV wall-systolic thickening. All these parameters were

unchanged and cardiac output was not reduced, indicating

preserved ejection. However, none of these parameters

specifically investigate the isovolumic phase. We therefore

turned our attention towards the isovolumic contraction

phase searching for alterations independent of ejection. In

contrast to the normal heart, isovolumic contraction time

remained unchanged. The ratio of isovolumic contraction

to total systolic time was paradoxically and significantly

increased after 4 weeks of angiotensin II infusion, i.e., the

systolic isovolumic contraction failed to accelerate with the

increase in heart rate. One could argue that increasing heart

rate would differently influence the various phases of the

cardiac cycle and, therefore, explain our results [16]. This

is unlikely as the analysis of these time intervals with

different levels of heart rate in basal conditions (at Day 0

before starting angiotensin II infusion) clearly shows

B

A

Filling timeIsovolumic relaxation time

Mit

ral

val

ve

clo

sure

Day 0

Day 28

0 100 200 300 400

ms0 100 200 300 400

Ao

rtic

val

ve

clo

sure

Ejection timeIsovolumic contraction time

Mit

ral

val

ve

clo

sure

Day 0

Day 28

ms

Isovolumic contraction time (% cycle)

Isovolu

mic

rel

axat

ion t

ime

(%

cycl

e)

8

10

12

14

16

6 8 10 12

Ang II +

Ang II -

Fig. 6 Relationship between isovolumic contraction and isovolumic

relaxation times in angiotensin II-treated animals. a Linear relation-

ship between isovolumic contraction time (% of cycle time) and

isovolumic relaxation time (% of cycle time) measured in the

presence (open squares, y = 0.77x ? 4.9) and the absence (open

circles, y = 0.72x ? 5.4) of angiotensin II infusion. Values were

measured at Days 0, 3, 7, 14, 21 and 28. b Representative waveforms

of left ventricular pressure measured at Day 0 and after 4 weeks of

angiotensin II infusion (Day 28). Dash lines distinguish isovolumic

contraction from ejection phase (left panel) and isovolumic relaxation

from filling (right panel). Bars on the bottom quantify the relative

time intervals. Similar absolute durations for isovolumic contraction

and isovolumic relaxation were observed between Day 0 and Day 28.

Despite decreases in cycle time, isovolumic contraction and relaxa-

tion durations failed to reduce. Both phases were tightly coupled and

changes in isovolumic contraction mirrored those of isovolumic

relaxation


123

opposite pattern. Moreover, in the presence of dobutamine,

the isovolumic contraction time failed to adequately

decrease. Again, this contrasts with the normal heart in

which there is a linear relationship between this pre-ejec-

tion period and R–R interval [34].

In the present study, changes in the two LV isovol-

umic phases were simultaneous and tightly coupled.

There was a linear correlation between isovolumic con-

traction and relaxation under normal and stress condi-

tions with dobutamine. In accordance with the concept

that the heart is a muscular pump rather than a hydraulic

pump [3], there was symmetry between isovolumic

contraction and relaxation as illustrated in Fig. 6b. One

could speculate that increased fibrosis and remodeling

[1, 24] could partly explain these alterations but further

investigations are needed.

Several limitations of the present study should be

stressed. First, we did not specifically investigate the cel-

lular mechanisms explaining the alteration in isovolumic

contraction. Abnormalities in calcium handling and cell

shortening may occur [10, 12, 28, 32]. Second, we did not

perform echocardiographic studies to measure myocardial

deformation and evaluate left ventricular asynchrony. One

could speculate that inappropriate prolonged isovolumic

contraction is linked to increased systolic asynchrony with

nonuniform activation. This would induce exacerbated

ventricular nonuniformity and diastolic asynchrony with

altered isovolumic relaxation. Furthermore, isovolumic

contraction and cross-bridge detachment during relaxation

are energy-consuming processes. With this regard,

increased isovolumic time and slow LV relaxation may

further jeopardize LV function during the development of

the disease and the reduction of myocardial energy reserve.

This pig model of hypertension does not induce heart

failure per se but we believe that it constitutes the basis for

future studies and the development of new pharmacologi-

cal strategies. Finally, it remains unknown whether our

results are limited to our experimental setting or rather

could be generalized. The evaluation of isovolumic con-

traction should be re-visited in other animal models and/or

humans. The use of pressure volume catheters may have

missed subtle alterations in isovolumic contraction as the

parameters usually investigated with PV loop do not spe-

cifically explore this phase and studies in patients with

conductance catheter report the use of low frequency of

acquisition (250 Hz) which may reduce the sensitivity of

the detection [35].

In conclusion, we provide evidence of impaired LV

function with isovolumic contraction and relaxation

abnormalities during chronic hypertension while ejection

remains preserved and no sign of heart failure is present.

The evaluation under unloaded conditions shows intrinsic

LV abnormalities.

Acknowledgments This work was supported by grants from

INSERM (Mario Rienzo, poste d’accueil 2008), the Societe Francaise

d’Hypertension Arterielle (2010), the Fondation de l’Avenir (ET9-

529) and the Region Ile de France (CODDIM). We thank the Labo-

ratoire Roche for providing diazepam (Valium") and Sanofi-Aventis

for providing heparin.

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123

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Table 5. Intervalles de temps chez les porcs trait�s par angiotensine-II

Day 28

Ang - Ang +

Dur�e totale du cycle (ms) 754 ± 19 587 ± 42* 654 ± 29*

Temps de contraction isovolumique (ms) 54 ± 2 56 ± 3 61 ± 3

Temps d'�jection (ms) 251 ± 6 196 ± 7* 210 ± 5*

Temps de relaxation isovolumique (ms) 74 2 78 5 78 4

Temps systolique (ms) 378 ± 8 330 ± 12* 349 ± 8

Temps de remplissage (ms) 376 16 258 32* 305 23*

Ratio temps systolique / temps du cycle (%) 50 ± 1 57 ± 2* 54,0 ± 2

Ratio temps de remplissage / temps du cycle (%) 50 ± 1 43 ± 2* 46,0 ± 2

Ratio temps de contraction isovolumique / temps systolique (%) 14 ± 1 17 ± 1* 17 ± 1*

Ratio temps d'�jaction / temps systolique (%) 66 ± 1 59 ± 1* 60 ± 1*

Ratio temps de relaxation isovolumique / temps systolique (%) 19 ± 1 23 ± 1* 22 ± 1*

Values are mean ± s.e.m., n = 8

* p<0.05 vs Day 0

Day 0

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B. Alt�ration de la relaxation isovolumique lors de lÕadministration de dobutamine

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70 80 90 100 110

Fr�quence cardiaque (batt/min)

Tem

ps

de

rela

xat

ion

iso

vo

lum

iqu

e (m

s)

*

55

65

75

85

Figure 21. Relation entre temps de relaxation isovolumique et fr�quence cardiaque.

Param�tres mesur�s � J0 avant d�marrage de la perfusion dÕangiotensine-II (n = 8). *p<0,05

(ANOVA)

!

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Fraction de raccourcissement

Jour 0 Jour 28, Ang II - Jour 28, Ang II +

Volume dÕ�jection

0

10

20

30

40

50

Epaississement pari�tale

0

1.0

2.0

3.0

mm

mL

D�bit cardiaque

0

1.0

2.0

3.0

4.0

5.0

0

5

10

15

20

25

%

L/m

in

* *

Figure 22. LÕ�jection chez les animaux trait�s par angiotensine-II. *p<0,05 vs J0 (n = 8).

!

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5TC>9@4C!=B9FC!,!C>E=;A>C!3>!B>9PGC;5A!3\=AI;5:>AC;A>!''[!

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E. Alt�ration de la contraction isovolumique lors de lÕadministration de dobutamine

V5GC!=@5AC!>6BH594!H\4@5HG:;5A!3G!:>EBC!3>!85A:9=8:;5A!;C5@5HGE;MG>!H59C!3\GA>!B>9PGC;5A!3>!

35TG:=E;A>! ^O;I[! *,_[! &! yY]! H>! :>EBC! 3>! 85A:9=8:;5A! ;C5@5HGE;MG>! C>! 943G;:! 3>! ,-e! =@>8!

H\=GIE>A:=:;5A! 3G! :9;BH>! B953G;:[! &B9FC! ,! C>E=;A>C! 3>! B>9PGC;5A! 3\=AI;5:>AC;A>! '']! H=! B>9PGC;5A!

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/>C!=A;E=G6!85A:9kH>C!E5A:9=;>A:!3>C!94B5AC>C!;A8J=AI4>C!Q!yY!>:!y*X!^9>CB>8:;@>E>A:]!<,*e!>:!<

,,e_[!

Figure 23. Relation entre temps de contraction isovolumique et fr�quence cardiaque.

Param�tres mesur�s � J0 avant d�marrage de la perfusion dÕangiotensine-II (n = 8). *p<0,05

(ANOVA)

70 80 90 100 110

*

35

45

55

65

Fr�quence cardiaque (batt/min)

Tem

ps

de

contr

acti

on i

sovolu

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ue

(ms)

!

!

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!

F. Anomalies du remplissage

?=9=HHFH>E>A:!=G6!=H:49=:;5AC!3>C!85A:9=8:;5A!>:!9>H=6=:;5A!;C5@5HGE;MG>C]!A5GC!=@5AC!5TC>9@4!

GA>! 943G8:;5A!C;IA;P;8=:;@>!3>! H=!3G94>!3>! 9>EBH;CC=I>! ^K=T[!-_[!0>8;!A\4:=;:!B=C!5TC>9@4!8J>U! H>C!

=A;E=G6!85A:9kH>C[!

G. Couplage contraction-relaxation

)A!C>!T=C=A:!CG9!H>!85A8>B:!3G!8oG9!85EE>!B5EB>!EGC8GH=;9>]!A5GC!=@5AC!4@=HG4!H=!9>H=:;5A!

85A:9=8:;5A<9>H=6=:;5A!3=AC!A5C!85A3;:;5AC!>6B49;E>A:=H>C[!V5GC!=@5AC!5TC>9@4!GA>!9>H=:;5A!H;A4=;9>!

>A:9>!H>C!3G94>C!3>!85A:9=8:;5A!>:!3>!9>H=6=:;5A!;C5@5HGE;MG>C!^>6B9;E4>C!85EE>!9=:;5!CG9!H=!3G94>!

3G! 878H>! 8=93;=MG>_! >A! B94C>A8>! >:! >A! H\=TC>A8>! 3\=AI;5:>AC;A>! ''! ^O;I[! *,_[! V5GC! =@5AC! G:;H;C4!

H\>AC>ETH>!3>C!E>CG9>C!5T:>AG>C!Q!yY]!y+]!yd]!y",!y!*"!>:!y*X[!0>8;!CGIIF9>!MG>!H>!34@>H5BB>E>A:!

3>C!=H:49=:;5AC!3>!H=!9>H=6=:;5A!;C5@5HGE;MG>!C\;AC:=HH>!85A85E;:=EE>A:!Q!8>HH>C!3>!H=!85A:9=8:;5A!

;C5@5HGE;MG>!^O;I[!*-_[!

*

Triple produit (x 107)

Tem

ps

de

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acti

on i

sovolu

miq

ue Base

Dobutamine

20

40

60

80

0 3 6 9 12 15

J 0

J 28

Contr�les Ang II

Figure 24. Relation entre le temps de contraction isovolumique et le triple produit [(Pression

VG)*FC*dP/dtmax] en r�ponse � la perfusion de dobutamine. Param�tres mesur�s � J0 (cercles

et carr�s ouverts) et � J28 (cercles et carr�s pleins), la perfusion dÕangiotensine-II �tant

suspendue(n = 6). *p<0,05 (ANOVA)

!

!

"Y+!

!

B

A

Filling timeIsovolumic

relaxation time

Mit

ral

val

ve

clo

sure

Day 0

Day 28

0 100 200 300 400

ms

0 100 200 300 400

ms

Ao

rtic

val

ve

clo

sure

Ejection timeIsovolumic

contraction time

Mit

ral

val

ve

clo

sure

Day 0

Day 28

Filling timeIsovolumic

relaxation time

Mit

ral

val

ve

clo

sure

Day 0

Day 28

0 100 200 300 400

ms

0 100 200 300 400

ms

0 100 200 300 400

ms

0 100 200 300 400

ms

0 100 200 300 400

ms

Ao

rtic

val

ve

clo

sure

Ejection timeIsovolumic

contraction time

Mit

ral

val

ve

clo

sure

Day 0

Day 28

Temps de contraction isovolumique (% cycle)

Tem

ps

de

rela

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ion i

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(%

cycl

e)

8

10

12

14

16

6 8 10 12

Ang II +

Ang II -

Jour 0

Jour 28

Jour 0

Jour 28

Temps de contraction

isovolumique

Temps de relaxation

isovolumique

Temps dÕ�jection Temps de remplissage

Fer

met

ure

de

la v

alv

e

mit

rale

Fer

met

ure

de

la v

alv

e

mit

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Figure 25. A) Relation entre temps de contraction et relaxation isovolumiques.

B) Courbes de pression ventriculaire repr�sentatives du m�me ph�nom�ne.

!

!

"Y,!

'L[!0$%%)VK&'()#!

&!H\=;3>!3>!A5:9>!E53FH>!3\J7B>9:>AC;5A!=9:49;>HH>!8J95A;MG>!;A3G;:>!B=9!H=!B>9PGC;5A!85A:;AG>!

3\=AI;5:>AC;A>!''!^C=GP!=G!E5E>A:!3>C!E>CG9>C_]!A5GC!A5GC!C5EE>C!P58=H;C4!CG9!H=!85A:9=8:;5A!>:!H=!

9>H=6=:;5A! ;C5@5HGE;MG>C[!)A! 94CGE4]!8>! :9=@=;H!E5A:9>!GA>!=H:49=:;5A!3>! H=! P5A8:;5A!@>A:9;8GH=;9>!

3=AC!C>C!3>G6!85EB5C=A:>C!;C5@5HGE;MG>]!H=!85A:9=8:;5A!>:!H=!9>H=6=:;5A[!&GCC;!T;>A!=G!9>B5C!^yY!>:!

y*X_!5G! H59C!3\GA>!=3E;A;C:9=:;5A!3>!35TG:=E;A>]!A5GC!=@5AC!5TC>9@4!3>C! 94B5AC>C! ;A=BB95B9;4>C!

3>C! BJ=C>C! ;C5@5HGE;MG>C! 3G! 878H>! 8=93;=MG>! Q! H=! CG;:>! 3\=GIE>A:=:;5AC! 3>! H=! P94MG>A8>! >:! 3>!

H\;A5:95B;CE>! 8=93;=MG>[! 2=AC! A5C! 85A3;:;5AC! >6B49;E>A:=H>C]! H>C! B9>CC;5AC! @>A:9;8GH=;9>C!

:4H43;=C:5H;MG>C! A\4:=;>A:! B=C! E53;P;4>C! >:! =G8GA! C;IA>! 85AI>C:;P! A\4:=;:! B94C>A:]! :9=3G;C=A:! GA>!

C;:G=:;5A!3>!37CP5A8:;5A!3;=C:5H;MG>[!&;AC;]!A5GC!=@5AC!5TC>9@4!1!

"<! GA>! =GIE>A:=:;5A! B=9=356=H>! 3>C! 3G94>C! 9>H=:;@>C! 3>! 85A:9=8:;5A! >:! 3>! 9>H=6=:;5A!

;C5@5HGE;MG>C!H59C!3\GA>!:=8J78=93;>!c!3=AC!H>C!85A3;:;5AC!BJ7C;5H5I;MG>C]!;H!>6;C:>!GA>!=3=B:=:;5A!

C>!:9=3G;C=A:!B=9!GA>!=884H49=:;5A!>:!H=!943G8:;5A!3>!H=!3G94>!3>!8>C!3>G6!B49;53>C!c!

*<! 3>C! 94B5AC>C! =A59E=H>C! 3>! H=! 85A:9=8:;5A! >:! 3>! H=! 9>H=6=:;5A! ;C5@5HGE;MG>C! H59C! 3>!

H\=3E;A;C:9=:;5A!3>!35TG:=E;A>!c!3>!ErE>]!>A!85A3;:;5A!BJ7C;5H5I;MG>]!H>C!BJ=C>C!C\=884HF9>A:!B5G9!

I=93>9! GA! 4MG;H;T9>! >A:9>! H>C! 3;PP49>A:>C! B49;53>C! 3G! 878H>! >:! B5G9! B94C>9@>9! H\4S>8:;5A! >:! H>!

9>EBH;CC=I>!@>A:9;8GH=;9>!c!

+<! GA>! 4:95;:>! 34B>A3=A8>! >A:9>! 8>C! 3>G6! BJ=C>C! ;C5@5HGE;MG>C!1! 8>8;!E5A:9>! T;>A! MG>! H>C!

=A5E=H;>! 3>! 8>C! 3>G6! BJ=C>C! C>! 34@>H5BB>A:! C;EGH:=A4E>A:! >:! GA>! =H:49=:;5A! 3>! H=! 9>H=6=:;5A!

;C5@5HGE;MG>! C\=885EB=IA>! 5TH;I=:5;9>E>A:! 3>! 8>HH>! 3>! H=! 85A:9=8:;5A! 3=AC! A5C! 85A3;:;5AC!

>6B49;E>A:=H>C[!!

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;C5@5HGE;MG>! A\>C:! B=C! B94C>9@4>! =G! 85G9C! 3>! 8>::>! J7B>9:>AC;5A! 8J95A;MG>! >:! 3G! B958>CCGC!

J7B>9:95BJ;MG>[! /=! B>9:>! 3>! H=! 8=B=8;:4! 3\=884H49=:;5A! 3>C! BJ=C>C! ;C5@5HGE;MG>C! C\>PP>8:G>! =G!

34:9;E>A:! 3G! 9>EBH;CC=I>]! H\4S>8:;5A! 4:=A:! E=;A:>AG>[! V5C! 94CGH:=:C! E5A:9>A:! 4I=H>E>A:! MG>! 8>C!

E53;P;8=:;5AC!C5A:!;A:9;ACFMG>C!=G!@>A:9;8GH>!I=G8J>[!

! !

!

!

"Y-!

CHAPITRE VIII : MODULATION

PHARMACOLOGIQUE DU COUPLAGE

CONTRACTION-RELAXATION

0>::>!4:G3>!=!P=;:!H\5TS>:!3\GA!E=AGC89;:!C5GE;C!Q!BGTH;8=:;5A!1!!Pivotal role of increased heart rate in the deterioration left ventricular function during

chronic hypertension in conscious pig.

!B=9!(;>AU5!%]!%>Hw=! y]!W;U4!&]! y5Uf;=w!%]!#=ET;A!/]!#G! yW]!N;::;AI>9!/]!W>93>=G6!&]!.J=H>J!W[!

Pivotal role of heart rate reduction to improve left ventricular

function during chronic hypertension in conscious pigs.

Mario Rienzo, MD 1,2,3,5,*

; Jonathan Melka, MsC 1,2,3, *

; Alain Biz�, BsC 1,2,3

;

Mathieu Jozwiak, MD, 1,2,3

; Lucien Sambin, BsC 1,2,3

; Jin Bo Su, PhD 1,2,3

,

Luc Hittinger, MD, PhD 1,2,3,4

; Alain Berdeaux, MD, PhD 1,2,3,4

; Bijan Ghaleh, PhD 1,2,3

.

1- Inserm, U955, Equipe 03, F-94000, Cr�teil, France;

2- Universit� Paris-Est, UMR_S955, UPEC, F-94000, Cr�teil, France;

3- Universit� Paris-Est, Ecole Nationale V�t�rinaire d'Alfort, F-94700, Maisons-Alfort,

France;

4- AP-HP, Groupe Hospitalier Henri Mondor, F�d�ration de Cardiologie, F-94000, Cr�teil,

France

5- AP-HP, H�pital Europ�en Georges Pompidou, Service dÕAnesth�sie-R�animation

Chirurgicale, F-75015, Paris, France

* : both author equally contributed

Author for correspondence

Pr Bijan GHALEH

INSERM U 955 Equipe 03

Facult� de M�decine

8 rue du G�n�ral Sarrail

94000 Cr�teil

Tel : +33-1-49.81.37.84

Fax : +33-1-49.81.37.97

2

Abstract

Objectives: we investigated the effects of acute selective HR reduction with ivabradine on

Left ventricular (LV) dysfunction during chronic hypertension.

Background: during chronic hypertension, increases in heart rate or adrenergic stimulation

induce maladaptive LV responses with paradoxical lack of reduction in isovolumic

contraction and relaxation durations, impeding LV filling.

Methods: 8 chronically instrumented pigs received continuous angiotensin II infusion during

4 weeks to induce chronic hypertension. A single intravenous dose of ivabradine was

administered at Day 0 and Day 28. The effects of dobutamine were also investigated.

Results: Heart rate was significantly increased at Day 28 vs Day 0 (104±6 vs. 75±2 beats/min,

respectively). Paradoxically, both isovolumic contraction and relaxation times failed to reduce

and remained unchanged (60±3 vs. 54±3 ms at Day 0 and 72±3 vs. 77±2 at Day 0,

respectively). At Day 28, ivabradine reduced heart rate to respective baseline value of Day 0

(77±3 vs. 75±2 beats/min, respectively). Concomitantly, both isovolumic contraction and

relaxation times were significantly reduced (-17% and -11%, respectively) while LV filling

time was improved. Similarly at Day 28, maladaptive responses of isovolumic contraction and

relaxation to dobutamine were overcome by heart rate reduction with ivabradine.

Conclusion: acute HR reduction with ivabradine corrects the maladaptive responses of

cardiac cycle phases during chronic hypertension by restoring a normal profile for isovolumic

contraction and relaxation both at rest and under stress stimuli, ultimately favouring LV

filling. This demonstrates the pivotal role of controlling HR to avoid the deterioration of LV

function.

Key words: isovolumic contraction, diastolic dysfunction, hypertension

3

Condensed abstract

During chronic hypertension, increases in heart rate (HR) or adrenergic stimulation induce

maladaptive left ventricular responses with paradoxical lack of reduction in isovolumic

contraction and relaxation durations, impeding LV filling. We investigated acute selective HR

reduction with ivabradine on LV during chronic hypertension induced by continuous infusion

of angiotensin II in chronically instrumented pigs. Ivabradine corrects the maladaptive

responses of cardiac cycle phases during chronic hypertension by restoring a normal profile

for isovolumic contraction and relaxation both at rest and under dobutamine, favouring LV

filling. This demonstrates the pivotal role of controlling HR to avoid the deterioration of LV

function.

4

Introduction

There is a growing interest in investigation of the link between left ventricular (LV)

diastolic dysfunction and heart failure with preserved ejection fraction (HF-pEF) (Borlaug

and Redfield 2011; De Keulenaer and Brutsaert 2011; Paulus and Tschope 2013). In this

setting, we previously developed a swine model of diastolic dysfunction with preserved

ejection but devoid of any sign of heart failure (Rienzo, Bize et al. 2012). In the normal heart,

the reduction of isovolumic contraction and relaxation durations is a physiological response to

increase in heart rate (HR). This allows the heart to maintain a constant and controlled

balance among the different phases of cardiac cycle for favouring both LV ejection and filling

(Lance and Spodick 1975; Kobayashi, Kotilainen et al. 1979; Miyamoto, Higuchi et al. 1983).

In conscious instrumented pigs, we evaluated LV function during chronic hypertension and

hypertrophy induced by continuous infusion of angiotensin II. Although no clinical signs of

heart failure were present and ejection was preserved, we observed early and simultaneous

maladaptive LV responses to chronotropic and inotropic stimuli that altered diastolic filling

time. The maladaptive LV responses displayed as (1) the lack of reduction in isovolumic

contraction and relaxation durations as HR increases and (2) abnormally blunted isovolumic

contraction and relaxation responses to dobutamine infusion. These observations led us to

consider a pivotal role of increased HR in the deterioration of LV function during chronic

hypertension.

Accordingly, our objective was to investigate the effects of acute selective HR reduction

with the If-channel blocker ivabradine (Thollon, Cambarrat et al. 1994) on LV dysfunction in

our chronic hypertensive pig model because this drug has the advantage that it does not

modify atrioventricular or intraventricular conduction, inotropy and lusitropy in animals and

humans (Simon, Ghaleh et al. 1995; Bois, Bescond et al. 1996; Colin, Ghaleh et al. 2004;

5

Vilaine 2006). Moreover, whether HR should be increased or decreased during diastolic

dysfunction and heart failure with preserved ejection fraction remains matter of debate. On

the one hand, reducing HR could severely impair cardiac output by reducing the number of

filling cycles per minute and rate-adaptive cardiac pacing is proposed (Borlaug and Kass

2006). On the other hand, reduction in HR could facilitate diastolic filling by prolonging

diastolic period (Colin, Ghaleh et al. 2002; Monnet, Colin et al. 2004), improving

arterioventricular coupling (Reil and Bohm 2007) or reducing myocardial ischemia (Monnet,

Ghaleh et al. 2006; Heusch, Skyschally et al. 2008). Here we hypothesized that selective HR

reduction with ivabradine could restore a normal balance between the different phases of the

cardiac cycle by normalizing the acceleration of isovolumic contraction and relaxation times

in response to stress. Through this mechanism, ivabradine could improve LV function at rest

and avoid its deterioration during combined inotropic and chronotropic stimulation.

6

Methods

The experiments were conducted in accordance with the French regulations concerning the

use of animals in research and were agreed by the local animal ethical committee [ComEth

AFSSA-ENVA-UPEC agreement #11-0059]

Surgical instrumentation

Under anesthesia, eight female pigs (20Ð30 kg) underwent left thoracotomy. Fluid-filled

Tygon catheters were implanted in the descending thoracic aorta, in the left atrium and in the

pulmonary artery for measurement of arterial blood pressure and angiotensin II infusion.

A

solid-state pressure transducer (Konigsberg Instruments, Pasadena, CA) was introduced into

LV. A flow probe (Transonic Systems Inc, Ithaca, NY) was implanted around the aortic root.

Piezoelectric crystals were implanted 1) on opposed LV anterior and posterior endocardial

surfaces to measure LV internal diameter, and 2) on opposed LV endocardial and epicardial

surfaces to measure wall thickness. All catheters and wires were exteriorized between the

scapulae. Animals were sedated with diazepam (0.2-0.4 mg/kg iv) for postoperative care.

Enrofloxacine (2 mg/kg/day, im) and long acting amoxicillin (15 mg/kg every two days, im)

were administered during ten days after surgery. Buprenorphine (0.3 mg sc) was administered

during five days after surgery. The position of all catheters and crystals was confirmed at

autopsy.

Hemodynamic measurements

All hemodynamic data were digitized, recorded, and analysed using HEM v4.2 software

(Notocord Systems, Croissy sur Seine, France). Aortic and left atrial pressures were measured

with P23XL pressure transducers (Becton-Dickinson, Franklin Lakes, NJ, USA). Cardiac

output was measured using a T206 blood flow-meter (Transonic Systems Inc., Ithaca, NY,

7

USA). LV pressure was cross-calibrated with the left atrial and aortic pressures. Change in

LV pressure over time (dP/dt) was computed from the LV pressure signal. Wall thickening

was defined as end-systolic minus end-diastolic wall thickness. The signals of LV wall

thickness, LV internal diameter and aortic flow were suitable in 4, 5 and 6 of the 8

instrumented pigs, respectively.

LV end-diastole was defined as the initiation of the upstroke of LV pressure tracing after

atrial contraction and indicated by the initial increase in LV dP/dt. Aortic valve opening and

closure were identified by crossing LV and aortic pressure waveforms. The isovolumic

contraction time was defined as the time interval between end-diastole and aortic valve

opening. The ejection time was defined as the time interval between aortic valve opening and

closure. Mitral valve opening was identified by crossing LV and atrial pressure waveforms

identified mitral valve opening. The isovolumic relaxation period was defined as the period

elapsed from aortic valve closure and mitral valve opening. The filling period was computed

from the end of isovolumic relaxation to end-diastole.

Protocol

The experiments were conducted 2-3 weeks after surgery when pigs were healthy and

apyretic. All animals were studied in conscious state staying in a sling. Protocol is shown in

Figure 1. At Day 0, a first set of recordings was performed at baseline and during infusion of

dobutamine (10 !g/kg/min, 5 min). Then, these responses were again evaluated after

intravenous injection of ivabradine (1 mg/kg iv bolus).

Thereafter, and as previously described (Rienzo, Bize et al. 2012), the animals received a

continuous angiotensin II infusion (30 ng/kg/min) during 4 weeks using external peristaltic

portable pumps to induce hypertension. In these conditions, the animals developed LV

hypertrophy (LV to body weight at 3.9 ± 0.2). At Day 28, responses to dobutamine were

8

again evaluated before and after administration of ivabradine. These recordings were

performed 1h after stopping the angiotensin II infusion in order to minimize the impact of

changes in loading conditions, i.e., to evaluate the intrinsic LV contractile properties. Each

animal served as its own control.

Data and statistical analyses

All results are means ± SEM. Statistical analysis was performed using two-way analyses of

variance (ANOVA) for repeated measures with drug effect, time effect and time*drug

interaction. Individual comparisons were performed by Student's t-test. Differences were

considered significant for P < 0.05 and the tests were two-sided. The statistical analysis was

performed with StatView version 5.0 (Abacus Concept, Berkeley, CA).

9

Results

Changes in hemodynamic and cycle time intervals in resting conditions at Day 0 and Day 28

Hemodynamic parameters measured in basal conditions and in response to dobutamine

at Day 0 and after four weeks of continuous angiotensin-II infusion (Day 28) are shown in

Table 1. All these parameters were obtained in the absence of angiotensin II. According to our

previous findings (Rienzo, Bize et al. 2012), HR was increased by 39% at Day 28 vs Day 0,

while mean arterial pressure and systolic LV pressure were similar. As a result of increase in

HR, cardiac output tended to increase. Under dobutamine infusion, basal HR was

significantly increased by 25% at Day 0 and by 14% at Day 28. At Day 0 but not at Day 28,

dobutamine lowered mean arterial pressure while systolic LV pressure was unchanged. LV

dP/dtmax was significantly increased at Day 28 vs Day 0 in basal conditions and dobutamine

exerted similar inotropic effects at both time points.

Regarding cardiac cycle time intervals, as a result of increased heart rate (Figure 2),

total cycle, ejection and filling times were significantly reduced. Paradoxically, as shown in

Table 3 and in agreement with our previous findings (Rienzo, Bize et al. 2012), both

isovolumic contraction and relaxation times failed to reduce and remained unchanged.

Therefore the time devoted to isovolumic contraction and relaxation phases during each

minute increased by 44% and 28% respectively (6.2±0.3 vs. 4.3±0.3 s/min and 7.4±0.4 vs.

5.8±0.2 s/min, at Day 28 vs. Day 0, respectively). Ejection time was unchanged (20.0 ± 0.8

vs. 20.7 ± 0.8 s/min) whereas filling time was reduced (26.3 ± 1.6 vs. 31.3 ± 1.4 s/min).

At Day 0, under dobutamine infusion, isovolumic contraction and relaxation times

decreased by 45% and 22%, respectively, with the normal increase in triple product of HR,

LV dP/dtmax and LV peak pressure (Figure 3). Similar results were obtained by examining the

10

relationships between these time intervals and HR alone. At Day 28, isovolumic contraction

and relaxation phases failed to properly adapt to dobutamine administration as their responses

were blunted (33% and 7% respectively) (Figure 3).

All these results observed both at rest and after dobutamine at Day 28 vs. Day 0 show a

maladaptive response to chronotropic and inotropic stimulation of these chronic hypertensive

hearts which are unable to reduce isovolumic contraction and relaxation times. As a

consequence, LV filling was impeded as the time devoted to this phase was reduced.

Selective heart rate reduction in resting conditions

We next examined whether selective HR reduction might correct the above mentioned

abnormalities. As shown in Table 2 and as expected, at Day 0, ivabradine significantly

reduced HR by 24%. Values of LV peak pressure and LV dP/dtmax were not significantly

different at baseline vs. after ivabradine. As a result of HR reduction, LV end-diastolic wall

thickness was reduced and LV end-diastolic internal diameter was increased. Concomitantly,

we observed increases in LV wall thickening and fractional shortening.

At Day 28, administration of ivabradine produced similar HR reduction (-26%) vs.

Day 0 (-24%). The effects on general hemodynamic and dimensions were not significantly

different from those observed at Day 0. Significant interaction with ANOVA detected more

pronounced reduction in LV end-diastolic wall thickness at Day 28.

Regarding time intervals (Table 3), administration of ivabradine at Day 0 significantly

increased total cycle time while leaving ejection time unchanged. Concomitantly, both

isovolumic and relaxation time were significantly reduced (-17% and -11%, respectively). As

a consequence, filling time rose by 70%. At Day 28, ivabradine induced similar effects on

isovolumic contraction and relaxation (-23%, -7%, respectively) while ejection time remained

11

unchanged. Significant interaction was detected with ANOVA for filling time yielding a

greater effect of ivabradine at Day 28 vs. Day 0 (+75% vs. +68%, respectively).

These results show that HR reduction favourably modifies the distribution of time

periods of cardiac cycle by preserving the ejection period, reducing both isovolumic

contraction and relaxation phases and finally increasing the time devoted to filling.

Interestingly, HR values at Day 28 after ivabradine were similar to Day 0 at baseline (77±3

and 75±3 beats/min, respectively). Therefore we examined the effects of this acute selective

HR reduction on the different time phases of cardiac cycle. While total cycle time remained

unchanged between these two conditions (793±35 vs. 839±35 ms for ivabradine at Day 28 vs.

baseline at Day 0), we observed that isovolumic contraction and relaxation times were

significantly lower at Day 28 after ivabradine than the corresponding ones at Day 0

(baseline). Concomitantly, ejection time was lower and filling time was greater (465±29 vs.

425±26 ms, respectively). As illustrated in Figure 4, selective heart rate reduction abolished

the abnormal LV behaviour observed at baseline of Day 28.

Selective heart rate reduction during dobutamine infusion

As selective HR reduction showed favourable influence on cycle phases at baseline, we

next investigated the combination of ivabradine and dobutamine. Interestingly, we observed

that HR values under the combination of ivabradine plus dobutamine at Day 28 were similar

to those observed under dobutamine alone at Day 0 (Table 4). As shown in Table 4 and

Figure 5, we observed that isovolumic contraction and relaxation times were similar while

filling period was prolonged. This indicates that HR reduction corrected the maladaptive

response of isovolumic phases. Taken together, these results show that under chronotropic

and inotropic stimulation with dobutamine, HR reduction by ivabradine favourably modifies

12

the distribution of time periods of cardiac cycle by normalizing both isovolumic phases and

finally increasing the time devoted to filling.

13

Discussion

In the present study, selective HR reduction with acute administration of the If-channel

selective blocker ivabradine reversed the LV maladaptive responses induced by chronic

hypertension. In this pig hypertensive model, (Rienzo, Bize et al. 2012), paradoxical

prolonged isovolumic contraction and relaxation times were abolished by selective HR

reduction. Indeed, their durations were normalized both at baseline and during chronotropic

and inotropic stimulation with dobutamine, which contributes to the increase in LV filling

time and preservation of LV ejection during chronic hypertension. These results indicate a

pivotal role of increased HR in the deterioration in LV function and HR reduction as a mean

to preserve LV performance.

We previously showed that the swine model of chronic hypertension induced by chronic

angiotensin II infusion is characterized by preserved ejection but simultaneous contraction

and relaxation abnormalities which are tightly coupled (Rienzo, Bize et al. 2012). We believe

that this symmetry between contraction and relaxation is in accordance with the concept of

the heart as a muscular pump rather than a hydraulic pump (Brutsaert 2006), which explains

the presence of subtle contraction alterations although the ejection fraction is preserved. In the

present study, we confirmed our previous results and observed paradoxical increases in

isovolumic contraction and relaxation times when HR and myocardial contractility were

increased by dobutamine. In addition, while ejection time was preserved, the filling was

hampered with the consecutive reduction of its duration.

Several classical physiological reports have clearly shown that a tuned balance exists

between HR and cardiac cycle phases in order to optimize ventricular ejection (Lance and

Spodick 1975; Abdullah, Siddiqui et al. 1977; Frey and Kenney 1979; Kobayashi, Kotilainen

et al. 1979; Miyamoto, Higuchi et al. 1983). When HR increases, ejection time exhibits a

14

different pattern than isovolumic contraction, and relaxation or filling times. As previously

observed, isovolumic contraction and relaxation as well as filling times proportionally

decreased while ejection time is preserved when HR increases above 70 bpm (Van Der

Hoeven, Clerens et al. 1977; Colin, Ghaleh et al. 2004). In pathological situations, this

balance is lost (De Scalzi, De Leonardis et al. 1986) and this can be unmasked under stress

conditions. In our experimental conditions, the loss of this balance among cardiac phases was

supported by abnormal behaviour of isovolumic contraction and relaxation when heart rate

was increased. Because heart rate has a pivotal role in adapting cardiac output to metabolic

demands by tuning all these cardiac phases, it could stand as an elective target in

cardiovascular therapeutics (Levine and Stray-Gundersen 1997; Reil and Bohm 2007; Heusch

2011). In this respect, selective HR by If-channel inhibition with ivabradine has been

proposed in several pathological conditions such as myocardial ischemia or heart failure

(Swedberg, Komajda et al. 2010). However, it is also thought that HR reduction is not to

useful because it would severely impair cardiac output by reducing the number of filling

cycles per minute and in this regard, the rate-adaptive cardiac pacing is rather proposed

(Borlaug and Kass 2006).

Taking into account all these considerations, we examined in the present study the

effects of acute HR reduction with ivabradine to test the hypothesis that selective HR

reduction could normalize the balance between the different phases of the cardiac cycle.

Ivabradine has several advantages upon other bradycardic agents as it modifies neither LV

contractility (Ferro, Spinelli et al. 1991; Simon, Ghaleh et al. 1995), nor mean ventricular

stress during ejection (Colin, Ghaleh et al. 2002) and preserves ventricular relaxation unlike

beta-blockers (Gaasch, Blaustein et al. 1980; Cheng, Freeman et al. 1990; Colin, Ghaleh et al.

2002). HR reduction exhibits also powerful anti-ischemic action (Guth, Heusch et al. 1987;

15

Indolfi, Guth et al. 1989; Monnet, Ghaleh et al. 2001; Fang, Debunne et al. 2012) and

increases diastolic coronary perfusion time (Colin, Ghaleh et al. 2004).

In this study, HR reduction with ivabradine decreased isovolumic contraction and

relaxation times in resting conditions. Moreover we compared their respective values

observed at baseline at Day 0 vs. after ivabradine at Day 28, i.e., when heart rate values were

matched, we found that these two isovolumic times were restored and their ratios were

normalized while ejection time was not altered but filling time was improved. These

beneficial effects were also observed under dobutamine. When comparing matched HR

conditions under dobutamine (dobutamine at Day 0 vs. dobutamine plus ivabradine at Day

28), a single dose of ivabradine restored the response of these two isovolumic times and

normalized their ratio. We chose acute administration in order to avoid the known long-terms

effects of ivabradine such as the modulation of the inflammatory response and collagen

turnover (Custodis, Baumhakel et al. 2008; Becher, Lindner et al. 2012), atherosclerosis

(Rogowski, Shapira et al. 2007; Dominguez-Rodriguez, Blanco-Palacios et al. 2011;

Schirmer, Degen et al. 2012), modulation of cardiac apoptosis and LV hypertrophy (Reil,

Hohl et al. 2012; Yue-Chun, Teng et al. 2012) or changes in protein expression (Couvreur,

Tissier et al. 2010). Therefore our results are rather the mechanical consequence of pure heart

rate reduction although we cannot rule out other pleiotropic effects (Heusch 2008). Such acute

mechanical effect of ivabradine is in agreement with previous findings showing that acute HR

reduction has a favourable effect on the depressed wall thickening and increased post-systolic

wall thickening during post-ischemic myocardial stunning (Monnet, Ghaleh et al. 2001;

Lucats, Ghaleh et al. 2007). Thus it appears that HR reduction per se is sufficient to modify

the balance between the different time phases among the cardiac cycle.

16

Previous experimental studies explored ivabradine in small animals with LV

dysfunction induced by angiotensin-II infusion with osmotic pumps (Becher, Lindner et al.

2012), aortic banding (Ciobotaru, Heimburger et al. 2008), diabetes with db/db mice (Reil,

Hohl et al. 2012) or hypercholesterolema (Busseuil, Shi et al. 2010) and reported favourable

effets of chronic HR reduction. Among these studies, the two hypertensive models and that

associated with diabetes evolved in global heart failure whereas the dyslipidaemic one

developed ÒpureÓ diastolic dysfunction. Our experimental setting is the first one to test the

mechanical consequences of acute administration of ivabradine in large animals displaying

LV dysfunction without ischemic heart disease and without heart failure. Our results are in

line with a recent clinical study showing a beneficial effect of short-course ivabradine

administration on exercise tolerance and LV function, especially LV filling, in patients with

HFpEF (Kosmala, Holland et al. 2013). Although speculative, the results of this study could

contribute to explain these improvements considering that the overall administration period

lasted only one week in this clinical study. In addition, our results showed that maladaptive

responses of isovolumic phases to adrenergic stimulation are normalized by ivabradine. This

may be the basis for further investigations concerning the combination of HR reduction with

ivabradine and inotropic stimulation to overcome the adverse effects of adrenergic stimulation

on isovolumic phases of cardiac cycle. It is tempting to speculate that combining dobutamine

and ivabradine, i.e., coupling positive inotropic and time cycle redistributing properties,

respectively, may improve LV function in HFpEF patients with signs of cardiac failure

(Roubille, Lattuca et al. 2013). Finally, the tight coupling of isovolumic contraction and

relaxation observed here further supports the concept of muscular pump (Brutsaert 2006) as a

basis for investigating the heart.

In conclusion, acute HR reduction with ivabradine restores normal LV function in a

large animal model of chronic hypertension with preserved ejection and without any sign of

17

cardiac failure. Selective HR reduction allowed to correct the maladaptive responses of

cardiac cycle phases that occur during chronic hypertension and which may contribute to

jeopardize LV function. This correction is made possible by restoring a normal profile for

isovolumic contraction and relaxation both at rest and under stress stimuli. This redistribution

among the cardiac phases ultimately favours LV filling. Thus, our results demonstrates the

beneficial effects of selective HR reduction during LV dysfunction of hypertensive hearts and

shows the pivotal role of controlling HR to avoid the deterioration of LV function.

18

Source of funding

This work was supported by grants from INSERM (Mario Rienzo, poste d'accueil 2008), the

Soci�t� Fran�aise d'Hypertension Art�rielle (2010), the Fondation de l'Avenir (ET9-529, ET2-

648), the R�gion Ile de France (CODDIM) and UPEC (Universit� Paris Est Cr�teil).

Acknowledgements

We thank the Laboratoire Roche for providing diazepam (Valium¨) and Servier for the gift

of ivabradine.

Conflict of interest

Alain Berdeaux has received honoraria for lectures and has served as consultant to Servier.

The other authors have no conflict of interest to declare. No pharmaceutical grant was

associated with this work.

19

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23

Figure legends

Figure 1

Experimental protocol

Figure 2

Total cycle, ejection, filling, isovolumic contraction and isovolumic relaxation times were

evaluated at Day 0 (open bars) and Day 28 (grey bars). *, P<0.05 vs Day 0 (n=8).

Figure 3

Relationship between triple product (heart rate x LV dP/dtmax x LV pressure) (left) or heart

rate (right) vs isovolumic contraction time (upper panel) or isovolumic relaxation time (lower

panel) measured at baseline (circles) and in response to dobutamine (10 !g/kg/min) (squares).

Responses were evaluated at Day 0 (open symbols and at Day 28 (closed). Changes in

isovolumic contraction and relaxation times were significantly reduced at Day 28 (significant

interaction detected by ANOVA when analysing these time periods) (n=8).

Figure 4

Isovolumic contraction, isovolumic relaxation, ejection and filling times were evaluated at

baseline at Day 0 (open circles) and at Day 28 before (open square) and after administration

of ivabradine (1 mg/kg) (closed square). *, P<0.05 vs. corresponding Day 0 (n=8); , P<0.05

vs. corresponding baseline at Day 28 (n=8).

24

Figure 5

Cycle times were analyzed under matched heart rate conditions. Isovolumic contraction,

isovolumic relaxation, ejection and filling times heart rate were evaluated under dobutamine

(10 !g/kg/min) at Day 0 (open circles) and at Day 28, with dobutamine infused after

administration of ivabradine (1 mg/kg) (closed circle). *, P<0.05 vs. corresponding baseline at

Day 0 (n=8).

25

Ta

ble

1. H

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od

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sure

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ne

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s an

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min

e a

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ay

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8

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Base

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875

±2

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±3

10

4±

61

19

±8

0.0

1<

0.0

50

.38

Mea

nart

eria

lp

ress

ure

(m

mH

g)

81

06

±2

93

±3

10

5±

41

04

±6

0.2

9<

0.0

50

.04

LV

pre

ssu

re (

mm

Hg

) 8

12

5±

211

9±

21

24

±6

12

9±

60

.49

0.7

00

.15

LV

en

d-d

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oli

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all

thic

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s(m

m)

59.1

±0.3

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12

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0.8

11.7

±0.6

<0.0

50.8

10

.24

LV

wa

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m)

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±0.4

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50

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LV

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0.0

50

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LV

Fra

ctio

na

l S

ho

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ing

(%

)5

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±0.7

13

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±0.6

<0.0

5<

0.0

50

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LV

dP

/dt

max

(mm

Hg

/s)

82

14

3±

14

14

20

7±

22

72

82

6±

33

44

66

7±

383

<0.0

5<

0.0

50

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Ca

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c O

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(l/m

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0.5

9<

0.0

50

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Mea

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0.7

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LV

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d-d

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all

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10

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wa

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LV

dP

/dt

max

(mm

Hg

/s)

82

14

3±

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14

20

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22

72

82

6±

33

44

66

7±

383

<0.0

5<

0.0

50

.15

Ca

rdia

c O

utp

ut

(l/m

in)

62.5

±0.6

3.9

±0.7

3.1

±0.6

3.7

±0.7

0.5

9<

0.0

50

.12

Val

ues

are

mea

n ±

s.e.

m.

AN

OV

A p

val

ue

26

Ta

ble

2.

Hem

od

yn

am

icp

ara

met

ers

mea

sure

din

ba

seli

ne

con

dit

ion

s an

d a

fter

iva

bra

din

e a

tD

ay

s0

an

d 2

8

nD

ay 0

Day 2

8

Base

lin

eIv

ab

rad

ine

Base

lin

eIv

ab

rad

ine

Tim

e ef

fect

Iva

bra

din

e

effe

ctIn

tera

ctio

n

Hea

rtra

te (

bea

ts/m

in)

87

5±

25

7±

31

04

±6

77

±3

<0

.05

<0

.05

0.1

Mea

na

rter

ial

pre

ssu

re (

mm

Hg

)8

10

6±

21

01

±2

10

5±

41

01

±4

0.8

5<

0.0

50

.65

LV

pre

ssu

re (

mm

Hg

) 8

12

5±

21

27

±3

12

4±

61

24

±5

0.7

50

.72

0.9

3

LV

en

d-d

iast

oli

cw

all

thic

knes

s(m

m)

59

.1±

0.3

8.6

±0

.31

2.2

±0

.81

0.8

±0

.6<

0.0

5<

0.0

5<

0.0

5

LV

wa

llth

icke

nin

g(m

m)

52

.9±

0.4

3.5

±0

.33

.5±

0.5

4.2

±0

.60

.11

<0

.05

0.7

4

LV

en

d-d

iast

oli

cin

tern

al

dia

met

er(m

m)

54

0.2

±0

.44

1.4

±0

.94

0.8

±1

.24

2.6

±1

.80

.47

<0

.05

0.4

3

LV

Fra

ctio

na

lS

ho

rten

ing

(%)

51

7.4

±1

.41

8.4

±1

.21

3.4

±0

.41

5.8

±1

.0<

0.0

5<

0.0

50

.34

LV

dP

/dt

max

(mm

Hg

/s)

82

14

3±

14

12

30

4±

23

82

82

6±

33

42

85

1±

23

8<

0.0

50

.31

0.5

1

Ca

rdia

c O

utp

ut

(l/m

in)

62

.5±

0.6

2.3

±0

.53

.1±

0.6

3.3

±0

.70

.07

0.8

10

.26

Val

ues

are

mea

n ±

s.e.

m.

AN

OV

A p

val

ue

Ta

ble

2.

Hem

od

yn

am

icp

ara

met

ers

mea

sure

din

ba

seli

ne

con

dit

ion

s an

d a

fter

iva

bra

din

e a

tD

ay

s0

an

d 2

8

nD

ay 0

Day 2

8

Base

lin

eIv

ab

rad

ine

Base

lin

eIv

ab

rad

ine

Tim

e ef

fect

Iva

bra

din

e

effe

ctIn

tera

ctio

n

Hea

rtra

te (

bea

ts/m

in)

87

5±

25

7±

31

04

±6

77

±3

<0

.05

<0

.05

0.1

Mea

na

rter

ial

pre

ssu

re (

mm

Hg

)8

10

6±

21

01

±2

10

5±

41

01

±4

0.8

5<

0.0

50

.65

LV

pre

ssu

re (

mm

Hg

) 8

12

5±

21

27

±3

12

4±

61

24

±5

0.7

50

.72

0.9

3

LV

en

d-d

iast

oli

cw

all

thic

knes

s(m

m)

59

.1±

0.3

8.6

±0

.31

2.2

±0

.81

0.8

±0

.6<

0.0

5<

0.0

5<

0.0

5

LV

wa

llth

icke

nin

g(m

m)

52

.9±

0.4

3.5

±0

.33

.5±

0.5

4.2

±0

.60

.11

<0

.05

0.7

4

LV

en

d-d

iast

oli

cin

tern

al

dia

met

er(m

m)

54

0.2

±0

.44

1.4

±0

.94

0.8

±1

.24

2.6

±1

.80

.47

<0

.05

0.4

3

LV

Fra

ctio

na

lS

ho

rten

ing

(%)

51

7.4

±1

.41

8.4

±1

.21

3.4

±0

.41

5.8

±1

.0<

0.0

5<

0.0

50

.34

LV

dP

/dt

max

(mm

Hg

/s)

82

14

3±

14

12

30

4±

23

82

82

6±

33

42

85

1±

23

8<

0.0

50

.31

0.5

1

Ca

rdia

c O

utp

ut

(l/m

in)

62

.5±

0.6

2.3

±0

.53

.1±

0.6

3.3

±0

.70

.07

0.8

10

.26

Val

ues

are

mea

n ±

s.e.

m.

AN

OV

A p

val

ue

27

Tab

le 3

. T

ime

inte

rvals

mea

sure

din

base

lin

eco

nd

itio

ns

an

d a

fter

iva

brad

ine

at

Da

ys

0 a

nd

28

Day 0

Day 2

8

Tim

e ef

fect

Ivabra

din

e

effe

ctIn

tera

ctio

n

Tota

l cy

cle

tim

e (m

s)839

±35

1104

±36

593

±38

793

±35

<0.0

5<

0.0

50.2

4

Isovo

lum

ic c

ontr

act

ion t

ime

(ms)

54

±3

48

±3

60

±3

46

±3

0.1

6<

0.0

50.1

7

Eje

ctio

n t

ime

(ms)

279

±13

275

±6

196

±7

215

±7

<0.0

50.3

40.1

9

Isovo

lum

ic r

ela

xati

on t

ime

(ms)

77

±2

69

±3

72

±3

67

±3

0.3

2<

0.0

50.4

6

To

tal

dia

sto

lic

fill

ing

tim

e (m

s)425

±26

713

±34

265

±28

465

±29

<0.0

5<

0.0

5<

0.0

5

Val

ues

are

mea

n±

s.e.

m.

AN

OV

A p

val

ue

Ivabra

din

eB

ase

lin

eIv

abra

din

eB

ase

lin

e

Tab

le 3

. T

ime

inte

rvals

mea

sure

din

base

lin

eco

nd

itio

ns

an

d a

fter

iva

brad

ine

at

Da

ys

0 a

nd

28

Day 0

Day 2

8

Tim

e ef

fect

Ivabra

din

e

effe

ctIn

tera

ctio

n

Tota

l cy

cle

tim

e (m

s)839

±35

1104

±36

593

±38

793

±35

<0.0

5<

0.0

50.2

4

Isovo

lum

ic c

ontr

act

ion t

ime

(ms)

54

±3

48

±3

60

±3

46

±3

0.1

6<

0.0

50.1

7

Eje

ctio

n t

ime

(ms)

279

±13

275

±6

196

±7

215

±7

<0.0

50.3

40.1

9

Isovo

lum

ic r

ela

xati

on t

ime

(ms)

77

±2

69

±3

72

±3

67

±3

0.3

2<

0.0

50.4

6

To

tal

dia

sto

lic

fill

ing

tim

e (m

s)425

±26

713

±34

265

±28

465

±29

<0.0

5<

0.0

5<

0.0

5

Val

ues

are

mea

n±

s.e.

m.

AN

OV

A p

val

ue

Ivabra

din

eB

ase

lin

eIv

abra

din

eB

ase

lin

e

28

Day 0

Day 2

8

Hea

rtra

te (

bea

ts/m

in)

94

±3

89

±4

0.2

6

Tota

l cy

cle

tim

e (m

s)635

±25

711

±17

0.1

Isovo

lum

ic c

ontr

act

ion t

ime

(ms)

31

±1

32

±2

0.6

1

Eje

ctio

n t

ime

(ms)

204

±4

191

±9

0.2

Isovo

lum

ic r

ela

xati

on t

ime

(ms)

60

±1

58

±2

0.3

2

To

tal

dia

sto

lic

fill

ing

tim

e (m

s)358

±25

431

±14

<0.0

5

Val

ues

are

mea

n±

s.e.

m.

Dobuta

min

eD

obuta

min

e +

Ivabra

din

e

Tab

le 4

. T

ime

inte

rvals

mea

sure

du

nd

erd

ob

uta

min

e a

lon

eat

Da

y 0

an

d d

ob

uta

min

e p

lus

ivab

rad

ine

at

Da

y 2

8 pval

ue

Day 0

Day 2

8

Hea

rtra

te (

bea

ts/m

in)

94

±3

89

±4

0.2

6

Tota

l cy

cle

tim

e (m

s)635

±25

711

±17

0.1

Isovo

lum

ic c

ontr

act

ion t

ime

(ms)

31

±1

32

±2

0.6

1

Eje

ctio

n t

ime

(ms)

204

±4

191

±9

0.2

Isovo

lum

ic r

ela

xati

on t

ime

(ms)

60

±1

58

±2

0.3

2

To

tal

dia

sto

lic

fill

ing

tim

e (m

s)358

±25

431

±14

<0.0

5

Val

ues

are

mea

n±

s.e.

m.

Dobuta

min

eD

obuta

min

e +

Ivabra

din

e

Tab

le 4

. T

ime

inte

rvals

mea

sure

du

nd

erd

ob

uta

min

e a

lon

eat

Da

y 0

an

d d

ob

uta

min

e p

lus

ivab

rad

ine

at

Da

y 2

8 pval

ue

29

Da

y 0

BaselineDo

bu

tam

ine

10

!g

/kg

/min

Baseline

Ivabradine

(1 mg/kg)D

ob

uta

min

e

10

!g

/kg

/min

4 w

eek

so

f

an

gio

ten

sin

II

infu

sio

n (

30

ng

/kg

/min

)

Da

y 2

8

BaselineDo

bu

tam

ine

10

!g

/kg

/min

Baseline

Ivabradine

(1 mg/kg)

Do

bu

tam

ine

10

!g

/kg

/min

Fig

ure

1

Da

y 0

BaselineDo

bu

tam

ine

10

!g

/kg

/min

Baseline

Ivabradine

(1 mg/kg)D

ob

uta

min

e

10

!g

/kg

/min

4 w

eek

so

f

an

gio

ten

sin

II

infu

sio

n (

30

ng

/kg

/min

)

Da

y 2

8

BaselineDo

bu

tam

ine

10

!g

/kg

/min

Baseline

Ivabradine

(1 mg/kg)

Do

bu

tam

ine

10

!g

/kg

/min

Da

y 0

BaselineDo

bu

tam

ine

10

!g

/kg

/min

Baseline

Ivabradine

(1 mg/kg)D

ob

uta

min

e

10

!g

/kg

/min

4 w

eek

so

f

an

gio

ten

sin

II

infu

sio

n (

30

ng

/kg

/min

)

Da

y 2

8

BaselineDo

bu

tam

ine

10

!g

/kg

/min

Baseline

Ivabradine

(1 mg/kg)

Do

bu

tam

ine

10

!g

/kg

/min

Fig

ure

1

30

Fig

ure

2 Baseline values atDays0 and 28 (ms)

To

tal

Cyc

le T

ime

0

100

200

300

400

Eje

ctio

n T

ime

0

200

400

600

Fil

lin

gT

ime

0

300

600

900

1200

Day

0D

ay 2

8D

ay 0

Day

28

Day

0D

ay 2

8

**

*

020

40

60

80

Day

0D

ay 2

8

Iso

volu

mic

Co

ntr

act

ion

020

40

60

80

100

Iso

volu

mic

Rel

axa

tio

n

Day

0D

ay 2

8

Fig

ure

2 Baseline values atDays0 and 28 (ms)

To

tal

Cyc

le T

ime

0

100

200

300

400

Eje

ctio

n T

ime

0

200

400

600

Fil

lin

gT

ime

0

300

600

900

1200

Day

0D

ay 2

8D

ay 0

Day

28

Day

0D

ay 2

8

**

*

020

40

60

80

Day

0D

ay 2

8

Iso

volu

mic

Co

ntr

act

ion

020

40

60

80

100

Iso

volu

mic

Rel

axa

tio

n

Day

0D

ay 2

8

31

40

60

80

100

120

140

40

60

80

100

120

140

20

30

40

50

60

70

02

46

8

50

60

70

80

90

02

46

8

Ba

seli

ne

Do

bu

tam

ine

Do

bu

tam

ine

Do

bu

tam

ine

Do

bu

tam

ine

Ba

seli

ne

Ba

seli

ne

Ba

seli

ne

Da

y 0

Da

y 2

8

Da

y 0

Da

y 2

8

Da

y 0

Da

y 2

8

Da

y 0

Da

y 2

8

Isovolu

mic

rela

xati

on

tim

e (

ms)

Tri

ple

pro

du

ct(x

10

7)

Hea

rtra

te (

bea

ts/m

in)

Tri

ple

pro

du

ct(x

10

7)

Hea

rtra

te (

bea

ts/m

in)

Isovolu

mic

con

tracti

on

tim

e (

ms)

** *

*

Figure 3

ms ms

40

60

80

100

120

140

40

60

80

100

120

140

20

30

40

50

60

70

02

46

8

50

60

70

80

90

02

46

8

Ba

seli

ne

Do

bu

tam

ine

Do

bu

tam

ine

Do

bu

tam

ine

Do

bu

tam

ine

Do

bu

tam

ine

Ba

seli

ne

Ba

seli

ne

Ba

seli

ne

Ba

seli

ne

Da

y 0

Da

y 2

8

Da

y 0

Da

y 2

8

Da

y 0

Da

y 2

8

Da

y 0

Da

y 2

8

Isovolu

mic

rela

xati

on

tim

e (

ms)

Tri

ple

pro

du

ct(x

10

7)

Hea

rtra

te (

bea

ts/m

in)

Tri

ple

pro

du

ct(x

10

7)

Hea

rtra

te (

bea

ts/m

in)

Isovolu

mic

con

tracti

on

tim

e (

ms)

** *

*

Figure 3

ms ms

32

30

40

50

60

70

60

65

70

75

80

150

200

250

300

100

200

300

400

500

600

Fil

lin

gti

me

Iso

volu

mic

rel

axa

tio

n t

ime

Iso

volu

mic

co

ntr

act

ion

tim

e

Eje

ctio

n t

ime

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

*

*

ms ms

ms ms

Fig

ure

4

30

40

50

60

70

60

65

70

75

80

150

200

250

300

100

200

300

400

500

600

Fil

lin

gti

me

Iso

volu

mic

rel

axa

tio

n t

ime

Iso

volu

mic

co

ntr

act

ion

tim

e

Eje

ctio

n t

ime

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

*

*

ms ms

ms ms

30

40

50

60

70

60

65

70

75

80

150

200

250

300

100

200

300

400

500

600

Fil

lin

gti

me

Iso

volu

mic

rel

axa

tio

n t

ime

Iso

volu

mic

co

ntr

act

ion

tim

e

Eje

ctio

n t

ime

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

Bas

elin

e

Day

0

Bas

elin

e

Day

28

Ivab

rad

ine

Day

28

*

*

ms ms

ms ms

Fig

ure

4

33

Fig

ure

5

Fil

lin

gti

me

Iso

volu

mic

rel

axa

tio

n t

ime

Iso

volu

mic

co

ntr

act

ion

tim

e

Eje

ctio

n t

ime

10

20

30

40

50

70

80

90

100

110

40

50

60

70

80

70

80

90

100

110

140

180

220

260

70

80

90

100

110

40

5060

70

70

80

90

100

110

Do

bu

tam

ine

atD

ay 0

Do

bu

tam

ine

+ i

vab

rad

ine

atD

ay 2

8M

atch

edh

eart

rate

con

dit

ion

s:

*

ms ms

ms ms

Fig

ure

5

Fil

lin

gti

me

Iso

volu

mic

rel

axa

tio

n t

ime

Iso

volu

mic

co

ntr

act

ion

tim

e

Eje

ctio

n t

ime

10

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BJ=C>C! ;C5@5HGE;MG>C! ^85A:9=8:;5A! >:! 9>H=6=:;5A_! 3G! 878H>! 8=93;=MG>]! A5:=EE>A:! H59C!

3\=GIE>A:=:;5AC!3>!H=!P94MG>A8>!8=93;=MG>!=G!85G9C!3>!H\J7B>9:>AC;5A!8J95A;MG>[!&H59C!ErE>!MG>!

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H\J4E537A=E;MG>!I4A49=H>!>:!H=!P5A8:;5A!@>A:9;8GH=;9>!I=G8J>!3>!:5GC!H>C!=A;E=G6!5A:!4:4!4@=HG4>C!

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H\J4E537A=E;MG>! I4A49=H>! >:! H=! P5A8:;5A! @>A:9;8GH=;9>! I=G8J>! 5A:! 4:4! 4@=HG4>C! Q! A5G@>=G]! =@=A:!

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H\;EB=8:!3>!:5G:!8J=AI>E>A:!3>!85A3;:;5A!3>!8J=9I>!CG9!H=!P5A8:;5A!@>A:9;8GH=;9>!I=G8J>[!

'''[!?('V0'?&lu!()#l/K&K#!

A. Fr�quence cardiaque

/=!P94MG>A8>!8=93;=MG>!4:=;:!C;IA;P;8=:;@>E>A:!=GIE>A:4>!Q!y*X!vs.!yY!^9>CB>8:;@>E>A:]!"Y,�g!

vs!d-�*!T=::DE;A_[!2>!ErE>]!H=!35TG:=E;A>!=]!>A:9>!=G:9>C]!;A3G;:!GA!8J95A5:95B;CE>!B5C;:;P!^Q!yY!1!

3>!d-�*! Q!j,�+!T=::DE;A! >:! Q! y*X!1! 3>!"Y,�g! Q!""j�X!T=::DE;A_[!/\=3E;A;C:9=:;5A!3\;@=T9=3;A>! =!

B>9E;C!3>!943G;9>!H=!P94MG>A8>!8=93;=MG>!3>*,�*e!Q!yY!^-d�+!T=::DE;A_!>:!3>!*g�+e!Q!y*X!^dd�+!

T=::DE;A_!>A!H\=TC>A8>!3>!=AI;5:>AC;A>!''[!'H!>C:!;A:49>CC=A:!3>!85AC:=:>9!MG>!H>C!@=H>G9C!=TC5HG>C!3>!

P94MG>A8>!8=93;=MG>!5TC>9@4>C!Q! y*X!=B9FC! H\=3E;A;C:9=:;5A!3\;@=T9=3;A>!4:=;>A:!B958J>C!3>!8>HH>C!

>A9>I;C:94>C!Q!yY!Q!H\4:=:!3>!W=C>[!V5GC!G:;H;C>95AC!GH:49;>G9>E>A:!8>::>!C;E;H;:G3>!=P;A!3>!34:>9E;A>9!

H>C!E48=A;CE>C!3>C!E53;P;8=:;5AC!;A3G;:>C!B=9!H\;@=T9=3;A>[!

!

B. Alt�ration des phases isovolumiques � lÕ�tat de base et r�duction de la fr�quence cardiaque

05EE>! H\;HHGC:9>! H=! P;IG9>! *g! >:! 85EE>! 3=AC! H=! B9>E;F9>! 4:G3>]! A5GC! =@5AC! 5TC>9@4! GA>!

4@5HG:;5A! =A59E=H>! 3>! H=! 85A:9=8:;5A! >:! 3>! H=! 9>H=6=:;5A! ;C5@5HGE;MG>C[! ?=9=HHFH>E>A:! Q!

H\=GIE>A:=:;5A! 3>! H=! P94MG>A8>! 8=93;=MG>! Q! y*X]! H>! :>EBC! 34@5HG! Q! H=! 85A:9=8:;5A! >:! Q! 9>H=6=:;5A!

;C5@5HGE;MG>! 9>C:=;:! B=9=356=H>E>A:! ;A8J=AI4! >A:9>! yY! >:! y*X! =H59C! MG\GA>! =3=B:=:;5A!

!

!

"YX!

BJ7C;5H5I;MG>! ;EB5C>! H>G9! 943G8:;5A[!)A!3\=G:9>C! :>9E>C]! H>! :>EBC!34@5HG!Q!8>C!3>G6!BJ=C>C!4:=;:!

:95B!;EB59:=A:]!=G!34:9;E>A:!3>!H\4S>8:;5A!>:!3G!9>EBH;CC=I>[!

!

/\=3E;A;C:9=:;5A! 3\;@=T9=3;A>! =! 943G;:! 3>! H=! 3G94>! 3>C! 3>G6! BJ=C>C! ;C5@5HGE;MG>C! Q! yY!

^9>CB>8:;@>E>A:! <"de! >:! <""e_! 8>! MG;! =! B>9E;C! 3>! P=@59;C>9! H>! 9>EBH;CC=I>! @>A:9;8GH=;9>! >A!

=GIE>A:=A:!C=!3G94>!3>!dYe[!&!y*X]!H\;@=T9=3;A>!=!B953G;:!3>C!>PP>:C!C;E;H=;9>C!^9>CB>8:;@>E>A:!<

*+e!>:! <de_[!05EE>! H\;HHGC:9>! H=! P;IG9>!*d]! ;H! >C:! ;A:49>CC=A:!3>!85AC:=:>9!MG\=H59C!MG>! H\4S>8:;5A!

4:=;:!B94C>9@4>!3=AC!8>::>!C;:G=:;5A]!H=!943G8:;5A!3>!H=!P94MG>A8>!8=93;=MG>!B>9E>::=;:!3\5T:>A;9!GA>!

0

100

200

300

400 Ejection

(ms)

0

200

400

600 Remplissage

(ms)

J 0 J 28 J 0 J 28

* *

0

20

40

60

80

J 0 J 28

Contraction

Isovolumique

(ms)

0

20

40

60

80

100

Relaxation

Isovolumique

(ms)

J 0 J 28

Figure 26 Evaluation des temps dÕ�jection, de remplissage, de contraction isovolumique et de

relaxation isovolumique � J0 et � J28. *, p<0,05 vs J0

!

!

"Yj!

=E4H;59=:;5A! 3>! 3G94>! 3G! 9>EBH;CC=I>! BHGC! ;EB59:=A:>! MG\Q! yY[! 0>C! >PP>:C! 4:=;>A:! 8H=;9>E>A:! H=!

85AC4MG>A8>!3>! H=! 943G8:;5A!3>! H=! P94MG>A8>!8=93;=MG>!BG;CMG>! H59CMG>! H\5A!85EB=9>! H=!3G94>!3>!

9>EBH;CC=I>!>A:9>!yY!Q! H\4:=:!3>!T=C>!>:!y*X!C5GC! ;@=T9=3;A>]!35A8!B5G9!3>C!@=H>G9C!3>! P94MG>A8>C!

8=93;=MG>C! C;E;H=;9>C]! 5A! 9>:95G@>! H\=GIE>A:=:;5A! 3G! :>EBC! 34@5HG! =G! 9>EBH;CC=I>[! 2=AC! 8>C!

85A3;:;5AC]!H>C!:>EBC!3>!3>G6!BJ=C>C!;C5@5HGE;MG>C!4:=;>A:!A59E=H;C4C[!

!

!

Figure 27 : Les phases isovolumiques, lÕ�jection et le remplissage ont �t� �valu�s � lÕ�tat de base �

J0 ainsi quÕ� J28 (�tat de base et pendant lÕadministration de dobutamine). *, p<0,05 vs. la valeur

correspondant � J0 ; , p<0,05 vs. lÕ�tat de base � J28

30

40

50

60

70

60

65

70

75

80

150

200

250

300

100

200

300

400

500

600

Remplissage

(ms)

Relaxation isovolumique

(ms)

Contraction isovolumique

(ms)

Ejection

(ms)

Base

J 0

Base

J 28

Ivabradine

J 28

Base

J 0

Base

J 28

Ivabradine

J 28

Base

J 0

Base

J 28

Ivabradine

J 28 Base

J 0

Base

J 28

Ivabradine

J 28

* *

!

!

""Y!

0[!&/K)(&K'$V!2)#!?N&#)#!'#$L$/l%'nl)#]!2$WlK&%'V)!)K!()2l0K'$V!2)!/&!O()nl)V0)!0&(2'&nl)!

&!H\;AC:=9!3>!8>!MG;!4:=;:!5TC>9@4!Q!H\4:=:!3>!T=C>!>:!3=AC!A5:9>!B94843>A:>!4:G3>]!H>C!BJ=C>C!3>!

85A:9=8:;5A! >:! 3>! 9>H=6=:;5A! ;C5@5HGE;MG>C! A>! C>! C5A:! B=C! =3=B:4>C! H59C! 3>! H\=3E;A;C:9=:;5A! 3>!

35TG:=E;A>!Q!y*X!>:!H>!@>A:9;8GH>!I=G8J>!=!4:4!;A8=B=TH>!3\=884H49>9!8>C!3>G6!BJ=C>C!>:!3\>A!943G;9>!

H>G9!3G94>[!!

!

!

Figure 27 : les dur�es de la contraction isovolumique, de la relaxation isovolumique, de lÕ�jection et

du remplissage ont �t� �valu�es au cours du protocole dÕadministration de dobutamine, et plus

particuli�rement pendant lÕadministration de dobutamine sans ivabradine � J0 et avec ivabradine �

J28. *<0,05 vs. J0.

Remplissage

(ms)

Relaxation isovolumique

(ms)

Contraction isovolumique

(ms)

Ejection

(ms)

10

20

30

40

50

80 90 100 40

50

60

70

80

80 90 100

140

180

220

260

80 90 100 40

50

60

70

80 90 100

*

Dobutamine at J 0 Dobutamine + ivabradine � J 28

Conditions avec des fr�quences cardiaques �quivalentes :

!

!

"""!

/\=3E;A;C:9=:;5A!3\;@=T9=3;A>!Q!y*X!=!;A3G;:!GA>!943G8:;5A!3>!8>C!B=9=EF:9>C!^O;IG9>!*X_[!2>!

P=q5A! ;A:49>CC=A:>]! H>C! @=H>G9C! =TC5HG>C! 3>! P94MG>A8>! 8=93;=MG>! 5TC>9@4>C! Q! y*X! B>A3=A:!

H\=3E;A;C:9=:;5A!3>!35TG:=E;A>!4:=;>A:! C;E;H=;9>C!Q!8>HH>C!>A9>I;C:94>C!Q! yY!C5GC!35TG:=E;A>!E=;C!

C=AC!;@=T9=3;A>!^9>CB>8:;@>E>A:!Xj�,!vs.!j,�+!T=::DE;A_[!0>::>!85EB=9=;C5A!B>9E>:!3>!34E5A:9>9!

GA>!A59E=H;C=:;5A!3>C!85A:9=8:;5AC!>:!9>H=6=:;5AC!;C5@5HGE;MG>C[!&;AC;!H=!943G8:;5A!3>!H=!P94MG>A8>!

8=93;=MG>! B>9E>:! 3>! 8599;I>9! H>C! =H:49=:;5AC! 3\=3=B:=:;5A! 3>C! BJ=C>C! ;C5@5HGE;MG>C[! ?=9! =;HH>G9C]!

A5GC! =@5AC! BG! 85AC:=:>9! MG>! H>! 9>EBH;CC=I>! 4:=;:! P=@59;C4! Q! A5G@>=G! H59C! 3>! H\=3E;A;C:9=:;5A! 3>!

35TG:=E;A>[!

!

!

""*!

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!

!

""+!

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=;IG>_[!!

!! !

!

!

"",!

CHAPITRE IX : DISCUSSION GENERALE

ET CONCLUSIONS

!

!

""-!

N;C:59;MG>E>A:]!HR=::>A:;5A!3>C!BJ7C;5H5I;C:>C!CR>C:!B9;A8;B=H>E>A:!B59:4>!CG9!H=!P5A8:;5A!

85A:9=8:;H>! >:! 35A8! CG9! H=! a!C7C:5H>!b! 3>! H=! B5EB>! 8=93;=MG>]! 8>! MG;! >C:! 85EB94J>AC;TH>! 3=AC! H=!

E>CG9>!5~!8\>C:! H\4S>8:;5A!@>A:9;8GH=;9>!MG;!B>9E>:!3\=CCG9>9! H=!B>9PGC;5A!3>C!3;PP49>A:C! :>99;:5;9>C!

@=C8GH=;9>C! 3>! H\59I=A;CE>[! ?95I9>CC;@>E>A:]! H>! 34@>H5BB>E>A:! 3>! A5G@>HH>C! :>8JA;MG>C!

3R>6BH59=:;5A! 35A:! H>! 8=:J4:49;CE>! 8=93;=MG>]! =! B>9E;C! 3R=BB94J>A3>9! H=! BJ7C;5H5I;>! 3G! 8oG9! 3>!

E=A;F9>!BHGC!85EBHF:>!1!H>C!35AA4>C!85ET;A4>C!3>!B9>CC;5A!;A:9=@>A:9;8GH=;9>!I=G8J>!>:!3G!@5HGE>!

8=@;:=;9>! B=9! 8;A4<=AI;5I9=BJ;>! 5A:! 9>A3G! B5CC;TH>! H=! 85AC:9G8:;5A! 3>! 85G9T>C! B9>CC;5A<@5HGE>!

>6BH59=A:!T;>A!4@;3>EE>A:! H=!BJ=C>!a!C7C:5H;MG>!b]!E=;C!4I=H>E>A:!a!3;=C:5H;MG>!b]! 8R>C:<Q<3;9>! H=!

B49;53>! B94843>A:! H=! 85A:9=8:;5A! @>A:9;8GH=;9>[! 0\>C:! H=! A=;CC=A8>! 3RGA>! `diastologie`! =@>8!

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85EBH>6>C!@;C=A:!Q!E534H;C>9!8>::>!B49;53>!3G!878H>!8=93;=MG>[!?=9!=;HH>G9C]!H=!@;C;5A!BJ7C;5H5I;MG>!

3G! 878H>! 8=93;=MG>! MG;! B94@=H=;:! ^8>HH>! 3>!p;II>9C_! 85AC;349=;:! MG\Q! B=9:;9! 3>! H=! P>9E>:G9>! 3>! H=!

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3;=C:=C>!>:!H=!85A:9=8:;5A!=:9;=H>!4:=;:!8H=CC4>!3=AC!H=!a!T5;:>!b!3;=C:5H;MG>[!

2>BG;C!GA>!:9>A:=;A>!3\=AA4>C]!GA>!3;C8GCC;5A!=A;E4>!=G:5G9!3>!H=!3;=C:5H>!C\>C:!;A;:;4>!

>A! 9=;C5A! 3>! H=! 85AC:=:=:;5A! 3>! BHGC! >A! BHGC! P94MG>A:>! 3>! H=! B94C>A8>! 3>! :=TH>=G6! 8H;A;MG>C!

3\;ACGPP;C=A8>! 8=93;=MG>! MG;! 4:=;>A:! 8>B>A3=A:! =CC58;4C! Q! GA>! P9=8:;5A! 3\4S>8:;5A! B=9=356=H>E>A:!

B94C>9@4>[!0>8;!=!=E>A4!Q!3;C:;AIG>9!HR'0<O)9!>:!HR'0<O)B!85EE>!3>G6!>A:;:4C!3;PP49>A:>C[!)A!>PP>:]!

8>! 9=885G98;! ;A:>HH>8:G>H! 94CGH:>! 3>! H=! A48>CC;:4! >A! 8H;A;MG>! JGE=;A>]! 3>! 34P;A;:;5AC! 8H=;9>C]!

P=8;H>E>A:!=BBH;8=TH>C!=G6!B=:;>A:C!>:!G:;H>C!B5G9! H>!8J5;6!3>! H=!B9;C>!>A!8J=9I>! :J49=B>G:;MG>[!0>!

85A8>B:! CR=BBG;>! CG9! H>C! =9IGE>A:C! CG;@=A:C!1! "_! =G! 85G9C! 3>! H\'0<O)B! H=! P5A8:;5A! C7C:5H;MG>! 3G!

@>A:9;8GH>! I=G8J>! 4@=HG4>! B=9! H=! E>CG9>! 3>! H=! P9=8:;5A! 3\4S>8:;5A! >C:! A59E=H>!c! *_! H>C! C:9=:4I;>C!

BJ=9E=85H5I;MG>C!MG;!5A:!E5A:94!H>G9!>PP;8=8;:4!>A!:>9E>C!3>!E59T;<E59:=H;:4!8J>U!H>C!B=:;>A:C!=@>8!

'0<O)9!5A:!48J5G4!8J>U!H>C!B=:;>A:C!=@>8!'0<O)B!c!+_!H\'0<O)9!>:!'0<O)B!C5A:!8=9=8:49;C4>C!B=9!3>C!

9>E53>H=I>C!EGC8GH=;9>C!>:!4H>8:9;MG>C!3;PP49>A:C!^OGwG:=!=A3!/;::H>!*YYd_!c!,_!H>C!B=:;>A:C!=@>8!'0<

O)9! >:! '0<O)B! B94C>A:>A:! 3>C! 8=9=8:49;C:;MG>C! 8H;A;MG>C! 3;PP49>A:>C! >A! :>9E>C! 3>! B94@=H>A8>! 3>!

85E59T;3;:4C[!

'H! 7! =! B5G9:=A:! =G:=A:! 3>! 9=;C5A! 3\=PP;9E>9! MG>! 8>C! a!3>G6!P59E>C!b! 3\;ACGPP;C=A8>!

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3>C! B=9=EF:9>C! =G:9>C! MG>! H=! P9=8:;5A! 3\4S>8:;5A]! >C:! =H:494>!c! *_! ;H! A\7! =! B=C! 3\4@;3>A8>! MG>! H>C!

8=9=8:49;C:;MG>C!E5H48GH=;9>C!Q! H\59;I;A>!3>!H=!BJ7C;5B=:J5H5I;>!3>!8>C!3>G6!P59E>C!3\;ACGPP;C=A8>!

8=93;=MG>! C5;>A:! 9=3;8=H>E>A:! 3;PP49>A:>C!E=HI94! H\;A>PP;8=8;:4! 3>C! :9=;:>E>A:C! G:;H;C4C! 3=AC! H\'0<

O)9!c! +_! H>! 9>E53>H=I>! @>A:9;8GH=;9>! >C:! H>! 94CGH:=:! 3>! H=! 85ET;A=;C5A! 3>! BHGC;>G9C! @5;>C! 3>!

!

!

""g!

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8=93;=MG>C]!B95E5G@=A:!=;AC;!H>!85A8>B:!3>!85A:;AGGE!3G!CB>8:9>!3>C!BJ4A5:7B>C[!)AP;A]!H>C!3>G6!

>A:;:4C!I=93>A:!3>C!8=9=8:49;C:;MG>C!85EEGA>C]!A5:=EE>A:!H=!37CP5A8:;5A!@>A:9;8GH=;9>!>:!@=C8GH=;9>!

^�;H>]!W=;8G!>:!=H[!*YY,c!OGwG:=!=A3!/;::H>!*YYd_]!H\=8:;@=:;5A!A>G95<J59E5A=H>!^i;:UE=A]!/;::H>!>:!

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K>HH>! 4:=;:! H=! @;C;5A! 3>! H\'0<O)B! MG=A3! H>! B94C>A:! :9=@=;H! =! 34TG:4!1! 5A! C>! B5C=;:! H=!

MG>C:;5A!3>!H=!85A:;AG;:4!3>!8>C!3>G6!>A:;:4C!B=:J5H5I;MG>C[!(>B94C>A:>A:<>HH>C!H\GA>!H>!C:=3>!;A;:;=H!

3>! H\=G:9>! 5G! C\=I;:<;H! 3>! 3>G6! >A:;:4C! :5:=H>E>A:! ;A34B>A3=A:>C! �! 2=AC! H>! TG:! 3\>6BH59>9! H>C!

BJ4A5EFA>C!BJ7C;5B=:J5H5I;MG>C!3>!H\'0<O)B]!A5GC!=@5AC!>A:9>B9;C!3>!E>::9>!=G!B5;A:!GA!E53FH>!

8J>U!H>!I95C!=A;E=H!=7=A:!3>C!a!8=9=8:49;C:;MG>C!b!H>C!BHGC!B958J>C!B5CC;TH>C!3>!8>HH>C!9>:95G@4>C!>A!

B=:J5H5I;>! JGE=;A>!c! =@>8! A5:=EE>A:! H=! B94C>A8>! 3\J7B>9:>AC;5A! =9:49;>HH>]! GA>! =TC>A8>!

3\;ACGPP;C=A8>!8595A=;9>]!>:!8>!=@>8!:5G:>!H=!3;PP;8GH:4!3>!H=!:9=ACH=:;5A!3RGA!BJ4A5EFA>!5TC>9@4!>A!

8H;A;MG>!JGE=;A>!@>9C!H>!H=T59=:5;9>[!V5GC!A5GC!C5EE>C!35A8!59;>A:4C!@>9C!GA!E53FH>!B598;A!9>A3G!

J7B>9:>A3G! I9v8>! Q! GA>! B>9PGC;5A! 8J95A;MG>! 3\=AI;5:>AC;A>! ''[! 05EE>! A5GC! HR=@5AC! ;A3;MG4!

B94843>EE>A:]! H>! 8J5;6! 3G! I95C! =A;E=H! =! 4:4! A5:=EE>A:! 3;8:4! B=9! H=! B956;E;:4! 3>C! @=H>G9C! 3>!

P94MG>A8>!8=93;=MG>!=@>8!8>HH>C!3>! HRN5EE>[!2=AC!8>C!85A3;:;5AC]! H=! 94IGH=:;5A!3>! H\J5E45C:=C;>!

8=H8;MG>! >:! H\>6B9>CC;5A! 3>C! ;C5P59E>C! B95:4;MG>C! 3G! C=985EF9>! C5A:! B958J>C! 3>C! 8=9=8:49;C:;MG>C!

JGE=;A>C[!?=9! =;HH>G9C]! ;H! C\=I;:! 3\GA!3;CB5C;:;P! `4@>;HH4! 8J95A;MG>E>A:! ;AC:9GE>A:4`!MG;!A\>C:!B=C!

;APHG>A84!B=9!H=!B94C>A8>!3RGA>!C43=:;5A!5G!3RGA>!=A>C:J4C;>!I4A49=H>[!/\J7B>9:>AC;5A!=9:49;>HH>!=!4:4!

;A3G;:>!Q!H\=;3>!3\GA>!B>9PGC;5A!85A:;AG>!3\=AI;5:>AC;A>!'']!>A!C=8J=A:!MG>!H\=8:;@=:;5A!3G!C7C:FE>!

94A;A>!=AI;5:>AC;A>!>C:!GA!4H4E>A:!8>A:9=H!3=AC! H\4H4@=:;5A!3>C!@=H>G9C!3>! H=!B9>CC;5A!=9:49;>HH>!>:!

3=AC! H>! 9>E53>H=I>!@>A:9;8GH=;9>[!2\=G:9>C! =G:>G9C! =@=;>A:!34SQ!B95B5C4!3\=3E;A;C:9>9!3>!E=A;F9>!

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*YYY_! 5G! 3\G:;H;C>9! H>! E53FH>! 3>! 85AC:9;8:;5A! 94A=H>! ^%GA=I=H=]! N=9:! >:! =H[! *YY-_]! E=;C! 8>C!

=BB958J>C!5A:!3>C!85AC4MG>A8>C!BJ7C;5B=:J5H5I;MG>C!;994@>9C;TH>C[!/=!B=9:;8GH=9;:4!3>!A5:9>!E53FH>!

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85A3;:;5AC!3>!T=C>]!>:!35A8!3R=BB948;>9!H>C!8=9=8:49;C:;MG>C!P5A8:;5AA>HH>C!;A:9;ACFMG>C!3G!@>A:9;8GH>!

I=G8J>[! 2>! BHGC]! A5:9>! 3;CB5C;:;P! A5GC! =! B>9E;C! 3\>6BH59>9! H>C! 94B5AC>C! J4E537A=E;MG>C! >A!

85A3;:;5AC! 3>! C:9>CC! ^35TG:=E;A>_! BG;CMG\GA>! ;A85EB4:>A8>! 8J95A5:95B>! >:! GA>! ;A:5H49=A8>! Q!

HR>6>98;8>!C5A:!85AAG>C!8J>U!H>C!B=:;>A:C!=@>8!'0!<O)B!^W59H=GI!=A3!i=CC!*YYgc!?J=A]!#J;@G!>:!=H[!

*Y"Y_[!

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TITLE: Physiopathological and pharmacological characterisation of a pig model of diastolic

dysfunction with preserved ejection.

NAME: Mario G. RIENZO

SUMMARY:

Approximately 20 millions individuals in the world experience heart failure symptoms;

heart failure prevalence is continuously rising with population aging. Left ventricular function

evaluation by the ejection fraction allows distinguishing two different patient sets: one with

and one other without ejection fraction alteration, respectively named Heart Failure with

Reduced Ejection Fraction (HF-rEF) and Heart Failure with Preserved Ejection Fraction

(HF-pEF). It is unknown if these two clinical presentations represent two different

pathologies or two manifestations of the same clinical entity. HF-pEF is found in about 40-

50% of patients with heart failure and its evolution is similar to that of patients with HF-rEF.

However, several conceptual difficulties deal with the HFpEF: on one hand, talking

about preserved ejection fraction implies the knowledge of its basal value; on the other, the

normality needs to be established. Moreover, considering the heart either as a hemodynamic

pump or as a muscular pump may modify the understanding of HFpEF physiopathology.

We therefore set up a swine model of diastolic dysfunction with preserved ejection

induced by chronic hypertension, which was obtained by continuous perfusion of angiotensin

II during 28 days. In these conditions, we clearly demonstrated a LV function impairment,

while the ejection phase parameters remained preserved. The LV impairment is demonstrated

by: 1) the paradox increase of the relative durations of isovolumic contraction and relaxation;

2) the blunted responses of the isovolumic phases of cardiac cycle to heart rate augmentation

and cardiac inotropisme; 3) a straight relationship between these two isovolumic phases

(contraction-relaxation relationship).

The mismatch between the heart rate and the isovolumic phases behaviour led us to

investigate the possible effects of the heart rate pharmacological modulation on the

contraction-relaxation coupling. The selective reduction of the heart rate by ivabradine

administration (a selective If channel inhibitor) was able to significantly reduce the

isovolumic contraction and relaxation phasesÕ durations, thus improving filling phase

dynamics. Anyway, this ÒnormalisationÓ was only apparent, because the contraction to

relaxation ratio was increased at day 28, to the detriment of the isovolumic contraction.

In conclusion, chronic hypertension induces a diastolic dysfunction with a preserved

ejection fraction paralleled by a systolic dysfunction which is responsible of a blunted

myocardial response to stress.

KEY WORDS: Diastolic Dysfunction, Heart Rate, Heart Rate with Preserved Ejection

Fraction, Systole, Heart as a Muscular Pump.

HOSTING LABORATORY: Pharmacology Laboratory, INSERM U955 Equipe 3, Ecole

Nationale V�t�rinaire dÕAlfort et Facult� de M�decine de Cr�teil, Universit� Paris-Est Cr�teil.

TITRE : Caract�risation physiopathologique et pharmacologique dÕun mod�le porcin de

dysfonction diastolique avec �jection pr�serv�e.

NOM : Mario G. RIENZO

RESUME :

On estime qu'approximativement 20 millions de personnes dans le monde souffrent

d'insuffisance cardiaque et la pr�valence de cette pathologie ne cesse dÕaugmenter avec le

vieillissement croissant de la population. L'�valuation de la fonction ventriculaire gauche par

la mesure de la fraction dÕ�jection permet en fait de distinguer deux populations distinctes de

patients insuffisants cardiaques : l'une avec et l'autre sans alt�ration de la fraction dÕ�jection,

encore d�nomm�es respectivement Heart Failure with Reduced Ejection Fraction (IC-FEr) et

Heart Failure with Preserved Ejection Fraction (IC-FEp). On ne sait pas aujourdÕhui si ces

deux entit�s repr�sentent deux pathologies distinctes ou, au contraire, deux entit�s intimement

li�es. L'IC-FEp est actuellement observ�e chez environ 40 � 50% des patients pr�sentant une

insuffisance cardiaque et son �volution est semblable � celle des patients IC-FEr.

Le concept d'IC-FEp soul�ve toutefois des difficult�s conceptuelles : dÕune part car la

notion d'une fraction d'�jection pr�serv�e implique la connaissance de sa valeur de base et

dÕautre part, les valeurs dites "normales" de la fraction d'�jection sont encore � �tablir. Par

ailleurs, la vision m�canique du cÏur comme une pompe h�modynamique ou

musculaire conditionne la compr�hension de la physiopathologie de la IF-FEp.

Dans ce contexte, nous avons mis au point un mod�le porcin de dysfonction diastolique

avec �jection pr�serv�e secondaire � une hypertension art�rielle induite par une perfusion

continue dÕangiotensine II pendant 28 jours. Dans ces conditions, nous avons d�montr� une

alt�ration de la fonction ventriculaire gauche alors m�me que lÕ�jection �tait pr�serv�e. Ceci

�tait objectiv� par 1) une augmentation paradoxale des dur�es relatives de contraction et de

relaxation isovolumiques, 2) des r�ponses inappropri�es des phases isovolumiques du cycle

cardiaque � des augmentations de la fr�quence et de lÕinotropisme cardiaques et 3) une �troite

relation entre ces deux phases isovolumiques (couplage contraction-relaxation).

LÕinad�quation entre les niveaux de fr�quence cardiaque et des phases isovolumiques nous a

amen� � �valuer les effets de la modulation pharmacologique de la fr�quence cardiaque sur le

couplage contraction-relaxation. Ainsi la r�duction s�lective de la fr�quence cardiaque par

lÕadministration dÕivabradine, un inhibiteur des canaux If, a r�duit significativement la dur�e

de ces deux phases et favoris� le remplissage. Cependant, cette normalisation nÕ�tait

quÕapparente puisque le ratio entre la contraction et la relaxation isovolumiques restait

augment� � J28, en d�faveur de la contraction isovolumique.

En conclusion, le d�veloppement dÕune dysfonction diastolique avec une �jection

pr�serv�e sÕaccompagne dÕune dysfonction systolique qui entrave une r�ponse ad�quate du

myocarde � un stress dans un contexte dÕhypertension chronique.

MOTS-CLES : Dysfonction diastolique, Fr�quence cardiaque, Insuffisance Cardiaque �

Fraction dÕEjection Pr�serv�e, Systole, Pompe musculaire cardiaque.

LABORATOIRE DÕACCUEIL : INSERM U955 Equipe 3, Ecole Nationale V�t�rinaire

dÕAlfort et Facult� de M�decine de Cr�teil, Universit� Paris-Est Cr�teil.

caractérisation physiopathologique et pharmacologique d'un … · 2021. 2. 18. · ludwig van...

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