title: Improvement of left ventricular filling by ivabradine during chronic hypertension: involvement of contraction-relaxation coupling.
abstract: Chronic hypertension is associated with left ventricular (LV) hypertrophy and LV diastolic dysfunction with impaired isovolumic relaxation and abnormal LV filling. Increased heart rate (HR) worsens these alterations. We investigated whether the I f channel blocker ivabradine exerts beneficial effects on LV filling dynamic. In this setting, we also evaluated the relationship between LV filling and isovolumic contraction as a consequence of contraction-relaxation coupling. Therefore, hypertension was induced by a continuous infusion of angiotensin II during 28 days in 10 chronically instrumented pigs. LV function was investigated after stopping angiotensin II infusion to offset the changes in loading conditions. In the normal heart, LV relaxation filling, LV early filling, LV peak early filling rate were positively correlated to HR. In contrast, these parameters were significantly reduced at day 28 vs. day 0 (18, 42, and 26 %, respectively) despite the increase in HR (108 ± 6 beats/min vs. 73 ± 2 beats/min, respectively). These abnormalities were corrected by acute administration of ivabradine (1 mg/kg, iv). Ivabradine still exerted these effects when HR was controlled at 150 beats/min by atrial pacing. Interestingly, LV relaxation filling, LV early filling and LV peak early filling were strongly correlated with both isovolumic contraction and relaxation. In conclusion, ivabradine improves LV filling during chronic hypertension. The mechanism involves LV contraction-relaxation coupling through normalization of isovolumic contraction and relaxation as well as HR-independent mechanisms.
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Melka
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.|AP-HP, Hôpital Européen Georges Pompidou, Service d'Anesthésie-Réanimation Chirurgicale, 75015, Paris, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Rienzo
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bizé
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Jozwiak
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.
authors.forename: Lucien
authors.initials: L
authors.lastname: Sambin
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.|AP-HP, Groupe Hospitalier Henri Mondor, Fédération de Cardiologie, 94000, Créteil, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Hittinger
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.
authors.forename: Jin Bo
authors.initials: JB
authors.lastname: Su
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France.|AP-HP, Groupe Hospitalier Henri Mondor, Fédération de Cardiologie, 94000, Créteil, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.affiliation: Faculté de Médecine, Inserm, U955, Equipe 03, 8 rue du Général Sarrail, 94000, Créteil, France. bijan.ghaleh@inserm.fr.|Université Paris-Est, UMR_S955, DHU A-TVB, UPEC, 94000, Créteil, France. bijan.ghaleh@inserm.fr.|Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, 94000, Maisons-Alfort, France. bijan.ghaleh@inserm.fr.
authors.forename: Bijan
authors.identifier: http://orcid.org/0000-0003-0061-5462
authors.initials: B
authors.lastname: Ghaleh
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000503:physiopathology*; D000077550:Ivabradine; D013552:Swine; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; D000077550:Ivabradine
keywords: Diastole; Heart rate; Hypertension; Systole