title: Afterload-induced diastolic dysfunction contributes to high filling pressures in experimental heart failure with preserved ejection fraction.
abstract: Myocardial stiffness and upward-shifted end-diastolic pressure-volume (P-V) relationship (EDPVR) are the key to high filling pressures in heart failure with preserved ejection fraction (HFpEF). Nevertheless, many patients may remain asymptomatic unless hemodynamic stress is imposed on the myocardium. Whether delayed relaxation induced by pressure challenge may contribute to high end-diastolic pressure (EDP) remains unsettled. Our aim was to assess the effect of suddenly imposed isovolumic afterload on relaxation and EDP, exploiting a highly controlled P-V experimental evaluation setup in the ZSF1 obese rat (ZSF1 Ob) model of HFpEF. Twenty-week-old ZSF1 Ob (n = 12), healthy Wistar-Kyoto rats (WKY, n = 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n = 10) underwent open-thorax left ventricular (LV) P-V hemodynamic evaluation under anesthesia with sevoflurane. EDPVR was obtained by inferior vena cava occlusions to assess LV ED chamber stiffness constant β, and single-beat isovolumic afterload acquisitions were obtained by swift occlusions of the ascending aorta. ZSF1 Ob showed increased ED stiffness, delayed relaxation, as assessed by time constant of isovolumic relaxation (τ), and elevated EDP with normal ejection fraction. Isovolumic afterload increased EDP without concomitant changes in ED volume or heart rate. In isovolumic beats, relaxation was delayed to the extent that time for complete relaxation as predicted by 3.5 × monoexponentially derived τ (τexp) exceeded effective filling time. EDP elevation correlated with reduced time available to relax, which was the only independent predictor of EDP rise in multiple linear regression. Our results suggest that delayed relaxation during pressure challenge is an important contributor to lung congestion and effort intolerance in HFpEF.
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal;
authors.forename: Sara
authors.initials: S
authors.lastname: Leite
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal;
authors.forename: Sara
authors.initials: S
authors.lastname: Rodrigues
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Cardiology, Hospital São João, Porto, Portugal;
authors.forename: Marta
authors.initials: M
authors.lastname: Tavares-Silva
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Vascular Surgery, Hospital São João, Porto, Portugal;
authors.forename: José
authors.initials: J
authors.lastname: Oliveira-Pinto
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Cardiothoracic Surgery, Suez Canal University, Ismaileya, Egypt;
authors.forename: Mohamed
authors.initials: M
authors.lastname: Alaa
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal;
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abdellatif
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal;
authors.forename: Dulce
authors.initials: D
authors.lastname: Fontoura
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal;
authors.forename: Inês
authors.identifier: http://orcid.org/0000-0003-1937-3782
authors.initials: I
authors.lastname: Falcão-Pires
authors.affiliation: Department of Cardiology, Ghent University, Ghent, Belgium;
authors.forename: Thierry C
authors.initials: TC
authors.lastname: Gillebert
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Cardiothoracic Surgery, Hospital São João, Porto, Portugal; and.
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal; Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Anesthesiology, Hospital São João, Porto, Portugal aplourenco@yahoo.com.
authors.forename: André P
authors.identifier: http://orcid.org/0000-0002-5756-9535
authors.initials: AP
authors.lastname: Lourenço
mesh_terms: D000818:Animals; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology; D054144:Heart Failure, Diastolic / Q000503:physiopathology*; D006439:Hemodynamics; D006973:Hypertension / Q000503:physiopathology*; D016014:Linear Models; D011312:Pressure; D051381:Rats; D011921:Rats, Inbred WKY; D013318:Stroke Volume / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
keywords: afterload; diastolic function; heart failure with preserved ejection fraction; relaxation