Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction

Sara Leite, Rui J. Cerqueira, Jaime Ibarrola, Dulce Fontoura, Amaya Fernández-Celis, Faiez Zannad, Inês Falcão-Pires, Walter J. Paulus, Adelino F. Leite-Moreira, Patrick Rossignol, Natalia López-Andrés, André P. Lourenço

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls. METHODS AND RESULTS: Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels. CONCLUSIONS: Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.
Original languageEnglish
Pages (from-to)e005596
JournalCirculation. Heart failure
Volume12
Issue number7
DOIs
Publication statusPublished - 2019
Externally publishedYes

Cite this

Leite, S., Cerqueira, R. J., Ibarrola, J., Fontoura, D., Fernández-Celis, A., Zannad, F., ... Lourenço, A. P. (2019). Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction. Circulation. Heart failure, 12(7), e005596. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005596
Leite, Sara ; Cerqueira, Rui J. ; Ibarrola, Jaime ; Fontoura, Dulce ; Fernández-Celis, Amaya ; Zannad, Faiez ; Falcão-Pires, Inês ; Paulus, Walter J. ; Leite-Moreira, Adelino F. ; Rossignol, Patrick ; López-Andrés, Natalia ; Lourenço, André P. / Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction. In: Circulation. Heart failure. 2019 ; Vol. 12, No. 7. pp. e005596.
@article{925da4ec6e4e438988aac3841bfd3852,
title = "Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction",
abstract = "BACKGROUND: The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls. METHODS AND RESULTS: Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels. CONCLUSIONS: Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.",
author = "Sara Leite and Cerqueira, {Rui J.} and Jaime Ibarrola and Dulce Fontoura and Amaya Fern{\'a}ndez-Celis and Faiez Zannad and In{\^e}s Falc{\~a}o-Pires and Paulus, {Walter J.} and Leite-Moreira, {Adelino F.} and Patrick Rossignol and Natalia L{\'o}pez-Andr{\'e}s and Louren{\cc}o, {Andr{\'e} P.}",
year = "2019",
doi = "10.1161/CIRCHEARTFAILURE.118.005596",
language = "English",
volume = "12",
pages = "e005596",
journal = "Circulation. Heart failure",
issn = "1941-3289",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

Leite, S, Cerqueira, RJ, Ibarrola, J, Fontoura, D, Fernández-Celis, A, Zannad, F, Falcão-Pires, I, Paulus, WJ, Leite-Moreira, AF, Rossignol, P, López-Andrés, N & Lourenço, AP 2019, 'Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction' Circulation. Heart failure, vol. 12, no. 7, pp. e005596. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005596

Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction. / Leite, Sara; Cerqueira, Rui J.; Ibarrola, Jaime; Fontoura, Dulce; Fernández-Celis, Amaya; Zannad, Faiez; Falcão-Pires, Inês; Paulus, Walter J.; Leite-Moreira, Adelino F.; Rossignol, Patrick; López-Andrés, Natalia; Lourenço, André P.

In: Circulation. Heart failure, Vol. 12, No. 7, 2019, p. e005596.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction

AU - Leite, Sara

AU - Cerqueira, Rui J.

AU - Ibarrola, Jaime

AU - Fontoura, Dulce

AU - Fernández-Celis, Amaya

AU - Zannad, Faiez

AU - Falcão-Pires, Inês

AU - Paulus, Walter J.

AU - Leite-Moreira, Adelino F.

AU - Rossignol, Patrick

AU - López-Andrés, Natalia

AU - Lourenço, André P.

PY - 2019

Y1 - 2019

N2 - BACKGROUND: The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls. METHODS AND RESULTS: Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels. CONCLUSIONS: Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.

AB - BACKGROUND: The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls. METHODS AND RESULTS: Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels. CONCLUSIONS: Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072260256&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31525070

U2 - 10.1161/CIRCHEARTFAILURE.118.005596

DO - 10.1161/CIRCHEARTFAILURE.118.005596

M3 - Article

VL - 12

SP - e005596

JO - Circulation. Heart failure

JF - Circulation. Heart failure

SN - 1941-3289

IS - 7

ER -