Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure

S. Andersen, Julie Birkmose Axelsen, Steffen Ringgaard, Jens Randel Nyengaard, Janus Adler Hyldebrandt, Harm Jan Bogaard, Frances S. de Man, Jens Erik Nielsen-Kudsk, A. Andersen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure. Methods: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks. Results: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function. Conclusions: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.

Original languageEnglish
Pages (from-to)203-210
Number of pages8
JournalInternational Journal of Cardiology
Volume293
DOIs
Publication statusPublished - 15 Oct 2019

Cite this

Andersen, S. ; Axelsen, Julie Birkmose ; Ringgaard, Steffen ; Nyengaard, Jens Randel ; Hyldebrandt, Janus Adler ; Bogaard, Harm Jan ; de Man, Frances S. ; Nielsen-Kudsk, Jens Erik ; Andersen, A. / Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure. In: International Journal of Cardiology. 2019 ; Vol. 293. pp. 203-210.
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title = "Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure",
abstract = "Background: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure. Methods: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks. Results: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function. Conclusions: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.",
keywords = "Angiotensin II, Animal models, Natriuretic peptides, Pulmonary hypertension, Right ventricular failure",
author = "S. Andersen and Axelsen, {Julie Birkmose} and Steffen Ringgaard and Nyengaard, {Jens Randel} and Hyldebrandt, {Janus Adler} and Bogaard, {Harm Jan} and {de Man}, {Frances S.} and Nielsen-Kudsk, {Jens Erik} and A. Andersen",
year = "2019",
month = "10",
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doi = "10.1016/j.ijcard.2019.06.065",
language = "English",
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pages = "203--210",
journal = "International Journal of Cardiology",
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Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure. / Andersen, S.; Axelsen, Julie Birkmose; Ringgaard, Steffen; Nyengaard, Jens Randel; Hyldebrandt, Janus Adler; Bogaard, Harm Jan; de Man, Frances S.; Nielsen-Kudsk, Jens Erik; Andersen, A.

In: International Journal of Cardiology, Vol. 293, 15.10.2019, p. 203-210.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure

AU - Andersen, S.

AU - Axelsen, Julie Birkmose

AU - Ringgaard, Steffen

AU - Nyengaard, Jens Randel

AU - Hyldebrandt, Janus Adler

AU - Bogaard, Harm Jan

AU - de Man, Frances S.

AU - Nielsen-Kudsk, Jens Erik

AU - Andersen, A.

PY - 2019/10/15

Y1 - 2019/10/15

N2 - Background: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure. Methods: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks. Results: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function. Conclusions: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.

AB - Background: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure. Methods: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks. Results: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function. Conclusions: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.

KW - Angiotensin II

KW - Animal models

KW - Natriuretic peptides

KW - Pulmonary hypertension

KW - Right ventricular failure

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U2 - 10.1016/j.ijcard.2019.06.065

DO - 10.1016/j.ijcard.2019.06.065

M3 - Article

VL - 293

SP - 203

EP - 210

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

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