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Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) leads to right ventricular cardiomyopathy and cardiac dysfunctions where in the clinical setting, cardiac arrest is the likely cause of death, in ~70% of PAH patients. We investigated the cardiac phenotype of PAH hearts and tested the hypothesis that the insulin...

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Autores principales: Martin, Brian, Vanderpool, Rebecca R., Henry, Brian L., Palma, Joshua B., Gabris, Beth, Lai, Yen-Chun, Hu, Jian, Tofovic, Stevan P., Reddy, Rajiv P., Mora, Ana L., Gladwin, Mark T., Romero, Guillermo, Salama, Guy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290063/
https://www.ncbi.nlm.nih.gov/pubmed/34295927
http://dx.doi.org/10.3389/fcvm.2021.668222
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author Martin, Brian
Vanderpool, Rebecca R.
Henry, Brian L.
Palma, Joshua B.
Gabris, Beth
Lai, Yen-Chun
Hu, Jian
Tofovic, Stevan P.
Reddy, Rajiv P.
Mora, Ana L.
Gladwin, Mark T.
Romero, Guillermo
Salama, Guy
author_facet Martin, Brian
Vanderpool, Rebecca R.
Henry, Brian L.
Palma, Joshua B.
Gabris, Beth
Lai, Yen-Chun
Hu, Jian
Tofovic, Stevan P.
Reddy, Rajiv P.
Mora, Ana L.
Gladwin, Mark T.
Romero, Guillermo
Salama, Guy
author_sort Martin, Brian
collection PubMed
description Pulmonary arterial hypertension (PAH) leads to right ventricular cardiomyopathy and cardiac dysfunctions where in the clinical setting, cardiac arrest is the likely cause of death, in ~70% of PAH patients. We investigated the cardiac phenotype of PAH hearts and tested the hypothesis that the insulin-like hormone, Relaxin could prevent maladaptive cardiac remodeling and protect against cardiac dysfunctions in a PAH animal model. PAH was induced in rats with sugen (20 mg/kg), hypoxia then normoxia (3-weeks/each); relaxin (RLX = 0, 30 or 400 μg/kg/day, n ≥ 6/group) was delivered subcutaneously (6-weeks) with implanted osmotic mini-pumps. Right ventricle (RV) hemodynamics and Doppler-flow measurements were followed by cardiac isolation, optical mapping, and arrhythmia phenotype. Sugen-hypoxia (SuHx) treated rats developed PAH characterized by higher RV systolic pressures (50 ± 19 vs. 22 ± 5 mmHg), hypertrophy, reduced stroke volume, ventricular fibrillation (VF) (n = 6/11) and bradycardia/arrest (n = 5/11); both cardiac phenotypes were suppressed with dithiothreitol (DTT = 1 mM) (n = 0/2/group) or RLX (low or high dose, n = 0/6/group). PAH hearts developed increased fibrosis that was reversed by RLX-HD, but not RLX-LD. Relaxin decreased Nrf2 and glutathione transferases but not glutathione-reductase. High-dose RLX improved pulmonary arterial compliance (measured by Doppler flow), suppressed VF even after burst-pacing, n = 2/6). Relaxin suppressed VF and asystole through electrical remodeling and by reversing thiol oxidative stress. For the first time, we showed two cardiac phenotypes in PAH animals and their prevention by RLX. Relaxin may modulate maladaptive cardiac remodeling in PAH and protect against arrhythmia and cardiac arrest.
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spelling pubmed-82900632021-07-21 Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension Martin, Brian Vanderpool, Rebecca R. Henry, Brian L. Palma, Joshua B. Gabris, Beth Lai, Yen-Chun Hu, Jian Tofovic, Stevan P. Reddy, Rajiv P. Mora, Ana L. Gladwin, Mark T. Romero, Guillermo Salama, Guy Front Cardiovasc Med Cardiovascular Medicine Pulmonary arterial hypertension (PAH) leads to right ventricular cardiomyopathy and cardiac dysfunctions where in the clinical setting, cardiac arrest is the likely cause of death, in ~70% of PAH patients. We investigated the cardiac phenotype of PAH hearts and tested the hypothesis that the insulin-like hormone, Relaxin could prevent maladaptive cardiac remodeling and protect against cardiac dysfunctions in a PAH animal model. PAH was induced in rats with sugen (20 mg/kg), hypoxia then normoxia (3-weeks/each); relaxin (RLX = 0, 30 or 400 μg/kg/day, n ≥ 6/group) was delivered subcutaneously (6-weeks) with implanted osmotic mini-pumps. Right ventricle (RV) hemodynamics and Doppler-flow measurements were followed by cardiac isolation, optical mapping, and arrhythmia phenotype. Sugen-hypoxia (SuHx) treated rats developed PAH characterized by higher RV systolic pressures (50 ± 19 vs. 22 ± 5 mmHg), hypertrophy, reduced stroke volume, ventricular fibrillation (VF) (n = 6/11) and bradycardia/arrest (n = 5/11); both cardiac phenotypes were suppressed with dithiothreitol (DTT = 1 mM) (n = 0/2/group) or RLX (low or high dose, n = 0/6/group). PAH hearts developed increased fibrosis that was reversed by RLX-HD, but not RLX-LD. Relaxin decreased Nrf2 and glutathione transferases but not glutathione-reductase. High-dose RLX improved pulmonary arterial compliance (measured by Doppler flow), suppressed VF even after burst-pacing, n = 2/6). Relaxin suppressed VF and asystole through electrical remodeling and by reversing thiol oxidative stress. For the first time, we showed two cardiac phenotypes in PAH animals and their prevention by RLX. Relaxin may modulate maladaptive cardiac remodeling in PAH and protect against arrhythmia and cardiac arrest. Frontiers Media S.A. 2021-07-06 /pmc/articles/PMC8290063/ /pubmed/34295927 http://dx.doi.org/10.3389/fcvm.2021.668222 Text en Copyright © 2021 Martin, Vanderpool, Henry, Palma, Gabris, Lai, Hu, Tofovic, Reddy, Mora, Gladwin, Romero and Salama. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Martin, Brian
Vanderpool, Rebecca R.
Henry, Brian L.
Palma, Joshua B.
Gabris, Beth
Lai, Yen-Chun
Hu, Jian
Tofovic, Stevan P.
Reddy, Rajiv P.
Mora, Ana L.
Gladwin, Mark T.
Romero, Guillermo
Salama, Guy
Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension
title Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension
title_full Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension
title_fullStr Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension
title_full_unstemmed Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension
title_short Relaxin Inhibits Ventricular Arrhythmia and Asystole in Rats With Pulmonary Arterial Hypertension
title_sort relaxin inhibits ventricular arrhythmia and asystole in rats with pulmonary arterial hypertension
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290063/
https://www.ncbi.nlm.nih.gov/pubmed/34295927
http://dx.doi.org/10.3389/fcvm.2021.668222
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