Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice

Abstract Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac...

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Autores principales:	Hongfei Ge, Gongxin Liu, Tracy M. Yamawaki, Caroline Tao, Shawn T. Alexander, Kimberly Ly, Preston Fordstrom, Artem A. Shkumatov, Chi-Ming Li, Sridharan Rajamani, Mingyue Zhou, Brandon Ason
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2f56b69ee6d54d0caa04b1fc1525bcf7
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spelling	oai:doaj.org-article:2f56b69ee6d54d0caa04b1fc1525bcf72021-12-02T15:28:57ZPhytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice10.1038/s41598-021-96936-x2045-2322https://doaj.org/article/2f56b69ee6d54d0caa04b1fc1525bcf72021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96936-xhttps://doaj.org/toc/2045-2322Abstract Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.Hongfei GeGongxin LiuTracy M. YamawakiCaroline TaoShawn T. AlexanderKimberly LyPreston FordstromArtem A. ShkumatovChi-Ming LiSridharan RajamaniMingyue ZhouBrandon AsonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hongfei Ge Gongxin Liu Tracy M. Yamawaki Caroline Tao Shawn T. Alexander Kimberly Ly Preston Fordstrom Artem A. Shkumatov Chi-Ming Li Sridharan Rajamani Mingyue Zhou Brandon Ason Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice
description	Abstract Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.
format	article
author	Hongfei Ge Gongxin Liu Tracy M. Yamawaki Caroline Tao Shawn T. Alexander Kimberly Ly Preston Fordstrom Artem A. Shkumatov Chi-Ming Li Sridharan Rajamani Mingyue Zhou Brandon Ason
author_facet	Hongfei Ge Gongxin Liu Tracy M. Yamawaki Caroline Tao Shawn T. Alexander Kimberly Ly Preston Fordstrom Artem A. Shkumatov Chi-Ming Li Sridharan Rajamani Mingyue Zhou Brandon Ason
author_sort	Hongfei Ge
title	Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice
title_short	Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice
title_full	Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice
title_fullStr	Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice
title_full_unstemmed	Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice
title_sort	phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2f56b69ee6d54d0caa04b1fc1525bcf7
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Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice

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