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Sepsis-Induced Myocardial Dysfunction (SIMD): the Pathophysiological Mechanisms and Therapeutic Strategies Targeting Mitochondria

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Abstract

Sepsis is a lethal syndrome with multiple organ failure caused by an inappropriate host response to infection. Cardiac dysfunction is one of the important complications of sepsis, termed sepsis-induced myocardial dysfunction (SIMD), which is characterized by systolic and diastolic dysfunction of both sides of the heart. Mechanisms that contribute to SIMD include an excessive inflammatory response, altered circulatory, microvascular status, nitric oxide (NO) synthesis impairment, endothelial dysfunction, disorders of calcium regulation, cardiac autophagy anomaly, autonomic nervous system dysregulation, metabolic reprogramming, and mitochondrial dysfunction. The role of mitochondrial dysfunction, which is characterized by structural abnormalities, increased oxidative stress, abnormal opening of the mitochondrial permeability transition pore (mPTP), mitochondrial uncoupling, and disordered quality control systems, has been gaining increasing attention as a central player in the pathophysiology of SIMD. The disruption of homeostasis within the organism induced by mitochondrial dysfunction may also be an important aspect of SIMD development. In addition, an emerging therapy strategy targeting mitochondria, namely, metabolic resuscitation, seems promising. The current review briefly introduces the mechanism of SIMD, highlights how mitochondrial dysfunction contributes to SIMD, and discusses the role of metabolic resuscitation in the treatment of SIMD.

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Abbreviations

PAMPs:

pathogen-associated molecular patterns

DAMPs:

damage-associated molecular patterns

O2 :

dioxygen

Ca2+ :

calcium bivalent

TLR:

toll-like receptor

ATP:

adenosine triphosphate

ROS:

reactive oxygen species

RNS:

reactive nitrogen species

LPS:

lipopolysaccharide

CLP:

cecal ligation and puncture

mtDNA:

mitochondrial DNA

mtTFA/TFAM:

mitochondrial transcription factor A

mPTP:

mitochondrial permeability transition pore

AMP:

adenosine monophosphate

MAMs:

mitochondrial-associated membranes

AMPK:

AMP-activated protein kinase

IL:

interleukin

HMGB1:

high mobility group protein B1

PGC1α:

peroxisome proliferator-activated receptor gamma coactivator-1 α

PGC1β:

peroxisome proliferator-activated receptor gamma coactivator-1 β

ICU:

intensive care unit

RCT:

randomized controlled trial

TNFα:

tumor necrosis factor

SOFA:

sequential organ failure assessment

CO:

carbon monoxide

NO:

nitric oxide

H2S:

hydrogen sulfide

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Acknowledgments

We thank Accdon for its linguistic assistance during the preparation of this manuscript.

Funding

Dr. Zhaocai Zhang received funding from National Natural Science Foundation of China (No. 81772110). Dr. Yinchuan Xu received research grants from National Natural Science Foundation of China (No. 81971860 and No. 81500876); Natural Science Foundation of Zhejiang Province, China (No. LQ16H020003).

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  1. Yao Lin and Yinchuan Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yao Lin & Zhaocai Zhang

  2. Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yinchuan Xu

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Dr. Yao Lin and Dr. Yinchuan Xu performed literature searches, wrote the article, and designed the tables and figures. Dr. Yinchuan Xu and Dr. Zhaocai Zhang designed and revised the review.

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Lin, Y., Xu, Y. & Zhang, Z. Sepsis-Induced Myocardial Dysfunction (SIMD): the Pathophysiological Mechanisms and Therapeutic Strategies Targeting Mitochondria. Inflammation 43, 1184–1200 (2020). https://doi.org/10.1007/s10753-020-01233-w

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