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Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis

Background: Atrial fibrillation (AF) is associated with calcium (Ca(2+)) handling remodeling and increased spontaneous calcium release events (SCaEs). Nevertheless, its exact mechanism remains unclear, resulting in suboptimal primary and secondary preventative strategies. Methods: We searched the Pu...

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Autores principales: Fong, Sarah Pei Ting, Agrawal, Shaleka, Gong, Mengqi, Zhao, Jichao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329373/
https://www.ncbi.nlm.nih.gov/pubmed/34355025
http://dx.doi.org/10.3389/fcvm.2021.662914
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author Fong, Sarah Pei Ting
Agrawal, Shaleka
Gong, Mengqi
Zhao, Jichao
author_facet Fong, Sarah Pei Ting
Agrawal, Shaleka
Gong, Mengqi
Zhao, Jichao
author_sort Fong, Sarah Pei Ting
collection PubMed
description Background: Atrial fibrillation (AF) is associated with calcium (Ca(2+)) handling remodeling and increased spontaneous calcium release events (SCaEs). Nevertheless, its exact mechanism remains unclear, resulting in suboptimal primary and secondary preventative strategies. Methods: We searched the PubMed database for studies that investigated the relationship between SCaEs and AF and/or its risk factors. Meta-analysis was used to examine the Ca(2+) mechanisms involved in the primary and secondary AF preventative groups. Results: We included a total of 74 studies, out of the identified 446 publications from inception (1982) until March 31, 2020. Forty-five were primary and 29 were secondary prevention studies for AF. The main Ca(2+) release events, calcium transient (standardized mean difference (SMD) = 0.49; I(2) = 35%; confidence interval (CI) = 0.33–0.66; p < 0.0001), and spark amplitude (SMD = 0.48; I(2) = 0%; CI = −0.98–1.93; p = 0.054) were enhanced in the primary diseased group, while calcium transient frequency was increased in the secondary group. Calcium spark frequency was elevated in both the primary diseased and secondary AF groups. One of the key cardiac currents, the L-type calcium current (I(CaL)) was significantly downregulated in primary diseased (SMD = −1.07; I(2) = 88%; CI = −1.94 to −0.20; p < 0.0001) and secondary AF groups (SMD = −1.28; I(2) = 91%; CI = −2.04 to −0.52; p < 0.0001). Furthermore, the sodium–calcium exchanger (I(NCX)) and NCX1 protein expression were significantly enhanced in the primary diseased group, while only NCX1 protein expression was shown to increase in the secondary AF studies. The phosphorylation of the ryanodine receptor at S2808 (pRyR-S2808) was significantly elevated in both the primary and secondary groups. It was increased in the primary diseased and proarrhythmic subgroups (SMD = 0.95; I(2) = 64%; CI = 0.12–1.79; p = 0.074) and secondary AF group (SMD = 0.66; I(2) = 63%; CI = 0.01–1.31; p < 0.0001). Sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) expression was elevated in the primary diseased and proarrhythmic drug subgroups but substantially reduced in the secondary paroxysmal AF subgroup. Conclusions: Our study identified that I(CaL) is reduced in both the primary and secondary diseased groups. Furthermore, pRyR-S2808 and NCX1 protein expression are enhanced. The remodeling leads to elevated Ca(2+) functional activities, such as increased frequencies or amplitude of Ca(2+) spark and Ca(2+) transient. The main difference identified between the primary and secondary diseased groups is SERCA expression, which is elevated in the primary diseased group and substantially reduced in the secondary paroxysmal AF subgroup. We believe our study will add new evidence to AF mechanisms and treatment targets.
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spelling pubmed-83293732021-08-04 Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis Fong, Sarah Pei Ting Agrawal, Shaleka Gong, Mengqi Zhao, Jichao Front Cardiovasc Med Cardiovascular Medicine Background: Atrial fibrillation (AF) is associated with calcium (Ca(2+)) handling remodeling and increased spontaneous calcium release events (SCaEs). Nevertheless, its exact mechanism remains unclear, resulting in suboptimal primary and secondary preventative strategies. Methods: We searched the PubMed database for studies that investigated the relationship between SCaEs and AF and/or its risk factors. Meta-analysis was used to examine the Ca(2+) mechanisms involved in the primary and secondary AF preventative groups. Results: We included a total of 74 studies, out of the identified 446 publications from inception (1982) until March 31, 2020. Forty-five were primary and 29 were secondary prevention studies for AF. The main Ca(2+) release events, calcium transient (standardized mean difference (SMD) = 0.49; I(2) = 35%; confidence interval (CI) = 0.33–0.66; p < 0.0001), and spark amplitude (SMD = 0.48; I(2) = 0%; CI = −0.98–1.93; p = 0.054) were enhanced in the primary diseased group, while calcium transient frequency was increased in the secondary group. Calcium spark frequency was elevated in both the primary diseased and secondary AF groups. One of the key cardiac currents, the L-type calcium current (I(CaL)) was significantly downregulated in primary diseased (SMD = −1.07; I(2) = 88%; CI = −1.94 to −0.20; p < 0.0001) and secondary AF groups (SMD = −1.28; I(2) = 91%; CI = −2.04 to −0.52; p < 0.0001). Furthermore, the sodium–calcium exchanger (I(NCX)) and NCX1 protein expression were significantly enhanced in the primary diseased group, while only NCX1 protein expression was shown to increase in the secondary AF studies. The phosphorylation of the ryanodine receptor at S2808 (pRyR-S2808) was significantly elevated in both the primary and secondary groups. It was increased in the primary diseased and proarrhythmic subgroups (SMD = 0.95; I(2) = 64%; CI = 0.12–1.79; p = 0.074) and secondary AF group (SMD = 0.66; I(2) = 63%; CI = 0.01–1.31; p < 0.0001). Sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) expression was elevated in the primary diseased and proarrhythmic drug subgroups but substantially reduced in the secondary paroxysmal AF subgroup. Conclusions: Our study identified that I(CaL) is reduced in both the primary and secondary diseased groups. Furthermore, pRyR-S2808 and NCX1 protein expression are enhanced. The remodeling leads to elevated Ca(2+) functional activities, such as increased frequencies or amplitude of Ca(2+) spark and Ca(2+) transient. The main difference identified between the primary and secondary diseased groups is SERCA expression, which is elevated in the primary diseased group and substantially reduced in the secondary paroxysmal AF subgroup. We believe our study will add new evidence to AF mechanisms and treatment targets. Frontiers Media S.A. 2021-07-20 /pmc/articles/PMC8329373/ /pubmed/34355025 http://dx.doi.org/10.3389/fcvm.2021.662914 Text en Copyright © 2021 Fong, Agrawal, Gong and Zhao. 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
Fong, Sarah Pei Ting
Agrawal, Shaleka
Gong, Mengqi
Zhao, Jichao
Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis
title Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis
title_full Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis
title_fullStr Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis
title_full_unstemmed Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis
title_short Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis
title_sort modulated calcium homeostasis and release events under atrial fibrillation and its risk factors: a meta-analysis
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329373/
https://www.ncbi.nlm.nih.gov/pubmed/34355025
http://dx.doi.org/10.3389/fcvm.2021.662914
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