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Atrial fibrillation rhythm is associated with marked changes in metabolic and myofibrillar protein expression in left atrial appendage

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Abstract

Atrial fibrillation (AF) is strongly associated with risk of stroke and heart failure. AF promotes atrial remodeling that increases risk of stroke due to left atrial thrombogenesis, and increases energy demand to support high rate electrical activity and muscle contraction. While many transcriptomic studies have assessed AF-related changes in mRNA abundance, fewer studies have assessed proteomic changes. We performed a proteomic analysis on left atrial appendage (LAA) tissues from 12 patients with a history of AF undergoing elective surgery; atrial rhythm was documented at time of surgery. Proteomic analysis was performed using liquid chromatography with mass spectrometry (LC/MS-MS). Data-dependent analysis identified 3090 unique proteins, with 408 differentially expressed between sinus rhythm and AF. Ingenuity Pathway Analysis of differentially expressed proteins identified mitochondrial dysfunction, oxidative phosphorylation, and sirtuin signaling among the most affected pathways. Increased abundance of electron transport chain (ETC) proteins in AF was accompanied by decreased expression of ETC complex assembly factors, tricarboxylic acid cycle proteins, and other key metabolic modulators. Discordant changes were also evident in the contractile unit with both up and downregulation of key components. Similar pathways were affected in a comparison of patients with a history of persistent vs. paroxysmal AF, presenting for surgery in sinus rhythm. Together, these data suggest that while the LAA attempts to meet the energetic demands of AF, an uncoordinated response may reduce ATP availability, contribute to tissue contractile and electrophysiologic heterogeneity, and promote a progression of AF from paroxysmal episodes to development of a substrate amenable to persistent arrhythmia.

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Full summary data are included in the manuscript and the accompanying online resources. Proteomic data have been uploaded to the PRIDE database.

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Acknowledgments

The Fusion Lumos LC MS/MS instrument was purchased via an NIH shared instrument grant, 1S10OD023436-01.

Funding

Funding was provided by a Strategically Focused Research Network in Atrial Fibrillation grant from the American Heart Association (18SFRN34110067, 18SFRN34170442) and by the National Institutes of Health (R01 HL111314).

Author information

Authors and Affiliations

  1. Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue, M/S ND50, Cleveland, OH, 44195, USA

    Julie H. Rennison, Cheryl R. Lin, Beth S. Lovano, Laurie Castel, Catherine C. Cantlay, Meghan McHale, Reena Mehra, Jonathan D. Smith, Mina K. Chung & David R. Van Wagoner

  2. Proteomics Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Ling Li & Belinda B. Willard

  3. Department of Cardiothoracic Surgery, Cleveland Clinic, Cleveland, OH, 44195, USA

    A. Marc Gillinov

  4. Sleep Center, Respiratory Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Reena Mehra

  5. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, OH, 44195, USA

    Reena Mehra, Jonathan D. Smith, Mina K. Chung, John Barnard & David R. Van Wagoner

  6. Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Sojin Youn Wass, Jonathan D. Smith, Mina K. Chung & David R. Van Wagoner

  7. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, 44195, USA

    John Barnard

Authors
  1. Julie H. Rennison
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  2. Ling Li
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  3. Cheryl R. Lin
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  4. Beth S. Lovano
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  5. Laurie Castel
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  6. Sojin Youn Wass
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  7. Catherine C. Cantlay
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  8. Meghan McHale
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  9. A. Marc Gillinov
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  10. Reena Mehra
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  11. Belinda B. Willard
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  12. Jonathan D. Smith
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  13. Mina K. Chung
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  14. John Barnard
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  15. David R. Van Wagoner
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Corresponding author

Correspondence to David R. Van Wagoner.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All surgical patients provided informed consent for research use of discarded atrial tissues. Prior to 2008, verbal consent was obtained and documented in the patient medical records in a process approved by the Cleveland Clinic Institutional Review Board (IRB, project 18-1501).

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This article is part of the special issue on Calcium Signal Dynamics in Cardiac Myocytes and Fibroblasts: Mechanisms in Pflügers Archiv—European Journal of Physiology

Supplementary Information

ESM 1

Online Resource 1 3090 proteins with UniProtKB identifiers were suitable for analysis. Previously identified potential AF risk genes detected in our analysis are identified in column J with yes (Y). Proteins are presented in alphabetical order. Online Resource 2 408 proteins were differentially expressed in atrial fibrillation vs. sinus rhythm. Proteins are identified by gene name and UniProtKB identifier. Online Resource 3 362 Canonical Pathways identified by Ingenuity Pathway Analysis. Pathway name, false discovery rate (-log(p-value)), and proteins that were differentially expressed in each pathway are identified. Pathways are presented in order of false discovery rate, with the most significant pathway listed first. Online Resource 4 Top upstream regulators identified by Ingenuity Pathway Analysis (IPA) of proteins that were differentially expressed in our analysis. Upstream regulators are predicted by IPA using previously published literature. Some of these upstream regulators were themselves proteins that were differentially expressed in our dataset and therefore the expression log ratio, a measure of fold change (column B), is included. Differentially expressed proteins that are predicted to be influenced by each upstream regulator are designated. Significance was determined using a false discovery rate p < 0.05. Upstream regulators are presented in order of false discovery rate, with the most significant upstream regulator listed first. Online Resource 5 Differentially expressed proteins in left atrial appendage of patients in sinus rhythm at the time of tissue acquisition, but with a clinical history of either paroxysmal (n = 4) or persistent AF (n = 4) (p < 0.05). Proteins are identified by gene name and UniProtKB identifier. Online Resource 6 Canonical Pathways identified by Ingenuity Pathway Analysis in patients in sinus rhythm at the time of tissue acquisition, but with a clinical history of either paroxysmal or persistent AF. Pathway name, false discovery rate (-log(p-value)), and proteins that were differentially expressed in each pathway are identified. Pathways are presented in order of false discovery rate, with the most significant pathway listed first. (XLSX 816 kb). Online Resource 7 Top upstream regulators identified by Ingenuity Pathway Analysis (IPA) of proteins that were differentially expressed in patients in sinus rhythm at the time of tissue acquisition, but with a clinical history of either paroxysmal or persistent AF. Upstream regulators are predicted by IPA using previously published literature. Some of these upstream regulators were themselves proteins that were differentially expressed in our dataset and therefore the expression log ratio, a measure of fold change (column B), is included. Differentially expressed proteins that are predicted to be influenced by each upstream regulator are designated. Significance was determined using a false discovery rate p < 0.05. Upstream regulators are presented in order of false discovery rate, with the most significant upstream regulator listed first

ESM 2

Supplemental Fig. 1 Proteins differentially expressed in patients in sinus rhythm at the time of tissue acquisition, but with a clinical history of either paroxysmal or persistent AF. Upregulated proteins are designated red, downregulated are designated green. Abbreviations used: adenylate kinase (AK4), armadillo repeat containing X-linked 1 (ARMCX1), aspartate β-hydroxylase (ASPH), calcyclin binding protein (CACYBP), enoyl-CoA δ isomerase 1 (ECI1), filamin C (FLNC), heterogeneous nuclear ribonucleoprotein A/B (HNRNPAB), mitochondrial ribosomal protein 47 (MRPL47), mitochondrial translation initiation factor (MTIF), NADH:ubiquinone oxidoreductase subunit A7 (NDUFA7), nipsnap homolog 3B (NIPSNAP3B), nuclear transport factor 2 (NUTF2), peptidylprolyl isomerase D (PPID), S100 calcium binding protein A8 (S100A8), splicing factor 3B subunit 1 (SF3B1), tubulin polymerization promoting protein family member 3 (TPPP3), triadin (TRDN), thyroid hormone receptor interactor 11 (TRIP11), and tryptophanyl TRNA synthetase 2, mitochondrial (WARS2). Supplemental Fig. 2 Top 35 canonical pathways identified by Ingenuity Pathway Analysis of proteins differentially expressed in patients in sinus rhythm at the time of tissue acquisition, but with a clinical history of either paroxysmal or persistent AF. Pathways are presented in order of significance, with the most significant pathway listed first. Significance was determined using a false discovery rate p < 0.05. Pathways that are predicted to be activated are designated in orange shades. Pathways that predicted to be inhibited are designated in blue shades. Gray designates pathways for which there was not sufficient information to predict directionality. (PDF 277 kb)

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Rennison, J.H., Li, L., Lin, C.R. et al. Atrial fibrillation rhythm is associated with marked changes in metabolic and myofibrillar protein expression in left atrial appendage. Pflugers Arch - Eur J Physiol 473, 461–475 (2021). https://doi.org/10.1007/s00424-021-02514-5

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