Whole Blood Gene Expression Differentiates between Atrial Fibrillation and Sinus Rhythm after Cardioversion

PLoS One. 2016 Jun 22;11(6):e0157550. doi: 10.1371/journal.pone.0157550. eCollection 2016.

Abstract

Background: Treatment to restore sinus rhythm among patients with atrial fibrillation (AF) has limited long-term success rates. Gene expression profiling may provide new insights into AF pathophysiology.

Objective: To identify biomarkers and improve our understanding of AF pathophysiology by comparing whole blood gene expression before and after electrical cardioversion (ECV).

Methods: In 46 patients with persistent AF that underwent ECV, whole blood samples were collected 1-2 hours before and 4 to 6 weeks after successful cardioversion. The paired samples were sent for microarray and plasma biomarker comparison.

Results: Of 13,942 genes tested, expression of SLC25A20 and PDK4 had the strongest associations with AF. Post-cardioversion, SLC25A20 and PDK4 expression decreased by 0.8 (CI 0.7-0.8, p = 2.0x10-6) and 0.7 (CI 0.6-0.8, p = 3.0x10-5) fold respectively. Median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations decreased from 127.7 pg/mL to 44.9 pg/mL (p = 2.3x10-13) after cardioversion. AF discrimination models combining NT-proBNP and gene expression (NT-proBNP + SLC25A20 area under the curve = 0.88, NT-proBNP + PDK4 AUC = 0.86) had greater discriminative capacity as compared with NT-proBNP alone (AUC = 0.82). Moreover, a model including NT-proBNP, SLC25A20 and PDK4 significantly improved AF discrimination as compared with other models (AUC = 0.87, Net Reclassification Index >0.56, p<5.8x10-3). We validated the association between SLC25A20 and PDK4 with AF in an independent sample of 17 patients.

Conclusion: This study demonstrates that SLC25A20, PDK4, and NT-proBNP have incremental utility as biomarkers discriminating AF from sinus rhythm. Elevated SLC25A20 and PDK4 expression during AF indicates an important role for energy metabolism in AF.

MeSH terms

  • Aged
  • Arrhythmia, Sinus / blood*
  • Arrhythmia, Sinus / genetics*
  • Atrial Fibrillation / blood*
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / therapy
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Cohort Studies
  • Demography
  • Diagnosis, Differential
  • Electric Countershock*
  • Female
  • Gene Expression Regulation*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Natriuretic Peptide, Brain / blood
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Reproducibility of Results

Substances

  • Biomarkers
  • Membrane Transport Proteins
  • PDK4 protein, human
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Natriuretic Peptide, Brain
  • SLC25A20 protein, human
  • Protein-Serine-Threonine Kinases

Grant support

This study was supported by a grant of the Mach Gaensslen Foundation (to David Conen). David Conen and Beat A. Kaufmann have received grants from the Swiss National Science Foundation (PP00P3_133681 and PP00P3_159322 to David Conen, 3232B0_141603 and 310030_149718 to Beat Kaufmann). Matthias Bossard was supported by a grant of the University of Basel and the “Freiwillige Akademische Gesellschaft (FAG)” Basel. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.