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Chronic Atrial Fibrillation Alters the Functional Properties of If in the Human Atrium

Authors


  • This work was supported by European Union (STREP Project “NORMACOR,” 6th European Framework Program, contract LSH M/CT/2006/018676 to E.C.) and Ministero Istruzione Università e Ricerca (PRIN2008 to A.M.). This work was also supported by Ente Cassa di Risparmio di Firenze and Istituto Nazionale Ricerche Cardiovascolari.

  • No disclosures.

Human Chronic Atrial Fibrillation and If

Introduction

Despite the evidence that the hyperpolarization-activated current (If) is highly modulated in human cardiomyopathies, no definite data exist in chronic atrial fibrillation (cAF). We investigated the expression, function, and modulation of If in human cAF.

Methods and Results

Right atrial samples were obtained from sinus rhythm (SR, n = 49) or cAF (duration >1 year, n = 31) patients undergoing corrective cardiac surgery. Among f-channel isoforms expressed in the human atrium (HCN1, 2 and 4), HCN4 mRNA levels measured by RT-PCR were significantly reduced. However, protein expression was preserved in cAF compared to SR (+85% for HCN4); concurrently, miR-1 expression was significantly reduced. In patch-clamped atrial myocytes, current-specific conductance (gf) was significantly increased in cAF at voltages around the threshold for If activation (−60 to −80 mV); accordingly, a 10-mV rightward shift of the activation curve occurred (P < 0.01). β-Adrenergic and 5-HT4 receptor stimulation exerted similar effects on If in cAF and SR cells, while the ANP-mediated effect was significantly reduced (P < 0.02), suggesting downregulation of natriuretic peptide signaling.

Conclusions

In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur, associated with a slight yet significant gain-of-function of If, which may contribute to enhanced atrial ectopy.

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