Molecular basis of funny current (If) in normal and failing human heart

Francesca Stillitano, Giuseppe Lonardo, Stephen Zicha, Andras Varro, Elisabetta Cerbai, Alessandro Mugelli, Stanley Nattel

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


If overexpression has been functionally demonstrated in ventricular myocytes from failing human hearts. Altered expression of If-channels as a consequence of electrophysiological remodeling may represent an arrhythmogenic mechanism in heart failure; however, the molecular basis of If overexpression in human cardiac disease is unknown. HCN1, 2 and 4 subtypes, which encode If-channels, have been identified in the heart. The present study was designed to characterize HCN isoform expression in failing and non-failing hearts. Ventricular and atrial samples were obtained from normal or failing hearts explanted from patients with end-stage ischemic cardiomyopathy. If was recorded in patch-clamped left ventricular myocytes. mRNA and protein expression of HCN subunits were measured in both atria and ventricles of control and diseased hearts. HCN2 and HCN4 were detected in human myocardium. Both mRNA and protein levels of HCN2/4 were significantly augmented in failing ventricles (p < 0.01 for mRNA, p < 0.05 for protein). These results are consistent with the electrophysiological data showing that, in failing ventricular myocytes, If is of larger amplitude and activates at less negative potential. Changes in mRNA and protein expression of both HCN2/4 isoforms in atrial specimens from patients with heart failure mirrored those observed in ventricles (p < 0.001 for mRNA, p < 0.05 for protein). No disease-dependent alteration was detected for MiRP1, the putative β-subunit of the If-channel. In conclusion, HCN4 is the predominant channel subtype in normal human heart, and its expression is further amplified by disease. HCN upregulation likely contributes to increased If and may play a role in ventricular and atrial arrhythmogenesis in heart failure.

Original languageEnglish
Pages (from-to)289-299
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Issue number2
StatePublished - Aug 2008
Externally publishedYes


  • Arrhythmias
  • Electrophysiology
  • Gene expression
  • Human heart failure
  • Hyperpolarization-activated Cyclin Nucleotide gated channel
  • Ischemic cardiomyopathy


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