Among arrhythmic diseases with increasing incidence in the aging population is Sinus Node Dysfunction (SND; or Sick Sinus Syndrome), a clinical condition caused by congenital or acquired failure to generate and/or propagate the cardiac impulse. SND is manifested clinically as bradycardia and is often associated with chronotropic incompetence and tachycardiabradycardia syndrome. SND –mediated brady-arrhythmias are documented in ~40% of sudden deaths of patients with heart failure. Moreover, SND may initially manifest as asymptomatic bradycardia that ultimately degenerates with disease progression to debilitating bradyarrhythmias requiring PPM implantation. International experts in basic research on sinus node physiology and clinicians working on SND compose the FANTASY network. We have shown recently that hyperpolarization-activated f-(HCN4) channels down-regulation is involved in a wide range of SND forms and that inhibition of G protein-activated K+ channels (GIRK4) prevents SND in animal models. We propose to investigate the mechanisms of the disease state in animal models of HCN4-mediated SND and in sinus nodes of human hearts with history of SND. We will identify and manipulate micro-RNAs regulating HCN4 to antagonize their activity and reverse the disease process. In addition, we will test pharmacologic inhibition of GIRK4 in human sinus nodes to help develop a new therapeutic option of SND capable of preventing the development of disease symptoms. We expect that the FANTASY network will provide a better knowledge of SND pathogenesis and establish the bases for new SND therapies that would reduce the need for electronic pacemaker implantation worldwide.