Among cardiac diseases with increasing incidence in the aging population is Sinus Node Dysfunction (SND; or Sick Sinus Syndrome), a condition caused by failure to generate and/or propagate cardiac electrical signals. Patients with SND have slow heart rates, which can lead to symptoms and even death. In patients with heart failure about 40% of the sudden deaths are due to slow heart rates. Moreover, SND may start as a slow heart rate without symptoms that ultimately progresses to debilitating slow heart rhythm requiring pacemaker implantation. International experts in basic research on sinus node physiology and clinicians working on SND compose this Leducq FANTASY network. We have shown recently that low levels of the hyperpolarization-activated f-(HCN4) channels are 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 this important disease in animal models and in sinus nodes of human hearts with history of SND. We will identify and manipulate micro-RNAs that regulate the HCN4 channel in order to reverse the disease process. In addition, we will test drugs that inhibit GIRK4 in human sinus nodes to help develop a new therapeutic option for 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