FANTASY: Fighting Against Sinus Node Dysfunction and Associated Arrhythmias
Mission of the project
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
Effort 1
To normalize heart rate in HCN4-mediated SND by pharmacologic targeting of GIRK4 channels. We will employ pharmacologic block of IKACh to normalize heart rate and rhythm in animal secondary SND models and in human sinus nodes ex vivo.
Effort 2
To validate target miRs in HCN4-mediated SND mechanisms. We will study miR expression in ex vivo human SAN with history of SND.
Effort 3
To model transient rescue of SND using preclinical models of HCN4-mediated secondary SND in vivo. We will attempt to normalize heart rhythm by transiently repressing the expression of identified target miR in animal models.
Effort 4
To develop vector-based gene therapy for long-term reversal of HCN4-mediated SND. We will create vectors for long-term miR antagonism. Vectors will be tested in animal models of SND and hiPSCs-CM, as well as PLhiPS-CM.
Effort 5
To identify new genetic variants leading to HCN4-mediated, GIRK4-mediated, or new primary forms of SND. We will perform a gene panel-based sequencing of the known disease genes in a large population of patients with primary SND.
Questions?
Contact Peter.Mohler@osumc.edu to get more information on the project