'Pacemaker' Hcn4 gene responsible for generation of repetitive activity in SAN tissue and heart rate regulation

The study of Dario DiFrancesco and his equipe identifies the "pacemaker" Hcn4 gene as the gene functionally responsible for the generation of repetitive activity in sinoatrial node tissue and for the regulation of heart rate. Hcn4 codes for HCN4 channels, the molecular components of "funny" ion channels of pacemaker cells of the sinoatrial node (SAN) tissue. Previous work by the same lab and by others had already highlighted the relevance of "funny" channels to cardiac pacemaking. For example, an inheritable sinus bradycardia has been found associated with a point-mutation in HCN4 in an italian family (Milanesi et al., New Engl J Med 2006;354:151-7); also, a drug developed as a pure heart rate-reducing agent with no cardiovascular side effects and presently used in the therapy against angina (ivabradine) is known to be a specific blocker of "funny" channels (Bucchi et al., 2002, 120;1-13). However, no direct evidence for rate generation and control was available.

The study of DiFrancesco and collaborators is based on the generation of a cardiac-specific, inducible Hcn4 KO mouse model. Mice where the Hcn4 gene is knocked out develop a deep bradycardia, and the time course of rate decrease parallels that of the reduction of "funny" channels expressed on the mambrane of pacemaker cells. Hcn4 is therefore shown to controls frequency, and to be essential to survival.

The clinical relevance of these findings is apparent. Knowing the functional role of "funny" channels in rate regulation opens new perspectives in the therapy of rhythm disorders.