Current understanding of the pathophysiological mechanisms responsible for inappropriate sinus tachycardia: role of the If "funny" current

Together with the afferent branches of the autonomic nervous system, the sinoatrial node (SAN) forms a functional unit whose function is to fire rhythmic action potentials at a rate optimal for coping with the metabolic needs of the body. Dysfunctional behavior of this complex unit may thus result in SAN rhythm disorders. Among these disorders, there is the inappropriate sinus tachycardia (IST) which occurs when an unjustified fast SAN rate is present. We here present a critical review of the role of pacemaker f/HCN channels in cardiac rhythm generation and modulation and their involvement in IST. Recent evidence demonstrates that a familial form of IST is associated with a gain-of-function mutation in the HCN4 pacemaker channel (R524Q) which confers an increased sensitivity to the second messenger cAMP, a key mediator in sympathetic modulation. This finding is consistent with the general view that hypersympathetic tone is one of the causes of IST and introduces the novel concept of defective funny channel-dependent tachyarrhythmias.