The Contribution of HCN4 to normal sinus node function in humans and animal models

Although sinus node bradycardia is a very common clinical condition, the cellular mechanisms contributing to abnormal sinus node function are not clearly delineated. In recent publications, mutations in the hyperpolarization-activated, cyclic nucleotide-gated (HCN) 4 channels have been associated with sinus bradycardia. These channels are thought to be crucial in generating the spontaneous sinus node action potential, in accelerating the heart rate during sympathetic drive, and decelerating heart rate during vagal stimulation. Humans carrying HCN4 mutations indeed display significant bradycardia. Recent studies generating HCN4 knock out mice suggested that although HCN4 is crucial in early development, other mechanisms may also play a role in the accelerated heat rate achieved during sympathetic drive. In this review, we focus on genotype-phenotype correlation of these mutations and discuss the relative contribution of various ion channels to sinus node function. We also discuss the importance of HCN in treating clinical conditions such as brady- and tachycardia.