The Role of HCN4 Variants in Human Systolic Heart Failure and Protein Interaction Network

Introduction: An elevated heart rate (HR) results in adverse outcomes in human systolic heart failure with a sinus rhythm. Genetic variants may alter HCN4 interactions with regulatory proteins and increase HR. This study aimed to generate a protein interaction network (PIN) associated with elevated HR and to determine HCN4 gene variants (718G>A, 1571G>A, and 2648C>G) in patients with systolic heart failure, sinus rhythm, and elevated heart. Methods: STRING protein database was used to generate a PIN. Laboratory exploration was performed to identify HCN4 gene variants in patients with systolic heart failure using PCR and DNA sequencing. Results: PIN revealed eight nodes and 13 edges. STRING functional enrichment showed the essential proteins (ADRB1 and HCN channels) involved in HR regulation. GNAS and ADCY1 contributed to the regulation process. HCN4 gene variants (718G>A, 1571G>A, and 2648C>G) alter the properties of HCN4 channel. STRING scores of protein-protein interactions that involved HCN4, ADRB1, GNAS, and ADCY1 were high (in the range of 0.879-0.979). The three gene variants were evaluated in 49 study participants with HR≥70 bpm after 10 mg bisoprolol therapy. However, only 718G>A was identified in three of 49 patients. Conclusion: PIN revealed that the three essential proteins associated with HCN4 channels in elevating HR were ADRB1, GNAS, and ADCY1. Only HCN4 718G>A was found in three out of 49 patients with systolic heart failure, sinus rhythm, and increased HR, according to a laboratory investigation on HCN4 gene variants