An HCN4 gain-of-function mouse model to study inappropriate sinus tachycardia and tachycardia-induced cardiomyopathy

• Applicant: Privatdozentin Dr. Stefanie Fenske
• Subject Area: Pharmacology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442356349

Tachycardia-induced cardiomyopathy (TIC) is a potentially reversible form of secondary cardiomyopathies that likely leads to full clinical manifestation of heart failure if the underlying trigger remains untreated. Several distinct forms of ventricular and supraventricular tachycardia might induce TIC. The most common and best characterized ones are atrial flutter and atrial fibrillation. A rare cause for the development of TIC that has not been well described and studied so far is inappropriate sinus tachycardia (IST). IST is defined as a persistent elevation in the resting heart rate (HR) to more than 100 beats/min that is inappropriate for the level of physiologic, pharmacologic, or pathophysiologic stress. Managing IST by reducing the HR remains a challenge. Even at high doses, ß-receptor blockers are ineffective in the majority of patients and adverse side effects are common. Ivabradine, a selective blocker of hyperpolarization-activated and cyclic-nucleotide gated (HCN) channels, effectively reduced minimum, mean and maximum HR, improved symptoms or resolved them completely in several clinical studies dealing with IST patients without TIC symptoms. It was also reported to successfully treat IST-induced TIC in three case reports. Together these outcomes indicate a potential and until recently undiscovered role of increased HCN channel activity in the development of IST-induced TIC. To get further insights into the disease and causing mechanisms we generated a knock-in mouse model carrying a gain-of-function mutation within the HCN4 cation channel. Marked sinus tachycardia was evident in telemetric ECG recordings from knock-in animals resembling IST in human patients. Minimum and mean HRs were elevated, whereas the maximum HR was similar to the values obtained from WT animals. Ventricular cross-sections revealed that persistent high heart rates lead to cardiac remodelling and ventricular dilation rendering our mouse model a valuable tool to promote this emerging research area.

• DFG Programme: Research Grants