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

Subject Area Pharmacology
Term from 2020 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 442356349
 
Final Report Year 2024

Final Report Abstract

The present study investigates the effects of the HCN4F gain-of-function mutation on heart electric activity using in vivo telemetric ECG recordings in mice. The findings show that HCN4F mice exhibit mild sinus tachycardia, characterized by elevated minimum and maximum heart rates compared to wild-type mice. Moreover, HCN4F mice have a prolonged QT interval at high heart rates and reduced heart rate variability across all frequency bands, suggesting that the HCN4F mutation leads to a more stable and synchronous heart rhythm. Electrophysiological studies further support these results by showing faster sinus node recovery time and sinoatrial conduction in HCN4F mice, indicating enhanced impulse formation and conduction. The mild sinus tachycardia of the HCN4F knock-in mouse line, with an increased heart rate (HR) of about 10%, does not induce tachycardia-induced cardiomyopathy (TIC). TIC can develop as a result of a persistently elevated HR. Numerous studies in experimental animal models subjected to chronic cardiac pacing have well established that prolonged tachycardia can cause progressive biventricular systolic dysfunction, which is reversible after normalisation of HR. The development of TIC and the progression of heart failure are frequency-dependent. One possible reason that TIC is not triggered in the HCN4F mouse model could be the relatively small increase in frequency. This is considerably smaller than the increase due to pacing used in larger experimental animal models such as dogs or pigs. In these models, the HR was increased by more than 100% by pacing. Another reason for the lack of TIC development in HCN4F animals could be that mice don´t develop TIC as easily as larger animal models due to their high baseline frequency. Interestingly, however, it was shown that WT and HCN4F mice react differently to increased afterload and pressure load of the left ventricle due to surgical aortic stenosis (TAC, transverse aortic constriction). In both genotypes, TAC surgery induces hypertrophy of the ventricular myocardium with an associated restriction of the heart's pumping function (heart failure). However, the progression of the disease and cardiac remodelling differ significantly. The histologic findings and hemodynamic parameters indicate that the WT animals develop cardiac hypertrophy with dilatation of the left ventricle after TAC surgery, whereas HCN4F animals develop concentric hypertrophy associated with a smaller cross-sectional area of the left ventricular lumen, reduced end-diastolic volume, and a greater increase in end-systolic pressure compared to the WT animals. Findings derived from histologic data and hemodynamic parameters suggest that the gain-of-function mutation of the HCN4 channel protects the knock-in animals from dilatation after TAC surgery. As a result, the hearts of HCN4F animals are better able to compensate for increased afterload in the longer term.

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