Key result
The p.V240M gain-of-function HCN4 mutation caused inappropriate sinus tachycardia in 9 family members, which was significantly reduced from 109 bpm to 94 bpm by ivabradine treatment.
Why the study?
To clinically study a family with inappropriate sinus tachycardia and functionally analyze a newly identified novel p.V240M mutation in the HCN4 channel.
Does the p.V240M HCN4 mutation cause inappropriate sinus tachycardia and is it reversible with ivabradine in affected family members?
Observational (n=15)
No
Does the p.V240M HCN4 mutation cause inappropriate sinus tachycardia and is it reversible with ivabradine in affected family members?
Absolute Event Rate: 94% vs 109%
p-value: p=<0.05
The novel p.V240M gain-of-function mutation in the HCN4 gene causes inappropriate sinus tachycardia and cardiomyopathy, which can be successfully reversed with ivabradine.
May support ivabradine in HCN4-related IST; leaves open validation before genetic screening changes practice.
Background In a family with inappropriate sinus tachycardia (IST) we identified a novel mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (I f ) in human sinoatrial node cells. Here we clinically study the family and functionally analyze the p.V240M variant. Methods Macroscopic (I HCN4 ) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. Results All p.V240M mutation carriers exhibited IST (mean heart rate 113[7] bpm, n=9), that in adults, was accompanied by cardiomyopathy. I HCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels. The variant, which lies in the N-terminal HCN domain, increased single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. Conclusions The p.V240M gain-of-function variant increases I f during diastole, which explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4 which stabilizes the channels in the closed state. Funding Ministerio de Ciencia e Innovación (PID2020-118694RB-I00); Comunidad Autónoma de Madrid (P2022/BMD-7229), European Structural and Investment Funds); and Instituto de Salud Carlos III (CIBERCV; CB16/11/00303).
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Cámara‐Checa et al. (2023) conducted an observational in Inappropriate sinus tachycardia (n=15). Ivabradine vs. Pre-treatment baseline was evaluated on Mean 24-hour heart rate (p=<0.05). The p.V240M gain-of-function HCN4 mutation caused inappropriate sinus tachycardia in 9 family members, which was significantly reduced from 109 bpm to 94 bpm by ivabradine treatment.
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