Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations

Figures

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  Figure 1. Incorporation of the effects of the 1795insD mutation observed in expression systems into the Fabbri–Severi model of a human SA nodal pacemaker cell. (A) Mutation-induced shifts of +8.1 and −7.3 mV, as indicated by horizontal arrows, in the steady-state INa activation and inactivation curves of the Fabbri–Severi model cell. The inset shows the effects of the shifts on the INa window current. (B) Current traces of the wild-type and the 1795insD mutant INa upon a simulated voltage clamp step from a holding potential of −100 mV to a test potential of −25 mV. The inset shows the persistent component of the mutant INa.

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  Figure 2. Effect of a +8.1 mV shift in steady-state activation and a −7.3 mV shift in steady-state inactivation as observed for the 1795insD mutation in SCN5A on the electrical activity of the Fabbri–Severi model cell at normal beating rate (normal autonomic tone). (A) Membrane potential (Vm). (B) Net membrane current (Inet). (C) Fast sodium current (INa). Effect of the shift in steady-state activation per se (red traces), the shift in steady-state inactivation per se (blue traces), and the combined effect (green traces). Note the difference in ordinate scales between panels B and C. In the model, INa is split into a wild-type and a mutant component, thus representing the effect of a heterozygous mutation.

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  Figure 3. Effect of a 50% decrease in fully-activated conductance (gNa) and a 1.0–1.5% persistent current (Ipst) as observed for the 1795insD mutation in SCN5A on the electrical activity of the Fabbri–Severi model cell at normal beating rate (normal autonomic tone). (A) Membrane potential (Vm). (B) Net membrane current (Inet). (C) Fast sodium current (INa). (D) Persistent component of the fast sodium current (Ipst). Effect of the reduced gNa per se (blue traces), the persistent INa per se (red traces), and the combined effect (green traces). In the model, INa is split into a wild-type and a mutant component, thus representing the effect of a heterozygous mutation.

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  Figure 4. Changes in the electrical activity of the Fabbri–Severi model cell at normal beating rate (normal autonomic tone) due to loss-of-function (reduced gNa and shifts in the steady-state activation and inactivation curves) and gain-of-function (Ipst) effects as observed for the 1795insD mutation in SCN5A. (A) Membrane potential (Vm). (B) Net membrane current (Inet). (C) Fast sodium current (INa). Effect of the loss-of-function effects per se (blue traces), the gain-of-function effects per se (red traces), and the combined effect (dashed green traces). In the model, INa is split into a wild-type and a mutant component, thus representing the effect of a heterozygous mutation.

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  Figure 5. Changes in the electrical activity of the Fabbri–Severi model cell at low beating rate (vagal tone) due to loss-of-function (reduced gNa and shifts in the steady-state activation and inactivation curves) and gain-of-function (Ipst) effects as observed for the 1795insD mutation in SCN5A. (A) Membrane potential (Vm). (B) Net membrane current (Inet). (C) Fast sodium current (INa). Effect of the loss-of-function effects per se (blue traces), the gain-of-function effects per se (red traces), and the combined effect (dashed green traces). In the model, INa is split into a wild-type and a mutant component, thus representing the effect of a heterozygous mutation.

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  Figure 6. Bradycardic effect of the heterozygous 1795insD mutation. (A) Clinically observed heart rate of 1795insD mutation carriers [21]. Data are mean ± SD (cf. Table 1). ** p < 0.001. (B) Beating rate of the Fabbri–Severi model cell.