SCN5A R222Q variant
SCN5A R222Q affects the positively charged arginine which lies on the S4 segment of the DI domain (DI/S4) - one of the four sodium channel voltage sensors of the primary sodium channel in the heart - Na
v1.5 [
11]. This variant was previously described in at least 8 families with DCM/arrhythmias/LQTS and segregated with disease among at least 38 relatives [
4,
10,
12‐
16]. The effect of the R222Q mutation on the Na
v1.5 function was experimentally investigated [
10,
14]. The
SCN5A R222Q varaint leads to a gain in the function of the mutated channel, which expresses many kinetic disturbances, such as an opening at more negative potentials. Mann et al. [
14] suggest that the increasing and rate dependent automaticity of the Purkinje fibre cell is the reason for the MPVCs. It is consistent with a previous study [
10], which described the mechanism of MPVCs triggered by an incomplete Purkinje fibre repolarisation and their propagation into the ventricles. In patients with the
SCN5A R222Q mutation, the entire Purkinje system is changed and can be a source of a variety of ectopic foci, resulting in a phenotype called the MEPPCs syndrome. DCM caused by the
SCN5A R222Q mutation, seems to be a secondary finding to ventricular arrhythmia, of note we have not observed myocardial muscle thinning in the course of the disease, like in our patient (LV wall thickness was 12-13 mm).
However, the mechanisms of left ventricular dilation in individuals carrying the
SCN5A R222Q mutation are not completely defined. The patient’s son, in whom we performed the WES study, also carried the well-known
SCN5A H558R polymorphism, which was previously described in patients carrying the
SCN5A R222Q variant [
12]. The altered current Na
+ activity may significantly deteriorate the left ventricular function along with the effects of MEPPCs or the presence of atrial fibrillation [
17]. In Mann’s study, the R222Q variant of
SCN5A presented a different expression related to sex, with more genotype-positive males (7 of 10) affected with DCM than females (1 of 7) [
14]. That fact was explained as a protective role associated with a higher heart rate in women due to a reduced Purkinje cell excitability.
We observed a significant difference in the course of HF and in terms of age at the onset of symptoms between the described patient (Fig.
1 – III:1) and his children. We only found that the
SCN5A H558R polymorphism, present in the proband’s son, was inherited from the unaffected mother. However its presence did not exacerbate the course of the disease in the study by Cheng et al. [
12].
Quinidine treatment
The phenotype caused by the
SCN5A R222Q mutation (DCM, MEPPCs) was found to be responsive to sodium channel blockers [
10,
14]. Laurent et al. first reported the association of MEPPCs and left ventricular dysfunction in 3 unrelated families with the
SCN5A R222Q mutation, stressing that DCM is a secondary consequence of the mutation. The authors found spectacular effect of the quinidine treatment in 2 patients with the arrhythmic phenotype within one family in whom the normalisation of the left ventricular function was noted and in two affecteds from another family who had a normal left ventricular function [
10] . Mann et al. in turn, found a substantial reduction of MPVCs in patients with the
SCN5A R222Q mutation by known sodium channel blocking agents, such as amiodarone or flecainide [
14].
Our data support the spectacular results by Laurent et al. [
10] of the quinidine treatment in another family with DCM and MEPPCs. The standard heart failure therapy in our patient and his children was ineffective. In younger generation, it led directly to HTx (son) and the death of the patient’s daugther. We observed a significant reduction of MPVCs during the quinidine treatment (reduction MPVCs > 80%/day to 3-5% /day) and a significant improvement of the LV function. The earlier treatment with amiodarone was partially successful but had to be stopped due to its toxicity. Of note, the quinidine treatment was effective in the patient who also had co-existing CAD.
The effects of quinidine were tested on the cellular model [
10]. Clinically, quinidine primarily works by blocking the fast inward sodium current (I
Na) and the transient outward current (I
to), by repolarising the delayed rectifier current I
Kr, and by inhibiting Ca
2+ and other K
+ currents [
18]. Quinidine usage caused the normalisation of Purkinje and ventricular cells potentials (maximal drug dose, remaining 50% I
Na and 30% I
Kr and I
to). Such effect was still observed when the drug dosage was reduced (remaining 75% I
Na and 45% I
Kr and I
to), but disappeared in the case of a lower dosage of quinidine (remaining 85% I
Na and 50% I
Kr and I
to) [
10].
Current guidelines inform that Class Ia antiarrhythmic agents are contraindicated both in heart failure and in CAD. The ESC/AHA guidelines for the treatment of CHF or Ventricular Arrhythmias do not recommend class I drugs (quinidine, flecainid) to treat MPVCs in DCM patients [
9,
19].
Current guidelines also advise genetic studies in patients with DCM and conduction disease [
9]. Recent data show that patients with familial DCM and accompaning MEPPCs also need individual clinical diagnostics, including genetic examination toward Na
v1.5 mutations. In such cases antiarrhythmic therapy containing sodium channel blockers is supposed to be successful. Only a limited number of published reports on families with the
SCN5A R222Q Na
v1.5 mutation, show a promising antiarrhythmic effect of the quinidine [
10], flecainid and amiodarone therapy [
14]. Case reports published up until now show that the reduction of MPVCs can partially or completely reverse LV dilation and reverse heart failure symptoms; however, the influence of the treatment on the prevention of sudden cardiac death is unknown. Our study adds to the existing literature with information that, the quinidine treatment was effective in the patient who also had co-existing CAD.
Translation medicine
The mutations of the SCN5A gene in the DCM patients are an important cause of life-threatening ventricular arrhythmias. Based on the confirmed individual specific SCN5A mutation and pharmacokinetic experimental models of antiarrhythmic drugs, we can treat patients with well-matched sodium channel blockers like quinidine in our case.
Unfortunately, genetic testing is still difficult to obtain in general cardiologist practice. However, it gives perspective for future mutation-specific therapy dedicated for Purkinje cell related arrhythmia. Our case highlights the value of genotype information for the treatment strategy.
In conclusion, patients with familial DCM and MPVCs should be investigated for SCN5A gene mutations. The antiarrhythmic treatment with quinidine can significantly reduce the number of MPVCs and reverse LV dilation in a few months even in the presence of concomittant CAD.