A New SCN5A Variant in a Patient with Idiopathic Ventricular Fibrillation: The Dark Side of Cardiac Imaging.

We present the case of a patient with recurrent episodes of ventricular fibrillation without evidence of structural cardiac diseases on imaging techniques and negative genetic testing for the most common primary arrhythmia syndromes. A new variant c.6023C>T p.Pro2008Leu of the SCN5A protein, responsible for the sodium inward current (INa) through the cardiomyocytes, was found. A likely pathogenic effect of this gene variant was hypothesized. Copyright:

INTRODUCTION

Idiopathic ventricular fibrillation (IVF) is a syndrome leading to sudden cardiac death (SCD) in individuals with an apparently normal heart, in whom structural cardiac disease, primary arrhythmia syndromes, respiratory, metabolic, and toxicological causes have been excluded through an extensive clinical evaluation.[1]

Despite the advancements in diagnostic tools, no specific guidelines exist regarding the diagnosis and management of this peculiar condition.

Cardiac imaging has a pivotal role in identifying potential structural abnormalities associated with arrhythmic disorders, but sometimes, it may result completely normal.

Undoubtedly, the greater knowledge and use of genetic testing had the important advantage of contributing in diagnosing primary syndromes complicated by malignant arrhythmias, but the detection of gene variants of uncertain clinical significance is more and more frequent and, often, the interpretation is problematic.

It is known that a subgroup of IVF patients may have mutations in cardiac Na+ channel α subunit gene (SCN5A), clearly described as responsible for Brugada syndrome (BrS), in the absence of typical electrocardiographic findings of BrS.[2]

Nevertheless, it is still controversial whether this IVF subgroup is a phenotypic variation of BrS or a distinct clinical entity.

The new-generation sequencing technologies attempt to provide new insights into genotype-phenotype correlations, but many issues remain to be elucidated. Therefore, the great challenge for clinicians is to identify this disorder despite negative imaging findings, after excluding other at least genetically overlapped diseases, to start a dedicated management.

CASE REPORT

A 24-year-old male presented to our Emergency Department for syncope, occurred at rest, while he was working at personal computer at home. A similar episode of sudden cardiac arrest already occurred in his past medical history, when he was 21 years old; ventricular fibrillation (VT) was detected and promptly treated with DC shock through automated external defibrillator. In that occasion, after few days of hospitalization in a primary care hospital, internal cardioverter defibrillator (ICD) was implanted for secondary prevention and beta-blocker therapy was started. Interestingly, no family history of SCD and no drug or substances abuse was referred.

At our clinical evaluation, the patient was asymptomatic for chest pain and/or palpitations and/or dyspnea. Blood pressure was 120/70 mmHg, heart rate 74 beats/min, oxygen saturation on room air 98%, and body temperature 36°C. Cardiac biomarkers, electrolytes, thyroid hormones, and toxicological examinations resulted normal. The electrocardiogram (EKG) showed sinus rhythm, in the absence of atrioventricular or intraventricular blocks and/or repolarization abnormalities, and QTc was 360 msec [Figure 1]. It was performed both in the conventional right precordial leads and one and two intercostal space higher. Furthermore, at transthoracic echocardiography (TTE), a normal left ventricular (LV) ejection fraction of 60% without significant valvular or structural diseases was described and LV global longitudinal strain resulted in normal range (−18.4; normal value >−18.9 ± 2.5 for Philips QLAB 7.11) [Figure 2].

Figure 1

Electrocardiogram showing sinus rhythm and no atrioventricular or intraventricular blocks

Figure 2

Transthoracic echocardiography showing in (a) apical four-chamber, in (b) apical two chamber and in (c) apical long-axis views. (d) Speckle-tracking echocardiographic analysis reporting Bull's eye plot of the left ventricle. Global longitudinal strain was 18.4 and resulted in normal range

ICD interrogation revealed an episode of VF, successfully treated with DC shock during the syncope [Figure 3].

Figure 3

At internal cardioverter defibrillator interrogation, during the episode of syncope, ventricular fibrillation was reported (in [a] red arrow) and successfully interrupted by the internal cardioverter-defibrillator shock (in [b] red circle)

Coronary angiography (CA) was also performed, revealing no coronary artery anomalies, no stenosis, or acetylcholine-inducible spasm. In-hospital course was uneventful; a strategy of overdrive pacing (90 beats/min) was applied to prevent recurrent ventricular arrhythmias in the setting of ventricular extrasystole. Genetic testing for the most common primary arrhythmia syndromes was suggested, and a mutation on SCN5A gene (NM001099404: C.6023C >T, pPro2008Leu) of unknown clinical significance was found.

In addition, flecainide test was also performed to unmask a potential silent SCN5A-related BrS, but upon drug administration, no change of EKG parameters in comparison with baseline was documented.

To complete the diagnostic work-up, cardiac magnetic resonance (CMR) was performed and no morpho-functional and/or tissue abnormalities involving the ventricles were detected on pre or postcontrast images [Figure 4]. The patient was discharged after 10 days in clinically stable conditions.

Figure 4

Image samples from the cardiac magnetic resonance study, all obtained in 3-chamber view using (a) a cine gradient-echo sequence for ventricular functional evaluation, (b) a T1-weighted fast-spin echo sequence to exclude myocardial fatty infiltration and (c) a T1-weighted inversion recovery gradient-echo sequence applied late after gadolinium-based contrast injection for the evaluation of myocardial fibrosis/necrosis

DISCUSSION

This is the first case in literature that reports the variant c.6023C >T, p.Pro2008Leu of the SCN5A protein in a patient with recurrent episodes of VF, without evidence of structural cardiac diseases on imaging techniques and negative genetic testing for primary arrhythmia syndromes.

The SCN5A gene encodes the alpha-subunit of the Nav 1.5 ion channel protein, which is responsible for the sodium inward current (INa), determining cardiac excitability and electrical conduction through the cardiomyocytes.[3]

Several mutations have been found in this gene and the clinical manifestations may be various, ranging from electrical disorders in the absence of structural cardiac diseases, such as BrS, long QT syndrome (LQTS), sick sinus syndrome, heart block, to cardiomyopathies characterized by clear structural changes, including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, atrial standstill.[4]

In our case, the novel variant c.6023C >T, p.Pro2008Leu is a missense single nucleotide polymorphism that replaces proline with leucine at codon 2008 of the SCN5A protein.

In catalog “ClinVar” of genetic mutations, the impact of this variant on protein function is unknown and the current evidence is insufficient to determine its role in individuals affected with cardiovascular disorders, conclusively. Therefore, it has been classified as a “Variant of Uncertain Significance.”

In management of our patient, a clinical dilemma emerged basal EKG, toxicological screening and all laboratory data were completely normal. Furthermore, CA excluded the presence of coronaropathies or coronary spams, as well as echocardiographic and CMR findings were negative for structural cardiac abnormalities. Furthermore, diagnostic screening for the most common inherited primary arrhythmia syndromes such as BrS, LQTS, short-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and early repolarization syndrome was negative. After the results of genetic testing that revealed the novel SCN5A variant, flecainide test was performed to exclude, definitely, silent BrS as potential cause of arrhythmic episodes, but also this examination was inconclusive. Accordingly, after extensive diagnostic testing, VF was labeled as idiopathic.

Some questions were brought up: Was cardiac imaging enough for the exclusion of arrhythmic disorder? What significance had genetic testing? Should a genotype-phenotype relationship be considered in our patient?

This case highlights the difficulty to exclude, in a holistic diagnostic pathway, specific cardiac diseases that may cause SCD and to interpret the variants of uncertain significance in a clinical context. Furthermore, being a diagnosis by exclusion, how and when classify VF as idiopathic is a matter of great discussion.[5]

In the last years, high-resolution imaging modalities have allowed to detect also small structural cardiac abnormalities, improving the diagnostic abilities of cardiomyopathy in early stages, as well as specific disease algorithms have shown good sensitivity and specificity.[6] This case highlights that, in some cases as ours, cardiac imaging has a dark side because no structural abnormalities were detected on TTE and CMR. Accordingly, when is imaging enough and when is it recommended to go beyond imaging? Has cardiac imaging a role in follow-up? These questions remain unanswered.

Genetic testing has undoubtedly contributed to increase the rate of diagnosis of inherited arrhythmia syndromes but also to detect new gene variants in clinical phenotypes not well defined.[7] The main problem remains the interpretation of the variants because not all have a functional effect and, also in the same family, not all carriers might show the same clinical phenotype.

According the European Society of Cardiology guidelines on ventricular arrhythmias and the prevention of SCD,[8] ICD implantation is recommended in survivors of IVF for secondary prevention and the use of beta-blockers and/or class III antiarrhythmic drugs may be helpful for reducing recurrent VF episodes.[9]

Interestingly, it has been reported that patients with IVF have a high recurrence rate of ventricular arrhythmias, varying from 11% to 45%.[10]

In our case, VF occurred always at rest. By the first episode of resuscitated cardiac arrest, after 3 years uneventful, the second event was identified by ICD and successfully interrupted.

CONCLUSION

The variant c.6023C >T, p.Pro2008Leu in the SCN5A gene is related with recurrent episodes of VF in the absence of any structural cardiac diseases on conventional imaging techniques. In our patient, the genotype-phenotype relationship suggests a likely pathogenic effect of this variant. Functional studies are warranted to better understand the molecular mechanisms and its role in arrhythmic disorders.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.