What's in a Name? Further Classification of Patients With Apparent Idiopathic Ventricular Fibrillation

Martijn H. van der Ree; Pieter G. Postema


Eur Heart J. 2021;42(29):2839-2841. 

Graphical Abstract: Historical timeline of the classification of disease entities previously considered idiopathic ventricular fibrillation Abbreviations: ARVD: arrhythmogenic right ventricular dysplasia, BrS: Brugada syndrome, CPVT: catecholaminergic polymorphic ventricular tachycardia, ERS: early repolarization syndrome, HCM: hypertrophic cardiomyopathy, IVF-SC: idiopathic ventricular fibrillation—short-coupled phenotype, LQTS: long QT syndrome, SCD: sudden cardiac death, SCVF: short-coupled ventricular fibrillation, SQTS: short QT syndrome.*:[6]

Diagnosing a patient comes down to identifying the nature of an illness and subsequent classification. The word diagnosis originates from the Greek word διαγιγνώσκειν (diagignōskein), meaning 'to distinguish'. Over time, improving knowledge and diagnostic tools enabled us to identify and further distinguish distinct disease entities. As an example, Hippocrates might have been the first physician who described sudden cardiac death based on diseases such as non-ischaemic cardiomyopathies and primary arrhythmia syndromes.[1] Although he was, however, not yet able to distinguish specific underlying cardiac diseases, he made very valuable observations on this subject:

"Those who are subject to frequent and severe fainting attacks without obvious cause, die suddenly"

During history, several other interesting observations have been made on unexplained sudden cardiac death, amongst others the report by Meissner in 1856 regarding a deaf girl who died suddenly during severe emotional distress. It turned out that several family members had also died suddenly at young age after intense emotions (without mentioning deafness as their comorbidity).[2] Meissner most likely described the first cases of familial long QT syndrome (LQTS—possibly Jervell Lange-Nielsen[3]) or, e.g., catecholaminergic polymorphic ventricular tachycardia (CPVT) with deafness as a bystander. Despite his perceptive observation, also Meissner was not yet able to determine the underlying disease and pathophysiological mechanisms.

Even now, this issue is still valid in patients with the diagnosis of idiopathic ventricular fibrillation (IVF). In patients with IVF, the cause of ventricular fibrillation remains unknown after extensive diagnostic and genetic testing. In most of these patients we thus do not understand the pathophysiological mechanisms behind the occurrence of their arrhythmias (yet).[4] Importantly, as IVF may be inheritable, we have many difficulties with identifying pre-symptomatic family members. This notwithstanding, with improving knowledge and diagnostic tools, more and more distinct disease entities have been identified in the past decennia. The majority of the primary arrhythmia syndromes such as LQTS, CPVT and Brugada syndrome were previously considered idiopathic as well (Graphical abstract).[5] Therefore, it is very plausible that new phenotypes and disease entities will be uncovered in the current spectrum of IVF, and that the incidence of IVF will subsequently further decrease over time.

Subclassification of IVF may further accelerate today due to the publication of Steinberg et al. in this issue of the European Heart Journal.[6] In this contribution the colleagues from multiple centers in Canada outline a specific subtype of IVF, which they describe as a distinct primary arrhythmia syndrome: short-coupled ventricular fibrillation (SCVF). In these patients, the arrhythmic event is triggered by short-coupled premature ventricular contractions (PVCs). This phenotype was previously often described as short-coupled torsades or short-coupled variant of torsade de pointes.[7] The distracting issue with short-coupled torsades vs. classical torsade de pointes, is that there is no relationship with prolongation of the QT interval in the former besides the characteristic long coupling interval of the initiating PVC in the latter. Although there is a difference in the electrocardiographic appearance of short-coupled PVCs that initiate torsade, vs. polymorphic ventricular tachycardia and ventricular fibrillation, we believe that in the absence of QT prolongation and in the presence of these short-coupled PVCs, these entities are probably very similar. The colleagues from Canada now describe this subtype of IVF, for which they suggest the name SCVF instead of short-coupled torsades, in a cohort of unexplained cardiac arrest survivors within the CASPER registry (NCT00292032). SCVF indeed appears to be very malignant as indicated by the very high risk of arrhythmia recurrence. The authors also propose standardized criteria to help facilitate the phenotypic diagnosis of SCVF. One could say, "What's in a name?", but the identification of such phenotypes and subtypes of diseases is of utter importance as it may guide phenotype specific treatments. This has previously been demonstrated in other disease with distinct subtypes such as the LQTS, in which the different phenotypes require different treatment strategies.[8] Despite the description of SCVF as a primary arrhythmia syndrome, we believe that this is rather arbitrary as we will exemplify in the following paragraph. In the Netherlands, with the identification of the DPP6 risk haplotype, the existence of a specific hereditary subset of SCVF has previously been described.[9] In this subset of patients, ventricular fibrillation also appeared to be initiated by short-coupled PVCs (mean coupling interval 247 ms).[10] However, only the DPP6 patients with documented ventricular fibrillation initiated by PVCs with a coupling interval of <350 ms would classify for the diagnosis SCVF whilst all patients with the DPP6 risk haplotype share the same arrhythmogenic substrate. Therefore, in our view, SCVF is indeed a distinct phenotype and mirrors short-coupled torsade IVF, but we believe it is too early to recognize SCVF as a distinct primary arrhythmia syndrome.

One of the most important issues with determining SCVF is that patients with the SCVF phenotype benefit from a specific treatment: quinidine.[11] In the 12 SCVF patients treated with this drug for recurrent ventricular fibrillation, excellent arrhythmia control was achieved. Likewise, in patients with the DPP6 risk haplotype, quinidine has also been an excellent treatment in most patients to prevent ventricular fibrillation recurrence. Unfortunately, no electrocardiographic phenotype which would enable preventive treatment was found. This however does not preclude that such distinctive phenotypical expression, apart from short-coupled ventricular fibrillation, is not present.[12] Hopefully, with future genetic, electrocardiographic and electrophysiology studies we will be able to earlier detect SCVF and treat these patients accordingly.

It is fortunate that the treatment of these newly identified phenotypes does not always require the development of new drugs. Previously developed and long existing drugs such as quinidine, or mexiletine for example, once again prove that they can be extremely effective. The (re)use of these longer existing drugs however comes with its own issues; availability, registration and reimbursement issues are unfortunate problems cardiologists currently encounter on a daily base when prescribing these long-known drugs.[13–15] It is very important that the continuity of these drugs remains guaranteed given the malignant nature of such disease—prevention is always better than treatment.

Lastly, now that the incidence of short-coupled torsades or SCVF has been further detailed as a distinct phenotype of IVF in Canada, it would be very relevant to evaluate the incidence and the clinical and genetic characteristics in other countries as well. As already mentioned, the existence of a specific hereditary subset of the SCVF phenotype has already been described in the Netherlands.[10] The discovery of the DPP6 risk haplotype allowed us to screen presymptomatic family members preventing sudden cardiac death in these high-risk patients. Undoubtedly, more (genetic) subsets of SCVF can be identified by multi-centre initiatives, which may lead to further optimalization of our patient care.

We would like to thank the authors for their in-depth analysis of this specific subset of IVF patients and congratulate them with the ensuing publication. To us, if identifying new phenotypes results in improving treatment strategies it is not just 'in a name'.