Cardiovascular Research

Cardiovascular Research 2001 50(2):218-223; doi:10.1016/S0008-6363(01)00224-3
© 2001 by European Society of Cardiology

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Copyright © 2001, European Society of Cardiology

Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation?

Silvia G Priori^a,b,*, Carlo Napolitano^a and Massimiliano Grillo^b

^aMolecular Cardiology, Fondazione Salvatore Maugeri, Via Ferrata 8, 27100 Pavia, Italy
^bDepartment of Cardiology, University of Pavia, Pavia, Italy

^* Corresponding author. Present address: Molecular Cardiology, Fondazione Salvatore Maugeri, Via Ferrata 8, 27100 Pavia, Italy. Tel.: +39-0382-592-051; fax: +39-0382-592-094 spriori{at}fsm.it

Received 1 November 2000; accepted 19 January 2001

	Abstract

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
In 6–10% of survivors of cardiac arrest no cardiac abnormality can be identified despite extensive clinical evaluation. Autopsy data confirm that in a similar percentage of victims of sudden death no structural heart disease can be identified at post mortem evaluation. Occurrence of cardiac arrest in the absence of a substrate is defined ‘idiopathic ventricular fibrillation’ thus admitting that the cause for the arrhythmic event has remained unknown. We present data supporting the hypothesis that incompletely penetrant genetic defects may underlie at least some of these unexplained deaths.

KEYWORDS Arrhythmia (mechanisms); Long QT syndrome; Ventricular arrhythmias; Sudden death

	1 Cardiac arrest in the structurally normal heart

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
Cardiac arrest occurs as a consequence of acute myocardial ischemia and plaque rupture, or it develops in the presence of structural abnormalities such as myocardial infarction, hypertrophy or dilation of the heart [1].

In a large proportion of cardiac arrest victims the sudden arrhythmic event is the first manifestation [2] of a previously unknown heart disease [3]. In most instances clinical evaluation of survivors of cardiac arrest or autopsy of cardiac arrest victims, discloses the presence of an unrecognized structural heart disease. In a minority of cases, however, no cause for the lethal arrhythmia is identified. Furthermore in 5–8% of cardiac arrest victims, autopsy fails to identify structural abnormalities of the heart or of the coronary arteries [4,5]. Even among survivors of cardiac arrest despite careful invasive and non-invasive evaluation, a similar percentage of individuals does not manifest signs of structural heart disease or coronary artery abnormalities [4]. Occurrence of cardiac arrest in the absence of an identifiable substrate is called ‘idiopathic ventricular fibrillation’ (IVF) [6].

	2 How normal is the ‘normal heart’ in a survivor of cardiac arrest?

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
In 1999 we advanced the hypothesis that concealed forms of arrhythmogenic disorders may underlie unexplained cardiac arrest [7]. We speculated that while the heart of IVF victims or resuscitated patients is ‘apparently normal’, it may harbor a subclinical ‘electrical disease’ such as long QT syndrome (LQTS) or Brugada syndrome (BS). Both LQTS and BS are caused by inherited abnormalities of cardiac ion channels [8] and are commonly diagnosed at ECG analysis: in the absence of an overt prolongation of the QT interval [9] or of a remarkable ST segment elevation [10] these diagnoses are excluded. Several considerations however challenge the concept that ECG evaluation allows exclusion of the diagnosis of LQTS and BS and suggest that clinical diagnosis may be missed because ECG analysis is less sensitive than commonly thought.

	3 Is sensitivity of ECGs for the diagnosis of LQTS and BS lower than expected?

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
The sensitivity of ECG analysis in LQTS and in BS is unknown, however it has been demonstrated that genetically affected individuals may have a normal ECG. Even before the genetic basis of LQTS was elucidated, Garson et al. [11] reported the presence of a normal QT interval in 6% of affected individuals, and later Vincent et al. [12] proved that in 63% of KvLQT1 genotyped family members the QT interval ranged between 410 and 470 ms, overlapping with the values measured among non-carriers spouses (range 380–470 ms). We recently investigated the possibility that clinical evaluation of the ECG may miss affected family members with LQTS. We compared clinical and molecular diagnoses in order to estimate the sensitivity of ECG analysis in LQTS. We studied nine individuals clinically identified as ‘sporadic cases’ because none of the family members presented a history of syncope or a prolongation of QT interval at 12-lead ECG. Molecular analysis demonstrated that five probands had inherited the genetic defect from a parent with a normal ECG [13]. In our study the penetrance of the disease was as low as 17% in some families, and ECG sensitivity was only 25%. This observation suggests that a high percentage of family members may have a concealed form of the disease that cannot be diagnosed with clinical tools.

Epidemiological considerations support the view that BS is likely to underlie a high proportion of cases defined as ‘idiopathic ventricular fibrillation’: both conditions share a male predominance and often manifest in the third decade of life. Additionally since the typical electrocardiographic pattern of BS (ST segment elevation in V1–V3 and incomplete right bundle branch block) is often intermittent, it increases the chances of missing the ECG diagnosis (Fig. 1). Repeated ECGs and 12-lead Holter recording may be extremely helpful in identifying the disease.

View larger version (64K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Electrocardiographic traces (leads V1, V2 and V3) recorded on 4 consecutive days in a survivor of IVF. The ST segment elevation pattern (diagnostic for Brugada syndrome) is intermittent. The patient carries a mutation in the SCN5A gene.

 
The existence of concealed forms of BS has been argued based on the alleged evidence [14] that provocative challenge with sodium channel blockers unmasks the disease in 100% of cases. We recently showed that the sensitivity of electrocardiographic analysis may be faulty even when combined with provocative pharmacological challenge. In two of the families that we have successfully genotyped as carriers of SCN5A gene defect, two had a penetrance of the clinical phenotype <20% [15]. We have also observed a BS proband symptomatic for ventricular tachycardia who developed a BS-like ECG (‘coved’ type) when treated with propafenone for atrial fibrillation. When propafenone was discontinued the ECG returned to normal and flecainide challenge failed to unmask ST segment elevation (Fig. 2).

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 The proband (arrow) of this family came to medical attention because of symptomatic ventricular tachycardia when he was treated with propafenone for atrial fibrillation. The ECG pattern was suggestive for Brugada syndrome. When propafenone was discontinued ECG traces normalized and flecainide test (right panel) failed to induce the ST segment elevation pattern. Genetic analysis (SSCP shown at the bottom) identified a mutation in the SCN5A gene. Affected family members are shown in the pedigree. The asterisk indicates gene carriers.

 

	4 The developing link between genetic defects and idiopathic ventricular fibrillation

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
The link between concealed genetic defects and sudden death is a sharp departure from the current view that links the severity of a genetic disease to the degree of abnormality of its electrocardiographic marker. However while it is certainly true that a very long or a marked ST segment elevation of the ‘coved’ type is associated with high risk of cardiac events, it is not possible to assume that, as a consequence, sudden cardiac death cannot occur in gene carriers with a normal electrocardiogram.

	5 Post mortem molecular screening in sudden death victims with negative autopsy

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
Recently Ackerman et al. [16] identified the presence of a silent KvLQT1 mutation in a young girl who died suddenly while swimming: this patient had a prolonged QT interval at the ECG recorded after cardiac arrest and the identification of the genetic defect provided the conclusive evidence that the disease was present in the patient.

We have initiated a systematic evaluation of post mortem samples obtained from sudden death victims with inconclusive autopsy findings without ECG data. DNA from 20 sudden death victims has been screened for mutations in the KvLQT1 gene and in five cases a genetic defect was identified. In one of these cases the victim was a 2-month-old baby who died suddenly and was therefore defined as a sudden infant death syndrome victim (unpublished data).

	6 Genetic analysis in sudden death survivors with negative clinical evaluation

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
To further support the possibility that a concealed genetic disease underlies unexplained cardiac arrest we are currently performing DNA screening in survivors of IVF with normal ECG: we have so far identified three mutations (3/20; 15%): one in the KvLQT1 gene and two in the SCN5A gene. Interestingly, the identification of a sodium channel defect in two IVF survivors has not clarified the clinical diagnosis [17]. In the absence of a clinical phenotype it is impossible to define whether these two patients are affected by a ‘forme fruste’ of LQTS or of BS: ongoing expression studies may clarify the consequences of the genetic defects thus allowing the establishment of a clinical diagnosis.

	7 Other genetic diseases as a cause of cardiac arrest in the normal heart

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
Despite the fact that LQTS and BS are the most widely known diseases associated with ‘primary’ electrical abnormalities, other inherited arrhythmogenic diseases may cause sudden death in individuals with a structurally intact heart and normal ECG.

7.1 Catecholaminergic polymorphic ventricular tachycardia
The first systematic description of this disease was made by Coumel [18] and Leenhardt [19] who described patients with a remarkably uniform pattern of stress induced bi-directional polymorphic ventricular tachycardia (VT) in the absence of structural heart disease and of repolarization abnormalities. Approximately one third of cases had a family history for juvenile sudden death and/or stress related syncope: interestingly most of the patients had no affected relatives thus suggesting that either they carried a de novo mutation or the disease had incomplete penetrance. The clinical symptoms occurred at a mean age of 8 years, so therefore the authors proposed that the disease is characterized by onset during childhood. In this initial cohort of patients, arrhythmias could be invariably reproduced with exercise stress test or with isoproterenol infusion.

In 1999 Swan et al. [20] described two families with stress induced polymorphic ventricular tachycardia and demonstrated linkage to chromosome 1q42–q43. The clinical phenotype of the patients resembled that described by Coumel [18] and Leenhardt [19], but arrhythmic events occurred later in life thus leading the authors to hypothesize that they had identified a novel disease. We recently identified mutations in the cardiac ryanodine receptor gene (hRyR2) in four probands affected by catecholaminergic VT [21] thus conclusively demonstrating that catecholaminergic bidirectional ventricular tachycardia is a genetic arrhythmogenic disorder occurring in individuals with a structurally intact heart. In our population symptoms related to ventricular tachyarrhythmias developed over a wide spectrum of ages ranging from childhood to adulthood and even gene carriers of the same mutation presented a wide range of clinical manifestations thus suggesting that Coumel [18] and Swan [20] had probably described the same disease.

Relevant to the hypothesis that unexplained juvenile cardiac arrest may be related to ‘clinically silent’ genetic defects, is the evidence that in the four-generation family that led to the identification of the hRyR2 gene, there were two sudden cardiac death victims who died at age 14 and 16 years: no explanation for their death was identified. Even when their sister sought medical attention for ventricular arrhythmias, no clinical diagnosis was established as clinical evaluation failed to identify ECG abnormalities or structural heart disease. In our experience hRyR2 accounts for 1/3 of clinical cases of unexplained polymorphic ventricular tachycardia and it is therefore likely that in analogy with long QT syndrome and with Brugada syndrome, the disease is genetically heterogeneous. Proteins regulating intracellular calcium should be regarded as candidate genes for other genetic variants of the disease.

Interestingly a rare form of arrhythmogenic right ventricular dysplasia has been mapped to the 1q42–q43 region [22] and recently it has been shown to be caused by defects on the hRyR2 gene [23], i.e. being allelic to catecholaminergic VT. Although this observation is intriguing, it remains to be explained how defects of hRyR2 cause right ventricular cardiomyopathy.

It is fascinating to observe that molecular genetics has shown that phenotypically ‘different’ diseases are caused by mutations on the same genes (i.e. are allelic diseases). For example the cardiac sodium channel gene, SCN5A, has been associated with three clinical phenotypes: long QT syndrome [24], Brugada syndrome [10] and Lev-Lenegre disease [25]. The most remarkable example of an unexpected genetic link between clinically unrelated diseases is represented by the association of both hypertrophic and dilated cardiomyopathies [26] with mutations on the β-myosin heavy chain and the cardiac Troponin T gene.

7.2 Short coupled torsades des pointes
Short coupled torsades des pointes is another familial arrhythmogenic syndrome associated with sudden cardiac death that was described by Leenhardt in 1994 [27]. Patients with this disease have a structurally normal heart: an overt familial distribution of the phenotype is the exception rather than the rule and sudden cardiac death may be the first manifestation of the disease. If this first event is lethal, post mortem analysis will not identify a cause for the death of the individual, and even if the patient is successfully resuscitated, clinical diagnosis may be missed unless the initiation of a ventricular tachyarrhythmia by a short coupled premature beat is documented. No genetic substrate has been so far identified and not even linkage data are available because large affected families are missing.

7.3 Hypertrophic cardiomyopathy with variable phenotype
Hypertrophic cardiomyopathy (HCM) is an arrhythmogenic genetic disease leading to sudden cardiac death. Interestingly however in analogy with the occurrence of LQTS with a normal QT interval and BS without ST segment elevation, a variant of hypertrophic cardiomyopathy with little or no hypertrophy has been described in association with genetic defects on the Troponin T (TnT) gene.

Watkins was the first to suggest that TnT mutations might be present in 15% of HCM patients and that they are associated with milder cardiac hypertrophy than other genetic variants of the disease, although they may manifest with a high proportion of arrhythmic events, and sudden cardiac death [28]. Incomplete penetrance has also been reported in TnT genetic defects: Moolman et al. [29] reported a penetrance in adult individuals of 40% by echocardiography and 80% with the combination of echocardiography and electrocardiography.

Molecular diagnosis may be extremely helpful in identifying the genetic substrate in patients with incompletely penetrant form of HCM. At this time however we are not aware of individuals initially diagnosed as IVF who subsequently were found to be affected by Troponin T variant of HCM, so therefore this hypothesis still awaits demonstration.

	8 Conclusions

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 
The recent progress in the understanding of genetic disorders has substantially modified the view of these diseases and has disclosed evidence that genetically transmitted abnormalities underlie a larger proportion of cardiac arrests than previously thought. Some of these studies have associated a specific electrocardiographic pattern with a genetic abnormality: this has occurred for BS [10], for LQTS [24] and for catecholaminergic VT [21], where the distinctive bidirectional morphology of the tachycardia may become the hallmark of the genetic variant associated with RyR2 defects. A most sophisticated genetic approach is again focusing the attention of cardiologists to careful analysis of the electrocardiogram in a search for unusual patterns that may reveal the cause of unexplained cardiac arrest.

At present, it is still impossible to define the percentage of unexplained sudden cardiac deaths that are caused by genetically transmitted defects in the absence of an overt clinical phenotype because genetic knowledge is still incomplete and in most cases even the prevalence of the uncommon genetic diseases is unknown. However evidence exists that: (1) incomplete penetrance is present in most genetic diseases, and (2) the number of arrhythmogenic conditions with a genetic substrate is probably much higher than previously considered. Based on these observations it is very appealing to speculate that IVF victims have an apparently normal heart that is electrically unstable because of a genetically determined concealed arrhythmogenic disease.

Time for primary review 19 days.

	References

Top Abstract 1 Cardiac arrest in... 2 How normal is... 3 Is sensitivity of... 4 The developing link... 5 Post mortem molecular... 6 Genetic analysis in... 7 Other genetic diseases... 8 Conclusions References

 

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