Familial cardiological evaluation in sudden arrhythmic death syndrome: essential but challenging

This editorial refers to ‘Family-based cardiac screening in relatives of victims of sudden arrhythmic death syndrome’ by C. McGorrian et al., on page 1050.

Sudden arrhythmic death syndrome (SADS) defines a sudden unexpected death that remains unexplained after comprehensive postmortem examination, histology, and toxicology studies. It accounts for up to 500 deaths in the UK every year, corresponding to an annual incidence of 1.34/100 000 population.^1,2 International estimates vary partly due to different populations and inclusion criteria. The incidence of SADS in other Caucasian populations ranges from 0.81/100 000 (Danish) to 1.2/100 000 (USA). South-east Asia demonstrates the highest annual incidence of unexplained sudden death with 38 per 100 000 men.³

A significant proportion of SADS cases have been demonstrated to be due to inherited channelopathies and cardiomyopathies. These have been identified through studies on familial cardiological evaluation and/or the mutation analysis of SADS victims' DNA, the ‘molecular autopsy’, and have laid the groundwork for much of our current clinical practice.^4–8

In this issue of the Journal, McGorrian et al.⁹ report on their experience at a single tertiary referral centre in the Republic of Ireland of familial evaluation following SADS-death. They studied 262 relatives from 73 families over 4 years from 2007 to 2011 and employed a standard screening protocol similar to that reported by our group in 2008; beginning with a review of clinical and family history followed by first-line investigations consisting a 12-lead electrocardiogram (ECG), 24 h Holter monitor, exercise stress test, and echocardiogram. Further testing with a signal-averaged ECG, cardiac magnetic resonance imaging, and ajmaline provocation were performed if deemed necessary.⁴

They identified an inheritable cardiac condition in 36 relatives (13.7%), leading to diagnoses in 22 families—representing a yield of 30.1% from the family screening. Channelopathies made up the majority of the diagnoses, with long QT syndrome being the most common (10/22 families) followed by Brugada syndrome (5 families) and catecholaminergic polymorphic ventricular tachycardia (4 families).

This replicates the findings of previous international studies that demonstrated a diagnostic yield of up to 53% in familial cardiological evaluation.^4–6 These consistent results serve to confirm the utility of family cardiac screening in SADS, adding strength to the structured screening programme advocated in various national and international guidelines. The yield in this study was increased by the use of second-line investigations. In particular, the use of ajmaline provocation led to the diagnosis of four families with Brugada syndrome, a previously recognized finding.⁴

Diagnosing an underlying cardiac condition not only provides psychological benefit to the bereaved family, but also allows the identification of at risk family members and for timely institution of appropriate potentially life-saving treatment. All diagnosed family members were given disease-specific lifestyle advice with 89% (32/36) commenced on medical therapy. Only five family members (14%) were deemed sufficiently high risk to require implantation of an implantable cardioverter defibrillator (ICD), again consistent with previous reports where 9–10% of diagnosed family members required an ICD implant.^4,10

Inaccurate pathology classification—the need for an expert cardiac autopsy

In this study, cardiomyopathies were found in three families: one hypertrophic cardiomyopathy, one dilated cardiomyopathy and one left ventricular non-compaction. This is slightly surprising as these cardiomyopathies would usually be picked up at postmortem. One possible explanation may be that some cardiomyopathies, most notably arrhythmogenic right ventricular cardiomyopathy, have an early concealed phase prior to the development of apparent morphological changes. This early phase is characterized by a predisposition to life threatening arrhythmias and thus sudden arrhythmic death.⁴ However, as SADS is a diagnosis of exclusion, this may be due to a diagnostic failure of the autopsy. Comprehensive cardiac examination including detailed histology is required to identify more subtle cardiomyopathic changes and could potentially be overlooked on a ‘routine’ postmortem. The importance of an expert cardiac autopsy in establishing the cause of a sudden cardiac death thus cannot be overstated.¹¹

The lack of an expert cardiac autopsy may also impact in other ways. With the majority of sudden cardiac deaths being due to ischaemic heart disease, many cases could potentially be wrongly classified on the basis of concomitant and erroneously perceived indicators of coronary artery disease such as non-occlusive atheroma without myocardial scar. Inaccurate diagnoses of cardiomyopathy on macroscopic and even microscopic appearances without further detailed histology could also cloud the true incidence of SADS deaths. This has far reaching implications beyond a simple death certificate as at risk families may not be correctly identified and screened for an inherited cardiac condition.

Molecular autopsy is complementary to family cardiological evaluation

In this study, only two cases were diagnosed following molecular autopsy. The low yield presumably is secondary to a low rate of molecular autopsy and genetic testing, attributed by the authors to capacity issues with the molecular genetics service. Previous studies have consistently demonstrated a significant yield from molecular autopsy, with up to 26% of cases carrying pathogenic channelopathy-associated mutations.⁷ Molecular autopsy should be seen as complementary to familial cardiac evaluation, with positive results confirming causation and helping to focus the screening and longer term management of relatives. Although the yield of molecular autopsy is lower compared with familial cardiac screening, it is likely to improve with the advancement of genetic sequencing techniques allowing cheaper, quicker, and more detailed testing of relevant cardiac genes.

However, several barriers to molecular autopsy exist in current practice. It is clear from sequencing studies that there is significant and previously unappreciated rare variation in the human genome that may confound the ability of a molecular autopsy to define single causative gene mutations in some SADS cases.¹² This may then limit its utility in families. There are also practical issues relating to the availability of appropriate material for genetic testing. Fresh frozen blood or tissue samples are the gold standard source of DNA for molecular autopsy. Tissue stored as formalin-fixed paraffin-embedded, the usual method for storing histological samples, is unreliable for molecular autopsy due to alterations to the DNA sequence introduced by the fixation process. However, retention of blood or tissue in SADS cases is ad hoc and dependent on the practice of individual pathologists. In the UK, this could partly be as a result of consent issues brought about by the Human Tissue Act, but could also be due to a lack of awareness regarding the utility of molecular autopsy in SADS cases. This is being addressed by new guidelines generated by an expert working group.¹³

Early repolarization: is it significant?

McCorrian et al. also reported the finding of early repolarization (ER) in one proband on an antemortem ECG and also found an ER pattern in ECGs of 25 relatives (9.5%),⁹ a prevalence not dissimilar to that reported in population studies.¹⁴ They have been cautious not to attribute the SADS death to ER syndrome. This underlines the difficulty, at present, of determining the significance of ER in a relative being screened with a family history of SADS.

Early repolarization is traditionally thought to be a benign ECG variant, more commonly seen in the anterolateral leads of young athletic men. However, in recent years, it has been demonstrated to be a marker for increased risk of sudden cardiac death in the general population and to be over-represented in survivors with idiopathic ventricular fibrillation.¹⁵ Several groups have attempted to develop risk stratification strategies based on the location and morphology of ER. Antzelevitch and Yan¹⁶ had proposed three subtypes of ER with type 1 being the benign pattern in the lateral leads and type 2 and 3 conferring increasing risk with additional involvement of the inferior and right precordial leads. Tikkanen et al.¹⁷ showed that the increased risk of sudden cardiac death, at least in the general population, was associated with horizontal/descending ST segments and not ascending/upsloping segments. The high prevalence of ER in asymptomatic individuals, however, renders these observations unhelpful as a clinical management tool. Moreover, although the estimated risk of sudden cardiac death is three-fold higher in an asymptomatic individual with an ER pattern, the absolute risk is still only 1 : 10 000 per annum and negligible in the clinical context.¹⁸

A study by Nunn et al.¹⁹ found that the ER pattern was more prevalent in relatives of SADS cases compared with matched controls and concluded that ER is an important pro-arrhythmic marker in SADS. However, caution needs to be applied when interpreting their findings in the context of family screening for SADS. The ER pattern had been demonstrated to be a heritable trait and will clearly be more common in certain families.²⁰ The difference in prevalence may be simply due to familial clustering rather than a marker of sudden death risk for the affected relatives. To conclude that ER confers increased risk for relatives sufficient to guide clinical practice would be premature at this time.

However, familial cardiological screening for SADS may provide an opportunity for us to better understand the true significance of ER in an asymptomatic individual. For example, Bastiaenen and Behr²¹ have shown that persistence of the ER pattern during exercise testing in individuals with a ‘higher a priori risk’ of sudden death, including SADS relatives, may identify those at higher risk of arrhythmic events. Following them up may provide much needed evidence for future risk stratification and management of these individuals.

Research over the past decade has clearly demonstrated the need for structured cardiogenetic evaluation of family members and a comprehensive molecular autopsy following a SADS death. Challenges still remain with putting that knowledge into practice in an ideal manner and ultimately prevent further tragedies in families who had already endured the loss of a loved one.

Conflict of interest: E.R.B. has received funds from Cardiac Risk in the Young for research.

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Author notes