Low Prevalence of Risk Markers in Cases of Sudden Death Due to Brugada Syndrome

Relevance to Risk Stratification in Brugada Syndrome

Study cohort

This study represents unselected, consecutive, familial diagnoses of BrS from 3 tertiary referral centers in the United Kingdom, in the context of unexplained familial sudden cardiac death (SCD). Data from clinical evaluations of the blood relatives of individuals who experienced sudden arrhythmic death syndrome (SADS) referred between 2003 and 2010 to specialist inherited cardiac disease clinics at Lewisham University, King's College, and St. George's Hospitals (London) were retrospectively reviewed. All SADS probands with at least 1 blood relative diagnosed with BrS were included.

Cardiological evaluation

An evaluation protocol for families with a member with SADS has been established (Fig. 1), with particular emphasis on evaluation for evidence of familial BrS. All family members were investigated with clinical history and noninvasive evaluation by ECG, transthoracic echocardiography (including close evaluation of the right ventricle), Holter ambulatory monitoring, and stress testing, with additional magnetic resonance imaging to exclude structural heart disease.

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Figure 1

Investigational Cascade for SADS Probands and Their Families

A summary of the investigation undertaken following referral of a family of an individual who experienced sudden arrhythmic death syndrome (SADS) and criteria for establishing a familial diagnosis of Brugada syndrome (BrS). ECG = electrocardiogram; ETT = exercise tolerance test; MRI = magnetic resonance imaging.

Genetic testing

Following appropriate genetic counseling, we offered sodium channel, voltage-gated, type V, alpha subunit (SCN5A) mutation analysis to family members with a clinical diagnosis of BrS.

Ajmaline provocation test

Ajmaline provocation was performed with 1 mg/kg intravenous ajmaline administered over 5 min, with real-time ECG monitoring and ECGs recorded for analysis at 10- to 30-s intervals for 15 min from the start of ajmaline administration or until return of the ECG to baseline. Before March 2006, standard 12-lead ECG monitoring was used during ajmaline provocation. Subsequently, further “high” right ventricular leads were added to improve diagnostic yield by using a 15-lead ECG recording machine. Initially, this technique used V₁, V₂, and V₃ cranially displaced by 1 intercostal space (16) in addition to the standard 12 conventional leads. In September 2009, the standard V₃ position was sacrificed in favor of including V₁ and V₂ cranially displaced in both the second and third intercostal spaces, in addition to conventional V₁ and V₂, thereby maintaining 6 right ventricular leads for diagnostic purposes. Diagnosis of a Brugada type 1 ECG pattern, either during peak ajmaline effect or at baseline, was established by ECG review by 2 investigators (H.R. and M.P.). Any individual's diagnosis of BrS was established as described in the Definitions section.

Characteristics of SADS probands

Prior familial SCD and presence of symptomatic events in each proband were determined by interviews with all evaluated family members by at least 1 of the investigators (H.R., M.P., S.S., and E.R.B.) and review of medical examiner and coroner reports. Structured clinical questions regarding the presence of prior transient loss of consciousness, seizures, or faints were retrospectively coded as probable syncopal events for the study analysis. All decisions regarding relevance of symptoms described were made by 2 investigators (H.R. and M.P.), with disputed results adjudicated by a senior investigator (E.R.B. or S.S.).

The presence of an antemortem ECG for all probands was sought by detailed questioning of evaluated family members. This included review of history of attendance at health screening events, any hospital attendance, or presence of any prior cardiovascular symptoms (palpitations or chest pain) that may have prompted an ECG. When any family members suggested the SADS proband may have attended for medical assessment prior to his or her death, the existence of an antemortem ECG was questioned by written communication to any medical professional involved in the proband's investigation. As with familial ECGs, all ECGs of probands taken before death were reviewed by 2 investigators for evidence of a spontaneous Brugada pattern.

Definitions

SADS is an umbrella term for unexpected and unexplained sudden death. It is characterized by the following conditions: sudden death; age 1 to 64 years; last seen alive and well within 12 h of being found dead; no prior recorded cardiac disease; and normal coroner's post-mortem, negative toxicology results, and normal expert cardiac pathologist's examination, when available (17). A proband represents any individual who experienced a SADS death.

A type 1 Brugada ECG pattern is defined as ≥2-mm coved-type ST elevation with or without right bundle branch block pattern in at least 2 right precordial or “high” right precordial (i.e., in the second or third intercostal space) leads (18–21).

Familial diagnosis of BrS was established by the identification of spontaneous or ajmaline-provoked Brugada type 1 ECG pattern in any one family member of a SADS proband. The cause of death in the proband was presumed to be BrS-related in all cases described, following a familial diagnosis of BrS. When the familial SADS proband died at age 45 years or older, the presence of other syndromic diagnostic criteria, such as more than 1 family member with typical Brugada ECG phenotype or syncopal symptoms, was determined by additional structured questioning and review of familial cardiological evaluation results.

Demographics

Details of associated familial evaluation are provided in Table 1. In total, 202 blood relatives of probands were cardiologically evaluated and contributed to the reported proband histories. Demographic characteristics and reported symptoms in the included probands are summarized in Table 2. The mean age of death of probands was 29.1 ± 10.6 years (range 4 to 56 years). A predominance of male BrS deaths was noted (41 male [82%] vs. 9 female [18%]; p < 0.05). Circumstances of death were obtained for 46 probands. Of these, 18 deaths (39%) occurred during sleep, with a further 19 (41%) at rest during the daytime; only 5 (11%) occurred during or immediately after significant exertion.

Genetic testing

Details of families for whom SCN5A mutation analysis was undertaken (n = 28) are given in Table 2. Of the 5 families with unequivocal mutations, 3 have mutations that have previously been reported as disease causing (2 families with E1784K and 1 family with I1377V mutations) and 2 have highly probable novel mutations (D349H and H558fs). Overall, unequivocal mutations have been found in 18% of families for whom SCN5A mutation analysis was undertaken.

Risk profile of probands

Antemortem ECGs were available for 5 probands (Fig. 2), 1 of which demonstrated a spontaneous type 1 pattern (Fig. 2A) and was taken during presentation with gastrointestinal symptoms in a previously asymptomatic individual. A further proband had evidence of a prior resting type 3 Brugada pattern in just 1 right ventricular lead (Fig. 2B). Both of these ECGs were taken more than 1 year before each proband's terminal event. None of the probands had undergone prior provocation testing for investigation of inducible Brugada ECG pattern or invasive electrophysiological assessment; none had a pre-established personal or familial diagnosis of BrS or other inherited cardiac disease. Probands' symptoms before death were reported reliably by family members in 45 cases, with the remainder uncertain of any prior medical history or symptoms. Only 9 of these 45 probands (20%) were reported to have experienced at least 1 syncopal episode before the fatal event. Seven probands (14%) had a prior family history of premature SCD, 1 of whom also had a personal history of syncope. Fifteen probands (30%) had either a prior family history of SCD or personal reported history of syncope. Among those who were previously symptomatic, 5 probands were male, whereas 4 were female.

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Figure 2

Antemortem ECGs in 5 SADS Probands With Brugada Syndrome

(A) The sole spontaneous type 1 antemortem ECG seen in our cohort of SADS probands with BrS. (B) An antemortem borderline type 3 Brugada phenotype seen in V₂ only. (C) A nondiagnostic antemortem adult ECG. (D) An antemortem ECG taken at age 8 years, with no spontaneous Brugada phenotype. (E) An antemortem ECG taken at age 4 years, with no spontaneous Brugada phenotype. Abbreviations as in Figure 1.

Markers of risk in BrS

Current data regarding prospective risk stratification in patients with BrS have predominantly been determined on the basis of short- and medium-term prospective cohort observation of those identified in life. The FINGER (France, Italy, the Netherlands, Germany) study remains the largest cohort studied thus far, with 1,029 consecutive patients and indicates that a prior cardiac arrest, spontaneous type 1 ECG, and syncope were the only independent indicators of arrhythmic risk in patients with Brugada ECG (13).

In our cohort of SADS probands with BrS, only 18% (9 of 50) had a confirmed prior identified syncopal event, as determined by reported symptoms and medical history from relatives. This suggests that the majority of sudden deaths in BrS occurred in asymptomatic individuals. The absence of symptoms, however, does not necessarily ensure absence of significant prior arrhythmia. Cohort observation of ICD interrogations in 19 patients with BrS with prior aborted sudden death revealed 64 episodes detected as ventricular fibrillation, 26 of which were asymptomatic by virtue of them being nocturnal and self-limiting, requiring no device discharge (1). This evidently limits the sensitivity of reported symptoms as a marker of prior ventricular arrhythmias. Furthermore, the specificity of syncope for ventricular arrhythmias among patients with BrS may be limited by the observation that there is a preponderance of other etiologies of syncope, including reports of significant vasovagal responses with head-up tilt testing among patients with BrS (23).

Although ECGs were available for a minority of probands, only 1 demonstrated a spontaneous type 1 pattern, calling into question the utility of its absence as a marker of low risk.

Of the total cohort, only 18% were identified as fulfilling 2005 consensus (1) criteria for ICD implantation on the basis of prior syncope. A further 14% may have warranted risk stratification with electrophysiological study according to consensus criteria because of the presence of a type 1 ECG before death (1 of 50) or a family history of prior SCD (6 of 50). Hence, current markers of risk for cardiac events and sudden death would have been insensitive, with 68% of our cohort categorized as low risk. Therefore, these markers may not have predicted the BrS deaths, even if a diagnosis of BrS had already been established. In particular, the majority of our cohort was asymptomatic before unheralded sudden death. Current data suggest that these asymptomatic individuals' risk would have been low, <1% per year (13), even if a spontaneous type 1 ECG pattern was seen. Given that current treatment is limited to ICD implantation, with its inherent complications in young patients, risk stratification in asymptomatic patients clearly requires improvement.

Case inclusion

The diagnosis of BrS was based primarily on the demonstration of a positive ajmaline provocation test using high right ventricular leads. Subsequent genetic evaluation of our cohort identified disease-causing SCN5A mutations in 18% of our included families. This figure is not dissimilar to that reported in previous genetic series in patients with BrS and supports our diagnostic assumption that in the context of a death from SADS, a positive ajmaline provocation test using high right ventricular leads is a genuine reflection of an underlying sodium ion channel disorder (3). The utility of high right ventricular leads has been confirmed in a few small series, predominantly in Southeast Asian patients (21,24,25). The 2005 Heart Rhythm Society and European Heart Rhythm Association consensus document recommends that this group be treated no differently than those with ECG changes in standard leads (1).

Study limitations

Despite being the largest cohort of its kind reported, this study remains limited by the relatively small number of SADS probands with BrS included. Only 5 probands had a documented prior ECG in this study. Hence, it is difficult to make judgments on the presence or absence of a spontaneous type 1 Brugada ECG in the absence of prior investigation. This is an important consideration, given its apparent importance in risk stratification (1), although syncope is a much more significant risk factor (13). Unsurprisingly, in light of their predominantly asymptomatic status, none of the SADS probands had undergone comprehensive cardiological evaluation before the terminal event. It is also possible that probands may not have relayed any prior symptoms to family members and medical practitioners.