Author + information
- Received December 8, 2010
- Revision received February 10, 2011
- Accepted March 1, 2011
- Published online July 12, 2011.
- Laurence M. Nunn, MD⁎,
- Justine Bhar-Amato, MD⁎,
- Martin D. Lowe, MD, PhD⁎,
- Peter W. Macfarlane, MD, DSc†,
- Pauline Rogers, MSc‡,
- William J. McKenna, MD⁎,
- Perry M. Elliott, MD⁎ and
- Pier D. Lambiase, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Pier D. Lambiase, The Heart Hospital, University College Hospital and Institute of Cardiovascular Sciences, UCL 16-18 Westmoreland Street, London W1G 8PH, England
Objectives The purpose of this study was to assess the prevalence of J-point elevation among the relatives of sudden arrhythmic death syndrome (SADS) probands.
Background J-point elevation is now known to be associated with idiopathic ventricular fibrillation. We hypothesized that this early repolarization phenomenon is an inherited trait responsible for a proportion of otherwise unexplained SADS cases.
Methods Families of SADS probands were evaluated in an inherited arrhythmia clinic. Twelve-lead electrocardiograms were analyzed for J-point elevation defined as >0.1 mV from baseline present in 2 or more of the inferior (II, III, and aVF) or lateral (1, aVL, V4 to V6) leads. Electrocardiographic data were compared with those of 359 controls of a similar age, sex, and ethnic distribution.
Results A total of 363 first-degree relatives from 144 families were evaluated. J-point elevation in the inferolateral leads was present in 23% of relatives and 11% of control subjects (odds ratio: 2.54, 95% confidence interval: 1.66 to 3.90; p < 0.001).
Conclusions J-point elevation is more prevalent in the relatives of SADS probands than in controls. This indicates that early repolarization is an important potentially inheritable pro-arrhythmic trait or marker of pro-arrhythmia in SADS.
J-point elevation occurs in 1% to 5% of normal individuals (1,2), particularly athletes, males, and those of African descent. Recent evidence demonstrates an increased prevalence in idiopathic ventricular fibrillation (VF) survivors (3–5) and an association with cardiovascular mortality in an unselected population (6), suggesting that it is a marker of increased susceptibility to lethal arrhythmia. Sudden arrhythmic death syndrome (SADS) accounts for approximately 500 deaths per year in England (7). Clinical evaluation of the first-degree relatives identifies inherited cardiovascular disease in as many as 50% of families (8–10), with the cause of death remaining undetermined in the remainder. Early repolarization may be an inherited pro-arrhythmic factor or marker of pro-arrhythmia in undiagnosed SADS cases and thus would be expected to have an increased prevalence in their relatives. We undertook a retrospective analysis examining the prevalence of early repolarization in first-degree relatives of SADS probands.
The study population comprised the first-degree relatives referred to the inherited arrhythmia clinic at the Heart Hospital between 2004 and 2009 after the sudden arrhythmic death of a family member defined according to established clinical and pathological criteria (11,12). All relatives underwent clinical screening as previously described (11). Second- and third-degree relatives were screened in selected families and so were excluded from this study to eliminate possible selection bias.
The control group consisted of 12-lead electrocardiograms (ECGs) from 359 unrelated healthy individuals from the University of Glasgow normal ECG database matched for age, sex, and ethnic profile. We were unable to match 4 of the 363 relatives from the study group with similar control subjects. To be included in the database, each individual completed a medical history, was examined by a physician, and was checked for any electrolyte abnormality.
The incidence of J-point elevation in the study population was determined from their first clinic ECG. J-point elevation was defined as previously described (3): QRS-ST junction elevation ≥0.1 mV from the baseline; a discrete notch or terminal slurring of the QRS complex into the ST-segment; in 2 or more inferior (II, III, and aVF) or lateral (1, aVL, V4 to V6) leads (Fig. 1). Anonymized ECGs were reviewed by a panel of 3 investigators blinded to the identity and history of the patients.
Data consisted of first-degree relatives clustered into family groups and healthy controls categorized as independent (i.e., clusters of 1). The intraclass correlation of the controls is 0 by definition. One-way analysis of variance was used to estimate the intraclass correlation of J-point elevation for the relatives of SADS probands at 0.1052. To compare the prevalence of J-point elevation between controls and the first-degree relatives of SADS probands, a logistic regression with J-point elevation as the outcome and control or relative as the explanatory variable was used, clustering the analysis on family group. A bootstrapping analysis was performed to assess the prevalence of J-point elevation: an individual was randomly selected from each group and the J-point recorded. This was performed 359 times from the pool of controls, 363 times from the pool of relatives, and 144 times taking a single member from each family at random. This was repeated 10,000 times in each group to determine a mean prevalence.
Groups are compared using a Student t test for continuous variables (summarized as mean ± SD) and the chi-square test or the Fisher exact test, as appropriate, for categorical variables. Statistical significance was declared at the 5% level. Calculation of the interobserver and intraobserver agreement is detailed in the Online Methods. The Stata version 11 statistical package (StataCorp, College Station, Texas) was used for statistical analysis.
The study population of 363 relatives and the control population of 359 unrelated individuals are well matched (Table 1). Inferolateral J-point elevation was present in 84 relatives (23%) of SADS probands and in 38 control subjects (11%) (odds ratio: 2.54, 95% confidence interval [CI]: 1.66 to 3.90; p < 0.001). The QTc interval was shorter and PR longer in the relatives compared with the controls, and there was no significant difference in the proportion of males and females with J-point elevation in SADS relatives. Bootstrap analysis estimated the prevalence of J-point elevation among the relatives of SADS probands to be 23% (95% CI: 19% to 28%) compared with 11% in controls (95% CI: 8% to 14%). Sampling 1 relative from each family at random estimated the prevalence of J-point elevation to be 24% (95% CI: 19% to 28%) among SADS probands' relatives. J-point elevation was more prevalent in relatives than controls for each group of leads analyzed except where J-point elevation was present in all inferolateral leads where there was a trend toward significance (p = 0.06).
Table 2 compares SADS relatives according to the presence of the J-point phenotype. Relatives and controls with J-point elevation are compared in Table 3. Relatives with J-point elevation have a longer PR interval, shorter QRS duration, and higher prevalence of elevation in leads V4 to V6 compared with J-point–positive controls. J-point elevation was present most commonly in the inferior leads in both groups. There was very good interobserver and intraobserver agreement for the reporting of J-point elevation (p < 0.001).
A definitive diagnosis of an inherited cardiovascular condition according to established criteria was made in 1 or more of the surviving relatives in 49 families (34%) (Fig. 2). Of the 51 relatives with a diagnosis, 22% had J-point elevation compared with 23% in those without a diagnosis (p = 0.86). In total, 14% of all relatives with J-point elevation were diagnosed with a cardiomyopathy or channelopathy. Five pathological or novel variants were discovered on genetic testing (listed in the Online Appendix), but in each case, mutations did not co-segregate with the J-point phenotype in the family.
This paper is the first to demonstrate that inferolateral J-point elevation is more prevalent in the first-degree relatives of SADS probands and is a potentially inheritable risk modifier for lethal arrhythmia. There are 3 possible hypotheses to explain this: a proportion of individuals will have benign J-point elevation; J-point elevation is a risk modifier in addition to the recognized arrhythmogenic syndromes; J-point elevation represents a primary pathology. Evidence of the cellular basis of J-point elevation and its involvement in the mechanism of VF initiation has been well described (13).
J-point elevation could represent an unusual manifestation of recognized inherited channelopathies/cardiomyopathies or, alternatively, a coincidental inheritable trait. It could act as a modifier of other pro-arrhythmic conditions promoting re-entry by exaggerating transmural repolarization gradients created by conduction delays in a cardiomyopathic heart or by creating interregional repolarization gradients and facilitating local conduction block in long QT syndrome. This “multiple hit hypothesis” has been demonstrated in long QT syndrome in which a single mutation becomes pathological through the amplifying effect of another ion channel polymorphism (14). The low prevalence of late potentials in SADS relatives with J-point elevation is consistent with previous findings and the hypothesis that J-point elevation reflects electrophysiological events during early repolarization (3).
J-point elevation in idiopathic VF survivors has been reported more commonly in males (3,4). In our study group, a higher proportion of females were affected, but this did not reach statistical significance. We cannot comment on racial differences in the data because the majority of our patients were Caucasian. The inferior location of J-point elevation has been used as 1 factor to differentiate benign from pathological J-wave elevation (13). In our study, J-point elevation is most frequently observed in the inferior leads of both groups with a greater prevalence in leads V4 to V6 in relatives versus controls.
To date, there is limited evidence of a genetic basis of J-point elevation. Mutations in L-type Ca channel subunits are under evaluation, accounting for 5.2% of idiopathic VF cases in 1 series (15). A novel missense mutation in the KCNJ8-encoded KATP channel has also been described (16,17). Review of our study population pedigrees suggests that J-point elevation has a probable autosomal dominant inheritance pattern with incomplete penetrance. Male-to-male transmission excludes mitochondrial and X-linked transmission, whereas the phenotype occurring in multiple generations rules out an autosomal recessive trait. A gene association study or linkage analysis to identify genetic candidates is a logical next step.
With 11% prevalence in healthy controls, the presence of J-point elevation in relatives of SADS probands can only currently raise suspicion of an underlying arrhythmogenic disorder. Further epidemiological and mechanistic research differentiating pathological from benign J-point elevation is required before proposing specific management advice. At this stage, asymptomatic SADS relatives with J-point elevation, especially those with a high burden of ventricular ectopy, should be offered regular follow-up.
There are no data available for a family history of sudden cardiac death in the control group. The database was established in the late 1980s, defined according to knowledge available at that time. A comparison is being made between related individuals in the patient group and unrelated individuals in the control group. The prevalence of early repolarization within the control group is in keeping with 5% to 13% described in previous studies (3,4,6); however, if it is an inherited trait, then it is possible that the use of unrelated controls underestimates the prevalence in healthy families. There is no database of ECGs in healthy families available. The bootstrapping analysis confirmed that even randomly selecting only a single relative from each family and repeating this 10,000 times, there was a still a significantly higher prevalence of J-point elevation among SADS relatives than normal controls.
There is a higher prevalence of J-point elevation in the family members of SADS probands compared with the general population. J-point elevation could be an important primary cause of sudden cardiac death in the young or act as a modifier of recognized primary arrhythmogenic syndromes. This has important implications for screening relatives of SADS probands and may provide the key to developing new strategies to prevent sudden death in the young.
For a supplemental Methods and Results section and accompanying table and references, please see the online version of this article.
This work was undertaken at UCLH/UCL, which received partial funding from the Department of Health's National Institute of Health Research Biomedical Research Centres funding scheme. Dr. Nunn has received an educational grant from St. Jude Medical. Dr. Bhar-Amato has received an educational grant from Heart Research UK. Dr. Lambiase has received funding from the Stephen Lyness Memorial Fund. All the other authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- confidence interval
- sudden arrhythmic death syndrome
- ventricular fibrillation
- Received December 8, 2010.
- Revision received February 10, 2011.
- Accepted March 1, 2011.
- American College of Cardiology Foundation
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