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The genetics of the J wave patterns
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ScienceDirect Journal of Electrocardiology 46 (2013) 395 – 398 www.jecgonline.com
The genetics of the J wave patterns☆,☆☆ Olujimi A. Ajijola, MD, PhD, a Albert Y. Sun, MD b, c, d,⁎ b
a University of California-Los Angeles Cardiac Arrhythmia Center, Los Angeles, CA, USA Section of Cardiac Electrophysiology, Division of Cardiology, Duke University Medical Center, Durham, NC, USA c Center for Human Genetics, Duke University Medical Center, Durham, NC, USA d Durham VA Hospital, Durham, NC, USA
Introduction The rapid growth of medical genetics over the past few decades has transformed the way we think about the fundamental properties of cardiac conduction. Recent studies have demonstrated associations of gene variants and complex traits such as QT and PR interval. 1,2 These findings would suggest that one’s QT interval is an inherited trait, similar to one’s eye color. In extreme cases, as in the monogenetic arrhythmia disorders Long QT Syndrome and Brugada Syndrome, single mutations in ion channel or ion channel-related genes lead to a prototypical appearance on 12 lead ECG, functional consequences, and an associated increase in risk of sudden cardiac death (SCD). In these disorders, the causative genetic mutations not only help define the disease, but in some cases are also used in risk stratification. 3 Recent studies have also demonstrated genetic variants and predictable patterns of inheritance with the early repolarization pattern found on ECG. This pattern has been defined as an elevation of the QRS–ST junction of at least 0.1 mV from baseline and QRS slurring or notching in at least two contiguous leads in the inferior or lateral location. 4 As this definition focuses on J point elevation associated with notches or slurs rather than the ST segment elevation classically associated with early repolarization, for the purposes of this review, we will use the term J wave pattern to describe the ECG pattern previously described as early repolarization. Additionally, this pattern was specifically described as J wave abnormalities in only the inferior and lateral ECG lead locations to avoid crossover with the Brugada syndrome (BrS). However as it has increasingly been associated with SCD, 4–6 analogies not only to BrS but other monogenetic
☆
Funding Support: A.P. Giannini Foundation Fellowship (OAA). The Greenfield Scholars Program (AYS). ☆☆ Disclosures: None. ⁎ Corresponding author. Division of Cardiac Electrophysiology, Duke University Medical Center, DUMC Box 3154, 2301 Erwin Rd, Durham, NC 27712, USA. E-mail address: [email protected] 0022-0736/$ – see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jelectrocard.2013.06.025
arrhythmia disorders are inevitable. Although the majority of the J wave pattern is likely benign, discriminating risk on ECG patterns alone remains elusive. Determining the genetic nature of the J wave pattern will not only add to our understanding of the underlying pathophysiology but may also lead to improved risk stratification. This review focuses on the heritability, known genetic variants, and future direction of genetic studies of the J wave pattern.
Heritability of the J wave pattern To access the hypothesis that the J wave pattern was heritable, Reinhard et al 7 investigated individuals from Caucasian British nuclear families. They demonstrated that individuals with at least one affected parent had a 2.5-fold increased risk of the J wave pattern on ECG. This appeared to be more frequent when the affected parent was the mother, with an odds ratio of 3.84. Though the mechanism of such an inheritance pattern is unclear, the authors postulate effects mediated via the sex chromosomes, parental imprinting of autosomal genes, or transmission through mitochondrial DNA. Another recent study from participants of the Framingham Heart Study and Health 2000 Survey demonstrated that male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of the J wave pattern. 8 Additionally in this population, siblings of individuals with the J wave pattern were more than 2 times likely to demonstrate the J wave pattern, indicating a genetic basis. Though both of these studies suggest a heritable quality of the J wave pattern in large population cohorts, neither was able to provide insight on associated adverse outcomes. Therefore whether the genetics of the J wave pattern equates to the J wave syndrome (defined as the J wave pattern and a history of SCD) is still unknown. This is an important distinction, as it is very likely that the J wave pattern does not equate to the J wave syndrome. To address this, recent studies in families with the J wave syndrome have also demonstrated a magnitude of
396
O.A. Ajijola, A.Y. Sun / Journal of Electrocardiology 46 (2013) 395–398
heritability that is consistent with that found in studies of electrocardiographic the J wave pattern. Nunn et al. analyzed the ECGs of family members of patients with SCD and found that the J wave pattern was 2.54 times more prevalent in the relatives of SCD probands than in controls. 9 More recently, Gourraud et al. also screened relatives of families affected by the J wave syndrome and demonstrated transmission of a J wave pattern compatible with an autosomal dominant mode of inheritance. 10 The families studied in both reports likely represent very rare cases of the J wave syndrome, and the findings should not be extrapolated to the general population. In fact, no causative mutations in previously reported loci were identified when the same families underwent genetic analysis, suggesting substantial genetic heterogeneity of the J wave syndrome. Also all of the studies were performed in families of European descent limiting the global applicability.
Candidate genes, variants, and pathophysiologic mechanisms Before a genetic basis was even entertained, cellular level dysregulation had been associated with the J wave pattern in animal models and mechanistically linked to ventricular fibrillation initiation. 11 Consistently, most of the limited number of genetic aberrations identified in patients with the J wave syndrome involve defects in sodium, potassium, and calcium channels 12–15 (Table 1). These genetic anomalies result in inadequate sodium or calcium currents, or excessive potassium currents early in cardiomyocyte repolarization. 16 As a consequence of these aberrant currents, membrane voltage may deviate from expected levels, be more pronounced on the epicardial surface, and result in significant transmural repolarization heterogeneity. The resulting dispersion in repolarization may enhance susceptibility to “phase 2 reentry”, the putative mechanism of arrhythmogenesis in the J wave syndrome. 16 Potassium channel mutations The first mutation linked to the J wave syndrome, a missense serine to lysine translation (S422L) in KCNJ8, was identified by Haissegurre et al in a 14-year-old female with the J wave pattern and idiopathic ventricular fibrillation (IVF). 12 The product of this gene, a subunit of the heterooctameric ATP-sensitive potassium channel (Kir6.1), dem-
onstrates a decreased sensitivity to cytoplasmic ATPlevels and incomplete closure. 13 This gain-of-function mutation causes an increase in IkATP in the early epochs of ventricular repolarization, resulting in rapid recovery from depolarization and shorter action potential duration (APD). 13,17 Enhanced IkATP during states of stress such as ischemia or hypoxia attenuates the duration of repolarization, induces the loss of the AP dome, and increases susceptibility to “phase 2 reentry”, the proposed mechanism of VF initiation. Studies of the transient outward potassium current (Ito) in BrS have provided important insights into the pathophysiologic mechanisms of the J wave syndrome. These studies have highlighted important parallels between the two syndromes and led to the suggestion that both conditions are different ends of the same spectrum. 18 This possible commonality is illustrated in a study by Sinner et al in which the investigators conducted a meta-analysis of genome-wide association studies in 3 large European and American cohorts to identify common genetic variants influencing the J wave pattern. After meta-analysis and replication no SNPs reached genome-wide significance, presumably due to insufficient statistical power and phenotype heterogeneity. Although not genome-wide significant, one identified locus was on chromosome 1 intronic to KCND3, the gene that encodes Kv4.3, a key channel underlying the Ito current. While no mutation in any genes encoding channelforming subunits of Ito has been linked to the J wave syndrome, such a mutation (KCNE3-R99H) has been described for BrS. 19 Calcium channel mutations To date, three mutations, each in a different subunit of the L-Type calcium channel (LTCC) have been identified in patients with the J wave syndrome. 20,21 These mutations in CACNA1C, CACNB2b, and CACNA2D1, encoding the α1, β2, and α2δ subunits of the LTCC, respectively, were identified from two separate studies 1: a cohort of over 200 patients with J wave syndrome, BrS, and IVF, 14 and 2 a cohort of patients with the J wave pattern and Short QT syndrome (SQTS). 22 Although the specific mutations identified were not functionally expressed for in vitro studies, two CACNA1C mutations from BrS patients were functionally expressed and demonstrated loss of function in the calcium channel current. 14 As previously noted,
Table 1 Genetic mutations or variants associated with the J wave syndrome. Mutation
Channel/current
Mechanism
Consequence
KCNJ8-S422L CACNA1C-E850del CACNB2-S160T CACNB2-R571C CACNA2D1-S956T SCN5A-L846R SCN5A-R367H SCN5A-A226D
IK-ATP LTCC LTCC
Gain of function Unknown Unknown
Enhanced outward current Decreased inward current Decreased inward current
LTCC Nav1.5
Unknown Loss of function
Decreased inward current Decreased inward current
Nav1.5
Abnormal trafficking to cell surface
Decreased inward current
LTCC – L type calcium channel.
O.A. Ajijola, A.Y. Sun / Journal of Electrocardiology 46 (2013) 395–398
attenuation of calcium current density during the plateau phase of the action potential creates an imbalance between inward and outward currents, favoring outward repolarizing potassium currents. The net result of this mismatch is more rapid repolarization, and a shortened action potential. The effect of these specific LTCC mutations in the J wave syndrome has not been studied in the transmural context. 23 Sodium channel mutations Genetic mutations in the voltage-gated sodium channel NaV1.5 have been established as a cause of BrS phenotype. Consistent with mechanistic similarities between BrS and the J wave syndrome, NaV1.5 mutations have also been identified in the J wave syndrome. Watanabe et el. 15 studied 50 patients with the J wave pattern and IVF, and 250 age and sex matched healthy controls. Three variants (A226D, L846R, and R367H) of SCN5A, the gene encoding Nav1.5, occurring at highly conserved sites across mammalian species were found in 3 unrelated patients. Na channel blocker challenge in these patients led to VF or augmented J waves, underscoring the pro-arrhythmic risk associated with these sodium channel variants. Functional expression of these channels in a cell line showed that all variants generated no current. Interestingly, the A226D variant exhibited abnormal trafficking to the cell membrane. The other two variants, however, showed normal targeting for the cell membrane. The mechanism underlying sodium channel dysfunction in the J wave syndrome is poorly understood, but may be related to an attenuation of the sodium current and imbalance between inward depolarizing currents and outward repolarizing currents. 16 Autonomic influences on the J wave pattern The autonomic nervous system (ANS) plays a critical and poorly understood role in the regulation of cardiac excitability. 24 Both limbs of the ANS exhibit proarrhythmic properties, with enhanced sympathetic tone increasing dispersion of repolarization and early or late after-depolarizations, while the parasympathetic nervous system may enhance bradycardia-mediated arrhythmias or alter acetylcholine sensitive currents. The relationship between vagal tone and sudden death in BrS is well recognized, and this relationship is being increasingly recognized for the J wave syndrome. Increased arrhythmias at night, slower heart rates in the J wave syndrome patients, enhanced J waves during bradycardia, attenuation of VT/VF storm by tachycardia (isoproterenol infusion), and unmasking or increase in J waves during the Valsalva maneuver 12,25,26 all support enhanced vagal tone as a possible modulator of J wave syndrome. The latter point represents a potentially important diagnostic tool in identifying patients with dynamic J waves at higher risk of IVF or for unmasking the J wave pattern in a patient with IVF. Although poorly understood, the potential role of the acetylcholine-activated potassium current (IK-Ach) in enhancing ventricular repolarization 27,28 may provide a link between vagal activation and J wave syndrome. Pharmacologic antagonism of this channel may therefore
397
represent an adjunctive therapeutic strategy in the management of VF in the J wave syndrome.
Challenges and future directions regarding the role of heritable variants in the J wave pattern Though great strides have been made in understanding the J wave pattern in recent years, many fundamental questions remain unanswered regarding the genetic basis of the J wave pattern. Can we apply what we know about familial forms of the J wave syndrome to the pattern seen in almost 6% of the population? Is the J wave pattern in this respect akin to the QT interval? Examining the prevalence of mildly prolonged QT (450–470 ms for females and 430–450 ms for males) and severely prolonged QT intervals (≥ 471 ms for females and ≥ 451 ms for males) in fact parallels the prevalence of mild J point elevation N 0.1 mV and marked J point elevation N 0.2 mV in the general population, respectively. Additionally, the extremes of phenotype of both QT interval and the J wave pattern convey similar magnitude risk of SCD. 6,29 Thus similar to investigation in genetic modifiers of the QT interval, hypothesis-free whole exome or genome wide studies are necessary. Multiple unbiased genome wide studies identified SNPs within the intronic regions of NOS1AP as modifiers of the QT interval. 30 This loci was previously unknown despite the multitude of investigations of families with the Long QT Syndrome using a candidate gene approach. Thus far, one GWAS meta-analysis was performed in the J wave pattern and did not reveal any genome-wide significant results. This leads us to another important question: is the J wave pattern a phenotype sufficiently defined? The inconsistencies in the literature on a unified terminology alone is evidence that surely this answer is no. In fact the phenotype is continuingly being refined, as recent evidence suggests certain morphologic factors infer greater risk. For example, Tikkanen et al suggest that the magnitude of J-point elevation further increases the risk of sudden death, with a relative risk of 2.92 in J-point elevations N 0.2 mV. 6 A horizontal or downward direction of the ST segments also has been shown to carry a 3 times higher risk of arrhythmic death. 31 These subtle phenotypic characteristics are essential when performing genetic association studies, and future studies would be wise to focus on such details and more accurately define the at risk pattern.
Conclusion Many questions remain regarding the genetic basis of the J wave pattern. However, recent studies have demonstrated a clear heritable pattern and identified genetic loci with strong biologic plausibility. These studies represent just the beginning of our understanding of the J wave pattern and J wave syndrome. Whether the J wave syndrome as defined in this review is another form of the Brugada Syndrome is yet to be seen but similarities cannot be ignored. Future studies will inevitably parallel that though of the other inherited arrhythmia disorders and not only broaden our
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understanding of the mechanisms behind the J wave pattern but aid in clinical management. References 1. Newton-Cheh C, Larson MG, Corey DC, et al. QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: The Framingham Heart Study. Heart Rhythm 2005;2:277. 2. Lodder EM, Scicluna BP, Milano A, et al. Dissection of a quantitative trait locus for PR interval duration identifies Tnni3k as a novel modulator of cardiac conduction. PLoS Genet 2012;8:e1003113. 3. Priori SG, Napolitano C, Vicentini A. Inherited arrhythmia syndromes: applying the molecular biology and genetic to the clinical management. J Interv Card Electrophysiol 2003;9:93. 4. Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016. 5. Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol 2008;52:1231. 6. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529. 7. Reinhard W, Kaess BM, Debiec R, et al. Heritability of early repolarization: a population-based study. Circ Cardiovasc Genet 2011;4:134. 8. Noseworthy PA, Tikkanen JT, Porthan K, et al. The early repolarization pattern in the general population: clinical correlates and heritability. J Am Coll Cardiol 2011;57:2284. 9. Nunn LM, Bhar-Amato J, Lowe MD, et al. Prevalence of J-point elevation in sudden arrhythmic death syndrome families. J Am Coll Cardiol 2011;58:286. 10. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large families in early repolarization syndrome. J Am Coll Cardiol 2013;61:164. 11. Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res 1988; 62:116. 12. Haissaguerre M, Chatel S, Sacher F, et al. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/ KATP channel. J Cardiovasc Electrophysiol 2009;20:93. 13. Barajas-Martinez H, Hu D, Ferrer T, et al. Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm 2012;9:548. 14. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 2010;7:1872. 15. Watanabe H, Nogami A, Ohkubo K, et al. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrilla-
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tion associated with early repolarization. Circ Arrhythm Electrophysiol 2011;4:874. Antzelevitch C. Genetic, molecular and cellular mechanisms underlying the J wave syndromes. Circ J 2012;76:1054. Medeiros-Domingo A, Tan BH, Crotti L, et al. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm 2010; 7:1466. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010; 7:549. Delpon E, Cordeiro JM, Nunez L, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol 2008;1:209. Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarization in short QT syndrome. Heart Rhythm 2010;7:647. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm 2010;7:1872. Watanabe H, Makiyama T, Koyama T, et al. High prevalence of early repolarization in short QT syndrome. Heart Rhythm 2010;7:647. Fulop L, Banyasz T, Magyar J, Szentandrassy N, Varro A, Nanasi PP. Reopening of L-type calcium channels in human ventricular myocytes during applied epicardial action potentials. Acta Physiol Scand 2004;180:39. Vaseghi M, Shivkumar K. The role of the autonomic nervous system in sudden cardiac death. Prog Cardiovasc Dis 2008;50:404. Gourraud JB, Le Scouarnec S, Sacher F, et al. Identification of large families in early repolarization syndrome. J Am Coll Cardiol 2013;61:164. Roberts JD, Gollob MH. Early Repolarization: A Rare Primary Arrhythmic Syndrome and Common Modifier of Arrhythmic Risk: Section Editor: Silvia G. Priori, M.D., Ph.D. Journal of Cardiovascular Electrophysiology 2013. Koumi SI, Martin RL, Sato R. Alterations in ATP-sensitive potassium channel sensitivity to ATP in failing human hearts. Am J Physiol 1997;272:H1656. Koumi S, Wasserstrom JA. Acetylcholine-sensitive muscarinic K+ channels in mammalian ventricular myocytes. Am J Physiol 1994;266: H1812. Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 2006;47:362. Arking DE, Pfeufer A, Post W, et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 2006;38:644. Tikkanen JT, Junttila MJ, Anttonen O, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation 2011;123:2666.
ScienceDirect Journal of Electrocardiology 46 (2013) 395 – 398 www.jecgonline.com
The genetics of the J wave patterns☆,☆☆ Olujimi A. Ajijola, MD, PhD, a Albert Y. Sun, MD b, c, d,⁎ b
a University of California-Los Angeles Cardiac Arrhythmia Center, Los Angeles, CA, USA Section of Cardiac Electrophysiology, Division of Cardiology, Duke University Medical Center, Durham, NC, USA c Center for Human Genetics, Duke University Medical Center, Durham, NC, USA d Durham VA Hospital, Durham, NC, USA
Introduction The rapid growth of medical genetics over the past few decades has transformed the way we think about the fundamental properties of cardiac conduction. Recent studies have demonstrated associations of gene variants and complex traits such as QT and PR interval. 1,2 These findings would suggest that one’s QT interval is an inherited trait, similar to one’s eye color. In extreme cases, as in the monogenetic arrhythmia disorders Long QT Syndrome and Brugada Syndrome, single mutations in ion channel or ion channel-related genes lead to a prototypical appearance on 12 lead ECG, functional consequences, and an associated increase in risk of sudden cardiac death (SCD). In these disorders, the causative genetic mutations not only help define the disease, but in some cases are also used in risk stratification. 3 Recent studies have also demonstrated genetic variants and predictable patterns of inheritance with the early repolarization pattern found on ECG. This pattern has been defined as an elevation of the QRS–ST junction of at least 0.1 mV from baseline and QRS slurring or notching in at least two contiguous leads in the inferior or lateral location. 4 As this definition focuses on J point elevation associated with notches or slurs rather than the ST segment elevation classically associated with early repolarization, for the purposes of this review, we will use the term J wave pattern to describe the ECG pattern previously described as early repolarization. Additionally, this pattern was specifically described as J wave abnormalities in only the inferior and lateral ECG lead locations to avoid crossover with the Brugada syndrome (BrS). However as it has increasingly been associated with SCD, 4–6 analogies not only to BrS but other monogenetic
☆
Funding Support: A.P. Giannini Foundation Fellowship (OAA). The Greenfield Scholars Program (AYS). ☆☆ Disclosures: None. ⁎ Corresponding author. Division of Cardiac Electrophysiology, Duke University Medical Center, DUMC Box 3154, 2301 Erwin Rd, Durham, NC 27712, USA. E-mail address: [email protected] 0022-0736/$ – see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jelectrocard.2013.06.025
arrhythmia disorders are inevitable. Although the majority of the J wave pattern is likely benign, discriminating risk on ECG patterns alone remains elusive. Determining the genetic nature of the J wave pattern will not only add to our understanding of the underlying pathophysiology but may also lead to improved risk stratification. This review focuses on the heritability, known genetic variants, and future direction of genetic studies of the J wave pattern.
Heritability of the J wave pattern To access the hypothesis that the J wave pattern was heritable, Reinhard et al 7 investigated individuals from Caucasian British nuclear families. They demonstrated that individuals with at least one affected parent had a 2.5-fold increased risk of the J wave pattern on ECG. This appeared to be more frequent when the affected parent was the mother, with an odds ratio of 3.84. Though the mechanism of such an inheritance pattern is unclear, the authors postulate effects mediated via the sex chromosomes, parental imprinting of autosomal genes, or transmission through mitochondrial DNA. Another recent study from participants of the Framingham Heart Study and Health 2000 Survey demonstrated that male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of the J wave pattern. 8 Additionally in this population, siblings of individuals with the J wave pattern were more than 2 times likely to demonstrate the J wave pattern, indicating a genetic basis. Though both of these studies suggest a heritable quality of the J wave pattern in large population cohorts, neither was able to provide insight on associated adverse outcomes. Therefore whether the genetics of the J wave pattern equates to the J wave syndrome (defined as the J wave pattern and a history of SCD) is still unknown. This is an important distinction, as it is very likely that the J wave pattern does not equate to the J wave syndrome. To address this, recent studies in families with the J wave syndrome have also demonstrated a magnitude of
396
O.A. Ajijola, A.Y. Sun / Journal of Electrocardiology 46 (2013) 395–398
heritability that is consistent with that found in studies of electrocardiographic the J wave pattern. Nunn et al. analyzed the ECGs of family members of patients with SCD and found that the J wave pattern was 2.54 times more prevalent in the relatives of SCD probands than in controls. 9 More recently, Gourraud et al. also screened relatives of families affected by the J wave syndrome and demonstrated transmission of a J wave pattern compatible with an autosomal dominant mode of inheritance. 10 The families studied in both reports likely represent very rare cases of the J wave syndrome, and the findings should not be extrapolated to the general population. In fact, no causative mutations in previously reported loci were identified when the same families underwent genetic analysis, suggesting substantial genetic heterogeneity of the J wave syndrome. Also all of the studies were performed in families of European descent limiting the global applicability.
Candidate genes, variants, and pathophysiologic mechanisms Before a genetic basis was even entertained, cellular level dysregulation had been associated with the J wave pattern in animal models and mechanistically linked to ventricular fibrillation initiation. 11 Consistently, most of the limited number of genetic aberrations identified in patients with the J wave syndrome involve defects in sodium, potassium, and calcium channels 12–15 (Table 1). These genetic anomalies result in inadequate sodium or calcium currents, or excessive potassium currents early in cardiomyocyte repolarization. 16 As a consequence of these aberrant currents, membrane voltage may deviate from expected levels, be more pronounced on the epicardial surface, and result in significant transmural repolarization heterogeneity. The resulting dispersion in repolarization may enhance susceptibility to “phase 2 reentry”, the putative mechanism of arrhythmogenesis in the J wave syndrome. 16 Potassium channel mutations The first mutation linked to the J wave syndrome, a missense serine to lysine translation (S422L) in KCNJ8, was identified by Haissegurre et al in a 14-year-old female with the J wave pattern and idiopathic ventricular fibrillation (IVF). 12 The product of this gene, a subunit of the heterooctameric ATP-sensitive potassium channel (Kir6.1), dem-
onstrates a decreased sensitivity to cytoplasmic ATPlevels and incomplete closure. 13 This gain-of-function mutation causes an increase in IkATP in the early epochs of ventricular repolarization, resulting in rapid recovery from depolarization and shorter action potential duration (APD). 13,17 Enhanced IkATP during states of stress such as ischemia or hypoxia attenuates the duration of repolarization, induces the loss of the AP dome, and increases susceptibility to “phase 2 reentry”, the proposed mechanism of VF initiation. Studies of the transient outward potassium current (Ito) in BrS have provided important insights into the pathophysiologic mechanisms of the J wave syndrome. These studies have highlighted important parallels between the two syndromes and led to the suggestion that both conditions are different ends of the same spectrum. 18 This possible commonality is illustrated in a study by Sinner et al in which the investigators conducted a meta-analysis of genome-wide association studies in 3 large European and American cohorts to identify common genetic variants influencing the J wave pattern. After meta-analysis and replication no SNPs reached genome-wide significance, presumably due to insufficient statistical power and phenotype heterogeneity. Although not genome-wide significant, one identified locus was on chromosome 1 intronic to KCND3, the gene that encodes Kv4.3, a key channel underlying the Ito current. While no mutation in any genes encoding channelforming subunits of Ito has been linked to the J wave syndrome, such a mutation (KCNE3-R99H) has been described for BrS. 19 Calcium channel mutations To date, three mutations, each in a different subunit of the L-Type calcium channel (LTCC) have been identified in patients with the J wave syndrome. 20,21 These mutations in CACNA1C, CACNB2b, and CACNA2D1, encoding the α1, β2, and α2δ subunits of the LTCC, respectively, were identified from two separate studies 1: a cohort of over 200 patients with J wave syndrome, BrS, and IVF, 14 and 2 a cohort of patients with the J wave pattern and Short QT syndrome (SQTS). 22 Although the specific mutations identified were not functionally expressed for in vitro studies, two CACNA1C mutations from BrS patients were functionally expressed and demonstrated loss of function in the calcium channel current. 14 As previously noted,
Table 1 Genetic mutations or variants associated with the J wave syndrome. Mutation
Channel/current
Mechanism
Consequence
KCNJ8-S422L CACNA1C-E850del CACNB2-S160T CACNB2-R571C CACNA2D1-S956T SCN5A-L846R SCN5A-R367H SCN5A-A226D
IK-ATP LTCC LTCC
Gain of function Unknown Unknown
Enhanced outward current Decreased inward current Decreased inward current
LTCC Nav1.5
Unknown Loss of function
Decreased inward current Decreased inward current
Nav1.5
Abnormal trafficking to cell surface
Decreased inward current
LTCC – L type calcium channel.
O.A. Ajijola, A.Y. Sun / Journal of Electrocardiology 46 (2013) 395–398
attenuation of calcium current density during the plateau phase of the action potential creates an imbalance between inward and outward currents, favoring outward repolarizing potassium currents. The net result of this mismatch is more rapid repolarization, and a shortened action potential. The effect of these specific LTCC mutations in the J wave syndrome has not been studied in the transmural context. 23 Sodium channel mutations Genetic mutations in the voltage-gated sodium channel NaV1.5 have been established as a cause of BrS phenotype. Consistent with mechanistic similarities between BrS and the J wave syndrome, NaV1.5 mutations have also been identified in the J wave syndrome. Watanabe et el. 15 studied 50 patients with the J wave pattern and IVF, and 250 age and sex matched healthy controls. Three variants (A226D, L846R, and R367H) of SCN5A, the gene encoding Nav1.5, occurring at highly conserved sites across mammalian species were found in 3 unrelated patients. Na channel blocker challenge in these patients led to VF or augmented J waves, underscoring the pro-arrhythmic risk associated with these sodium channel variants. Functional expression of these channels in a cell line showed that all variants generated no current. Interestingly, the A226D variant exhibited abnormal trafficking to the cell membrane. The other two variants, however, showed normal targeting for the cell membrane. The mechanism underlying sodium channel dysfunction in the J wave syndrome is poorly understood, but may be related to an attenuation of the sodium current and imbalance between inward depolarizing currents and outward repolarizing currents. 16 Autonomic influences on the J wave pattern The autonomic nervous system (ANS) plays a critical and poorly understood role in the regulation of cardiac excitability. 24 Both limbs of the ANS exhibit proarrhythmic properties, with enhanced sympathetic tone increasing dispersion of repolarization and early or late after-depolarizations, while the parasympathetic nervous system may enhance bradycardia-mediated arrhythmias or alter acetylcholine sensitive currents. The relationship between vagal tone and sudden death in BrS is well recognized, and this relationship is being increasingly recognized for the J wave syndrome. Increased arrhythmias at night, slower heart rates in the J wave syndrome patients, enhanced J waves during bradycardia, attenuation of VT/VF storm by tachycardia (isoproterenol infusion), and unmasking or increase in J waves during the Valsalva maneuver 12,25,26 all support enhanced vagal tone as a possible modulator of J wave syndrome. The latter point represents a potentially important diagnostic tool in identifying patients with dynamic J waves at higher risk of IVF or for unmasking the J wave pattern in a patient with IVF. Although poorly understood, the potential role of the acetylcholine-activated potassium current (IK-Ach) in enhancing ventricular repolarization 27,28 may provide a link between vagal activation and J wave syndrome. Pharmacologic antagonism of this channel may therefore
397
represent an adjunctive therapeutic strategy in the management of VF in the J wave syndrome.
Challenges and future directions regarding the role of heritable variants in the J wave pattern Though great strides have been made in understanding the J wave pattern in recent years, many fundamental questions remain unanswered regarding the genetic basis of the J wave pattern. Can we apply what we know about familial forms of the J wave syndrome to the pattern seen in almost 6% of the population? Is the J wave pattern in this respect akin to the QT interval? Examining the prevalence of mildly prolonged QT (450–470 ms for females and 430–450 ms for males) and severely prolonged QT intervals (≥ 471 ms for females and ≥ 451 ms for males) in fact parallels the prevalence of mild J point elevation N 0.1 mV and marked J point elevation N 0.2 mV in the general population, respectively. Additionally, the extremes of phenotype of both QT interval and the J wave pattern convey similar magnitude risk of SCD. 6,29 Thus similar to investigation in genetic modifiers of the QT interval, hypothesis-free whole exome or genome wide studies are necessary. Multiple unbiased genome wide studies identified SNPs within the intronic regions of NOS1AP as modifiers of the QT interval. 30 This loci was previously unknown despite the multitude of investigations of families with the Long QT Syndrome using a candidate gene approach. Thus far, one GWAS meta-analysis was performed in the J wave pattern and did not reveal any genome-wide significant results. This leads us to another important question: is the J wave pattern a phenotype sufficiently defined? The inconsistencies in the literature on a unified terminology alone is evidence that surely this answer is no. In fact the phenotype is continuingly being refined, as recent evidence suggests certain morphologic factors infer greater risk. For example, Tikkanen et al suggest that the magnitude of J-point elevation further increases the risk of sudden death, with a relative risk of 2.92 in J-point elevations N 0.2 mV. 6 A horizontal or downward direction of the ST segments also has been shown to carry a 3 times higher risk of arrhythmic death. 31 These subtle phenotypic characteristics are essential when performing genetic association studies, and future studies would be wise to focus on such details and more accurately define the at risk pattern.
Conclusion Many questions remain regarding the genetic basis of the J wave pattern. However, recent studies have demonstrated a clear heritable pattern and identified genetic loci with strong biologic plausibility. These studies represent just the beginning of our understanding of the J wave pattern and J wave syndrome. Whether the J wave syndrome as defined in this review is another form of the Brugada Syndrome is yet to be seen but similarities cannot be ignored. Future studies will inevitably parallel that though of the other inherited arrhythmia disorders and not only broaden our
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