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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 14  |  Issue : 2  |  Page : 59-64

Haissaguerre syndrome: The gray area still exists


Department of Cardiovascular, Cairo University, Cairo, Egypt

Date of Web Publication26-Oct-2017

Correspondence Address:
Noha Hassanin Hanboly
Assistant Professor of Cardiovascular Diseases Cardiovascular Department, Cairo University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njc.njc_5_17

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  Abstract 

The term early repolarization (ER) is defined electrocardiographically by either a sharp well-defined positive deflection or notch immediately following a positive QRS complex at the onset of the ST-segment, or slurring at the terminal part of the QRS complex. This pattern is frequently observed in the general population. For decades, ER was regarded as a benign electrocardiographic variant. However, in 2008, Haïssaguerre et al described a strong relationship between J-waves and many different forms of ventricular arrhythmias in the absence of known heart disease. It seems likely that ER results from a net increase in outward current caused by a loss of inward-channel function or a gain in outward-channel function. It remains unclear whether these mutations are more functionally important in the epicardium, or whether they simply exaggerate the magnitude of preexisting epicardial-endocardial differences by increasing overall net outward current flow. This review will discuss the underlying mechanisms, genetic basis, risk stratification and management.

Keywords: Brugada patterns, early repolarization, J-wave syndromes


How to cite this article:
Hanboly NH. Haissaguerre syndrome: The gray area still exists. Nig J Cardiol 2017;14:59-64

How to cite this URL:
Hanboly NH. Haissaguerre syndrome: The gray area still exists. Nig J Cardiol [serial online] 2017 [cited 2017 Dec 10];14:59-64. Available from: http://www.nigjcardiol.org/text.asp?2017/14/2/59/217279


  Introduction Top


Early repolarization (ER), is an electrocardiogram (ECG) pattern and syndrome named after Haïssaguerre et al.[1] who first reported it.

What complicates matter is that physicians have been taught since the 70s to consider “ER” a normal variant of ST elevation. The challenge in studying ER is the lack of agreement on the definition. Most of the individuals with ER are at no or minimal risk for arrhythmic events. However, ER substrate may increase the arrhythmic risk in others if they have underlying cardiac disease. This review addressed an approach to the clinical evaluation and management of these patients.


  Terminology Top


ER was first used to describe ST-segment elevation in the absence of chest pain to differentiate these findings from acute myocardial infarction or pericarditis. In the absence of chest pain, these findings were considered benign.

ER pattern (ERP) can represent distinct pathological conditions, including acute myocardial injury or infarction, takotsubo cardiomyopathy, pericarditis, and hypothermia (Osborn waves).

In the absence of these conditions, ERP is considered a variant of the normal electrocardiographic [2]

The 2009 American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society recommendations for the standardization and interpretation of the ECG define ER as “a normal variant commonly characterized by J-point elevation and rapidly upsloping or normal ST segment.”[3]

J-point has been characterized as the junction at the end of the QRS complex and beginning of the ST segment [3] [Figure 1].
Figure 1: Electrocardiogram segments and intervals

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ERP, ER was defined as an elevation of the J-point of at least 0.1 mV above the baseline in at least two continuous inferior or lateral leads that manifested as QRS slurring or notching. It has long been considered a benign phenomenon. Recent studies have used more complex definitions of ER, including J-wave [Figure 2] or J-point elevation and QRS complex notching or slurring, with or without concomitant ST-segment elevation.[4] A different pattern is illustrated in [Figure 3].
Figure 2: Electrocardiogram demonstrating J wave

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Figure 3: Examples of early repolarization patterns[4]

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  J-Wave Syndromes Top


ER syndrome (ERS) and Brugada syndrome are characterized by similar clinical features and J-wave abnormalities; they are often described as representing parts of a continuum of J-wave syndromes.[5]

Early repolarization syndrome

This is defined as occurring in patients with ERP who have survived idiopathic ventricular fibrillation (VF) with clinical evaluation unrevealing for other explanations. Familial cases have been described [6] and associated with rare genetic variants in several ion channel-encoding genes.

Types of early repolarization syndrome

Type 1 displays an ERP predominantly in the lateral precordial leads, is prevalent among healthy male athletes and rarely seen in VF survivors.

Type 2 displays an ERP predominantly in the inferior or inferolateral leads, is associated with a higher level of risk.

Type 3 displays an ERP globally in the inferior, lateral, and right precordial leads, is associated with the highest level of risk for the development of malignant arrhythmias and is often associated with VF storms.[5]

Brugada pattern

A series of ST-segment abnormalities, including downward coved and saddleback ST-segment elevations, associated with sudden cardiac death (SCD). These patterns are usually located in precordial leads V1 through V3 [Figure 4].
Figure 4: Brugada patterns[7]

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Clinical studies, including those by Haïssaguerre et al.,[1] excluded V1–V3 leads to differentiate ER from Brugada patterns.[7]

Epidemiology of early repolarization

Published observational studies suggest that the prevalence of ERP ranges between 1% and 18%.[8] One of the first studies to describe ERP was an investigation of 4-lead ECGs in 200 men and women published in 1936, which reported a frequency of 25% in men and 16% in women. Subsequent studies have shown that ERP is more frequent in blacks, men, younger individuals (age <40 years), and athletes.[9] Caution is mandatory when interpreting ECG in the black population. It was found Q, T, R, and S wave amplitudes were higher among Nigerian children at Ilorin teaching hospital compared to Caucasians.[10]

It was found that patients with malignant ER have a higher prevalence of low-amplitude T waves (T-wave amplitude <0.1 mV and <10% of R-wave amplitude in lead I, II, or V4-V6), lower T-wave/R-wave (T/R) ratio (lead II or V5), and longer QTc interval. The combination of these parameters with J-wave amplitude and distribution of J waves may allow for improved identification of malignant ER.[11]


  Genetic Basis Top


In 2000, Gussak and Antzelevitch [12] presented evidence in support of the hypothesis that the ERP denoted the presence of a substrate that may predispose to development of life-threatening ventricular arrhythmias. Their definition of the pattern included the presence of prominent J waves, or QRS notching or slurring, together with ST-segment elevation. It was 8 years later that idiopathic VF was first linked with large numbers of individuals having the ERP.[13]

Repolarization or depolarization

Not all investigators are in complete agreement about the electrophysiological basis of ER, but there is a consensus that the pattern of end-QRS notching and slurring may, on occasion, be due to late depolarization rather than ER.[14] The depolarization theory proposes that J-point elevation is a manifestation of delayed activation of specific regions of the myocardium, a “current-to-load” mismatch.

However, it was found that that J-point elevation is a marker of increased transmural heterogeneity of ventricular repolarization, which increases the vulnerability to ventricular tachyarrhythmia.[15] Evidence in support of the repolarization theory has been more compelling.

Genetic mutations implicated in patients with early repolarization syndrome

Gain-of-function mutations in KCNJ8 (ERS) and KCND2 (in an atypical J-wave syndrome) result in augmented KATP and Ito currents, respectively.

Loss-of-function mutations in CACNA2D1, CACNA1C, and CACNB2 result in an attenuated ICa while SCN5A mutations are predicted to result in an attenuation of INa.

The overall effect is an outward shift in the balance of currents, which is predicted to preferentially accentuate the epicardial AP notch (red).[16] [Figure 5].
Figure 5: Genetic mutations implicated in patients with early repolarization

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  Early Repolarization Pattern: Innocent Finding or Marker of Risk? Top


Haïssaguerre et al. noted that ER is not an uncommon electrocardiographic finding, occurring in 2%–5% of the population, often in men, young adults, blacks, and athletes. “It was considered a variant,” said Haïssaguerre et al., “a funny electrocardiographic finding. However, there was a sort of discrepancy between this seemingly benign aspects of ER, while there were papers saying it could create a malignant condition.”[1]

It is also important to determine whether the ERP in inferior leads is a sign of a genetic ion-channel disorder or a marker for a structural cardiac abnormality since a previous report suggested that the ERP may be related to both electrophysiological instability and cardiomyopathies.[15]

Rosso et al. also revealed that inferolateral ER was more frequent in 45 patients with idiopathic VF compared with 121 age- and sex-matched controls.[17]

Tikkanen et al. found that J-point elevation in the inferior leads on standard ECG is not an innocuous finding in middle-aged individuals.[18] [Figure 6].
Figure 6: Baseline electrocardiogram of two male individuals with J-Point elevation of more than 0.2 mV in the inferior leads[18]

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However, Uberoi et al.[19] found no association with ERP and increased cardiovascular mortality in 29 281 patients within the VA Palo Alto Health Care System. Moreover, Meta-analysis of observational studies has revealed increased arrhythmic risk; however, the magnitude of this risk is low, with an estimated absolute risk difference of 0.0007%/y.[20]


  Gender, Family History, Pattern Top


Male sex is of limited value because it predominates among patients with cardiac arrest related to ERP as well as for asymptomatic healthy controls with ERP, especially healthy athletes. The recognition of ERP in the ECG of an asymptomatic family member of a sudden death victim generally causes concern.[21]

Practically, familial history of unexplained sudden death at a young age mandates systematic evaluation of all surviving family members regardless of the presence or absence of ERP. A history of syncope at rest is strongly associated with ERS and is attributable to pause-dependent augmentation of J waves that precede episodes of VF [17],[23] [Figure 7].
Figure 7: The amplitude of J waves was measured in the 2-3 beats before the pause and averaged and compared with those of the postpause J waves[23]

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The arrhythmogenic form of ERP involves tall J waves with limited ST-segment elevation, mainly in the inferior leads.[17] The pattern of J waves followed by a horizontal or descending ST-segment is associated with increased arrhythmic risk.[22]


  Clinical Implications Top


Since the risk of SCD in asymptomatic patients without a family history is very low, further investigation is unwarranted on the basis of current data.

Patients with arrhythmic syncope or a family history of SCD should be evaluated further with respect to high-risk clinical and ECG features. Moreover, Patients with aborted sudden death or resuscitated VF who have ECG findings of ER, programmed ventricular stimulation performed on the basis of ERP alone is not recommended.[4]

Among the survivors of SCD due to idiopathic VF without structural heart disease are best treated with an implantable cardioverter-defibrillator.[24]

Quinidine has been demonstrated to suppress VF storm in patients with ERS [25] by suppressing the Ito current.[26] Isoproterenol has been shown to suppress electrical storm in ERS patients.[25] The effect is likely to be mediated by heart rate acceleration, which is predicted to reduce Ito, and an increase in ICa, that restores the phase 2 dome and hence transmural AP homogeneity.[27]

However, number of antiarrhythmic drugs including beta-blockers, lidocaine, mexiletine, and verapamil were demonstrated to be ineffective.[25]

The response to ajmaline has not been consistent in all studies. Based on genetic studies reporting loss-of-function SCN5A mutations in ERS ajmaline would be predicted to accentuate J waves in ERS patients. However, a number of studies found that ajmaline attenuates J waves.[28]


  Conclusion Top


The J-deflection presenting as either QRS slurring or notching was first described since many decades and was considered a normal ECG variant.

In 2008, Haïssaguerre et al. described a strong relationship between J-waves and many different forms of ventricular arrhythmias in the absence of known heart disease.

The pathophysiologic basis of the ER is currently not fully understood. ER occurs in the early phase of the cardiac action potential and is caused by the cardiac transient outward potassium current (Ito).

If a situation arises where there is a reduced density of the Ito channels in the endocardium compared with epicardium or mid-myocardium, a large Ito current can occur that results in electrocardiographic ER.

Although mechanisms of ventricular arrhythmia in patients with acute myocardial infarction are thought to be similar to those in patients with ERS, still remains uncertainty regarding the underlying links between ER and increased risk of ventricular arrhythmia in patients with coronary artery disease.

The identification of high-risk patients with ERS remains challenging. There is no current risk stratification strategy for asymptomatic patients with ERP in general population and within families with ERP. It is not possible to identify asymptomatic individuals with a primary arrhythmogenic disorder caused by ER.

All patients with ER should modify their underlying cardiac risk profile.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Haïssaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016-23.  Back to cited text no. 1
    
2.
Maury P, Rollin A. Prevalence of early repolarisation/J wave patterns in the normal population. J Electrocardiol 2013;46:411-6.  Back to cited text no. 2
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3.
Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: The ST segment, T and U waves, and the QT interval: A scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: Endorsed by the International Society for Computerized Electrocardiology. Circulation 2009;119:e241-50.  Back to cited text no. 3
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4.
Patton KK, Ellinor PT, Ezekowitz M, Kowey P, Lubitz SA, Perez M, et al. Electrocardiographic early repolarization: A Scientific Statement from the American Heart Association. Circulation 2016;133:1520-9.  Back to cited text no. 4
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5.
Antzelevitch C, Yan GX, Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarization. J Am Coll Cardiol 2011;57:1587-90.  Back to cited text no. 5
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6.
Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, et al. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. Circ Arrhythm Electrophysiol 2011;4:874-81.  Back to cited text no. 6
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7.
Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, et al. Brugada syndrome: Report of the second consensus conference. Heart Rhythm 2005;2:429-40.  Back to cited text no. 7
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8.
Sinner MF, Reinhard W, Müller M, Beckmann BM, Martens E, Perz S, et al. Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: A population-based prospective cohort study (MONICA/KORA). PLoS Med 2010;7:e1000314.  Back to cited text no. 8
    
9.
Walsh JA 3rd, Ilkhanoff L, Soliman EZ, Prineas R, Liu K, Ning H, et al. Natural history of the early repolarization pattern in a biracial cohort: CARDIA (Coronary Artery Risk Development in Young Adults) study. J Am Coll Cardiol 2013;61:863-9.  Back to cited text no. 9
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10.
Kolawole AJ, Omokhodion SI. Normal limits for pediatric electrocardiogram in Ilorin, Nigeria. Niger J Cardiol 2014;11:112-23.  Back to cited text no. 10
    
11.
Roten L, Derval N, Maury P, Mahida S, Pascale P, Leenhardt A, et al. Benign vs. malignant inferolateral early repolarization: Focus on the T wave. Heart Rhythm 2016;13:894-902.  Back to cited text no. 11
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12.
Gussak I, Antzelevitch C. Early repolarization syndrome: Clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000;33:299-309.  Back to cited text no. 12
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13.
Wellens HJ. Early repolarization revisited. N Engl J Med 2008;358:2063-5.  Back to cited text no. 13
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14.
Ghosh S, Cooper DH, Vijayakumar R, Zhang J, Pollak S, Haïssaguerre M, et al. Early repolarization associated with sudden death: Insights from noninvasive electrocardiographic imaging. Heart Rhythm 2010;7:534-7.  Back to cited text no. 14
    
15.
Boineau JP. The early repolarization variant – An electrocardiographic enigma with both QRS and J-STT anomalies. J Electrocardiol 2007;40:3.e1-10.  Back to cited text no. 15
    
16.
Mercer BN, Begg GA, Page SP, Bennett CP, Tayebjee MH, Mahida S. Early repolarization syndrome; Mechanistic theories and clinical correlates. Front Physiol 2016;7:266.  Back to cited text no. 16
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17.
Rosso R, Kogan E, Belhassen B, Rozovski U, Scheinman MM, Zeltser D, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: Incidence and clinical significance. J Am Coll Cardiol 2008;52:1231-8.  Back to cited text no. 17
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18.
Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529-37.  Back to cited text no. 18
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19.
Uberoi A, Jain NA, Perez M, Weinkopff A, Ashley E, Hadley D, et al. Early repolarization in an ambulatory clinical population. Circulation 2011;124:2208-14.  Back to cited text no. 19
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20.
Wu SH, Lin XX, Cheng YJ, Qiang CC, Zhang J. Early repolarization pattern and risk for arrhythmia death: A meta-analysis. J Am Coll Cardiol 2013;61:645-50.  Back to cited text no. 20
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21.
Viskin S. Idiopathic ventricular fibrillation “Le Syndrome d'Haïssaguerre” and the fear of J waves. J Am Coll Cardiol 2009;53:620-2.  Back to cited text no. 21
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22.
Adler A, Rosso R, Viskin D, Halkin A, Viskin S. What do we know about the “malignant form” of early repolarization? J Am Coll Cardiol 2013;62:863-8.  Back to cited text no. 22
    
23.
Aizawa Y, Sato A, Watanabe H, Chinushi M, Furushima H, Horie M, et al. Dynamicity of the J-wave in idiopathic ventricular fibrillation with a special reference to pause-dependent augmentation of the J-wave. J Am Coll Cardiol 2012;59:1948-53.  Back to cited text no. 23
    
24.
Letsas KP, Charalampous C, Korantzopoulos P, Tsikrikas S, Bramos D, Kollias G, et al. Novel indexes of heterogeneity of ventricular repolarization in subjects with early repolarization pattern. Europace 2012;14:877-81.  Back to cited text no. 24
    
25.
Haïssaguerre M, Chatel S, Sacher F, Weerasooriya R, Probst V, Loussouarn G, et al. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol 2009;20:93-8.  Back to cited text no. 25
    
26.
Antzelevitch C, Yan GX. J-wave syndromes: Brugada and early repolarization syndromes. Heart Rhythm 2015;12:1852-66.  Back to cited text no. 26
    
27.
Patocskai B, Barajas-Martinez H, Hu D, Gurabi Z, Koncz I, Antzelevitch C. Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome. Heart Rhythm 2016;13:1326-34.  Back to cited text no. 27
    
28.
Kawata H, Noda T, Yamada Y, Okamura H, Satomi K, Aiba T, et al. Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome. Heart Rhythm 2012;9:77-83.  Back to cited text no. 28
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]



 

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  In this article
Abstract
Introduction
Terminology
J-Wave Syndromes
Genetic Basis
Early Repolariza...
Gender, Family H...
Clinical Implica...
Conclusion
References
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