|Year : 2017 | Volume
| Issue : 2 | Page : 59-64
Haissaguerre syndrome: The gray area still exists
Noha Hassanin Hanboly
Department of Cardiovascular, Cairo University, Cairo, Egypt
|Date of Web Publication||26-Oct-2017|
Noha Hassanin Hanboly
Assistant Professor of Cardiovascular Diseases Cardiovascular Department, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
Early repolarization (ER), is an electrocardiogram (ECG) pattern and syndrome named after Haïssaguerre et al. 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|| |
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 
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.”
J-point has been characterized as the junction at the end of the QRS complex and beginning of the ST segment  [Figure 1].
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. A different pattern is illustrated in [Figure 3].
| J-Wave Syndromes|| |
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.
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  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.
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].
Clinical studies, including those by Haïssaguerre et al., excluded V1–V3 leads to differentiate ER from Brugada patterns.
Epidemiology of early repolarization
Published observational studies suggest that the prevalence of ERP ranges between 1% and 18%. 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. 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.
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.
| Genetic Basis|| |
In 2000, Gussak and Antzelevitch  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.
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. 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. 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). [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?|| |
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.”
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.
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.
Tikkanen et al. found that J-point elevation in the inferior leads on standard ECG is not an innocuous finding in middle-aged individuals. [Figure 6].
|Figure 6: Baseline electrocardiogram of two male individuals with J-Point elevation of more than 0.2 mV in the inferior leads|
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However, Uberoi et al. 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.
| Gender, Family History, Pattern|| |
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.
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 , [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|
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The arrhythmogenic form of ERP involves tall J waves with limited ST-segment elevation, mainly in the inferior leads. The pattern of J waves followed by a horizontal or descending ST-segment is associated with increased arrhythmic risk.
| Clinical Implications|| |
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.
Among the survivors of SCD due to idiopathic VF without structural heart disease are best treated with an implantable cardioverter-defibrillator.
Quinidine has been demonstrated to suppress VF storm in patients with ERS  by suppressing the Ito current. Isoproterenol has been shown to suppress electrical storm in ERS patients. 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.
However, number of antiarrhythmic drugs including beta-blockers, lidocaine, mexiletine, and verapamil were demonstrated to be ineffective.
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.
| Conclusion|| |
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
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]