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Arrhythmias and the electrocardiogram in inherited arrhythmia disorders
Journal of Electrocardiology 40 (2007) S7 – S8 www.elsevier.com/locate/jelectrocard
Arrhythmias and the electrocardiogram in inherited arrhythmia disorders Arthur A.M. Wilde4 Department of Cardiology, Amsterdam, The Netherlands
Introduction In recent years we have witnessed an enormous revolution in clinical electrophysiology due to the identification of a number of genes causally related to primary arrhythmia syndromes.1 As a result, disease entities are subdivided based on their molecular subtype and new arrhythmia syndromes are recognized. This has caused a significant increase in our knowledge on the pathophysiology of these disease entities and has improved and tailored treatment in groups of patients or in individual cases. The long QT syndrome The molecular genetic basis has subdivided the long QT syndrome, a primary cardiac arrhythmia disorder identified by prolongation of the QT interval on the electrocardiogram (ECG), into several subtypes (LQTS types 1, 2, 3, etc). The common pathophysiological mechanism underlying QT interval prolongation is a net reduction in repolarizing (ie, outward) current. Genes encoding for potassium (K+) channels, ie, the primary contributors to the repolarization process, were involved. Mutations in these genes leading to a loss of function effect, ie, less potassium outward current, prolong the cardiac action potential and the QT interval. The cardiac sodium channel gene with gain of function mutations appeared to be involved as well. In rare forms, the L-type calcium channel gene and genes encoding proteins involved in ion channel protein transport are also involved.1 The subclassification of the long QT syndromes has prompted a number of genotype-phenotype studies (in the first 3 types, accounting for over 90% of genotyped individuals) over the past few years that have demonstrated that the underlying genetic defect impacts on ECG morphology, trigger and onset of symptoms, ECG appearance of the characteristic arrhythmia, prognosis, and, most importantly, therapy.2 The genotype-specific ECG features (high-amplitude, wide, symmetric T wave in LQT1, lowamplitude T wave in LQT2, and long isoelectric segment 4 Tel.: +31 20 5662904. E-mail address: [email protected] 0022-0736/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jelectrocard.2006.10.017
and sharp T wave in LQT3) are not too well understood, but probably relate to the transmural inhomogeneity of aberrant ion channels. Recently, we were able to demonstrate that the typical pause dependency of the torsades de pointes arrhythmia is actually only observed in LQT2.3 In LQT1, it is often observed during an increase in rate, which is in accordance with adrenergic triggers in LQT1 (see next paragraph). Whether different mechanisms underlie these genotype-specific arrhythmia onset features is unknown, but seems likely. Gene specificity of symptom-related triggers were described for LQT1, -2, and -3. This underlies the rationale for tailored therapeutic management of genotyped LQT patients. In particular, lifestyle adjustments to avoid genotype-specific triggers are pertinent and, in concordance with the predominant adrenergic triggers, b-blocking therapy seems most effective in LQT1 and to some extent in LQT2. In patients with LQT3, b-blockers seem of no use. Finally, the identification of a causal genotype in a specific family enables presymptomatic counseling leading to timely treatment of affected individuals; at the same time, unaffected family members can be reassured. Brugada syndrome Brugada syndrome is increasingly recognized as a disease entity associated with sudden cardiac death. The typical ECG is characterized by right precordial ST-segment elevation and discrete prolongation of diverse conduction parameters. Three ECG types have been recognized with, in particular, type 1 (ie, the bcoved-typeQ ST segment) being mandatory for the diagnosis. Structural heart disease should be absent. The diagnosis of Brugada syndrome is made when type 1 ECG (at baseline or after drug challenge) is observed in combination with documented (or inducible) ventricular arrhythmias or premature sudden cardiac death or similar ECGs in family members or nocturnal agonal respiration.4 The electrophysiological basis for the ECG is disputed. Whether it is a repolarization disorder or a depolarization disorder is an unsettled issue. Arguments in favor of both theories are present and summarized in a recent review from our group.5 Of critical importance in this whole
S8
A.A.M. Wilde / Journal of Electrocardiology 40 (2007) S7–S8
discussion is the fact that every pathoanatomical study in patients with Brugada syndrome has revealed structural abnormalities that apparently escape clinical detection by current imaging techniques. In addition, the presence of mutations in the gene encoding for the cardiac sodium channel, responsible for 20% to 30% of patients with Brugada syndrome and initially regarded as the proof for a bpureQ electrical disorder, does not preclude the presence of structural abnormalities. Recent evidence coming from experimental studies on mice with hampered sodium channel function have shown that reduced sodium channel function is indeed associated with increased age-dependent development of fibrose. Another heavily discussed issue is that the risk for malignant ventricular arrhythmias of patients with a spontaneous or drug-induced coved-type ECG is ill defined. This is discussed elsewhere in this issue.6 Discrepant data center, in particular, around the predictive value of programmed electrical stimulation. Other arrhythmia syndromes Other primary arrhythmia syndromes are even less encountered than the two discussed above. However, from the point of pathophysiological interest they are of equal importance. The short QT syndrome is one of them and the only one briefly discussed in this short overview. The time between the first description of the disease and the identification of the causal gene(s) has become very short
(ie, b 5 years).7 Three ion channel genes are involved in different families/patients and short QT syndrome–related mutations in all three genes are associated with gain of function of the respective encoded ion channel. Loss of function of the same genes is responsible for diverse types of the LQTS (ie, type 2, type 1, and type 7). The number of patients currently described is less than 100 worldwide but is already exceeded by the number of publications on this topic. This is a clear example of the current interest in these rare arrhythmia syndromes. References 1. Wilde AAM, Bezzina CR. Genetics in cardiac arrhythmias. Heart 2005; 91:1352. 2. Shimizu W. The long QT syndrome. Therapeutic implications of a genetic diagnosis. Cardiovasc Res 2005;67:347. 3. Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long QT syndrome: possible therapy implications. Circulation [in press]. 4. Wilde AAM, Antzelevitch Ch, Borggrefe M, et al, for the study group on the molecular basis of arrhythmias of the European Society of Cardiology. Diagnostic criteria for the Brugada syndrome. A Consensus Report. Eur J Heart 2002;23:1648. 5. Meregalli PG, Wilde AAM, Tan HL. Pathophysiology of Brugada syndrome: repolarization, depolarization disorder or more. Cardiovasc Res 2005;67:367. 6. Antzelevitch C, Hiraoka M, Corrado D, Wilde AAM, Eckardt L. Diagnostic and genetic aspects of the Brugada and other inherited arrhythmias syndromes. J Electrocardiol 2007;40:S11. 7. Giustetto C, Di F, Monte C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006;27:2440.
Arrhythmias and the electrocardiogram in inherited arrhythmia disorders Arthur A.M. Wilde4 Department of Cardiology, Amsterdam, The Netherlands
Introduction In recent years we have witnessed an enormous revolution in clinical electrophysiology due to the identification of a number of genes causally related to primary arrhythmia syndromes.1 As a result, disease entities are subdivided based on their molecular subtype and new arrhythmia syndromes are recognized. This has caused a significant increase in our knowledge on the pathophysiology of these disease entities and has improved and tailored treatment in groups of patients or in individual cases. The long QT syndrome The molecular genetic basis has subdivided the long QT syndrome, a primary cardiac arrhythmia disorder identified by prolongation of the QT interval on the electrocardiogram (ECG), into several subtypes (LQTS types 1, 2, 3, etc). The common pathophysiological mechanism underlying QT interval prolongation is a net reduction in repolarizing (ie, outward) current. Genes encoding for potassium (K+) channels, ie, the primary contributors to the repolarization process, were involved. Mutations in these genes leading to a loss of function effect, ie, less potassium outward current, prolong the cardiac action potential and the QT interval. The cardiac sodium channel gene with gain of function mutations appeared to be involved as well. In rare forms, the L-type calcium channel gene and genes encoding proteins involved in ion channel protein transport are also involved.1 The subclassification of the long QT syndromes has prompted a number of genotype-phenotype studies (in the first 3 types, accounting for over 90% of genotyped individuals) over the past few years that have demonstrated that the underlying genetic defect impacts on ECG morphology, trigger and onset of symptoms, ECG appearance of the characteristic arrhythmia, prognosis, and, most importantly, therapy.2 The genotype-specific ECG features (high-amplitude, wide, symmetric T wave in LQT1, lowamplitude T wave in LQT2, and long isoelectric segment 4 Tel.: +31 20 5662904. E-mail address: [email protected] 0022-0736/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jelectrocard.2006.10.017
and sharp T wave in LQT3) are not too well understood, but probably relate to the transmural inhomogeneity of aberrant ion channels. Recently, we were able to demonstrate that the typical pause dependency of the torsades de pointes arrhythmia is actually only observed in LQT2.3 In LQT1, it is often observed during an increase in rate, which is in accordance with adrenergic triggers in LQT1 (see next paragraph). Whether different mechanisms underlie these genotype-specific arrhythmia onset features is unknown, but seems likely. Gene specificity of symptom-related triggers were described for LQT1, -2, and -3. This underlies the rationale for tailored therapeutic management of genotyped LQT patients. In particular, lifestyle adjustments to avoid genotype-specific triggers are pertinent and, in concordance with the predominant adrenergic triggers, b-blocking therapy seems most effective in LQT1 and to some extent in LQT2. In patients with LQT3, b-blockers seem of no use. Finally, the identification of a causal genotype in a specific family enables presymptomatic counseling leading to timely treatment of affected individuals; at the same time, unaffected family members can be reassured. Brugada syndrome Brugada syndrome is increasingly recognized as a disease entity associated with sudden cardiac death. The typical ECG is characterized by right precordial ST-segment elevation and discrete prolongation of diverse conduction parameters. Three ECG types have been recognized with, in particular, type 1 (ie, the bcoved-typeQ ST segment) being mandatory for the diagnosis. Structural heart disease should be absent. The diagnosis of Brugada syndrome is made when type 1 ECG (at baseline or after drug challenge) is observed in combination with documented (or inducible) ventricular arrhythmias or premature sudden cardiac death or similar ECGs in family members or nocturnal agonal respiration.4 The electrophysiological basis for the ECG is disputed. Whether it is a repolarization disorder or a depolarization disorder is an unsettled issue. Arguments in favor of both theories are present and summarized in a recent review from our group.5 Of critical importance in this whole
S8
A.A.M. Wilde / Journal of Electrocardiology 40 (2007) S7–S8
discussion is the fact that every pathoanatomical study in patients with Brugada syndrome has revealed structural abnormalities that apparently escape clinical detection by current imaging techniques. In addition, the presence of mutations in the gene encoding for the cardiac sodium channel, responsible for 20% to 30% of patients with Brugada syndrome and initially regarded as the proof for a bpureQ electrical disorder, does not preclude the presence of structural abnormalities. Recent evidence coming from experimental studies on mice with hampered sodium channel function have shown that reduced sodium channel function is indeed associated with increased age-dependent development of fibrose. Another heavily discussed issue is that the risk for malignant ventricular arrhythmias of patients with a spontaneous or drug-induced coved-type ECG is ill defined. This is discussed elsewhere in this issue.6 Discrepant data center, in particular, around the predictive value of programmed electrical stimulation. Other arrhythmia syndromes Other primary arrhythmia syndromes are even less encountered than the two discussed above. However, from the point of pathophysiological interest they are of equal importance. The short QT syndrome is one of them and the only one briefly discussed in this short overview. The time between the first description of the disease and the identification of the causal gene(s) has become very short
(ie, b 5 years).7 Three ion channel genes are involved in different families/patients and short QT syndrome–related mutations in all three genes are associated with gain of function of the respective encoded ion channel. Loss of function of the same genes is responsible for diverse types of the LQTS (ie, type 2, type 1, and type 7). The number of patients currently described is less than 100 worldwide but is already exceeded by the number of publications on this topic. This is a clear example of the current interest in these rare arrhythmia syndromes. References 1. Wilde AAM, Bezzina CR. Genetics in cardiac arrhythmias. Heart 2005; 91:1352. 2. Shimizu W. The long QT syndrome. Therapeutic implications of a genetic diagnosis. Cardiovasc Res 2005;67:347. 3. Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long QT syndrome: possible therapy implications. Circulation [in press]. 4. Wilde AAM, Antzelevitch Ch, Borggrefe M, et al, for the study group on the molecular basis of arrhythmias of the European Society of Cardiology. Diagnostic criteria for the Brugada syndrome. A Consensus Report. Eur J Heart 2002;23:1648. 5. Meregalli PG, Wilde AAM, Tan HL. Pathophysiology of Brugada syndrome: repolarization, depolarization disorder or more. Cardiovasc Res 2005;67:367. 6. Antzelevitch C, Hiraoka M, Corrado D, Wilde AAM, Eckardt L. Diagnostic and genetic aspects of the Brugada and other inherited arrhythmias syndromes. J Electrocardiol 2007;40:S11. 7. Giustetto C, Di F, Monte C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006;27:2440.