EDITORIAL
Familial primary arrhythmia syndromes Nice to know or need to know n recent years, studies emerge almost weekly reporting new molecular I genetic findings related to cardiovascular electrophysiology syndromes. Without doubt, the identification ofcausally involved genes has significantly enhanced our knowledge in basic and clinical electrophysiology. But it has also increased the complexity of arrhythmia management, which merits the question whether, for the general cardiologist, all this is 'nice to know or need to know'. An attempt is made to address this and related issues in this editorial.
An update Arrhythmia syndromes are subdivided into 'primary electrical disease', i.e. arrhythmias in the absence of structural heart disease (as determined by invasive and non-invasive routine diagnostic methods), and 'secondary arrhythmia syndromes', i.e. in the presence of structural heart disease. The latter group includes familial cardiomyopathies, i.e. hypertrophic or dilated cardiomyopathy, and arrhythmogenic right ventricle cardiomyopathy, which are relatively common diseases. The former diagnosis implies that structural heart disease has been excluded (as far as possible) and that the arrhythmogenic substrate should be looked for in the excitable and conducting properties of the heart. Indeed, aberrations in genes encoding ion channels underlie the congenital long-QT-interval syndrome (LQTS) and Brugada's syndrome.' Also the most recent genetically unravelled syndromes relate to dysfunctioning ion channels (Andersen's syndrome)2 or receptors implied in calcium homeostasis (exercise-induced polymorphic
WI/VF) 3,4 At present, the LQTS is subdivided into more than six subtypes (table 1). Five causally related genes have been identified and they all encode ion channels (subunits). The underlying gene defect impacts on several clinical aspects including symptom-related triggers, electrocardiographic appearance (ST-segment morphology, heart rate, etc), age of onset of symptoms and prognosis.5 As such, the underlying gene defect is relevant for treatment, both in terms of lifestyle advice as well as in the choice for pharmacological (which drugs and from what age onward) or nonpharmacological treatment. Hence, attempts to identify the underlying gene defect are strongly recommended. In approximately 30% of families, no gene defect is identified. In part this is caused by the existence of as yet unknown causally related genes. The more commonly encountered acquired LQTS has intrigued researchers from the beginning of this genetic era and the straightforward hypothesis that LQT genes were causally related has immediately been challenged. Indeed, in individual patients mutations or polymorphisms in LQT genes have been identified,6 but in the vast majority of patients with an abnormal QT-prolonging drug response, i.e. the most typical form of acquired LQTS, no genetic aberrations have been found as yet. Another ion channel defect associated with QT prolongation has recently been identified (table 1). It concerns I,,, the potassium channel acting as the main regulator ofthe resting membrane potential. Mutations Netherlands Heart Journal, Volume 10, Number 5, May 2002
225
Editorial
encoding gene KCNJ2 underlie Andersen's syndrome, a clinical entity with mild QT prolongation and related arrhythmias, and facial and extremity dysmorphology.2 The disease is probably very rare. Brugada's syndrome is increasingly identified as an important cause of (aborted) sudden death in patients without structurl heart disease. Typical in the
ECG appearance (i.e. right precordial ST-segment elevation and distinct conduction disturbances) are combined with a significant risk of sudden death due to malignant tachyarrhythmias. Prior syncope may occur and should be regarded as a red flag in the presence of a typical ECG. Genetic heterogeneity is also present with as yet only one causaly related gene identified (table 1). This gene (SCN5A) encodes the cardiac sodium channel and is also involved in one of the subtypes of LQTS (type 3) and m inherited forms ofisolated cardiac conduction disease.8 The impact on channel function of a specific mutation determines the clinical phenotype. Patients with overlap syndromes are increasingly described, for example patients with right precordial ST-segment elevation and QT-interval prolongation or progressive conduction disease. Isolated conduction !5 disorders have also been linked to unknown genes on chromosome 16 and 19 (table 1).910 Familial exercise-induced tachyarrhythmias, often leading to sudden .gga death at young age, have recently been inked to genetic aberrations in genes . encoding proteins which form the ryanodine-receptor complex, i.e. hRyR2 encoding the cardiac ryanodine receptor in the membrane separating the sarcoplasmic reticulum from the cytoplasma in cardiac cells and CASQ2 encodng the calsequestrn 2 protei, a related calcium bidig protei (table ...i.;.. ; ).34 Both proteins are imprtant determinants ofcalcium homeostasis of myocardial cells and, apparently, malfunction leads to potentialy lethal m arrhythmias upon catecholamine exposure. During exercise, stress and/or emotion, i.e. condtions with enhanced adrenergic tone, both supraventricular and ventricular arrhythmias may appear. The latter appear to be polymorphic but on a closer look display a typical bidirectional pattern. They may deteriorate into ventricular fibrillation and give rise to sudden *; cardiac death, which may actually be the first symptom. This is not exceptional in affected families. A genetic diagnosis is thus of importance because prophylactic treatment can be installed in carriers of the gene defect and others can be reassured. The role of CASQ2 is as yet not .t , . completely clear, because it has only been described as an autosomal ':';!S. ..'. recessive trait n a large Bedouin family.4 The very common arrhythmia atrial fibrilation (AF) occasionally displays a clear familial patter. In particular, idiopathic AF in young individuals may be based on a causal genetic factor. In 1997 lnkage to lOq (the long arm of chromosome 1 0) was reported," but as yet the causal gene awaits identification. x
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may have a genetic component. Indeed, in population-based studies as well as in cohort studies a family history of sudden cardiac death (SCD) has been shown to be an independent predictor for subsequent SCD.'2"' An active search for underlying genetic aberrations, including common polymorphisms in candidate genes, is ongoing.'4
The importance ofthese genetic findings is not irrelevant for the patients or families suffering from one ofthese rare diseases. These affected patients ','-iiht-
Familial primary arrhythmia syndromes Nice to know or need to know n recent years, studies emerge almost weekly reporting new molecular I genetic findings related to cardiovascular electrophysiology syndromes. Without doubt, the identification ofcausally involved genes has significantly enhanced our knowledge in basic and clinical electrophysiology. But it has also increased the complexity of arrhythmia management, which merits the question whether, for the general cardiologist, all this is 'nice to know or need to know'. An attempt is made to address this and related issues in this editorial.
An update Arrhythmia syndromes are subdivided into 'primary electrical disease', i.e. arrhythmias in the absence of structural heart disease (as determined by invasive and non-invasive routine diagnostic methods), and 'secondary arrhythmia syndromes', i.e. in the presence of structural heart disease. The latter group includes familial cardiomyopathies, i.e. hypertrophic or dilated cardiomyopathy, and arrhythmogenic right ventricle cardiomyopathy, which are relatively common diseases. The former diagnosis implies that structural heart disease has been excluded (as far as possible) and that the arrhythmogenic substrate should be looked for in the excitable and conducting properties of the heart. Indeed, aberrations in genes encoding ion channels underlie the congenital long-QT-interval syndrome (LQTS) and Brugada's syndrome.' Also the most recent genetically unravelled syndromes relate to dysfunctioning ion channels (Andersen's syndrome)2 or receptors implied in calcium homeostasis (exercise-induced polymorphic
WI/VF) 3,4 At present, the LQTS is subdivided into more than six subtypes (table 1). Five causally related genes have been identified and they all encode ion channels (subunits). The underlying gene defect impacts on several clinical aspects including symptom-related triggers, electrocardiographic appearance (ST-segment morphology, heart rate, etc), age of onset of symptoms and prognosis.5 As such, the underlying gene defect is relevant for treatment, both in terms of lifestyle advice as well as in the choice for pharmacological (which drugs and from what age onward) or nonpharmacological treatment. Hence, attempts to identify the underlying gene defect are strongly recommended. In approximately 30% of families, no gene defect is identified. In part this is caused by the existence of as yet unknown causally related genes. The more commonly encountered acquired LQTS has intrigued researchers from the beginning of this genetic era and the straightforward hypothesis that LQT genes were causally related has immediately been challenged. Indeed, in individual patients mutations or polymorphisms in LQT genes have been identified,6 but in the vast majority of patients with an abnormal QT-prolonging drug response, i.e. the most typical form of acquired LQTS, no genetic aberrations have been found as yet. Another ion channel defect associated with QT prolongation has recently been identified (table 1). It concerns I,,, the potassium channel acting as the main regulator ofthe resting membrane potential. Mutations Netherlands Heart Journal, Volume 10, Number 5, May 2002
225
Editorial
encoding gene KCNJ2 underlie Andersen's syndrome, a clinical entity with mild QT prolongation and related arrhythmias, and facial and extremity dysmorphology.2 The disease is probably very rare. Brugada's syndrome is increasingly identified as an important cause of (aborted) sudden death in patients without structurl heart disease. Typical in the
ECG appearance (i.e. right precordial ST-segment elevation and distinct conduction disturbances) are combined with a significant risk of sudden death due to malignant tachyarrhythmias. Prior syncope may occur and should be regarded as a red flag in the presence of a typical ECG. Genetic heterogeneity is also present with as yet only one causaly related gene identified (table 1). This gene (SCN5A) encodes the cardiac sodium channel and is also involved in one of the subtypes of LQTS (type 3) and m inherited forms ofisolated cardiac conduction disease.8 The impact on channel function of a specific mutation determines the clinical phenotype. Patients with overlap syndromes are increasingly described, for example patients with right precordial ST-segment elevation and QT-interval prolongation or progressive conduction disease. Isolated conduction !5 disorders have also been linked to unknown genes on chromosome 16 and 19 (table 1).910 Familial exercise-induced tachyarrhythmias, often leading to sudden .gga death at young age, have recently been inked to genetic aberrations in genes . encoding proteins which form the ryanodine-receptor complex, i.e. hRyR2 encoding the cardiac ryanodine receptor in the membrane separating the sarcoplasmic reticulum from the cytoplasma in cardiac cells and CASQ2 encodng the calsequestrn 2 protei, a related calcium bidig protei (table ...i.;.. ; ).34 Both proteins are imprtant determinants ofcalcium homeostasis of myocardial cells and, apparently, malfunction leads to potentialy lethal m arrhythmias upon catecholamine exposure. During exercise, stress and/or emotion, i.e. condtions with enhanced adrenergic tone, both supraventricular and ventricular arrhythmias may appear. The latter appear to be polymorphic but on a closer look display a typical bidirectional pattern. They may deteriorate into ventricular fibrillation and give rise to sudden *; cardiac death, which may actually be the first symptom. This is not exceptional in affected families. A genetic diagnosis is thus of importance because prophylactic treatment can be installed in carriers of the gene defect and others can be reassured. The role of CASQ2 is as yet not .t , . completely clear, because it has only been described as an autosomal ':';!S. ..'. recessive trait n a large Bedouin family.4 The very common arrhythmia atrial fibrilation (AF) occasionally displays a clear familial patter. In particular, idiopathic AF in young individuals may be based on a causal genetic factor. In 1997 lnkage to lOq (the long arm of chromosome 1 0) was reported," but as yet the causal gene awaits identification. x
..'.
,:.!','''
...~~~~~~~~Fnly
;C '' i I'
U
:aM ;;.M- g ^
....
.e::
:. .
'.
H:
z.~;4:
f,
;X ; : !; A
226
Li.
............in arrhythmis in th set.... of.act isc.hto,i.
may have a genetic component. Indeed, in population-based studies as well as in cohort studies a family history of sudden cardiac death (SCD) has been shown to be an independent predictor for subsequent SCD.'2"' An active search for underlying genetic aberrations, including common polymorphisms in candidate genes, is ongoing.'4
The importance ofthese genetic findings is not irrelevant for the patients or families suffering from one ofthese rare diseases. These affected patients ','-iiht-
