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Idiopathic VF and short repolarization: Intriguing new concept
EDITORIAL COMMENTARY
Idiopathic VF and short repolarization: Intriguing new concept Wojciech Zareba, MD, PhD From the Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, NY. The growing list of inherited arrhythmia disorders includes long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. Hopefully fewer and fewer cases will be called idiopathic ventricular fibrillation (VF) without a recognized cause. Short QT syndrome is a recently recognized arrhythmia disorder manifested by an unusually short QTc, in the order of 300 milliseconds, and propensity to sudden cardiac death.1 Interestingly, this rare genetic disorder is caused by a mutation of the HERG gene, the same gene that is involved in the pathogenesis of long QT syndrome type 2.2 We already learned that different mutations of the sodium channel gene (SCN5A) might cause LQT3, Brugada syndrome, progressive conduction disorder, and atrial fibrillation. Recent data on the HERG mutations causing prolongation or shortening indicate complexity of the gene and ion channel function and its regulation. In this issue of the journal, Viskin et al3 described a study evaluating ECGs of 28 patients with idiopathic VF in order to determine whether such patients present with a shorter QT than healthy controls. The comparison group consisted of 270 age- and gender-matched subjects. The authors found that QTc of idiopathic VF patients was on average shorter than that of controls (371 ⫾ 22 vs. 385 ⫾ 19ms; P ⫽ .034). This difference, although statistically significant, was small - 14 ms on average. Such a small difference raises the question whether this is a real finding or an accidental observation related to unbiased, but still selected ECGs obtained in different conditions and at different heart rates. The comparison group is 10 times larger than the VF group, which could favorably influence the statistical significance of the tested difference. It is worth emphasizing that idiopathic VF patients described by Viskin et al3 had a much longer QTc than cases of genetically confirmed short QT syndrome.1 Viskin’s finding that males with idiopathic VF are more likely to present with shorter QTc than females, when compared to respective controls, raises a possibility that heart rate might affect this relationship. Men are known to have a lower heart rate and shorter QTc than females.4,5 Address for correspondence: Wojciech Zareba, MD, PhD, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center; Rochester, NY 14642-8653. Tel: 585-275-5391; Fax: 585-2735283. E-mail address: [email protected].
Lack of statistically significant differences in QTc between females with idiopathic VF versus controls further raises the question whether the suggested association is not purely due to heart rate effect. One could expect that if short QT were a typical feature of patients with idiopathic VF, at least a trend in this direction would be expected in females whereas QTc is even higher in VF females than controls. It has to be also recognized that QT shows substantial variability and a single measurement might not reflect subject-specific values reflecting the duration of repolarization. QT duration is influenced by the autonomic nervous system, circulating catecholamines, and other circulating substances including hormones, all of them affecting heart rate as well. Changes in heart rate might cause a subject-specific response of repolarization duration, not accounted for by RR intervals measured in short ECG strips. As recently described by Fujiki et al,6 idiopathic VF patients have less steep QT-RR slopes than controls, this phenomenon favoring a shorter QT at a low heart rate. Despite some limitations of the study by Viskin,3 the authors should be commended on undertaking the task of QT analysis in idiopathic VF patients. It is possible that idiopathic VF patients have a more homogeneous repolarization of myocardium leading to facilitated spread of initiating ventricular beats. Normal ventricular myocardium shows a degree of transmural heterogeneity that probably serves as a protective antiarrhythmic mechanism. Increased heterogeneity of repolarization could facilitate reentry phenomena leading to ventricular tachyarrhythmias. This more homogeneous myocardium (similar action potential duration in endocardial, midmyocardial, and epicardial zones) could be manifested on the ECG as a shorter QTc. Unfortunately, the ECG is not able to provide direct quantification of the magnitude of repolarization heterogeneity. Antzelevitch and coworkers7 favor using T peak – T end interval as a measure of heterogeneous repolarization. Shimizu et al8 found increased T peak –T end in LQT1 patients undergoing epinephrine challenge. It is possible that a shorter T peak – T end could be observed in idiopathic VF patients but so far there are no data on this association including the paper by Viskin et al.3 Idiopathic VF is awaiting further advancements in the genetics of cardiac arrhythmias and in the understanding of kinetics of ion channels. Since myocardial ischemia might
1547-5271/$ -see front matter © 2004 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2004.09.007
Zareba
Editorial Commentary
contribute to a shortening of repolarization duration and facilitation of VF in acute myocardial infarction, it is plausible that genetically-driven repolarization shortening could underlie idiopathic VF.
593
4. 5.
References 1. Gaita F, Giustetto C, Bianchi F, Wolpert C, Schimpf R, Riccardi R, Grossi S, Richiardi E, Borggrefe M. Short QT Syndrome: a familial cause of sudden death. Circulation 2003;108:965–970. 2. Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004;109:30 –35. 3. Viskin S, Zeltser D, Ish-Shalom M, Katz A, Glikson M, Justo D, Tekes-Manova D, Belhassen B. Is idiopathic ventricular fibrillation a
6.
7.
8.
short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004;1:587–591. Moss AJ, Robinson J. Clinical features of the idiopathic long QT syndrome. Circulation 1992;85:I140 –I144. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, Davignon A. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992;8:690 – 695. Fujiki A, Sugao M, Nishida K, Sakabe M, Tsuneda T, Mizumaki K, Inoue H. Repolarization abnormality in idiopathic ventricular fibrillation: assessment using 24-hour QT-RR and QaT-RR relationships. J Cardiovasc Electrophysiol 2004;15:59 – 63. Antzelevitch C. Molecular genetics of arrhythmias and cardiovascular conditions associated with arrhythmias. J Cardiovasc Electrophysiol 2003;14:1259 –1272. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, Suyama K, Aihara N, Kamakura S, Sunagawa K, Echigo S, Nakamura K, Ohe T, Towbin JA, Napolitano C, Priori SG. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003;41:633– 642.
Idiopathic VF and short repolarization: Intriguing new concept Wojciech Zareba, MD, PhD From the Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, NY. The growing list of inherited arrhythmia disorders includes long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. Hopefully fewer and fewer cases will be called idiopathic ventricular fibrillation (VF) without a recognized cause. Short QT syndrome is a recently recognized arrhythmia disorder manifested by an unusually short QTc, in the order of 300 milliseconds, and propensity to sudden cardiac death.1 Interestingly, this rare genetic disorder is caused by a mutation of the HERG gene, the same gene that is involved in the pathogenesis of long QT syndrome type 2.2 We already learned that different mutations of the sodium channel gene (SCN5A) might cause LQT3, Brugada syndrome, progressive conduction disorder, and atrial fibrillation. Recent data on the HERG mutations causing prolongation or shortening indicate complexity of the gene and ion channel function and its regulation. In this issue of the journal, Viskin et al3 described a study evaluating ECGs of 28 patients with idiopathic VF in order to determine whether such patients present with a shorter QT than healthy controls. The comparison group consisted of 270 age- and gender-matched subjects. The authors found that QTc of idiopathic VF patients was on average shorter than that of controls (371 ⫾ 22 vs. 385 ⫾ 19ms; P ⫽ .034). This difference, although statistically significant, was small - 14 ms on average. Such a small difference raises the question whether this is a real finding or an accidental observation related to unbiased, but still selected ECGs obtained in different conditions and at different heart rates. The comparison group is 10 times larger than the VF group, which could favorably influence the statistical significance of the tested difference. It is worth emphasizing that idiopathic VF patients described by Viskin et al3 had a much longer QTc than cases of genetically confirmed short QT syndrome.1 Viskin’s finding that males with idiopathic VF are more likely to present with shorter QTc than females, when compared to respective controls, raises a possibility that heart rate might affect this relationship. Men are known to have a lower heart rate and shorter QTc than females.4,5 Address for correspondence: Wojciech Zareba, MD, PhD, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center; Rochester, NY 14642-8653. Tel: 585-275-5391; Fax: 585-2735283. E-mail address: [email protected].
Lack of statistically significant differences in QTc between females with idiopathic VF versus controls further raises the question whether the suggested association is not purely due to heart rate effect. One could expect that if short QT were a typical feature of patients with idiopathic VF, at least a trend in this direction would be expected in females whereas QTc is even higher in VF females than controls. It has to be also recognized that QT shows substantial variability and a single measurement might not reflect subject-specific values reflecting the duration of repolarization. QT duration is influenced by the autonomic nervous system, circulating catecholamines, and other circulating substances including hormones, all of them affecting heart rate as well. Changes in heart rate might cause a subject-specific response of repolarization duration, not accounted for by RR intervals measured in short ECG strips. As recently described by Fujiki et al,6 idiopathic VF patients have less steep QT-RR slopes than controls, this phenomenon favoring a shorter QT at a low heart rate. Despite some limitations of the study by Viskin,3 the authors should be commended on undertaking the task of QT analysis in idiopathic VF patients. It is possible that idiopathic VF patients have a more homogeneous repolarization of myocardium leading to facilitated spread of initiating ventricular beats. Normal ventricular myocardium shows a degree of transmural heterogeneity that probably serves as a protective antiarrhythmic mechanism. Increased heterogeneity of repolarization could facilitate reentry phenomena leading to ventricular tachyarrhythmias. This more homogeneous myocardium (similar action potential duration in endocardial, midmyocardial, and epicardial zones) could be manifested on the ECG as a shorter QTc. Unfortunately, the ECG is not able to provide direct quantification of the magnitude of repolarization heterogeneity. Antzelevitch and coworkers7 favor using T peak – T end interval as a measure of heterogeneous repolarization. Shimizu et al8 found increased T peak –T end in LQT1 patients undergoing epinephrine challenge. It is possible that a shorter T peak – T end could be observed in idiopathic VF patients but so far there are no data on this association including the paper by Viskin et al.3 Idiopathic VF is awaiting further advancements in the genetics of cardiac arrhythmias and in the understanding of kinetics of ion channels. Since myocardial ischemia might
1547-5271/$ -see front matter © 2004 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2004.09.007
Zareba
Editorial Commentary
contribute to a shortening of repolarization duration and facilitation of VF in acute myocardial infarction, it is plausible that genetically-driven repolarization shortening could underlie idiopathic VF.
593
4. 5.
References 1. Gaita F, Giustetto C, Bianchi F, Wolpert C, Schimpf R, Riccardi R, Grossi S, Richiardi E, Borggrefe M. Short QT Syndrome: a familial cause of sudden death. Circulation 2003;108:965–970. 2. Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004;109:30 –35. 3. Viskin S, Zeltser D, Ish-Shalom M, Katz A, Glikson M, Justo D, Tekes-Manova D, Belhassen B. Is idiopathic ventricular fibrillation a
6.
7.
8.
short QT syndrome? Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls. Heart Rhythm 2004;1:587–591. Moss AJ, Robinson J. Clinical features of the idiopathic long QT syndrome. Circulation 1992;85:I140 –I144. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, Davignon A. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992;8:690 – 695. Fujiki A, Sugao M, Nishida K, Sakabe M, Tsuneda T, Mizumaki K, Inoue H. Repolarization abnormality in idiopathic ventricular fibrillation: assessment using 24-hour QT-RR and QaT-RR relationships. J Cardiovasc Electrophysiol 2004;15:59 – 63. Antzelevitch C. Molecular genetics of arrhythmias and cardiovascular conditions associated with arrhythmias. J Cardiovasc Electrophysiol 2003;14:1259 –1272. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, Suyama K, Aihara N, Kamakura S, Sunagawa K, Echigo S, Nakamura K, Ohe T, Towbin JA, Napolitano C, Priori SG. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003;41:633– 642.