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ASSOCIATE EDITOR: PENG-SHENG CHEN
Peng-Sheng Chen, MD From the Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center and David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Heart Rhythm Society Meeting The HRS Meeting was held in San Francisco, California, in May 2004. The meeting was well attended. The hot issue in basic science is the relation between intracellular calcium (Cai) dynamics and the mechanisms of cardiac arrhythmia. Rajawat et al (Heart Rhythm 2004;S5) developed a transgenic mouse of Andersen syndrome by overexpressing a mutant gene that encodes slow rectifying K channel (Kir2.1). The mouse developed bidirectional ventricular tachycardia, suggesting abnormalities of Cai dynamics. Tian et al (Heart Rhythm 2004;S5) developed a transgenic mouse with selective cardiac expression of a mutated sodium channel gene (SCN5A, N1325S). There was arrhythmia and up-regulated cardiac ryanodine receptor (RyR2) and downregulated NaCaX in this model. The authors concluded that arrhythmogenic effects of gain of function mutation contribute to Cai imbalance, which in turn triggers lethal arrhythmias. These two studies are interesting because the mutations are in the K channel and in the Na channel, but the arrhythmogenesis is related to abnormal Cai dynamics. Miyoshi et al (Heart Rhythm 2004;S190) performed a computer simulation study of Brugada syndrome. Their results showed that the dispersion of ICaL density in the right ventricular epicardium can simulate the ECG changes associated with Brugada syndrome. The authors suggest that it is possible to develop Brugada syndrome without SCN5A mutation. This third study further highlights the possible importance of calcium dynamics in arrhythmogenesis. In addition to these mouse models and simulation studies, several invited speakers summarized the importance of Cai dynamics in cardiac arrhythmogenesis. For example, rapid heart rate can lead to Cai accumulation, which in turn might result in spontaneous (voltage-independent) calcium release and trigger ventricular arrhythmia. Others showed significant heterogeneity in the transmural distribution of calcium handling proteins. These changes may contribute to the electrical heterogeneity of the ventricles.
Calstabin2 and cardiac arrhythmia The relation between Cai dynamics and cardiac arrhythmia is further supported by a study by Wehrens et al (Science Address correspondence: Dr. Peng-Sheng-Chen, Room 5342, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail address: [email protected].
2004;304:292). The study focused on the RyR2 receptor, which is required for Ca release from the sarcoplasmic reticulum during systole. Binding of calstabin2 to RyR2 helps maintain the channel in a closed state to prevent the leakage of Ca into the cytoplasm during diastole. In heart failure and catecholaminergic polymorphic ventricular tachycardia, depletion of calstabin2 results in “leaky” RyR2 channels during diastole. Diastolic Ca release may induce delayed afterdepolarizations and arrhythmia. The authors used a mouse model with heterozygous abnormality of the calstabin2 gene (calstabin2⫹/⫺). When given epinephrine during exercise, these mice develop ventricular arrhythmia. JTV519, a drug that reduces diastolic Ca leak, prevents cardiac arrhythmia in these mice. The authors suggested that enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias. An additional implication of this study is that the arrhythmogenic mechanism in this model is related to diastolic Ca leak. These results do not predict antiarrhythmic efficacy of calcium channel blockers, which act by blocking systolic Ca entry.
COMPANION trial Bristow et al (N Engl J Med 2004;350:2140) reported the results of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial. The study was conducted at 128 US centers. The authors tested the hypothesis that prophylactic cardiac resynchronization therapy (CRT) in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays. They randomized a total of 1,520 patients who had advanced heart failure and a QRS interval of at least 120 ms. The primary composite endpoint was the time to death from, or hospitalization for, any cause. Results showed that, compared with optimal pharmacologic therapy alone, CRT with a pacemaker decreased the risk of the primary endpoint as did CRT with a pacemaker-defibrillator. The authors concluded that in patients with advanced heart failure and a prolonged QRS interval, CRT decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.
1547-5271/$ -see front matter © 2004 Heart Rhythm Society. All rights reserved. S1547-5271(04)00304-2
Heart Rhythm (2004) 3, 369 –370
370
DEFINITE trial Kadish et al (N Engl J Med 2004;350:2151) reported the results of the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial. Patients with nonischemic dilated cardiomyopathy (NIDCM) are at substantial risk for sudden death from cardiac causes. However, the value of prophylactic implantation of an implantable cardioverter-defibrillator (ICD) to prevent sudden death in such patients is unknown. The authors enrolled 458 patients with NIDCM, a left ventricular ejection fraction ⬍0.36, and premature ventricular complexes or nonsustained ventricular tachycardia. A total of 229 patients were randomly assigned to receive standard medical therapy and 229 to receive standard medical therapy plus a single-chamber ICD. After an average of 29 months of follow-up, 68 deaths occurred. Among them, 28 were in the ICD group, compared with 40 in the standard-therapy group (P ⫽ 0.08). There were 17 sudden deaths from arrhythmia: 3 in the ICD group, compared with 14 in the standard-therapy group (P ⫽ 0.006). The authors concluded that in patients with severe NIDCM, implantation of an ICD significantly reduced the risk of sudden death from arrhythmia and was associated with a nonsignificant reduction in the risk of death from any cause.
Left cardiac sympathetic denervation to reduce risk of arrhythmia Schwartz et al (J Cardiovasc Electrophysiol 1992;3:2) previously reported that left cardiac sympathetic denervation (LCSD) can reduce sudden death after first myocardial infarction. The same procedure has been applied to manage long QT syndrome (LQTS) patients who continue to have cardiac events despite beta-blocker therapy. Schwartz et al (Circulation 2004;109:1826) assessed the long-term efficacy of LCSD, which involves ablation of the lower half of the left stellate ganglion, together with the thoracic ganglia T2 to T4. The authors proposed that this procedure provides adequate cardiac denervation with no or minimal Horner’s syndrome because most of the sympathetic fibers directed to the ocular region usually cross the upper portion of the left stellate ganglion and thus are spared. The authors identified
Heart Rhythm, Vol 1, No 3, September 2004 147 LQTS patients who underwent LCSD for symptomatic LQTS. Among them, 48% had a cardiac arrest and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first cardiac event and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. The mean yearly number of cardiac events per patient dropped by 91% (P ⬍ 0.001). In 5 patients with preoperative ICD and multiple discharges, the post-LCSD count of shocks decreased by 95%. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. The authors concluded that LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients compared with preLCSD events.
Tumor necrosis factor-alpha and HERG K channel Wang et al (J Biol Chem 2004;279:13289) performed a study to determine the relationship between tumor necrosis factor-alpha (TNF-␣) and K channel function. Congestive heart failure (CHF) is associated with susceptibility to lethal arrhythmias and typically increases levels of TNF-␣ and its receptor, TNFR1. CHF down-regulates rapid delayed rectifier K current (IKr), delays cardiac repolarization, and prolongs action potential duration (APD). The authors studied the effects of TNF-␣ on cloned HERG K channel (human ether-a-go-go-related gene) in HEK293 cells and native IKr in canine cardiomyocytes with whole-cell patch clamp techniques. TNF-␣ consistently and reversibly decreased HERG current. Effects of TNF-␣ were concentration dependent, increased with longer incubation period, and occurred at clinically relevant concentrations. TNF-␣ had similar inhibitory effects on IKr and markedly prolonged APD in canine cardiomyocytes. TNF-␣ caused robust increases in intracellular reactive oxygen species in both HEK293 cells and canine ventricular myocytes. The authors concluded that the TNF-␣/TNFR1 system impairs HERG/IKr function mainly by stimulating reactive oxygen species and not by altering HERG expression. The effect may contribute to APD prolongation by TNF-␣ and may be a novel mechanism for electrophysiologic abnormalities and sudden death in CHF.
ASSOCIATE EDITOR: PENG-SHENG CHEN
Peng-Sheng Chen, MD From the Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center and David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Heart Rhythm Society Meeting The HRS Meeting was held in San Francisco, California, in May 2004. The meeting was well attended. The hot issue in basic science is the relation between intracellular calcium (Cai) dynamics and the mechanisms of cardiac arrhythmia. Rajawat et al (Heart Rhythm 2004;S5) developed a transgenic mouse of Andersen syndrome by overexpressing a mutant gene that encodes slow rectifying K channel (Kir2.1). The mouse developed bidirectional ventricular tachycardia, suggesting abnormalities of Cai dynamics. Tian et al (Heart Rhythm 2004;S5) developed a transgenic mouse with selective cardiac expression of a mutated sodium channel gene (SCN5A, N1325S). There was arrhythmia and up-regulated cardiac ryanodine receptor (RyR2) and downregulated NaCaX in this model. The authors concluded that arrhythmogenic effects of gain of function mutation contribute to Cai imbalance, which in turn triggers lethal arrhythmias. These two studies are interesting because the mutations are in the K channel and in the Na channel, but the arrhythmogenesis is related to abnormal Cai dynamics. Miyoshi et al (Heart Rhythm 2004;S190) performed a computer simulation study of Brugada syndrome. Their results showed that the dispersion of ICaL density in the right ventricular epicardium can simulate the ECG changes associated with Brugada syndrome. The authors suggest that it is possible to develop Brugada syndrome without SCN5A mutation. This third study further highlights the possible importance of calcium dynamics in arrhythmogenesis. In addition to these mouse models and simulation studies, several invited speakers summarized the importance of Cai dynamics in cardiac arrhythmogenesis. For example, rapid heart rate can lead to Cai accumulation, which in turn might result in spontaneous (voltage-independent) calcium release and trigger ventricular arrhythmia. Others showed significant heterogeneity in the transmural distribution of calcium handling proteins. These changes may contribute to the electrical heterogeneity of the ventricles.
Calstabin2 and cardiac arrhythmia The relation between Cai dynamics and cardiac arrhythmia is further supported by a study by Wehrens et al (Science Address correspondence: Dr. Peng-Sheng-Chen, Room 5342, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail address: [email protected].
2004;304:292). The study focused on the RyR2 receptor, which is required for Ca release from the sarcoplasmic reticulum during systole. Binding of calstabin2 to RyR2 helps maintain the channel in a closed state to prevent the leakage of Ca into the cytoplasm during diastole. In heart failure and catecholaminergic polymorphic ventricular tachycardia, depletion of calstabin2 results in “leaky” RyR2 channels during diastole. Diastolic Ca release may induce delayed afterdepolarizations and arrhythmia. The authors used a mouse model with heterozygous abnormality of the calstabin2 gene (calstabin2⫹/⫺). When given epinephrine during exercise, these mice develop ventricular arrhythmia. JTV519, a drug that reduces diastolic Ca leak, prevents cardiac arrhythmia in these mice. The authors suggested that enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias. An additional implication of this study is that the arrhythmogenic mechanism in this model is related to diastolic Ca leak. These results do not predict antiarrhythmic efficacy of calcium channel blockers, which act by blocking systolic Ca entry.
COMPANION trial Bristow et al (N Engl J Med 2004;350:2140) reported the results of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial. The study was conducted at 128 US centers. The authors tested the hypothesis that prophylactic cardiac resynchronization therapy (CRT) in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays. They randomized a total of 1,520 patients who had advanced heart failure and a QRS interval of at least 120 ms. The primary composite endpoint was the time to death from, or hospitalization for, any cause. Results showed that, compared with optimal pharmacologic therapy alone, CRT with a pacemaker decreased the risk of the primary endpoint as did CRT with a pacemaker-defibrillator. The authors concluded that in patients with advanced heart failure and a prolonged QRS interval, CRT decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.
1547-5271/$ -see front matter © 2004 Heart Rhythm Society. All rights reserved. S1547-5271(04)00304-2
Heart Rhythm (2004) 3, 369 –370
370
DEFINITE trial Kadish et al (N Engl J Med 2004;350:2151) reported the results of the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial. Patients with nonischemic dilated cardiomyopathy (NIDCM) are at substantial risk for sudden death from cardiac causes. However, the value of prophylactic implantation of an implantable cardioverter-defibrillator (ICD) to prevent sudden death in such patients is unknown. The authors enrolled 458 patients with NIDCM, a left ventricular ejection fraction ⬍0.36, and premature ventricular complexes or nonsustained ventricular tachycardia. A total of 229 patients were randomly assigned to receive standard medical therapy and 229 to receive standard medical therapy plus a single-chamber ICD. After an average of 29 months of follow-up, 68 deaths occurred. Among them, 28 were in the ICD group, compared with 40 in the standard-therapy group (P ⫽ 0.08). There were 17 sudden deaths from arrhythmia: 3 in the ICD group, compared with 14 in the standard-therapy group (P ⫽ 0.006). The authors concluded that in patients with severe NIDCM, implantation of an ICD significantly reduced the risk of sudden death from arrhythmia and was associated with a nonsignificant reduction in the risk of death from any cause.
Left cardiac sympathetic denervation to reduce risk of arrhythmia Schwartz et al (J Cardiovasc Electrophysiol 1992;3:2) previously reported that left cardiac sympathetic denervation (LCSD) can reduce sudden death after first myocardial infarction. The same procedure has been applied to manage long QT syndrome (LQTS) patients who continue to have cardiac events despite beta-blocker therapy. Schwartz et al (Circulation 2004;109:1826) assessed the long-term efficacy of LCSD, which involves ablation of the lower half of the left stellate ganglion, together with the thoracic ganglia T2 to T4. The authors proposed that this procedure provides adequate cardiac denervation with no or minimal Horner’s syndrome because most of the sympathetic fibers directed to the ocular region usually cross the upper portion of the left stellate ganglion and thus are spared. The authors identified
Heart Rhythm, Vol 1, No 3, September 2004 147 LQTS patients who underwent LCSD for symptomatic LQTS. Among them, 48% had a cardiac arrest and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first cardiac event and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. The mean yearly number of cardiac events per patient dropped by 91% (P ⬍ 0.001). In 5 patients with preoperative ICD and multiple discharges, the post-LCSD count of shocks decreased by 95%. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. The authors concluded that LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients compared with preLCSD events.
Tumor necrosis factor-alpha and HERG K channel Wang et al (J Biol Chem 2004;279:13289) performed a study to determine the relationship between tumor necrosis factor-alpha (TNF-␣) and K channel function. Congestive heart failure (CHF) is associated with susceptibility to lethal arrhythmias and typically increases levels of TNF-␣ and its receptor, TNFR1. CHF down-regulates rapid delayed rectifier K current (IKr), delays cardiac repolarization, and prolongs action potential duration (APD). The authors studied the effects of TNF-␣ on cloned HERG K channel (human ether-a-go-go-related gene) in HEK293 cells and native IKr in canine cardiomyocytes with whole-cell patch clamp techniques. TNF-␣ consistently and reversibly decreased HERG current. Effects of TNF-␣ were concentration dependent, increased with longer incubation period, and occurred at clinically relevant concentrations. TNF-␣ had similar inhibitory effects on IKr and markedly prolonged APD in canine cardiomyocytes. TNF-␣ caused robust increases in intracellular reactive oxygen species in both HEK293 cells and canine ventricular myocytes. The authors concluded that the TNF-␣/TNFR1 system impairs HERG/IKr function mainly by stimulating reactive oxygen species and not by altering HERG expression. The effect may contribute to APD prolongation by TNF-␣ and may be a novel mechanism for electrophysiologic abnormalities and sudden death in CHF.