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O14-02 The mechanism underlying arrhythmogenesis of lysophosphatidylcholine during early phase of acute global ischemia in isolated perfused rabbit hearts
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Abstracts/International Journal of Cardiology 97 SuppL 2 (2004) S 1 ~ 7 5
0.53±0.22, 75±13.5, and 13±8.12, respectively. There was significant correlation between combined impaired heart rate response parameters and presence of stenosis in all coronary arteries except the left circm~flex. ChrI was positively correlated with HRR. Conclusion: The cllronotropic response and heart rate ~ecovery are valuable parameters in the detection of CAD. Patients with significant CAD, specifically involving the left anterior descending, right coronary artery and left main coronary artery have lower cllronolropic response and chronotropic index and lower heart rate recovery.
O14-02 THE M E C H A N I S M UNDERLYING ARRHYTHMOGENESIS OF LYSOPHOSPHATIDYLCHOLINE DURING EARLY PHASE OF ACUTE GLOBAL ISCHEMIA IN ISOLATED PERFUSED RABBIT HEARTS Jin~xion~ Wan~, Marc Antoine ~lllit, Yiqiang Zhang, Stanley Nattel, Zhiguo Wang. Research Center, Montreal Heart Institute, University of
Montreal, 5000 Belanger, Montreal, PQ H1T1CS, Canada Inlroduelion: Extracellular K+ accumulation ([K+] o ~') and action poten tial shortening (APD $) evoked by lysophosphatidylcholine (LPC) during acute myocardial ischemia is a major cause for the initial high incidence of an-hytlmrias. The mechailism underlying this an-hythmogenesis of LPC remains unclear and the documental results are controversial. We recently found that LPC markedly enhances the K + current expressed by HERG (human ether-a-go-go related gene) which encodes cardiac rapid delayed rectifier K + current (IK0, suggesting that increased IHER~/IKr by LPC would lead to increased K + efflux thereby [K+]o ~" and APD $. Hypothesis: IHERUIKrenhancement by LPC contributes to [K+]o J" and APD $ and the associated an-hytlmrias during acute myocardial ischemia. Inhibition of IHERUI~ and of LPC can prevent the ischemic electrical disturbances. Objective: To establish the role of IHERG/IKrin [K+]o J" and APD $ caused by accumulation of LPC and to decipher the underlying mechanisms. Methods and Results: Global myocardial ischemic model with Lan gendorff perfused rabbit hearts was used to determine the QTc interval and incidence of arrhytlmrias from ECG, and [K+]o J" was evaluated by measuring K + contents in the effluents. The effects of IHER@/II6blockade by dofetilide, KATpinhibition by glybenclamide, and cardiac slow delayed rectifier K + current (I~) suppression by chromanol 293B and HMR 1556 were investigated. In non ischemic hearts, perfusion with LPC~ontaining ~I~rode solution resulted in concentration dependant increases (17.2 ± 2.2%, 31.9 ± 3.4%, 66.0 ± 4.8% and 81.8 ± 5.6% for 1, 2, 3, and 4 pM, respectively; n 4; P< 0.001) in K + contents and shortening of QTc interval (5.6 ± 0.9%, 7.9 ± 1.2%, 14.0 ± 1.4% and 19.8 ±1.6%). Perfusion with LPC at 5 p~M for 5 rain evoked lethal cardiac fibrillation associated with significant increase in effluent K + contents (from 4.6 ± 0.8 to 11.4 ± 2.8 nkM). Pretreatment with dofetilide (20 nM) abolished the increase in effluent K + contents and the QTc shortening caused by LPC or global ischemia. Glybenclamide (10 p~M), 293B (50 p~M) and HMR (100 nM) failed to affect [K+]o J" and QTc shortening induced by either LPC or global ischemia. Moreover, pretreatment with dofetilide remarkably prevented the an-hythmias occuffing during global ischemia. Conclusion: IHERUI~ enhancement by LPC contributes to [K+]o J" and QTc shortening and the associated arrhytlmrias during early stage of acute myocardial ischemia in isolated perfused rabbit hearts.
O14-03 FUNCTIONAL AND CLINICAL CHARACTERIZATIONOF A MUTATION IN KCNJ2 ASSOCIATED W I T H ANDERSEN SYNDROME Jiuann Huey Lin 1, Yadavendia S. Rajawat 2, Chun Wei Lu 3, Henry Jerng4, Tapam G. Rami 2, Geoffrey Miiler 5, Hua Li 6, Ming Tal Lin 7, Paul J. Pfaffinger 4, Neff E. Bowles 6, Dhar S. Khoury 2, Jeffrey A. Towbin 1,6. 1Cardiovascular Sciences Program, Baylor College
of Medicine, Houston, USA; 2Department of Medicine (Cardiology), Baylor College of Medicine, Houston, USA; 3Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 4Division of Neuroscience, Baylor College of Medicine, Houston, USA; 5Department of Neurology, Texas Children's Hospital, Houston, USA; 6Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, USA; 7Department of Pediatrics (Cardiology), national Taiwan UniversitN Tuipei, Taiwan Baekground: Andersen syndrome is a rare inherited disorder, which is characterized by periodic paralysis, cardiac dysan-hytlmrias and dysmor pNc features. Mutations in KCNJ2, which encodes the inward ~ectifier potassium channel Kh2.1, have been reported to cause this disease. OB JECTIVE: This study sought to identify a mutation in the gene KCNJ2 in a family with Andersen Syndrome and to characterize the functional consequences of fflis mutation Design and Methods: We screened a family with Andersen syndrome for Mutations in KCNJ2, by direct DNA sequencing. The Xenopus oocyte expression system and whole cell patch~zlamp analysis to demonstrate the dominant negative effect of tNs mutant. Subsequently, Wansgenic (TG) mice were generated by insert Kit2.1 cDNA into ~ M HC expression vector and performed ECG recording and intracardiac electrophysiology studies (8 electrode 1.1 F catheters) on 26 TG and 9 nontransgenic mice. Results: A mismutation was identified in the three affected members of this family. The patch clamp analysis showed that the T75R mutant is nonfunctional and exerts a strong dominant negative effect when co expressed with wild type Kit2.1. The electrophysiology study showed. Mutant TG mice presented prolonged QTc interval compared to NTG mice (117ms vs. 105 ms, p < 0.05). Ventricular arrhytlmrias were observed in 5/19 mutant TG mice and 4/7 wild type TG mice. The Wild type TG mice also showed shorten VERP (18 ms vs. 39 ms; P: 0.00017). Conclusions: The T75R mutation is located in the cytoplasmic N terminal domain of Kit2.1, a region highly conserved between inward ~ectifier potassium channels. The dominant negative phenotype exhibited in vitro and dysan-ythemiaphenotype in vivo supports the observation that this disease is inherited as an autosomal dominant trait.
O14-04 ACCURATE EVALUATION OF LEFT VENTRICULAR SYSTOLIC FUNCTION DURING ATRIAL FIBRILLATIONBY AVERAGING THREE BEATS W I T H EQUAL PRECEDING AND PRE-PRECEDING INTERVALS Chun Li Wan~, Chi Tal Kuo, Lung An Hsu, Pao Hsien Chu, Kuo Hung Lin. First Division of Cardiovascular Department,
Chang-Gung Memorial Hospital, Linkou, Taiwan Introduetion: It has been demonstrated that the left ventricular (LV) systolic function positively correlated with the ratio of preceding (RR1) and pre precednig (RR2) intervals and the values at RR1/RR2 1 in the regression line were reasonable esthnates of the average values. We sought to determine whether the measured mean LV stroke volmne (SV) and ejection fraction (EF) of 3 beats with RR1 RR2 were accurate. Methods: In 65 patients with AF (42 men; age 64 ± 14 years), SV and EF were determined from simultaneous biplane views of LV using modified Sunpson's method for >20 cardiac cycles. The Bland~ltman analysis was applied to evaluate the agreement between the measured mean values of 3 beats with RR1 RR2 (defined as RR1/RR2:0.95 1.05) and the average values over all cardiac cycles.
Abstracts/International Journal of Cardiology 97 SuppL 2 (2004) S 1 ~ 7 5
0.53±0.22, 75±13.5, and 13±8.12, respectively. There was significant correlation between combined impaired heart rate response parameters and presence of stenosis in all coronary arteries except the left circm~flex. ChrI was positively correlated with HRR. Conclusion: The cllronotropic response and heart rate ~ecovery are valuable parameters in the detection of CAD. Patients with significant CAD, specifically involving the left anterior descending, right coronary artery and left main coronary artery have lower cllronolropic response and chronotropic index and lower heart rate recovery.
O14-02 THE M E C H A N I S M UNDERLYING ARRHYTHMOGENESIS OF LYSOPHOSPHATIDYLCHOLINE DURING EARLY PHASE OF ACUTE GLOBAL ISCHEMIA IN ISOLATED PERFUSED RABBIT HEARTS Jin~xion~ Wan~, Marc Antoine ~lllit, Yiqiang Zhang, Stanley Nattel, Zhiguo Wang. Research Center, Montreal Heart Institute, University of
Montreal, 5000 Belanger, Montreal, PQ H1T1CS, Canada Inlroduelion: Extracellular K+ accumulation ([K+] o ~') and action poten tial shortening (APD $) evoked by lysophosphatidylcholine (LPC) during acute myocardial ischemia is a major cause for the initial high incidence of an-hytlmrias. The mechailism underlying this an-hythmogenesis of LPC remains unclear and the documental results are controversial. We recently found that LPC markedly enhances the K + current expressed by HERG (human ether-a-go-go related gene) which encodes cardiac rapid delayed rectifier K + current (IK0, suggesting that increased IHER~/IKr by LPC would lead to increased K + efflux thereby [K+]o ~" and APD $. Hypothesis: IHERUIKrenhancement by LPC contributes to [K+]o J" and APD $ and the associated an-hytlmrias during acute myocardial ischemia. Inhibition of IHERUI~ and of LPC can prevent the ischemic electrical disturbances. Objective: To establish the role of IHERG/IKrin [K+]o J" and APD $ caused by accumulation of LPC and to decipher the underlying mechanisms. Methods and Results: Global myocardial ischemic model with Lan gendorff perfused rabbit hearts was used to determine the QTc interval and incidence of arrhytlmrias from ECG, and [K+]o J" was evaluated by measuring K + contents in the effluents. The effects of IHER@/II6blockade by dofetilide, KATpinhibition by glybenclamide, and cardiac slow delayed rectifier K + current (I~) suppression by chromanol 293B and HMR 1556 were investigated. In non ischemic hearts, perfusion with LPC~ontaining ~I~rode solution resulted in concentration dependant increases (17.2 ± 2.2%, 31.9 ± 3.4%, 66.0 ± 4.8% and 81.8 ± 5.6% for 1, 2, 3, and 4 pM, respectively; n 4; P< 0.001) in K + contents and shortening of QTc interval (5.6 ± 0.9%, 7.9 ± 1.2%, 14.0 ± 1.4% and 19.8 ±1.6%). Perfusion with LPC at 5 p~M for 5 rain evoked lethal cardiac fibrillation associated with significant increase in effluent K + contents (from 4.6 ± 0.8 to 11.4 ± 2.8 nkM). Pretreatment with dofetilide (20 nM) abolished the increase in effluent K + contents and the QTc shortening caused by LPC or global ischemia. Glybenclamide (10 p~M), 293B (50 p~M) and HMR (100 nM) failed to affect [K+]o J" and QTc shortening induced by either LPC or global ischemia. Moreover, pretreatment with dofetilide remarkably prevented the an-hythmias occuffing during global ischemia. Conclusion: IHERUI~ enhancement by LPC contributes to [K+]o J" and QTc shortening and the associated arrhytlmrias during early stage of acute myocardial ischemia in isolated perfused rabbit hearts.
O14-03 FUNCTIONAL AND CLINICAL CHARACTERIZATIONOF A MUTATION IN KCNJ2 ASSOCIATED W I T H ANDERSEN SYNDROME Jiuann Huey Lin 1, Yadavendia S. Rajawat 2, Chun Wei Lu 3, Henry Jerng4, Tapam G. Rami 2, Geoffrey Miiler 5, Hua Li 6, Ming Tal Lin 7, Paul J. Pfaffinger 4, Neff E. Bowles 6, Dhar S. Khoury 2, Jeffrey A. Towbin 1,6. 1Cardiovascular Sciences Program, Baylor College
of Medicine, Houston, USA; 2Department of Medicine (Cardiology), Baylor College of Medicine, Houston, USA; 3Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 4Division of Neuroscience, Baylor College of Medicine, Houston, USA; 5Department of Neurology, Texas Children's Hospital, Houston, USA; 6Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, USA; 7Department of Pediatrics (Cardiology), national Taiwan UniversitN Tuipei, Taiwan Baekground: Andersen syndrome is a rare inherited disorder, which is characterized by periodic paralysis, cardiac dysan-hytlmrias and dysmor pNc features. Mutations in KCNJ2, which encodes the inward ~ectifier potassium channel Kh2.1, have been reported to cause this disease. OB JECTIVE: This study sought to identify a mutation in the gene KCNJ2 in a family with Andersen Syndrome and to characterize the functional consequences of fflis mutation Design and Methods: We screened a family with Andersen syndrome for Mutations in KCNJ2, by direct DNA sequencing. The Xenopus oocyte expression system and whole cell patch~zlamp analysis to demonstrate the dominant negative effect of tNs mutant. Subsequently, Wansgenic (TG) mice were generated by insert Kit2.1 cDNA into ~ M HC expression vector and performed ECG recording and intracardiac electrophysiology studies (8 electrode 1.1 F catheters) on 26 TG and 9 nontransgenic mice. Results: A mismutation was identified in the three affected members of this family. The patch clamp analysis showed that the T75R mutant is nonfunctional and exerts a strong dominant negative effect when co expressed with wild type Kit2.1. The electrophysiology study showed. Mutant TG mice presented prolonged QTc interval compared to NTG mice (117ms vs. 105 ms, p < 0.05). Ventricular arrhytlmrias were observed in 5/19 mutant TG mice and 4/7 wild type TG mice. The Wild type TG mice also showed shorten VERP (18 ms vs. 39 ms; P: 0.00017). Conclusions: The T75R mutation is located in the cytoplasmic N terminal domain of Kit2.1, a region highly conserved between inward ~ectifier potassium channels. The dominant negative phenotype exhibited in vitro and dysan-ythemiaphenotype in vivo supports the observation that this disease is inherited as an autosomal dominant trait.
O14-04 ACCURATE EVALUATION OF LEFT VENTRICULAR SYSTOLIC FUNCTION DURING ATRIAL FIBRILLATIONBY AVERAGING THREE BEATS W I T H EQUAL PRECEDING AND PRE-PRECEDING INTERVALS Chun Li Wan~, Chi Tal Kuo, Lung An Hsu, Pao Hsien Chu, Kuo Hung Lin. First Division of Cardiovascular Department,
Chang-Gung Memorial Hospital, Linkou, Taiwan Introduetion: It has been demonstrated that the left ventricular (LV) systolic function positively correlated with the ratio of preceding (RR1) and pre precednig (RR2) intervals and the values at RR1/RR2 1 in the regression line were reasonable esthnates of the average values. We sought to determine whether the measured mean LV stroke volmne (SV) and ejection fraction (EF) of 3 beats with RR1 RR2 were accurate. Methods: In 65 patients with AF (42 men; age 64 ± 14 years), SV and EF were determined from simultaneous biplane views of LV using modified Sunpson's method for >20 cardiac cycles. The Bland~ltman analysis was applied to evaluate the agreement between the measured mean values of 3 beats with RR1 RR2 (defined as RR1/RR2:0.95 1.05) and the average values over all cardiac cycles.