臺灣博碩士論文加值系統

實驗背景
敘利亞先天性心肌病變倉鼠（Biobreeders strain Bio 14.6）是經常被用來作為研究心臟衰竭的重要動物模式。近來研究顯示，鬱血性心衰竭會增加心房顫動的發生率。肺靜脈已知可以形成異位性節律點的來源以引發心房顫動，且藉由導管電燒肺靜脈病灶，可以成功地治療心房顫動。過去在狗及大白兔的實驗中已證實，在肺靜脈管壁含有心肌細胞，可以出現自動節律或非自動節律之電生理特性。但心衰竭對於肺靜脈異位節律的影響仍未知。

實驗目的
利用傳統電生理及whole-cell patch-clamp的實驗技術，探討心肌病變和健康倉鼠在左心房及肺靜脈中心肌動作電位及離子電流的差異。



實驗方法
一、心電圖紀錄
取健康及心肌病變的敘利亞倉鼠（36～40週）作為實驗動
物以heparin (5000 iu/kg) 由腹腔注射，15分鐘後，再以　　　
Sodium　pentobarbital (50 mg/kg) 進行腹腔注射麻醉，
待動物完全麻醉，沿胸中隔剪開迅速取出心臟置於含飽和
混合氣 (97 % O2、3 % CO2)之 Krebs-Henseleit 溶液中
(pH=7.2- 7.4)，並以鐵針插管與主動脈相接，藉由主動脈
逆向灌流Krebs-Henseleit溶液，以提供心臟跳動所需的養分。灌流流速維持，灌流壓力60-100 mmHg。一開始掛上心臟後，等至穩定5分鐘後開始進行實驗。
心電圖紀錄儀器為Hugo Sachs Elektronik-Harvard
apparatus GmbH (Germany) ，其中紀錄導極置於右心房和左心室尖，如一般心電圖lead Ⅱ的位置。藉此觀察心臟整體的功能。

二、離體左心房-肺靜脈組織實驗
1. 取健康及心肌病變的敘利亞倉鼠（36～40週）作為實驗動物，以sodium pentobarbital（50 mg/kg, i.p.）麻醉後，取出心臟及肺臟置於經混合氣 (97% O2、3% CO2) 飽和之 Normal Tyrode solution 中 (pH= 7.4)。
2. 將組織放置於特殊灌流盒中給予灌流持續打入混和氣及加熱的Normal Tyrode solution。
3. 給予1Hz的電刺激紀錄收縮及應用傳統玻璃微電極 (內含3 M KCl)紀錄左心房及肺靜脈不同位置的動作電位。
二、倉鼠肺肺靜脈心肌細胞的分離
1. 取健康及心肌病變的敘利亞倉鼠（36～40週）作為實驗動物，以sodium pentobarbital（50 mg/kg, i.p.）麻醉後，取出心臟及肺臟，置於室溫下100 ﹪氧氣飽和的HEPES- Tyrode solution中。
2. 再以PE管經由主動脈、左心室而灌流入左心房，逆流進行肺靜脈灌流，PE管的另一端與 Langendorff灌流柱接合，先以37℃的normal Tyrode solution灌流，直到流出的液體沒有血液。
3. 接著以Ca2+-free Tyrode solution灌流15分鐘，讓心臟組 織完全鬆弛、不再跳動。
4. 再以含有collagenase（1 mg/ml）及protease（0.01 mg/ml）的Ca2+-free Tyrode solution灌流30-40分鐘，分離出肺靜脈心肌細胞，儲存於室溫下的高鉀溶液中。
5. 將溶液逐步的換成HEPES-Tyrode solution，以恢復生理狀況下的鈣離子濃度。
三、單一肺靜脈心肌細胞的電生理研究
取良好的細胞置於倒立顯微鏡上的容器，並灌流細胞外液，然後利用whole-cell patch-clamp的方法，觀察比較心肌病變及健康倉鼠的肺靜脈心肌細胞之動作電位和各個離子電流變化。

實驗結果
一、在心電圖的實驗中，心肌病變倉鼠較容易誘發心律不整。
二、在兩組的倉鼠肺靜脈組織中，心房及肺靜脈動作電位有所差異其中心房動作電位期間在心肌病變的倉鼠相較於健康倉鼠有較長的動作電位。而肺靜脈動作電位期間在心肌病變倉鼠則是較短的。
三、在電位箝定下，發現心肌病變組有顯著上較小的INa¬及INCX，但在Ik1（Inward rectifier K current）並無顯著差異。
四、在電位箝定下發現衰竭病人及心肌病變倉鼠INCX較小。

結論
心肌病變倉鼠由於心衰竭而造成左心房電性的重塑使得動作電位期間相較於健康倉鼠較為延長，而在之前的研究可以發現動作電位的延長則較易引發激發性節律心律不整，這可能與心房異位性節律點的產生有關。
然而肺靜脈組織的動作電位期間在心肌病變倉鼠則是縮短的。在這個實驗中我們也去探討與動作電位組成相關的離子流，我們發現心肌病變倉鼠的INa及INCX減少，而合併研究室之前的研究發現病變倉鼠的ICa,L是減少的。所以心肌病變倉鼠肺靜脈動作電位期間縮短可能就是因為這些離子流的減少所造成的。肺靜脈心肌動作電位的縮短的改變則容易造成組織間電性的差異進而造成再迴旋心律不整的產生。

Introduction
Hereditary myopathic Syrian hamster (Biobreeders strain Bio 14.6) had been frequently used as an experimental model for the study of congestive heart failure (CHF). Recently, there is an increase in AF prevalence in patients afflicted with more advance CHF. The pulmonary veins (PVs) are an important source of ectopic beats, initiating frequent paroxysms of AF. These foci respond to treatment with radio-frequency ablation. Previous studies in multiple cells or single cell from dogs and rabbits have shown that PVs contain cardiomyocytes with or without spontaneous activities. It is not clear whether CHF alters the arrhythmogenic activity of PVs.

Aim
The aim of the present experiments was to study alternations in the ionic currents and action potential (AP) of the myopathic versus healthy left atrial (LA)-PV.


Material and Methods
A. ECG recording
Male myopathic Syrian hamsters (Bio 14.6, 41-57 week-old) and
age-matched male healthy hamsters (Biobreeders strain F1B) were
anesthetized with pentobarbital and the heart and lungs quickly
removed and immersed in Tyrode solution. ECG was recorded by
using Hugo Sachs Elektronik-Harvard apparatus GmbH (Germany)

B. Preparation of hamster LA-PV tissues :
The animals preparation were the same in ECG recording. LA-PV tissue were perfused in vitro at 37℃. Action potentials were recorded by microelectrode techniques and twitch force by a transducer.

C. Isolation of PV cardiomyocytes After getting the heart, PVs were perfused in a retrograde manner via polyethylene tube connected through the aorta and left ventricular into the left atrium. The free end of the polyethylene tubing was connected to a Langendorff perfusion column for perfusion with Tyrode solution at 37℃. The perfusate was replaced with Ca2+-free Tyrode solution containing collagenase (1 mg/ml) and protease (0.01 mg/ml) for 30-40 min. The piece of tissue was cut into fine pieces and gently shaken in 5-10 ml of high-K+ storage solution until single cardiomyocytes were obtained.

D. Electrophysiology study
The isolated cells were placed in a 1-ml chamber mounted on the stage of an inverted microscope and superfused ( at 3 mL/min ) with extracellular solution appropriate to each patch-clamp experiment. The LA-PV cardiomyocytes obtained from 14 myopathic hamsters and 16 healthy hamsters were used for experiments on the following ionic currents and membrane potentials by means of whole-cell patch-clamp techniques.

Results
1. The myopathic hamster was easier inducing arrhythmia by using isoproterenol.
2. The LA tissue has a longer APD in myopathic hamster.
3. But, PV tissue APD in myopathic hamster is shorter than healthy.
4. The densities of the INa and INCX in PV cardiomyocytes were smaller in myopathic hamster than the healthy control. But in IK1 have no significant differences. The densities of the INCX in myopathic hamster and failing human heart ventricular myocytes were small. Conclusion
In addition to previous findings from our Lab that myopathic hamsters had smaller ICa,L but no difference in IK and IK1, the present experiments show that the myopathic hamsters have smaller INa,and INCX. Change of these currents could lead to shorter APD in myopathic hamster PVs than in healthy PVs. In contrast, myopathic hamsters LAs have longer APD. Thus our results suggest that CHF can promote LA-PV and ventricle ionic remodeling.

目錄 I
圖目錄 IV
表目錄 V
中文摘要 VI
英文摘要 X
第一章 緒言 1
第一節 心房顫動 1
第二節 肺靜脈之基礎及臨床電生理的角色 2
第三節 心律不整的機轉 5
第四節 敘利亞心肌病變倉鼠 7
第五節 離子流的簡介 9
第二章 研究目的 12
第三章 材料與方法 13
第一節 實驗動物 13
第二節 心電圖紀錄 13
第三節 離體左心房-肺靜脈組織實驗 14
第四節 左心房-肺靜脈心肌細胞實驗 15
壹、倉鼠肺靜脈心肌細胞分離 15
貳、實驗用玻璃微電極製備 17
参、全細胞膜電位箝定方法 18
第五節 實驗溶液的配製 19
第六節 實驗數據與統計 21
第四章 實驗結果 22
第一節 健康及心肌病變倉鼠在正常及給予1M Isoproterenol下心電圖的變化 22
第二節 健康及心肌病變倉鼠之肺靜脈左心房組織動作電位
比較 22
第三節 健康及心肌病變倉鼠之肺靜脈肺靜脈組織動作電位
比較 23
第四節 健康及心肌病變倉鼠之個別左心房與肺靜脈組織動作電位的比較 23
第五節 左心房及肺靜脈中心肌細胞之型態差異 23
第六節 健康及心肌病變倉鼠之肺靜脈心肌細胞的各離子流
比較 24
（一） 鈉離子流的比較 24
（二） 鉀離子流的比較 24
（三） 鈉鈣交換離子流的比較 24
第七節 健康及心肌病變倉鼠之心室肌細胞的鈉鈣交換離子流的
比較 25
第八節 心衰竭病人心室肌細胞鈉鈣交換離子流及加入1M
　　　　　 島素後的變化 25
第五章 討論 42
第一節 健康倉鼠與病變倉鼠心電圖的變化 42
第二節 左心房-肺靜脈心肌組織及細胞電生理紀錄 43
第三節 心肌病變倉鼠與健康倉鼠左心房及肺靜脈電生理上的差異 43
第四節 心肌病變倉鼠於單一肺靜脈心肌細胞上的電生理
變化 44
第五節 心房及心室鈉鈣交換表現量 48
第六節 胰島素對於心肌病變病人心室肌細胞鈉鈣交換離子流
的影響 49
第六章 結論 50
第七章 參考文獻 51



圖目錄
圖一、健康及心肌病變倉鼠心電圖 27
圖二、健康及心肌病變倉鼠左心房組織動作電位 28
圖三、健康及心肌病變倉鼠肺靜脈組織動作電位 29
圖四、倉鼠左心房肺靜脈心肌細胞圖 30
圖五、健康及心肌病變倉鼠肺靜脈心肌細胞鈉離子流 31
圖六、健康及心肌病變倉鼠肺靜脈心肌細胞鋇敏感性內向整流型鉀
離子流 32
圖七、健康及心肌病變倉鼠肺靜脈心肌細胞的鈉鈣交換離子流 33
圖八、健康及心肌病變倉鼠心室肌細胞的鈉鈣交換離子流 34
圖九、心衰竭病人心室肌細胞的鈉鈣交換離子流及加入1M胰島
素後的變化 35
圖十、實驗中鈉鈣交換離子流電位電流關係圖 36













表目錄

表一、心肌病變及健康倉鼠左心房組織APD20、APD50、APD90 37
表二、心肌病變及健康倉鼠肺靜脈組織APD20、APD50、APD90 38
表三、健康及心肌病變倉鼠細胞大小之比較 39
表四、健康倉鼠與心肌病變倉鼠肺靜脈心肌細胞離子流比較 40
表五、健康、病變倉鼠及心衰竭病人心肌細胞鈉鈣交換離子流比較 41

1.Jalife J, Delmar M, Davidenko JM. Basic mechanisms of cardiac arrhythmias. In: Basic cardiac electrophysiology for the clinician, edited by Jalife J, Delmar M, Davidenko JM, Anumonwo JMB: NY: Futura, 1999, pp. 200-201.
2.Ahmmed GU, Dong PH, Song G, Ball NA, Xu Y, Walsh RA, and Chiamvimonvat N. Changes in Ca(2+) cycling proteins underlie cardiac action potential prolongation in a pressure-overloaded guinea pig model with cardiac hypertrophy and failure. Circ Res 86: 558-570, 2000.
3.Allessie MA, Bonke FI, and Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The "leading circle" concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res 41: 9-18, 1977.
4.Armoundas AA, Hobai IA, Tomaselli GF, Winslow RL, and O'Rourke B. Role of sodium-calcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts. Circ Res 93: 46-53, 2003.
5.Arora R, Verheule S, Scott L, Navarrete A, Katari V, Wilson E, Vaz D, and Olgin JE. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation 107: 1816-1821, 2003.
6.Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, and Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98: 946-952, 1998.
7.Bers DM. Cardiac excitation-contraction coupling. Nature 415: 198-205, 2002.
8.Blom NA, Gittenberger-de Groot AC, DeRuiter MC, Poelmann RE, Mentink MM, and Ottenkamp J. Development of the cardiac conduction tissue in human embryos using HNK-1 antigen expression: possible relevance for understanding of abnormal atrial automaticity. Circulation 99: 800-806, 1999.
9.Bond M, Jaraki AR, Disch CH, and Healy BP. Subcellular calcium content in cardiomyopathic hamster hearts in vivo: an electron probe study. Circ Res 64: 1001-1012, 1989.
10.Brunton TL, and Fayrer J. Note on Independent Pulsation of the Pulmonary Veins and Vena Cava. Proc R Sco Lond 25: 174-176, 1876.
11.Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, Hsu TL, Ding YA, and Chang MS. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 100: 1879-1886, 1999.
12.Chen SA, Tai CT, Yu WC, Chen YJ, Tsai CF, Hsieh MH, Chen CC, Prakash VS, Ding YA, and Chang MS. Right atrial focal atrial fibrillation: electrophysiologic characteristics and radiofrequency catheter ablation. J Cardiovasc Electrophysiol 10: 328-335, 1999.
13.Chen YJ, Chen SA, Chang MS, and Lin CI. Arrhythmogenic activity of cardiac muscle in pulmonary veins of the dog: implication for the genesis of atrial fibrillation. Cardiovasc Res 48: 265-273, 2000.
14.Chen YJ, Chen SA, Chen YC, Yeh HI, Chan P, Chang MS, and Lin CI. Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation. Circulation 104: 2849-2854, 2001.
15.Chen YJ, Chen SA, Chen YC, Yeh HI, Chang MS, and Lin CI. Electrophysiology of single cardiomyocytes isolated from rabbit pulmonary veins: implication in initiation of focal atrial fibrillation. Basic Res Cardiol 97: 26-34, 2002.
16.Cheung DW. Electrical activity of the pulmonary vein and its interaction with the right atrium in the guinea-pig. J Physiol 314: 445-456, 1981.
17.Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, and Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311: 819-823, 1984.
18.Despa S, Islam MA, Weber CR, Pogwizd SM, and Bers DM. Intracellular Na(+) concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation 105: 2543-2548, 2002.
19.DiFrancesco D. The pacemaker current (I(f)) plays an important role in regulating SA node pacemaker activity. Cardiovasc Res 30: 307-308, 1995.
20.Ehrlich JR, Cha TJ, Zhang L, Chartier D, Melnyk P, Hohnloser SH, and Nattel S. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties. J Physiol 551: 801-813, 2003.
21.Fabiato A, and Fabiato F. Contractions induced by a calcium-triggered release of calcium from the sarcoplasmic reticulum of single skinned cardiac cells. J Physiol 249: 469-495, 1975.
22.Ferrier GR, Saunders JH, and Mendez C. A cellular mechanism for the generation of ventricular arrhythmias by acetylstrophanthidin. Circ Res 32: 600-609, 1973.
23.Finkel MS, Shen L, Oddis CV, and Romeo RC. Verapamil regulation of a defective SR release channel in the cardiomyopathic Syrian hamster. Life Sci 52: 1109-1119, 1993.
24.Finkel MS, Shen L, Romeo RC, Oddis CV, and Salama G. Radioligand binding and inotropic effects of ryanodine in the cardiomyopathic Syrian hamster. Cardiovasc Pharmacol 19: 610-617, 1992.
25.Garrey WE. The nature of fiibrillatry contraction of the heart.-It`s relation to tissue mass and form. Am J Physiol 33: 397-414, 1914
26.Gertz EW. Cardiomyopathic Syrian hamster: a possible model of human disease. Prog Exp Tumor Res 16: 242-260, 1972.
27.Gorgels AP, De Wit B, Beekman HD, Dassen WR, and Wellens HJ. Triggered activity induced by pacing during digitalis intoxication: observations during programmed electrical stimulation in the conscious dog with chronic complete atrioventricular block. Pacing Clin Electrophysiol 10: 1309-1321, 1987.
28.GR M. On circulating excitations in heart muscles and their possible relation to tachycardia and fibrillation. Proc Trans R Soc Can 8: 43-53, 1914.
29.Hack AA, Groh ME, and McNally EM. Sarcoglycans in muscular dystrophy. Microsc Res Tech 48: 167-180, 2000.
30.Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, and Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 339: 659-666, 1998.
31.Han X, and Ferrier GR. Ionic mechanisms of transient inward current in the absence of Na(+)-Ca2+ exchange in rabbit cardiac Purkinje fibres. J Physiol 456: 19-38, 1992.
32.Hano O, Mitsuoka T, Matsumoto Y, Ahmed R, Hirata M, Hirata T, Mori M, Yano K, and Hashiba K. Arrhythmogenic properties of the ventricular myocardium in cardiomyopathic Syrian hamster, BIO 14.6 strain. Cardiovasc Res 25: 49-57, 1991.
33.Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, Holtz J, Holubarsch C, Posival H, Just H, and Drexler H. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ Res 75: 434-442, 1994.
34.Hassink RJ, Aretz HT, Ruskin J, and Keane D. Morphology of atrial myocardium in human pulmonary veins: a postmortem analysis in patients with and without atrial fibrillation. J Am Coll Cardiol 42: 1108-1114, 2003..
35.Hatem SN, Sham JS, and Morad M. Enhanced Na(+)-Ca2+ exchange activity in cardiomyopathic Syrian hamster. Circ Res 74: 253-261, 1994.
36.Henderson SA, Goldhaber JI, So JM, Han T, Motter C, Ngo A, Chantawansri C, Ritter MR, Friedlander M, Nicoll DA, Frank JS, Jordan MC, Roos KP, Ross RS, and Philipson KD. Functional adult myocardium in the absence of Na+-Ca2+ exchange: cardiac-specific knockout of NCX1. Circ Res 95: 604-611, 2004.
37.Hilgemann DW, Matsuoka S, Nagel GA, and Collins A. Steady-state and dynamic properties of cardiac sodium-calcium exchange. Sodium-dependent inactivation. J Gen Physiol 100: 905-932, 1992.
38.Hirano Y, Moscucci A, and January CT. Direct measurement of L-type Ca2+ window current in heart cells. Circ Res 70: 445-455, 1992.
39.Ho KK, Pinsky JL, Kannel WB, and Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 22: 6A-13A, 1993.
40.Ho SY, Cabrera JA, Tran VH, Farre J, Anderson RH, and Sanchez-Quintana D. Architecture of the pulmonary veins: relevance to radiofrequency ablation. Heart (British Cardiac Society) 86: 265-270, 2001.
41.Ho SY, Sanchez-Quintana D, Cabrera JA, and Anderson RH. Anatomy of the left atrium: implications for radiofrequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol 10: 1525-1533, 1999.
42.Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, Jais P, Janse MJ, Haissaguerre M, and De Bakker JM. Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation. Circulation 105: 2442-2448, 2002.
43.Homburger F. Myopathy of hamster dystrophy: history and morphologic aspects. Ann N Y Acad Sci 317: 1-17, 1979.
44.Hsieh MH, Chen SA, Tai CT, Tsai CF, Prakash VS, Yu WC, Liu CC, Ding YA, and Chang MS. Double multielectrode mapping catheters facilitate radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. J Cardiovasc Electrophysiol 10: 136-144, 1999.
45.Hsu CH, Wei J, Chen YC, Yang SP, Tsai CS, and Lin CI. Cellular mechanisms responsible for the inotropic action of insulin on failing human myocardium. J Heart Lung Transplant 25: 1126-1134, 2006.
46.Hwang C, Karagueuzian HS, and Chen PS. Idiopathic paroxysmal atrial fibrillation induced by a focal discharge mechanism in the left superior pulmonary vein: possible roles of the ligament of Marshall. J Cardiovasc Electrophysiol 10: 636-648, 1999.
47.Jais P, Haissaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, and Clementy J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 95: 572-576, 1997.
48.Jais P, Hocini M, Macle L, Choi KJ, Deisenhofer I, Weerasooriya R, Shah DC, Garrigue S, Raybaud F, Scavee C, Le Metayer P, Clementy J, and Haissaguerre M. Distinctive electrophysiological properties of pulmonary veins in patients with atrial fibrillation. Circulation 106: 2479-2485, 2002.
49.January CT, and Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 64: 977-990, 1989.
50.Kannel WB, Abbott RD, Savage DD, and McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med 306: 1018-1022, 1982.
51.Karagueuzian HS, and Katzung BG. Voltage-clamp studies of transient inward current and mechanical oscillations induced by ouabain in ferret papillary muscle. J Physiol 327: 255-271, 1982.
52.Kass RS, Lederer WJ, Tsien RW, and Weingart R. Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres. J Physiol 281: 187-208, 1978.
53.Katz AM. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J Med 322: 100-110, 1990.
54.Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, Molkentin JD, and Radice GL. Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res 96: 346-354, 2005.
55.Koumi S, Backer CL, and Arentzen CE. Characterization of inwardly rectifying K+ channel in human cardiac myocytes. Alterations in channel behavior in myocytes isolated from patients with idiopathic dilated cardiomyopathy. Circulation 92: 164-174, 1995.
56.Lau CP, Tse HF, and Ayers GM. Defibrillation-guided radiofrequency ablation of atrial fibrillation secondary to an atrial focus. J Am Coll Cardiol 33: 1217-1226, 1999.
57.Lederer WJ, and Tsien RW. Transient inward current underlying arrhythmogenic effects of cardiotonic steroids in Purkinje fibres. J Physiol 263: 73-100, 1976.
58.Lewinski Dv, Bruns S, Walther S, Kögler H, and Pieske B. Insulin Causes [Ca2+]i-Dependent and [Ca2+]i-Independent Positive Inotropic Effects in Failing Human Myocardium Circulation 111: 2588-2595, 2005.
59.Li D, Fareh S, Leung TK, and Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100: 87-95, 1999.
60.Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, and Nattel S. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation 101: 2631-2638, 2000.
61.Luo CH, and Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res 74: 1071-1096, 1994.
62.Allessie MA, Lammers WJEP, Bonke FIM, and Hollen J. Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation. In: Cardiac electrophysiology and arrthymias, edited by DP Z, and J J. Orlando: Grune and Stratton, 1985, p. 265-275.
63.Macle L, Jais P, Scavee C, Weerasooriya R, Shah DC, Hocini M, Choi KJ, Raybaud F, Clementy J, and Haissaguerre M. Electrophysiologically guided pulmonary vein isolation during sustained atrial fibrillation. J Cardiovasc Electrophysiol 14: 255-260, 2003.
64.Malfatto G, Rosen TS, and Rosen MR. The response to overdrive pacing of triggered atrial and ventricular arrhythmias in the canine heart. Circulation 77: 1139-1148, 1988.
65.Masani F. Node-like cells in the myocardial layer of the pulmonary vein of rats: an ultrastructural study. J Anat 145: 133-142, 1986.
66.Matsuoka N, Arakawa H, Kodama H, and Yamaguchi I. Characterization of stress-induced sudden death in cardiomyopathic hamsters. J Pharmacol Exp Ther 284: 125-135, 1998.
67.McDonald RL, Colyer J, and Harrison SM. Quantitative analysis of Na+-Ca2+ exchanger expression in guinea-pig heart. Eur J Biochem 267: 5142-5148, 2000.
68.Mitra R, and Morad M. Two types of calcium channels in guinea pig ventricular myocytes. Proc Natl Acad Sci U S A 83: 5340-5344, 1986.
69.Moe GK, and Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 58: 59-70, 1959.
70.Murgatroyd FD, and Camm AJ. Atrial arrhythmias. Lancet 341: 1317-1322, 1993.
71.Nathan H, and Eliakim M. The junction between the left atrium and the pulmonary veins. An anatomic study of human hearts. Circulation 34: 412-422, 1966.
72.Nattel S. New ideas about atrial fibrillation 50 years on. Nature 415: 219-226, 2002.
73.Pogwizd SM. Clinical potential of sodium-calcium exchanger inhibitors as antiarrhythmic agents. Drugs 63: 439-452, 2003.
74.Pogwizd SM, and Bers DM. Cellular basis of triggered arrhythmias in heart failure. Trends Cardiovasc Med 14: 61-66, 2004.
75.Pogwizd SM, Schlotthauer K, Li L, Yuan W, and Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res 88: 1159-1167, 2001.
76.Pogwizd SM, Sipido KR, Verdonck F, and Bers DM. Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res 57: 887-896, 2003.
77.Rensma PL, Allessie MA, Lammers WJ, Bonke FI, and Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Cir Res 62: 395-410, 1988.
78.Reuter H, Pott C, Goldhaber JI, Henderson SA, Philipson KD, and Schwinger RH. Na(+)--Ca2+ exchange in the regulation of cardiac excitation-contraction coupling. Cardiovasc Res 67: 198-207, 2005.
79.Rossner KL, and Sachs HG. Electrophysiological study of Syrian hamster hereditary cardiomyopathy. Cardiovasc Res 12: 436-443, 1978.
80.Saito T, Waki K, and Becker AE. Left atrial myocardial extension onto pulmonary veins in humans: anatomic observations relevant for atrial arrhythmias. J Cardiovasc Electrophysiol 11: 888-894, 2000.
81.Sakamoto A, Ono K, Abe M, Jasmin G, Eki T, Murakami Y, Masaki T, Toyo-oka T, and Hanaoka F. Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex. Proc Natl Acad Sci U S A 94: 13873-13878, 1997.
82.Samson RA, and Lee HC. Delayed afterdepolarizations and triggered arrhythmias in hypertrophic cardiomyopathic hearts. J Lab Clin Med 124: 242-248, 1994.
83.Schwinger RH, Bohm M, Schmidt U, Karczewski P, Bavendiek U, Flesch M, Krause EG, and Erdmann E. Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts. Circulation 92: 3220-3228, 1995.
84.Shah DC, Haissaguerre M, and Jais P. Catheter ablation of pulmonary vein foci for atrial fibrillation: PV foci ablation for atrial fibrillation. Thorac Cardiovasc Surg 47 Suppl 3: 352-356, 1999.
85.Spach MS, Barr RC, and Jewett PH. Spread of excitation from the atrium into thoracic veins in human beings and dogs. . Am J Cardiol 30: 844-854, 1972.
86.Tada H, Oral H, Ozaydin M, Greenstein R, Pelosi F, Jr., Knight BP, Strickberger SA, and Morady F. Response of pulmonary vein potentials to premature stimulation. J Cardiovasc Electrophysiol 13: 33-37, 2002.
87.Tomaselli GF, and Marban E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42: 270-283, 1999.
88.Undrovinas AI, Shander GS, and Makielski JC. Cytoskeleton modulates gating of voltage-dependent sodium channel in heart. Am J Physiol 269: H203-214, 1995.
89.Vaidya PN, Bhosley PN, Rao DB, and Luisada AA. Tachyarrhythmias in old age. J Am Geriatr Soc 24: 412-414, 1976.
90.Vatner DE, Vatner SF, Fujii AM, and Homcy CJ. Loss of high affinity cardiac beta adrenergic receptors in dogs with heart failure. J Clin Invest 76: 2259-2264, 1985.
91.Verdonck F, Volders PG, Vos MA, and Sipido KR. Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells. Cardiovasc Res 57: 1035-1043, 2003.
92.Verkerk AO, Schumacher CA, van Ginneken AC, Veldkamp MW, and Ravesloot JH. Role of Ca(2+)-activated Cl(-) current in ventricular action potentials of sheep during adrenoceptor stimulation. Exp Physiol 86: 151-159, 2001.
93.Volders PG, Kulcsar A, Vos MA, Sipido KR, Wellens HJ, Lazzara R, and Szabo B. Similarities between early and delayed afterdepolarizations induced by isoproterenol in canine ventricular myocytes. Cardiovasc Res 34: 348-359, 1997.
94.Wagner JA, Weisman HF, Snowman AM, Reynolds IJ, Weisfeldt ML, and Snyder SH. Alterations in calcium antagonist receptors and sodium-calcium exchange in cardiomyopathic hamster tissues. Circ Res 65: 205-214, 1989.
95.Waldo AL, and Wit AL. Mechanisms of cardiac arrhythmias. Lancet 341: 1189-1193, 1993.
96.Wang J, Schwinger RH, Frank K, Muller-Ehmsen J, Martin-Vasallo P, Pressley TA, Xiang A, Erdmann E, and McDonough AA. Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart. J Clin Invest 98: 1650-1658, 1996.
97.Wang Z, Nolan B, Kutschke W, and Hill JA. Na+-Ca2+ exchanger remodeling in pressure overload cardiac hypertrophy. J Biol Chem 276: 17706-17711, 2001.
98.Wrogemann K, and Nylen EG. Mitochondrial calcium overloading in cardiomyopathic hamsters. J Mol Cell Cardiol 10: 185-195, 1978.
99.Yue L, Feng J, Gaspo R, Li GR, Wang Z, and Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res 81: 512-525, 1997.
100.Zeng J, and Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J 68: 949-964, 1995.
101.Zicha S, Maltsev VA, Nattel S, Sabbah HN, and Undrovinas AI. Post-transcriptional alterations in the expression of cardiac Na+ channel subunits in chronic heart failure. J Mol Cell Cardiol 37: 91-100, 2004.
102.Zipes DP, and Knope RF. Electrical properties of the thoracic veins. Am J Cardiol 29: 372-376, 1972.