Cheng-I Lin

Publications (51)179.87 Total impact

• Article: Antiarrhythmic effects of (-)-epicatechin-3-gallate, a novel sodium channel agonist in cultured neonatal rat ventricular myocytes.

  Adonis Zhi-Yang Wu, Shih-Hurng Loh, Tzu-Hurng Cheng, Hsin-Hsiang Lu, Cheng-I Lin
  [show abstract] [hide abstract]
  ABSTRACT: (-)-epicatechin-3-gallate (ECG), a polyphenol extracted from green tea, has been proposed as an effective compound for improving cardiac contractility. However, the therapeutic potential of ECG on the treatment of arrhythmia remains unknown. We investigated the direct actions of ECG on the modulation of ion currents and cardiac cell excitability in the primary culture of neonatal rat ventricular myocyte (NRVM), which is considered a hypertrophic model for analysis of myocardial arrhythmias. By using the whole-cell patch-clamp configurations, we found ECG enhanced the slowly inactivating component of voltage-gated Na(+) currents (I(Na)) in a concentration-dependent manner (0.1-100μM) with an EC(50) value of 3.8μM. ECG not only shifted the current-voltage relationship of peak I(Na) to the hyperpolarizing direction but also accelerated I(Na) recovery kinetics. Working at a concentration level of I(Na) enhancement, ECG has no notable effect on voltage-gated K(+) currents and L-type Ca(2+) currents. With culture time increment, the firing rate of spontaneous action potential (sAP) in NRVMs was gradually decreased until spontaneous early after-depolarization (EAD) was observed after about one week culture. ECG increased the firing rate of normal sAP about twofold without waveform alteration. Interestingly, the bradycardia-dependent EAD could be significantly restored by ECG in fast firing rate to normal sAP waveform. The expression of dominant cardiac sodium channel subunit, Nav1.5, was consistently detected throughout the culture periods. Our results reveal how ECG, the novel I(Na) agonist, may act as a promising candidate in clinical applications on cardiac arrhythmias.
  Biochemical pharmacology 10/2012; · 4.25 Impact Factor
• Article: Xin proteins and intercalated disc maturation, signaling and diseases.

  Qinchuan Wang, Jenny Li-Chun Lin, Kuo-Ho Wu, Da-Zhi Wang, Rebecca S Reiter, Haley W Sinn, Cheng-I Lin, Chung-Jing J Lin
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  ABSTRACT: Intercalated discs (ICDs) are cardiac-specific structures responsible for mechanical and electrical communication among adjacent cardiomyocytes and are implicated in signal transduction. The striated muscle-specific Xin repeat-containing proteins localize to ICDs and play critical roles in ICD formation and cardiac function. Knocking down the Xin gene in chicken embryos collapses the wall of developing heart chambers and leads to abnormal cardiac morphogenesis. In mammals, a pair of paralogous genes, Xinalpha and Xinbeta exist. Ablation of the mouse Xinalpha (mXinalpha) does not affect heart development. Instead, mXinalpha-deficient mice show adult late-onset cardiac hypertrophy and cardiomyopathy with conduction defects. The mXinalpha-deficient hearts up-regulate mouse Xinbeta (mXinbeta, suggesting a partial compensatory role of mXinbeta. Complete loss of mXinbeta however, leads to failure of forming ICD, mis-localization of mXinalpha, and early postnatal lethality. In this review, we will briefly discuss recent advances in the anatomy and function of ICDs. We will then review what we know about Xin repeat-containing proteins and how this protein family promotes ICD maturation and stability for normal cardiac function.
  Frontiers in Bioscience 01/2012; 17:2566-93. · 3.52 Impact Factor
• Article: Heart failure enhanced pulmonary vein arrhythmogenesis and dysregulated sodium and calcium homeostasis with increased calcium sparks.

  Shih-Lin Chang, Yao-Chang Chen, Yung-Hsin Yeh, Yung-Kuo Lin, Tsu-Juey Wu, Cheng-I Lin, Shih-Ann Chen, Yi-Jen Chen
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  ABSTRACT: Late sodium currents and intracellular Ca(2+) (Ca(2+) (i)) dynamics play an important role in arrhythmogenesis of pulmonary vein (PV) and heart failure (HF). It is not clear whether HF enhances PV arrhythmogenesis through modulation of Ca(2+) homeostasis and increased late sodium currents. The aim of this study was to investigate the sodium and calcium homeostasis in PV cardiomyocytes with HF. METHODS AND RESULTS: Whole-cell patch clamp was used to investigate the action potentials and ionic currents in isolated rabbit single PV cardiomyocytes with and without rapid pacing induced HF. The Ca(2+) (i) dynamics were evaluated through fluorescence and confocal microscopy. As compared to control PV cardiomyocytes (n = 18), HF PV cardiomyocytes (n = 13) had a higher incidence of delayed afterdepolarization (45% vs 13%, P < 0.05) and faster spontaneous activity (3.0 ± 0.2 vs 2.1 ± 0.2 Hz, P < 0.05). HF PV cardiomyocytes had increased late Na(+) currents, Na(+) /Ca(2+) exchanger currents, and transient inward currents, but had decreased Na(+) currents or L-type calcium currents. HF PV cardiomyocytes with pacemaker activity had larger Ca(2+) (i) transients (R410/485, 0.18 ± 0.04 vs 0.11 ± 0.02, P < 0.05), and sarcoplasmic reticulum Ca(2+) stores. Moreover, HF PV cardiomyocytes with pacemaker activity (n = 18) had higher incidence (95% vs 70%, P < 0.05), frequency (7.8 ± 3.1 vs 2.3 ± 1.2 spark/mm/s, P < 0.05), amplitude (F/F(0) , 3.2 ± 0.8 vs 1.9 ± 0.5, P < 0.05), and longer decay time (65 ± 3 vs 48 ± 4 ms, P < 0.05) of Ca(2+) sparks than control PV cardiomyocytes with pacemaker activity (n = 18). CONCLUSIONS: Dysregulated sodium and calcium homeostasis, and enhanced calcium sparks promote arrhythmogenesis of PV cardiomyocytes in HF, which may play an important role in the development of atrial fibrillation.
  Journal of Cardiovascular Electrophysiology 12/2011; 22(12):1378-86. · 3.06 Impact Factor
• Source

  Available from: Chung-Lieh Hung

  Article: Slow conduction and gap junction remodeling in murine ventricle after chronic alcohol ingestion.

  Yu-Jun Lai, Chung-Lieh Hung, Ray-Ching Hong, Ya-Ming Tseng, Cheng-I Lin, Yu-Shien Ko, Cheng-Ho Tsai, Hung-I Yeh
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  ABSTRACT: Long-term heavy alcohol drinkers are prone to the development of cardiac arrhythmia. To understand the mechanisms, we evaluated the cardiac structural and electrophysiological changes in mice chronically drinking excessive alcohol. Male C57BL/6J mice were given 36% alcohol in the drinking water. Those given blank water were used as control. Twelve weeks later, the phenotypic characteristics of the heart, including gap junctions and electrical properties were examined. In the alcohol group the ventricles contained a smaller size of cardiomyocytes and a higher density of capillary networks, compared to the control. Western blots showed that, after drinking alcohol, the content of connexin43 (Cx43) protein in the left ventricle was increased by 18% (p < 0.05). Consistently, immunoconfocal microscopy demonstrated that Cx43 gap junctions were up-regulated in the alcohol group with a disorganized distribution, compared to the control. Optical mapping showed that the alcohol group had a reduced conduction velocity (40 ± 18 vs 60 ± 7 cm/sec, p < 0.05) and a higher incidence of ventricular tachyarrhythmia (62% vs 30%, p < 0.05). Long-term excessive alcohol intake resulted in extensive cardiac remodeling, including changes in expression and distribution of gap junctions, growth of capillary network, reduction of cardiomyocyte size, and decrease of myocardial conduction.
  Journal of Biomedical Science 09/2011; 18:72. · 2.01 Impact Factor
• Article: Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium.

  Yung-Kuo Lin, Mei-Shou Lai, Yao-Chang Chen, Chen-Chuan Cheng, Jen-Hung Huang, Shih-Ann Chen, Yi-Jen Chen, Cheng-I Lin
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  ABSTRACT: Ischaemia and reperfusion contribute to the genesis of AF (atrial fibrillation). PVs (pulmonary veins) and the atria are important foci for AF initiation and maintenance. However, the effect of ischaemia and reperfusion on PVs and the atria has not yet been fully elucidated. In the present study, conventional microelectrodes were used to record the APs (action potentials) in isolated rabbit PV, LA (left atrium) and RA (right atrium) specimens during hypoxia and reoxygenation, and pharmacological interventions. Hypoxia reduced the PV beating rates from 1.8±0.1 to 1.3±0.2 and 0.8±0.1 Hz at 30 and 60 min respectively (n=8, P<0.005), and induced EAD (early after depolarization) in three (37.5%) of the PVs and DAD (delayed after depolarization) in one (12.5%) of the PVs. Reoxygenation increased the PV spontaneous rate to 1.4±0.2 Hz (P<0.05) and induced PV burst firings (3.5±0.1 Hz, P<0.001) in six (75%) of the PVs. Hypoxia shortened the AP duration in the LA and PVs, but not in the RA. Pretreatment with glibenclamide attenuated hypoxia-induced decreases in the PV spontaneous activity and the shortening of the LA and PV AP duration. Similar to those in hypoxia, the K(ATP) (ATP-sensitive potassium) channel opener pinacidil (30 μM) decreased PV spontaneous activity and shortened the AP duration. Pretreatment with 5 mM N-MPG [N-(mercaptopropionyl)glycine; a hydroxyl (•OH) free-radical scavenger] or 300 μM chloramphenicol [a cytochrome P450 inhibitor that reduces ROS (reactive oxygen species)] attenuated the rate changes induced by hypoxia and reoxygenation, and also decreased the burst firing incidence. In conclusion, hypoxia and reoxygenation significantly increased PV arrhythmogenesis and induced different electrophysiological responses in the RA and LA, which may play a role in the pathophysiology of AF.
  Clinical Science 08/2011; 122(3):121-32. · 4.61 Impact Factor
• Article: Heart failure enhances arrhythmogenesis in pulmonary veins.

  Shih-Lin Chang, Yao-Chang Chen, Yung-Hsin Yeh, Yu-Jun Lai, Hung-I Yeh, Cheng-I Lin, Yung-Kuo Lin, Yenn-Jiang Lin, Tsu-Juey Wu, Yi-Kung Huang, Shih-Ann Chen, Yi-Jen Chen
  [show abstract] [hide abstract]
  ABSTRACT: 1. Heart failure (HF) predisposes to atrial fibrillation (AF) as a result of substrate remodelling. The present study aimed to investigate the impact of HF on the electrical remodelling of the pulmonary veins (PV) and left atrium (LA). 2. The electrical activity was recorded in LA and PV from control rabbits and rabbits with rapid ventricular pacing-induced HF, using a multi-electrode array system and conventional microelectrodes. 3. Compared with the control-PV (n = 21), the HF-PV (n = 13) had a higher incidence and frequency of rapid pacing-induced spontaneous activity (85 vs 29%, P = 0.005; 3.5 ± 0.2 vs 1.7 ± 0.1 Hz, P < 0.001) and high-frequency irregular electrical activity (92 vs 38%, P = 0.01; 23 ± 1 vs 19 ± 1 Hz, P = 0.003), greater depolarized resting membrane potential (-59 ± 1 vs -70 ± 2 mV, P < 0.001), higher incidence of early afterdepolarizations (EAD; 69 vs 6%, P = 0.001) and delayed afterdepolarizations (DAD; 92 vs 25%, P = 0.001), and slower conduction velocity (38 ± 2 vs 63 ± 2 cm/s, P < 0.05). In comparison to the HF-LA, the HF-PV had a higher incidence of spontaneous activity and high-frequency irregular electrical activity (85 vs 39%, P = 0.04; 92 vs 46%, P = 0.03), and higher incidence of EAD and DAD, and those differences were not found between the control-LA and control-PV. The control-PV with high-frequency irregular electrical activity had a higher incidence of DAD and spontaneous activity as compared with those without it. 4. HF contributed to an increased automaticity, triggered activity and conduction disturbance in the PV. The PV possessed more arrhythmogenic properties, which might play an important role in the genesis of AF in HF.
  Clinical and Experimental Pharmacology and Physiology 06/2011; 38(10):666-74. · 1.85 Impact Factor
• Article: Intercalated disc-associated protein, mXin-alpha, influences surface expression of ITO currents in ventricular myocytes.

  Fu-Chi Chan, Chiao-Pei Cheng, Kuo-Ho Wu, Yao-Chang Chen, Chih-Hsiung Hsu, Elisabeth A Gustafson-Wagner, Jenny Li-Chun Lin, Qinchuan Wang, Jim Jung-Ching Lin, Cheng-I Lin
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  ABSTRACT: Mouse Xin-alpha (mXin-alpha) encodes a Xin repeat-containing, actin-binding protein localized to the intercalated disc (ICD). Ablation of mXin-alpha progressively leads to disrupted ICD structure, cardiac hypertrophy and cardiomyopathy with conduction defects during adulthood. Such conduction defects could be due to ICD structural defects and/or cell electrophysiological property changes. Here, we showed that despite the normal ICD structure, juvenile mXina-null cardiomyocytes (from 3~4-week-old mice) exhibited a significant reduction in the transient outward K+ current (ITO), similar to adult mutant cells. Juvenile but not adult mutant cardiomyocytes also had a significant reduction in the delayed rectifier K+ current. In contrast, the mutant adult ventricular myocytes had a significant reduction in the inward rectifier K+ current (IK1) on hyperpolarization. These together could account for the prolongation of action potential duration (APD) and the ease of developing early afterdepolarization observed in juvenile mXin-alpha-null cells. Interestingly, juvenile mXin-alpha-null cardiomyocytes had a notable decrease in the amplitude of intracellular Ca2+ transient and no change in the L-type Ca2+ current, suggesting that the prolonged APD did not promote an increase in intracellular Ca2+ for cardiac hypertrophy. Juvenile mXin-alpha-null ventricles had reduced levels of membrane-associated Kv channel interacting protein 2, an auxiliary subunit of ITO, and filamin, an actin cross-linking protein. We further showed that mXin-alpha interacted with both proteins, providing a novel mechanism for ITO surface expression.
  Frontiers in bioscience (Elite edition) 01/2011; 3:1425-42.
• Article: Atherosclerosis modulates the electrophysiological effects of a peroxisome proliferator-activated receptor-gamma activator on pulmonary veins.

  Chen-Chuan Cheng, Nan-Hung Pan, Yao-Chang Chen, Hung-I Yeh, Cheng-I Lin, Shih-Ann Chen, Yi-Jen Chen
  International journal of cardiology 12/2010; 145(3):578-82. · 7.08 Impact Factor
• Article: Diverse cell morphology and intracellular calcium dynamics in pulmonary vein cardiomyocytes.

  Ming-Chih Yu, Chun-Feng Huang, Che-Ming Chang, Yao-Chang Chen, Cheng-I Lin, Shih-Ann Chen
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  ABSTRACT: Pulmonary veins (PVs) contain cardiomyocytes with a complex cellular morphology and high arrhythmogenesis. Ca(2+) regulation and Ca(2+) sparks play a pivotal role in the electrical activity of cardiomyocytes. The purpose of this study was to investigate whether the cell morphology can determine the PV electrical activity and Ca(2+) homeostasis. Through confocal microscopy with fluo-3 Ca(2+) fluorescence, Ca(2+) sparks and Ca(2+) transients were evaluated in isolated single rabbit left atria (LA) and PV cardiomyocytes according to the cell morphology (rod, rod-spindle and spindle/bifurcated). Twenty-two (20%) rod, 49 (43%) rod-spindle and 41 (37%) spindle/bifurcated cardiomyocytes were identified in the LA (n = 29) and PV (n = 83) cardiomyocytes. The PV cardiomyocytes with pacemaker activity had a higher incidence of spindle/bifurcated morphology than LA and PV cardiomyocytes without pacemaker activity. As compared to those in the rod or rod-spindle cardiomyocytes, spindle/bifurcated cardiomyocytes had a larger Ca(2+) transient amplitude and higher frequency of the Ca(2+) sparks with larger amplitude and longer duration. In contrast, rod-spindle and rod cardiomyocytes had similar Ca(2+) transients and Ca(2+) sparks. The cell length correlated well with the amplitude of the Ca(2+) transient and Ca(2+) spark duration with a linear regression. In conclusion, cell morphology and cell length play a potential role in the Ca(2+) homeostasis and Ca(2+) spark. The large Ca(2+) transients and high frequency of Ca(2+) sparks in spindle/bifurcated cardiomyocytes may cause a high arrhythmogenesis in the PV cardiomyocytes with pacemaker activity.
  Heart and Vessels 10/2010; 26(1):101-10. · 2.05 Impact Factor
• Article: Oxidative stress on pulmonary vein and left atrium arrhythmogenesis.

  Yung-Kuo Lin, Feng-Zhi Lin, Yao-Chang Chen, Chen-Chuan Cheng, Cheng-I Lin, Yi-Jen Chen, Shih-Ann Chen
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  ABSTRACT: Oxidative stress and pulmonary veins (PVs) play critical roles in the pathophysiology of atrial fibrillation. The purpose of the present study was to investigate whether oxidative stress and antioxidant agents can change the electrophysiological characteristics of the left atrium (LA) and PVs. Conventional microelectrodes were used to record the action potentials (APs) in isolated rabbit PV and LA specimens before and after H(2)O(2) administration with or without ascorbic acid or N-mercaptopropionyl-glycine (N-MPG, a free radical .OH scavenger). H(2)O(2) (0.02 and 0.2 mmol/L) decreased the PV spontaneous rates from 2.0+/-0.1 Hz to 1.6+/-0.1 Hz, and 1.7+/-0.1 Hz (n=10, P<0.05), but H(2)O(2) (2 mmol/L) increased PV spontaneous rates from 2.0+/-0.1 Hz to 2.8+/-0.2 Hz. H(2)O(2) easily induced PV burst firing and early afterdepolarizations, but not in the LA. H(2)O(2) shortened the AP duration and increased the contractile force to a greater extent in the LA than in PVs. In addition, the H(2)O(2)-induced PV burst firing and increasing spontaneous rates were suppressed or attenuated by pretreatment with ascorbic acid (1 mmol/L) or N-MPG (10 mmol/L). H(2)O(2) significantly changed the electrophysiological characteristics of PV and LA through activation of free radicals and may facilitate the occurrence of atrial fibrillation.
  Circulation Journal 08/2010; 74(8):1547-56. · 3.77 Impact Factor
• Source

  Available from: Qinchuan Wang

  Article: Essential roles of an intercalated disc protein, mXinbeta, in postnatal heart growth and survival.

  Qinchuan Wang, Jenny Li-Chun Lin, Benjamin E Reinking, Han-Zhong Feng, Fu-Chi Chan, Cheng-I Lin, Jian-Ping Jin, Elisabeth A Gustafson-Wagner, Thomas D Scholz, Baoli Yang, Jim Jung-Ching Lin
  [show abstract] [hide abstract]
  ABSTRACT: The Xin repeat-containing proteins mXinalpha and mXinbeta localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXinalpha directly interacts with beta-catenin, p120-catenin, and actin filaments. Ablation of mXinalpha results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXinbeta in mXinalpha-deficient hearts suggests a partial compensation. The essential roles of mXinbeta in cardiac development and intercalated disc maturation were investigated. Ablation of mXinbeta led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXinalpha. Postnatal upregulation of mXinbeta in wild-type hearts, as well as altered apoptosis and proliferation in mXinbeta-null hearts, suggests that mXinbeta is required for postnatal heart remodeling. The mXinbeta-null hearts exhibited a misorganized myocardium as detected by histological and electron microscopic studies and an impaired diastolic function, as suggested by echocardiography and a delay in switching off the slow skeletal troponin I. Loss of mXinbeta resulted in the failure of forming mature intercalated discs and the mislocalization of mXinalpha and N-cadherin. The mXinbeta-null hearts showed upregulation of active Stat3 (signal transducer and activator of transcription 3) and downregulation of the activities of Rac1, insulin-like growth factor 1 receptor, protein kinase B, and extracellular signal-regulated kinases 1 and 2. These findings identify not only an essential role of mXinbeta in the intercalated disc maturation but also mechanisms of mXinbeta modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival.
  Circulation Research 04/2010; 106(9):1468-78. · 9.49 Impact Factor
• Article: Reduced Ca²⁺transport across sarcolemma but enhanced spontaneous activity in cardiomyocytes isolated from left atrium-pulmonary veins tissue of myopathic hamster

  Yue-Xia Loh, Kuo-Ho Wu, Yao-Chang Chen, Chih-Hsiung Hsu, Jeng Wei, Cheng-I Lin
  [show abstract] [hide abstract]
  ABSTRACT: Abstract Background Several lines of evidence point to a particularly important role of the left atrium (LA) in initiating and maintaining atrial fibrillation (AF). This role may be related to the location of pulmonary veins (PVs) in the LA. The aim of the present study was to investigate the action potential (AP) and ionic currents in LA-PV cardiomyocytes isolated from Bio14.6 myopathic Syrian hamsters (36-57 week-old) versus age-matched F1B healthy control hamsters. Methods and Results Whole-cell patch-clamp techniques were used to record AP in current-clamp mode and ionic currents in voltage-clamp mode. The results obtained show that in both healthy and myopathic LA-PV tissue spontaneously discharging cardiomyocytes can be found, but they are more numerous in myopathic (9/29) than in healthy hamsters (4/42, p < 0.05 by χ²analysis). Myopathic myocytes have shorter AP duration (APD) with smaller I_Ca,Land I_NCXthan the healthy control. The currents I_TO, I_K, I_K1and I_Ca,Tare not significantly different in myopathic versus healthy cells. Conclusions Our results indicate that in myopathic Syrian hamsters LA-PV cardiomyocytes are more prone to automatic rhythms. Also, they show altered electrophysiologic properties, which may be due to abnormal Ca²⁺channels and may account for contractile dysfunction.
  Journal of Biomedical Science. 01/2009;
• Source

  Available from: Jeng Wei

  Article: Reduced Ca2+ transport across sarcolemma but enhanced spontaneous activity in cardiomyocytes isolated from left atrium-pulmonary veins tissue of myopathic hamster.

  Yue-Xia Loh, Kuo-Ho Wu, Yao-Chang Chen, Chih-Hsiung Hsu, Jeng Wei, Cheng-I Lin
  [show abstract] [hide abstract]
  ABSTRACT: Several lines of evidence point to a particularly important role of the left atrium (LA) in initiating and maintaining atrial fibrillation (AF). This role may be related to the location of pulmonary veins (PVs) in the LA. The aim of the present study was to investigate the action potential (AP) and ionic currents in LA-PV cardiomyocytes isolated from Bio14.6 myopathic Syrian hamsters (36-57 week-old) versus age-matched F1B healthy control hamsters. Whole-cell patch-clamp techniques were used to record AP in current-clamp mode and ionic currents in voltage-clamp mode. The results obtained show that in both healthy and myopathic LA-PV tissue spontaneously discharging cardiomyocytes can be found, but they are more numerous in myopathic (9/29) than in healthy hamsters (4/42, p < 0.05 by chi2 analysis). Myopathic myocytes have shorter AP duration (APD) with smaller ICa,L and INCX than the healthy control. The currents ITO, IK, IK1 and ICa,T are not significantly different in myopathic versus healthy cells. Our results indicate that in myopathic Syrian hamsters LA-PV cardiomyocytes are more prone to automatic rhythms. Also, they show altered electrophysiologic properties, which may be due to abnormal Ca2+ channels and may account for contractile dysfunction.
  Journal of Biomedical Science 01/2009; 16:114. · 2.01 Impact Factor
• Article: On the mechanisms of arrhythmias in the myocardium of mXinalpha-deficient murine left atrial-pulmonary veins.

  Yu-Jun Lai, Eagle Yi-Kung Huang, Hung-I Yeh, Yen-Lin Chen, Jim Jung-Ching Lin, Cheng-I Lin
  [show abstract] [hide abstract]
  ABSTRACT: We have previously shown that left atrial-pulmonary vein tissue (LA-PV) can generate reentrant arrhythmias (atrial fibrillation, AF) in wild-type (mXinalpha+/+) but not in mXinalpha-null (mXinalpha-/-) mice. With the present experiments, we investigated the arrhythmogenic activity and the underlying mechanisms in mXinalpha+/+ vs. mXinalpha-/- LA-PV. Electrical activity and conduction velocity (CV) were recorded in LA-PV by means of a MED64 system. CV was significantly faster in mXinalpha+/+ than in mXinalpha-/- LA-PV and it was increased by 1 muM isoproterenol (ISO). AF could be induced by fast pacing in the mXinalpha+/+ but not in mXinalpha-/- LA-PV where automatic rhythms could occur. ISO increased the incidence of AF in Xinalpha+/+ whereas it increased that of automatic rhythms in mXinalpha-/- LA-PV. In LA-PV with the right atrium attached (RA-LA-PV), automatic rhythms occurred in all preparations. In mXinalpha+/+ RA-LA-PV simultaneously treated with ISO, strophanthidin and atropine, the incidence of the automatic rhythm was about the same, but AF increased significantly. In contrast, in mXinalpha-/- RA-LA-PV under the same condition, the automatic rhythm was markedly enhanced, but still no AF occurred. Conventional microelectrode techniques showed a longer APD(90) and a less negative maximum diastolic potential (MDP) in mXinalpha-/- than mXinalpha+/+ LA-PV tissues. Whole-cell current clamp experiments also showed a less negative MDP in mXinalpha-/- vs. mXinalpha+/+ LA-PV cardiomyocytes. The fact that AF could be induced by fast pacing under several conditions in mXinalpha+/+ but not in mXinalpha-/- LA-PV preparations appears to be due to a slower CV, a prolonged APD(90), a less negative MDP and possibly larger areas of conduction block in mXinalpha-/- myocardial cells. In contrast, the non-impairment of automatic and triggered rhythms in mXinalpha-/- preparations may be due to the fact that the mechanisms underlying these rhythms do not involve cell-to-cell conduction.
  Life Sciences 08/2008; 83(7-8):272-83. · 2.53 Impact Factor
• Source

  Available from: tmu.edu.tw

  Article: Endothelin-1 modulates the arrhythmogenic activity of pulmonary veins.

  Ameya R Udyavar, Yao-Chang Chen, Yi-Jen Chen, Chen-Chuan Cheng, Cheng-I Lin, Shih-Ann Chen
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  ABSTRACT: Endothelin-1 has important cardiovascular effects and is activated during atrial fibrillation. Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. The aim of this study was to evaluate whether endothelin-1 affects PV arrhythmogenic activity. Conventional microelectrodes were used to record the action potentials (APs) and contractility in isolated rabbit PV tissue specimens before and after the administration of endothelin-1 (0.1, 1, 10 nM). The ionic currents of isolated PV cardiomyocytes were investigated before and after the administration of endothelin-1 (10 nM) through whole-cell patch clamps. Results: In the tissue preparation, endothelin-1 (1, 10 nM) concentration dependently shortened the AP duration and decreased the PV firing rates. Endothelin-1 (10 nM) decreased the resting membrane potential. Endothelin-1 (0.1, 1, 10 nM) decreased the contractility and increased the resting diastolic tension. In single PV cardiomyocytes, endothelin-1 (10 nM) decreased the PV firing rates from 2.7 +/- 1.0 Hz to 0.8 +/- 0.5 Hz (n = 16). BQ-485 (100 microM, endothelin-1 type A receptor blocker) reversed and prevented the chrono-inhibitory effects of endothelin-1 (10 nM). Endothelin-1 (10 nM) reduced the L-type calcium currents, transient outward currents, delayed rectifier currents, transient inward currents, and sodium-calcium exchanger currents in the PV cardiomyocytes with and without pacemaker activity. Endothelin-1 (10 nM) increased the inward rectifier potassium current, hyperpolarization-induced pacemaker current, and the sustained outward potassium current in PV cardiomyocytes with and without pacemaker activity. Endothelin-1 may have an antiarrhythmic potential through its direct electrophysiological effects on the PV cardiomyocytes and its action on multiple ionic currents.
  Journal of Cardiovascular Electrophysiology 04/2008; 19(3):285-92. · 3.06 Impact Factor
• Article: Endothelin‐1 Modulates the Arrhythmogenic Activity of Pulmonary Veins

  AMEYA R. UDYAVAR M.D, YAO-CHANG CHEN M.Sc, Ph.D. YI-JEN CHEN M.D, CHEN-CHUAN CHENG M.D, CHENG-I LIN Ph.D, SHIH-ANN CHEN M.D
  [show abstract] [hide abstract]
  ABSTRACT: Objective: Endothelin-1 has important cardiovascular effects and is activated during atrial fibrillation. Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. The aim of this study was to evaluate whether endothelin-1 affects PV arrhythmogenic activity.Methods: Conventional microelectrodes were used to record the action potentials (APs) and contractility in isolated rabbit PV tissue specimens before and after the administration of endothelin-1 (0.1, 1, 10 nM). The ionic currents of isolated PV cardiomyocytes were investigated before and after the administration of endothelin-1 (10 nM) through whole-cell patch clamps.Results: In the tissue preparation, endothelin-1 (1, 10 nM) concentration dependently shortened the AP duration and decreased the PV firing rates. Endothelin-1 (10 nM) decreased the resting membrane potential. Endothelin-1 (0.1, 1, 10 nM) decreased the contractility and increased the resting diastolic tension. In single PV cardiomyocytes, endothelin-1 (10 nM) decreased the PV firing rates from 2.7 ± 1.0 Hz to 0.8 ± 0.5 Hz (n = 16). BQ-485 (100 μM, endothelin-1 type A receptor blocker) reversed and prevented the chrono-inhibitory effects of endothelin-1 (10 nM). Endothelin-1 (10 nM) reduced the L-type calcium currents, transient outward currents, delayed rectifier currents, transient inward currents, and sodium–calcium exchanger currents in the PV cardiomyocytes with and without pacemaker activity. Endothelin-1 (10 nM) increased the inward rectifier potassium current, hyperpolarization-induced pacemaker current, and the sustained outward potassium current in PV cardiomyocytes with and without pacemaker activity.Conclusion: Endothelin-1 may have an antiarrhythmic potential through its direct electrophysiological effects on the PV cardiomyocytes and its action on multiple ionic currents.
  Journal of Cardiovascular Electrophysiology 02/2008; 19(3):285 - 292. · 3.06 Impact Factor
• Chapter: Ionic Currents and Mechanisms of Ectopy from the Thoracic Veins

  Yi‐Jen Chen, Yao‐Chang Chen, Cheng‐I Lin, Shih‐Ann Chen
  12/2007: pages 111 - 120; , ISBN: 9780470751442
• Article: Loss of mXinalpha, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects.

  Elisabeth A Gustafson-Wagner, Haley W Sinn, Yen-Lin Chen, Da-Zhi Wang, Rebecca S Reiter, Jenny L-C Lin, Baoli Yang, Roger A Williamson, Ju Chen, Cheng-I Lin, Jim J-C Lin
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  ABSTRACT: The intercalated disk protein Xin was originally discovered in chicken striated muscle and implicated in cardiac morphogenesis. In the mouse, there are two homologous genes, mXinalpha and mXinbeta. The human homolog of mXinalpha, Cmya1, maps to chromosomal region 3p21.2-21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here we report that mXinalpha-null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXinbeta likely provides partial compensation and accounts for the viability of the mXinalpha-null mice. Ultrastructural studies of mXinalpha-null mouse hearts reveal intercalated disk disruption and myofilament disarray. In mXinalpha-null mice, there is a significant decrease in the expression level of p120-catenin, beta-catenin, N-cadherin, and desmoplakin, which could compromise the integrity of the intercalated disks and functionally weaken adhesion, leading to cardiac defects. Additionally, altered localization and decreased expression of connexin 43 are observed in the mXinalpha-null mouse heart, which, together with previously observed abnormal electrophysiological properties of mXinalpha-deficient mouse ventricular myocytes, could potentially lead to conduction defects. Indeed, ECG recordings on isolated, perfused hearts (Langendorff preparations) show a significantly prolonged QT interval in mXinalpha-deficient hearts. Thus mXinalpha functions in regulating the hypertrophic response and maintaining the structural integrity of the intercalated disk in normal mice, likely through its association with adherens junctional components and actin cytoskeleton. The mXinalpha-knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects.
  AJP Heart and Circulatory Physiology 12/2007; 293(5):H2680-92. · 3.71 Impact Factor
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  Available from: tmu.edu.tw

  Article: Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulation agents.

  Wanwarang Wongcharoen, Yao-Chang Chen, Yi-Jen Chen, Szu-Ying Chen, Huang-I Yeh, Cheng-I Lin, Shih-Ann Chen
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  ABSTRACT: Aging and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation. Abnormal Ca(2+) regulation and ryanodine receptors are known to contribute to PV arrhythmogenesis. The purpose of this study was to investigate whether aging alters PV electrophysiology, Ca(2+) regulation proteins, and responses to rapamycin, FK-506, ryanodine, and ouabain. Conventional microelectrodes were used to record action potential and contractility in isolated PV tissue samples in 15 young (age 3 months) and 16 aged (age 3 years) rabbits before and after drug administration. Expression of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a), ryanodine receptor, and Na(+)/Ca(2+) exchanger was evaluated by western blot. Aged PVs had larger amplitude of delayed afterdepolarizations, greater depolarized resting membrane potential, longer action potential duration, and higher incidence of action potential alternans and contractile alternans with increased expression of Na(+)/Ca(2+) exchanger and ryanodine receptor and decreased expression of SERCA2a. Rapamycin (1,10,100 nM), FK-506 (0.01, 0.1, 1 microM), ryanodine (0.1, 1 microM), and ouabain (0.1, 1 microM) concentration-dependently increased PV spontaneous rates and the incidence of delayed afterdepolarizations in young and aged PVs. Compared with results in young PVs, rapamycin and FK-506 in aged PVs increased PV spontaneous rates to a greater extent and exhibited a larger delayed afterdepolarization amplitude. In PVs without spontaneous activity, rapamycin and FK-506 induced spontaneous activity only in aged PVs, but ryanodine and ouabain induced spontaneous activity in both young and aged PVs. Aging increases PV arrhythmogenesis via abnormal Ca(2+) regulation. These findings support the concept that ryanodine receptor dysfunction may result in high PV arrhythmogenesis and aging-related arrhythmogenic vulnerability.
  Heart Rhythm 11/2007; 4(10):1338-49. · 4.10 Impact Factor
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  Available from: tmu.edu.tw

  Article: Calmodulin kinase II inhibition prevents arrhythmic activity induced by alpha and beta adrenergic agonists in rabbit pulmonary veins.

  Li-Wei Lo, Yao-Chang Chen, Yi-Jen Chen, Wanwarang Wongcharoen, Cheng-I Lin, Shih-Ann Chen
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  ABSTRACT: The autonomic nervous system and calcium regulation play important roles in the pathophysiology of atrial fibrillation. Calmodulin regulates the calcium homeostasis and may mediate the proarrhythmic effects of autonomic nervous agents. The purpose of this study was to compare the effects of beta- and alpha-adrenoceptor agonists on the pulmonary vein electrical activity and evaluate whether calmodulin kinase II inhibitors may change the effects of the adrenoceptor agonists on the pulmonary vein arrhythmogenesis. Conventional microelectrodes were used to record the action potentials in isolated rabbit pulmonary vein tissue specimens before and after the administration of isoproterenol, phenylephrine and KN-93 (a calmodulin kinase II inhibitor). In the tissue preparation, isoproterenol (0, 0.1, 3 microM) increased the beating rates (1.5+/-0.2, 1.6+/-0.2, 2.3+/-0.3 Hz, n=10, P<0.001) with the genesis of early afterdepolarizations (EADs, 0%, 40%, 50%, P<0.05) and increased the amplitude of the delayed afterdepolarizations (DADs, 0.6+/-0.3, 1.7+/-0.4, 3.9+/-1.0 mV, P<0.05). Phenylephrine (0, 1, 10 microM) also increased the beating rates (1.4+/-0.2, 1.6+/-0.2, 1.9+/-0.2 Hz, n=12, P<0.001), incidence of EADs (0%, 8%, 50%, P<0.05) and amplitude of the DADs (0.4+/-0.2, 1.2+/-0.4, 2.6+/-0.8 mV, P<0.05). KN-93 did not change the pulmonary vein beating rates or action potential duration. However, in the presence of KN-93 (1 microM), isoproterenol (3 microM) and phenylephrine (10 microM) did not induce any EADs or DADs in the pulmonary veins. In conclusion, calmodulin kinase II inhibition may prevent adrenergic induced pulmonary vein arrhythmogenesis.
  European Journal of Pharmacology 10/2007; 571(2-3):197-208. · 2.52 Impact Factor