The Role of the Calcium and the Voltage Clocks in Sinoatrial Node Dysfunction

정보영,Shien-Fong Lin,Peng-Sheng Chen 연세대학교의과대학 2011 Yonsei medical journal Vol.52 No.2

Recent evidence indicates that the voltage clock (cyclic activation and deactivation of membrane ion channels) and Ca^(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca^(2+) release) jointly regulate sinoatrial node (SAN) automaticity. However,the relative importance of the voltage clock and Ca^(2+) clock for pacemaking was not revealed in sick sinus syndrome. Previously, we mapped the intracellular calcium (Cai) and membrane potentials of the normal intact SAN simultaneously using optical mapping in Langendorff-perfused canine right atrium. We demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with robust late diastolic Cai elevation (LDCAE) during β-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic sarcoplasmic reticulum (SR) Ca^(2+) release and was closely related to heart rate changes. In contrast, in pacing induced canine atrial fibrillation and SAN dysfunction models, Ca^(2+ )clock of SAN was unresponsiveness to β-adrenergic stimulation and caffeine. Ryanodine receptor 2 (RyR2) in SAN was down-regulated. Using the prolonged low dose isoproterenol together with funny current block, we produced a tachybradycardia model. In this model, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the right atrium, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Finally,if the LDCAE was too small to trigger an action potential, then it induced only delayed afterdepolarization (DAD)-like diastolic depolarization (DD). The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis. We conclude that dysfunction of both the Ca^(2+) clock and the voltage clock are important in sick sinus syndrome.

The Calcium and Voltage Clocks in Sinoatrial Node Automaticity

정보영,Masahiro Ogawa,Shien-Fong Lin,Peng-Sheng Chen, 대한심장학회 2009 Korean Circulation Journal Vol.39 No.6

Recent evidence indicates that the voltage (cyclic activation and deactivation of membrane ion channels) and Ca2+ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca2+ release) jointly regulate sinoatrial node (SAN) automaticity. Since the intact SAN is a heterogeneous structure that includes multiple different cell types interacting with each other, the relative importance of the voltage and Ca2+ clocks for pacemaking may be variable in different regions of the SAN. Recently, we performed optical mapping in isolated and Langendorff-perfused canine right atria. We mapped the intracellular calcium (Cai) and membrane potentials of the intact SAN simultaneously. Using previously described criteria of the timing of the late diastolic Cai elevation (LDCAE) relative to the action potential upstroke to detect Ca2+ clock activity, we demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with the robust LDCAE during β-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic SR Ca2+ release and was closely related with heart rate changes. We conclude that the Ca2+ and voltage clocks work synergistically to generate SAN automaticity.

Effects of carvedilol on cardiac autonomic nerve activities during sinus rhythm and atrial fibrillation in ambulatory dogs

Choi, Eue-Keun,Shen, Mark J.,Lin, Shien-Fong,Chen, Peng-Sheng,Oh, Seil WB SAUNDERS CO LTD 2014 EUROPACE -LONDON- Vol.16 No.7

<P><B>Aims</B></P><P>We hypothesized that carvedilol can effectively suppress autonomic nerve activity (ANA) in ambulatory dogs during sinus rhythm and atrial fibrillation (AF), and that carvedilol withdrawal can lead to rebound elevation of ANA. Carvedilol is known to block pre-junctional β2-adrenoceptor responsible for norepinephrine release.</P><P><B>Methods and results</B></P><P>We implanted radiotransmitters to record stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and superior left ganglionated plexi nerve activity (SLGPNA) in 12 ambulatory dogs. Carvedilol (12.5 mg orally twice a day) was given for 7 days during sinus rhythm (<I>n</I> = 8). Four of the eight dogs and an additional four dogs were paced into persistent AF. Carvedilol reduced heart rate [from 103 b.p.m. (95% confidence interval (CI), 100–105) to 100 b.p.m. (95% CI, 98–102), <I>P</I> = 0.044], suppressed integrated nerve activities (Int-NAs, SGNA by 17%, VNA by 19%, and SLGPNA by 12%; all <I>P</I> < 0.05 vs. the baseline), and significantly reduced the incidence (from 8 ± 6 to 3 ± 3 episodes/day, <I>P</I> < 0.05) and total duration (from 68 ± 64 to 16 ± 21 s/day, <I>P</I> < 0.05) of paroxysmal atrial tachycardia (PAT). Following the development of persistent AF, carvedilol loading was associated with AF termination in three dogs. In the remaining five dogs, Int-NAs were not significantly suppressed by carvedilol, but SGNA significantly increased by 16% after carvedilol withdrawal (<I>P</I> < 0.001).</P><P><B>Conclusion</B></P><P>Carvedilol suppresses ANA and PAT in ambulatory dogs during sinus rhythm.</P>

Cervical Vagal Nerve Stimulation Activates the Stellate Ganglion in Ambulatory Dogs

이경석,Chia-Hsiang Hsueh,Jessica A. Hellyer,박형욱,이영수,Jason Garlie,Patrick Onkka,Anisiia T. Doytchinova,John B. Garner,Jheel Patel,Lan S. Chen,Michael C. Fishbein,Thomas Everett 4th,Shien-Fong Lin,Peng-She 대한심장학회 2015 Korean Circulation Journal Vol.45 No.2

Background and Objectives: Recent studies showed that, in addition to parasympathetic nerves, cervical vagal nerves contained significantsympathetic nerves. We hypothesized that cervical vagal nerve stimulation (VNS) may capture the sympathetic nerves within the vagalnerve and activate the stellate ganglion. Materials and Methods: We recorded left stellate ganglion nerve activity (SGNA), left thoracic vagal nerve activity (VNA), and subcutaneouselectrocardiogram in seven dogs during left cervical VNS with 30 seconds on-time and 30 seconds off time. We then compared theSGNA between VNS on and off times. Results: Cervical VNS at moderate (0.75 mA) output induced large SGNA, elevated heart rate (HR), and reduced HR variability, suggestingsympathetic activation. Further increase of the VNS output to >1.5 mA increased SGNA but did not significantly increase the HR, suggestingsimultaneous sympathetic and parasympathetic activation. The differences of integrated SGNA and integrated VNA between VNSon and off times (ΔSGNA) increased progressively from 5.2 mV-s {95% confidence interval (CI): 1.25–9.06, p=0.018, n=7} at 1.0 mA to13.7 mV-s (CI: 5.97–21.43, p=0.005, n=7) at 1.5 mA. The difference in HR (ΔHR, bpm) between on and off times was 5.8 bpm (CI: 0.28–11.29, p=0.042, n=7) at 1.0 mA and 5.3 bpm (CI 1.92 to 12.61, p=0.122, n=7) at 1.5 mA. Conclusion: Intermittent cervical VNS may selectively capture the sympathetic components of the vagal nerve and excite the stellateganglion at moderate output. Increasing the output may result in simultaneously sympathetic and parasympathetic capture.

Delayed Afterdepolarization in Intact Canine Sinoatrial Node as a Novel Mechanism for Atrial Arrhythmia

JOUNG, BOYOUNG,ZHANG, HONG,SHINOHARA, TETSUJI,MARUYAMA, MITSUNORI,HAN, SEONGWOOK,KIM, DAEHYEOK,CHOI, EUE‐,KEUN,ON, YOUNG‐,KEUN,LIN, SHIEN‐,FONG,CHEN, PENG‐,SHENG Blackwell Publishing Inc 2011 Journal of cardiovascular electrophysiology Vol.22 No.4

<P> <B>Delayed Afterdepolarization in Sinoatrial Node. <I>Introduction:</I></B> Recent evidence indicates that spontaneous sarcoplasmic reticulum Ca release and Na‐Ca exchanger current activation contribute to the sinoatrial node (SAN) automaticity. These findings suggest that SAN activity may share mechanisms that underlie both automaticity and triggered activity. The aim of this study is to test the hypothesis that spontaneous, nonvoltage gated, intracellular Ca (Ca<SUB>i</SUB>) elevation may induce delayed afterdepolarization (DAD) in intact SAN during isoproterenol infusion.</P><P> <B> <I>Methods and Results:</I> </B> We simultaneously mapped Ca<SUB>i</SUB> and membrane potential in 31 isolated Langendorff‐perfused canine right atriums (RA). Isoproterenol increased heart rate and late diastolic Ca<SUB>i</SUB> elevation (LDCAE) of the superior SAN, leading to consistent SAN automaticity in all 31 RAs. However, DAD‐like diastolic depolarizations (DD) were transiently observed in 4 RAs during isoproterenol infusion. These DAD‐like DDs were preceded by LDCAE, but did not trigger a full action potential. The LDCAE preceding DAD‐like DDs had smaller amplitude (0.41 ± 0.08 AU vs 0.48 ± 0.07 AU, P = 0.001) and less steep slopes (3.7 ± 1.3 AU/s vs 4.8 ± 1.4 AU/s, P = 0.001) than that of sinus beats. The coupling interval of DAD‐like DDs was longer than that of the preceding normal beats (407 ± 48 ms vs 371 ± 44 ms, P = 0.002).</P><P> <B> <I>Conclusion:</I> </B> The isoproterenol‐induced LDCAE of superior SAN induced a full action potential in most cases. However, if the LDCAE was too small to trigger an action potential, then it induces only DAD‐like DD. The failure of DAD‐like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis. <I>(J Cardiovasc Electrophysiol, Vol. 22, pp. 448‐454)</I></P>