Tetsuji Shinohara

Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States

Are you Tetsuji Shinohara?

Claim your profile

Publications (18)101.86 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The membrane voltage clock and calcium (Ca(2+)) clock jointly regulate sinoatrial node (SAN) automaticity. VK-II-36 is a novel carvedilol analog that suppresses sarcoplasmic reticulum (SR) Ca(2+) release but does not block the β-receptor. The effect of VK-II-36 on SAN function remains unclear. The purpose of this study was to evaluate whether VK-II-36 can influence SAN automaticity by inhibiting the Ca(2+) clock. We simultaneously mapped intracellular Ca(2+) and membrane potential in 24 isolated canine right atriums using previously described criteria of the timing of late diastolic intracellular Ca elevation (LDCAE) relative to the action potential upstroke to detect the Ca(2+) clock. Pharmacological interventions with isoproterenol (ISO), ryanodine, caffeine, and VK-II-36 were performed after baseline recordings. VK-II-36 caused sinus rate downregulation and reduced LDCAE in the pacemaking site under basal conditions (P < 0.01). ISO induced an upward shift of the pacemaking site in SAN and augmented LDCAE in the pacemaking site. ISO also significantly and dose-dependently increased the sinus rate. The treatment of VK-II-36 (30 μmol/l) abolished both the ISO-induced shift of the pacemaking site and augmentation of LDCAE (P < 0.01), and it suppressed the ISO-induced increase in sinus rate (P = 0.02). Our results suggest that the sinus rate may be partly controlled by the Ca(2+) clock via SR Ca(2+) release during β-adrenergic stimulation.
    Heart and Vessels 07/2013; · 2.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We hypothesize that inferior vena cava-inferior atrial ganglionated plexus nerve activity (IVC-IAGPNA) is responsible for ventricular rate (VR) control during atrial fibrillation (AF) in ambulatory dogs. We recorded bilateral cervical vagal nerve activity (VNA) and IVC-IAGPNA during baseline sinus rhythm and during pacing-induced sustained AF in 6 ambulatory dogs. Integrated nerve activities and average VR were measured every 10 seconds over 24 hours. Left VNA was associated with VR reduction during AF in 5 dogs (from 211 bpm [95% CI, 186-233] to 178 bpm [95% CI, 145-210]; P<0.001) and right VNA in 1 dog (from 208 bpm [95% CI, 197-223] to 181 bpm [95% CI, 163-200]; P<0.01). There were good correlations between IVC-IAGPNA and left VNA in the former 5 dogs and between IVC-IAGPNA and right VNA in the last dog. IVC-IAGPNA was associated with VR reduction in all dogs studied. Right VNA was associated with baseline sinus rate reduction from 105 bpm (95% CI, 95-116) to 77 bpm (95% CI, 64-91; P<0.01) in 4 dogs, whereas left VNA was associated with sinus rate reduction from 111 bpm (95% CI, 90-1250) to 81 bpm (95% CI, 67-103; P<0.01) in 2 dogs. IVC-IAGPNA is invariably associated with VR reduction during AF. In comparison, right or left VNA was associated with VR reduction only when it coactivates with the IVC-IAGPNA. The vagal nerve that controls VR during AF may be different from that which controls sinus rhythm.
    Circulation Arrhythmia and Electrophysiology 05/2012; 5(3):571-80. · 5.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies using isolated sinoatrial node (SAN) cells indicate that rhythmic spontaneous sarcoplasmic reticulum calcium release (Ca clock) plays an important role in SAN automaticity. In the intact SAN, cross-contamination of optical signals from the SAN and the right atrium (RA) prevent the definitive testing of Ca clock hypothesis. The aim of this study was to use a novel approach to selectively mapping the intact SAN to examine the Ca clock mechanism. We simultaneously mapped intracellular Ca (Ca(i)) and membrane potential (V(m)) in 10 isolated, Langendorff-perfused normal canine RAs. The excitability of the RA was suppressed with high-potassium Tyrode's solution, allowing selective optical mapping of V(m) and Ca(i) of the SAN. Isoproterenol (ISO, 0.03 µmol/L) decreased the cycle length of the sinus beats, and shifted the leading pacemaker site from the middle or inferior SAN to the superior SAN in all RAs. The Ca(i) upstroke preceded the V(m) in the leading pacemaker site by up to 18 ± 2 ms. ISO-induced changes to SAN were inhibited by ryanodine (3 µmol/L), but not ZD7288 (3 µmol/L), a selective I(f) blocker. We conclude that, in the isolated canine RA, a high extracellular potassium concentration can suppress atrial excitability thus leading to SAN-RA conduction block, allowing selective optical mapping of the intact SAN. Acceleration of Ca cycling in the superior SAN underlies the mechanism of sinus tachycardia during sympathetic stimulation.
    Circulation Journal 11/2011; 76(2):309-16. · 3.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We tested the hypothesis that heart failure (HF) results in right atrial ganglionated plexus (RAGP) denervation that contributes to sinoatrial node dysfunction. HF is associated with sinoatrial node dysfunction. However, the detailed mechanisms remain unclear. We recorded nerve activity (NA) from the RAGP, right stellate ganglion (SG), and right vagal nerve in 7 ambulatory dogs at baseline and after pacing-induced HF. We also determined the effects of RAGP stimulation in isolated normal and HF canine RA. NAs in both the SG and vagal were significantly higher in HF than at baseline. The relationship between 1-minute integrated NAs of vagal and RAGP showed either a positive linear correlation (Group 1, n = 4) or an L-shaped correlation (Group 2, n = 3). In all dogs, a reduced heart rate was observed when vagal-NA was associated with simultaneously increased RAGP-NA. On the other hand, when vagal-NA was not associated with increased RAGP-NA, the heart rate was not reduced. The induction of HF significantly decreased RAGP-NA in all dogs (P < 0.05). Stimulating the superior RAGP in isolated RA significantly reduced the sinus rate in normal but not the HF hearts. Immunohistochemical staining revealed lower densities of tyrosine hydroxylase- and choline acetyltransferase-positive nerve tissues in HF RAGP than normal (P < 0.001 and P = 0.001, respectively). The RAGP-NA is essential for the vagal nerve to counterbalance the SG in sinus rate control. In HF, RAGP denervation and decreased RAGP-NA contribute to the sinus node dysfunction.
    Journal of Cardiovascular Electrophysiology 10/2011; 23(4):404-12. · 3.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We hypothesize that left-sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. We implanted a neurostimulator in 12 dogs to stimulate the left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activity, vagal nerve activities, and ECGs. Group 1 dogs (N=6) underwent 1 week of continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated stellate ganglion nerve activity was significantly reduced during LL-VNS (7.8 mV/s; 95% confidence interval [CI] 6.94 to 8.66 versus 9.4 mV/s [95% CI, 8.5 to 10.3] at baseline; P=0.033) in group 1. The reduction was most apparent at 8 am, along with a significantly reduced heart rate (P=0.008). Left-sided low-level vagus nerve stimulation did not change vagal nerve activity. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion 1 week after cessation of LL-VNS were 99 684 μm(2)/mm(2) (95% CI, 28 850 to 170 517) in LL-VNS dogs and 186 561 μm(2)/mm(2) (95% CI, 154 956 to 218 166; P=0.008) in normal dogs. In group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/d (95% CI, 0.5 to 5.1) and 8.0/d (95% CI, 5.3 to 12.0), respectively, significantly lower than during sham stimulation (9.2/d [95% CI, 5.3 to 13.1]; P=0.001 and 22.0/d [95% CI, 19.1 to 25.5], P<0.001, respectively). Left-sided low-level vagus nerve stimulation suppresses stellate ganglion nerve activities and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident 1 week after cessation of continuous LL-VNS.
    Circulation 05/2011; 123(20):2204-12. · 15.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). We hypothesized that activation of apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels is responsible for the postshock APD shortening in failing ventricles. A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca(2+) and membrane potential (V(m)) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF and increased postshock APD(80) in the SVF group from 126±5 to 153±4 ms (P<0.05) and from 147±2 to 162±3 ms (P<0.05) in the no-SVF group but did not change APD(80) in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K(+) current (I(KAS)) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial I(KAS) density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca(2+) response of I(KAS) was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca(2+) sensitivity of I(KAS) in failing ventricles. The K(d) was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes (P=0.002). Heart failure heterogeneously increases the sensitivity of I(KAS) to intracellular Ca(2+), leading to upregulation of I(KAS), postshock APD shortening, and recurrent SVF.
    Circulation Research 02/2011; 108(8):971-9. · 11.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whether autonomic nerve activity is important in the development of pacing-induced sustained atrial fibrillation (AF) is unclear. The purpose of this study was to test the hypothesis that patterns of baseline autonomic nerve activity are important in the development of pacing-induced sustained AF. Radiotransmitters were implanted in 12 ambulatory dogs to record left stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA). Sustained (>48 hours) AF was induced with intermittent rapid atrial pacing. At baseline (before pacing), 1-minute integrated nerve activity between SGNA and VNA demonstrated either a single linear relationship with excellent correlation (group 1, N = 3, r = 0.816 ± 0.105) or nonlinear relationships with poor correlation (group 2, N = 9, r = 0.316 ± 0.162, P <.05 vs group 1). Group 1 dogs had higher VNA (97.0 ± 11.5 mV-s) compared to group 2 (33.4 ± 21.7 mV-s, P <.001). Group 1 dogs had more frequent sympathovagal co-activation episodes than did group 2 (50 ± 19 per day vs 15 ± 6 per day, P <.05) and more paroxysmal atrial tachycardia (PAT; 5 ± 1 per day vs 2 ± 1 per day, P <.05) at baseline. Sustained AF occurred after 16 ± 4 days (range 13-20 days) of pacing in group 1 and after 46 ± 18 days (range 23-72 days) of pacing in group 2 (P <.05). In the week before development of sustained AF, VNA of group 2 dogs was significantly increased compared to baseline (P <.05). Ambulatory dogs with good linear sympathovagal correlation and higher vagal tone at baseline have more PAT episodes at baseline and faster induction of sustained AF by rapid pacing. Rapid atrial pacing increased the VNA of the remaining dogs before induction of sustained AF.
    Heart rhythm: the official journal of the Heart Rhythm Society 11/2010; 8(4):583-9. · 4.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Both phase 2 and phase 3 early afterdepolarizations (EADs) occur in long-QT syndromes, but their respective roles in generating arrhythmias in intact cardiac tissue are incompletely understood. Intracellular Ca (Ca(i)) and membrane voltage (V(m)) were optically mapped in a quasi 2-dimensional model of cryoablated Langendorff-perfused rabbit ventricles (n=16). E-4031 (an I(Kr) blocker) combined with reduced extracellular K ([K(+)](o)) and Mg ([Mg(2+)](o)) prolonged action potential duration heterogeneously and induced phase 2 and phase 3 EADs. Whereas phase 2 EADs were Ca(i)-dependent, phase 3 EADs were not. The origins of 47 triggered activity episodes were attributed to phase 2 EADs in 12 episodes (26%) and phase 3 EADs in 35 episodes (74%). When phase 2 EADs accompanied phase 3 EADs, they accentuated action potential duration heterogeneity, creating a large V(m) gradient across the boundary between long and short action potential duration regions from which triggered activity emerged. The amplitude of phase 3 EADs correlated with the V(m) gradient (r=0.898, P<0.001). Computer simulation studies showed that coupling of cells with heterogeneous repolarization could extrinsically generate phase 3 EADs via electrotonic current flow. Alternatively, reduced I(K1) caused by low [K(+)](o) could generate intrinsic phase 3 EADs capable of inducing triggered activity at the boundary zone. Phase 3 EADs can be extrinsic as the result of electrotonic current across steep repolarization gradients or intrinsic as the result of low I(K1) and do not require spontaneous sarcoplasmic reticulum Ca release. Reduction of I(K1) by low [K(+)](o) strongly promotes ventricular arrhythmias mediated by phase 3 EADs in acquired long-QT syndrome caused by I(Kr) blockade.
    Circulation Arrhythmia and Electrophysiology 11/2010; 4(1):103-11. · 5.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The mechanism of sinoatrial node (SAN) automaticity is traditionally attributed to membrane ion currents. Recent evidence indicates spontaneous sarcoplasmic reticulum (SR) Ca(2+) cycling also plays an important role. A computer simulation on SAN cell and 1D tissue model was performed. In the SAN cells, SR Ca(2+) cycling broadly modulated the sinus rate from 1.74 Hz to 3.87 Hz. Shortening of the junctional SR refilling time and increase of SR Ca(2+) release were responsible for sinus rate acceleration. However, under the fast SR Ca(2+) cycling, decreased L-type Ca(2+) current (I(CaL)) resulted in irregular firing. When Ca(2+) cycling was suppressed, I(f) and I(CaT) both acted to stabilize the pacemaker rhythm, but I(CaT) had less effect than I(f). At the 1D level, the electrical coupling between neighboring cells had little effect on the earliest pacemaker location. The leading pacemaking site always colocalized with the site with the highest SR Ca(2+) cycling rate, but shifted to the site with less inhibited I(CaL). The rate of SR Ca(2+) cycling can effectively and broadly modulate the sinus rate. I(f), I(CaL) and I(CaT) play integral roles to guarantee SAN cell rhythmic firing. The leading pacemaker site is determined by intracellular Ca(2+) dynamics and membrane currents, indicating the synergistic dual automaticity not only exists in single SAN cells, but also at the tissue level. 
    Circulation Journal 10/2010; 74(10):2079-88. · 3.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms of sinoatrial node (SAN) dysfunction in heart failure (HF) remain unclear. We hypothesized that impaired rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release (Ca(2+) clock) plays an important role in SAN dysfunction in HF. HF was induced in canine hearts by rapid ventricular pacing. The location of pacemaking sites was determined in vivo using computerized electrical mapping in acute open-chest preparations (normal, n = 3; and HF, n = 4). Isoproterenol (Iso, 0.2 μg·kg(-1)·min(-1)) infusion increased heart rate and shifted the pacemaking site to the superior SAN in all normal hearts. However, in failing hearts, Iso did not induce superior shift of the pacemaking site despite heart rate acceleration. Simultaneous optical recording of intracellular Ca(2+) and membrane potential was performed in Langendorff-perfused isolated right atrium (RA) preparations from normal (n = 7) and failing hearts (n = 6). Iso increased sinus rate, enhanced late diastolic Ca(2+) elevation (LDCAE), and shifted the pacemaking sites to the superior SAN in all normal but in none of the HF RAs. Caffeine (2 ml, 20 mmol/l) caused LDCAE and increased heart rate in four normal RAs but in none of the three HF RAs. Iso induced ectopic beats from lower crista terminalis in five of six HF RAs. These ectopic beats were suppressed by ZD-7288, a specific pacemaker current (I(f)) blocker. We conclude that HF results in the suppression of Ca(2+) clock, resulting in the unresponsiveness of superior SAN to Iso and caffeine. HF also increases the ectopic pacemaking activity by activating the I(f) at the latent pacemaking sites in lower crista terminalis.
    AJP Heart and Circulatory Physiology 10/2010; 299(6):H1805-11. · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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(i)) elevation may induce delayed afterdepolarization (DAD) in intact SAN during isoproterenol infusion. We simultaneously mapped Ca(i) and membrane potential in 31 isolated Langendorff-perfused canine right atriums (RA). Isoproterenol increased heart rate and late diastolic Ca(i) 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). 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.
    Journal of Cardiovascular Electrophysiology 10/2010; 22(4):448-54. · 3.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms of sinoatrial node (SAN) dysfunction in patients with chronically elevated sympathetic tone and reduced pacemaker current (I(f); such as heart failure) are poorly understood. We simultaneously mapped membrane potential and intracellular Ca(2+) in the Langendorff-perfused canine right atrium (RA). Blockade of either I(f) (ZD-7288) or sarcoplasmic reticulum Ca(2+) release (ryanodine) alone decreased heart rate by 8% (n = 3) and 16% (n = 3), respectively. Combined treatment of ZD-7288 and ryanodine consistently resulted in prolonged (> or =3 s) sinus pauses (PSPs) (n = 4). However, the middle SAN remained as the leading pacemaking site after these treatments. Prolonged exposure with isoproterenol (0.01 micromol/l) followed by ZD-7288 completely suppressed SAN but triggered recurrent ectopic atrial tachycardia. Cessation of tachycardia was followed by PSPs in five of eight RAs. Isoproterenol initially increased heart rate by 75% from baseline with late diastolic intracellular Ca(2+) elevation (LDCAE) from the superior SAN. However, after a prolonged isoproterenol infusion, LDCAE disappeared in the superior SAN, the leading pacemaker shifted to the inferior SAN, and the rate reduced to 52% above baseline. Caffeine (2 ml, 20 mmol/l) injection after a prolonged isoproterenol infusion produced LDCAE in the SAN and accelerated the SAN rate, ruling out sarcoplasmic reticulum Ca(2+) depletion as a cause of Ca(2+) clock malfunction. We conclude that in an isolated canine RA preparation, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the RA, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Combined malfunction of both membrane and Ca(2+) clocks underlies the mechanisms of PSPs.
    AJP Heart and Circulatory Physiology 09/2010; 299(3):H634-42. · 4.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to test the hypothesis that rhythmic spontaneous sarcoplasmic reticulum calcium (Ca) release (the "Ca clock") plays an important role in atrioventricular junction (AVJ) automaticity. The AVJ is a primary backup pacemaker to the sinoatrial node. The mechanisms of acceleration of AVJ intrinsic rate during sympathetic stimulation are unclear. We simultaneously mapped transmembrane potential and intracellular Ca in Langendorff-perfused canine AVJ preparations that did not contain sinoatrial node (n = 10). Baseline AVJ rate was 37.5 +/- 4.0 beats/min. The wavefront from leading pacemaker site propagated first through the slow pathway, then the fast pathway and atria. There was no late diastolic Ca elevation (LDCAE) at baseline. Isoproterenol up to 3 micromol/l increased heart rate to 100 +/- 6.8 beats/min, concomitant with the appearance of LDCAE that preceded the phase 0 of action potential by 97.3 +/- 35.2 ms and preceded the onset of late diastolic depolarization by 23.5 +/- 3.5 ms. Caffeine also produced LDCAE and AVJ acceleration. The maximal slope of LDCAE and diastolic depolarization always colocalized with the leading pacemaker sites. Ryanodine markedly slowed the rate of spontaneous AVJ rhythm. Isoproterenol did not induce LDCAE in the presence of ryanodine. The I(f) blocker ZD 7288 did not prevent LDCAE or AVJ acceleration induced by isoproterenol (n = 2). Isoproterenol and caffeine induced LDCAE and accelerated intrinsic AVJ rhythm. Consistent colocalization of the maximum LDCAE and the leading pacemaker sites indicates that the Ca clock is important to the intrinsic AVJ rate acceleration during sympathetic stimulation.
    Journal of the American College of Cardiology 08/2010; 56(10):805-12. · 14.09 Impact Factor
  • Heart Rhythm. 01/2010; 7(11):1711-1711.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence indicates that spontaneous sarcoplasmic reticulum (SR) calcium (Ca) release underlies the mechanism of sinoatrial node (SAN) acceleration during beta-stimulation, indicating the importance of the Ca clock in SAN automaticity. Whether or not the same mechanism applies to atrial ectopic pacemakers (AEPs) remains unclear. The purpose of this study was to assess the mechanism of AEP. We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 12 isolated canine right atria. The late diastolic Ca(i) elevation (LDCAE) was used to detect the Ca clock activity. Pharmacological interventions with isoproterenol (ISO), ryanodine, and ZD7288, a blocker of the I(f) membrane current, were performed. Ryanodine, which inhibits SR Ca release, reduced LDCAE in SAN, resulting in an inferior shift of the pacemaking site. Cycle length increased significantly in a dose-dependent way. In the presence of 3 to 10 mumol/l of ryanodine, ISO infusion consistently induces AEPs from the lower crista terminalis. All ectopic beats continuing over 30 seconds were located at the lower crista terminalis. These AEPs were resistant to ryanodine treatment even at high doses. Subsequent blockade of I(f) inhibited the AEP and resulted in profound bradycardia. Spontaneous SR Ca release underlies ISO-induced increase of superior SAN activity. As compared with SAN, the AEP is less dependent on the Ca clock and more dependent on the membrane clock for its automaticity. AEPs outside the SAN can effectively serve as backup pacemakers when the Ca clock functionality is reduced.
    Heart rhythm: the official journal of the Heart Rhythm Society 01/2010; 7(1):110-6. · 4.56 Impact Factor
  • Heart Rhythm. 01/2010; 7(11):1712-1713.
  • [Show abstract] [Hide abstract]
    ABSTRACT: During a normal lifetime, the heart may beat over 2 billion times, but the mechanisms by which the heart beats are initiated remain a subject of intense investigation. Since the discovery of a pacemaker current (I(f)) in 1978, multiple studies have shown that rhythmic changes in membrane voltage (the "membrane voltage clock") underlie the mechanisms of automaticity. The I(f) is a depolarization current activated during hyperpolarization. Therefore, when the cardiac cells recover, the I(f) is activated and slowly depolarizes the cell membrane, leading to the onset of action potential. Recent studies, however, suggest that increased intracellular Ca (Ca(i)) induced by spontaneous rhythmic sarcoplasmic reticulum Ca release (the "calcium clock") is also jointly responsible for the initiation of the heart beat. Elevated Ca(i) activates another ionic current (the sodium-calcium exchanger current or I(NCX)), leading to spontaneous phase 4 depolarization. Under normal conditions, both clocks are needed to initiate the heart beat. Malfunction of the clocks is associated with sinus node dysfunction in heart failure and atrial fibrillation. More studies are needed to determine how both clocks work together to initiate heart beat under normal and disease conditions.
    Circulation Journal 12/2009; 74(2):221-5. · 3.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recurrent ventricular arrhythmias after initial successful defibrillation are associated with poor clinical outcome. We tested the hypothesis that postshock arrhythmias occur because of spontaneous sarcoplasmic reticulum Ca release, delayed afterdepolarization (DAD), and triggered activity (TA) from tissues with high sensitivity of resting membrane voltage (V(m)) to elevated intracellular calcium (Ca(i)) (high diastolic Ca(i)-voltage coupling gains). We simultaneously mapped Ca(i) and V(m) on epicardial (n=14) or endocardial (n=14) surfaces of Langendorff-perfused rabbit ventricles. Spontaneous Ca(i) elevation (SCaE) was noted after defibrillation in 32% of ventricular tachycardia/ventricular fibrillation at baseline and in 81% during isoproterenol infusion (0.01 to 1 micromol/L). SCaE was reproducibly induced by rapid ventricular pacing and inhibited by 3 mumol/L of ryanodine. The SCaE amplitude and slope increased with increasing pacing rate, duration, and dose of isoproterenol. We found TAs originating from 6 of 14 endocardial surfaces but none from epicardial surfaces, despite similar amplitudes and slopes of SCaEs between epicardial and endocardial surfaces. This was because DADs were larger on endocardial surfaces as a result of higher diastolic Ca(i)-voltage coupling gain, compared to those of epicardial surfaces. Purkinje-like potentials preceded TAs in all hearts studied (n=7). I(K1) suppression with CsCl (5 mmol/L, n=3), BaCl(2) (3 micromol/L, n=3), and low extracellular potassium (1 mmol/L, n=2) enhanced diastolic Ca(i)-voltage coupling gain and enabled epicardium to also generate TAs. Higher diastolic Ca(i)-voltage coupling gain is essential for genesis of TAs and may underlie postshock arrhythmias arising from Purkinje fibers. I(K)(1) is a major factor that determines the diastolic Ca(i)-voltage coupling gain.
    Circulation Research 11/2009; 106(2):399-408. · 11.86 Impact Factor

Publication Stats

227 Citations
101.86 Total Impact Points

Institutions

  • 2009–2013
    • Indiana University-Purdue University Indianapolis
      • • Krannert Institute of Cardiology
      • • Department of Medicine
      Indianapolis, IN, United States
  • 2010–2012
    • Indiana University-Purdue University School of Medicine
      • Department of Medicine
      Indianapolis, IN, United States
    • Taichung Veterans General Hospital
      臺中市, Taiwan, Taiwan
    • Beth Israel Deaconess Medical Center
      • Department of Medicine
      Boston, Massachusetts, United States