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1.  Apamin-Sensitive Calcium-Activated Potassium Currents in Rabbit Ventricles with Chronic Myocardial Infarction 
Introduction
Apamin-sensitive small-conductance calcium-activated potassium current (IKAS) is increased in heart failure. It is unknown if myocardial infarction (MI) is also associated with an increase of IKAS.
Methods and Results
We performed Langendorff perfusion and optical mapping in 6 normal hearts and 10 hearts with chronic (5 weeks) MI. An additional 6 normal and 10 MI hearts were used for patch clamp studies. The infarct size was 25% [95% confidence interval, 20 to 31] and the left ventricular ejection fraction was 0.5 [0.46 to 0.54]. The rabbits did not have symptoms of heart failure. The action potential duration measured to 80% repolarization (APD80) in the peri-infarct zone (PZ) was150 [142 to 159] ms, significantly (p=0.01) shorter than in the normal ventricles (158 to 177] ms). The intracellular Ca transient duration was also shorter in the PZ (148 [139 to 157] ms) than in normal ventricles (168 [157 to 180] ms; P=0.017). Apamin prolonged the APD80 in PZ by 9.8 [5.5 to 14.1] %, which is greater than in normal ventricles (2.8 [1.3 to 4.3] %, p=0.006). Significant shortening of APD80 was observed at the cessation of rapid pacing in MI but not in normal ventricles. Apamin prevented postpacing APD80 shortening. Patch clamp studies showed that IKAS was significantly higher in the PZ cells (2.51 [1.55 to 3.47] pA/pF, N=17) than in the normal cells (1.08 [0.36 to 1.80] pA/pF, N=15, p=0.019).
Conclusion
We conclude that IKAS is increased in MI ventricles and contributes significantly to ventricular repolarization especially during tachycardia.
doi:10.1111/jce.12176
PMCID: PMC4207647  PMID: 23718850
action potentials; intracellular calcium; ion channels; repolarization reserve; potassium currents; myocardial infarction
2.  Apamin Induces Early Afterdepolarizations and Torsades de Pointes Ventricular Arrhythmia From Failing Rabbit Ventricles Exhibiting Secondary Rises in Intracellular Calcium 
Heart rhythm : the official journal of the Heart Rhythm Society  2013;10(10):10.1016/j.hrthm.2013.07.003.
Background
A secondary rise of intracellular Ca2+ (Cai) and an upregulation of IKAS are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific IKAS blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai.
Objectives
To test the hypothesis that small conductance Ca2+ activated apamin sensitive K+ current (IKAS) maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF).
Methods
We performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular (AV) block was created by cryoablation to allow pacing at slow rates.
Results
The left ventricular ejection fraction reduced from 69.1 [95% confidence interval 62.3–76.0]% pre-pacing to 30.4 [26.8–34.0]% (N=7, p<0.001) post-pacing. The QTc in failing ventricles was 337 [313–360] ms at baseline and 410 [381–439] ms after applying 100 nmol/L of apamin (p=0.01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of the EADs and PVBs always occurred at the site with long APD and large amplitude of the secondary rises of Cai. Apamin induced secondary rises of Cai in 1 non-failing ventricles, but no EAD or TdP were observed.
Conclusion
In HF ventricles, apamin induces EADs, PVBs and TdP from areas with secondary rises of Cai. IKAS is important in maintaining repolarization reserve and preventing TdP in HF ventricles.
doi:10.1016/j.hrthm.2013.07.003
PMCID: PMC3832504  PMID: 23835258
Action potential duration; apamin; optical mapping; potassium channels; torsades de pointes
3.  Low-Level Vagus Nerve Stimulation Upregulates Small Conductance Calcium Activated Potassium Channels in the Stellate Ganglion 
Background
Small conductance calcium activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges.
Objectives
To test the hypotheses that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the LSG.
Methods
Six dogs (Group 1) underwent 1-wk LL-VNS of the left cervical vagus nerve. Five normal dogs (Group 2) were used as control. SK2 protein levels were examined by western blotting. The ratio between SK2 and glyceraldehydes-3-phosphate-dehydrogenase (GAPDH) levels was used as an arbitrary unit (AU).
Results
We found higher SK2 expression in Group 1 (0.124 ± 0.049 AU) than Group 2 (0.085 ± 0.031 AU, P < 0.05). Immunostaining showed that the density of nerve structures stained with SK2 antibody was also higher in Group 1 (11,546 ± 7,271 μm2/mm2) than in Group 2 (5,321 ± 3,164 μm2/mm2, P < 0.05). There were significantly more ganglion cells without immunoreactivity to TH in Group 1 (11.4 ± 2.3%) than Group 2 (4.9 ± 0.7%; P < 0.05). The TH-negative ganglion cells mostly stained positive for choline acetyltransferase (ChAT) (95.9 ± 2.8% in Group 1 and 86.1 ± 4.4% in Group 2, P = 0.10). Immunofluorescence confocal microscopy revealed a significant decrease in the SK2 staining in the cytosol but an increase in the SK2 staining on the membrane of the ganglion cells in Group 1 compared to Group 2.
Conclusion
Left LL-VNS results in the upregulation of SK2 proteins, increased SK2 protein expression in the cell membrane and the increased TH-negative (mostly ChAT-positive) ganglion cells in the LSG. These changes may underlie the antiarrhythmic efficacy of LL-VNS in ambulatory dogs.
doi:10.1016/j.hrthm.2013.01.029
PMCID: PMC3671581  PMID: 23357541
Autonomic nervous system; Vagus nerve stimulation; Stellate ganglion; Small conductance calcium activated potassium channel; Western blot
4.  Apamin Sensitive Potassium Current Modulates Action Potential Duration Restitution and Arrhythmogenesis of Failing Rabbit Ventricles 
Background
Apamin-sensitive K currents (IKAS) are upregulated in heart failure (HF). We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and reduce ventricular fibrillation (VF) duration in failing ventricles.
Methods and Results
We simultaneously mapped membrane potential and intracellular Ca (Cai) in 7 rabbits hearts with pacing-induced HF and in 7 normal hearts. A dynamic pacing protocol was used to determine APDR at baseline and after apamin (100 nM) infusion. Apamin did not change APD80 in normal ventricles, but prolonged APD80 in failing ventricles at either long (≥300 ms) or short (≤170 ms) pacing cycle length (PCL), but not at intermediate PCL. The maximal slope of APDR curve was 2.03 [95% CI, 1.73 to 2.32] in failing ventricles and 1.26 [95% CI, 1.13 to 1.40] in normal ventricles at baseline (p=0.002). After apamin administration, the maximal slope of APDR in failing ventricles decreased to 1.43 [95% CI, 1.01 to 1.84] (p=0.018) whereas no significant changes were observed in normal ventricles. During VF in failing ventricles, the number of phase singularities (baseline vs apamin, 4.0 vs 2.5), dominant frequency (13.0 Hz vs 10.0 Hz), and VF duration (160 s vs 80 s) were all significantly (p<0.05) decreased by apamin.
Conclusions
Apamin prolongs APD at long and short, but not at intermediate PCL in failing ventricles. IKAS upregulation may be antiarrhythmic by preserving the repolarization reserve at slow heart rate, but is proarrhythmic by steepening the slope of APDR curve which promotes the generation and maintenance of VF.
doi:10.1161/CIRCEP.111.000152
PMCID: PMC3678988  PMID: 23420832
ventricular fibrillation; optical mapping; experimental models heart failure; electrophysiology
5.  Sympathetic nerve fibers and ganglia in canine cervical vagus nerves: Localization and quantitation 
Background
Cervical vagal nerve (CVN) stimulation may improve left ventricular ejection fraction in patients with heart failure.
Objectives
To test the hypothesis that sympathetic structures are present in the CVN and to describe the location and quantitate these sympathetic components of the CVN.
Methods
We performed immunohistochemical studies of the CVN from 11 normal dogs and simultaneously recorded stellate ganglion nerve activity, left thoracic vagal nerve activity, and subcutaneous electrocardiogram in 2 additional dogs.
Results
A total of 28 individual nerve bundles were present in the CVNs of the first 11 dogs, with an average of 1.87 ± 1.06 per dog. All CVNs contain tyrosine hydroxylase-positive (sympathetic) nerves, with a total cross-sectional area of 0.97 ± 0.38 mm2. The sympathetic nerves were nonmyelinated, typically located at the periphery of the nerve bundles and occupied 0.03%–2.80% of the CVN cross-sectional area. Cholineacetyltransferase-positive nerve fibers occupied 12.90%–42.86% of the CVN cross-sectional areas. Ten of 11 CVNs showed tyrosine hydroxylase and cholineacetyltransferase colocalization. In 2 dogs with nerve recordings, we documented heart rate acceleration during spontaneous vagal nerve activity in the absence of stellate ganglion nerve activity.
Conclusions
Sympathetic nerve fibers are invariably present in the CVNs of normal dogs and occupy in average up to 2.8% of the cross-sectional area. Because sympathetic nerve fibers are present in the periphery of the CVNs, they may be susceptible to activation by electrical stimulation. Spontaneous activation of the sympathetic component of the vagal nerve may accelerate the heart rate.
doi:10.1016/j.hrthm.2012.12.015
PMCID: PMC3758134  PMID: 23246597
Cervical vagus nerves; Sympathetic nerves; Ganglion cells; Heart failure; Vagal nerve stimulation
6.  Carvedilol Analogue Inhibits Triggered Activities Evoked by Both Early and Delayed Afterdepolarizations 
BACKGROUND
Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor (RyR2).
OBJECTIVE
We tested a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs).
METHODS
Intracellular Ca2+ and membrane voltage were simultaneously recorded using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue, VK-II-36 that does not have significant beta-blocking effects.
RESULTS
Spontaneous intracellular Ca2+ elevations (SCaEs) during diastole was induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496+/− mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs using a rabbit model of acquired long QT syndrome in which phase-2 and phase-3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase-2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase-3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied.
CONCLUSION
A carvedilol analogue, VK-II-36 inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs.
doi:10.1016/j.hrthm.2012.09.006
PMCID: PMC3534812  PMID: 22982970
afterdepolarization; intracellular calcium; long-QT syndrome
7.  Epicardial Adipose Tissue and Neural Mechanisms of Atrial Fibrillation 
doi:10.1161/CIRCEP.112.974956
PMCID: PMC3438902  PMID: 22895598
atrial fibrillation; Editorials; inflammation; nervous system, autonomic
8.  Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles 
BACKGROUND
Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs.
OBJECTIVE
To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles.
METHODS
We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Cai) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats.
RESULTS
SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02–0.06] vs 0.23 arbitrary units [95% confidence interval 0.18–0.28] at baseline; n = 6 hearts; P < .001). Lidocaine also significantly reduced the SCaE but was significantly (P < .05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of INa.
CONCLUSIONS
Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.
doi:10.1016/j.hrthm.2012.02.031
PMCID: PMC3572724  PMID: 22387372
Depolarization; Action potentials; Calcium; Antiarrhythmic agents
9.  Neural Control of Ventricular Rate in Ambulatory Dogs with Pacing Induced Sustained Atrial Fibrillation 
Background
We hypothesize that inferior vena cava-inferior atrial ganglionated plexus nerve activity (IVC-IAGPNA) is responsible for the ventricular rate (VR) control during atrial fibrillation (AF) in ambulatory dogs.
Methods and Results
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-s over 24-hour periods. LVNA was associated with VR reduction during AF in 5 dogs (from 211 bpm, 95% confidence interval [CI], 186 to 233 to 178 bpm [95% CI, 145 to 210], p<0.001) and RVNA in 1 dog (208 bpm [95% CI, 197 to 223] to 181 bpm [95% CI, 163 to 200], p<0.01). There were good correlations between IVC-IAGPNA and LVNA in the former 5 dogs, and between IVC-IAGPNA and RVNA in the latter dog. IVC-IAGPNA was associated with VR reduction in all dogs studied. RVNA was associated with baseline sinus rate reduction from 105 bpm (95% CI, 95 to 116) to 77 bpm (95% CI, 64 to 91, p<0.01) in 4 dogs while LVNA was associated with sinus rate reduction from 111 bpm (95% CI, 90 to 1250) to 81 bpm (95% CI, 67 to 103, p<0.01) in 2 dogs.
Conclusions
IVC-IAGPNA is invariably associated with VR reduction during AF. In comparison, right or left VNA was associated with VR reduction only when it co-activates with the IVC-IAGPNA. The vagus nerve that controls VR during AF may be different than that controls sinus rhythm.
doi:10.1161/CIRCEP.111.967737
PMCID: PMC3405983  PMID: 22586260
atrial fibrillation; atrioventricular node; ECG; nervous system, autonomic; ventricular rate
10.  Alternans of Diastolic Intracellular Calcium Elevation as the Mechanism of Bidirectional Ventricular Tachycardia in a Rabbit Model of Andersen-Tawil Syndrome 
Heart Rhythm  2010;9(4):626-627.
doi:10.1016/j.hrthm.2010.12.021
PMCID: PMC3065532  PMID: 21167318
Bidirectional ventricular tachycardia; Andersen-Tawil Syndrome; Alternans
11.  Triggered Firing and Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Induced by Overexpression of TGF-β1 
Background
Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Cai) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1).
Methods and Results
MHC-TGFcys33ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Cai transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Cai transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca2+-ATPase 2a.
Conclusions
Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Cai transient, EAD and triggered activity. Inhibition of Ca2+ release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.
PMCID: PMC3593311  PMID: 22447020
Arrhythmia; Atrial fibrillation; Ca2+ triggers; Intracellular calcium; Optical mapping; Transgenic mice models
12.  Neural mechanisms of atrial fibrillation 
Current Opinion in Cardiology  2012;27(1):24-28.
Purpose of review
The autonomic nerve system is a potentially potent modulator of the initiation and perpetuation of atrial fibrillation (AF). This review will briefly summarize the neural mechanisms of AF.
Recent findings
Complex interactions exist between the sympathetic and parasympathetic nervous system on the atrial electrophysiologic properties. Direct autonomic recordings in canine models demonstrated simultaneous sympathovagal discharges are the most common triggers of paroxysmal atrial tachycardia and paroxysmal AF. Also, intrinsic cardiac autonomic nerve can serve as a sole triggering factor for the initiation of AF. Modulation of autonomic nervous system (ANS) by electrical stimulation has been tried as a treatment strategy clinically and experimentally. Recent studies showed that autonomic nervous system modulation can suppress the stellate ganglion nerve activity and reduce the incidence of paroxysmal atrial tachyarrhythmias in ambulatory dogs.
Summary
The autonomic nerve system influences the initiation and perpetuation of AF. Scientific advances toward a better understanding of the complex interrelationships of the various components of the ANS will hopefully lead to improvement of treatments for this common arrhythmia.
doi:10.1097/HCO.0b013e32834dc4e8
PMCID: PMC3279730  PMID: 22139702
Autonomic nerve; atrial fibrillation; vagal nerve stimulation
13.  Intracellular Calcium and the Mechanism of Anodal Supernormal Excitability in Langendorff Perfused Rabbit Ventricles 
Circulation Journal  2011;75(4):834-843.
Background
Anodal stimulation hyperpolarizes cell membrane and increases intracellular Ca2+ (Cai) transient. This study tested the hypothesis that The maximum slope of Cai decline (–(dCai/dt)max) corresponds to the timing of anodal dip on the strength-interval curve and the initiation of repetitive responses and ventricular fibrillation (VF) after a premature stimulus (S2).
Methods and Results
We simultaneously mapped membrane potential (Vm) and Cai in 23 rabbit ventricles. A dip was observed on the anodal strength-interval curve. During the anodal dip, ventricles were captured by anodal break excitation directly under the S2 electrode. The Cai following anodal stimuli is larger than that following cathodal stimuli. The S1-S2 intervals of the anodal dip (203 ± 10 ms) coincided with the -(dCai/dt)max (199 ± 10 ms, p=NS). BAPTA-AM (n=3), INCX inhibition by low extracellular Na+ (n=3), and combined ryanodine and thapsigargin infusion (n=2) eliminated the anodal supernormality. Strong S2 during the relative refractory period (n=5) induced 29 repetitive responses and 10 VF episodes. The interval between S2 and the first non-driven beat was coincidental with the time of -(dCai/dt)max.
Conclusions
Larger Cai transient and INCX activation induced by anodal stimulation produces anodal supernormality. Time of maximum INCX activation is coincidental to the induction of non- driven beats from the Cai sinkhole after a strong premature stimulation.
PMCID: PMC3366464  PMID: 21301131
anodal dip; anodal stimulus; intracellular calcium; Na+-Ca2+ exchanger current
14.  Chronic Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines 
Circulation  2011;123(20):2204-2212.
Background
We hypothesize that left sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs.
Methods and Results
We implanted in 12 dogs a neurostimulator to stimulate left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activities (SGNA), vagal nerve activities (VNA) and electrocardiograms. Group 1 dogs (N=6) underwent 1 week continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated SGNA was significantly reduced during LL-VNS (7.8 mV-s; 95% confidence interval [CI] 6.94 to 8.66] vs. 9.4 mV-s [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). LL-VNS did not change VNA. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion one week after cessation of LL-VNS were 99684 µm2/mm2 (CI, 28850 to 170517) in LL-VNS dogs and 186561 µm2/ mm2 (CI, 154956 to 218166; P=0.008) in normal dogs. In Group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/day (CI, 0.5/day to 5.1/day) and 8.0/day (CI, 5.3/day to 12.0/day), respectively, significantly lower than during sham stimulation (9.2/day [CI, 5.3/day to 13.1/day], P=0.001 and 22.0/day [CI, 19.1/day to 25.5/day], P<0.001, respectively).
Conclusions
LL-VNS suppresses SGNA and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident one week after cessation of chronic LL-VNS.
doi:10.1161/CIRCULATIONAHA.111.018028
PMCID: PMC3101282  PMID: 21555706
nervous system, autonomic; vagal stimulation; tachyarrhythmias; atrial fibrillation
15.  Small-Conductance Calcium-Activated Potassium Channel and Recurrent Ventricular Fibrillation in Failing Rabbit Ventricles 
Circulation research  2011;108(8):971-979.
Rationale
Fibrillation-defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF).
Objective
We hypothesized that activation of apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels are responsible for the postshock APD shortening in failing ventricles.
Methods and Results
A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca2+ and membrane potential (Vm) was performed in failing and non-failing ventricles. Three failing ventricles developed SVF (SVF group), 9 did not (no-SVF group). None of the 10 non-failing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF, increased postshock APD80 in SVF group from 126±5 ms to 153±4 ms (p<0.05), in no-SVF group from147±2 ms to 162±3 ms (p<0.05) but did not change of APD80 in non-failing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K+ current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density is significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca2+ response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca2+ sensitivity of IKAS in failing ventricles. The Kd was 232 ± 5 nM for failing myocytes and 553 ± 78 nM for normal myocytes (p = 0.002).
Conclusions
Heart failure heterogeneously increases the sensitivity of IKAS to intracellular Ca2+, leading to upregulation of IKAS, postshock APD shortening and recurrent SVF.
doi:10.1161/CIRCRESAHA.110.238386
PMCID: PMC3086382  PMID: 21350217
arrhythmia; intracellular calcium; ion channels; ventricular fibrillation
16.  Delayed Afterdepolarization in Intact Canine Sinoatrial Node as a Novel Mechanism for Atrial Arrhythmia 
Introduction
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, non-voltage gated, intracellular Ca (Cai) elevation may induce delayed afterdepolarization (DAD) in intact SAN during isoproterenol infusion.
Methods and Results
We simultaneously mapped Cai and membrane potential in 31 isolated Langendorff-perfused canine right atriums (RA). Isoproterenol increased heart rate and late diastolic Cai 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).
Conclusion
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.
doi:10.1111/j.1540-8167.2010.01905.x
PMCID: PMC3077449  PMID: 21040091
calcium dynamics; sympathetic nervous system; triggered activity; sinoatrial node; afterdepolarization
17.  Patterns of Baseline Autonomic Nerve Activity and the Development of Pacing-Induced Sustained Atrial Fibrillation 
Background
Whether autonomic nerve activity is important in the development of pacing-induced sustained atrial fibrillation (AF) is unclear.
Objective
We tested the hypothesis that patterns of baseline autonomic nerve activities are important in the development of pacing-induced sustained AF.
Methods
We implanted radiotransmitters in 12 ambulatory dogs to record left stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA). Sustained (>48 hrs) AF was induced with intermittent rapid atrial pacing.
Results
At baseline (before pacing), the one-min 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 non-linear relationships with poor correlation (Group 2, N=9, r=0.316±0.162, P<0.05 compared with 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<0.001). Group 1 dogs had more frequent sympathovagal coactivation episodes than Group 2 (50±19/d vs. 15±6/d, P<0.05) and more paroxysmal atrial tachycardia (PAT; 5±1/d vs. 2±1/d, P<0.05) at baseline. Sustained AF occurred after 16±4 d (range 13–20 d) of pacing in Group 1 and after 46±18 d (range 23–72 d) of pacing in Group 2 (P<0.05). In the week before the development of sustained AF, the VNA of Group 2 dogs had significantly (P<0.05) increased compared to baseline.
Conclusions
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 the induction of sustained AF.
doi:10.1016/j.hrthm.2010.11.040
PMCID: PMC3065927  PMID: 21118728
Autonomic nervous system; Nerve recording; Atrial fibrillation; Arrhythmia; Atrial pacing
18.  Genesis of Phase-3 Early Afterdepolarizations and Triggered Activity in Acquired Long QT Syndrome 
Background
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.
Methods and Results
Intracellular Ca (Cai) and membrane voltage (Vm) were optically mapped in a quasi 2-dimensional model of cryoablated Langendorff-perfused rabbit ventricles (n = 16). E-4031 (an IKr blocker) combined with reduced extracellular K ([K+]o) and Mg ([Mg2+]o) prolonged action potential duration (APD) heterogeneously and induced phase-2 and phase-3 EADs. While phase-2 EADs were Cai-dependent, phase-3 EADs were not. The origins of 47 triggered activity (TA) 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 APD heterogeneity, creating a large Vm gradient across the boundary between long and short APD regions from which TA emerged. The amplitude of phase-3 EADs correlated with the Vm 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 IK1 caused by low [K+]o could generate intrinsic phase-3 EADs capable of inducing TA at the boundary zone.
Conclusions
Phase-3 EADs can be extrinsic due to electrotonic current across steep repolarization gradients, or intrinsic due to low IK1, and do not require spontaneous sarcoplasmic reticulum Ca release. Reduction of IK1 by low [K+]o strongly promotes ventricular arrhythmias mediated by phase-3 EADs in acquired long QT syndrome due to IKr blockade.
doi:10.1161/CIRCEP.110.959064
PMCID: PMC3045276  PMID: 21078812
action potentials; calcium; depolarization; long-QT syndrome; torsade de pointe
20.  Intrinsic Cardiac Nerve Activity and Paroxysmal Atrial Tachyarrhythmia in Ambulatory Dogs 
Circulation  2010;121(24):2615-2623.
Background
Little is known about the relationship between intrinsic cardiac nerve activity (ICNA) and spontaneous arrhythmias in ambulatory animals.
Methods and Results
We implanted radiotransmitters to record extrinsic cardiac nerve activity (ECNA, including stellate ganglion nerve activity, SGNA; vagal nerve activity, VNA) and ICNA (including superior left ganglionated plexi nerve activity, SLGPNA; ligament of Marshall nerve activity, LOMNA) in 6 ambulatory dogs. Intermittent rapid left atrial pacing was performed to induce paroxysmal atrial fibrillation (PAF) or atrial tachycardia (PAT). The vast majority (94%) of LOMNA were preceded or co-activated with ECNA (SGNA or VNA), whereas 6% of episodes were activated alone without concomitant SGNA or VNA. PAF and PAT were invariably (100%) preceded (<5 s) by ICNA. Most of PAT events (89%) were preceded by ICNA and sympathovagal co-activation, whereas 11% were preceded by ICNA and SGNA-only activation. Most of PAF events were preceded only by ICNA (72%); the remaining 28% by ECNA and ICNA together. Complex fractionated atrial electrograms (CFAEs) were observed during ICNA discharges that preceded the onset of PAT and PAF. Immunostaining confirmed the presence of both adrenergic and cholinergic nerve at ICNA sites.
Conclusions
There is a significant temporal relationship between ECNA and ICNA. However, ICNA can also activate alone. All PAT and PAF episodes were invariably preceded by ICNA. These findings suggest that ICNA (either alone or in collaboration with ECNA) is an invariable trigger of paroxysmal atrial tachyarrhythmias. ICNA might contaminate local atrial electrograms, resulting in CFAE-like activity.
doi:10.1161/CIRCULATIONAHA.109.919829
PMCID: PMC2890034  PMID: 20529998
nervous system; autonomic; atrium; arrhythmia; ligament of Marshall
21.  Arrhythmogenic Foci and the Mechanisms of Atrial Fibrillation 
doi:10.1161/CIRCEP.110.936385
PMCID: PMC3057413  PMID: 20160176
ablation; arrhythmia; electrophysiology; tachyarrhythmias; tachycardia
22.  Calcium Dynamics and the Mechanisms of Atrioventricular Junctional Rhythm 
Objectives
To test the hypothesis that rhythmic spontaneous sarcoplasmic reticulum (SR) calcium (Ca) release (the “Ca clock”) plays an important role in atrioventricular junction (AVJ) automaticity.
Background
The AVJ is a primary backup pacemaker to the sinoatrial node. The mechanisms of acceleration of AVJ intrinsic rate during sympathetic stimulation are unclear.
Methods
We simultaneously mapped transmembrane potential (Vm) and intracellular Ca (Cai) in Langendorff-perfused canine AVJ preparations that did not contain sinoatrial node (N=10).
Results
Baseline AVJ rate was 37.5 ± 4.0 bpm. 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 μmol/L increased heart rate to 100 ± 6.8 bpm, 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 co-localized 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 If blocker ZD 7288 did not prevent LDCAE or AVJ acceleration induced by isoproterenol (N=2).
Conclusions
Isoproterenol and caffeine induced LDCAE and accelerated intrinsic AVJ rhythm. Consistent co-localization of the maximum LDCAE and the leading pacemaker sites indicates that Ca clock is important to the intrinsic AVJ rate acceleration during sympathetic stimulation.
doi:10.1016/j.jacc.2010.03.070
PMCID: PMC3050609  PMID: 20797495
Automaticity; sympathetic stimulation; optical mapping; electrophysiology; arrhythmia
23.  Cryoablation of the Stellate Ganglia and Atrial Arrhythmia in Ambulatory Dogs With Pacing-Induced Heart Failure 
Objective
The purpose of the present study is to test the hypothesis that stellate ganglia ablation can reduce the incidences of atrial arrhythmias in a canine model of pacing-induced heart failure (HF).
Background
There is an association between autonomic nerve discharges and atrial arrhythmias (including both bradycardia and tachycardia) in ambulatory dogs with pacing-induced HF.
Methods
We performed cryoablation of the caudal half of left and right stellate ganglia and T2–4 thoracic sympathetic ganglia in 6 dogs (Experimental Group). We then continuously recorded left upper stellate ganglia nerve activity (SGNA), vagal nerve activity (VNA) and electrocardiogram using an implanted radiotransmitter.
Results
After two weeks of baseline recording, rapid right ventricular pacing (28 ± 4 days) was used to induce HF. Control Group (N=6) underwent the same procedures except for cryoablation. The Experimental Group had no paroxysmal atrial tachyarrhythmia (PAT) episodes (P<0.0001 compared with Control). Cryoablation significantly (p=0.0097) reduced prolonged (> 3 s) sinus pause (PSP) episodes from 5±6 to 0 in day 1, from 250 ± 424 to 11±11 in day 7 and from 123 ± 206 to 30±33 in day 14 after induction of HF. In experimental group only, VNA may occur alone without concomitant SGNA. However, these isolated VNA episodes did not result in PSP. Histological studies confirmed successful cryoablation of the caudal half of the stellate ganglia.
Conclusions
We conclude that cryoablation of bilateral stellate and T2–T4 thoracic ganglia significantly reduced PAT and PSP episodes induced by sympathetic discharges in dogs with pacing-induced HF.
doi:10.1016/j.hrthm.2009.08.011
PMCID: PMC2805174  PMID: 19959128
24.  Mechanisms of Recurrent Ventricular Fibrillation in a Rabbit Model of Pacing-Induced Heart Failure 
Objectives
To determine the mechanisms of spontaneous ventricular fibrillation (SVF) after initial successful defibrillation in a rabbit model of heart failure (HF).
Background
Successful defibrillation may be followed by recurrent SVF. The mechanisms of postshock SVF are unclear.
Methods
We performed simultaneous optical mapping of intracellular calcium (Cai) and membrane potential (Vm) in 12 rabbit hearts with chronic pacing-induced heart failure, in 4 sham operated hearts and in 5 normal hearts during fibrillation-defibrillation episodes.
Results
We recorded 28 SVF episodes after initial successful defibrillation in 4 failing hearts (SVF Group) but not in the remaining 8 failing hearts (no-SVF Group) or in the normal or sham operated hearts. The action potential duration (APD80) before pacing-induced VF was 209±9 ms (SVF-Group) and 212±14 ms (no-SVF Group, P=NS). After successful defibrillation, the APD80 in SVF Group shortened to 147±26 ms while in no-SVF Group shortened to 176±14 ms (P=0.04). However, the duration of Cai after defibrillation was not different between these two groups (246±21 ms vs. 241±17 ms, p=NS), resulting in elevated Cai during late phase 3 or phase 4 of the action potential. Standard glass microelectrode recording in an additional 5 failing hearts confirmed postshock APD shortening and afterdepolarizations. The APD80 of normal and sham operated hearts was not shortened after defibrillation.
Conclusions
HF promotes acute shortening of the APD immediately after termination of VF in failing hearts. Persistent Cai elevation during the late phase 3 and phase 4 of the shortened action potential result in afterdepolarizations, triggered activity and SVF.
doi:10.1016/j.hrthm.2009.02.017
PMCID: PMC2752449  PMID: 19467505
heart failure; action potential duration; intracellular calcium; spontaneous ventricular fibrillation; electrophysiology; sudden cardiac death
25.  Upper Limit of Vulnerability and Heterogeneity 
doi:10.1016/j.hrthm.2008.11.032
PMCID: PMC2672425  PMID: 19251213

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