atrial fibrillation; Editorials; inflammation; nervous system, autonomic
Bidirectional ventricular tachycardia; Andersen-Tawil Syndrome; Alternans
ablation; arrhythmia; electrophysiology; tachyarrhythmias; tachycardia
Early afterdepolarizations (EADs) are secondary voltage depolarizations during the repolarizing phase of the action potential, which can cause lethal cardiac arrhythmias. The occurrence of EADs requires a reduction in outward current and/or an increase in inward current, a condition called reduced repolarization reserve. However, this generalized condition is not sufficient for EAD genesis and does not explain the voltage oscillations manifesting as EADs. Here, we summarize recent progress that uses dynamical theory to build on and advance our understanding of EADs beyond the concept of repolarization reserve, towards the goal of developing a holistic and integrative view of EADs and their role in arrhythmogenesis. We first introduce concepts from nonlinear dynamics that are relevant to EADs, namely, Hopf bifurcation leading to oscillations and basin of attraction of an equilibrium or oscillatory state. We then present a theory of phase-2 EADs in nonlinear dynamics, which includes the formation of quasi-equilibrium states at the plateau voltage, their stabilities, and the bifurcations leading to and terminating the oscillations. This theory shows that the L-type calcium channel plays a unique role in causing the nonlinear dynamical behaviours necessary for EADs. We also summarize different mechanisms of phase-3 EADs. Based on the dynamical theory, we discuss the roles of each of the major ionic currents in the genesis of EADs, and potential therapeutic targets.
Early afterdepolarizations; Repolarization reserve; Nonlinear dynamics; Oscillation; Arrhythmias
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.
Calcium; Sinoatrial node; Sarcoplasmic reticulum; Sympathetic nervous system
This review focuses on the importance of autonomic nervous system (ANS) activity in the induction of paroxysmal atrial fibrillation (PAF). Clinical studies suggest that both sympathetic and parasympathetic nervous systems are important in mediating PAF. Consistent with that hypothesis, heart rate variability analyses showed that sympathovagal imbalance is present before the onset of PAF episodes. The importance of the ANS in PAF is further supported by animal experiments and recent clinical studies showing that vagal denervation enhances the efficacy of circumferential pulmonary vein ablation in preventing AF recurrence. In vitro studies show that ANS activation facilitates early afterdepolarization and triggered activity by simultaneously prolonging the intracellular calcium (Cai) transient (sympathetic effect) and shortening the action potential duration (parasympathetic effect). By simultaneously mapping the membrane potential and Cai transient in canine pulmonary vein during sympathetic stimulation, we demonstrated that spontaneous (voltage-independent) sarcoplasmic reticulum calcium release underlies the mechanisms of focal discharges. We developed and studied canine models of PAF induced by electrical, structural, and neural remodeling. We also have developed methods for long-term continuous recording of sympathetic and vagal nerve activity in ambulatory dogs. Preliminary results show that simultaneous sympathovagal discharges precede the onset of PAF in these dogs. ANS activity and Cai transient dynamics are important in the development of PAF. These studies suggest that new methods or drugs aimed at modification of cardiac ANS activity may lead to new opportunities for AF control.
Intracellular calcium current; Optical mapping; Triggered activity; Afterdepolarization
Small conductance calcium activated potassium channels (SKCa) are voltage insensitive and are activated by intracellular calcium. Genome wide association studies revealed that a variant of SKca is associated with lone atrial fibrillation (AF) in humans. Roles of SKca in atrial arrhythmias remain unclear.
The purpose of this study was to determine roles of SKCa in atrial arrhythmias.
Optical mapping using isolated canine left atrium was performed. The optical action potential duration (APD) and induction of arrhythmia were evaluated before and after the addition of specific SKCa blockers, Apamin or UCL-1684.
SKCa blockade significantly increased APD80 (188±19 ms vs 147±11ms, p< 0.001). The pacing cycle length (PCL) thresholds to induce 2:2 alternans and wave breaks were prolonged by SKCa blockade. Increased APD heterogeneity was observed following SKCa blockade, as measured by the difference between maximum and minimum APD (39±4ms vs 26±5ms, p<0.05), by standard deviation (12.43±2.36ms vs 7.49±1.47ms, p<0.001), or by coefficient of variation (6.68±0.97% vs 4.90±0.84%, p<0.05). No arrhythmia was induced at baseline by S1–S2 protocol. After SKCa blockade, 4 out of 6 atria developed arrhythmia.
Blockade of SKCa promotes arrhythmia and prolongs the PCL threshold of 2:2 alternans and wave breaks in the canine left atrium. The proarrhythmic effect could be attributed to the increased APD heterogeneity in the canine left atrium. This study provides supportive evidence of GWAS studies showing association of KCNN3 and lone AF
Atrial arrhythmia; SKCa; action potential duration; repolarization; optical mapping
Apamin is commonly used as a small-conductance Ca2+-activated K+ (SK) current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear.
To test the hypothesis that apamin does not inhibit any major cardiac ion currents.
We studied human embryonic kidney (HEK) 293 cells that expressed human voltage-gated Na+, K+ and Ca2+ currents and isolated rabbit ventricular myocytes. Whole-cell patch clamp techniques were used to determine ionic current densities before and after apamin administration.
Ca2+ currents (CACNA1c+CACNB2b) were not affected by apamin (500 nM) (data are presented as median [25th percentile;75th percentile] (from –16 [–20;–10] to –17 [–19;–13] pA/pF, P = NS), but were reduced by nifedipine to –1.6 [–3.2;–1.3] pA/pF (p = 0.008). Na+ currents (SCN5A) were not affected by apamin (from –261 [–282;–145] to –268 [–379;–132] pA/pF, P = NS), but were reduced by flecainide to –57 [–70;–47] pA/pF (p = 0.018). None of the major K+ currents (IKs, IKr, IK1 and Ito) were inhibited by 500 nM of apamin (KCNQ1+KCNE1, from 28 ;  to 23 ;  pA/pF; KCNH2+KCNE2, from 28 ;  to 27 ;  pA/pF; KCNJ2, from –46 [–48;–40] to –46 [–51;–35] pA/pF; KCND3, from 608 [505;748] to 606 [454;684]). Apamin did not inhibit the INa or ICaL in isolated rabbit ventricular myocytes (INa, from –67 [–75;–59] to –68 [–71;–59] pA/pF; ICaL, from –16 [–17;–14] to –14 [–15;–13] pA/pF, P = NS for both).
Apamin does not inhibit human cardiac Na+ currents, L-type Ca2+ currents or other major K+ currents. These findings indicate that apamin is a specific SK current inhibitor in hearts as well as in other organs.
The purpose of this study was to evaluate the changes of left stellate ganglionic nerve activity (SGNA) and left thoracic vagal nerve activity (VNA) after acute myocardial infarction (MI).
Whether MI results in remodeling of extracardiac nerve activity remains unclear.
We implanted radiotransmitters to record the SGNA, VNA, and electrocardiogram in 9 ambulatory dogs. After baseline monitoring, MI was created by 1-h balloon occlusion of the coronary arteries. The dogs were then continuously monitored for 2 months. Both stellate ganglia were stained for growth-associated protein 43 and synaptophysin. The stellate ganglia from 5 normal dogs were used as control.
MI increased 24-h integrated SGNA from 7.44 ± 7.19 Ln(Vs)/day at baseline to 8.09 ± 7.75 Ln(Vs)/day after the MI (p < 0.05). The 24-h integrated VNA before and after the MI was 5.29 ± 5.04 Ln(Vs)/day and 5.58 ± 5.15 Ln(Vs)/day, respectively (p < 0.05). A significant 24-h circadian variation was noted for the SGNA (p < 0.05) but not the VNA. The SGNA/VNA ratio also showed significant circadian variation. The nerve densities from the left SG were 63,218 ± 34,719 μm2/mm2 and 20,623 ± 4,926 μm2/mm2 for growth-associated protein 43 (p < 0.05) and were 32,116 ± 8,190 μm2/mm2 and 16,326 ± 4,679 μm2/mm2 for synaptophysin (p < 0.05) in MI and control groups, respectively. The right SG also showed increased nerve density after MI (p < 0.05).
MI results in persistent increase in the synaptic density of bilateral stellate ganglia and is associated with increased SGNA and VNA. There is a circadian variation of the SGNA/VNA ratio. These data indicate significant remodeling of the extracardiac autonomic nerve activity and structures after MI.
acute myocardial infarction; autonomic nervous system; nerve recordings
Cervical vagal nerve (CVN) stimulation may improve left ventricular ejection fraction in patients with heart failure.
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.
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.
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.
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.
Cervical vagus nerves; Sympathetic nerves; Ganglion cells; Heart failure; Vagal nerve stimulation
To elucidate the mechanism of late-phase 3 early after depolarization (EAD) in ventricular arrhythmogenesis, we hypothesized that intracellular calcium (Cai) overloading and action potential duration (APD) shortening may promote late phase 3 EAD and triggered activity, leading to development of ventricular fibrillation (VF).
Methods and Results
In isolated rabbit hearts, we performed microelectrode recording and simultaneous dual optical mapping of transmembrane potential (Vm) and Cai transient on left ventricular endocardium. An IKATP channel opener, pinacidil, was used to abbreviate action potential duration (APD). Rapid-pacing was then performed. Upon abrupt cessation of rapid pacing with cycle lengths of 60–200 ms, there were APD90 prolongation and the corresponding Cai overloading in the first post-pacing beats. The duration of Cai transient recovered to 50% (DCaT50) and 90% (DCaT90) in the first post-pacing beats was significantly longer than baseline. Abnormal Cai elevation coupled with shortened APD produced late-phase 3 EAD induced triggered activity and VF. In additional 6 preparations, the heart tissues were treated with BAPTA-AM, a calcium chelator. BAPTA-AM significantly reduced the maximal Cai amplitude (26.4±3.5% of the control; p<0.001) and the duration of Cai transients in the mapped region, preventing the development of EAD and triggered activity that initiated VF.
IKATP channel activation along with Cai overloading are associated with the development of late phase 3 EAD and VF. Because acute myocardial ischemia activates the IKATP channel, late phase 3 EADs may be a mechanism for VF initiation during acute myocardial ischemia.
ventricular fibrillation; early afterdepolarization; triggered activity; calcium; APD shortening
Protein complex of the cardiac junctional sarcoplasmic reticulum (SR) membrane formed by type 2 ryanodine receptor, junction, triadin, and calsequestrin is responsible for controlling SR calcium (Ca) release. Increased intracellular calcium (Cai) activates the electrogenic sodium–Ca exchanger current, which is known to be important in afterdepolarization and triggered activities (TAs). Using optical-mapping techniques, it is possible to simultaneously map membrane potential (Vm) and Cai transient in Langendorff-perfused rabbit ventricles to better define the mechanisms by which Vm and Cai interactions cause early afterdepolarizations (EADs). Phase 3 EAD is dependent on heterogeneously prolonged action potential duration (APD). Electrotonic currents that flow between a persistently depolarized region and its recovered neighbors underlies the mechanisms of phase 3 EADs and TAs. In contrast, “late phase-3 EAD” is induced by APD shortening, not APD prolongation. In failing ventricles, upregulation of apamin-sensitive Ca-activated potassium (K) channels (IKAS) causes APD shortening after fibrillation-defibrillation episodes. Shortened APD in the presence of large Cai transients generates late-phase 3 EADs and recurrent spontaneous ventricular fibrillation. The latter findings suggest that IKAS may be a novel antiarrhythmic targets in patients with heart failure and electrical storms.
Triggered activity; After depolarization; Ventricular fibrillation; Calcium dynamics; Optical mapping
Although the adult mammalian myocardium exhibits a limited ability to undergo regenerative growth, its intrinsic renewal rate is insufficient to compensate for myocyte loss during cardiac disease. Transplantation of donor cardiomyocytes or cardiomyogenic stem cells is considered a promising strategy to reconstitute cardiac mass, provided the engrafted cells functionally integrate with host myocardium and actively contribute to its contractile force. We have previously developed a two-photon fluorescence microscopy-based assay that allows in situ screening of donor cell function following their intracardiac delivery. Here we review the techniques and summarize its application for quantitation of the extent to which a variety of donor cell types stably and functionally couple with the recipient myocardium.
Cellular transplantation; myocardial regeneration; intracellular calcium regulation; two-photon fluorescence microscopy
Apamin sensitive potassium current (IKAS), carried by the type 2 small conductance Ca2+-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles.
To test the hypothesis that amiodarone inhibits IKAS in human embryonic kidney 293 (HEK-293) cells.
We used the patch-clamp technique to study IKAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration.
Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca2+). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca2+ (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of IKAS induced with 1 µM Ca2+ (n = 4), and 16.4±4.9% with 250 nM Ca2+ (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca2+ dependent inhibition of IKAS.
Both amiodarone and desethylamiodarone inhibit IKAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.
Myocardial infarction (MI) results in cardiac nerve sprouting in the myocardium. Whether or not similar neural remodeling occurs in the stellate ganglia (SG) is unknown. We aimed to test the hypothesis that MI induces bilateral SG nerve sprouting.
Acute MI was created by coronary artery ligation in rabbits (n=12). Serum nerve growth factor (NGF) level was measured by enzyme-linked immunosorbent assay (ELISA). The hearts and bilateral SGs were harvested for immunohistochemistry after 1 week in 6 rabbits, and after 1 month in 6 rabbits. Immunostaining for tyrosine hydroxylase (TH), growth-associated protein 43 (GAP43), cholineacetyltransferase (ChAT) and synaptophysin (SYN) was performed to determine the magnitude of nerve sprouting. Tissues from 6 normal rabbits were used as controls. Nerve density was determined by computerized morphometry.
MI results in increased serum NGF levels at 1 week (1519.8±632.2 ng/ml) that persists to 1 month (1361.2±176.3 ng/ml) as compared to controls (89.6±34.9 ng/ml), (p=.0002, and , p=.0001, respectively). Immunostaining demonstrated nerve sprouting and hyperinnervation in both SGs after MI. The nerve densities (µm2/ganglion cell) in SG 1 week after MI, 1 month after MI and in control groups, respectively, were: GAP43, 278±96, 225±39 and 149±57 (p=.01); SYN, 244±152, 268±115 and 102±60 (p=.02); TH, 233±71, 180±50 and 135±68 (p=.047); ChAT, 244±100, 208±46 and 130±41 µm2/cell (p=.01).
MI increases serum NGF levels and induces nerve sprouting and hyperinnervation in bilateral SGs for at least 1 month after MI. The hyperinnervation includes both postganglionic adrenergic axons and preganglionic cholinergic axons in the SG.
Myocardial Infarction; Ventricular Arrhythmia; Autonomic Nervous System; Stellate Ganglion; Nerve Sprouting; Sudden Cardiac Death
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.
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.
Arrhythmia; Atrial fibrillation; Ca2+ triggers; Intracellular calcium; Optical mapping; Transgenic mice models
We previously reported that IKAS are heterogeneously upregulated in failing rabbit ventricles and play an important role in arrhythmogenesis. This study goal is to test the hypothesis that subtype 2 of the small‐conductance Ca2+ activated K+ (SK2) channel and apamin‐sensitive K+ currents (IKAS) are upregulated in failing human ventricles.
Methods and Results
We studied 12 native hearts from transplant recipients (heart failure [HF] group) and 11 ventricular core biopsies from patients with aortic stenosis and normal systolic function (non‐HF group). IKAS and action potential were recorded with patch‐clamp techniques, and SK2 protein expression was studied by Western blotting. When measured at 1 μmol/L Ca2+ concentration, IKAS was 4.22 (median) (25th and 75th percentiles, 2.86 and 6.96) pA/pF for the HF group (n=11) and 0.98 (0.54 and 1.72) pA/pF for the non‐HF group (n=8, P=0.008). IKAS was lower in the midmyocardial cells than in the epicardial and the endocardial cells. The Ca2+ dependency of IKAS in HF myocytes was shifted leftward compared to non‐HF myocytes (Kd 314 versus 605 nmol/L). Apamin (100 nmol/L) increased the action potential durations by 1.77% (−0.9% and 7.3%) in non‐HF myocytes and by 11.8% (5.7% and 13.9%) in HF myocytes (P=0.02). SK2 protein expression was 3‐fold higher in HF than in non‐HF.
There is heterogeneous upregulation of IKAS densities in failing human ventricles. The midmyocardial layer shows lower IKAS densities than epicardial and endocardial layers of cells. Increase in both Ca2+ sensitivity and SK2 protein expression contributes to the IKAS upregulation.
arrhythmia; calcium; heart failure; ion channels
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.
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.
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.
Autonomic nerve; atrial fibrillation; vagal nerve stimulation
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive. We generated Jup mutant mice by ablating Jup in cardiomyocytes. Jup mutant mice largely recapitulated the clinical manifestation of human ARVC: ventricular dilation and aneurysm, cardiac fibrosis, cardiac dysfunction and spontaneous ventricular arrhythmias. Ultra-structural analyses revealed that desmosomes were absent in Jup mutant myocardia, whereas adherens junctions and gap junctions were preserved. We found that ventricular arrhythmias were associated with progressive cardiomyopathy and fibrosis in Jup mutant hearts. Massive cell death contributed to the cardiomyocyte dropout in Jup mutant hearts. Despite the increase of β-catenin at adherens junctions in Jup mutant cardiomyoicytes, the Wnt/β-catenin-mediated signaling was not altered. Transforming growth factor-beta-mediated signaling was found significantly elevated in Jup mutant cardiomyocytes at the early stage of cardiomyopathy, suggesting an important pathogenic pathway for Jup-related ARVC. These findings have provided further insights for the pathogenesis of ARVC and potential therapeutic interventions.
We hypothesize that unresponsiveness of superior sinoatrial node (SAN) to sympathetic stimulation is strongly associated with the development of symptomatic bradycardia in patients with atrial fibrillation (AF).
Methods and Results
We performed 3-dimensional endocardial mapping in healthy control (Group 1, n=10) and in patients with AF without (Group 2, n=57) or with (Group 3, n=15) symptomatic bradycardia at baseline and during isoproterenol infusion. Corrected SAN recovery time was abnormal in 0%, 11% and 36% of groups 1, 2 and 3, respectively (p=0.02). At baseline, 90%, 26% and 7% (p<0.001) of the patients had multicentric SAN activation patterns. For groups 1, 2 and 3, respectively, the median distance from the superior vena cava-right atrial junction to the most cranial earliest activation site (EAS) was 5.0 (25–75 percentile range, 3.5–21.3) mm, 10.0 (4–20) mm and 17.5 (12–34) mm at baseline (p=0.01), and was 4.0 (0–5) mm, 5.0 (1–10) mm and 15.0 (5.4–33.3) mm during isoproterenol infusion (p=0.01), suggesting upward shift of EAS during isoproterenol infusion. However, while the EAS during isoproterenol infusion was at the upper 1/3 of crista terminalis in 100% of Group 1 and 78% of Group 2 patients, only 20% of the groups 3 patients moved EAS to that region (p < 0.001).
Superior SAN serves as the EAS during sympathetic stimulation in normal patients and in most patients with AF without symptomatic bradycardia. In contrast, unresponsiveness of superior SAN to sympathetic stimulation is a characteristic finding in patients with AF and symptomatic bradycardia.
sinoatrial node; nervous system; sympathetic; atrial fibrillation; sick sinus syndrome; pacemakers
AHA Scientific Statements; atrial fibrillation; atrium; epidemiology; prevention; risk factors