Background-We have previously demonstrated that selective atrioventricular nodal (AVN) vagal stimulation (AVN-VS) can be used to control ventricular rate during atrial fibrillation (AF) in acute experiments. However, it is not known whether this approach could provide a long-term treatment in conscious animals. Thus, this study reports the first observations on the long-term efficacy and safety of this novel approach to control ventricular rate during AF in chronically instrumented dogs.Methods and Results-In 18 dogs, custom-made bipolar patch electrodes were sutured to the epicardial AVN fat pad for ;delivery of selective AVN- VS by a subcutaneously implanted nerve stimulator ( pulse width 100 mu s or 1 ms, frequency 20 or 160 Hz, amplitude 6 to 10 V). Fast-rate right atrial pacing ( 600 bpm) was used to induce and maintain AF. ECG, blood pressure, and body temperature were monitored telemetrically. One week after the induction of AF, AVN- VS was delivered and maintained for at least 5 weeks. It was found that AVN- VS had a consistent effect on ventricular rate slowing ( on average 45 +/- 13 bpm) over the entire period of observation. Echocardiography showed improvement of cardiac indices with ventricular rate slowing. AVN- VS was well tolerated by the animals, causing no signs of distress or discomfort.Conclusions-Beneficial long-term ventricular rate slowing during AF can be achieved by implantation of a nerve stimulator attached to the epicardial AVN fat pad. This novel concept is an attractive alternative to other methods of rate control and may be applicable in a selected group of patients.

OBJECTIVES The aim of this study was to assess whether Frank-Starling mechanism has an independent effect on left ventricular (LV) performance in atrial fibrillation (AF).BACKGROUND Ventricular performance in AF depends on variable contractility through the interval-force mechanism based on the ratio of preceding and pre-preceding RR intervals (RRp/RRPP). The impact of end-diastolic volume (EDV) variability, through the Frank-Starling mechanism, is not well understood.METHODS We induced AF in 16 open chest dogs. RR intervals, LV pressure, LV volume, and aortic flow were collected for > 400 beats during rapid AF (ventricular cycle length 29 +/- 66 ms). In six of the dogs, additional data were collected while average ventricular cycle length was prolonged from 258 +/- 34 ms to 445 +/- 80 ms by selective vagal nerve stimulation of the AV node.RESULTS The relations of maximal LV power (LVPower) and peak LV pressure derivative (dP/dt) versus RRP/RRPP were fitted to the equation y = A * (1 - EXP (RRP/RR(pp)min - RRP/RRPP)/C) and the residuals (RES) of these relations were analyzed. LVPower and dP/dt strongly correlated with RRP/RRPP (r(2) = 0.67 +/- 0.12 and 0.66 +/- 0.12, P < .0001 for all correlations). Importantly, RES-LVPower and RES-dP/dt showed linear correlation with EDV (r(2) = 0.20 +/- 0.14 and r(2) = 0.24 +/- 0.17, P < .01 for all correlations). In the six dogs with slowed average ventricular rate, the slope of both residual relationships (RES-LVPower vs EDV and RES-dP/dt vs EDV) decreased (P < .03 for both).CONCLUSIONS The Frank-Starling mechanism contributes to ventricular performance in AF independently of the interval-force effects of the beat-to-beat variability in cardiac contractility. The Frank-Starling mechanism is sensitive to the average ventricular rate. (C) 2004 Heart Rhythm Society. All rights reserved.

Objectives: Atrioventricular node (AVN) modification is one of the alternatives for ventricular rate control in patients with drug refractory atrial fibrillation (AF). However, the underlying mechanisms, and in particular the role of the dual pathway electrophysiology is not clear. By using a novel index, His electrogram (HE) alternans, we have previously demonstrated in rabbits that both the slow (SP) and the fast pathways (FP) are involved in AVN conduction during AF. This electrophysiological-morphological study was designed to address the role of selective FP ablation on AVN conduction during AF. Methods and Results: In 12 rabbit AVN preparations dual pathway conduction was confirmed by HE alternans during A1A2 pacing protocol, as well as during AF. On average 48% of the conducted beats during AF utilized the FP. Selective FP ablation (n=12) guided by HE alternans resulted in only-SP conduction, with longer AVN conduction time at basic beats, but without change of AVN effective refractory period (ERP). Interestingly, despite elimination of all FP-conducted beats during AF, the selective FP ablation allowed previously concealed SP beats to be conducted, resulting in little net effect on the ventricular rate (average His-His interval 199 +/- 10 ms before versus 201 +/- 13 ms after FP ablation, p>0.05). Morphological evidence indicated that FP ablation created lesions within the transitional cells of the superior approaches at the junction between the central fibrous body and the AVN. However, extension of FP ablation lesion into the compact AVN domain resulted in non-selective AVN modification and slowing of ventricular rate during AF. Conclusions: Despite its longer ERP, FP is responsible for a substantial number of ventricular beats during AF. However, selective FP ablation has a minor effect on ventricular rate. The most likely mechanism for this phenomenon is that FP ablation allows previously concealed SP beats to be conducted. On the other hand, ventricular rate slowdown could be achieved if FP ablations caused collateral damage in the compact node. This study highlights the usefulness of HE alternans as a novel tool to monitor dual pathway conduction during AF and to guide AVN modification. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Coupled pacing (CP), a method for controlling ventricular rate during atrial fibrillation (AF), consists of a single electrical stimulation applied to the ventricles after each spontaneous activation. CP results in a mechanical contraction rate approximately one-half the rate during AF. Paired stimulation in which two electrical stimuli are delivered to the ventricles has also been proposed as a therapy for heart failure. Although paired stimulation enhances contractility, it greatly increases energy consumption. The primary hypothesis of the present study is that CP improves cardiac function during acute AF without a similar increase in energy consumption because of the reduced rate of ventricular contractions. In a canine model, CP was applied during four stages: sinus rhythm (SR), acute AF, cardiac dysfunction ( CD), and AF in the presence of cardiac dysfunction. The rate of ventricular contraction decreased in all four stages as the result of CP. In addition, we determined the changes in external cardiac work, myocardial oxygen consumption, and myocardial efficiency in the each of four stages. CP partially reversed the effects of AF and CD on external cardiac work, whereas myocardial oxygen consumption increased only moderately. In all stages but SR, CP increased myocardial efficiency because of the marked increases in cardiac work compared with the moderate increases in total energy consumed. Thus this pacing therapy may be a viable therapy for patients with concurrent atrial fibrillation and heart failure.

Left ventricular ( LV) diastolic function during atrial fibrillation ( AF) remains poorly understood due to the complex interaction of factors and beat- to- beat variability. The purpose of the present study was to elucidate the physiological determinants of beat- to- beat changes in LV diastolic function during AF. The RR intervals preceding a given cardiac beat were measured from the right ventricular electrogram in 12 healthy open- chest mongrel dogs during AF. Doppler echocardiography and LV pressure and volume beat- to-beat analyses were performed. The LV filling time ( FT) and early diastolic mitral inflow velocity- time integral ( E-vti) were measured using the pulsed Doppler method. The LV end- diastolic volume ( EDV), peak systolic LV pressure ( LVP), minimum value of the first derivative of LV pressure curve ( dP/dt(min)), and the time constant of LV pressure decay ( tau) were evaluated with the use of a conductance catheter for 100 consecutive cardiac cycles. Beat- to- beat analysis revealed a cascade of important causal relations. LV- FT showed a significant positive linear relationship with E-vti ( r = 0.87). Importantly, there was a significant positive linear relationship between the RR interval and LV- EDV in the same cardiac beat ( r = 0.53). Consequently, there was a positive linear relationship between LV-EDV and subsequent peak systolic LVP ( r = 0.82). Furthermore, there were significant positive linear and negative curvilinear relationships between peak systolic LVP and dP/dt(min) ( r = 0.95) and tau ( r = - 0.85), respectively, in the same cardiac beat. In addition, there was a significant negative curvilinear relationship between dP/dt(min) ), and tau ( r = - 0.86). We have concluded that the determinants of LV diastolic function in individual beats during AF depend strongly on the peak systolic LVP. This suggests that the major benefit of slower ventricular rate appears related to lengthening of LV filling interval, promoting subsequent higher peak systolic LVP and greater LV relaxation.

Atrial tachycardia (AT) and fibrillation (AF) result in rapid ventricular rates that are detrimental to optimal cardiac function. The purpose of this study was to determine whether the application of a coupled pacing (CP) regimen would improve ventricular function by decreasing the ventricular rate of mechanical contractions (VRMCs). We simulated AT by pacing either atrium at a rate that resulted in a rapid but regular ventricular rate in seven anesthetized dogs. AF was induced by increasing the atrial pacing rate until atrial activation did not follow the pacing. After the induction of either AT or AF, we applied CP after each intrinsic ventricular activation. We measured the VRMCs and left ventricular (LV) pressures and volumes via a pressure-conductance catheter. The marked reductions in VRMCs during CP resulted in increases in LV end-diastolic volume. The CP resulted in virtually no mechanical contractions, whereas the strength of contractions from the normal electrical activation increased. The increases in the positive LV rate of pressure development over time and LV ejection fraction during CP were the result of postextrasystolic potentiation. The average stroke work (area of the pressure-volume loops) increased as a result of CP during both AT and AF. Despite the large increases in stroke volume (approximately 2x) during CP, the changes in cardiac output were moderate because the VRMCs markedly decreased (approximately 1/2). We conclude that CP therapy may be a viable therapy for slowing the heart rate and improving cardiac performance in patients with AT and AF.

Background-Traditional tools to study dual-pathway atrioventricular nodal (AVN) electrophysiology are not applicable in subjects with permanent atrial fibrillation (AF). The presence of fast-pathway (FP) and slow-pathway (SP) wavefronts and their possible modification remain uncertain in this condition. We demonstrated previously that His electrogram (HE) alternans can determine whether the FP or the SP reaches the His bundle on a beat-by-beat basis. We have now applied this novel index to monitor dual-pathway conduction and the effects of SP modification during AF.Methods and Results-In 12 rabbit AVN preparations, HE alternans were confirmed during a standard A(1)A(2) pacing protocol. During AF, in 9 of the 12 hearts, HE alternans indicated the presence of dual pathways. Successful SP modification guided by the HE alternans eliminated the SP, resulting in a predominantly FP conduction during AF in all hearts. This increased the average His-His interval (204+/-14 versus 276+/-51 ms, P<0.001). Morphological studies revealed that SP modification damaged only the posterior extension of the AVN.Conclusions-We have demonstrated for the first time in rabbits that HE alternans permit "visualization" of dual-pathway electrophysiology and confirmed the presence of both FP and SP wavefronts during AF. This novel index has been used in a selective SP ablation that resulted in a significant slowing of the ventricular rate. HE alternans provide a new insight into the mechanisms of AVN conduction and could guide AVN modification for ventricular rate control in AF clinically.

HomeCirculationVol. 107, No. 13Inappropriate Use of Atrioventricular Nodal Vagal Stimulation in Atrial Fibrillation Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBInappropriate Use of Atrioventricular Nodal Vagal Stimulation in Atrial Fibrillation Bernard G. Krohn, MD Bernard G. KrohnBernard G. Krohn Good Samaritan Hospital, Los Angeles, Calif, Originally published8 Apr 2003https://doi.org/10.1161/01.CIR.0000064686.11947.12Circulation. 2003;107:e90To the Editor:Zhuang et al1 showed well that slowing the ventricular rate by atrioventricular nodal vagal stimulation (AVN-VS) improved hemodynamics during atrial fibrillation (AF). This gave better hemodynamic responses than slowing the ventricular rate by atrioventricular nodal ablation with right ventricular pacing, which caused adverse effects that the authors cited. The authors then wrongly concluded, "…we believe that this novel strategy (AVN-VS) might be applicable in some patients, eg, postoperative patients with AF."However, atrial fibrillation after surgical operations, especially cardiac operations, is peculiar because it is self-limiting. This arrhythmia commonly starts on the second or third postoperative day, and it reverts to regular sinus rhythm in a few days if the fast ventricular rate is slowed. The ventricular rate can be slowed promptly and safely by giving intravenous digoxin, 15 to 19 micrograms per kg of lean body weight,2,3 using the dosing calculations of Roger Jelliffe et al.4 Digoxin stimulates the vagus nerve actively. β-blockers can be used in addition to digoxin.Many doctors are rightly reluctant to estimate these higher digoxin doses because estimating can cause toxicity. In contrast, the calculations by Jelliffe et al of doses for dangerous drugs, including digoxin, are used in more than 100 institutions and are available (Laboratory of Applied Pharmacokinetics, University of Southern California, Los Angeles, Calif. [email protected]). AVN-VS is an effective treatment. However, doctors should give postoperative patients the benefits of digoxin therapy controlled by the same calculations of doses that they use for other dangerous drugs, such as aminoglycosides. This costs less money and is less disturbing to the patients than other treatments.1 Zhuang S, Zhang Y, Mowrey KA, et al. Ventricular rate control by selective vagal stimulation is superior to rhythm regularization by atrioventricular nodal ablation and pacing during atrial fibrillation. Circulation. 2002; 106: 1853–1858.LinkGoogle Scholar2 Krohn BG, Saenz JM, Eto KK. The critical dose of digoxin for treating supraventricular tachycardias after heart surgery. Chest. 1989; 95: 729–734.CrossrefMedlineGoogle Scholar3 Krohn BG, Kay JH, Mendez MA, et al. Rapid sustained recovery after cardiac operations. J Thorac Cardiovasc Surg. 1990; 100: 194–197.CrossrefMedlineGoogle Scholar4 Jelliffe RW, Buell J, Kalaba R. Reduction of digitalis toxicity by computer-assisted glycoside dosage regimes. Ann Int Med. 1972; 77: 891–906.CrossrefMedlineGoogle ScholarcirculationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & WilkinsResponseZhuang Shaowei, , MD, Zhang Youhua, , MD, PhD, Mowrey Kent A., , MS, Tabata Tomotsugu, , MD, PhD, Wallick Don W., , PhD, Popović Zoran B., , MD, Grimm Richard A., , DO, Natale Andrea, , MD, Mazgalev Todor N., , PhD, and Li Jianbo, , PhD08042003Although we appreciate the comments of Dr Krohn, it appears that he has inappropriately interpreted our study.1 We reported a novel method for slowing of the ventricular rate during atrial fibrillation (AF) and evaluated it in juxtaposition to the atrioventricular (AV) nodal ablation accompanied by right ventricular pacing. We suggested that because of the demonstrated advantages of the selective AV nodal vagal stimulation, this alternative approach might deserve clinical consideration in a selected group of patients.This suggestion, however, does not deserve to be presented as an "inappropriate use of atrioventricular nodal vagal stimulation in AF." Indeed, one cannot make any conclusions about its appropriateness before an objective evaluation is performed and comparisons between alternatives are made. Dr Krohn's letter, therefore, simply refers to his experience using digoxin for ventricular rate control. This neither relates to our study nor compares digoxin with other pharmacological agents.We felt that the novel technology reported in our study would be most suitable for evaluation in postoperative patients because temporary pacing wires are frequently used and kept for several days in this group of patients. In fact, 2 clinical laboratories have already used similar technologies in patients. In one,2 the presence of the AV nodal fat pad and its use for modulation of the conduction were confirmed in open-heart surgery patients. The other,3 using standard intracardiac electrophysiological catheters, concluded that parasympathetic nerve stimulation "may serve as an adjunctive tool for the diagnosis/treatment of supraventricular tachycardias and may be beneficial for ventricular rate slowing during tachycardiac AF in patients with congestive heart failure." In view of the preliminary observations of its effectiveness and ease of use, selective vagal stimulation may prove to be an appropriate tool in certain cases.As to use of digoxin in postoperative AF patients, it was never a goal of our report to evaluate its appropriateness. This has been done repetitively by others, however, and it is well established that digoxin has no advantages as a single agent. In fact, ventricular rate control occurs more rapidly with both β-blocking agents and calcium antagonists than digoxin,4,5 and in general a combination of drugs is most often the recommended approach.6 Previous Back to top Next FiguresReferencesRelatedDetails April 8, 2003Vol 107, Issue 13 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000064686.11947.12PMID: 12682036 Originally publishedApril 8, 2003 PDF download Advertisement

Little is known about the mechanisms of vulnerability and defibrillation under ischemic conditions. We investigated these mechanisms in 18 Langendorff-perfused rabbit hearts during 75% reduced-flow ischemia. Electrical activity was optically mapped from the anterior epicardium during right ventricular shocks applied at various phases of the cardiac cycle while the excitation-contraction decoupler 2,3-butanedione monoxime (BDM; 15 mM) was used to suppress motion artifacts caused by contraction of the heart. During ischemia, vulnerable window width increased [from 30-90% of the action potential duration (APD) in the control to -10 to 100% of the APD in ischemia]. Moreover, arrhythmia severity increased along with the reduction of APD (176 +/- 9 ms in control and 129 +/- 26 ms in ischemia, P < 0.01) and increased dispersion of repolarization (45 +/- 17 ms in control and 73 +/- 28 ms in ischemia, P < 0.01). Shock-induced virtual electrode polarization was preserved. Depolarizing (contrary to hyperpolarizing) response time constants increased. Virtual electrode-induced wavefronts of excitation had much more tortuous pathways leading to wavefront fractionation. Defibrillation failure at all shock strengths was observed in four hearts. Optical mapping revealed that the shock extinguished the arrhythmia; however, the arrhythmia self-originated after an isoelectric window of 339 +/- 189 ms. In conclusion, in most cases, virtual electrode-induced phase singularity (VEIPS) was responsible for shock-induced arrhythmogenesis during acute global ischemia. Enhancement of arrhythmogenesis was associated with an increased dispersion of repolarization and altered deexcitation. In four hearts, arrhythmogenesis could not be explained by VEIPS.

Background— Selective atrioventricular nodal (AVN) vagal stimulation (AVN-VS) has emerged as a novel strategy for ventricular rate (VR) control in atrial fibrillation (AF). Although AVN-VS preserves the physiological ventricular activation sequence, the resulting rate is slow but irregular. In contrast, AVN ablation with pacemaker implantation produces retrograde activation (starting at the apex), with regular ventricular rhythm. We tested the hypothesis that, at comparable levels of VR slowing, AVN-VS provides hemodynamic benefits similar to those of ablation with pacemaker implantation. Methods and Results— AVN-VS was delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN in 12 dogs during AF. A computer-controlled algorithm adjusted AVN-VS beat by beat to achieve a mean ventricular RR interval of 75%, 100%, 125%, or 150% of spontaneous sinus cycle length. The AVN was then ablated, and the right ventricular (RV) apex was paced either irregularly (i-RVP) using the RR intervals collected during AVN-VS or regularly (r-RVP) at the corresponding mean RR. The results indicated that all 3 strategies improved hemodynamics compared with AF. However, AVN-VS resulted in significantly better responses than either r-RVP or i-RVP. i-RVP resulted in worse hemodynamic responses than r-RVP. The differences among these modes became less significant when mean VR was slowed to 150% of sinus cycle length. Conclusions— AVN-VS can produce graded slowing of the VR during AF without destroying the AVN. It was hemodynamically superior to AVN ablation with either r-RVP or i-RVP, indicating that the benefits of preserving the physiological antegrade ventricular activation sequence outweigh the detrimental effect of irregularity.

Although the beneficial effects of ventricular rate (VR) slowing during atrial fibrillation (AF) are axiomatic, the precise relationship between VR and hemodynamics has not been determined. We hypothesized that selective atrioventricular node (AVN) vagal stimulation (AVN-VS) by varying the nerve stimulation intensity could achieve precise graded slowing and permit evaluation of an optimal VR during AF. The aims of the present study were the following: 1) to develop a method for computerized vagally controlled VR slowing during AF, 2) to determine the hemodynamic changes at each level of VR slowing, and 3) to establish the optimal anterograde VR during AF. AVN-VS was delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN in 14 dogs. Four target average VR levels, corresponding to 75%, 100%, 125%, and 150% of the sinus cycle length (SCL), were achieved by computer feedback algorithm. VR slowing resulted in improved hemodynamics and polynomial fit analysis found an optimum for the cardiac output at VR slowing of 87% SCL. We conclude that this novel method can be used to maintain slow anterograde conduction with best hemodynamics during AF.

Atrial fibrillation (AF) is characterized by short and irregular ventricular cycle lengths (VCL). While the beneficial effects of heart rate slowing (i.e., the prolongation of VCL) in AF are well recognized, little is known about the impact of irregularity. In 10 anesthetized dogs, R-R intervals, left ventricular (LV) pressure, and aortic flow were collected for >500 beats during fast AF and when the average VCL was prolonged to 75%, 100%, and 125% of the intrinsic sinus cycle length by selective atrioventricular (AV) nodal vagal stimulation. We used the ratio of the preceding and prepreceding R-R intervals (RR(p)/RR(pp)) as an index of cycle length irregularity and assessed its effects on the maximum LV power, the minimum of the first derivative of LV pressure, and the time constant of relaxation by using nonlinear fitting with monoexponential functions. During prolongation of VCL, there was a pronounced decrease in curvature with the formation of a plateau, indicating a lesser dependence on RR(p)/RR(pp). We conclude that prolongation of the VCL during AF reduces the sensitivity of the LV performance parameters to irregularity.