Don W. Wallick

Ventricular Rate Control by Selective Vagal Stimulation Is Superior to Rhythm Regularization by Atrioventricular Nodal Ablation and Pacing During Atrial Fibrillation

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.

Chronic Atrioventricular Nodal Vagal Stimulation First Evidence for Long-Term Ventricular Rate Control in Canine Atrial Fibrillation Model

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 &mgr;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.

Assessment of Beat‐by‐Beat Control of Heart Rate by the Autonomic Nervous System: Molecular Biology Techniques Are Necessary, But Not Sufficient

Neural Control of Heart Rate. Vagus nerve activity can change heart rate substantially within one cardiac cycle, and the chronotropic effects decay almost completely within one cardiac cycle after cessation of vagal activity. The ability of the vagus nerves to regulate heart rate beat by beat can be explained in large part by the speed at which the neural signal is transduced to a cardiac response and by the rapidity of the processes that restore the basal heart rate when vagal activity ceases. Currently, the question of whether the cardiac tells can transduce the sympathetic neural signals rapidly enough to implement beatwise regulation is controversial. Emphasis on the speed of the processes that initiate the responses may, however, be misplaced. Instead, the processes that terminate the responses to autonomic neural activity (especially those processes that remove the released neurotransmitters) are probably the main determinants of the ability of the vagal and sympathetic systems to affect beatwise control. The norepinephrine (NE) released from the sympathetic nerve endings is removed from the cardiac tissues much more slowly than is the acetylcholine that is released from the vagal terminals. As a consequence of the potential deleterious effects associated with the slow removal of NE, the cardiac neural control system has evolved such that the sympathetic nerves ordinarily release NE at a slow rate. Hence, changes in sympathetic neural activity can alter cardiac behavior only slightly from beat to beat. Hence, beatwise control of cardiac function would be negligible, regardless of how swiftly the sympathetic nerve impulse is transduced t o a change in cardiac‐performance.

Frequency dependence of vasoactive intestinal polypeptide release and vagally induced tachycardia in the canine heart.

We evaluated the frequency dependence of vasoactive intestinal polypeptide (VIP) release from the parasympathetic nerves to the canine heart. In intact animals in the presence of beta-adrenergic receptor blockade (propranolol, 0.5 mg/kg), the cervical vagosympathetic trunks were stimulated at various frequencies before and after the administration of atropine (0.1 mg/kg). The stimulations before atropine produced a classical bradycardia that progressed to cardiac arrest when the stimulation frequency was raised above 10 to 15 Hz. After atropine, vagal stimulation at various frequencies increased heart rate. The heart rate reached a maximum increase of 21 +/- 3 beats per min at a stimulation frequency of 20 Hz. In an isolated atrial preparation in which the VIP outflow was measured, the tachycardia elicited after atropine had a frequency dependence similar to that obtained in vivo. The peak increase of 23 +/- 3% above the basal rate (95 +/- 8 beats per min) occurred at a stimulation frequency of 20 Hz. The VIP outflow paralleled the tachycardia response (r = 0.95); the maximum outflow of VIP was 172 +/- 54 pg/(min . 100 g wet wt) and was evoked at a stimulation frequency of 20 Hz. This suggests that the vagally induced tachycardia is mediated, at least partly, by VIP.

Nonexcitatory stimulus delivery improves left ventricular function in hearts with left bundle branch block.

Nonexcitatory Stimulation. Introduction: Preliminary data in a heart failure animal model and isolated muscle preparation have suggested that nonexcitatory stimulation (NES) improves left ventricular (LV) function.

Prolongation of cardiac cycle length attenuates negative dromotropic response to selective vagal stimuli

We stimulated intracardiac parasympathetic nerve fibers that selectively innervated the atrioventricular (AV) nodal area (AV parasympathetic stimulation), and the sinoatrial (SA) nodal area (SA parasympathetic stimulation), in autonomically decentralized, anesthetized dogs. We then compared these responses to those elicited by stimulation of the cervical vagus nerves. We investigated the interactions between the dromotropic and chronotropic responses to simultaneous AV and SA parasympathetic stimulation. AV parasympathetic stimulation increased the AV interval (AV conduction time) but did not alter the interval between atrial depolarizations (sinus cycle length). SA parasympathetic stimulation increased the sinus cycle length and evoked small changes in the AV interval. Simultaneous AV and SA parasympathetic stimulation, at different combinations of frequencies, induced negative dromotropic and chronotropic responses that were similar to those evoked by cervical vagal stimulation. The greater the increase in sinus cycle length, the less did a given parasympathetic stimulation prolong the AV interval. The prolongation of the AV interval by parasympathetic stimulation did not affect the sinus cycle length. These results suggest that the direct pure negative dromotropic response to parasympathetic nerve stimulation is attenuated by the prolongation of the sinus cycle length, e.g. a concomitant negative chronotropic effect of the parasympathetic stimulation, in the dog heart. This attenuation reflects a mechanism that does not depend on the relative timing of the stimulus impulses in the cardiac cycle, i.e. a phase-independent, as well as the previously reported phase-dependent, mechanism.

Effects of ionic channel antagonists barium, cesium, and UL-FS-49 on vagal slowing of atrial rate in dogs

In response to a brief vagal stimulus, the atrial rate initially slows, then transiently accelerates, and slows a second time. We determined the effects of three antagonists to two ionic channels on this characteristic triphasic pacemaker response. Brief bursts of vagal stimulation were delivered to anesthetized dogs, and atrial cycle lengths were recorded. Either barium, cesium, or UL-FS-49 was administered. Barium, which primarily blocks the acetylcholine-sensitive potassium current (IK,ACh), attenuated the initial vagally induced bradycardia by > 50% without affecting the subsequent acceleration or the secondary slowing. Cesium and UL-FS-49 [both of which primarily block the pacemaker current (If)] did not affect the initial vagal slowing of atrial rate but abolished the acceleratory portion of the response. The secondary slowing was abolished by cesium but not by UL-FS-49. We conclude that the initial rapid atrial response to acetylcholine is mediated mainly by the IK,ACh, with little contribution from the If. The subsequent acceleration is mediated by activation of the If.In response to a brief vagal stimulus, the atrial rate initially slows, then transiently accelerates, and slows a second time. We determined the effects of three antagonists to two ionic channels on this characteristic triphasic pacemaker response. Brief bursts of vagal stimulation were delivered to anesthetized dogs, and atrial cycle lengths were recorded. Either barium, cesium, or UL-FS-49 was administered. Barium, which primarily blocks the acetylcholine-sensitive potassium current ( I K,ACh), attenuated the initial vagally induced bradycardia by >50% without affecting the subsequent acceleration or the secondary slowing. Cesium and UL-FS-49 [both of which primarily block the pacemaker current ( I f)] did not affect the initial vagal slowing of atrial rate but abolished the acceleratory portion of the response. The secondary slowing was abolished by cesium but not by UL-FS-49. We conclude that the initial rapid atrial response to acetylcholine is mediated mainly by the I K,ACh, with little contribution from the I f. The subsequent acceleration is mediated by activation of the I f.

Non-invasive assessment of left ventricular relaxation during atrial fibrillation using mitral flow propagation velocity

AIMS To elucidate the usefulness of the early diastolic mitral flow propagation velocity (V(p)) obtained from colour M-mode Doppler for non-invasively assessing left-ventricular (LV) relaxation during atrial fibrillation (AF). METHODS AND RESULTS Ten healthy adult dogs were studied to correlate V(p) with the invasive minimum value of the first derivative of LV pressure decay (dP/dt(min)) and the time constant of isovolumic LV pressure decay (tau) at baseline, during rapid and slow AF, and during AF after inducing myocardial infarction. There were significant positive and negative curvilinear relationships between V(p) and dP/dt(min) and tau, respectively, during rapid AF. After slowing the ventricular rate, the average value of V(p) increased, while dP/dt(min) increased and tau decreased. After inducing myocardial infarction, the average value of V(p) decreased, while dP/dt(min) decreased and tau increased. CONCLUSION The non-invasively obtained V(p) evaluates LV relaxation even during AF regardless of ventricular rhythm or the presence of pathological changes.

Coupled pacing improves left ventricular function during simulated atrial fibrillation without mechanical dyssynchrony

AIMS Electrical stimulation [coupled pacing (CP)] applied near the end of the T-wave is able to create a retrograde activation of the atrioventricular (AV) node in turn to prevent rapid ventricular conduction during atrial fibrillation (AF). The impact of this pacing modality associated with cardiac resynchronization therapy (CRT) has been evaluated in the present experimental study. METHODS AND RESULTS After inducing AF by rapid pacing in six dogs, we applied the following pacing modalities: rapid right ventricular (RV) pacing, rapid CRT, CRT with an additional RV paced beat (CP) at a specific delay (CRT + CP), and CRT with vagal stimulation (CRT-VS). Left ventricular (LV) pressure recordings and echocardiography for 2D strain analysis were performed. CRT + CP reduced the ventricular response rate and increased the LV systolic pressure and cardiac output compared with CRT alone (136 +/- 6 vs. 86 +/- 13 mmHg, P < 0.05 and 2.0 +/- 0.4 vs.1.2 +/- 0.1, P < 0.05 L/m, respectively). Compared with CRT-VS, CRT + CP increased the LV ejection fraction (LVEF = 51 +/- 10 vs. 28 +/- 4%, P < 0.05), peak global circumferential strain (-17 +/- 2 vs. -11 +/- 3%), and diastolic filling time (49 +/- 6 vs. 28 +/- 3%, P < 0.02) suggesting beneficial effects of CP beyond rate control. CRT + CP did not result in increased dyssynchrony [CRT (8.3 +/- 2%) vs. CRTCP (8.4 +/- 3%, P = NS)]. CONCLUSION CRT + CP effectively reduces ventricular contractile rate and leads to an increase in systolic and diastolic performance without inducing mechanical dyssynchrony.

Single capacitive discharge utilizing an auxiliary shock in the coronary venous system reduces the defibrillation threshold

Auxiliary shocks (AS) from electrodes sutured to the left ventricle (LV) prior to primary biphasic shocks (PS) have been shown to reduce defibrillation thresholds (DFT). Two capacitors are required to generate these waveforms. We investigate delivery of AS from one capacitor using a novel waveform. The epicardial surface of the LV is accessed transvenously via the middle cardiac vein (MCV) avoiding a thoracotomy. Methods: A defibrillation electrode was placed in the right ventricle (RV) and superior vena cava (SVC) in 12 pigs (37±2kg). A 50×1.8mm electrode was inserted in the MCV through a guide catheter. A can was placed in the left pectoral region. A monophasic AS (100μF, 1.5J) was delivered along one pathway before switching to deliver a biphasic waveform (40% tilt, 2ms phase 2) along another. DFTs (PS+AS) were assessed using a binary search. Two configurations not incorporating AS acted as controls. DFTs were compared using repeated measures analysis of variance. Results: DFTs of the four novel configurations (AS/PS) were: RV→Can/MCV→Can=14.9±3.7J, MCV→Can/RV→Can=17.2±5.7J, RV→SVC+Can/MCV→SVC+Can=13.4±4.6J, MCV→SVC+Can/RV→SVC+Can=17.1±5.9J. Delivering AS in the RV followed by PS in the MCV reduced the DFT (RV→Can (19.9±7.3 J, P<0.01) and RV→SVC+Can (19.2±6.0 J, P<0.05)). Conclusions: Delivering AS prior to PS in the MCV reduces the DFT by up to a third compared to conventional configurations of RV→Can and RV→SVC+Can. This is possible using only a single capacitor and an entirely transvenous approach to the LV.