Voltage dependent conduction abnormalities in His bundle pacing in patients without His Purkinje system disease

Journal Pre-proof Voltage dependent conduction abnormalities in His bundle pacing in patients without His Purkinje system disease

Rehan Mahmud, Shakeel Jamal, Mohamed Musheinesh PII:

S0022-0736(19)30731-9

DOI:

https://doi.org/10.1016/j.jelectrocard.2019.12.005

Reference:

YJELC 52980

To appear in:

Journal of Electrocardiology

Please cite this article as: R. Mahmud, S. Jamal and M. Musheinesh, Voltage dependent conduction abnormalities in His bundle pacing in patients without His Purkinje system disease, Journal of Electrocardiology(2019), https://doi.org/10.1016/ j.jelectrocard.2019.12.005

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© 2019 Published by Elsevier.

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Voltage Dependent Conduction abnormalities in His Bundle Pacing in Patients Without His Purkinje System Disease.

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Rehan Mahmud MD, Shakeel Jamal MD, Mohamed Musheinesh BA,

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Total word count: 3351

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Brief title: Conduction abnormalities in His Bundle Pacing

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Disclosures: None Financial support: None

Tel: 989-894 6935 [email protected]

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Address for correspondence: Rehan Mahmud MD Bay Heart and Vascular 1900 Columbus Ave Bay City MI 48708

Tweet Ventricular activation time is faster with higher voltage. An alternative explanation for observed phenomenon during His bundle pacing.

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Abstract Background: During His bundle (HB) pacing, the active fixation of HB lead may cause disruption of the enclosed conduction fibers and cause conduction delay. His Purkinje conduction delays have been shown to revert to normal with higher voltage pacing. Objective: To determine if conduction delays seen with penetrative HB pacing are voltage dependent and can resolve with higher stimulus voltage. Methods: In 17 patients undergoing HBP, the effect of voltage on a composite His Purkinje system-ventricular activation time (hVAT) as well as electrocardiographic (ECG) evidence of conduction delay, was systematically evaluated. Results: There was highly significant prolongation of hVAT indicative of conduction delay in13/17 patients. ECG changes of rightward delay were also seen in 9/13 patients. Both types of delays were manifest at lower voltages and were uniquely resolved by higher stimulation voltage. A pre-excitation like abnormality was also seen in 15/17 patients. This conduction abnormality was manifest at higher voltage without prolongation of hVAT. In 6/15 patients the pre-excitation like abnormality ceased at lower voltage. Conclusion: HB pacing is associated with evidence of significant conduction delay noted at low voltage, which resolves with higher stimulation voltage. The more common pre-excitation like abnormality appears to occur at high voltage and, in of itself, does not appear to prolong hVAT.

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Key Words: 1) His Bundle pacing. 2) His Purkinje system conduction block. 3) Voltage dependent conduction block.

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Condensed Abstract

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Prolongation of ventricular activation time observed during penetrative

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His bundle (HB) pacing appears to be voltage dependent, suggesting that

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injury to HB conduction fibers was the likely cause of delay.

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The commonly seen pre-excitation like abnormality did not prolong

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ventricular activation time.

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Introduction The technique of His bundle pacing (HBP) requires penetrating the bundle of His (HB) (1). As such, injury to the enclosed conduction fibers may occur. Experimental evidence suggests that damage to His Purkinje system (HPS) may prolong activation time (2,3) and that higher voltage pacing may overcome such conduction delay (3). Furthermore, disruption of HB insulation with a helical screw, in the vicinity of the crest of the muscular septum (1), may also cause abnormalities which have not been systematically studied. Current explanations of observed phenomenon do not take into account the effect of possible injury to HB and its fibrous sheath. Conduction delays in QRS, including a pre-excitation like conduction abnormality, are felt to be due to concomitant stimulation of septal muscle and termed nonselective HB capture (4,5). We hypothesized that analyzing the relationship between a composite His purkinje system-ventricular activation time and pacing voltage may serve to differentiate injury related conduction delays from those felt to occur from septal muscle stimulation.

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Methods Patient population: Patient population: Seventeen patients (10 males) who had undergone a pacemaker for symptomatic bradycardia. These patients did not have manifest evidence of His Purkinje system conduction abnormalities or underlying cardiac disease. Mean age was 649 years. All patients had normal QRS axis, duration and voltage, as well as normal H-V intervals. An informed consent was obtained, and data was analyzed offline. Associated diseases in this group included, diabetes (5), hypertension (4) and pulmonary disease (4) The left ventricular ejection fraction was 586 % for the group. 1. Implantation of His bundle lead. Using a Medtronic HIS-C315 guide catheter, a Medtronic 3830 4.1 Fr fixed screw lead was 4

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deployed in the lower right atrial septum using fluoroscopy. While recording a unipolar electrogram from the lead tip, lead and guide catheter assembly was advanced towards coronary sinus os and then advanced superiorly and anteriorly until the His bundle electrogram was recorded. 2. The multicenter group defines His bundle pacing (HBP) as maximal functional engagement right and left fascicles (5). In our study, HBP was felt to be obtained when the His bundle (HB) electrogram could be clearly recorded both before and after active fixation of the lead and the H-V interval was >than 35 msec (5). However, based on recent concern regarding determination of ‘actual’ QRS duration and hence conduction delay in non-selective HBP (4,5); we instead measured time from His bundle electrogram to the onset of intrinsicoid deflection of the QRS; or H-V interval + ventricular activation time (hVAT), as the time it took for sinus pulse to travel from the lead tip to complete activation of the ventricles (Figure1). This was then compared to the interval from His bundle pacing artifact (h) to the onset of intrinsicoid deflection of the QRS, in essence the combined activation time of the His Purkinje system and the ventricular activation time (hVAT)) (Figure 1).

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Figure 1: Note: All figures are shown at sweep speed of 100 mm/sec In the left panel, the sum of H-V interval and VAT or hVAT of the sinus beat recorded from the post fixation His bundle (HB) lead is shown as 84 ms. In the left panel the time from pacing stimulus to onset of intrinsicoid deflection of Lead I (which encompasses activation of both the His purkinje system and ventricle) or hVAT, of HB paced beat at 5V, is 80 ms. Also note that rightward normal septal q wave in lead I (left panel) is replaced by an initial leftward pre-excitation like conduction abnormality. The positive ‘delta wave’ in Leads I and II and the initial negative polarity with notching seen in the descending limb of V1 resembles clinical pre-excitation seen in fasciculoventricular pathways.

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3. His bundle pacing (HBP) was done using 1.0 ms pulse width (5), starting at 5V with stepwise decrements to 1V with both unipolar and bipolar pulses. 4. At each 1 volt decrement the interval from His bundle pacing artifact (h) to the onset of intrinsicoid deflection of the QRS, in hVAT of paced beat) (Figure 1). This composite interval was compared to the hVAT of sinus beat (Figure1). 5. Thus, each paced QRS was evaluated for: a) Prolongation of hVAT in Lead I. b) Presence or absence of pre-excitation like abnormality of initial portion of QRS. c) Development of S wave in Lead 1(rightward conduction delay) as well as notching in Leads 1,2 as indicators of leftward conduction delay. d) Finally, the QRS axis in frontal plane, lead 1 voltage and slew rate of intrinsicoid deflection was recorded at each pacing voltage. . While 12 lead data were analyzed; Leads 1, 2 and V1 were substantially representative of changes being described and are shown in figures 1-5

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A Cardiolab system with signal acquisition computer with analog to digital converter was used, to display 12 lead ECG and His bundle electrogram in real-time during the procedure, and then stored on a computer drive. Twelve lead ECG was displayed at a bandwidth of 0.5 Hz to 50 Hz, the filter setting for His bundle electrogram was 0.05 Hz500Hz. The ECG and intra-cardiac electrograms were displayed at a sweep speed of 100 mm/sec during the implant procedure. Study data including QRS morphology was analyzed offline on a review monitor. Activation times were measured using on screen multi-leg calipers.

Results:

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Statistics: A paired t test was applied to the data, using an online statistics calculator (GraphPad). Mean difference at a p value <0.05 was considered significant.

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Baseline parameters: The mean His bundle (HB) pacing threshold was 1.30.2 V. For simplicity, the results for 2V and 5V are presented as representation of low voltage and high voltage His bundle pacing (HBP). There was no significant change with in the baseline measurements of H-V interval, ventricular activation time (VAT), frontal plane QRS axis, lead 1 voltage or slew rate of intrinsicoid deflection before and after active lead fixation of the pacing lead (Table 1).

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Table 1 H-V

QRS QRS VAT ID Axis Voltage mV/ms ms degrees mv ms Baseline 46.44.4 26.69.7 0.720.20 39.65.7 0.030.01 After lead fixation 48.13.1 2710.1 0.680.19 38.45.1 0.030.01 P value ns ns ns ns ns H-V = HV interval, VAT= ventricular activation time, ID=intrinsicoid deflection

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Effect of pacing voltage on prolonged combined His Purkinje systemVentricular Activation Time (hVAT). At higher voltage pacing of 5V, there was no significant difference between the combined activation time (H-V interval + VAT) in sinus rhythm and the paced stimulus to completion of ventricular time (hVAT) (Table 2) (figure1,3). In 6/17 patients the initial hVAT at 5V pacing was shorter than the HV+VAT interval (Figure 1,3), in rest the hVAT was slightly longer (Table 2).

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Table 2 Comparison of H-V interval +VAT with HVAT at 5 V (ms) Unipolar Pulse 5V Bipolar Pulse 5V hVAT = 93.613 hVAT= 92.310 H-V+VAT=86.1 5 H-V+VAT=86.56 P =0.06 mean diff.=7.4 ms P=0.3 mean diff= 5.8 ms There was, however, a highly significant prolongation of hVAT, as measured in Lead 1; as the pacing voltage was decreased (Table 3) and was seen in 13/17 patients. In most patients an abrupt larger increase which typically occurred from one beat to next was seen (Figure 4). Notching suggestive of leftward conduction delay was also seen at low voltage HB pacing (Figure 4,5). In these 13 patients 4 showed a smaller gradual increase in hVAT was seen as the pacing voltage was lowered before the abrupt change (Figure 4).

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Effect of pacing voltage on ECG evidence of rightward conduction delay: In 9/17 patients a terminal rightward conduction delay of varying duration was seen at lower voltages, which resolved at higher voltage pacing (Figure 3). At lower voltage range where the hVAT was often prolonged, there appeared to be no additional change in hVAT interval in Lead I as the rightward conduction delay manifest itself (Figure 3).

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Effect of pacing voltage on Pre-excitation like Conduction Delay: A pre-excitation like conduction delay was seen, following the pacing artifact, for a mean of duration 487ms in 15/17 patients (Figure 1-5). The pre-excitation vector was positive in Lead 1, reversing the normal left to right activation of the ventricular septum (i.e., masking the ‘septal’ q wave). The pre-excitation vector was associated with initial negative polarity in V1 with notching seen in the descending limb of QS wave in V1 (Figures 1-5). In all 15 patients the pre-excitation like conduction delay was observed at higher voltage (between 3V-5V) and did not appear to prolong hVAT in Lead I, (Table 2) (Figure 1,3). In 9/15 it persisted at lower voltage and duration of pre-excitation was seen to prolong (Figures 2,4,5). In 6/15 patients the pre-excitation like delay disappeared abruptly at lower voltage (Figures 2,3) a narrow QRS with stimulus to QRS interval similar to H-V interval was restored along with normal left to right septal activation (Figure 2,3). The dissipation of pre-excitation like delay at lower voltage was typically associated with evidence of HPS conduction delay, such as prolonged hVAT (Figure 2), or a rightward conduction delay (Figure 3) or both (Figure3). The Lead 1 QRS voltage increased significantly when the paced complex showed pre excitation abnormality as compared to baseline (Table 2. Figures 1,3). In patients who showed loss of pre excitation the voltage decreased towards baseline (figure 2,3).

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Figure 2. Left panel shows the pre-excitation like conduction abnormality at higher voltage (Leads 1, I1 and V1). Its duration prolongs as hVAT measurement also prolongs at lower voltage (first beat right panel). The second beat (right panel) shows the pre-excitation disappears with apparently narrow QRS (‘selective HB pacing’), however the hVAT remains prolonged.

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Figure 3. Left panel shows a sinus beat with hVAT of 84 ms. In right panel, His bundle pacing at 1.8V, the first beat shows significant pre-excitation in Lead II without prolongation of hVAT. As the voltage is lowered in the next 2 beats the

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pre-excitation disappears however, there is now rightward conduction delay manifest as broad S wave in Lead I and in rSR’ in V1 (RBBB like). This slide also shows that disappearance of preexcitation was typically associated with evidence of conduction delay.

Table 3 Comparison of HVAT at 2V and 5V pacing (ms) hVAT at 2V pacing 10415 5V vs 2V p=0.0008 * post lead fixation H-V+VAT is given for comparison

hVAT at 5V pacing 93.613

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Baseline H-V+VAT* 86.56

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Figure 4. In left panel, a short hVAT of 75 ms is noted at 2 volts. In right panel, a gradual (first beat) followed abrupt large increase is seen in hVAT from one beat to next. The pre-excitation like delay (Lead II) prolongs along with increase in hVAT.

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Figure 5. This ECG also show the prolongation of hVAT from left panel to right panel as the voltage is decreased. The pre-excitation like delay (Lead I, II, in particular the downward notch in V1, prolongs along with increase in hVAT (right panel). Note the initial low amplitude conduction abnormality in V1(right panel), it accompanies the pre-excitation in L1 and is inconsistent with rapid depolarization of a large volume septal mass, which would occur if the electrode was in direct contact with septal muscle.

Voltage dependent prolongation of ventricular activation time. Our data shows a significant unidirectional relationship between the combined His Purkinje system (HPS)/ventricular activation time (hVAT) and pacing voltage. High voltage His Bundle (HB) pacing was associated with short hVAT, whereas lowering voltage prolonged the hVAT. Tis observation is highly suggestive that conduction delay associated with penetrative HB pacing is voltage dependent (Figures 2,4,5).

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Experimental studies have similarly shown that both acute and chronic HPS conduction delay resolve with higher voltage pacing (3,6,7). Thus, both fixation injury to conduction fibers and transverse (instead of coaxial) excitation of HB may cause slow conduction (8) (figure 3). In HB pacing, high voltage pacing may restore more rapid conduction and result in narrow QRS, perhaps, either by overcoming an increased current requirement (3,6,7), or by virtue of a larger electric field causing activation of a more distal uninjured HB.

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Observations against electrode stimulation of septal muscle

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The one-way relationship of hVAT and pacing voltage argues against current explanations of QRS widening, where it is assumed that lead tip location, as it relates to HB and septal muscle, determines the QRS duration (5,9). If that were true, narrowing of hVAT (not just the QRS duration) would also have been seen, with low voltage pacing, with some regularity. A septal paced wide QRS complex caused by rapid depolarization of large volume of septal mass at low voltage, requires that lead electrode be in actual contact with septal muscle. However, there is little evidence that physical contact of HB lead tip with septum itself is likely. Recording an HV interval of 45 ms would place the 1.8 mm lead tip 1.5 to 2 cm from the branching right bundle which straddles the muscular septum (10). In an autopsy analysis, the HB lead tip was several millimeters away from the ventricular crest (11). Also, perhaps quite importantly, we did not observe ‘high voltage pacing causing a wide pre excited septal complex’ as reported by Williams et al (9). Catheter orientation, 10 mm inter electrode spacing, and smaller canine hearts may explain why they regularly observed slurred wide QRS at high voltages (up to 70 V). On the contrary, we had a fixed lead location determined by a measured HV interval. While we commonly observed pre-excitation with high voltage pacing, the QRS

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was always narrow; and the wide paced complex only occurred at low voltage preceded by hVAT prolongation (Figure 4).

Possible cause of observed septal muscle pre-excitation.

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In comparing the pre-excitation abnormality to clinically occurring accessory pathways, there appeared to be a remarkably similarity to fasciculoventricular (FV) bypass tracts (12), in particular, to that of His bundle pacing in a patient with FV pathway in whom the paced complex has a striking similarity to paced complex in figure 5 left panel (13). The pre-excitation was short and rapid at high voltage pacing and became slow and prolonged as the voltage was lowered, apparently in tandem with hVAT prolongation (Figures 2,4 and 5). When preexcitation ceased there was associated conduction delay and block (Figure 2,3). Thus, both appearance and functional behavior of the preexcitation abnormality, would suggest that a FV tract like connection with septum was established with HB lead fixation. It is not beyond the realm of possibility, that the disruption of HB insulation allows activation of nearby muscle strands (figure 6). Much like accessory pathways, the abrupt transition of activation wavefront from a narrow strand to a large volume of septal myocardium will cause the conduction velocity to decrease as ‘wavefront curvature expansion’ or ‘impedance mismatch’ occurs (14) (Figure 5). These phenomena are felt to cause the abnormal QRS in WPW syndrome (14) and may well explain the pre-excited complex in HB pacing.

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Atrium Membranous septum

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Figure 6: This figure is a stylized adaptation of a histological section where the His bundle (His) after penetrating the central fibrous body, emerges covered in fibrous sheath and in close proximity to the membranous septum and left crest of the muscular septum. Lead fixation may disrupt the fibrous insulation and expose the conduction fibers to the septum thus allowing current from His bundle stimulation to excite nearby strands of septal muscle.

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The possibility of such HB to septum connections, resulting in FV pathways like pre-excited QRS have, been reported following repair of conoventricular septal defect. The authors suggest “disruption of the His-Purkinje fiber insulation, permitting direct connections from the His bundle to adjacent ventricular myocardium” as a possible mechanism (15). Such hypotheses are also supported by experimental studies that have demonstrated current leaks from the cut Purkinje fiber insulation (16).

Clinical significance and future directions: Measuring the hVAT may be an accurate way to assess the all-important left ventricular activation time and avoid observation bias inherent in 15

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determining QRS duration in a pre-excited complex (4). Recognizing that a conduction delay is voltage dependent may allow the implanting physician to address the delay with higher pacing voltage. Understanding the pathogenesis of the pre-excited complex may help us determine its role in HB pacing. Thus far, its association with a normal QRS axis and hVAT similar to that during sinus rhythm, would suggest that activation sequence and activation time is primarily being determined by normal HPS activation (7,17).

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Study Limitation

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The electrophysiologic observation that His Purkinje system conduction block are voltage dependent, were made following acute lead fixation. Further studies will be required to determine the response of chronic conduction blocks to higher pacing voltage. The correlation between H-V plus VAT interval in sinus rhythm with paced hVAT interval at high voltage is observational and will need to be tested with larger study population to determine the ‘acceptable’ hVAT values during implant procedure and utility of this parameter in patients with HPS disease.

References 1. Nagarajan VD, Ho SY, Ernst. Anatomical Considerations for His Bundle Pacing. Circulation Arrhythmia and Electrophysiology 2019;12(7):1-10

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2. Spach MS, Barr RC, Johnson EA, Kootsey JM Cardiac Extracellular Potentials. Circulation Research 1973; 33(4): 465473. 3. Dodge FA, Cranefield PF Normal and abnormal conduction in the heart. Nonuniform conduction in cardiac Purkinje fibers. Futura Publishing Company Inc, Mount Kisco New York 1998. 379p 4. Upadhyay GA, Tung R. Selective versus non-selective his bundle pacing for cardiac resynchronization therapy. Journal of Electrocardiology 2017;50(2):191-194. 5. Vijayaraman P, Dandamudi G, Zanon F, Sharma PS, Tung R, Huang W. Permanent His bundle pacing: Recommendations from a Multicenter His Bundle Pacing Collaborative Working Group for standardization of definitions, implant measurements, and follow-up. Heart Rhythm2018;15(3):460-468. 6. Joyner R. (1981). Mechanisms of unidirectional block in cardiac tissues. Biophysical Journal1981;35(1):113-125. 7. Boineau JP, Spach MS. (). The relationship between the electrocardiogram and the electrical activity of the heart. Journal of Electrocardiology 19681;(1):117-124. 8. Myerburg RJ. Nilsson K, Befelev B, Castellanos A, Gelband H. Transverse spread and longitudinal dissociation in distal A-V conducting system. J Clin Invest 1977;52: 885-895 9. Williams DO, Scherlag BJ, Hope RR, El-Sherif N, Lazzara R, Samet P. Selective versus non-selective His bundle pacing. Cardiovascular Research1976;10(1):91-100. doi:10.1093/cvr/10.1.91 10. Kupersmith J, Krongrad E, Waldo AL, Conduction Intervals and Conduction Velocity in the Human Cardiac Conduction System. 1973 Circulation;47(4):776-785 11. Correa deSa DD, Hardin NJ, Crespo EM, Nicholas KB, Lustgarten DL,. Autopsy Analysis of the Implantation Site of a Permanent Selective Direct His Bundle Pacing Lead. Circ Arrythm Electrophysiol 2012;5:244-246 12. Suzuki, T., Nakamura, Y., Yoshida, S., Yoshida, Y., & Shintaku, H. Differentiating fasciculoventricular pathway from 17

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Wolff-Parkinson-White syndrome by electrocardiography (2014). Heart Rhythm,11(4), 686-690. 13. Bortone A, Leclercq F, Grolleau-Raoux R, Pasquié J. Intermittent fasciculoventricular pathway: ECG and electrophysiologic findings, clinical implications. EP Europace 2007;9(8):702-705. 14. Cabo C, Pertsov AM, Baxter WT, Davidenko JM, Gray RA, Jalife J. Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle. Circ Res 1994;75:1014–1028 15. Chang PM, Patel AR, Aziz P, Shah MJ. Fasciculoventricular accessory pathways following repair of ventricular septal defects. HeartRhythm Case Reports2015;1(5):331-336. 16. Weidmann S. The electrical constants of purkinje fibers. The Journal of Physiology1952;118(3):348-360. 17. Durrer D, Dam RT, Freud GE, Janse MJ, Meijler FL, Arzbaecher RC. Total Excitation of the Isolated Human Heart. Circulation 1970;41(6):899-912.

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Acknowledgements

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The authors appreciate the help of Patti Wesenick and Kim Heath in researching and collection of data respectively.

What’s New Conduction delay observed during His bundle pacing resolved with higher voltage, suggesting that injury to conduction fibers was the cause of QRS widening 18

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Current explanations that direct septal activation, is the cause of QRS widening is unlikely as high voltage pacing never resulted in a wide QRS.

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The septal activation results, perhaps, from activation of nearby muscle strands which cause a pre-excitation like abnormality and does not prolong activation time.

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AUTHOR STATEMENT JOURNAL OF ELECTROCARDIOLOGY Rehan Mahmud: Conceptualization, Methodology, Data curation Writing-

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Reviewing and Editing Shakeel Jamal.: Data analysis Mohamed Musheinesh: Data Analysis

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