Web viewWord Count:15,178. Correspondence. Michael O. Sweeney, MD. Cardiac Arrhythmia Service....

Electrocardiographic Method of Wave Interference for Characterizing Ventricular Fusion during Cardiac

Resynchronization Therapy

Michael O. Sweeney, MD, Anne S. Hellkamp, MS

From: Brigham and Women's Hospital, Boston, MA

Short Title: Wave Interference for QRS Fusion during CRT

Word Count: 15,178

Correspondence

Michael O. Sweeney, MDCardiac Arrhythmia ServiceShapiro Cardiovascular CenterBrigham and Women's Hospital70 Francis StreetBoston, MA 02115

Vmail: 857-307-1948 Fax: 857-307-1944 Email: [email protected]

Introduction

The standard 12-lead ECG is the most readily available, widely applied, least expensive, and

easily interpreted means of describing ventricular activation. The translational mechanism for

improvement in ventricular pump function and reverse remodeling during CRT is activation

sequence change induced by pacing. Exploratory work using QRS fusion complex analysis for

activation sequence changes established that one expression of BV fusion (new or increasing R

wave in leads V1-V2) predicted increased probability of reverse remodeling after adjusting for

substrate conditions (LV scar and conduction delay)1. R wave change in leads V1-V2 was used as

a test case because it is an easily recognized, quantifiable and widely cited pattern of change in

activation opposing the dominant electrical wave forces in LBBB, indicating effective LV capture

during BV pacing 2,3. This proof-of-principle experiment did not exclude the existence of other

QRS-derived fusion patterns or electrical parameters (e.g., change in electrical asynchrony, EAS)

indicative of effective or ineffective LBBB remediation.

The first published example of ventricular fusion by Sir Thomas Lewis in 1913, accompanied by

the following mechanistic explanation, is reproduced in Figure 1. “When a premature

contraction falls very late in diastole, the disturbance of ventricular rhythm is slight, for it comes

at an instant close to that at which a rhythmic beat is expected. The auricle may even contract

before the premature beat appears, so that there is an appreciable, though shortened, interval

between the auricular beat and the premature one. The origin of the latter is nevertheless

clearly shown by the shape of its electric complex. But suppose that the premature beat comes

so late that an auricular impulse is already well on its way to the ventricle, then two waves of

1

contraction, one from the normal source and one from the source of the irritation in the

ventricle, may travel over that chamber and meet somewhere in the walls. Under these

circumstances, the electrical complex of the ventricular contraction will be of transitional form.

The resultant ventricular curve has a distinct form, in which traces of the normal and traces of

the abnormal electric curves are seen. Such a contraction is the result of two impulses giving

rise to simultaneous contraction curves, which meet in the ventricular walls.” 4

Refinements to the ECG method for analysis of LBBB remediation during CRT were acquired

from analysis of QRS patterns during spontaneous BV fusion in classical electrocardiology. The

principles of fusion resulting from the interaction between two independent ventricular

activation wavefronts stipulate a conformational change in the QRS complex, generating a

hybrid combined wave complex possessing recognizable features of the patterns produced by

each wavefront alone 4, 5. The QRS fusion contour is most often intermediate in shape and

duration between the QRS contours of the independent wavefronts. The appearance of the

combined wave QRS contour reflects the volume of myocardium controlled by each advancing

wavefront. The exception to this principle occurs when the interacting wavefronts, each

generating a uniquely abnormal QRS complex, fuse to create a normal looking narrow complex

that bears no resemblance to one or both component complexes (Figure 2).These fusion QRS

contours are explained by interference and the principle of superposition during periodic wave

propagation. These concepts were transferred to QRS complex analysis for classifying and

quantifying BV electrical wave fusion.

2

Wave Interference for QRS Fusion

When 2 or more waves arrive at the same point and time they interact, or interfere, to create a

unique disturbance. The waves superimpose according to the principle of superposition, which

states that when two waves interfere the resulting wave is the sum of their individual effects.

Algebraically, the resultant displacement is the sum of the displacements of the individual waves

at that same point, irrespective of the individual wave shapes and amplitudes. If the two

interfering waves are identical in shape and amplitude and exactly in phase (peaks aligned with

peaks, troughs aligned with troughs), the displacements add, yielding a fusion wave that is twice

the amplitude of the individual waves but has the same wavelength. This superposition

produces pure constructive interference. If the two interfering waves are identical in shape and

amplitude but exactly out of phase (peaks aligned with troughs), the displacements completely

destroy each other, or cancel, and the resulting amplitude is zero. This superposition produces

pure destructive interference. Pure constructive and pure destructive interference require

precisely aligned identical waves. Most interacting waves are not identical and are at least

partially out of phase. The superposition of non-identical waves produces a mosaic of

constructive and destructive interference, displayed as a conformational hybrid of the two

interfering waves, which can vary from place to place and time to time. Therefore,

superposition of simple but dissimilar waves generates complex fusion wave patterns due to

mixed addition and subtraction of wave forces (Figure 3).

3

Wave Interference and the QRS during Normal Activation, LBBB, and Biventricular Fusion.

Cardiac electrical activation can be characterized as a volume model of periodic wave

propagation. Wave interference is responsible for the expression of the normal QRS complex.

Normal synchronous ventricular electrical activation generates a large number of wavefronts

propagating simultaneously in many directions. Most of these wavefronts are anti-phase and

undergo cancellation (destructive interference). The QRS complex is therefore formed by

residual in-phase (non-cancelled) wavefronts, which add forces (constructive interference) to

generate the normal narrow QRS.

During LBBB, RV and LV activation occur sequentially, therefore a large number of wavefronts

are in-phase, forces add (constructive interference), cancellation (destructive interference) is

reduced, and the electrocardiographically recorded potential has greater amplitude and

duration as compared to normal synchronous electrical activation.

Similarly, wave interference accounts for the classical examples of QRS fusion exemplified in

Figure 2. The naturally occurring spontaneous phenomenon of two independent and opposing

pacemakers generating ventricular fusion simulates the objective of BV pacing to correct LV

conduction delay. Idioventricular RV activation duplicates RV monochamber pacing (LBBB

activation), idioventricular LV activation duplicates LV monochamber pacing (RBBB activation),

and the QRS fusion contour is the predictable wave interference product of these opposing

wavefronts.

4

Consequently, a methodological solution for QRS fusion analysis was reexamined using the

principles of wave interference. In this model, BV fusion is an example of stable two-point

source interference where electrical wave generation is controlled by timed pacing stimulation.

Since the point sources produce waves at the same frequency they have identical wavelengths

but typically different shapes and amplitudes, which influence the interference pattern of the

combined wave. The interference pattern is also potentially influenced by the difference in

distance the two waves travel from their respective source to a common point. This path

difference is described in terms of the number of full waves that travel from each point source

to the interference point. Path difference influences superposition; constructive interference

occurs when the path difference between two wavefronts is equal to a whole number of

wavelengths, whereas destructive interference occurs when the path difference is equal to a

half number of wavelengths. During BV pacing single waves from each stimulation site interact

and complete before the subsequent wave from each site is emitted. However, the path length

and conduction velocity from each site to the interference point (e.g., different ECG lead

viewpoints) may differ depending on the contribution of muscle path conduction and Purkinje

system engagement influencing the superposition pattern. For example, dominantly

constructive interference may be observed from one point of view, whereas mixed constructive

and destructive interference observed from another (see below).

Updated Electrocardiographic Method for Analysis of QRS Fusion during CRT

5

The principles of wave interference, exemplified by the examples in Figures 1-3, were applied to

QRS fusion pattern recognition. Accordingly, initial attention was focused on the QRS contour

before and after BV pacing in leads V1-V2 which provide a reproducible pivot point between

anterior and posterior directed activation 1-3, 6, suitable for preliminarily characterizing LBBB

remediation. Four distinctive QRS Fusion Types were identified and ordered by observed

frequency: (1) new or increased R wave, with or without QRSd shortening; (2) no new or

increased R wave, QRSd shortening mandatory (QRS normalization); (3) no new or increased R

wave, QRSd unchanged or increased (LBBB reinforcement). Real-time manipulation of

ventricular activation using BV timing parameters identified a fourth QRS Type superficially

similar to Type 3, but where timing changes can induce a transformation to Type 1.

These 4 QRS Fusion Types recite the principles of BV fusion epitomized in Figures 1-3.

QRS Type 1 is characterized by a conformational change in the QRS complex, bearing

recognizable components of each independent activation wavefront. The QRS contour is a

hybrid, intermediate in shape between the shapes of the interacting wavefronts, and follows the

rule that the fusion complex admixture resembles both independent QRS types, e.g. shows

features of both. Reduction in QRSd is variably observed.

QRS Type 2 is characterized by QRS normalization. Conformational change is absent; wavefronts

interact to yield a normal looking, or normally narrow QRS contour. Reduction in QRSd is

obligatory.

QRS Type 3 is characterized by no conformational change in the QRS complex, which duplicates

or reinforces LBBB and RV monochamber pacing activation. QRSd is either neutral or increased.

6

QRS Type 4 is identical to Type 3 and is a form of concealed fusion. Transformation to Type 1 is

revealed by manipulation of BV timing parameters to alter ventricular activation.

Since stimulation from the lateral/posterolateral LV generates a large monophasic R wave in V1-

V2 1-3, 6, which opposes the QS in V1-V2 during typical LBBB and RV pacing, QRS Types 1 and 2

must be variations on the interference product of RV and LV paced wavefronts. The QRS Type 1

conformational change is due to a mosaic of constructive and destructive interference. The

resulting QRS contour represents the extent to which elements of the interfering wavefronts

reinforce or cancel one another; similarly, QRSd may increase or decrease depending on the

balance of constructive and destructive interference. QRS Type 2 is dominated by destructive

interference, generating greater cancellation, wave suppression, and QRSd shortening. The

greater contribution of destructive interference accounts for the larger reduction in QRSd

observed in QRS Type 2 vs. Type 1. QRS Types 1 and 2 are therefore distinguished primarily on

the extent to which wavefront cancellation due to destructive interference contributes to the

final QRS contour. QRS Types 3 and 4 are dominated by constructive interference.

Illustrations of the origin of these QRS Types as electrical wave interference products of RV and

LV stimulation are displayed in Figures 4-5.

These observations regarding wave interference and the genesis of QRS fusion patterns during

spontaneous or pacing-initiated BV activation support the following conceptualization of the

electrical mechanism of ventricular resynchronization:

1. Normal synchronous ventricular electrical activation is the interference product of a

multitude of simultaneously activating and cancelling wavefronts.

7

2. Sequential ventricular activation during LBBB reduces wavefront cancellation and increases

electrical asynchrony (EAS) due to unopposed wavefronts. Wavefronts are reinforcing, wave

forces sum, conduction delay is amplified.

3. BV fusion restores wavefront cancellation and reduces EAS with two large opposing

wavefronts that simulate normal ventricular activation. Wavefronts are highly oppositional,

wave forces cancel, LBBB conduction delay is reduced, EAS is reduced. The overall pattern

approximates normal ventricular activation.

4. QRS Types 1-2 are the interference products of 2 opposing wavefronts that represent

different forms of LBBB remediation. QRS Type 2 generally displays greater restoration of

cancellation and reduction of EAS as compared to QRS Type 1. QRS Type 3 is the interference

product of 2 non-opposing wavefronts. Wavefronts are reinforcing, wave forces sum, LBBB

conduction delay is amplified, EAS is increased. QRS Type 4 resembles Type 3; however,

manipulation of interventricular (I-V) timing reveals the concealed oppositional LV wavefront.

In summary, LBBB reduces wave cancellation, which results in electrical asynchrony; BV fusion

restores wave cancellation, which results in electrical resynchronization.

Primer for Method to Characterize and Quantify QRS Fusion Using Wave Interference

8

A QRS complex-based symbol language for rapid visual identification and numerical

quantification of ventricular activation sequences before and after BV pacing1 was developed.

This consists of two basic elements: (1) a quantifiable visual measure for ventricular activation

sequence change indicative of LBBB remediation (QRS fusion), using the principles of

superposition during wave interference, (2) a quantifiable numerical measure for change in EAS

using ventricular activation time (VAT) to characterize restoration of wavefront cancellation due

to fusion.

Briefly, LBBB and post-pacing QRS complexes are deconstructed into four possible waveform

components (i.e., R, S, Q, QS). Ventricular activation in each ECG lead is characterized by 9

possible QRS complex patterns1. Each QRS complex type, or glyphA, characterizes the pattern of

ventricular activation from a single unique point of view; combinations of QRS complexes are

used to express activation from multiple points of view. Amplitude, directionality, duration

(milliseconds) and other aspects of QRS complexes can be numerically analyzed to quantify

ventricular activation before and after pacing manipulation.

Typical ventricular activation during LBBB registration is right-to-left in the frontal plane (positive

forces in I, aVL; QRS = R, Rs), and anterior-to-posterior in the horizontal plane (negative forces in

V1-V2; QRS =QS, rS). These patterns may be influenced regionally by LV scar 1, 7.

BV fusion requires that (1) stimulation must occur from a site capable of reversing LV conduction

delay; (2) stimulation must be delivered in a fashion that effectuates reversal of LV conduction

delay. Changes in the QRS complex provide evidence for or against effective wavefront

A A symbol, such as a stylized figure or arrow on a public sign, that imparts information nonverbally

9

opposition to LBBB (LBBB remediation). These include (1) change in directionality of specific QRS

waveform components, (2) change in amplitude of specific QRS waveform components

(emergence of, or increased amplitude; regression of, or decreased amplitude), (3) change in

VAT as a surrogate for EAS. QRS waveform changes should demonstrate opposition to LBBB

forces.

For example, in the case of QRS Type 1 (conformational change), rS, RS, Rs, R (BV fusion) replace

QS or rS (LBBB) in leads V1-V2, indicating LBBB wavefront opposition in the horizontal plane

(LBBB: anterior-to-posterior → BV fusion posterior-to-anterior). Likewise, qR, QR, and QS (BV

fusion) replace R, Rs, or RS (LBBB) in leads I and aVL indicating LBBB opposition in the frontal

plane (LBBB: right-to-left → BV fusion: left-to-right). The QRS fusion complex shows

recognizable elements of the interfering RV and LV wavefronts as expected due to mixed

constructive and destructive interference. In this manner the morphology of the QRS complex is

correlated with the spread of BV activation.

For QRS Type 2 (non-conformational change), wavefront opposition to LBBB is manifest by QRS

normalization rather than a recognizable interference hybrid of the independent RV and LV

wavefronts. For example, QS or rS persist in leads V1-V2; R, Rs, or RS in leads I-aVL, during BV

fusion. However, QRSd is shortened and waveform component amplitudes are reduced (e.g.,

QS regression), as expected due to dominant destructive interference. This effect is termed

wave suppression. The fusion QRS complex therefore appears “normally narrow”; electrical axis

may be normalized.

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For QRS Type 3, wavefront opposition is not demonstrated. For example, QS and S waves in

leads V1-V2, and R, Rs, or RS in leads I-aVL persist and are often amplified; QRSd is increased.

LBBB activation is reinforced due to constructive interference.

The following method was used to objectively identify and quantify these QRS wave

interference products before and after BV pacing. First level QRS complex analysis was initially

confined to leads V1 and V2 because they are best positioned to register the interference

product of RV and LV pacing which are typically anti-phase in this vector. This arrangement is

also consistent with the classical ECG examples of BV fusion generated by 2 independent and

opposing idioventricular pacemakers (Figure 2). For QRS Types 1 and 2, R wave change is the

primary differentiating feature. QRS Type 1 was defined as new or increased R wave ≥ 1 mV (the

smallest amplitude change that could be reliably measured with electronic calipers at 200%

magnification)1 in leads V1-V2; QRS Type 2 was defined as the absence of new or increased R

wave. A change measure for EAS was needed to further differentiate QRS Types. Since EAS

cannot be directly measured on the 12 lead ECG, change in VAT to estimate EAS before and after

CRT was quantified by QRS difference (QRSdiff, ms) = [BV paced QRS (QRSBV) – QRSLBBB]1.

(-)QRSdiff indicates ↓VAT, neutral indicates no change, (+) indicates ↑VAT. This assumes that

when VAT is reduced during BV pacing LV conduction delay has been reduced. It is

acknowledged that there is some preliminary evidence that electrical synchronization may occur

at BV stimulation sites even when VAT is increased.8, 9

Finally, QRS Type 3 is neither conformational change nor QRS normalization and shows LBBB

reinforcement. VAT equals or exceeds LBBB activation time because wavefronts are reinforcing,

wave forces sum, conduction delay is amplified

11

This simplified scheme using QRS Fusion Types to represent BV activation wavefronts is

summarized as follows. From the viewpoint of leads V1-V2:

QRS Type 1: Conformational change in the QRS contour showing new R wave and QRSdiff any

value (QRSBV <, =, > QRSLBBB). “The QRS fusion complex is a transitional complex; in shape it is

intermediate between the natural complex and that resulting purely from the artificial

stimulus”4.

QRS Type 2: Non-conformational change in the QRS contour showing QRS normalization and

obligatory (-) QRSdiff (QRSBV < QRSLBBB) and no new R wave.

QRS Type 3: Persistent LBBB QRS contour 2, 3, 8, 10, no new R wave and neutral or (+) QRSdiff

(QRSBV ≥ QRSLBBB); LBBB reinforcement.

QRS Type 4: “Pseudo-persistent LBBB” QRS contour resembling QRS Type 3. QRS contour

duplicating LBBB (or RV pacing), no new R wave and neutral or (+) QRSdiff (QRSBV ≥ QRSLBBB).

Concealed QRS fusion is only revealed by manipulation of BV timing.B

This methodology is demonstrated in Figure 5 by returning to the examples of QRS fusion

generated by 2 spontaneous idioventricular pacemakers in Figure 2. The QRS complexes are

now annotated using the updated ECG method for QRS fusion complex analysis. All

measurements are made with digital calipers at 200% magnification adjusted for paper speed 25

mm/sec. From the viewpoint of lead V1: 1st column displays the RV monochamber QRS (LBBB),

2nd displays LV monochamber QRS, 4th displays I-V timing, 5th displays wave interference pattern,

B (1) LV lead dislodgment, conductor fracture, and capture threshold exceeding output are excluded, and (2) the lead must be sited in a location demonstrably capable of generating an activation wavefront opposing LBBB (or RV pacing).

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6th displays BV fusion contours, 7th shows QRSdiff (∆VAT) for QRS fusion contour, 8th indicates

QRS Fusion Type and directionality of VAT change. In cases of AV block, RV QRS is surrogate for

LBBB QRS.

These examples of spontaneous BV QRS fusion are the wave interference products of

independent RV and LV activation. The appearance of the QRS fusion contour is an admixture

that necessarily reflects the extent to which each activation wavefront controls the ventricular

muscle mass, and displays sensitivity to (1) site of origin of interfering wavefronts (e.g., RV and

LV are anti-phase) and (2) relative timing of the interfering wavefronts. Consequently, more

than one QRS fusion type can occur in a single patient. This phenomenology duplicates the

electrical wavefront interactions generated by BV pacing in experimental models11.

This method for QRS fusion complex recognition explains the inaccuracy of simple ECG

algorithms to correctly identify LV capture and LV stimulation sites during BV pacing. These

share the common limitation of relying solely on QRS Type 1 (conformational change e.g., new R

wave emergence) to identify LV activation during BV pacing. This is a recurring error when QRS

fusion is not resolved using the method of wave interference. Failure to recognize QRS Type 2

(non-conformational change) results in erroneous declaration of (1) LV non-capture2, (2) non-

lateral (middle cardiac, anterior) stimulation site3, (3) incorrect placement of lead V1, (4) LV lead

dislodgement, (5) LV capture latency or exit block, etc.12, 13

Effects of Stimulation Timing and Site on QRS Fusion Wave Interference

13

Interactions between the PR interval, the atrioventricular delay (AVD), and I-V timing during BV

pacing for LBBB are displayed in Figure 6 (modified from 14,15). During LBBB the RV is activated

by RBB conduction (RBBc) before the LV and the time difference between RV(TRV) and LV(TLV),

activation is the intrinsic I-V conduction delay.9 Experimental models show that maximally

effective ventricular resynchronization occurs when electrical wavefronts fuse midway between

earliest (RBBc) and latest LV activation sites. The optimum AVD achieves maximally effective

ventricular resynchronization by advancing LV activation sufficiently to minimize the I-V interval.

When the AVD is substantially shorter than the PR interval, RV and LV advance and ventricular

conduction is completely controlled by pacing wavefronts (Column 1). Intermediate AVDs

approaching the PR interval result in three-way fusion between RBBc, RV paced activation and

LV paced activation (Column 2).9, 11 Moreover, LV activation can still be advanced when the AVD

is equal to, or exceeding the PR interval, since the LV is delayed relative to the RV 9, 16, 17 (Column

3). Then, BV fusion occurs between RBBc and LV pacing wavefronts; RV pacing is not required to

achieve fusion. Consequently, correction of LV conduction delay is possible across a range of

AVDs and I-V timing arrangements to time the relative prematurity of LV stimulation.

BV fusion wave interference patterns should display sensitivity to timing manipulations and

stimulation site due to their effects on activation wavefront shapes, conduction path, and

superposition patterns. Several exemplary QRS Fusion Type response scenarios are

systematically illustrated using this ECG method (Figures 7-17). (1) The nominal QRS Fusion

Type was established during simultaneous BV (BV_sim) pacing at short AVD = 100 ms (150 ms

during obligatory atrial pacing), a typically applied value within the observed range for LV

preload optimization and utilized in CRT trials and clinical practice.18-24 (2) BV sequential

(BV_Seq) pacing (R→L, L→R) was introduced (e.g., 10, 20, 30....80 ms) at AVD 100 ms. (3) The

AVD was shortened (80, 60, 40 ms) during BV_sim pacing. (4) The AVD was lengthened (100,

14

110, 120, 130 ms, etc.) during BV_sim pacing until the PR interval was reached. (5) RBBc-LV

pacing fusion was assessed using Ventricular Sense Response (VSR, Medtronic, Inc.). In this

manner the effects of several different but related methods for manipulating LV and RV

activation timing on QRS Fusion Type were assessed. Comparisons between QRS Fusion Types

by LV site for selected patients are displayed during BV_sim pacing at AVD=100 ms in order to

isolate the LV stimulation site change effect.

Manipulation of RV and LV wave behavior should have predictable effects on the QRS Fusion

response pattern.

1) During BV_sim pacing when the AVD is substantially less than the PR interval, further AVD

shortening should not alter the QRS fusion pattern since BV pacing activation has already

completely replaced native ventricular conduction and the wave interference pattern is fixed.

Likewise, the wave interference pattern is fixed across all AVDs in complete AV block. Under

either of these conditions, only manipulation of the contribution of the RV and LV wavefronts

with BV_seq pacing can alter the QRS fusion pattern (Figure 6, column 1).

2. Lengthening the AVD during BV_sim pacing should alter the QRS fusion pattern to reflect

lesser LV wavefront contribution to the fusion wave (Figure 6, columns 2-3). At short AVDs this is

expressed between RV and LV pacing wavefronts. At longer AVDs, this method results in

progressive 3-way fusion between RV pacing, RBBc and LV pacing wavefronts as the PR is

reached and RV sensing inhibits pacing.

3. Delaying the onset of RV activation relative to LV activation (BV_seq pacing, LV-first) should

alter the QRS fusion pattern to reflect greater LV wavefront contribution to the fusion wave at

the given AVD. Likewise, delaying the onset of LV activation relative to RV activation (BV_seq

15

pacing, RV-first) should alter the QRS fusion pattern to reflect greater RV wavefront contribution

to the fusion wave at the given AVD. This method does not directly modify the timing of LV pre-

excitation relative to LV conduction delay, which is controlled by the AVD. Shorter AVD

advances LV activation irrespective of RV-LV relative onset timing and is the primary control

parameter for correcting LV conduction delay.

4. LV activation can still be advanced when the AVD is equal to, or exceeding the PR interval,

since the LV is delayed relative to the RV. The RV pacing wavefront contribution is eliminated

and the QRS fusion pattern is determined by the interaction between the RBBc and LV pacing

wavefronts. This can be achieved in one form with VSR. During BV_sim pacing at AVD > PR, RV

sensing triggers an immediate pacing stimulus to both ventricles. The RV stimulus is ineffectual

(pseudo-fusion) since the RV is refractory after RBBc. Consequently, LV-only pacing is delivered

at AVD = PR, or exceeding the PR interval in the case of RV sensing latency. This method results

in pure fusion between RBBc and simultaneously triggered LV pacing (Figure 6, columns 2-3).

Effective LV preexcitation is still possible at very long AVD if the PR is long and the LV is

significantly delayed relative to RV. In this arrangement, however, AV asynchrony is

uncorrected.

These examples demonstrate that BV wavefront timing changes alter the wave interference

pattern, generating predictable effects on QRS Fusion Type.

1. Advancing the LV activation wavefront reinforces QRS Type 1, and transforms QRS Type 2 and

QRS Type 4 to Type 1. These conformational changes reflect a phase shift resulting in greater

contribution of LV wavefront forces to the BV wave interference pattern. During typical

activation from a lateral or posterolateral LV site this change is represented as increasing R wave

amplitude in V1-V2 (e.g., QS, rS → RS, Rs, R) and ↑ VAT (↓wavefront cancellation). S wave

16

regression due to diminished contribution of RV wavefront forces to the BV fusion wave may

coexist. Advancing the LV activation wavefront amplifies QRS Type 3 since RV and LV

wavefronts are non-oppositional, wavefronts are reinforcing, and wave forces sum.

2. Withdrawing the LV activation wavefront progressively transforms QRS Type 1 → Type 2 →

Type 4 → LBBB conduction. These changes reflect a phase shift resulting in lesser contribution

of LV wavefront forces to the BV wave interference pattern ending in reemergence of LBBB

conduction. For QRS Type 1 this represents a reverse conformational change. For QRS Type 2

the “normalized” QRS complex is transformed to a wide QRS duplicating LBBB conduction.

Withdrawing LV activation regresses QRS Type 3 by reducing wavefront reinforcement.

3. Advancing the RV activation wavefront progressively transforms QRS Type 1 and Type 2 →

Type 4 → RV monochamber pacing conduction. These changes reflect a phase shift resulting in

greater contribution of RV wavefront forces to the BV wave interference pattern. For QRS Type

1 this represents a “reverse” conformational change. For QRS Type 2 the “normalized” QRS

complex is transformed to a wide QRS duplicating RV pacing. Advancing the RV activation

wavefront amplifies QRS Type 3 since RV and LV wavefronts are non-oppositional, wavefronts

are reinforcing and wave forces sum.

Advancing RV activation exerts similar effects as withdrawing LV activation on the wave

interference pattern. Likewise, advancing LV activation and withdrawing RV activation exert

similar, but reciprocal, effects on the wave interference pattern.

These examples of wave behavior confirm that cancellation due to wavefront superposition is

the mechanism of QRS shortening during CRT. The combined wave has shorter VAT than either

independent wave, both of which typically exceed LBBB duration during muscle path

17

conduction. Cancellation is reflected in wave suppression (reduced wave amplitude),

restoration of normal QRS forces, and ↓VAT. Moreover, complete wavefront destruction occurs

when the interfering waves are antiphase and have equivalent amplitudes (Figure 18). These

examples also demonstrate that 2 simple waves interact differently at separate points

throughout the ventricular muscle. This can generate complex waves with multiple

superposition patterns due to changes in wave shapes and path length as the wavefronts

propagate from their sources to the different interference boundaries displayed by the 12-lead

ECG. The magnitude of constructive and destructive interference displayed in the QRS fusion

wave complex therefore may be the same or vary from point to point, which accounts for

concordance or discordance of QRS Fusion Types (conformational change, QRS normalization)

between ECG viewpoints. Wavefront fusion during CRT is a complex process functioning on

multiple levels and in multiple dimensions.

Several examples displaying sensitivity of the BV wave interference pattern to change of LV

stimulation site (within vein, between veins) are shown (Figure 19). Since the RV stimulation

site, AVD and I-V timing parameters were fixed, the anatomic sensitivity of the QRS fusion

contour is necessarily due to changes in LV wavefront characteristics (shape, amplitude,

duration) and conduction path, both of which influence BV wavefront superposition. This is a

useful observation because change in stimulation site may overcome anatomic barriers to fusion

wavefront propagation that limit the extent of change that can be achieved by chamber timing

manipulations at a specific LV combination of LV and RV sites. Likewise, a single QRS Fusion Type

can occur at widely spaced LV sites. This presumably indicates a relative insensitivity of broad

wavefronts over long muscle conduction paths to change in stimulation site in some patients.

18

Implications for QRS Fusion Titration.

The base condition QRS Fusion Type was established at a conventionally short AVD during

BV_sim pacing.18-24 Timing manipulation of the wave interference pattern induces multiple QRS

Fusion Types in some patients. QRS Type 1 is predictably achievable when RV and LV

wavefronts are oppositional. QRS Type 4 occurs when RV and LV wavefront opposition is

spontaneously concealed by conduction latency or block, or simulated by delaying LV activation

onset during BV_seq pacing. QRS Type 3 occurs when RV and LV wavefronts are non-

oppositional; transformation to an effective QRS Fusion Type (1 or 2) is not logically possible

without change in LV stimulation site.C QRS Type 2 (QRS normalization, highly oppositional

wavefronts) is more complex and occurs in two forms: (1) spontaneously at short AVD in some

patients (Figures 13-15), (2) only during withdrawal of the LV wavefront by lengthening the AVD

in other patients, where shortening the AVD results in QRS Type 1 transformation (Figures 7-10).

This is not explained by simple differences in the shape and duration of the LV monochamber

activation wavefront per se, since LV wavefront shapes are similarly typical of epicardial origin

and muscle propagation and VAT exceeds RV monochamber wavefront in both situations. The

most likely explanation is that QRS Type 2 fusion that occurs at a short AVD is due to

engagement of the Purkinje system during wave propagation. Despite similar epicardial muscle

origin, rapid spread of activation after the LV wavefront gains access to the Purkinje system

cancels the QRS Type 1 LV dominance typically observed during muscle path propagation at

C “No two points when stimulated yield precisely the same curve (QRS wave shape), and an infinite variety of forms may be obtained from one and the same heart; but if the two points lie close together the corresponding curves resemble each other, and the resemblance is greater the nearer the points approach each other. Stimulation of a given point always yields the same ventricular curve.” Lewis, regarding electrical stimuli applied to the ventral surface of the heart, P. 212-213.

19

short AVDs. Whereas QRS Type 2 fusion that occurs only at longer AVDs (e.g., LV wavefront

withdrawal) is the result of BV wave interference during muscle path propagation, which also

accounts for typical QRS Type 1 transformation (LV dominance) at shorter AVDs in those same

patients. Both forms of QRS Type 2 fusion express the principals of wave interference and

achieve large ↓VAT due to cancellation, but in the case of the former, a large amount of

activation during wave interference is achieved through Purkinje system engagement.

Moreover, while QRS Type 1 and QRS Type 2 at longer AVDs can be induced and regressed by

timing manipulations, QRS Type 2 at short AVDs is apparently a spontaneous phenomenon in

certain patients, and may be a unique property of some hearts. This phenomenon may display

sensitivity to LV stimulation site (see below). This is likely explained by a change in muscle

conduction path that enables the LV activation wavefront to enter the Purkinje system,

otherwise unachievable from a different stimulation siteD. Conversely, QRS Type 2 at short AVDs

may be unachievable (by any means) in some patients because the Purkinje system has been

destroyed, leaving only muscle path conduction irrespective of timing manipulations and LV

stimulation site.25

Preliminarily, individual best QRS fusion wave efficiency occurred at AVDs in the range

corresponding to peak acute hemodynamic improvement during BV pacing.18 AVD for best QRS

fusion wave response was 50-80% of the PR interval, consistent with experimental studies18 and

best clinical outcomes.24 Longer AVDs (e.g., LV wavefront withdrawal) to reduce LV dominance

in the QRS fusion waveform during muscle path conduction were required to achieve QRS Type

2 fusion in some patients, particularly those with QRSd < 150 ms.26 However, good QRS fusion

D “The form of the electrocardiogram yielded by stimulating the surface of the ventricle seems to depend upon two chief factors, the relation of the point stimulated to the two networks of Purkinje and its relation to the mass of the ventricular muscle as a whole. Of these two factors the first exerts the dominant influence” Lewis, p. 216-117

20

wave responses also occurred at nearby AVD values, and during simultaneous and sequential BV

pacing since fusion of electrical wavefronts can be achieved by a variety of approaches.9, 27,11

This implies some flexibility in timing titration of the BV wave interference pattern to achieve

the simultaneous goals of maximizing ventricular preload and achieving ventricular electrical

resynchronization. Moreover, QRS Types 1 (QRS conformational change) and 2 (QRS

normalization) can be generated by manipulation of wave interference during stimulation from

any LV site that produces wavefront opposition to LBBB, irrespective of coronary venous

anatomic designation. This argues against rigid adherence to anatomic targets for LV pacing, and

in favor of identifying sites that yield wavefront opposition to LBBB.

This method for wave interference analysis also underscores the challenges in achieving efficient

BV fusion when LBBB conduction delay is not severe (QRSd < 150 ms). Conventional short AVD

BV pacing in this situation typically results in QRS Type 1 with ↑ EAS (↑VAT, + QRSdiff) due to

muscle path conduction. Consequent electrical asynchrony due to LV dominant pacing

“overcorrection” may worsen outcomes. Withdrawing LV activation by lengthening the AVD

can generate QRS Type 2 but at an overlong PR interval that may contribute to worsened

outcomes.24 QRS Type 2 at short AVD appears to resolve these issues even when LBBB QRSd is

relatively short, but early engagement of the Purkinje system appears to be a spontaneous

phenomenon that may not be transferable between patients.

These examples support the conceptualization of QRS fusion during BV pacing as a problem of

interference during electrical wave propagation. Moreover the QRS fusion wave interference

pattern can be predictably manipulated by electrical timing instructions to achieve certain goals.

From this perspective BV pacing is a two-source generator of electrical wave interference and

the AVD and I-V timing operate as wave interference control parameters.

21

The translation of these perturbations to the final fusion interference wave is complex. At a

typical short AVD the RV activation wavefront characteristics (shape, amplitude, duration) are

constant. Changes in the BV fusion wave interference product are therefore due to the effects

of (1) LV stimulation site on LV activation wavefront characteristics and conduction path

(muscle, Purkinje, both), (2) AVD and I-V timing parameters on the superposition relationship

between the interfering wavefronts, and presumably (3) substrate conditions (ventricular

conduction delay and block8, 10, 28) which cannot be directly assessed by this method. Change in

LV stimulation site influences LV wave constituents (shape, amplitude, duration), muscle path to

the interference boundary, and possibly access to the Purkinje system.

There were exceptions to the expected QRS fusion wave interference response to wavefront

timing changes. Limited or absent QRS contour changes during progressive LV-first BV_seq

pacing starting from nominal QRS Type 1 and QRS Type 2 fusion at short AVD (100) were

observed. This occurred in the absence of significant differences in monochamber I-V

conduction times and is not explained by intra-LV fusion since the short AVD substantially

abbreviates the PR interval and BV pacing activation has already completely replaced native

ventricular conduction (see above, Figure 7). Moreover, this phenomenon was consistently

observed in QRS Type 2 patients (Figures 13-15) and some QRS Type 1 patients (Figures 7-9) but

not others (Figures 10-12). This is likely explained by differences in wavefront conduction paths

as described above. For QRS Type 1, limited conformational change reflecting LV dominance

during LV-first BV_seq pacing is best explained by LV conduction delay or block during muscle

path conduction at that LV stimulation site.8, 10, 28 For QRS Type 2, limited non-conformational

change showing is most likely a consequence of Purkinje system engagement early during wave

propagation where delaying onset of RV activation does not change the timing of LV

preexcitation relative to LV conduction delay and therefore has limited effect on rapid spread of

22

the LV wavefront. In both situations, further shortening of the AVD can induce greater

conformational change, apparently due to greater recruitment of muscle path conduction

(Figures 7-9, 13-15).

The two methods for advancing LV activation differ significantly in effect. BV_seq pacing delays

the onset of RV activation relative to LV activation at any AVD, which may alter the wavefront

superposition pattern resulting in a QRS conformational change to display greater contribution

of the LV wavefront. This method does not change the relationship between LV preexcitation

and LV conduction delay, which is controlled by the AVD. Shorter AVD advances LV activation

irrespective of RV timing and is the primary control parameter for correcting LV conduction

delay. LV-first BV_seq pacing isolates changes in LV activation timing relative to fixed RV

activation timing, whereas simultaneous BV pacing at progressively shorter AVD advances both

RV and LV activation timing. This accounts for the scenario described above where delaying the

onset of RV activation relative to LV activation during BV_seq pacing generates little or no

conformational change in the QRS fusion complex, whereas advancing LV activation relative to

LV conduction delay by shortening the AVD induces a larger conformational change. Inability to

overcome conduction blocks may require a change in LV stimulation site in some cases.

These deliberations emphasize that the AVD is the primary control parameter in BV pacing that

has 2 independent but simultaneous effects that are frequently conflicting11: (1) maximize LV

preload (AV resynchronization), (2) unload the over-stretched LV (ventricular

resynchronization).E

Summary

E Angelo Auricchio, MD, personal communication

23

An electrocardiographic method for characterization of QRS fusion during CRT for LBBB heart

failure is presented. The QRS fusion contour displays predictable sensitivity to timing

manipulations and stimulation site consistent with the principals of wave interference. These

changes are instantaneously expressed on the 12 lead ECG, and could guide quantitative

assessment of activation sequence titration to improve LV reverse remodeling odds.

24

Figure Legends

Figure 1. ECG taken from single limb lead (II). “Premature ventricular contractions (P-B) are

shown which arise in the right ventricle late in diastole. There are three such in the curve; in the

second and third instances the wave has spread thought the whole ventricle from the point at

which the new pulse arose. The first abnormal beat has fallen later in diastole, so late that the

ventricle responds in part to the natural impulse and in part to the new impulse; the ventricular

complex is therefore transitional...in shape it is intermediate between the natural complex and

the extrasystolic form…due to interference between two excitation waves”.4, 29

Figure 2.

Top left: ECG taken from single anterior precordial lead (V1) showing complete AV block with

two competing idioventricular escape rhythms5. First and fourth rows show RV rhythm (RV)

generating LBBB activation. Third row shows LV rhythm (LV) generating RBBB activation.

Narrow beats in second and fifth rows are fusion (F) QRS complexes generated by simultaneous

activation of RV and LV by competing idioventricular rhythms. Note the QRS fusion contour

contains recognizable features of both activation wavefronts (R wave component from LV

escape QRS, S wave component from RV escape QRS) but is normally narrow. This exemplifies

the exception to the rule that the fusion QRS must be intermediate in form and width between

the fusing complexes.

25

Top right: ECG taken from single anterior precordial lead (V1)5. Rhythm is 2:1 AV block. Note

LBBB activation (RV) at beginning of top strip and second half of bottom strip. Last 2 beats on

top strip and first 2 beats on bottom strip are competitive idioventricular escape pacemaker

from LV (RBBB activation). Third and fourth beats in top strip are fusion (F) beats; note large

reduction in QRSd and absence of conformational change (R emergence is absent) in QRS fusion

contour. Fourth beat (2nd fusion complex) is “normally narrow”; note QS regression.

Bottom left: ECG taken from single anterior precordial lead (V1)30. Rhythm is complete AV block

with 2 competing idioventricular escape pacemakers. QRS complexes 1, 3, 5 and 9 are RV

escape pacemakers; QRS complexes 2, 7, 8 and 11 arise in the LV. QRS complexes 4, 6, and 10

are fusion complexes generated by simultaneous activation of the RV and LV. Note that QRS

fusion complex 4 is similar to the RV escape pacemaker except that QRSd is reduced; fusion QRS

complexes 6 and 10 are conformational hybrids of the competing RV and LV idioventricular

escape pacemakers. The explanation for the variation in QRS contour is that the timing of the

idioventricular escape rhythms differs: for fusion QRS 4, they are simultaneous; for QRS 6 and 10

they are sequential with LV first, which accounts for the new R wave emergence.

Bottom right: Rhythm is AF with conducted LBBB (RV), LV escape rhythm with RBBB, and

normalization of the QRS complex as represented by the third beat in V131. This is due to

ventricular fusion between RBBB conduction in AF and the LV escape rhythm.

Figure 3. Wave interference superposition. Top. Two waves having identical shape and

displacement amplitudes are depicted moving along the same line in opposite directions. At the

first point of interaction, the negative component (trough or downward displacement) of the

rightward wave and the positive component (peak or upward displacement) of the leftward

wave are precisely aligned and cancel, yielding a combined fusion wave contour intermediate in

26

shape between the two independent interfering waves, termed conformational change. At the

second point of interaction, the positive (peaks) and negative (troughs) displacements of both

waves reinforce due to constructive interference; note wave contour duplicating independent

interfering waves but with increased amplitudes. At the third point of interaction, the

reinforced positive (peak) and negative (trough) components are perfectly aligned and

completely cancel (zero amplitude). Waves are destroyed.

Figure 4. Waves are depicted to represent typical QRS complex interactions between RV

monochamber (QS), LV monochamber (R), and BV pacing from the viewpoint of leads V1-V2.

Assume LBBB activation displays typical QS complex (not shown). Note, wave shapes,

amplitudes and durations vary and influence the interference product. Row 1: RV pacing

generates QS complex (moving right → left and anterior → posterior), lateral LV pacing

generates R complex (moving left → right and posterior → anterior). In column 1, wave shapes

are similar but amplitudes differ and forces are opposing. In column 2, wave shapes and

amplitudes are nearly identical and forces are opposing. In column 3 wave shapes and

amplitudes are identical and forces are reinforcing because LV pacing is conducted from a site

that does not oppose LBBB conduction. Row 2: Onset of fusion results in conformational

change in QRS complex showing recognizable elements of the independent interacting waves

(e.g., qR in column 1, QR in column 2, QrS in column 3). Row 3. Column 1: Final fusion QRS

complex is R, Rs, rS, etc. (conformational hybrid); note admixture of constructive and destructive

interference. Amplitudes and duration are reduced vs. baseline waveforms if destructive

interference (cancellation) dominates. These are exemplary forms of QRS Type 1 (new R wave,

with or without reduction in QRSd) as compared to LBBB. Column 2: Final fusion complex is qs

(QRS normalization, non-conformational change); note destruction of both R wave and QS

waves (wave suppression) and marked reduction in wave duration vs. baseline waveforms due

27

to large, dominant cancellation effect. This is an example of QRS Type 2. Column 3: Final fusion

complex is QS; note QS complex is increased in amplitude and duration due to dominant

constructive interference effect. This is an example of QRS Types 3-4.

Figure 5.

A. (Figure 2 top left). RV = rS, 133 ms; LV = R, 167 ms, BV fusion contour = RS, 63 ms, QRSdiff =

63-133 = -70 ms. Note R emergence (and S regression) indicating conformational hybrid of the

independent RV and LV idioventricular escape pacemakers → QRS Fusion Type 1, large ↓VAT.

B. (Figure 2 top right). RV = QS, 184 ms; LV = qR, 154 ms, BV fusion contour A = QS, 97 ms,

QRSdiff = 97-184 = -87 ms. BV fusion contour B = QS, 75 ms, QRSdiff = 75-184 = -109 ms. Note

R emergence is absent, QRS shortening is present. Fusion QRS complexes are “normally

narrow”→ QRS Fusion Type 2, large ↓VAT. Note, greater S regression in QRS fusion contour B is

due to sequential (LV > RV) activation timing.

C. (Figure 2 bottom left). RV=QS, 154 ms; LV=R, 176 ms. BV fusion contour A = qs, 102 ms,

QRSdiff = 102-154 = -52 ms. Note R emergence is absent, QRS shortening is present, fusion QRS

is normally narrow as compared to the RV escape pacemaker → QRS Type 2. BV fusion contour

B = qR, 114 ms, QRSdiff = 114-154 = -40 ms. Note R emergence indicating conformational hybrid

of the RV and LV idioventricular escape pacemakers → QRS Type 1. R emergence in QRS fusion

contour B is due to sequential (LV > RV) activation timing; increase in VAT vs. BV fusion contour

A is typical due to greater contribution of LV wave to interference product.

28

D. (Figure 2, bottom right). RV = rS, 160 ms; LV = rsR, 170 ms). BV fusion contour = rS, 93 ms,

QRSdiff= 93-160 = -67 ms. Note R emergence is absent, QRS shortening is present, fusion QRS is

normally narrow as compared to RV escape pacemaker → QRS Fusion Type 2, large ↓VAT.

Figure 6. Interactions between the PR interval, AVD, and I-V timing during BV pacing for LBBB.

Figure 7. QRS Fusion Type 1; lateral LV lead.

A. Left: LBBB, monochamber pacing waveforms, and nominal QRS fusion wave during

BV_sim/AVD 100. Monochamber I-V conduction times are non-equivalent (R → L< L → R).

Right: QRS fusion wave progressions during I-V timing titration. Selected results are displayed

for illustrative purposes. BV_sim/AVD 100 (left, top) generates typical QRS Type 1

conformational change from LBBB: rS → Rs, ↑VAT, and slightly (+)QRSdiff. Delaying the onset of

RV activation relative to LV activation during BV_seq/AVD 100 (A) initially amplifies QRS Type 1

conformational change to reflect greater LV wavefront contribution to the QRS fusion wave (↑R

amplitude, ↑VAT, ↑(+)QRSdiff → less efficient electrical resynchronization) but has no effect

beyond LV-40. This may indicate LV wavefront propagation delay or block at this AVD.

Advancing LV activation relative to LV conduction delay by shortening AVD during BV_sim (B)

does not alter the nominal QRS fusion wave because BV pacing activation has already

completely replaced native ventricular conduction and I-V timing is fixed, as observed in

complete AV block (see Figure 11). Withdrawing LV activation by lengthening AVD during

BV_sim (C) induces a reverse conformational change from QRS Type 1 to reflect lesser LV

wavefront contribution to the QRS fusion wave (↓R wave amplitude, ↓VAT, ↑(-)QRSdiff →

more efficient electrical resynchronization). Peak BV fusion efficiency (dashed circle) is achieved

at AVD 190 ms (82% of PR) which generates QRS Type 2 transformation (rS, QRS normalization),

minimum VAT, maximum (-)QRSdiff. Delaying the onset of LV activation relative to RV activation

29

during BV_seq/AVD 100 (D) regresses the nominal QRS Type 1 conformational change reflecting

greater RV wavefront contribution to the QRS fusion wave (↓R wave amplitude, ↑VAT,

↑(+)QRSdiff → least efficient electrical resynchronization) duplicating RV monochamber

pacing/LBBB activation (rS, RV-60, -80; QRS Type 4). VAT now exceeds LBBB activation time

because wavefronts are reinforcing, wave forces sum, conduction delay is amplified.

Best QRS fusion result is achieved during simultaneous BV pacing despite slightly asymmetric I-V

conduction times. Delaying the onset of RV activation relative to LV activation to compensate for

asymmetric I-V times degrades fusion efficiency.

B. Top center: LBBB. Left: RV and LV monochamber activation sequences. Right, top: QRS

Type 1 during BV_sim/AVD 100; Middle: QRS Type 1 during BV_seq/AVD 100/LV-80. Bottom:

QRS Type 2 (best result) during BV_sim/AVD 190.

During QRS Type 1 fusion (BV_sim/AVD 100), concordant conformational changes indicating

LBBB activation reversal are observed in the frontal (R → QR in I, R → qR in aVL) and horizontal

planes (QS → RS in V1-V2).1 QRS notching persists in multiple leads indicating non-uniform

wavefront propagation probably due to lines of block (slow conduction). These conformational

changes are exaggerated during BV_seq/AVD 100/LV-80 pacing (↑↑R wave in V1-V5, ↑QRS

notching, ↑VAT) due to LV wavefront dominance. In contrast, during QRS Type 2 fusion

conformational changes have been replaced by concordant QRS normalization and wave

suppression in multiple leads (I, aVL, II, III, aVF, V1-V3). VAT is minimized and QRS notching is

nearly eliminated indicating more uniform, faster wavefront propagation. These are visual

manifestations of wavefront cancellation and more efficient fusion. Wavefronts are highly

oppositional, wave forces cancel, conduction delay is reduced. The overall pattern now closely

approximates normal ventricular activation.

30



BV_sim/AVD 100. Monochamber I-V conduction times are slightly asymmetric (R → L< L→R).


for illustrative purposes. BV_sim/AVD 100 (left, top) generates typical QRS Type 1

conformational change from LBBB: QS → Rs, ↑VAT, and large (+)QRSdiff. Delaying the onset of

RV activation relative to LV activation during BV_seq/AVD 100 (A) initially amplifies QRS Type 1

conformational change to reflect greater LV wavefront contribution to the QRS fusion wave (↑R

wave amplitude, ↑VAT, ↑(+)QRSdiff → less efficient electrical resynchronization) but has no

effect beyond LV-40. This may indicate LV wavefront propagation delay or block at this AVD.


does not alter the nominal QRS fusion wave because BV pacing activation has already

completely replaced native ventricular conduction and I-V timing is fixed. Withdrawing LV

activation by lengthening AVD during BV_sim (C) induces a reverse conformational change from

QRS Type 1 to reflect lesser LV wavefront contribution to the QRS fusion wave (↓R wave

amplitude, ↓VAT, ↑(-)QRSdiff → more efficient electrical resynchronization). Peak BV fusion

efficiency (dashed circle) is achieved at AVD 160 ms (75% of PR) which generates QRS Type 2

transformation (QRS normalization, qs), minimum VAT, maximum (-)QRSdiff. Delaying the onset

of LV activation relative to RV activation during BV_seq/AVD 100 (D) regresses the nominal QRS

Type 1 conformational change reflecting greater RV wavefront contribution to the QRS fusion

wave (↓R wave amplitude, ↑VAT, ↑(+)QRSdiff → least efficient electrical resynchronization)

duplicating RV monochamber pacing/LBBB activation (QS, RV-80; QRS Type 4). VAT now equals

RV monochamber pacing.

31


conduction times.

B. Top center: “Incomplete” LBBB.32, 33 Note absence of QRS upstroke slurring and QRS

notching in I, L, V5-V6. Left: RV and LV monochamber activation sequences. Right, top: QRS

Type 1 during BV_sim/AVD 100; Middle: QRS Type 2 (peak BV fusion efficiency) during

BV_seq/AVD 160. Bottom: Pseudo-LV pacing during RBBc-LV fusion pacing using VSR.

During QRS Type 1 fusion (BV_sim/AVD 100), concordant conformational changes indicating

LBBB activation reversal are observed in the frontal (R → qR, aVL) and horizontal planes (QS →

Rs, qR in V1-V2)1, accompanied by ↑VAT and ↑(+)QRSdiff. Moderate withdrawal of the LV

wavefront results in transformation to QRS Type 2 fusion (BV_sim/AVD 160). Conformational

changes are now replaced by concordant QRS normalization, ↓VAT and ↑(-)QRSdiff and

regional wave suppression in leads V4-V6. Wave suppression is localized to the LV region closest

to the stimulation site because LV conduction delay is mild and matched by limited conduction

replacement at AVD 160. These are visual manifestations of wavefront cancellation, faster

wavefront propagation and more efficient fusion. Wavefronts are oppositional, wave forces

cancel, conduction delay is reduced. The overall pattern now closely approximates normal

ventricular activation. LV-only pacing (VSR) at effective AVD =PR (212 ms) duplicates LBBB. In

this situation there is insufficient LV conduction delay for this method of RBBc-LV pacing fusion

to advance LV activation.


32


BV_sim/AVD 100. Monochamber I-V conduction times are equivalent. Right: QRS fusion wave

progressions during I-V timing titration. Selected results are displayed for illustrative purposes.

BV_sim/AVD 100 (left, top) yields QRS Type 1 conformational change from LBBB: QS → R, ↓VAT,

modest (-)QRSdiff. Delaying the onset of RV activation relative to LV activation during

BV_seq/AVD 100 (A) induces slight change in QRS Type 1 contour (dome → peaked R) but no

change in VAT or QRSdiff indicating LV wavefront propagation delay or block at this AVD.


does not alter the the nominal QRS fusion wave because BV pacing activation has already

completely replaced native ventricular conduction and I-V timing is fixed, as is observed in

complete AV block. Withdrawing LV activation by lengthening the AVD during BV_sim (C)

induces a reverse conformational change from QRS Type 1 reflecting lesser LV wavefront

contribution to the QRS fusion wave (↓R wave amplitude, ↓VAT, ↑(-) QRSdiff → more efficient

electrical resynchronization). Peak BV fusion efficiency (dashed circle) is achieved at AVD 150 ms

(85% of PR) which generates QRS Type 2 transformation (QRS normalization, qs), minimum VAT,

maximum (-)QRSdiff. Delaying the onset of LV activation relative to RV activation during

BV_seq/AVD 100 (D) regresses the nominal QRS Type 1 conformational change reflecting

greater RV wavefront contribution to the QRS fusion wave (↓R wave amplitude, ↑VAT,

↑(+) QRSdiff) duplicating RV monochamber pacing (QS, RV-80, QRS Type 4). Note wave

destruction in V1 (RV-60). VAT now equals RV monochamber pacing. Best QRS fusion result is

achieved during simultaneous BV pacing.

B. Top center: LBBB. Left: RV and LV monochamber activation sequences. Right, top: QRS Type

1 during BV_sim/AVD 100; Middle: QRS Type 2 (peak BV fusion efficiency) during BV_sim/AVD

150; Bottom: QRS Type 2 during BV_sim/AVD 180.

33

During QRS Type 1 fusion (BV_sim/AVD 100) concordant conformational changes indicating

LBBB reversal are observed in the frontal (V1-V2: QS → R = posterior → anterior activation

reversal) and horizontal planes (I, aVL: R → qR = left → right activation reversal) accompanied

by ↓VAT, moderate (-)QRSdiff, and elimination of QRS notching (I, aVL, II, III, aVF), indicating

large wavefront cancellation effect and more uniform wavefront propagation. During QRS Type

2 fusion (BV_sim/AVD 150) QRS normalization is observed in V1-V4; conformational changes

persist in I, L, V5-V6. Note larger ↓VAT (118 ms), ↑(-)QRSdiff (-36 ms), wave suppression in V5-

V6 (see earlier). QRS notching is abolished indicating more uniform, faster wavefront

propagation. These are visual manifestations of wavefront cancellation and more efficient

fusion. Wavefronts are oppositional, wave forces cancel, conduction delay is reduced. The

overall pattern now closely approximates normal ventricular activation. Further withdrawal of

the LV wavefront results in regression of electrical resynchronization (BV_sim/AVD 180). The

QRS pattern now duplicates LBBB activation across 12 leads except that VAT is slightly shorter.

This is explained by RV pseudofusion (AVD = PR interval) resulting in RBBc-LV pacing fusion

(BV_sim/AVD 180), which advances LV activation slightly.





BV_sim/AVD 100 (left, top) yields QRS Type 1 conformational change from LBBB: QS → RS,

↓VAT, large (-) QRSdiff. Delaying the onset of RV activation relative to LV activation during

BV_seq/AVD 100 (A) amplifies QRS Type 1 conformational change to reflect greater LV

wavefront contribution to the QRS fusion wave (↑R wave amplitude, ↓VAT, ↑(+)QRSdiff → less

34

efficient electrical resynchronization). In this example, QRS Type 1 conformational changes are

progressive as RV activation onset is further delayed. Advancing LV activation relative to LV

conduction delay by shortening AVD during BV_sim (B) does not alter the nominal QRS fusion

wave because BV pacing activation has already completely replaced native ventricular

conduction and I-V timing is fixed. Withdrawing LV activation by lengthening the AVD during

BV_sim (C) induces a reverse conformational change from QRS Type 1 reflecting lesser LV

wavefront contribution to the QRS fusion wave (↓R wave amplitude, ↓VAT, ↑(-) QRSdiff →

more efficient electrical resynchronization). Peak BV fusion efficiency (dashed circle) is achieved

at AVD 130 ms (76% of PR) which generates best QRS Type 1 fusion (rS, minimum VAT,

maximum (-)QRSdiff). Delaying the onset of LV activation relative to RV activation during

BV_seq/AVD 100 (D) regresses the nominal QRS Type 1 conformational change reflecting

greater RV wavefront contribution to the QRS fusion wave (↓R wave amplitude, ↑VAT, ↑(+)

QRSdiff) duplicating RV monochamber pacing (rS, RV-80, QRS Type 4). VAT now equals RV

monochamber pacing. Best QRS fusion result is achieved during simultaneous BV pacing.


1 during BV_sim /AVD 100; Middle: QRS Type 1 (peak BV fusion efficiency) during BV_sim/AVD

130; Bottom: QRS Type 2 during RBBc-LV fusion pacing using VSR.

During QRS Type 1 fusion (BV_sim/AVD 100) concordant conformational changes indicating

LBBB reversal are observed in the frontal (V1-V2: QS → RS, qR = posterior → anterior activation

reversal) and horizontal planes (I, aVL: R → qR = left → right activation reversal) accompanied

by ↓VAT, large (-)QRSdiff, and elimination of QRS notching, indicating large wavefront

cancellation effect, more uniform and faster wavefront propagation. During best QRS Type 1

fusion (BV_sim/AVD 130) note even larger ↓VAT and ↑(-)QRSdiff. These are visual

35

manifestations of wavefront cancellation and more efficient fusion. Wavefronts are

oppositional, wave forces cancel, conduction delay is reduced. The overall pattern now closely

approximates normal ventricular activation, similar to Type 2 fusion except for slight but

persistent conformational changes indicative of LV stimulation. Further withdrawal of the LV

wavefront results in regression of electrical resynchronization and transformation to QRS Type 2

(VSR pacing). The QRS pattern now duplicates LBBB activation across 12 leads except that VAT is

slightly shorter (-8 ms). This is explained by RV pseudofusion (AVD = PR interval) resulting in

RBBc-LV pacing fusion that advances LV activation slightly.

Figure 11. QRS Fusion Type 1. Anterolateral LV lead.

A. Left: Monochamber pacing waveforms and nominal QRS fusion wave during BV_sim/AVD 150

(obligatory atrial pacing). Monochamber I-V conduction times are non-equivalent (R→L > L→R).

Underlying rhythm is sinus bradycardia + complete AVB + ventricular asystole; QRS fusion waves

are compared to RV pacing (LBBB surrogate). Selected results are displayed for illustrative

purposes. Note anterolateral LV monochamber waveform generates lower amplitude R wave

(RS configuration) in V1 as compared to large R wave during typical lateral LV pacing (see prior

Figures), indicating indirect posterior → anterior activation and less wavefront opposition to

LBBB (RV pacing) wavefront forces. Right: QRS fusion wave progressions during I-V timing

titration. BV_sim/AVD 100 (left, top) generates typical QRS Type 1 conformational change from

LBBB (RV pacing): rS → RR’, ↓VAT, and large (-)QRSdiff. Delaying the onset of RV activation

relative to LV activation during BV_seq/AVD 100 progressively amplifies QRS Type 1

conformational change reflecting greater LV wavefront contribution to the QRS fusion wave (↑R

wave amplitude, ↑VAT, ↓(-)QRSdiff) and less efficient electrical resynchronization. Neither

advancing LV activation relative to LV conduction delay by shortening AVD during BV_sim (B)

36

nor withdrawing LV activation by lengthening the AVD (C) has any further effect on the QRS

fusion wave because pacing activation completely controls ventricular conduction and I-V timing

is fixed. Delaying the onset of LV activation relative to RV activation during BV_seq/AVD 100 (D)

regresses the nominal QRS Type 1 conformational change reflecting greater RV wavefront

contribution to the QRS fusion wave (↓R wave amplitude, ↑S wave amplitude, ↑VAT,

↓(-) QRSdiff → least efficient electrical resynchronization) duplicating RV pacing (RV-80, QRS

Type 4). VAT now equals RV monochamber pacing. In this case, complete AV block, ↑↑↑VAT

during obligatory RV pacing, and lack of QRS fusion wave changes at any AVD probably indicate

destruction of large portions of the ventricular conduction system (LBBB, Purkinje).25

QRS Type 1 conformational changes by advancing LV activation are progressive throughout the

entire range. QRS Type 2 cannot be generated at any I-V timing arrangement, possibly because

RV and LV wavefronts are indirectly opposed and the Purkinje system has been destroyed;

nonetheless, a large amount of cancellation during muscle path conduction occurs. Best QRS

fusion is achieved at BV_seq/AVD 150/RV-20 (dashed circle) which compensates precisely for

non-equivalent I-V conduction times.

B. Top: Obligatory RV pacing. Left: LV monochamber activation. Right, top: QRS Type 1 during

BV_sim/AVD 150; Middle: QRS Type 1 during BV_seq/LV-80, which duplicates LV monochamber

pacing. Note amplified QRS Type 1 conformational change (↑R wave amplitude, ↑VAT, ↑(+)

QRSdiff → less efficient electrical resynchronization). Right, bottom: QRS Type 4 during

BV_seq/RV-80. QRS fusion wave duplicates RV monochamber pacing.

Figure 12. Permanent atrial fibrillation, QRS Fusion Type 1, lateral LV lead.

37


ventricular-only (VVI) BV_sim pacing. I-V conduction times are slightly non-equivalent (R→L >

L→R). Right: BV QRS fusion wave progressions during I-V timing titration. Selected results are

displayed for illustrative purposes. BV_sim (left, top) generates typical QRS Type 1

conformational change from LBBB: QS → rS, ↓VAT, (-)QRSdiff. Delaying the onset of RV

activation relative to LV activation during BV_seq pacing (A) amplifies QRS Type 1

conformational change reflecting greater LV wavefront contribution to the QRS fusion wave (↑R

wave amplitude, ↑VAT, ↑(+)QRSdiff → less efficient electrical resynchronization). In this

example, QRS Type 1 conformational changes are progressive as RV activation onset is further

delayed. Delaying the onset of LV activation relative to RV activation (B) regresses the nominal

QRS Type 1 conformational change reflecting greater RV wavefront contribution to the QRS

fusion wave (↓R wave amplitude, ↑VAT, ↑(+)QRSdiff) → least efficient electrical

resynchronization duplicating RV monochamber/LBBB activation (RV-80, QRS Type 4). VAT now

exceeds both RV monochamber and LBBB activation time because wavefronts are reinforcing,

wave forces sum, conduction delay is amplified. Note progressive rightward displacement of the

LV stimulus in the predominantly RV paced waveform.

Peak BV fusion efficiency (dashed circle) is achieved during RBBc-LV only pacing (VSR), indicated

by QRS Type 2 transformation (qs), minimum VAT, maximum (-)QRSdiff. Delaying the onset of LV

activation relative to RV activation to compensate for asymmetric I-V times degrades fusion

efficiency

B. Ventricular fusion does not require AV synchronization (AF). Left (top to bottom): LBBB, RV,

and LV monochamber activation sequences. Right, top: QRS Type 1 during BV_sim (VVI)

concordant conformational changes are observed in frontal (V1), and horizontal (aVL and L)

38

planes; Middle: QRS Type 1 during BV_seq/LV-80 (VVI) duplicates LV monochamber pacing.

Note amplified QRS Type 1 conformational change (↑R wave amplitude, ↑VAT, ↑(+) QRSdiff →

less efficient electrical resynchronization). Right, bottom: QRS Type 2 (peak BV fusion efficiency)

during RBBc-LV fusion pacing using VSR. QRS normalization and wave suppression is observed in

all leads except I, aVL which display conformation change; QRS is nearly isoelectric QRS in I, II, III,

aVR, aVF. QRS notching is abolished indicating more uniform, faster wavefront propagation.

These are visual manifestations of wavefront cancellation and highly efficient fusion. Wavefronts

are oppositional, wave forces cancel, conduction delay is reduced. The overall pattern now

closely approximates normal ventricular activation.





BV_sim/AVD 100 (left, top) generates QRS Type 2 non-conformational change from LBBB: QS →

qs, ↓↓↓VAT, and large (-)QRSdiff. The QRS is normalized. Delaying the onset of RV activation

relative to LV activation during BV_seq/AVD 100 (A) initially results in subtle QRS Type 1

conformational change reflecting greater LV wavefront contribution to the QRS fusion wave (QS

→ rS, ↑VAT, ↓(-)QRSdiff → less efficient electrical resynchronization) but has no effect beyond

LV-40, probably because rapid wave propagation through Purkinje engagement is already

underway (see text). Advancing LV activation relative to LV conduction delay by shortening AVD

during BV_sim (B) results in more pronounced QRS Type 1 conformational change (↑R wave,

↓S wave, ↑VAT, ↓(-)QRSdiff) reflecting greater muscle path contribution of the LV wavefront

to the QRS fusion wave (see text). Withdrawing LV activation by lengthening the AVD during

39

BV_sim (C) initially enhances QRS Type 2 fusion; peak BV fusion efficiency (dashed circle) is

achieved at AVD 120 ms (78% of PR), which generates QRS normalization (qs), minimum VAT,

maximum (-)QRSdiff. Further withdrawal of the LV wavefront results in regression of electrical

resynchronization and gradual transformation to QRS Type 4 (BV_sim/AVD 180). Delaying the

onset of LV activation relative to RV activation during BV_seq/AVD 100 (D) regresses the

nominal QRS Type 1 conformational change reflecting greater RV wavefront contribution to the

QRS fusion wave (persistent QS, ↑VAT and ↑(+)QRSdiff → least efficient electrical

resynchronization) duplicating RV monochamber pacing/LBBB activation (QS, RV-80, QRS Type

4). VAT now exceeds both RV monochamber and LBBB activation times because wavefronts are

reinforcing, wave forces sum, conduction delay is amplified. Best QRS fusion result is achieved

during simultaneous BV pacing.

B. Top center: LBBB. Left: RV and LV monochamber activation sequences. Right, top: QRS

Type 2 during BV_sim/AVD 100; Middle: QRS Type 2 (best result) during BV_sim/AVD 120;

Bottom: QRS Type 4 during BV_sim/AVD 180.

Same arrangement as prior figures. Top. LBBB. Lower left. Ideal wavefront conditions for QRS

Type 2 fusion. (1) Monochamber ventricular activation wavefronts are antiphase in all 12 leads

(e.g., Lead 1: RV pacing = R, LV pacing = QS; Leads V1-V6: RV pacing = QS, LV pacing = R, etc.);

(2) opposing wave amplitudes are nearly equivalent in all 12 leads; (3) wave durations are nearly

identical (RV monochamber 174 ms, LV monochamber 178 ms). Mirror image wavefront

activation yields BV fusion wave suppression due to destructive interference (cancellation). Top

right: QRS Type 2 during BV_sim/AVD 100. Note ↓↓VAT and ↑↑(-)QRSdiff (-20 ms). QRS

normalization and extreme wave suppression is observed across all 12 leads. Middle right: QRS

Type 2 fusion during BV_sim/AVD 120 ms. Leniency in LV preexcitation by lengthening the AVD

40

slightly during BV_sim (C) achieves peak QRS Type 2 electrical resynchronization efficiency

(minimum VAT, maximum (-)QRSdiff) and QRS normalization across all 12 leads. Wavefronts are

oppositional, wave forces cancel, conduction delay is reduced. QRS notching is abolished

indicating more uniform, faster wavefront propagation. Bottom right. Further withdrawal of the

LV wavefront results in regression of electrical resynchronization and transformation to QRS

Type 4 (BV_sim/AVD 180).



BV_sim/AVD 100. Monochamber I-V conduction times are equivalent (R→L = L→R). Right: QRS

fusion wave progressions during I-V timing titration. Selected results are displayed for

illustrative purposes. BV_sim/AVD 100 (left, top) generates typical QRS Type 2 non-

conformational change from LBBB: QS → qs, ↓↓↓VAT, and large (-)QRSdiff. Delaying the onset

of RV activation relative to LV activation during BV_seq/AVD 100 (A) generates subtle

conformational change (rS emergence) to QRS Type 1 reflecting greater LV wavefront

contribution to the QRS fusion wave and less efficient electrical resynchronization (↑VAT,

↓(-)QRSdiff). Minimal conformational change occurs beyond LV-20 probably because rapid

wave propagation through Purkinje engagement is already underway (see text). Advancing LV

activation relative to LV conduction delay by shortening AVD during BV_sim (B) results in more

pronounced QRS Type 1 conformational change (↑R wave, ↓S wave, ↑VAT, ↓(-)QRSdiff)

reflecting greater muscle path contribution of the LV wavefront to the QRS fusion wave (see

text). Withdrawing LV activation by lengthening the AVD during BV_sim (C) initially enhances

QRS Type 2 fusion; peak BV fusion efficiency (dashed circle) is achieved at AVD 120 ms (68% of

PR), indicated by QRS Type 2 normalization, minimum VAT, maximum (-)QRSdiff. Further

41

withdrawal of the LV wavefront results in regression of electrical resynchronization and gradual

transformation to QRS Type 4 (BV_sim/AVD 180). Similarly, delaying the onset of LV activation

relative to RV activation during BV_seq/AVD 100 (D) also results in regression of electrical

resynchronization and transforms QRS Type 2 to QRS Type 4 reflecting greater RV wavefront

contribution to the QRS fusion wave (persistent QS, ↑VAT, ↑(+)QRSdiff → least efficient

electrical resynchronization) duplicating RV monochamber/LBBB activation (QS, RV-80, QRS

Type 4). VAT now exceeds both RV monochamber and LBBB activation times because

wavefronts are reinforcing, wave forces sum, conduction delay is amplified.

Best QRS fusion result is achieved during simultaneous BV pacing.

B. Same arrangement as prior figures. Top center: LBBB. Left: RV and LV monochamber

activation sequences. Right, top: QRS Type 1 during BV_sim/AVD 80 ms; Middle: QRS Type 2

during BV_sim/AVD 100 ms; Bottom: QRS Type 2 during BV_sim/AVD 120 ms.

Uncommon variation on ideal wavefront conditions for QRS Type 2 fusion. Monochamber

ventricular activation wavefronts are antiphase in horizontal plane (e.g., Leads V1-V6: RV pacing

= QS, LV pacing = R or qR). However, monochamber wavefronts appear to be in-phase in frontal

plane (R or Rs in I, aVL). Despite this apparent contradiction, BV fusion generates QRS

normalization due to large cancellation effect. This is an example of the “Lead I paradox”,

reported incidence 0.5% patients 34. A positive QRS complex (R) in lead I (and aVL) during LV

pacing is explained by posterior-basal LV stimulation site combined with a more horizontal

position of the LV long axis or rotation of the LV. The LV wavefront moves L → R, generating

paradoxical R in Lead I (and aVL), and posterior → anterior, generating expected QS in V1. The

result is “normally narrow” R waves in I and aVL rather than wave destruction. Anodal

stimulation was excluded.

42

Top right: QRS Type 1 during BV_sim/AVD 80; typical concordant conformational changes in

frontal plane (Leads V1-V2: QS → r; posterior → anterior activation reversal) and horizontal

plane (Lead I: R → qR; L→ R activation reversal). Note ↓VAT. Middle right: QRS Type 2 fusion

during BV_sim/AVD 100 ms. Note QRS normalization across 12 leads, large ↓VAT and large

(-)QRSdiff. The overall pattern approximates normal ventricular activation. QRS notching is

abolished indicating more uniform and faster wavefront propagation. These are visual

manifestations of wavefront cancellation and highly efficient fusion. Wavefronts are

oppositional, wave forces cancel, conduction delay is reduced. Lower right: Even better QRS

Type 2 fusion during BV_sim/AVD 120 ms. Note QRS normalization across 12 leads, large ↓VAT

and largest (-)QRSdiff. The overall pattern approximates normal ventricular activation.



BV_sim/AVD 100. Monochamber I-V conduction times are non-equivalent (R→L < L→R). Right:

QRS fusion wave progressions during I-V timing titration. Selected results are displayed for

illustrative purposes. BV_sim/AVD 100 (left, top) generates exemplary QRS Type 2 non-

conformational change from LBBB: QS → qs, ↓↓↓VAT, and large (-)QRSdiff. Delaying the onset

of RV activation relative to LV activation during BV_seq/AVD 100 (A) has a minor effect on the

QRS fusion wave, probably because rapid wave propagation through Purkinje engagement is

already underway (see text). Peak BV fusion efficiency (dashed circle) is achieved at

BV_seq/AVD 100/LV-40 (61% of PR), indicated by QRS normalization, minimum VAT, maximum

(-)QRSdiff. Advancing LV activation relative to LV conduction delay by shortening AVD during

BV_sim (B) results in QRS Type 1 conformational change (↑R wave, ↓S wave, ↑VAT,

43

↓(-)QRSdiff) reflecting greater muscle path contribution of the LV wavefront to the QRS fusion

wave (see text). Withdrawing LV activation by lengthening the AVD during BV_sim (C) results in

regression of electrical resynchronization approaching QRS Type 4 (BV_sim/AVD 160). Similarly,

delaying the onset of LV relative activation to RV activation during BV_seq/AVD 100 (D) also

results in regression of electrical resynchronization and transforms QRS Type 2 to QRS Type 4

reflecting greater RV wavefront contribution to the QRS fusion wave (persistent QS, ↓VAT,

↑(+)QRSdiff → least efficient electrical resynchronization) duplicating RV monochamber/LBBB

activation (QS, RV-80, QRS Type 4). VAT now exceeds both RV monochamber and LBBB

activation times because wavefronts are reinforcing, wave forces sum, conduction delay is

amplified.

Best QRS fusion is achieved at BV_seq/AVD 100/LV-40 which compensates nearly precisely for

non-equivalent I-V conduction times.

B. Same arrangement as prior figures. Top center: LBBB. Left: RV and LV monochamber

activation sequences. Right, top: QRS Type 2 during BV_sim/AVD 100 ms; Middle: QRS Type 2

during BV_seq/AVD 100/LV-40 ms; Bottom: QRS Type 1 during BV_sim/AVD 60 ms.

Top right. QRS Type 2 fusion during BV_sim/AVD 100 ms. Note QRS normalization in multiple

leads (I, L, V1-V4), ↓↓VAT, large (-)QRSdiff. Monochamber ventricular activation wavefronts

are antiphase in horizontal plane (e.g., Leads V1-V6: RV pacing = QS, LV pacing = R), whereas

wavefronts appear in-phase in frontal plane (R or Rs in I, aVL) due to “Lead I paradox” (see prior

slide). BV fusion generates QRS normalization due to large cancellation effect. Middle right.

Best QRS Type 2 fusion. QRS normalization is observed in all leads. QRS notching is nearly

abolished indicating more uniform, faster wavefront propagation. These are visual

manifestations of wavefront cancellation and highly efficient fusion. Wavefronts are

44

oppositional, wave forces cancel, conduction delay is reduced. The overall pattern approximates

normal ventricular activation. Bottom right: QRS Type 1 with ↑VAT and typical concordant

conformational changes in frontal plane (Leads V1-V2: QS → Rs; posterior → anterior activation

reversal) and horizontal plane (Lead I: R → qR; left → right activation reversal).

Figure 16. QRS Fusion Type 3; Apical MCV LV lead.


BV_sim/AVD 100. LBBB activation sequence is typical. RV pacing displays atypical R complex in

V1-V2. Apical MCV (“LV”) lead duplicates RV pacing activation except that QRSd is longer due to

epicardial location. I-V (RV-LV interval) is zero because RV and MCV stimulation sites are

physically overlapping and activated simultaneously. Right: Pseudo-BV QRS fusion waves during

I-V timing titration. Selected results are displayed for illustrative purposes. BV_sim/AVD 100

yields QRS Type 3 change from LBBB, duplicating RV pacing: rS → Rr’, ↑VAT, large (+)QRSdiff. In

this situation, delaying the onset of RV activation relative to LV activation during BV_seq/AVD

100 (A) yields but has little effect. Withdrawing LV activation by lengthening the AVD during

BV_sim (B) induces a reverse conformational change from QRS Type 3 to baseline LBBB (AVD

190) reflecting lesser BV wavefront contribution to the QRS fusion wave (R → rS, ↓VAT,

↓(+)QRSdiff). Delaying the onset of LV activation relative to RV activation (C) exaggerates QRS

Type 3 activation reflecting greater RV wavefront contribution to the QRS fusion wave

(persistent QS, ↑VAT and ↑(+)QRSdiff → least efficient electrical resynchronization) duplicating

RV monochamber pacing (RV-80). VAT now exceeds both RV monochamber and LBBB activation

45

times because wavefronts are reinforcing, wave forces sum, conduction delay is amplified. BV

fusion cannot be achieved by any manipulation of IV timing because neither wavefront

generates opposition to one another or LBBB activation.

B. LV lead repositioned to lateral coronary vein → QRS Type 1.

Left: LBBB, monochamber pacing waveforms, and nominal QRS fusion wave during BV_sim/AVD

100. LBBB and RV pacing waveforms are unchanged; LV monochamber activation from lateral

wall is typical and indicates genuine wavefront opposition to LBBB activation. I-V conduction

timing intervals now reflect maximally separated RV and LV stimulation sites and sequential

ventricular activation timing during LBBB and monochamber pacing. Monochamber I-V

conduction times are non-equivalent (R→L < L→R). Right: QRS fusion wave progressions during

I-V timing titration. Selected results are displayed for illustrative purposes. BV_sim/AVD 100

yields QRS Type 1 conformational change from LBBB: QS → Rs, ↑VAT, and large (+)QRSdiff. In

this situation, RV and LV wavefronts contribute to V1R emergence. Delaying the onset of RV

activation relative to LV activation during BV_seq/AVD 100 (A) results in minimal conformational

change, modest ↑VAT and ↑(+) QRSdiff through LV-80 → less efficient electrical

resynchronization, indicating LV wavefront propagation delay or block at this AVD. Withdrawing

LV activation by lengthening the AVD during BV_sim (B) induces a reverse conformational

change during QRS Type 1 fusion reflecting lesser LV wavefront contribution to the QRS fusion

wave (R → rS, ↓VAT, ↑(-) QRSdiff). Most efficient electrical resynchronization occurs at AVD

190 (73% of PR interval). Effective BV fusion can now be achieved by manipulation of I-V timing

because RV and LV wavefronts are oppositional, as compared to RV+MCV pacing. Delaying the

onset of LV activation relative to RV activation (C) regresses the nominal QRS type 1

conformational change reflecting greater RV wavefront contribution to the QRS fusion wave

46

(persistent QS, ↑VAT and ↑(+)QRSdiff → least efficient electrical resynchronization),

duplicating RV monochamber pacing (RV-80). VAT now exceeds both RV monochamber and

LBBB activation times because wavefronts are reinforcing, wave forces sum, conduction delay is

amplified.


conduction times. Delaying the onset of RV activation relative to LV activation to compensate for

asymmetric I-V times degrades fusion efficiency.

C. Effect of change in LV stimulation site on BV wave interference patterns is displayed. Note

that lateral LV pacing (bottom left) generates typical wavefront opposition to LBBB activation

(top) in pivotal leads I and L (R → QS; L → R activation reversal) and V1-V2 (QS → R; posterior →

anterior activation reversal). Ordinarily, uncomplicated RV apical and Apical MCV pacing

duplicate LBBB activation (QS in V1-V2, dominant R in I). However, in this case, atypical

activation pattern during RV and MCV pacing, presumably due to scar, misleadingly resembles

lateral LV pacing. During lateral LV pacing, large dominant R waves in V1-V5 (posterior →

anterior forces) and QS in I/aVL (L → R forces) indicate genuine activation wavefront opposition

to LBBB. In the case of RV and Apical MCV pacing opposition to LBBB is not demonstrated,

wavefronts are reinforcing, wave forces sum, conduction delay is worsened. In the case of RV

and proper lateral LV pacing, wavefronts are oppositional, wave forces cancel, conduction delay

is reduced. During QRS Type 1 fusion (peak electrical resynchronization efficiency) there is wave

destruction in leads I, II, III, R, L, F and QRS normalization in leads V1-V6. Wavefronts are

oppositional, wave forces cancel, conduction delay is reduced.

47



BV_sim/AVD 100. Monochamber I-V conduction times are slightly non-equivalent (R→L > L→R).


for illustrative purposes. BV_sim/AVD 100 (left, top) yields typical QRS Type 4 fusion: no

conformational change from LBBB (QS → QS, ↑VAT, and large (+)QRSdiff). Non-lateral LV lead

site, LV non-capture, LV capture latency have been excluded; LV monochamber pacing

wavefront is directly opposed to RV pacing in V1. Therefore, the explanation must be L → R line

of block preventing LV wavefront advancement. Delaying the onset of RV activation relative to

LV activation during BV_seq/AVD 100 (A) induces QRS Type 1 conformational change to reflect

greater LV wavefront contribution to the QRS fusion wave8 (↑R wave amplitude, ↑VAT,

↑(+)QRSdiff), and best obtainable electrical resynchronization under these operating

conditions, despite asymmetric I-V conduction times favoring L → R. Peak BV fusion efficiency

(dashed circle) is achieved at BV_seq/AVD 100/LV-60 (earliest R emergence at shortest

achievable VAT). Advancing LV activation relative to LV conduction delay by shortening AVD

during BV_sim (B) does not alter the nominal QRS fusion wave because BV pacing activation has

already replaced native ventricular conduction and I-V timing is fixed. Withdrawing LV activation

by lengthening AVD during BV_sim (C) exaggerates QRS Type 4 reflecting lesser LV wavefront

contribution to the QRS fusion wave (persistent QS, ↑VAT, and ↑(+)QRSdiff). VAT now exceeds

both RV monochamber and LBBB activation times because RV pacing reinforces LBBB

conduction delay → less efficient electrical resynchronization). Delaying the onset of LV

activation relative to RV activation (D) exaggerates QRS Type 4 activation reflecting greater RV

wavefront contribution to the QRS fusion wave (persistent QS, ↑VAT, ↑(+)QRSdiff → least

efficient electrical resynchronization) duplicating RV monochamber pacing (RV-80, QRS Type 4).

48

VAT now exceeds both RV monochamber and LBBB activation times because wavefronts are

reinforcing, wave forces sum, conduction delay is amplified.

Best QRS fusion result is achieved during sequential BV pacing by advancing LV activation

substantially beyond the differential in monochamber conduction times. QRS Type 4 → QRS

Type 1 transformation occurs at LV-60 though I-V conduction times differ by only 10 ms.


4 during BV_sim/AVD 100; Middle: QRS Type 1 during BV_seq/AVD 100/LV-60. Bottom: QRS

Type 4 during BV_seq/AVD 100/RV-80.

During BV_sim/AVD 100, QRS Type 4 (persistent LBBB activation + ↑VAT despite functioning

lateral lead) is observed despite typical oppositional wavefront patterns during RV and LV

monochamber pacing (note Lead I paradox during LV pacing; see earlier). Delaying the onset of

RV activation relative to LV activation (BV_seq/AVD 100/LV-60) induces QRS Type 1

conformational change, presumably by overcoming a line of block encountered by the

advancing LV wavefront. Emergence of R waves in V1-V2 indicates manifest wavefront

opposition to LBBB conduction. Delaying the onset of LV activation relative to RV activation

during BV_seq/AVD 100/RV-80 amplifies QRS Type 4 (persistent LBBB) activation reflecting

greater RV wavefront contribution to the QRS fusion wave.

49

Figure 18. Unusual manifestation of wavefront cancellation during BV fusion: Total destructive

interference.

Panel 1

A (left): RV monochamber pacing (baseline rhythm atrial fibrillation, complete AV block,

pacemaker dependent). Typical LBBB activation sequence, QRSd 182 ms. A (right): BV_sim

(VVI) (lateral lead) yields typical QRS Type 1 conformational change from LBBB: QS → Rs (V1-V2),

↓VAT (170 ms), and modest (-)QRSdiff.

B (left). Typical LBBB sequence, QRSd 166 ms. B (right): BV_sim/AVD 100 (lateral lead) yields

typical QRS Type 2 non-conformational change from LBBB: QS → qs, ↓VAT, and large

(-)QRSdiff).

In both examples, total destructive interference is seen in lead I (dashed circle); QRS complexes

have zero displacement. BV fusion waves are completely cancelled mimicking lack of electrical

activity (e.g., loss of electrode contact).

Panel 2

Monochamber pacing generates typical activation wavefront contours in lead I and V1

Monochamber interventricular conduction times are equivalent (A. RV-pace → LV-sense = 153

ms; LV-pace → RV-sense = 150 ms; B. RV-pace → LV-sense = 153 ms; LV-pace → RV-sense = 150

ms).

Exemplary monochamber ventricular activation wavefronts contours are antiphase in Leads 1

(RV pacing = R, LV pacing = QS) and V1 (RV pacing = rS, LV pacing = RR’). Opposing wave

50

amplitudes and durations are nearly equivalent in lead I. During BV_sim pacing mirror image

wavefront activation in lead I yields total wave destruction due to cancellation, and typical QRS

Type 2 fusion contour in V1. Complete wavefront destruction occurs when the interfering waves

are antiphase and have equivalent amplitudes. This provides absolute evidence that cancellation

due to wavefront superposition is the mechanism of QRS shortening during CRT.

Advancing LV activation by BV_seq/LV-80 pacing generates typical QRS Type 1 conformational

change (isoelectric → QS in lead I, rs → R in V1), ↑VAT, ↑(+)QRSdiff. This proves that apparent

absence of electrical activity is in fact complete wavefront cancellation.

Figure 19. Effect of change in LV stimulation site on QRS Fusion Type.

A. Underlying rhythm is sinus + complete AVB + ventricular asystole; BV wave interference

products (bottom) are compared to RV pacing (LBBB surrogate, top). RV apical site is fixed

during BV_sim/AVD 100 pacing. BV fusion during LV stimulation from mid-chamber AIV (Site 1)

generates QRS Type 3 (RV pacing/LBBB reinforcement). BV fusion during LV stimulation from

mid-chamber lateral vein (Site 2) generates QRS Type 1 with ↓↓↓ VAT indicating large

cancellation effect (LBBB remediation). Note in AP view AIV and Lateral stimulation sites appear

to be anatomically overlapping. However, in lateral view, posterior location of lateral site and

anterior location of AIV site are realized.

B. BV wave interference products (bottom) are compared to LBBB (top). RV apical site is fixed

during BV_sim/AVD 100 pacing. QRS Type 2 fusion is generated during LV stimulation from

distal lateral site (bottom left); QRS Type 1 fusion is generated by stimulation from mid-lateral

site (same coronary vein, bottom right). Both sites demonstrate LBBB wavefront remediation

and ↓↓↓ VAT (wavefront cancellation); best result occurs at Site 1 (mid-lateral). This is likely

51

explained by a change in muscle conduction path that enables the LV activation wavefront to

engage the Purkinje system (see earlier).

C. BV wave interference products (bottom) are compared to LBBB (top). RV apical site is fixed

during BV_sim/AVD 100 pacing. QRS Type 1 fusion is generated during LV stimulation from

distal inferior lateral site (bottom left) and proximal antero-lateral site (bottom middle). Though

QRS Type 1 contours differ, ↓VAT is equivalent between these 2 sites. QRS type 1 (best result)

occurs at mid-lateral site (bottom right) which generates QRS normalization and ↓↓↓ VAT

(wavefront cancellation). This is likely explained by a change in muscle conduction path that

enables the LV activation wavefront to engage the Purkinje system (see earlier).

52

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