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

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, MD

Cardiac Arrhythmia Service

Shapiro Cardiovascular Center

Brigham and Women's Hospital

70 Francis Street

Boston, MA 02115

Vmail: 857-307-1948Fax: 857-307-1944Email:

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 changesestablished 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, quantifiableand 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 itselectric 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 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 oftenintermediate 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.

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).

Wave Interference and the QRS duringNormal 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.

Consequently, a methodological solution for QRS fusion analysis was reexaminedusing the principles of wave interference. In this model, BV fusion is an example of stable two-point source interferencewhere 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 commonpoint. This path differenceis described in terms of the number of full waves that travel from each point source to the interference point. Pathdifference 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, thepath length and conduction velocityfrom 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

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-V2which provide a reproducible pivot point between anterior and posterior directed activation1-3, 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, QRSdshortening 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 Typesuperficially similar to Type 3, but where timing changes can induce a transformation to Type 1.

These 4 QRS Fusion Typesrecite 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 narrowQRS 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.

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-V21-3, 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 aselectrical 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.

2. Sequentialventricular 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 EASwith two largeopposing 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 toCharacterize and Quantify QRS Fusion Using Wave Interference

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 measurefor ventricular activation sequence change indicative of LBBB remediation (QRS fusion), using the principles of superposition during wave interference, (2) a quantifiable numericalmeasurefor change in EAS using ventricular activation time (VAT)to characterizerestoration 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 glyph[A], 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 scar1, 7.

BV fusion requires that(1) stimulation must occur from a site capable of reversing LVconduction 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 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 VATas 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)replaceR, 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.

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 V2because they are bestpositioned 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)1in 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

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]