The effect of conduction velocity slowing in left ventricular midwall on the QRS complex morphology: A simulation study

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The effect of conduction velocity slowing in left ventricular midwall on the QRS complex morphology: A simulation study Ljuba Bacharova, MD, DSc, MBA, a, b,⁎ Vavrinec Szathmary, RNDr, PhD, c Jana Svehlikova, RNDr, PhD, d Anton Mateasik, RNDr, PhD, a Julia Gyhagen, b Milan Tysler, Ing, PhD d a

International Laser Center, Bratislava, Slovakia Institute of Pathological Physiology, Medical Faculty, Comenius University, Bratislava, Slovakia Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic d Institute of Measurement Science, Slovak Academy of Sciences, Bratislava, Slovak Republic b

c

Abstract

Midwall fibrosis is a frequent finding in different types of left ventricular hypertrophy. Fibrosis presents a local conduction block that can create a substrate for ventricular arrhythmias and lead to the continuous generation of reentry. Having also impact on the sequence of ventricular activation it can modify the shape of QRS complex. In this study we simulated the effects of slowed conduction velocity in the midwall in the left ventricle and in its anteroseptal region on the QRS morphology using a computer model. Material and methods: The model defines the geometry of cardiac ventricles analytically as parts of ellipsoids; the left ventricular wall is represented by five layers. The impulse propagation velocity was decreased by 50% in one and two midwall layers, respectively, in the whole left ventricle and in LV anterior region. The effects of slowed conduction velocity on the QRS complex of the 12-lead electrocardiogram are presented as 12-lead electrocardiograms and corresponding values of ECG criteria for left ventricular hypertrophy (ECG-LVH criteria): Gubner criterion, Sokolow–Lyon index (SLI) and Cornell voltage. Results: All simulated situations led to increased R wave amplitude in the lead I and of S wave in the lead III, showing a leftward shift of the electrical axis and increased values of ECG-LVH criteria based on limb leads alone or in combination with precordial leads (Gubner criterion, Cornell voltage). The slowed conduction velocity in the whole LV influenced the QRS complex voltage in precordial leads, having an impact on the SLI and Cornell voltage. The changes were pronounced if two layers were involved. Conclusion: Using computer modeling we showed that the midwall slowing in conduction velocity modified the QRS complex morphology. The QRS complex changes were consistent with ECGLVH criteria, i.e. QRS patterns usually interpreted as the effect of left ventricular hypertrophy (the increased left ventricular mass). © 2016 Elsevier Inc. All rights reserved.

Keywords:

Conduction velocity; Midwall; QRS complex; Left ventricular hypertrophy

Introduction Electrocardiographic diagnosis of left ventricular hypertrophy is characterized by a wide variety of criteria, unsatisfactory estimation of left ventricular mass (LVM) and disagreements between increased LVM and QRS voltage [1,2]. On the other hand, the ECG-LVH signs are documented as independent ⁎ Corresponding author at: International Laser Center, Ilkovicova 3, 841 04 Bratislava, Slovak Republic. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jelectrocard.2015.12.009 0022-0736/© 2016 Elsevier Inc. All rights reserved.

cardiovascular risk factors [3–6], and thus represent a long lasting theoretical and practical diagnostic challenge. In our previous simulation studies we indicated that altered electrical properties of hypertrophied myocardium could be one of the factors contributing to the discrepancies between the increased LVM and QRS complex voltage [7–9]. The transmural slowing in conduction velocity either in the whole left ventricle [7] or in the anteroseptal region [8] resulted in QRS complex voltage changes even in the reference (“nonhypertrophied”) heart, showing several characteristics typical for ECG finding in patients with LVH.

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Cardiac magnetic resonance (CMR) allows detecting tissue characteristics of hypertrophied myocardium additional to estimating LVM [10–15]. Both diffuse fibrosis detected by T1 mapping and replacement/regional fibrosis detected by late gadolinium enhancement in midwall of the left ventricle were observed in patients with LVH of different etiology [16–23]. Fibrosis represents a burden to the impulse propagation. It is one of the factors predisposing to arrhythmia [24,25], and it has been repeatedly shown that the finding of fibrosis in LVH patients is associated with increased incidence of arrhythmia [26]. Its early detection is therefore of utmost importance. In the previous study we showed a possible effect of the diffuse slowing in conduction velocity on the QRS pattern. A question arises, if the mid-wall fibrosis could also have an effect on the QRS pattern. In this study we simulated slowed conduction velocity in the midwall of the left ventricle using a computer model, to demonstrate the effect on the QRS complex morphology and consequently on the ECG-LVH criteria. Material and methods Model description Details of the model were described previously [27]. In brief, the model is defined in a three-dimensional grid of elements. The geometry of model cardiac ventricles is defined analytically as segments of ellipsoids representing their inner (endocardial) and outer (epicardial) surfaces. The myocardial cellular elements of the model are represented as cubiform parts of the excitable cardiac tissue, with defined model ventricular transmembrane action potentials (MAPs). The depolarization sequence in ventricular walls from predetermined starting elements is performed by a procedure simulating the Huygens principle of wavefront propagation.

AS

165

After depolarizing of a model cell, its consecutive repolarization is governed by its MAPs. The ventricular wall of the model left ventricle is represented by five layers, and of the right ventricle by 3 layers which allow to introduce changes in action potential and conduction velocity in individual layers. The layer L1 represents the model Purkinje fiber mesh of the left ventricle; layers L2 to L5, the layers of the working myocardium. Simulated changes The following changes were simulated in the left ventricular midwall (Fig. 1): • Slowed conduction velocity in the midwall layers L3 (19.1% of the left ventricular volume), and L3 + L4 (28.1% of the LV volume) in the anteroseptal region. The affected area involved the anterior wall of the left ventricle and adjacent parts of interventricular septum and apex. The shape and the extent of areas with slowed conduction are presented in Fig. 1 • Slowed conduction velocity in the midwall layers L3 (30.7% of the LV volume) and L3 + L4 (53.8% of the LV volume) in the whole left ventricle; The ventricular activation velocity was slowed by 50%. The resultant heart vectors were adjusted for the anatomical position of the model ventricles in the thorax, and vectorcardiographic vectors were calculated. The vectorcardiographic vectors were converted to 12-lead electrocardiograms, using the Dower transformation matrix [28]. The results are presented as 12-lead electrocardiogram, and values of selected ECG-LVH criteria: Gubner criterion [29], Sokolow–Lyon index [30] and Cornell voltage [31].

LV

Fig. 1. Long axis and short axis cross-sections of the model ventricles. The left ventricular wall is divided into five layers L1–L5.The conduction velocity was slowed in layers L3, and L3 + L4, respectively, either in the whole left ventricle (LV), or in the anteroseptal area (AS). The layers of slowed conduction are highlighted by shades of gray.Lines assigned A–A’, and B–B’, indicate the levels of the short axis cross-sections.

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layers were affected. The increase was more apparent in the right precordial leads.

Results Maximum QRS spatial vector magnitude Remarkable increase of the QRS max by more than 40% resulted from slowed conduction velocity in two layers in the whole LV (Fig. 2). QRS duration The QRS complex duration was not affected by the slowed conduction velocity in one layer, either in anteroseptal area or in the whole LV. A slight increase by 8% was observed by slowing the conduction velocity in two layers in AS area, and by 16% in the whole LV, respectively (Fig. 2). 12-Lead electrocardiograms

As is demonstrated in the Fig. 3, the slowed conduction velocity in the midwall both in the AS region and the whole ventricle affected those ECG-LVH criteria that are based on the voltage of limb leads and leftward shift of the electrical axis (Gubner, Cornell, Romhilt–Estes). Additionally, the slowed conduction velocity in the whole LV influenced the precordial leads, having impact on the SLI and Cornel voltage. The values of the ECG-LVH criteria under study are presented in Fig. 4. Discussion

The difference of the 12-lead ECGs as compared to the reference ECG is presented in Fig. 3. The common effect of the slowed conduction velocity in the LV midwall was an increase in RI and appearance of SIII, as well as the increase in RaVL, more pronounced if two layers were affected, indicating a shift of the electrical axis in the frontal plane to the left; the QRS complex duration and the intrinsicoid deflection were prolonged if two layers were affected. Regarding the precordial leads, the slowing in AS region did not increase the QRS amplitude. On the other hand, the slowing in conduction velocity in the whole LV resulted in an increase of QRS amplitude, more pronounced if two

QRSdur

%

ECG-LCG criteria

140

Main results of this study: • Changes in limb leads that are the key for the ECG-LVH criteria based on limb leads alone or in combination with precordial leads (Gubner criterion, Cornell voltage) in all simulated situations; • Increased QRS complex voltage in precordial leads if the conduction velocity was slowed in the whole LV, having impact on the Sokolow–Lyon and Cornell voltage; • The maximum spatial QRS vector magnitude increased only in the situation if two layers in the whole LVH were affected. • Only a slight prolongation of QRS duration if two layers were affected.

120 100 80 60 40 20 0 AS L3

AS L3+L4

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QRSmax

% 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0 AS L3

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LV L3

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Fig. 2. Relative values (percent) of the QRS complex duration (QRSdur) and the maximum QRS spatial vector magnitude (QRSmax).AS L3: Slowed conduction velocity in the layer 3 in the anteroseptal region of the left ventricle.AS L3 + 4: Slowed conduction velocity in the layers 3 and 4 in the anteroseptal region of the left ventricle.LV L3: Slowed conduction velocity in the layer 3 in the whole left ventricle.LV L3 + 4: Slowed conduction velocity in the layer 3 and 4 in the whole left ventricle.Reference = 100%.

In this study we simulated the effect of LV midwall slowing in impulse propagation velocity, considering published CMR findings that show midwall fibrosis in different types of conditions [16–23]. We supposed that regional replacement fibrosis could lead to regional intramyocardial slowing in impulse propagation and deform the activation front, thus having impact on the QRS complex morphology. We selected ECG-LVH criteria representative for the criteria based on limb leads (Gubner criterion), precordial leads (Sokolow–Lyon index); and the combination of limb and precordial leads (Cornell voltage). Consistent QRS complex changes in all simulated situations were observed in the limb leads: the increased RI, an appearance of SIII waves, and the increase in the R wave amplitude in aVL, shifting the electrical axis to the left. Consequently, the values of Gubner criterion, as well as the Cornel voltage increased in all simulated situations. These changes in limb leads were described as the early ECG-LVH criteria [29,30,32], they are included in the Romhilt–Estes score [33], and they are a part of combined criteria of limb and precordial voltage [31,34]. Also now, RaVL is still quoted as a solid index of LVH [35,36], associated with major cardiovascular events, cardiovascular and all-cause mortality [37–40,5] The voltage in precordial leads increased when the proportion of slowing was more pronounced: either when the

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AS L3

AS L3+4

LV L3

LV L3+4

Fig. 3. Derived 12-lead electrocardiograms, showing the effect of the slowed conduction velocity in the left ventricular midwall.The major changes appeared in the limb leads: the increase in RI and appearance of SIII, as well as the increase in RaVL, more pronounced if two layers in anteroseptal region was affected. In the precordial leads, the conduction velocity slowing in two layers of the left ventricle increased the QRS amplitude, more pronounced in the right precordial leads. The QRS complex duration and the intrinsicoid deflection were prolonged if two layers either in the anteroseptal region or in the whole left ventricle were affected.Blue: Reference electrocardiogram.Red: Pathological electrocardiogram.AS L3: Slowed conduction velocity in the layer 3 in the anteroseptal region of the left ventricle.AS L3 + 4: Slowed conduction velocity in the layers 3 and 4 in the anteroseptal region of the left ventricle.LV L3: Slowed conduction velocity in the layer 3 in the whole left ventricle.LV L3 + 4: Slowed conduction velocity in the layer 3 and 4 in the whole left ventricle.

whole LV was affected or when the slowing in AS region involved two layers. Accordingly, the values of SLI increased, as well as the Cornell voltage. Because the Cornell voltage includes changes in both the limb leads and precordial leads, it increased considerably when the whole left ventricle was affected. These findings are consistent with our previous results simulating the effect of the transmural slowing in conduction velocity [7,8]. The results of this study showed that also the mid-wall conduction slowing affected the QRS complex morphology, and the effect is related to the volume of the myocardium with slowed conduction. The results of this study thus showed that the regional slowing in conduction velocity leads to deformation of the activation front resulting in changes in QRS complex that are seen in patients with LVH. The QRSmax reflects the maximal extent of the activation front; in LVH it is considered to be increased due to increased LV dimensions. The increased QRSmax is then reflected in the increased QRS voltage of 12-lead ECG. However, in this simulation study the dimensions of LV were not changed, and the QRSmax was increased only in one simulated situation (in the slowed conduction velocity in two layers in the whole ventricle when the conductivity was slowed in 53.8% of the left ventricular volume). However, the QRS voltage in the limb leads voltage criteria and RaVL increased in all simulated situations. It follows, that the

increased QRS voltage in limb leads observed in this study could not be attributed to the increase in the anatomical dimensions of LV and/or the increased extend of activation front, but to the changes in the orientation/spatial position of the activation front in relation to the recording electrodes, in other words to the different angles the limb leads viewed the activation front. The QRS duration increased only slightly if two midwall layers were involved, while the slowing in conduction velocity in one layer did not affect the QRS duration. However, the QRS duration prolongation was minor (8 and 16%, respectively). Taking the duration of the reference QRS complex of 80 ms, the slowing in two layers would correspond to the QRS duration of 86.4 ms and 92.8 ms, respectively, i.e. theoretically they would be within normal limits. The QRS duration is frequently increased in LVH and is attributed to the increased thickness of the left ventricle wall and to intramural fibrosis [1]. In our previous simulation study we showed that the transmural slowing in conduction velocity in the LV myocardium was the major determinant of the prolonged QRS duration and not the thickness of the LV wall or LV dimension [7]. The slowed conduction velocity documented in LVH is intensively studied as an arrhythmogenic substrate [41–43]. The recognized ECG indicator of slowed conduction is the QRS complex prolongation. However, in this simulation

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continuous generation of reentry [26]. Recognizing early changes in QRS indicating intramyocardial conduction problems that might identify incipient arrhythmia problems is a challenge for electrocardiography. The results of this simulation study support the statement of the Working Group on ECG-LVH that outlines a new model of ECG diagnosis of LVH [45] stressing the primary info provided by ECG i.e. the electrical properties of myocardium, and their alteration in LVH.

Gubner

% 600 500 400 300 200 100 0 AS L3

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SLI

% 250 200 150 100 50 0 AS L3

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% 700 600

Limitation of the study The limitations of the model include the analytically defined shape of the heart as well as of the areas of impaired activation. It allowed reduction of conduction velocity in ventricular myocardium only by 50%. A reduction in 50% could represent an advanced pathology presumably with critical gap junctional uncoupling in combination with ischemia and presence of “non-myocardial” cells (fibrotic tissue) [46–48]. In spite of these limitations, this model helped to visualize some of the assumed processes/concepts related to the interpretation of electrocardiograms in patients with midwall fibrosis, and their relation to the electrocardiogram. Our results are consistent with the variety of QRS changes attributed to LVH and recommended as ECG-LVH criteria [1]. It could be assumed that midwall fibrosis and consequently altered sequence of depolarization could be one of the underlying mechanisms.

500 400

Conclusion

300 200 100 0 AS L3

AS L3+L4

LV L3

LV L3+L4

reference

Fig. 4. Relative values (percent) of the Gubner criterion, Sokolow–Lyon index and Cornell voltage.AS L3: Slowed conduction velocity in the layer 3 in the anteroseptal region of the left ventricle.AS L3 + 4: Slowed conduction velocity in the layers 3 and 4 in the anteroseptal region of the left ventricle.LV L3: Slowed conduction velocity in the layer 3 in the whole left ventricle.LV L3 + 4: Slowed conduction velocity in the layer 3 and 4 in the whole left ventricle.Reference = 100%.

study we demonstrated that slowing in the LV midwall was not associated with clinically important QRS prolongation, but it had remarkable effect on the QRS morphology. Our findings indicate that not only the prolonged QRS duration, but also QRS morphology changes could be indicators of intramyocardial slowed conduction. Clinical implications LVH is associated with a greater risk of ventricular arrhythmias and sudden death [for a review see e.g. 44]. Re-entry is one of proposed electrophysiological mechanisms that could cause ventricular arrhythmias where intramyocardial slowed conduction velocity plays an important role. Increased fibrosis provides a site for conduction block, leading to the

Computer simulations showed that slowing of conduction velocity in the midwall of the left ventricle resulted in QRS changes mimicking classical ECG signs of LVH, although neither LV dimensions nor LVM was increased, and the LV shape was not changed. The results of this study support the assumption that the QRS complex could contain information about the presence and location of regional ventricular activation slowing. These results emphasize the importance of considering regional conduction alterations in the interpretation of QRS patterns, and thus create a link between the interpretation of QRS complex morphology and the pathogenesis of arrhythmias. Acknowledgment This study was supported partly by the projects VEGA 2/ 0131/13 and APVV 0134-11. References [1] Hancock EW, Deal BJ, Mirvis DM, Okin P, Kligfield P, Gettes LS, et al. American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; American College of Cardiology Foundation; Heart Rhythm Society. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International

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