Articles in PresS. Am J Physiol Heart Circ Physiol (December 31, 2015). doi:10.1152/ajpheart.00639.2015
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Septal flash and septal rebound stretch
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have different underlying mechanisms
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Running Head: Relation between septal flash and rebound stretch
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John Walmsley*1, Peter R. Huntjens1,2, Frits W. Prinzen1, Tammo
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Delhaas1, Joost Lumens1,2
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1) CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands; 2) L’Institut de Rythmologie et Modélisation Cardiaque (IHU-LIRYC), Université de Bordeaux, Pessac, France.
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* Address for Correspondence:
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John Walmsley
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Maastricht University Medical Center
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CARIM School for Cardiovascular Diseases
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P.O. Box 616
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6200 MD Maastricht, The Netherlands
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[email protected]
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Tel: +31433881278
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Fax: +31433881725
19 20 21 1 Copyright © 2015 by the American Physiological Society.
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Author Contributions:
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Conception and design of research: JW, PRH, FWP, TD, JL
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Performed simulations: JW, PRH
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Analyzed data: JW
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Interpreted results of simulations: JW, PRH, FWP, TD, JL
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Prepared figures: JW, PRH
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Drafted manuscript: JW
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Edited and revised manuscript: JW, PRH, FWP, TD, JL
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Approved final version: JW, PRH, FWP, TD, JL
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Key words: ventricular interaction; left bundle-branch block; computer modeling;
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cardiac mechanics; echocardiography
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Word count (abstract onwards): 6891
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2
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Abstract
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BACKGROUND: Abnormal left-right motion of the inter-ventricular septum in early
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systole, known as septal flash (SF), is frequently observed in patients with left
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bundle-branch block (LBBB). Trans-septal pressure gradient and early active septal
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contraction have been proposed as explanations for SF. Similarities in timing (early
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systole) and location (septum) suggest SF may be related to septal systolic rebound
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stretch (SRSsept). We aim to clarify the mechanisms generating SF and SRSsept.
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METHODS AND RESULTS: The CircAdapt computer model was used to isolate the
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effects of timing of activation of the left ventricular free wall (LVFW), right ventricular
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free wall (RVFW), and septum on SF and SRSsept. LVFW and septal activation times
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were varied by ±80 ms relative to RVFW activation time. M-mode derived wall
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motions and septal strains were computed and used to quantify SF and SRSsept,
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respectively. SF depended on early activation of the RVFW relative to the LVFW. SF
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and SRSsept occurred in LBBB-like simulations and against a rising trans-septal
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pressure gradient. When the septum was activated before both LVFW and RVFW,
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no SF occurred despite presence of SRSsept.
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CONCLUSIONS: Computer simulations indicate that SF and SRSsept have different
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underlying mechanisms, even though both can occur in LBBB. The mechanism of
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leftwards motion during SF is early RVFW contraction pulling on and straightening
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the septum when unopposed by the LVFW. SRSsept is caused by late LVFW
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contraction following early contraction of the septum. Changes in trans-septal
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pressure gradient are not the main cause of SF in LBBB.
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New & Noteworthy
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Simulations demonstrate that in left bundle-branch block, septal flash is caused by
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early activation of the right ventricular free wall before the left ventricular free wall,
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whereas septal rebound stretch requires early septal activation. Septal flash may
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therefore not occur if both left and right sided conduction delays are present.
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Introduction
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Left bundle-branch block (LBBB) causes asynchronous electrical activation of the
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ventricular myocardium, resulting in dis-coordinated contraction and inefficient pump
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function (36). A commonly-observed echocardiographic feature of LBBB is an
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abnormal early-systolic left-right motion of the inter-ventricular septum referred to as
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septal beaking or septal flash (SF) (8). Presence of SF has been associated with
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reduced left ventricular (LV) pump function (15). Septal systolic rebound stretch
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(SRSsept) as detected by strain measurements is another septal mechanical anomaly
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observed in patients with LBBB. SRSsept is a stretch during early systole following
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pre-ejection shortening in the septum (7, 19, 20, 36).
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LBBB and other ventricular conduction delays are observed in patients with heart
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failure (HF), typically manifesting as changes in the duration and morphology of the
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QRS complex on the ECG (28, 30). Cardiac resynchronization therapy (CRT) is an
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increasingly common treatment for HF when LV electrical asynchrony is present
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(21). CRT aims to restore a more synchronous activation of the LV by pacing the
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right ventricular (RV) apex and the LV free wall (LVFW), thereby improving pump
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function. CRT is most effective when an LBBB-like pattern on the 12-lead ECG is
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present and QRS duration is above 150 ms. CRT is not recommended when QRS
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duration is less than 120 ms, and clinical uncertainty remains when the QRS 4
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duration is between 120-150ms or when the ECG does not show an LBBB
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morphology (34). There is considerable interest in finding additional indications for
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CRT in this intermediate group.
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Recent studies have shown that patients exhibiting SF or SRSsept are likely to
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respond to CRT and that correction of SF and SRSsept by CRT indicates an
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increased likelihood of LV volumetric reverse remodelling (7, 9, 27). SF and SRSsept
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may therefore be additional clinical indicators for stratification of patients prior to
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CRT device implantation (6, 12, 19), although some patients with no observable SF
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still do respond to CRT (27). It is therefore important to understand the mechanisms
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through which SRSsept and SF do, or do not, occur when ventricular activation is
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abnormal.
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The similarities in timing (early systole) and location (septum) imply that SF and
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SRSsept may reflect the same phenomenon. SF and SRSsept are therefore sometimes
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conflated in the literature. The purpose of this study is to investigate how the relative
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timing of activation in the RV free wall (RVFW), LVFW, and septum together
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determine the presence or absence of SF and SRSsept. We aim to clarify the
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connection between SF and SRSsept. We use a computational model to isolate the
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effects of the timing of activation of the ventricular walls, and determine ventricular
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cavity pressures, septal motion, and myocardial deformation.
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Materials and Methods
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The CircAdapt Model
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We used the CircAdapt computational model of the human heart and circulatory
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system (2) to investigate the mechanisms of SF. CircAdapt consists of modules 5
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representing the aortic, mitral, pulmonary, and tricuspid valves; systemic and
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pulmonary arteries, veins, and peripheral microvasculatures; left and right atria; and
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left and right ventricles including inter-ventricular mechanical interaction through the
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interventricular septum (23). Cardiac myofiber mechanics are described using the
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sarcomere module (23). These modules are coupled together to represent the
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healthy human adult circulation (Fig. 1A). Realistic model boundary conditions and
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tissue properties are obtained through adaptation of cardiac and vascular tissues to
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mechanical load as previously described (3). We did not simulate heart failure
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because heart failure was not induced in the experimental canine data used for
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comparison. The version of the CircAdapt model used for all simulations has been
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previously published (37) and can also be downloaded from the CircAdapt website
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(www.circadapt.org). Matlab® (The MathWorks, Natick, MA) scripts to perform all
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simulations and analysis are provided as an online data supplement.
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Simulation of activation delay
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Each of the three ventricular walls in the CircAdapt model can be assigned an
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activation time, representing the time at which, on average, the tissue in that wall
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begins to actively generate tension (20). We varied the delay of activation onset in
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the LV free wall and interventricular septum by ±80 ms relative to the time of RV
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activation to investigate the sensitivity of SF to different activation times of the three
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ventricular walls (Fig. 1B). Activation time was varied in steps of 20 ms. The PQ
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interval was set at 150 ms in all simulations, and defined as the time from right atrial
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(RA) activation to the time of activation of the earliest ventricular wall, which could be
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the RVFW, LVFW, or the septum depending on their timings relative to each other.
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Simulations were performed using a heart rate of 70 beats per minute. A cardiac
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output (CO) of 5 l/min and mean aortic pressure (MAP) of 92 mmHg were 6
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maintained in the simulations. Hemodynamics reached steady state before the
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simulations were analysed. We defined the trans-septal pressure (PTS) to be the LV
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pressure minus the RV pressure. Hence, PTS > 0 mmHg means that LV pressure
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exceeds RV pressure, and a rising PTS means that LV pressure is rising more quickly
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than RV pressure. Simulated results representing normal physiology and LBBB were
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compared to canine experimental data originally published by Gjesdal et al. (14). We
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prevented diastolic mitral regurgitation from occurring in the model when the
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effective atrioventricular delay was prolonged by delayed onset of activation to
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remove a potential confounder.
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Calculation of M-mode and quantification of septal flash
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Pseudo M-mode images were calculated from the CircAdapt model as described
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previously (16). All distances were measured from the LV epicardium when plotting
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the pseudo M-mode images. SF was quantified from this image by calculating the
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distance from the LV side of the septum to the lateral LVFW (DLVS-LW) as shown in
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Fig. 2. SF magnitude was quantified as the magnitude of rightwards motion of the
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septum (increase in DLVS-LW) following leftwards motion (decrease in DLVS-LW),
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occurring after the first onset of ventricular excitation and before the end of LV
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systole (Fig. 2).
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Quantification of Septal Rebound Stretch
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Fiber strain is calculated from the simulations using the segment length (Ls) from the
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sarcomere module in CircAdapt (23). Strain is calculated relative to the sarcomere
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length at the onset of ventricular activation (Ls,0). The engineering strain, E, is used
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to determine strain patterns, where
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L E = 100 × s − 1 . L s ,0
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SRSsept was calculated from the simulated strain patterns as follows (Fig. 2); 1) find
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the first shortening in the septal strain pattern that occurs after mitral valve closure;
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2) find the first stretch following this period of shortening; 3) SRSsept is defined as the
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total stretch during this period that occurs before closure of the aortic valve.
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Sensitivity Analysis
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We performed a sensitivity analysis to determine the effects of other model
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parameters on the output variables (OVs) SF and SRSsept. Parameter values were
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changed by ±30% relative to their baseline values. Three baseline cases were
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considered; ‘Normal’ with simultaneous LVFW, RVFW, and septal activation onset;
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‘LBBB’ with LVFW activation onset delayed by 60ms relative to the septum and
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RVFW; and ‘Early Septum’ with septal activation onset 60ms prior to the LVFW and
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RVFW. The input parameters we investigated were wall volume (Vwall), contractility
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(Sf,act), and passive stiffness (Sf,pas) of the LVFW, septum, RVFW, and all three
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simultaneously (ALL); the opening areas of the aortic (AAoV) and pulmonary (APuV)
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valves; and heart rate (HR). Activation times relative to the RVFW of the LVFW
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(TALVFW-RV) and septum (TASEPT-RV) were also included for comparative purposes,
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and were varied by ±20ms from the baseline simulations with PR interval kept
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constant as described above. MAP and CO were maintained in these sensitivity
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analysis simulations at 92 mmHg and 5 l/min, respectively. We additionally
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performed simulations where the maintained CO was varied by ±30%. For each of
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the three baseline simulations, the normalized effect size resulting from a parameter
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change was calculated as
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Effect =
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OVbaseline±30% − OVbaseline , OVLBBB
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where OVx is the value of SF or SRSsept in simulation x. Baseline can be the Normal,
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LBBB, or Early Septum simulation.
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Results
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Early right ventricular activation gives rise to septal flash
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Simulations of synchronous ventricular activation produced no SF in the pseudo M-
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mode images, as in normal human physiology and in canine experimental data from
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the study by Gjesdal et al. (Fig. 3). When a delay of the LV free wall was introduced
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into the CircAdapt model, a decrease of the distance between the septum and the
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LVFW was observed that closely resembled the beaking seen in M-mode images
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recorded during experiments in a canine model of LBBB by left bundle-branch
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ablation (Fig. 3). Inwards motion of the LVFW epicardium in the simulated M-Mode is
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not present because the LVFW epicardium is used as the reference point for
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calculation.
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Figure 4A shows the sensitivity of SF magnitude to the relative timing of all three
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ventricular walls. Almost no septal flash appears unless the RVFW is activated
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before the LVFW, as demonstrated by the sensitivity map of SF magnitudes and the
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corresponding traces of distance between LV and septal walls. The horizontal
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dashed line in Fig. 4A indicates where LVFW activation becomes later than RVFW
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activation. The timing of septal activation then determines the magnitude of SF, with
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a larger activation delay of the septum relative to the RVFW causing a larger SF.
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Consequently, the greatest magnitude of SF (the top-right corner of the sensitivity
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map in Fig. 4A) occurs when both the septum and the LVFW have a large activation
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delay relative to the RVFW. When the septum is prematurely activated relative to the
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RVFW, SF magnitude is decreased or even abolished, unless the LVFW has a very
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large delay.
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Early septal activation gives rise to septal systolic rebound stretch
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Fig. 4B confirms that almost no SRSsept appears unless the septum is activated
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before the LVFW, as illustrated by the diagonal dashed line. When the septum is
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activated later than the LVFW, SRSsept does not occur since any stretch of the
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septum is not preceded by an initial shortening as the septum is inactive. A small
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exception is observed when the LVFW and septum are simultaneously activated and
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SF is extremely large due to very early RVFW activation. Deformation of the septum
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during SF then causes a small degree of early fibre shortening. The shape of the
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SRSsept sensitivity map is visually different to the SF sensitivity map, with SRSsept
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magnitude becoming greater towards the top-left hand corner of Fig. 4B, indicating a
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very prematurely activated septum relative to the RVFW, and a very large delay of
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the LVFW.
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Septal flash can occur without a falling left-right trans-septal pressure gradient
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In Fig. 5, we compare the normal simulation and a simulation representing LBBB
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with the experimental results presented by Gjesdal et al. (14). Both the simulations
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and the experiments demonstrate similar patterns of septal displacement relative to
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the LV free wall. The maximum deflection of the septum in LBBB occurs against a
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rising PTS in both the LBBB simulation and the canine experiment. The pattern of
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myocardial deformation is also similar between the simulations and the experiments.
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In both simulated and experimental LBBB, a characteristic pre-ejection shortening of
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the septum followed by stretch and then shortening is observed, coinciding with the
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timing of SF and indicating SRSsept.
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In Fig. 6 the LVFW is activated 60ms later than the RVFW and the septum is allowed
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to vary its activation time between being simultaneous with the RVFW and
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simultaneous with the LVFW. When the septum is activated after the RVFW, a
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reversal in PTS begins to appear. As septal activation becomes later, SF magnitude
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and PTS reversal across the septum both increase, but SRSsept decreases.
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Role of early septal activation in septal flash and systolic septal rebound stretch
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To investigate whether early septal activation alone is sufficient to cause SF and
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SRSsept, we simulated the septum activating first, with delayed activation of both LV
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and RV free walls 60ms later (Fig. 7). Under these conditions, SRSsept occurred but
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no SF, showing that early-systolic septal shortening is not necessarily related to
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early septal leftward motion (SF).
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Sensitivity Analysis
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The results of the parameter sensitivity analyses for SF and SRSsept are shown in
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Fig. 8. For the baseline simulations with little/no SF (Normal and Early Septum),
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changing parameter values other than activation time had very little effect upon the
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magnitude of SF. In the LBBB simulation, where a SF of 0.38cm exists, varying other
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tissue parameters had a much larger effect on the magnitude of SF. After activation
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time, the largest effects were due to HR and LVFW Vwall.
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For SRSsept, the effect of changing parameters was minimal in the normal simulation
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where no SRSsept was present at baseline. A much larger effect of changing the
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parameters was recorded in the LBBB and Early Septum simulations where SRSsept
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of 6.6% and 4.9%, respectively, was present. Again, changing activation time, HR 11
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and CO had the largest effect on SRSsept. Other parameters which gave a significant
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effect were LVFW Vwall, Sf,act, and Sf,pas and global Vwall and Sf,pas.
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Variations in HR and CO both have the effect of changing LV stroke volume. Stroke
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volume increases with decreasing HR and increasing CO. The sensitivity of both SF
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and SRSsept to these parameters indicates a dependence on stroke volume and
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preload, with the difference between the two arising from the effect of cycle time.
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Discussion
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Septal flash and septal rebound stretch represent different phenomena
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The main finding of our simulation study is that SF and SRSsept have different
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mechanisms. The generation of leftwards motion of the septum in SF relies critically
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on an early onset of RVFW active stress generation relative to the LVFW. Early
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septal shortening followed by SRSsept depends primarily on early onset of septal
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active stress generation relative to the LVFW (20). Both SF and SRSsept require the
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LVFW to be late-activated. Our simulations mechanistically support the hypothesis
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that the main mechanism of the initial leftward septal motion during SF is
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deformation of the septum due to contraction of the RVFW that is unopposed
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because contraction of the LVFW is delayed (15). The subsequent return motion of
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the septum is caused by an increased septal curvature resulting from forceful
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contraction of the LVFW. A decrease in PTS was not necessary for SF or SRSsept to
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occur, although a decrease in PTS was present in many of the simulations. We
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therefore propose that the mechanism of SF in LBBB is hinging of the septum at the
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attachment points of the RV and the septum. Hinging occurs due to an imbalance of
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forces at the RV attachment points resulting from early RVFW contraction. The
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proposed mechanism is explained diagrammatically in Fig. 9.
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Role of trans-septal pressure and septal contraction
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It is well-established that septal position is related to trans-septal pressure gradient
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(33). Pacing studies in canines have shown that SF-like septal motion can be
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explained by the interventricular septum being forced leftwards when RV pressure
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transiently increases relative to LV pressure, due to early activation in the RV (18,
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22). A more recent canine experimental study has shown that when LBBB is induced
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by ablation of the left bundle branch, SF was apparent despite a rising LV pressure
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relative to RV pressure (14). In LBBB, as opposed to cardiac pacing, SF was
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therefore attributed primarily to an active mechanism arising from early contraction of
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the septum relative to the LVFW. The latter suggests a direct physical relation
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between SF and SRSsept, the systolic lengthening following initial pre-ejection
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shortening of septal myofibers (7, 19, 20, 36).
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Results consistent with both passive pressure-driven and active contraction-driven
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hypotheses of SF generation were observed in our simulations, depending on the
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timing of RVFW activation relative to the septum and LVFW. Deformation of the
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septum with a transient increase in RV pressure relative to LV pressure was
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observed when the RVFW was activated before the septum and LVFW, consistent
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with RV outflow tract pacing as in the experiments of Little et al. and Kingma et al.
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(18, 22). When the RVFW and septum were simultaneously activated before the
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LVFW, behaviour closely resembling that observed by Gjesdal et al. (14) was
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apparent, with SF occurring without a decrease in PTS. Myocardial strain in the
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simulations also closely resembled deformation recorded in the experimental study
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of Gjesdal et al. 13
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Early septal contraction is not sufficient for septal flash
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We were able to isolate the effect of septal timing using our computer model. If early
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contraction of the septum sufficed to generate SF, then the simulation presented in
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Fig. 7, where the septum contracted before either the RVFW or the LVFW, ought to
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exhibit SF. Early contraction of the septum relative to the LVFW alone did not cause
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SF, although a large amount of SRSsept was present. Therefore, there must be some
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role for the RV in the generation of SF. This finding is consistent with the
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experimental study by Little et al. (22), which showed that pacing the LV side of the
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interventricular septum gave no SF, but pacing the RV side of the septum did give
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SF. In the latter case, but not the former, the RVFW would be expected to activate
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before the LVFW due to trans-septal conduction (31), and the septum is activated
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first in both cases. Conversely, this form of pacing may also reduce the delay
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between septal and LVFW activation, particularly if fast-conducting endocardial
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tissue is activated (17, 32). The simulations in Fig. 6 and Fig. 7 also clearly illustrate
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that SRSsept is not necessarily the same phenomenon as SF. Care should therefore
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be taken to differentiate between abnormal early systolic motion of the septum as
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observed in M-mode echocardiography, referred to in this study as SF, and pre-
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ejection septal shortening followed by systolic stretching observed in strain
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measurements, known as SRSsept.
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Modulation of septal flash and septal rebound stretch
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Trans-septal pressure gradient and septal activation modulate magnitudes of SF and
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SRSsept. In the case of early septal activation, LV cavity pressure increases due to
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septal contraction, and passive stress within the LVFW is increased, opposing the
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stress generated by the RVFW and therefore diminishing SF. Similarly, a late
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activation of the septum relative to the LVFW will not only delay the rise of LV cavity 14
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pressure but it will also decrease preload on the LVFW, diminishing its opposition to
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the RVFW and therefore allowing a larger SF to take place. Presence of SRSsept in
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our simulations depended primarily on an activation delay between the septum and
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the LVFW, as we have previously shown (20). However, according to our definition,
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SRSsept could be induced by a large SF when both septum and LVFW were activated
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much later than the RVFW (10). This septal strain pattern was qualitatively different
323
to those observed when the septum was activated before the LVFW, as it represents
324
an interrupted stretch during filling rather than an interrupted shortening during LV
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systole. It may therefore be possible to record SRSsept from a non-active septum if
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SF is sufficiently large.
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Clinical significance
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Several research groups have shown that presence of SF may improve prediction of
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response to cardiac resynchronization therapy (CRT) (6, 9, 12, 27, 29). It is therefore
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important to understand the mechanisms why SF might, or might not, occur in
331
patients. Our simulations predict that SF may not occur if both left- and right-sided
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conduction delays are present, despite the presence of pre-ejection shortening in the
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septum. This situation, known as a bilateral or masquerading bundle-branch block,
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can sometimes occur in patients and could respond to CRT (4, 13, 26, 38). We
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therefore suggest that, although the lack of SF in a patient with an LBBB-like
336
morphology on the 12-lead ECG is likely to indicate some form of co-existing
337
pathology, it should not exclude CRT without further investigation of what that
338
pathology is. Septal infarction has been associated with lack of SF (8, 11), and a
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simulation study by Huntjens et al. (16) has also demonstrated that reduced LVFW
340
contractility may prevent SF from appearing due to slowing of the return of the
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septum into the right ventricle. Hence, other mechanisms than delayed RV activation 15
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can prevent SF from occurring and these mechanisms may well preclude response
343
to CRT.
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Use of the CircAdapt model
345
Our use of a computational model for this study was motivated by the difficulty of
346
developing a closed chest animal model in which LVFW, RVFW, and septal
347
activation times can be independently varied. Ventricular pacing may not be
348
sufficient as shown by the qualitative differences in pressure behaviour between the
349
pacing studies of Kingma et al. (18) and Little et al. (22), and the left bundle-branch
350
ablation study of Gjesdal et al. (14). Furthermore, use of computer models is
351
consistent with the reduction, replacement, and refinement of animal experiments
352
where possible. We used the CircAdapt model because it has been shown to
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produce realistic simulations of ventricular deformation observed in pacing studies
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and dyssynchronous heart failure as measured by both strain and M-mode
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echocardiography, including SF and SRSsept (20, 24, 25, 37). CircAdapt also allows
356
for control of hemodynamic boundary conditions as it incorporates the systemic and
357
pulmonary circulations and both atria. We used the most recently published version
358
of CircAdapt (37) to be consistent with our other recent studies and to allow others to
359
reproduce our findings.
360
The CircAdapt model is a lumped-parameter model that contains a simplified
361
geometry of the heart consisting of three spherical caps (23). The model therefore
362
does not accurately describe geometry of the junction of the ventricular septum with
363
the atrioventricular septum or apex and is based on a simplified description of the
364
complex ventricular fiber structure (1). We therefore cannot exclude that early septal
365
activation could cause SF if these factors were taken into account. No bending
366
stiffness of the septal junction points is included in CircAdapt, which may influence 16
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the magnitude of SF (5). The model represents a generalised human physiology but
368
comparison was made to canine experiments so length and time scales are
369
qualitatively but not quantitatively comparable. In light of these limitations, our results
370
should be considered hypothesis-generating and they require validation in more
371
complex settings such as geometrically-accurate finite element models, animal
372
experiments, or patient studies.
373
Conclusion
374
Computer simulations showed that SF does not represent the same phenomenon as
375
SRSsept, even though both occur at a similar time in early systole when LBBB is
376
present. RV-LV pressure difference and early active contraction of the septum alone
377
were not always required to generate SF. Simulations demonstrated that the
378
mechanism driving SF is early contraction of the RVFW that exerts force on the
379
septum and pulls it leftwards when unopposed by contraction of the LVFW. SRSsept
380
depended on early shortening of the septum being terminated by late contraction of
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the LVFW.
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Funding Sources
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J. Lumens received a grant within the framework of the Dr E. Dekker program of the
384
Dutch Heart Foundation (NHS-2012T010).
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Disclosures
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F.W. Prinzen has received research grants from Medtronic Inc, Boston Scientific
387
Corp, MSD, Biological Delivery System Cordis, and EBR Systems.
17
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understanding response to cardiac resynchronization therapy: left ventricular dyssynchrony is only one of multiple mechanisms. Eur Heart J 30: 940-949, 2009. 28. Shenkman HJ, Pampati V, Khandelwal AK, McKinnon J, Nori D, Kaatz S, Sandberg KR, and McCullough PA. Congestive heart failure and QRS duration: establishing prognosis study. Chest 122: 528-534, 2002. 29. Sohal M, Amraoui S, Chen Z, Sammut E, Jackson T, Wright M, O'Neill M, Gill J, Carr-White G, Rinaldi CA, and Razavi R. Combined identification of septal flash and absence of myocardial scar by cardiac magnetic resonance imaging improves prediction of response to cardiac resynchronization therapy. J Interv Card Electrophysiol 40: 179-190, 2014. 30. Strauss DG, Selvester RH, and Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Cardiol 107: 927-934, 2011. 31. Strik M, van Deursen CJ, van Middendorp LB, van Hunnik A, Kuiper M, Auricchio A, and Prinzen FW. Transseptal conduction as an important determinant for cardiac resynchronization therapy, as revealed by extensive electrical mapping in the dyssynchronous canine heart. Circ Arrhythm Electrophysiol 6: 682-689, 2013. 32. Taccardi B, Punske BB, Macchi E, Macleod RS, and Ershler PR. Epicardial and intramural excitation during ventricular pacing: effect of myocardial structure. Am J Physiol Heart Circ Physiol 294: H1753-1766, 2008. 33. Tanaka H, Tei C, Nakao S, Tahara M, Sakurai S, Kashima T, and Kanehisa T. Diastolic bulging of the interventricular septum toward the left ventricle. An echocardiographic manifestation of negative interventricular pressure gradient between left and right ventricles during diastole. Circulation 62: 558-563, 1980. 34. Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NA, 3rd, Ferguson TB, Jr., Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD, Ellenbogen KA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hayes DL, Page RL, Stevenson LW, and Sweeney MO. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected]. Circulation 126: 1784-1800, 2012. 35. Vassallo JA, Cassidy DM, Marchlinski FE, Buxton AE, Waxman HL, Doherty JU, and Josephson ME. Endocardial activation of left bundle branch block. Circulation 69: 914-923, 1984. 36. Vernooy K, Verbeek XA, Peschar M, Crijns HJ, Arts T, Cornelussen RN, and Prinzen FW. Left bundle branch block induces ventricular remodelling and functional septal hypoperfusion. Eur Heart J 26: 91-98, 2005. 37. Walmsley J, Arts T, Derval N, Bordachar P, Cochet H, Ploux S, Prinzen FW, Delhaas T, and Lumens J. Fast simulation of mechanical heterogeneity in the electrically asynchronous heart using the MultiPatch module. PLoS Comput Biol 11: e1004284, 2015. 38. Xiao HB, Roy C, and Gibson DG. Nature of ventricular activation in patients with dilated cardiomyopathy: evidence for bilateral bundle branch block. Br Heart J 72: 167-174, 1994.
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Figure Captions 20
533
Figure 1: CircAdapt simulations of asynchronous ventricular activation. The
534
structure of the CircAdapt model of the heart and circulation is shown, together with
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the relative average activation times of the three ventricular walls used in this study.
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The first ventricular wall is activated 150ms after the RA, mimicking the PQ interval.
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Activation times of the septum and LVFW are given relative to the RVFW.
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Abbreviations in figure: left ventricle (LV), right ventricle (RV), free wall (FW), right
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atrium (RA), left atrium (LA), aortic valve (AV), mitral valve (MV), pulmonary valve
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(PV), tricuspid valve (TV). Panel A is adapted from Lumens et al. (2009) (23).
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Figure 2: Calculations for determining presence of septal flash and systolic
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septal rebound stretch. We compute a pseudo M-Mode by tracking the inner and
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outer surfaces of the LVFW and the septum and plotting their locations relative to the
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LV epicardial surface as a function of time. DLVS-LW is the distance between the LV
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lateral wall endocardium and the LV side of the septum. SF is computed from DLVS-
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LW
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and aortic valve closure. Septal strain (E) is shown in the right hand panel, together
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with a diagrammatic representation of the calculation of SRSsept. Onset of ventricular
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activation (dashed line), closure of the mitral valve (solid line), and LV ejection (grey
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bar) are shown. New abbreviations: distance from left ventricular septum to lateral
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wall (DLVS-LW), septal flash (SF), septal systolic rebound stretch (SRSsept), MV closure
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(MVC), AV closure (AVC).
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Figure 3: CircAdapt simulations produce realistic septal motion. Panel A shows
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M-mode echocardiography recordings from a canine model at baseline and with left
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LBBB induced by left bundle branch ablation. Image is modified from Gjesdal et al.
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(14). The ECG is shown below and the dashed vertical line indicates onset QRS.
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Septal beaking (or SF) is indicated in the LBBB recording. Panel B shows
as the maximum rightwards movement between onset of ventricular activation
21
558
corresponding simulations at baseline (simultaneous onset of ventricular activation)
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and LBBB (60ms average delay of the LVFW relative to the RVFW). The septum is
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shown in black and LVFW is shown in red. The dashed vertical line indicates the
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time of first ventricular activation. Closure of the mitral valve (solid line), and LV
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ejection (grey bar) are also shown for the simulated data. Activation times and the
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line used for pseudo M-mode calculation are indicated below the figure for the
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simulations. Only one beat is shown for the simulations. Time 0 ms in the simulations
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corresponds to the onset of RA excitation. New abbreviations: septum (SEPT.), left
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bundle-branch block (LBBB).
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Figure 4: Sensitivity of SF and SRSsept to relative timing of ventricular walls. A)
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The left-hand panel shows the sensitivity of SF magnitude to the timing of the LVFW
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and the septum, relative to the RVFW, for all 81 simulations. Calculation of SF
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magnitude is described in Fig. 2. Above the dashed line, the LVFW is activated after
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the RVFW. Traces of DLVS-LW used for calculation of SF are also shown for 25
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simulations in the right hand panel. Activation time relative to the RVFW is shown on
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the large axes, DLVS-LW is shown on the small y-axis, and time from onset RA
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activation is shown on the small x-axis. The grey bar indicates LV ejection, the
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dashed vertical line indicates onset of ventricular excitation, and the solid vertical line
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indicates mitral valve closure. B) SRSsept from the same simulations, with SRSsept
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magnitude in the left-hand panel. To the left of the dashed line the septum is
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activated before the LVFW. Septal strain patterns are shown in the right hand panel.
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New abbreviations: septal systolic rebound stretch (SRSsept).
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Figure 5: Septal position, trans-septal pressure, and septal deformation in
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simulations and experiments at baseline and with left bundle-branch block.
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The top pane compares hemodynamics and ventricular mechanics at baseline and in 22
583
LBBB in a canine experiment. The figure is reproduced from Gjesdal et al. (14). The
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bottom panel shows simulations representing normal ventricular activation and
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LBBB. LBBB was simulated as a 60 ms average delay in activation in the LVFW
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compared to the RVFW and septum. Septal and lateral wall circumferential (Circ.)
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and longitudinal (Long.) deformation are shown for the experiments, and compared
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to fiber strain in the LVFW and septum for the simulations. Activation patterns from
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intra-myocardial electromyograms (EMG) and the electrocardiogram (ECG) are
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shown for the experiments. New abbreviations: aortic pressure (PAo), LV pressure
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(PLV), RV pressure (PRV), AV opening (AVO), PV opening (PVO), MV closure (MVC),
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AV closure (AVC), PV closure (PVC), end diastole (ED).
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Figure 6: Delayed septal activation leads to reversal of trans-septal pressure
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gradient. PTS, pseudo M-mode and septal strain from four simulations are shown.
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The simulation on the left-hand side is the LBBB simulation from Fig. 5 with the
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septum activated simultaneously with the RVFW and the LVFW 60ms delayed. The
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next three simulations delay the septum by 20ms, 40ms, and 60ms, until the septum
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is activated with the LVFW. Onset of ventricular activation (dashed line), closure of
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the mitral valve (solid line), and LV ejection (grey bar) are shown in all plots.
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Figure 7: Early septal contraction is not sufficient for septal flash to occur. The
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septum is activated 60ms before both the LVFW and the RVFW. No SF is apparent
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in either DLVS-LW or the pseudo M-mode image. Early shortening and SRSsept in the
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septal strain pattern not corresponding to SF is indicated. Onset of ventricular
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activation (dashed line), closure of the mitral valve (solid line), and LV ejection (grey
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bar) are shown in all plots.
23
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Figure 8: Activation changes are the most significant cause of SF and SRSsept.
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The results of the parameter sensitivity analysis are shown for both SF (left panel)
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and SRSsept (right panel). The three baseline situations refer to the activation time of
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the LVFW and septum, relative to the RVFW. Activation times for the LVFW and
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septum relative to the RVFW in the baseline simulations were +0ms, +0ms (Normal);
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+60ms, +0ms (LBBB); and +0ms, -60ms (Early Septum); respectively. The effect is
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measured as the change in SF or SRSsept arising from a ±30% change in the
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parameter value, normalised by the value of SF or SRSsept in the LBBB case as
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appropriate (0.38cm and 6.6%, respectively). A darker colour indicates a larger effect
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and a minus sign indicates that the effect causes a decrease in SF or SRSsept as a
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result of the parameter change. New abbreviations: heart rate (HR), cardiac output
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(CO), contractility (Sf,act), passive stiffness (Sf,pas), wall volume (Vwall), activation time
618
relative to the RVFW (TA), valve opening area (Aopen), all ventricular walls (ALL).
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Figure 9: Early right ventricular contraction and force balance as a mechanism
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for septal flash. Diastole: At end-diastole, passive forces at the septal junction and
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right ventricular attachment points are balanced due to the septal position (5, 23).
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Leftward motion: In LBBB, activation begins in the RVFW and the septum (30, 35),
623
initiating active force generation in the septum and RVFW. Active force generation
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by the septum contributes to LV cavity pressure, which may prevent PTS from
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reversing. Forces acting on the junction point become imbalanced because the
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RVFW is not opposed by the LVFW. RVFW contraction exerts force on the septum
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through the attachment points, causing the septum to hinge inwards and flatten,
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displacing blood towards the LVFW and restoring force balance at the septal junction
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through the change in septal position. Rightward motion: The LVFW then becomes
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activated due to conduction through the myocardium from the septum and RV. Pre24
631
stretch of the LVFW due to septal contraction and displacement of blood from septal
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leftwards movement results in powerful contraction of the LVFW, causing a force
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imbalance towards the LV. LVFW contraction exerts force on the septum, which
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hinges about the attachment points and curves back into the RV, restoring force
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balance. RV pressure is increased by septal return, causing RV ejection.
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