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JACC: CARDIOVASCULAR IMAGING
VOL. 6, NO. 8, 2013
ª 2013 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 1936-878X/$36.00
http://dx.doi.org/10.1016/j.jcmg.2013.07.002
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EDITOR’S PAGE
Cardiac Resynchronization: The Flow of Activation Sequence
Partho P. Sengupta, MD,* Christopher M. Kramer, MD,y Jagat Narula, MD, PHD*
A
lthough cardiac resynchronization therapy
(CRT) has become a mainstay of therapy
for systolic heart failure refractory to medical management for over a decade, more
than 30% of CRT recipients do not respond clinically to the intervention. Ideally, cardiologists should
be able to predict those who might not respond to
CRT in advance and withhold these costly devices
in likely nonresponders. However, because of conflicting results and difficulties in mapping the
3-dimensional sequence of left ventricular (LV)
electromechanical activation, an effective approach
to quantifying dyssynchrony is yet to be established.
The normal electromechanical activation sequence
of the LV develops from a close interaction of the
specialized conduction system with the myocyte architecture. Nearly the entire LV endocardial layer is
directly activated within approximately 40 ms by
Purkinje cells (Fig. 1) (1). The epicardial layer, which
is void of Purkinje cells, experiences delayed activation
through cell-to-cell propagation of electrical activity.
Recently, Ramanathan et al. (2) noninvasively studied
the normal epicardial activation sequence in intact
healthy adults. The endocardial-to-epicardial activation of the LV free wall occurred with a breakthrough
seen first over the LV apex. Subsequent apex-to-base
spread of activation was associated with the latest
activation occurring in the LV posterolateral basal
region.
The timing of mechanical activation follows the
electrical sequence, but the transmural speed of myofiber shortening (0.25 m/s) lags the speed of electrical
conduction (0.49 m/s) (3). This delay is related to the
development of a transient stretch in the late-activated
epicardial regions of the left ventricle. This stretch
of the late-activated regions of the left ventricle is due
to shortening of early-activated regions and a steep rise
in LV pressure in the absence of a change in LV volume during isovolumic contraction. This stretch (of
From the *Icahn School of Medicine at Mount Sinai, New York,
New York; and the yUniversity of Virginia, Charlottesville, Virginia.
up to 10%) of the late depolarized myofibers (which
also accounts for transient clockwise rotation of the
apex during isovolumic contraction) is helpful in
generating more shortening during ejection (with
subsequent counterclockwise rotation of the apex
during ejection). The pre-ejection stretch increases the
sarcomeric length in subepicardial myofibers and enhances shortening strains per the Frank-Starling
mechanism (4,5). The reciprocal shortening and
stretching of the LV wall also alters the LV geometry,
which helps preferential streaming of blood flow toward the LV outflow (5).
The specific patterns of delay in LV activation in
cardiomyopathic patients who benefit from CRT
may also be better understood by considering the
sequence of electromechanical coupling and the
overall effects on the timing of LV contraction and
blood flow. First, electrical activation delays that
result from a transmural pattern of block (particularly from the left bundle) may be more amenable
to CRT. Recent observations in the Multicenter
Automatic Defibrillator Implantation Trial With
Cardiac Resynchronization Therapy study suggest
that the benefit of CRT in patients with class I and
II heart failure was confined to those who had classic
complete left bundle branch block (LBBB), whereas
those with a non-LBBB configuration did not derive
as much benefit (6). Thus, there has been an increase
in the importance of separating LBBB from diffuse
intraventricular conduction disturbances. Auricchio
et al. (7) used 3-dimensional mapping systems to
study the sequence of LV activation in patients with
heart failure with LBBB QRS configuration during
intrinsic rhythm (as also during asynchronous pacing). They demonstrated a U-shaped conduction
pattern in the activation sequence of the left ventricle
in patients with LBBB. Noncontact mapping
showed that the activation wave front could not
cross directly to the lateral wall from the anterior
region. Instead, this wave front reached the lateral or
posterolateral regions by propagating from the site of
earliest septal LV breakthrough, inferiorly around
the apex and across the inferior wall (Fig. 1). This
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AUGUST 2013:924–6
U-shaped block, however, was altered on asynchronous pacing. Moreover, the presence of near
normal amplitude on unipolar and bipolar electrocardiography excluded the presence of scar tissue,
and the presence of fractionated electrocardiographic results suggested that the block was functional and resulted from the nonuniform conduction
within the transmural layers of the myocardium.
Interestingly, the study by Sohal et al. (8) in this
issue of iJACC also revealed the presence of a
U-shaped mechanical activation block between the
septum and lateral wall, and this pattern of block
was commonly associated with response to CRT.
Just as the transmural electrical activation delay
manifests on the surface as a U-shaped block, the
observations regarding mechanical activation delay
between the septum and the lateral wall may only
signify a disruption of LV mechanics between the
transmural layers. Normal radial LV wall thickening
during ejection requires mechanical interaction of
both the early-activated subendocardial and the lateactivated subepicardial regions. Activity of both regions needs to be developed in concert for optimal
wall thickening; the subendocardial myofibers must
further thicken and slide inward, and this inward
slippage (shearing) accounts for the larger radial
thickening strains (>40%) and segmental volume
change (>60%) despite relatively small myocyte
contraction developed within the layers (about 15%).
Thus, the identification of transmural functional
block rather than segmental or regional blocks may
better identify patients likely to benefit from CRT.
Transmural mechanical activation delay may also
impair diastolic function, because LV systolic and
diastolic performances are closely coupled. In
normal subjects, the untwisting and recoil of the LV
wall in early diastole releases elastic energy stored by
the preceding systolic deformation. This creates
early diastolic suction with the formation of a vortex
ring at the mitral valve tip (9). The vortex rings store
part of the kinetic energy of the entering flow into
its rotary motion and help redirect the flow toward
the outflow tract. A recent study showed that
deactivation of CRT results in a delayed onset of
LV filling in early diastole, with a delayed onset of
blood flow vortex formation (10). A weaker early
diastolic vortex further restricted the energy transfer
from diastole to systole, impeding the timely onset
of LV ejection. Thus, the normal sequence of
electromechanical activation can also be valued in
synchronizing an optimal transfer of kinetic energy
from diastole into systole.
In summary, there are different hierarchical domains for considering the patterns of disruption of
Sengupta et al.
Editor's Page
925
Figure 1. Wave Front of the Ventricular Electrical Activation Sequence
The activation sequence in the normal heart (Top) and with left bundle branch block (LBBB)
conduction defect (Bottom) is presented; the anterior wall of the ventricle is flipped open
and placed (cavity en face) on the right. The activation sequence is represented by the time
scale color bar; the activation spreads in a wave front, with each colored zone representing
successive 10 to 20 ms. During normal conduction, activation begins within both the left
ventricular (LV) and right ventricular endocardium but in LBBB, activation begins only in the
right ventricle and proceeds through the septum before reaching the LV endocardium. The
line of activation sequence block in the anterior wall in LBBB is shown by a dashed line
(between substantially different time zones). Figure developed on the basis of data from
Durrer et al. (1) and Strauss et al. (11), by Craig Skaggs.
cardiac activation and the potential benefits of
CRT. We urge investigators to provide a better
mechanistic understanding, such that the seemingly
complex events in cardiac electrical, muscle, and
flow mechanics observed during ventricular dyssynchrony are simplified. Identifying potential
responders to CRT is an extremely important
and vexing question in the present-day care of
patients with heart failure and an important piece
of the puzzle, which will be solved only by
addressing the cascade of activation-contractionflow sequences.
Address for correspondence: Dr. Jagat Narula, Icahn
School of Medicine at Mount Sinai, Mount Sinai Heart,
One Gustave L. Levy Place, Mail box 1030, New York,
New York 10029. E-mail: [email protected].
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Sengupta et al.
Editor's Page
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AUGUST 2013:924–6
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